Digestive Involvement in Systemic Autoimmune Diseases

Handbook ofSystemic Autoimmune Diseases

Volume 8

Digestive Involvement in Systemic Autoimmune Diseases


Series Editor: Ronald A. Asherson

Volume 1 The Heart in Systemic Autoimmune DiseasesEdited by: Andrea Doria and Paolo Pauletto

Volume 2 Pulmonary Involvement in Systemic Autoimmune DiseasesEdited by: Athol U. Wells and Christopher P. Denton

Volume 3 Neurologic Involvement in Systemic Autoimmune DiseasesEdited by: Doruk Erkan and Steven R. Levine

Volume 4 Reproductive and Hormonal Aspects of Systemic Autoimmune DiseasesEdited by: Michael Lockshin and Ware Branch

Volume 5 The Skin in Systemic Autoimmune DiseasesEdited by: Piercarlo Sarzi-Puttini, Andrea Doria, Giampiero Girolomoni andAnnegret Kuhn

Volume 6 Pediatrics in Systemic Autoimmune DiseasesEdited by: Rolando Cimaz and Thomas Lehman

Volume 7 The Kidney in Systemic Autoimmune DiseasesEdited by: Justin C. Mason and Charles D. Pusey

Volume 8 Digestive Involvement in Systemic Autoimmune DiseasesEdited by Josep Font, Manuel Ramos-Casals, and Juan Rodes


Volume 8


Edited by:

Josep Fontw

Department of Autoimmune Diseases, ‘‘Instituto de Investigaciones Biomedicas August PiI Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona, Spain

Manuel Ramos-CasalsLaboratory of Autoimmune Diseases ‘‘Josep Font’’, ‘‘Instituto de InvestigacionesBiomedicas August Pi I Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona, Spain

Juan RodesLiver Unit, ‘‘Instituto de Investigaciones Biomedicas August Pi I Sunyer (IDIBAPS)’’,Hospital Clinic, Barcelona, Spain

Series Editor

Ronald A. Asherson

Amsterdam – Boston – Heidelberg – London – New York – OxfordParis – San Diego – San Francisco – Singapore – Sydney – Tokyo

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Dedication

This book is one of the last projects led by Josep Font before his unexpected death, and the remainingEditors wish to dedicate these lines as a means of paying a deeply felt homage. Dr. Josep Font (Barcelona,1953–2006) devoted his professional career to the care of patients with systemic autoimmune diseases(SAD). Dr. Font trained in Internal Medicine at the Hospital Clinic of Barcelona from 1978 to 1982 andobtained his PhD in 1984 for his thesis on systemic lupus erythematosus (SLE). His post-doctoralexperience was closely linked with the Lupus Research Unit at St. Thomas’ Hospital in London. Hisresearch output was prodigious, with a total of over 500 scientific articles published in 25 years. In addition,he designed and coordinated many international projects including the Eurolupus, Europhospholipid,CAPS Registry, SS-HCV Registry, and HISPAMEC, and was an active member of some of the mostprestigious international research groups such as the Eurolupus Nephritis Trial and the SLICC.

In 1995, Josep Font created the Department of Autoimmune Diseases at the Hospital Clinic, a pioneeringunit in Europe specifically dedicated to the clinical management of patients with SAD. Dr. Font played aleading role in creating a network of different specialists at the Hospital Clinic dedicated to the care of thesepatients. A key characteristic of his clinical research was its multidisciplinary design and the closecollaboration between different medical specialities, of which this book is an excellent example.

Josep Font was working actively until the last days of his life, and died like a soldier ‘‘with his boots on’’.His integrity, intelligence, and loyalty made him a formidable physician and a wonderful colleague andfriend. He was undoubtedly one of the foremost figures in the field of autoimmune diseases in recentdecades, and the immense human and professional legacy that he leaves must be maintained and continuedby all who had the great fortune to know and work with him.

Manuel Ramos-Casals and Juan Rodes

v

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Foreword

I was pleased to be asked to write the Foreword for this new volume which aims to bring togetherknowledge on a group of auto-immune disorders involving the digestive tract with systemic involvement.It is surely going to be an important volume and one fulfilling a long-felt need by intensivists,rheumatologists, as well as hepatologists and gastroenterologists who are involved in the care of patientssuffering from this fascinating group of disorders.

Much is known about the nature of immunological reactions that underlie auto-immune disorders, withcytoxic CD8 T cells, NK cells, and b-cell auto-antibody production interacting in the disease process.However, what initiates these processes and gives rise to a particular organ or system involvement is still inmost instances uncertain, involving as it may infectious agents, environmental toxins, and with anunderlying constitutional predisposition. The overlap syndromes between them are particularly fascinating.Thus PBC and auto-immune hepatitis are usually quite distinct disorders in terms of clinical manifestationsand in response to immunosuppressive therapy—highly effective in auto-immune hepatitis, little effect inprimary biliary cirrhosis, yet occasional cases have features of both disorders. Primary sclerosing cholangitisin adults is characterised by a progressive fibrosing obliteration of intra and extrahepatic bile ducts but inchildren there is often an initial phase of an auto-immune hepatitis-like picture with a response tocorticosteroids. Arthropathies are common in auto-immune hepatitis and rheumatoid arthritis in primarybiliary cirrhosis. Sjogren’s syndrome too is a feature of PBC and there are many other overlap associations.However, lupid hepatitis which was the term applied—because of the finding of LE cells in the serum towhat later became known as active chronic hepatitis and then presently auto-immune hepatitis, is not partof disseminated lupus erythematosus in which hepatic involvement is mild or non-existent.

Separate chapters in the volume are devoted to the extrahepatic manifestations of chronic hepatitisconsequent on HBV and HVC infection, including glomerulonephritis, thyroiditis, arthropathies, andattributable to the development of an auto-immune reactivity. One of the mechanisms involved maybemolecular mimicry in which antigens of external organisms, bacterial or viral which show homology withself-molecules trigger auto-immunity in an attempt to neutralise the infectious organisms.

With outstanding editorship and the acknowledged expertise of the writing contributors this will be anexciting volume to read.

Professor Roger Williams, CBE

vii


List of Contributors

Rupert Abdalian

Division of Gastroenterology, Department ofMedicine, Toronto Western Hospital, UniversityHealth Network, Toronto, Ont., Canada

Graciela S. Alarcon

Department of Medicine, Division of ClinicalImmunology and Rheumatology, 510 20th StreetSouth, FOT 830, The University of Alabama atBirmingham, Birmingham, AL 35294, USA

Carmen Ayuso

Radiology Department, Diagnostic Imaging Centre,Hospital Clinic, University of Barcelona, AbdomenUnit (CT and MRI), IDIBAPS, Villarroel 170,08036 Barcelona, Spain

John M. Cafardi

Department of Medicine, Division of ClinicalImmunology and Rheumatology, 510 20thStreet South, FOT 830, The University of Ala-bama at Birmingham, Birmingham, AL 35294,USA

Ricard Cervera

Department of Autoimmune Diseases, HospitalClınic, Villarroel 170, 0836 Barcelona, Catalonia,Spain

Roger Chapman

Department of Gastroenterology, John RadcliffeHospital, Headington, Oxford OX3 9DU, UK

Albert J. Czaja

Division of Gastroenterology and Hepatology,Mayo Clinic College of Medicine, 200 First StreetSW, Rochester, MN 55905, USA

Lara Dani

Rheumatology Unit, Department of Medicine,Karolinska University Hospital, Solna, KarolinskaInstitutet, SE-171 76 Stockholm, Sweden

Salvatore De Vita

Rheumatology Clinic, Azienda Ospedaliero-Universitaria ‘‘S. Maria della Misericordia’’,DPMSC, University of Udine, Udine, Italy

Luis Donoso

Diagnostic Imaging Centre, Hospital Clinic,University of Barcelona, IDIBAPS, Villarroel170, 08036 Barcelona, Spain

Gerard Espinosa

Department of Autoimmune Diseases, Hospital Clı-nic, Villarroel 170, 0836 Barcelona, Catalonia, Spain

Gianfranco Ferraccioli

Division of Rheumatology, School of Medicine,Catholic University of the Sacred Heart, Rome, Italy

Xavier Forns

Liver Unit, ICMD, Ciberehd, ‘‘Instituto deInvestigaciones Biomedicas August Pi I Sunyer(IDIBAPS)’’, Hospital Clinic, Barcelona, Spain

Elisa Gremese

Division of Rheumatology, School of Medicine,Catholic University of the Sacred Heart, Rome, Italy

Loıc Guillevin

Department of Internal Medicine, NationalReferral Center for Necrotizing Vasculitides andSystemic Sclerosis, Hopital Cochin, UniversiteParis 5 – Rene Descartes, 27 rue du faubourgSaint-Jacques, 75679 Paris cedex 14, France

Jenny Heathcote

Division of Gastroenterology, Department ofMedicine, Toronto Western Hospital, UniversityHealth Network, Toronto, Ont., Canada

Iain R.L. Kean

Biomedical Research Centre, Sheffield HallamUniversity, Sheffield S1 1WB, England, UK

ix

Walter F. Kean

Department of Medicine, McMaster UniversityFaculty of Health Sciences, Suite #401, 1 YoungStreet, Hamilton, Ont., Canada L8N 1T8

Dinesh Khanna

Division of Rheumatology, Department of Medi-cine, David Geffen School of Medicine, 1000Veterans Avenue, Rm 32–59, Rehabilitation Build-ing, Los Angeles, CA 90095, USA

Ingrid E. Lundberg

Rheumatology Unit, Department of Medicine,Karolinska University Hospital, Solna, KarolinskaInstitutet, SE-171 76 Stockholm, Sweden

Michael P. Manns

Department of Gastroenterology, Hepatology,and Endocrinology, Hannover Medical School,Carl-Neuberg-Str. 1, 30625 Hannover, Germany

Giorgina Mieli-Vergani

Institute of Liver Studies, King’s College LondonSchool of Medicine at King’s College Hospital,Denmark Hill, London SE5 9RS, UK

Heiko Mix

Department of Gastroenterology, Hepatology,and Endocrinology, Hannover Medical School,Carl-Neuberg-Str. 1, 30625 Hannover, Germany

Josep Ordi-Ros

Internal Medicine Department, Vall D’HebronGeneral Hospital, Universitat Autonoma deBarcelona, 08035 Barcelona, Spain

Mario Pages

Radiology Department, Diagnostic Imaging Centre,Hospital Clinic, University of Barcelona, AbdomenUnit (CT and MRI), IDIBAPS, Villarroel 170,08036 Barcelona, Spain

Christian Pagnoux

Department of Internal Medicine, National ReferralCenter for Necrotizing Vasculitides and Systemic

Sclerosis, Hopital Cochin, Universite Paris 5 – ReneDescartes, 27 rue du faubourg Saint-Jacques, 75679Paris cedex 14, France

Neophytos P. Papageorgiou

Center for Autoimmune Diseases, Departmentof Medicine B, Chaim Sheba Medical Center(Affiliated to Tel-Aviv University), Tel-Hashomer52621, Israel

Luca Quartuccio

Rheumatology Clinic, Azienda Ospedaliero-Univer-sitaria ‘‘S. Maria della Misericordia’’, DPMSC,University of Udine, Udine, Italy

K.D. Rainsford

Biomedical Research Centre, Sheffield HallamUniversity, Sheffield S1 1WB, England, UK

Herbert Rakatansky

Department of Medicine, Division of Gastroente-rology, Warren Alpert School of Medicine, BrownUniversity Providence, RI, USA

Manuel Ramos-Casals

Laboratory of Autoimmune diseases ‘‘Josep Font’’,‘‘Instituto de Investigaciones Biomedicas August PiI Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona,Spain

Juan Rodes


Juanita Romero-Dıaz

Department of Immunology and Rheumatology,Instituto Nacional de Ciencias Medicas y Nutri-cion Salvador Zubiran, Mexico City, Mexico

Jorge Sanchez-Guerrero

Department of Immunology and Rheumatology,Instituto Nacional de Ciencias Medicas yNutricion Salvador Zubiran, Mexico City,Mexico

List of Contributorsx

Jose-Maria Sanchez-Tapias


Albert Selva-O’Callaghan


Yehuda Shoenfeld

Center for Autoimmune Diseases, Department ofMedicine B, Chaim ShebaMedical Center (Affiliatedto Tel-Aviv University), Tel-Hashomer 52621, Israel

Elke Theander

Department of Rheumatology, Malmo UniversityHospital, Malmo, Sweden

Athanasios G. Tzioufas

Department of Pathophysiology, School of Medi-cine, University of Athens, Greece

Diego Vergani

Institute of Liver Studies, King’s CollegeLondon School of Medicine at King’s CollegeHospital, Denmark Hill, London SE5 9RS,UK

Miquel Vilardell-Tarres


Claudio Vitali

Department of Internal Medicine and Rheuma-tology, Ospedale Villamaria, Piombino, Italy

List of Contributors xi


Contents

Dedication vForeword viiList of Contributors ix

I Introduction

Digestive System and Autoimmunity 3Heiko Mix, Michael P. Manns

Imaging Techniques in Digestive Diseases 15Carmen Ayuso, Mario Pages, Luis Donoso

II Systemic Autoimmune Diseases

Systemic Lupus Erythematosus 31Miquel Vilardell-Tarres, Albert Selva-O’Callaghan, Josep Ordi-Ros

Antiphospholipid Syndrome 39Gerard Espinosa, Ricard Cervera

Gastrointestinal Involvement in Systemic Sclerosis 51Dinesh Khanna

Inflammatory Myopathies 63Lara Dani, Ingrid E. Lundberg

Digestive Involvement in Primary Sjogren’s Syndrome 71Manuel Ramos-Casals, Elke Theander, Athanasios G. Tzioufas, Claudio Vitali

Gastrointestinal Involvement in Systemic Vasculitis 83Salvatore De Vita, Luca Quartuccio, Elisa Gremese, Gianfranco Ferraccioli

Mixed Connective Tissue Disease 101Juanita Romero-Dıaz, Jorge Sanchez-Guerrero

Gastrointestinal Manifestations of Rheumatoid Arthritis 109John M. Cafardi, Herbert Rakatansky, Graciela S. Alarcon

III Autoimmune Liver Diseases

Immunopathogenesis of Autoimmune Liver Damage 121Albert J. Czaja

xiii

Primary Biliary Cirrhosis 141Rupert Abdalian, Jenny Heathcote

Autoimmune Hepatitis 153Diego Vergani, Giorgina Mieli-Vergani

Primary Sclerosing Cholangitis 169Roger Chapman

IV Autoimmunity and Viral Hepatitis

Systemic and Autoimmune Manifestations of Hepatitis B Virus Infection 191Christian Pagnoux, Loıc Guillevin

Extrahepatic Manifestations in Patients with Chronic Hepatitis C Virus Infection 209Manuel Ramos-Casals, Xavier Forns, Jose-Maria Sanchez-Tapias, Juan Rodes

V Other Conditions

Autoantibodies in Gastrointestinal Autoimmune Diseases 231Neophytos P. Papageorgiou, Yehuda Shoenfeld

Gastrointestinal Complications of Anti-Rheumatic Drugs 243K.D. Rainsford, Iain R.L. Kean, Walter F. Kean

Subject Index 277

Colour Plate Section

Contentsxiv

PART I:

Introduction


Handbook of Systemic Autoimmune Diseases, Volume 8


Josep Font, Manuel Ramos-Casals and Juan Rodes, editors

CHAPTER 1

Digestive System and Autoimmunity

Heiko Mix, Michael P. Manns�

Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School,

Carl-Neuberg-Str. 1, 30625 Hannover, Germany

1. The digestive system and gut-associated

immunity

Mammals depend on feeding and digestion. Whilesingle-celled organisms can directly take in nutri-ents from their outside environment, multi-cellularorganisms, with most of their cells removed fromdirect contact with the outside environment, havedeveloped specialized structures for obtaining andbreaking down their food. Large, complex mole-cules must be broken down into monomers thatcan then be distributed throughout the body toevery cell. This vital function is accomplished bya series of specialized organs that comprise thedigestive system. The human digestive system is acoiled, muscular tube about 6–9m in length whenfully extended, stretching from the mouth to theanus. Several specialized compartments occuralong this length: mouth, pharynx, esophagus,stomach, small intestine, large intestine, and anus.Accessory digestive organs are connected to themain system by a series of ducts, including salivaryglands, the pancreas, and the liver with the biliarysystem. Like the skin, the digestive tract is situatedat the interface between external and internalmilieus. In order to maintain homeostasis, physicaland chemical mechanisms as elements of the innateimmune response are utilized to protect againstexogenous, potentially noxious agents. The

membranes of the digestive tract provide aphysical barrier against invading pathogens. Ahuge number of chemical factors, including lowpH in the stomach, pepsin, lysozyme, anti-microbialsubstances like cryptidins and defensins, limit thegrowth and invasion of microorganisms (Dann andEckmann, 2007) (Table 1).

In addition to innate defense mechanisms, thedigestive system is lined by mucosal lymphatictissues. It consists of diffuse lymphocytic infiltratesthroughout the epithelium and lamina propria ofthe mucosa or nonencapsulated lymphoid nodulesin the submucosa of the intestinal tract. Peyer’spatches are the prototypical mucosal lymphatictissue, specialized to sample environmental anti-gens. The Peyer’s patches contain lymphoid com-partments that are analogous to the cortex andfollicles of lymph nodes. Each follicle is covered bya single-layered follicle-associated epithelium, anda more diffuse area immediately below, calledsubepithelial dome. The follicle-associated epithe-lium is interrupted by specialized membraneouscells (M cells) that have luminal microfoldsinstead of microvilli and lack the normal thicklayer of mucus. The M cells differentiate fromenterocytes under the influence of membrane-bound lymphotoxin-a1b2 present on local lym-phoid cells (Debard et al., 2001; Kerneis et al.,1997; Golovkina et al., 1999). These cells endocy-tose and transport various materials (Nicoletti,2000). Antigen is delivered to lymphocytes, mono-nuclear phagocytes, and dendritic cells immediatelybeneath M cells. The germinal centers contain B cellblasts, follicular dendritic cells, macrophages, andE-mail address: [email protected]

�Corresponding author.

Tel.: +49-511-532-3305; Fax: +49-511-532-4896

r 2008 Elsevier B.V. All rights reserved.

DOI: 10.1016/S1571-5078(07)00001-3

dx.doi.org/10.1016/S1571-5078(07)00001-3.3d

unique T cells. B cells undergo immunoglobulinclass switching from expression of IgM to IgAunder the influence of several local factors, inclu-ding transforming growth factor-b (TGF-b), inter-leukin-10 (IL-10), and other cellular signals that aredelivered by dendritic cells and T cells (McIntyreand Strober, 1999). Lymphocytes exit the Peyer’spatches through the draining lymphatics to themesenteric lymph nodes, from where they migrateinto the bloodstream and finally home to themucosa. The exit of lymphocytes from the blood-stream into the mucosa is mediated by loss ofL-selectin expression and selective upregulation ofa4b7 integrin. The ligand for a4b7 integrin, mucosaladdressin cell-adhesion molecule 1 (MADCAM1),is highly expressed by the vasculature of mucosalsurfaces and mediates the emigration from thebloodstream (Butcher et al., 1999). In addition,expression of the chemokine receptor CCR9 isinduced in gut-derived T cells, allowing them torespond to the chemokine CCL25, which isexclusively expressed by small-bowel epithelial cells(Bowman et al., 2002; Campbell and Butcher,2002). In contrast, T cells primed in peripherallymphoid organs acquire the a4b1 integrin very lateantigen 4 (VLA4) and the chemokine receptorCCR4 and do not migrate to mucosal surfaces(Campbell and Butcher, 2002).

Lymphocytes that home into the mucosa of thegut redistribute into distinct compartments. IgA-producing plasma cells remain in the laminapropria. CD4+ T cells are distributed more evenly

throughout the villus–crypt unit within the laminapropria. CD8+ T cells preferentially reside in theepithelium. A memory phenotype of CD4+ andCD8+ T cells predominates in both the epitheliumand the lamina propria, indicating that the cellshave been exposed to antigen. CD4+ T cells in thelamina propria are of particular importance tolocal immune regulation. They produce largeamounts of cytokines, particularly interferon-g(IFN-g), but also IL-4 and IL-10 (Braunsteinet al., 1997; Carol et al., 1998; Hurst et al., 1999).Lamina propria CD8+ T cells can have potentcytotoxic T lymphocyte (CTL) activity (Lefranc-oiset al., 1999). Many of the properties of the laminapropria CD4+ T cells are similar to those ofregulatory T cells in other systems (Read andPowrie, 2001; Shevach, 2002). The unresponsive-ness of lamina propria T cells to commensalbacteria can be reversed by the depletion ofIL-10 or TGF-b (Khoo et al., 1997).

Mesenteric lymph nodes have a crucial role inthe induction of mucosal immunity and tolerance.Antigen recognition in the mesenteric lymph nodesoccurs within a few hours of feeding proteinantigen (Gutgemann, 1998; Van Houten andBlake, 1996; Blanas et al., 2000; Lee et al., 2000).More importantly, induction of oral tolerance isnot possible in lymphotoxin-a-deficient or lym-photoxin-a-deficient�TNF-deficient mice, whichlack mesenteric lymph nodes (Spahn et al., 2002).Furthermore, total and specific IgA-antibodyresponses are absent in mice lacking mesenteric

Table 1

Mechanisms to minimize self-reactive lymphocyte differentiation and activation

Clonal deletion Induction of apoptosis by inhibition of pro-survival pathways (BIM induction) or by

activation of death receptors (FAS activation)

Receptor editing Receptor editing through V(D)J recombination in primary lymphatic tissues (in T cells

and B cells) or by somatic hypermutation in secondary lymphatic tissues (in B cells)

Clonal anergy and tuning Intrinsic regulation by B or T cell receptor downregulation

Induction of inhibitory receptors (CD5, CTLA4)

Induction of phosphatases (SHP1, SHIP)

Induction of ubiquitin ligases (cbl, GRAIL, Itch, Roquin)

Extrinsic regulation Limitation of survival factors (BAFF, IL-7)

Limitation of costimulation (CD40L, TLR ligands, B7 molecules)

Active suppression (regulatory T cells)

H. Mix, M.P. Manns4

lymph nodes, while responses to parenterallyadministered antigens are preserved in these mice(Kang et al., 2002; Yamamoto et al., 2000).

Generally, immune responses to most tissueantigens are initiated in the draining lymph nodes.Recent evidence has suggested that naıve intestinalT cells first encounter antigen in the mesentericlymph nodes and not in Peyer’s patches(MacPherson and Liu, 1999; Huang et al., 2000).While priming of T cells selectively in Peyer’spatches would lead to efficient local immuneresponses or tolerance, priming of T cells in themesenteric lymph nodes could explain the factthat intestinal antigens are able to induce systemicimmunity or tolerance.

Peyer’s patches harbor distinctive subsets ofdendritic cells, which have unusual phenotypic andfunctional characteristics (Ruedl et al., 1996).Conventional subsets of CD8a�CD11b+ (mye-loid) and CD8a+CD11b� (lymphoid) dendriticcells are present next to a large number of CD8a�CD11b� dendritic cells. Currently, little informa-tion is available about this subset of dendritic cells.They can be found outside the organized lymphoidareas, especially in the dome region, which isimmediately beneath the follicle-associated epithe-lium, together with CD8a�CD11b+ dendritic cells.Their presence is dependent on the production ofmacrophage inflammatory protein 3a (MIP3a), orCCL20, by local epithelial cells (Iwasaki and Kelsall,2000, 2001). The predominant CD8a�CD11b+dendritic cell subset is distinctive in that it secretesIL-10. Interestingly, after ligation of the costimulatormolecule receptor activator of NF-kB (RANK), thedentritic cells of Peyer’s patches respond by secretionof IL-10. Outside Peyer’s patches, i.e. in the spleen,the same conditions result in the production of IL-12(Williamson et al., 2002). Dendritic cells in Peyer’spatches are also able to stimulate antigen-specificT cells to produce T helper type 2 (TH2) cytokinesand IL-10. Collectively, these observations under-score an important role of Peyer’s patch dendriticcells in maintaining a state of tolerance against foodantigens and commensal bacteria in the digestivesystem.

In addition, intestinal epithelial cells (IECs)have recently been identified as key elements inthe development and regulation of mucosal

immunity (Zaph et al., 2007). These cells havebeen implicated in the regulation of innateimmunity and chronic inflammation before (Neishet al., 2000; Rimoldi et al., 2005); however,supporting data from in vivo experiments werelacking. The authors could show that mice,deficient in IkB kinase-b (IKK-b), producereduced levels of the epithelial-cell-restricted cyto-kine thymic stromal lymphopoietin. The mice wereunable to mount an efficient CD4+ TH2 responseagainst the parasite Trichuris. Severe intestinalinflammation was the result of exacerbated den-dritic-cell-derived IL-12/23p40 and tumor necrosisfactor-a production, as well as increased levelsof CD4+ T-cell-derived IFN-g and IL-17. Theresults were proof that the balance of IKK-b-dependent gene expression in the intestinal epithe-lium is crucial in intestinal immune homeostasisin addition to established pathways involved inpathogen recognition and initiation of immuneresponses in the gastrointestinal tract, which includeM cells and specialized dendritic cell subsets thatdirectly sample the luminal environment.

The nervous innervation of the gastrointestinaltract is extensive, including Peyer’s patches, andthe diversity of adrenergic, cholinergic, andpeptidergic nerve endings in patches is greaterthan for any other peripheral lymphatic tissue.Noradrenergic fibers form interfollicular plexusesthat ramify through the diffuse T-dependent areasnear high endothelial venules (HEV). It is likelythat the extensive innervation of Peyer’s patchesis involved in regulating traffic and reactivity ofmucosal immune cells. The nervous system,through the vagus nerve, was shown to signifi-cantly and rapidly inhibit the release of macro-phage-derived tumor necrosis factor-a, therebyattenuating systemic inflammatory responses(Borovikova et al., 2000; Bernik et al., 2002;Tracey, 2002). It could be demonstrated thatthis cholinergic anti-inflammatory pathway ofacetylcholine-mediated vagus nerve signals wasmediated via the nicotinic acetylcholine receptora7 subunit (Wang et al., 2003).

The liver as a member of the accessory digestiveorgans plays an important role in systemic immu-nity (Racanelli and Rehermann, 2006). It containslarge amounts of professional antigen-presenting

Digestive System and Autoimmunity 5

cell, including liver sinusoidal endothelial cells,Kupffer cells, and dendritic cells. Potential anti-gen-rich blood is filtered and pathogens are quicklyeliminated by phagocytes or by the huge populationof natural killer cells or natural killer T cellspresent in liver. The liver has a high capacity toinduce antigen-specific tolerance. It acts as a centralregulator in systemic immune responses by synthe-sizing and secreting acute-phase proteins and othermediators.

2. Self-tolerance and autoimmunity

Adaptive immune responses are essential fornormal health. In some cases, adaptive immuneresponses are elicited by antigens not associatedwith infectious agents. The responses are essen-tially identical to adaptive immune responses toinfectious agents; however, the antigens aredifferent. Autoimmunity is the response to self-antigens in the absence of infection.

The mammalian immune system is able tomount a response to any chemical structureimaginable. B cells and T cells express receptorswith huge receptor diversity able to achievespecificity that differentiates molecules at theatomic level. This huge receptor diversity isencoded in the mammalian genome and is possiblethrough two processes of somatic genome mod-ification that occurs selectively in lymphocytes. Incentral lymphoid organs, i.e. bone marrow for Bcells and the thymus for T cells, V(D)J recombina-tion assembles unique receptor genes for B andT cells. In peripheral lymphoid tissues, B cellreceptor genes can further be modified by single-nucleotide substitutions through somatic hyper-mutation. The random processes of V(D)Jrecombination and somatic hypermutation gene-rate huge amounts, i.e. between 20 and 50%, ofself-reactive B cells and T cells (Ignatowicz et al.,1996; Zerrahn et al., 1997; Laufer et al., 1996;Wardemann et al., 2003). Remarkably, only 3–8%of the population develops an autoimmune disease(Jacobson et al., 1997).

Currently, four mechanisms have been identifiedthat limit the number of self-reactive lymphocytes.

First, clonal deletion is used to trigger apoptosis ofcells with self-reactive receptors. Second, cells withself-reactive receptors can edit their specificity byfurther V(D)J recombination or somatic hyper-mutation until the receptor does not bind to self-antigens (Nemazee and Hogquist, 2003). Third,clonal anergy or tuning is the unresponsivenessof cells to signals from self-reactive receptors bychanges in intrinsic biochemical processes andgene expression (Healy and Goodnow, 1998;Schwartz, 2003; Grossman and Paul, 2000).Collectively, these first three mechanisms are calledimmunologic ignorance. When cells have evadedall the three mechanisms, extrinsic controls canlimit the potential of an autoimmune response bylimiting the supply of growth factors, costimuli,pro-inflammatory mediators and other factors, orthrough active suppression by regulatory T cells.

3. Tolerance mechanisms for autoreactive B

cells in the bone marrow

A series of events has been identified that occursif an immature B cell displays a self-reactivereceptor in the bone marrow. The immature Bcell internalizes the self-reactive receptor when thestrength of receptor crosslinking and intracellularsignaling exceeds a certain threshold (Hartleyet al., 1993; Fields and Erikson, 2003). As a result,homing receptors like CD62 ligand (CD62L),required to enter the lymph nodes, are notexpressed (Hartley et al., 1993). In addition,B-cell-activating factor (BAFF) receptors are onlypoorly induced (Mackay et al., 2003). BAFF isrequired to sustain peripheral B cell survival.Furthermore, recombination-activating gene 1(RAG1) and RAG2, which encode the coreenzymes for V(D)J recombination, continue to beexpressed, allowing further editing of B cellreceptors by rearranging a replacement B cellreceptor light chain (Jankovic et al., 2004). If thereceptor cannot be edited to be less self-reactive,cell death is induced, either by withdrawal ofgrowth factors and/or through increasing levels ofBCL-2-interacting mediator of cell death (BIM), apro-apoptotic factor that inhibits essential B cell

H. Mix, M.P. Manns6

survival proteins of the BCL-2 family (Strasser andBouillet, 2003). Interestingly, BIM-deficient micespontaneously produce anti-DNA autoantibodies(Strasser and Bouillet, 2003).

4. Tolerance mechanisms for autoreactive

T cells in the thymus

While B cells are designed to recognize nativeantigen, T cell receptors bind to peptide fragmentsof antigen displayed on MHC molecules. Anarray of self-peptides is displayed on corticalthymic epithelial cells, and T cells that weaklybind to these ligands receive maturation signalsthat inhibit further RAG gene expression. Theyincrease the level of surface receptor expressionand upregulate homing receptors for chemokinesfound in the thymic medulla and the peripherallymphoid tissues. This so-called positive selectionis unique to the thymic cortical epithelium. Self-reactive T cells are further edited by downregula-ting the self-reactive receptor, and RAG expressioncontinues until the self-reactive T cell receptora-chain is replaced with another, less self-reactivechain.

In the thymic medulla, the process of testing forself-reactivity continues with the help of medullarythymic epithelial cells and dendritic cells. The cellsin the medulla express costimulatory molecules,including CD80 (B7.1) and CD86 (B7.2), theligands for CD28. Here, T cell receptors that bindstrongly to self-peptide-MHC complexes are trig-gered to induce cell death (negative selection). Inanimals, deficient in this process either throughlack of medullary MHC expression or B7 expres-sion, huge amounts of self-reactive T cells reachthe periphery, causing pathologies resemblinggraft-versus-host disease (Gao et al., 2002). It canbe speculated that the well-established associationbetween particular MHC molecules and suscep-tibility to specific autoimmune diseases may stemfrom inefficient presentation of particular self-peptides during this phase of T cell receptordeletion (Kanagawa et al., 1998; Wicker et al.,1995).

Negative selection requires the tyrosine kinasex-chain-associated protein kinase of 70 kDa(ZAP70). Mice deficient in ZAP70 develop asystemic inflammatory disorder resembling rheu-matoid arthritis (Sakaguchi et al., 2003). Inaddition, the following factors have been identifiedas being essential for negative selection: growth-factor-receptor-bound (GRB) protein 2 (Gonget al., 2001), misshapen-Nck-interacting kinase(NIK) related kinase (MINK) (McCarty et al.,2005), extracellular signal-regulated kinase (ERK),and p38 and Jun kinase (JNK) activation (Palmer,2003). Induction of cell death of autoreactiveT cells requires BIM expression, which antago-nizes BCL-2 and related proteins to release pro-apoptotic BAX and BAK. Furthermore, membersof the Nur77 family of orphan nuclear receptorsare induced during negative selection. T cellreceptor-induced thymocyte death is blocked inthe absence of Nur77 (Zhou et al., 1996).

5. Clonal anergy and tuning

The intrinsic cellular mechanisms of anergy areparticularly well studied in B cells with self-reactive receptors (Benschop et al., 2001). Self-reactive B cell receptors can be internalizedthrough accelerated endocytosis, resulting inreduction of up to 99% of the initial surfaceexpression of a self-reactive receptor. Similarly, thetransport of new receptors to the surface can beblocked (Bell and Goodnow, 1994). It has beenreported that self-reactive B cell receptors activatetyrosine kinase signaling poorly, which limits cellsurvival because of weak NF-kB1 activation. Inparallel, weak signaling induces BIM expressionto promote cell death (Lesley et al., 2004) andERK pathways that block Toll-like receptor 9(TLR9)-induced differentiation into plasma cells(Rui et al., 2003).

So-called biochemical tuning can be achieved byincreasing the threshold of B cell receptor activa-tion, regardless of its specificity. Recruitment ofthe SH2-domain-containing protein tyrosine phos-phatase 1 (SHP1) through the surface proteinsCD22 and PD1 to the activated B cell receptors


increases its threshold for signaling (Healy andGoodnow, 1998). Another example is the recruit-ment of the lipid phosphatase SH2-domain-containing inositol-5-phosphatase (SHIP) to theactivated B cell receptor through Fc receptor-g(Ravetch and Lanier, 2000). Spontaneous auto-antibody production can occur if either one ofthese mechanisms is defective.

Tuning of self-reactive T cells is achieved byincreased expression of the inhibitory receptorCD5 (Wong et al., 2001; Smith et al., 2001).Cytotoxic T-lymphocyte antigen 4 (CTLA4) isanother inhibitory receptor that acts throughcompetition with CD28 for ligation with B7molecules and transmitting inhibitory signals.CTLA4 was found to be upregulated in self-reactive T cells (Sharpe and Freeman, 2002;Walker and Abbas, 2002). Massive accumulationof self-reactive T cells occurs in peripherallymphoid and nonlymphoid tissues in the absenceof CTLA4. Functional variants of the CTLA4gene can lead to thyroid autoimmunity and type 1diabetes in humans and mice (Ueda et al., 2003).

The ubiquitin ligases cbl-b, GRAIL and Itchhave been identified to be highly expressedin chronic T cell receptor signaling in vitro(Heissmeyer et al., 2004; Anandasabapathy et al.,2003; Jeon et al., 2004). Ubiquitinylation of T cellreceptors, CD28 and cytokine receptor signalingmolecules can alter intracellular trafficking, pro-mote proteolytic degradation or can allostericallyinterfere with signaling (Naramura et al., 2002;Liu, 2004). Their importance for preventingautoimmunity in rodents has been clearly demon-strated: cbl-b deficiency coupled with a particularMHC haplotype causes type 1 diabetes in theKomeda diabetes prone (KDP) rat strain (Yokoiet al., 2002). Large numbers of activated T cellsand high titers of autoantibodies can be found inmice lacking Itch, or cbl-b and its close relativec-cbl (Naramura et al, 2002; Liu, 2004).

6. Extrinsic controls of self-reactive

lymphocytes

A well-documented extrinsic control mechanism ofautoreactive B cells is their dependence on BAFF,

which is produced in limiting quantities by lym-phoid stromal cells (Mackay et al., 2003). Bindingof BAFF to its receptor increases NF-kB2 activitymaintaining peripheral B cell survival throughinduction of BCL-2 expression (Claudio et al.,2002). It also induces the expression of PIM2, aserin-threonie kinase, which has pro-survival effectsby interfering with the pro-apoptotic protein BAD(Fox et al., 2003). On the one hand, given the largenumbers of circulating B cells with strong receptorsignaling through high affinity to antigen, the self-reactive B cells do not receive enough BAFF andare competitively deleted (Thien et al., 2004). Onthe other hand, in states of B cell lymphopenia or inphases when BAFF synthesis is high, i.e. duringinfection, self-reactive B cells are more likely tosurvive (Mackay et al., 2003; Lesley et al., 2004).

As with B cells, T cell survival in the peripherydepends on continuous signaling through contactwith MHC ligands and exposure to IL-7 (Sprentand Surh, 2002; Marrack and Kappler, 2004;Barthlott et al., 2003). Under normal circum-stances, IL-7 levels are low and maintain T cells ininterphase. However, in lymphopenia, IL-7 levelsrise and amplify T cell receptor signaling andproliferation. This so-called homeostatic prolifera-tion may also activate self-reactive T cells causingautoimmune diseases in extralymphatic sites, acommon feature seen in people after T lympho-penia. Lymphopenia and defective T cell functionin Wiskott–Aldrich syndrome is leading to anarray of autoimmune and inflammatory conditions(Dupuis-Girod et al., 2003).

7. Limitation of costimuli

In order to secrete antibodies, B cells must receivetwo signals: First, an antigen must bind to the Bcell receptor; second, T helper cells must signalthrough CD40 ligand (CD40L) and cytokinesIL-2, IL-4, IL-5, and IL-21 to initiate B cellproliferation and differentiation into plasma cells(Foy et al., 1996; Kovanen and Leonard, 2004).Since negative selection in the thymus should havereduced the number of self-antigen-specific T cells,the latter signal to self-reactive B cells is limited.

H. Mix, M.P. Manns8

However, self-reactive B cells may receive signalsfrom T helper cells responding to foreign antigensduring infections, so-called bystander activation.More importantly, infections only rarely triggerautoantibody diseases, like Guillain–Barre syn-drome. Efficient B cell intrinsic tolerance mecha-nisms must be responsible for the fact that only 1in 1000 people infected with Campylobacter pylori

develops autoantibodies that cross-react withcomponents of peripheral nerves (Ang et al., 2004).

Interestingly, antibody production can be par-tially independent of T cell help, when B cellsreceive stimulatory signals from bacterial flage-llins, cell-wall lipopolysaccharides, and unmethy-lated CpG dinucleotides, which are recognized byToll-like receptors (TLR) (Beutler, 2004). Howthis potentially dangerous pathway is dampened isnot known in detail. Dysregulated activity of theTLR9 pathway leads to pathological accumulationof circulating IgG–self-DNA complexes, and is apotent driver of the production of autoantibodiesagainst IgG and DNA (Leadbetter et al., 2002).Inadequate clearance of apoptotic cells withexposed CpG DNA and other nuclear antigensmay account for the striking association betweensystemic lupus erythematosus (SLE) and geneticdeficiencies in classical complement pathwaycomponents (Taylor et al., 2000).

Mature T cells are activated by T cell receptorligation and costimulation. Without costimulation,tolerance is favored. The most important costimu-lus is the interaction of CD28 on T cells and the B7proteins CD80 and CD86 on antigen-presentingcells. TLR signaling induces expression of B7molecules and enhances the survival and clonalexpansion of T cells. Therefore, blocking B7–CD28interactions may be an attractive way to inducetolerance. However, this treatment may alsodecrease thymic deletion and interfere with regula-tory T cell function and intrinsic T cell regulationby CTLA4.

8. Regulation of self-reactive lymphocytes

in follicles

Somatic hypermutation occurs in the periphery ingerminal center follicles of secondary lymphoid

organs (Radic and Weigert, 1994; Ray et al., 1996).Antibodies created by this process can havemarkedly increased affinities for self-antigens.Follicular B cell differentiation generates long-lived plasma and memory cells, which are able tosecret antibodies indefinitely (Slifka et al., 1998).Autologous DNA, an important self-antigentarget in systemic lupus erythematosus (SLE), isabundantly presented by numerous apoptotic cellsin germinal centers (Rosen and Casciola-Rosen,2001), where it represents a powerful potentialstimulus for autoantibody production. It has beenfound that anti-double-stranded DNA antibodiesare somatically mutated in animal models of SLE(Radic and Weigert, 1994).

In addition to CD40L, follicular T cells displayhigh levels of ICOS, which is required for germinalcenter antibody responses in mice and humans(Sharpe and Freeman, 2002; Kroczek et al., 2004).Follicular T cells are also dependent on costimula-tion through OX40L (Walker et al., 2000). T cellentry into follicles is not induced in the absenceof microbial TLR agonist (Kearney et al., 1994).Since self-antigens usually do not stimulate TLRsignaling, this strict regulation of follicular Thelper cell differentiation may block self-reactiveT cells from delivering help to germinal center Bcells.

9. Tolerance at the effector phase

The mechanisms involved in preventing autoim-munity at target organs are only just beginning tobe elucidated. Often pathology is limited to focalareas, like circumscribed skin lesions in pemphigusor single-joint inflammation in rheumatoid arthri-tis. Pathology depends on multiple factors, inclu-ding immunologic cascades involving Fc receptors,mast cells, neutrophils, and complement (Wipkeet al., 2004; Monach et al., 2004).

10. Conclusions

The mucosa of the gastrointestinal tract is a majorsite of pathogen entry. The gut-associated immune


system needs to remain hyporesponsive to foodantigens and commensal bacteria while mountingan efficient response against pathogens. Immuneresponses must be exactly coordinated and regu-lated in order to effectively cure an infection andto avoid chronic inflammation. Autoimmunediseases can be considered as immune responseswith defects in mechanisms that control self-tolerance. Every organ of the digestive systemcan be the target of an autoimmune response,either in systemic or in organ-specific autoimmunediseases. Although many self-tolerance mecha-nisms exist, defects in a single checkpoint can leadto autoimmune disease. Clinical manifestationsof autoimmune diseases are often seen only after alatent period of many years and then only againsta few proteins or organs. There seems to behundreds of genes involved in the checkpoints ofself-tolerance. Common analysis of DNA poly-morphisms will not be effective in identifyingpredisposing defects, rather exon resequencing ofindividuals with autoimmune disease will berequired.

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CHAPTER 2

Imaging Techniques in Digestive Diseases

Carmen Ayusoa, Mario Pagesa, Luis Donosob,�aRadiology Department, Diagnostic Imaging Centre, Hospital Clinic, University of Barcelona,

Abdomen Unit (CT and MRI), IDIBAPS, Villarroel 170, 08036 Barcelona, SpainbDiagnostic Imaging Centre, Hospital Clinic, University of Barcelona, IDIBAPS, Villarroel 170,

08036 Barcelona, Spain

1. Introduction

Gastrointestinal (GI) manifestations are common inpatients with autoimmune diseases and can involveany part of the GI tract or the hepatobiliary system.Furthermore, abdominal symptoms may overlapthose due to other factors related to the specialcircumstances of autoimmune disease, such as side-effects of medication. Imaging techniques have animportant role in the diagnosis and management ofpathologic abdominal conditions in these patients.Recent technological advances have brought aboutconsiderable improvement in abdominal imaging.This chapter provides an overview of the imagingmodalities available in the diagnosis of GI involve-ment in the context of autoimmune diseases. A briefdescription of the basic principles underlying eachtechnique is provided and the advantages andlimitations of the different imaging techniques,including the newest contrast agents for ultrasound(US) and magnetic resonance (MR), are discussed.

2. Imaging modalities

2.1. Plain abdominal film and barium studies

Plain abdominal films are currently mostly indi-cated in the clinical context of acute abdominal

disorders. Plain films can depict bowel distensionor abnormalities in the distribution of abdominalgas, such as free intraperitoneal air, pneumatosisintestinalis, ileus or pseudo-obstructive pattern, orpylephlebitis. Although the imaging examinationbased on plain films of the abdomen sometimesprovides enough definitive information to indicatea particular surgical or conservative treatment, itmore often represents the first step in a morecomplex diagnostic imaging process.

Endoscopic procedures for the study of the GIpathology have dramatically decreased the indica-tions for contrast-enhanced bowel radiographs.However, barium studies carried out usingdynamic techniques such as videofluoroscopy areincreasingly used to study the functional disordersof the pharynx and esophagus.

2.2. Ultrasound or ultrasonography

The commercial availability of high-resolution‘gray scale’ equipment since 1974 has made USone of the mainstays in the study of the abdomenand particularly the hepatobiliary system. Thebasic principle underlying US is the transmissionof sound waves into the abdominal organs froma transducer, which converts electrical energy intosound waves and vice versa. As the US wavepasses through the abdominal tissues, it is affectedby changes in tissue type and is refracted andreflected at interfaces between tissues withE-mail address: [email protected]


Tel.: +34-93-227-5412; Fax: +34-93-227-9323


DOI: 10.1016/S1571-5078(07)00002-5

dx.doi.org/10.1016/S1571-5078(07)00002-5.3d

differing acoustic impedance. The transducer isable to detect the reflected sound waves and usesthe time delay from the transmission to calculatedepth within the body. The incoming vibrationsare converted into electrical pulses and trans-formed into images by the US scanner. Currentstandard US of the abdomen uses state-of-the-arthardware and software together with a 3.5 or5MHz transducer and optional Doppler facilities.

The general availability and relatively low costof US, together with the fact that it does notemploy ionizing radiation, have ensured that itis widely used to rule out abdominal pathology.US is often performed as the first step in theevaluation of abdominal emergencies. Moreover, itis the imaging technique of choice for screeningpatients with suspected focal liver lesions andalso for evaluating gallbladder and biliary treepathology.

US enables real-time studies, and the radiologistcan select the most appropriate cross-sectionalplane to obtain the desired information. Thisproperty enables US to guide a wide range ofinterventional procedures, such as aspirationbiopsies, drainage of abdominal collections, orpercutaneous ablative treatments of primarytumors and metastases.

There are no contraindications for US, althoughits effectiveness decreases in obese patients and inthose with air-distended bowel loops, which makeit difficult to evaluate the underlying tissues. Infact, air interposed between the transducer and thepancreas often limits the assessment of this organ.

Color, spectral, and power Doppler imagingprovide a non-invasive method of measuring flowin the abdominal vessels and assessing vascularitywithin a lesion. Spectral Doppler provides atracing of the Doppler wave from which it ispossible to calculate various indices, includingpeak systolic velocity and resistive indices. ColorDoppler enables the direction of blood flow to bedetermined. Power Doppler displays the integratedpower of the color signal to depict the presence ofblood flow. The pulsed Doppler technique canprovide Doppler shift data selectively from a smallsegment along the US beam, enabling us to selecta small vessel and quantify the velocity of flowthrough it (Fig. 1).

Tissue harmonic imaging uses secondary fre-quencies which are multiples of the fundamentaltransmitted frequency. The resulting harmonicimages have fewer artifacts and better spaceresolution. Harmonic imaging is especially usefulwhen contrast agents are used.

US contrast agents consist of very small gas-filled microbubbles, which are supported by a shellof biologically inert material. Microbubbles pro-duce unique acoustic signatures that allow theirsignal to be separated from tissue echoes. The USsystem takes advantage of the strong echogenicityof the contrast agent to create an enhanced imageof the area of interest. US contrast agents areespecially useful for characterizing liver lesions(von Herbay et al., 2004; Burns and Wilson, 2007)and assessing the efficacy of percutaneous treat-ments.

2.3. Computed tomography (CT)

CT shows cross-sectional views of patient ana-tomy. CT involves multiple X-ray transmissionmeasurements through the patient. The informa-tion acquired is processed by a computer, whichuses mathematical techniques to generate a pictureof the internal structures in cross-section. Body CTwas introduced in 1974. Rapid development ledto the early abandonment of the initial dual-slicescanner in favor of single-detector row scannersand incremental technology. At the end of 1980s,improvements in tube technology and computingled to the advent of helical CT. This fastervolumetric acquisition allowed better qualityimage reconstructions to be obtained in differentplanes. The development of multidetector CT(MDCT) began in earnest in 1998 when four-slicescanners were introduced. Systems with 6-, 8-, 10-,16-, 40-, and 64-detector arrays have since becomeavailable.

The simultaneous acquisition of multiple(16, 64, or even more) continuous slices duringone sub-second gantry rotation has improvedacquisition speed, resulting in faster imagingprotocols. Furthermore, improvements in the z-axiscoverage speed have enabled nearly isotropic

C. Ayuso et al.16

image acquisition, providing high-resolution mul-tiplanar reformations (MPR) and making excellentthree-dimensional (3-D) displays possible (Prokop2005). The advantages of MDCT are a conse-quence of (1) shorter scan duration, which reducesmotion artifacts and enables a well-defined solidparenchymal phase of contrast enhancement andthus better adjustment of contrast medium injec-tion rate, volume, and concentration; (2) longerscan ranges that permit very good quality CTangiographic studies of the whole body; and (3)thinner sections that permit arbitrary imagingplanes, MPR (Fig. 2), and 3-D rendering (Fig. 3).

A challenge presented by multidetector-row CTis posed by the substantial increase in the numberof reconstructed cross-sections (easily more than1000 axial images) that are rapidly created and inneed of analysis. This situation requires moresophisticated visualization techniques for theassessment of volumetric data, not only in terms

of 3-D workstations but also in fast automatedprocessing and user interfaces to replace theanalysis of transverse reconstructions by otheralternatives. The large data load means that newways of viewing, processing, archiving, and dis-playing images are necessary, and more time isneeded to analyze the data than with single-slicehelical CT.

Images obtained with MDCT show increasedimage noise as the section collimation is reduced.To keep the noise low, thicker sections have to bereconstructed. Special attention has to be paid toavoid a dramatic increase in the radiation dose tothe patients using MDCT protocols, and acquisi-tion protocols must be carefully adjusted to reducethe radiation dose.

The indications for abdominal CT in patientswith autoimmune diseases cover a wide spectrumranging from inflammatory conditions, such asabdominal sepsis or acute pancreatitis, to

Figure 1. Doppler ultrasound demonstrates patency of portal vein. Doppler is displayed in images (Color Doppler) and graphically

(Spectral Doppler). (See Colour Plate Section.)

Imaging Techniques in Digestive Diseases 17

Figure 2. Computed tomography angiogram. (a) Arterial phase: MPR in a sagittal view shows the normal anatomy of the abdominal

aorta and the superior mesenteric artery. (b) Portal phase: MPR in an oblique-coronal plane shows the regular patency of the portal,

and superior mesenteric veins.

C. Ayuso et al.18

neoplastic diseases, such as lymphoma or othersolid tumors, where CT is a useful tool to definethe tumor extension. One of the most importantindications for CT is to rule out vascularcomplications that are fairly common in thiscontext, such as Budd–Chiari syndrome; however,the most common and most challenging diagnosticand therapeutic problem is acute abdominal pain.Ischemic bowel disease is a very common andsevere complication in patients with autoimmunediseases, and it has a very poor prognosis when thediagnosis is delayed.

CT can also be used to direct percutaneousinterventional diagnostic procedures such asfine-needle biopsy of solid focal lesions (Fig. 4),tru-cut biopsies of solid organs (liver, kidney)to rule out diffuse parenchymal disease, orpercutaneous therapeutic procedures such as thedrainage of abdominal fluid collections. Low-doseCT fluoroscopy allows continuous control of thetip of the needle in real-time mode to avoiddamage to vital structures during interventionalprocedures.

MDCT angiography has become a valuableminimally invasive tool for the visualization ofnormal vascular anatomy and its variants, as wellas pathologic conditions of abdominal vessels. Asabdominal pain is a frequent clinical problem inpatients with autoimmune diseases and bowelischemia has to be ruled out, the discussion ofMDCT angiography in this chapter will focus onthe mesenteric vessels. Although mesentericMDCT angiography can be specifically performedas a single study, it is often carried out incombination with studies of solid organs or moregeneralized abdominal imaging. In patients withsuspected mesenteric ischemia, CT may help detectischemic changes in the affected small bowel loopsand mesentery, such as bowel wall thickening,submucosal hemorrhage, increased or decreasedenhancement of the bowel wall, or even pathologicchanges in the mesenteric vasculature like athero-sclerotic stenosis, thrombosis, or occlusion (Fig. 5).To depict these findings, both unenhanced andbiphase CT abdominal studies (arterial and venousphases) are usually performed. Bowel opacificationshould be avoided to improve vascular visualiza-tion in 3-D imaging post-processing. A total of

Figure 3. Computed tomography angiogram provides exquisite

detail of the anatomic distribution of the celiac artery and

superior mesenteric artery. The hepatic artery and its segmental

branches are also displayed. (a) Maximum intensity projection

image. (b) Volume-rendered image.


100–150ml of non-ionic iodinated contrastmaterial (300–370mg of iodine per milliliter) isusually administered with a power injector at arate of 2–4ml/s. Three-dimensional imaging post-processing of data sets from the arterial andvenous phases in the workstation allows real-timeviewing of axial and multiplanar images andprovides additional sophisticated renderingoptions, such as thick and curved MPR, thin-slabmaximum intensity projection (MIP), and volumerendering (VR) reconstructions (Fig. 6). Thesensitivity of CT in detecting bowel ischemia hasreached 82% (Klein et al., 1995) and is comparableto that of angiography. For this reason, theindications for angiography are moving fromdiagnostic to therapeutic aspects. Angiographyenables endovascular treatment, such as percuta-neous transluminal angioplasty or stent place-ment, in selected patients with acute mesentericischemia caused by vascular occlusion (Reschet al., 2005).

2.4. Magnetic resonance

MR is based on the relaxation properties ofhydrogen atoms when they are subjected to astrong magnetic field, and the power of MRequipment is quantified by Teslas (T), a measure-ment of magnetic flux density. The first commer-cial MR scanners became available in the early1980s. MR applications in relatively motionlessbody parts, such as the brain, spine, or muscu-loskeletal system, quickly took hold in the field ofmedical diagnosis, because high-quality images notconditioned by artifacts due to bone structureswere obtained, with far better contrast resolutionthan CT. However, abdominal MR imaging waslimited by long acquisition times that producedsevere motion artifacts due to respiratory andperistaltic movements. These limitations wereovercome through technical advances such as thedevelopment of ultrafast single-shot sequences,and images providing excellent anatomic detail can

Figure 4. CT-fluoroscopy-guided fine-needle biopsy. Irregular thickening of the bladder wall can be seen secondary to a primary

bladder neoplasm. A 20-gauge needle is placed in an enlarged left iliac lymph node. Metastatic tumor nests were found in the pathologic

study of the sample.

C. Ayuso et al.20

now be obtained routinely. Abdominal MR iscurrently a widely accepted imaging technique forthe study of multiple pathologies of the GI,including pancreatic and hepatobiliary diseases.Technical improvements have led to the develop-ment of new MR techniques, such as MR cholan-giopancreatography (MRC) or MR angiography.

2.4.1. MR techniqueMR abdominal studies are routinely obtained witha torso phased-array surface coil. MR examinations

consist of the acquisition of different sequencesaccording to particular study protocols, dependingon the abdominal organ studied or the suspectedpathology. However, most of the abdominal pro-tocols include T1-weighted sequences (in-phase/opposed phase to detect fatty infiltration, and/orfat-suppressed sequences), T2-weighted sequences(useful in tumor characterization), and a dynamiccontrast-enhanced sequence (to demonstrate theenhancing vascular pattern of the lesions).

MR’s multiplanar capacity is one of the mostinteresting characteristics of this imaging

Figure 5. Acute intestinal ischemia due to nearly total occlusion of the superior mesenteric artery (SMA). (a) Axial CT section at the

level of the SMA origin shows a very significant reduction in the patent lumen of the artery. (b) A small amount of gas can be seen in

the superior mesenteric vein. (c) There is some gas collection in the wall of the right colon and also in the wall of the terminal ileum due

to intestinal pneumatosis.


Figure 6. Acute embolic intestinal ischemia. (a) CT topogram shows dilated small bowel loops. (b) MPR demonstrates multiple filling

defects into the SMA. (c) Volume-rendered image of the same patient showing an almost complete occlusion of the SMA.

C. Ayuso et al.22

modality: MR images can be acquired in anysectional plane. This property was initially one ofthe main advantages of MR over CT, althoughcurrently MDCT also allows high-quality recon-structions in any orientation.

MR has higher contrast resolution than CT,although it has less spatial resolution. In otherwords, there are more signal intensity changesbetween tissues, although less definition in limitingstructures.

2.4.2. Contrast agentsThe most common MR contrast agents are thechelates of gadolinium, which are non-specificextracellular contrast agents. After intravenousadministration, they are initially distributed in theintravascular space, but they are rapidly clearedinto the interstitial space, filtered through thecapillaries into the extracellular space, and areeventually excreted by the kidneys. The mainindications of contrast-enhanced MR include thestudy of neoplastic lesions to assess tumorvascularity, vascular pathologies, and MR angio-graphy. One advantage of these contrast agentsversus the iodinated contrast media used in CTexaminations is their lower or non-existentnephrotoxicity, and gadolinium contrast-enhanced

MR studies have long been a viable alternativein patients with renal failure or iodine allergy.However, a new severe entity which seems to berelated to some gadolinium chelates has recentlybeen reported in patients with renal failure:nephrogenic systemic fibrosis (Marckmann et al.,2006). Thus, the chelates of gadolinium shouldonly be administered in these patients when it isessential.

Hepatobiliary contrast agents partially passfrom blood through the hepatobiliary system withpartial excretion through the kidneys and thebile ducts. These liver-specific contrast agents areselectively uptaken by the hepatocytes, leadingto an increase in signal intensity on T1-weightedsequences of the normal liver parenchyma and alsoof the focal hepatocellular liver lesions. Some ofthe hepatobiliary contrast agents can be rapidlyinjected and dynamic hepatic studies can beperformed to assess the anatomy of the biliarytree, to detect bile leaks, and also to detect andcharacterize hepatic tumors (Fig. 7).

Reticuloendothelial contrast agents are removedfrom the blood by the reticuloendothelial cellsof the liver and the spleen. These tissue-specificcontrast agents consist of small particles ofiron oxide. They are injected intravenously andcleared by the reticuloendothelial system, located

Figure 7. Focal nodular hyperplasia studied by MR imaging. (a) T1-weighted gradient-echo MR image with fat suppression. The lesion

exhibits homogeneous intense enhancement in the arterial phase (20 s following the injection of hepatobiliary contrast agent). (b) 20min

after injection (same sequence as (a)), the lesion is slightly hyperintense in comparison to normal liver parenchyma due to its

hepatocellular nature.


predominantly in the Kupffer cells of the liver.Reticuloendothelial contrast agents produce anegative enhancement by decreasing signal inten-sity in T2-weighted sequences. Iron is added to theiron pool and excreted by the kidneys. Thesecontrast agents are useful in characterizing somefocal hepatic lesions, such as focal nodularhyperplasia.

2.4.3. Indications and limitationsAbsolute contraindications for MR studies arepacemakers and other ferromagnetic implants,such as cochlear implants, vagus nerve stimulators,or insulin pumps. Although other modern medicaldevices are mainly manufactured without ferro-magnetic materials, the magnetic properties ofvalvular prostheses and stents must be evaluatedbefore a patient can undergo MR. Patients mustbe queried about possible ferromagnetic foreignbodies, and a plain film X-ray is sometimesnecessary to rule out their presence.

Liver MR is an excellent imaging technique tocharacterize non-specific focal lesions previouslydetected in US or CT studies. Among other indica-tions, hepatic MR is widely used to stage primaryhepatic tumors, to evaluate potential living liverdonors, and to evaluate complications after livertransplantation. It is also usually performed inpatients with liver metastasis prior to surgicalresection.

MRC is a non-invasive technique to depict thebiliary tree and the pancreatic ducts. The imagesobtained are comparable to endoscopic retrogradecholangiography (ERC). MRC is performed usingheavily T2-weighted sequences that demonstrate thefluid-containing bile ducts as high-signal-intensitystructures. This technique has demonstratedhigh sensitivity and specificity in the diagnosis ofthe location and etiology of biliary obstruction(Fig. 8) to the extent that ERC is usually indicatedonly when a therapeutic approach is needed.

MR enteroclysis is an emerging technique for theevaluation of small bowel diseases. It combines thestudy of luminal, mural, and extramural abnorm-alities. It can evaluate not only bowel wall ulcersbut also transmural complications in inflammatorybowel disease (Wiarda et al., 2006). (Fig. 9)

Figure 8. MR cholangiography depicts the biliary tree and

pancreatic ducts. Multiple filling defects typical of stones are

shown in the lumen of the common bile duct.

Figure 9. MR enteroclysis shows anatomic demonstration of

the small bowel. Coronal MR image clearly depicts fluid-filled

bowel loops and provides excellent contrast between the bowel

wall and surrounding structures.

C. Ayuso et al.24

Figure 10. Images for staging an anaplastic lymphoma. PET/CT images. (a) Axial CT image at the pelvis shows an enlarged external

iliac lymph node. (b) Corresponding axial maximum intensity projection image showing intense FDG uptake in the external iliac lymph

node. (c) PET/CT fused image at the same pelvic level confirms the coincidence of both pathologic images. (See Colour Plate Section.)


MR angiography provides high-quality arterialand venous images without ionizing irradiation.MR angiography is an alternative to CT angio-graphy in patients with allergies to iodinatedcontrast media.

2.5. Positron emission tomography

Positron emission tomography (PET) is an opera-tor-independent, non-invasive metabolic imagingmodality based on the regional distribution of18F-fluorodeoxyglucose ([18F]FDG); PET plays amajor role in the management of oncology patients(Endo et al., 2006; Rao et al., 2006). Furthermore,activated inflammatory cells have also been shownto overexpress glucose transporters and to accu-mulate increased amounts of glucose and structu-rally related substances such as [18F]FDG. Someauthors have reported the usefulness of thisimaging technique in assessing the activity and theextent of large-vessel vasculitis (Meller et al., 2003;Walter et al., 2005).

Recently, functional PET images have been usedin combination with CT to enable the anatomic ormorphologic features of tumors to be assessed aswell. PET and CT images obtained at the sameposition provide the precise localization of lesionswith increased glucose metabolism over the wholebody in a single session (Fig. 10). PET and/orPET/CT using FDG is now widely employed as anadvanced clinical imaging tool for the diagnosis,staging, and restaging of cancer, as well as for theassessment of tumor therapy.

3. Future prospects

Recent years have witnessed enormous technolo-gical advances in abdominal imaging techniquesas well as the development or improvement ofdifferent contrast media for use with US, CT, andMRI. Consequently, a wide variety of high-qualitydiagnostic images can quickly be obtained andmore functional protocols can be applied withnon-invasive or minimally invasive procedures,while classic invasive imaging techniques have

moved toward therapeutic indications. On theother hand, many percutaneous diagnostic andtherapeutic procedures can be guided by imagingtechniques, especially US and CT fluoroscopy,leading to faster diagnosis and treatment ofabdominal pathologic conditions.

In the near future, the development of hybridtechnology might allow high-resolution images,functional images, and metabolic information tobe combined. This ‘one store shop’ would con-tribute to a quicker and earlier specific diagnosisleading to improved management of abdominaldiseases and thus improved prognoses.

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bowel diseases. AJR 187 (2), 522–531.



PART II:

Systemic Autoimmune Diseases





CHAPTER 3

Systemic Lupus Erythematosus

Miquel Vilardell-Tarres�, Albert Selva-O’Callaghan, Josep Ordi-Ros

Internal Medicine Department, Vall D’Hebron General Hospital, Universitat Autonoma de Barcelona, 08035

Barcelona, Spain

1. Introduction

Systemic lupus erythematosus (SLE) is a systemicautoimmune disease with a broad range of clinicalmanifestations. It is characterized by an immunedysregulation resulting in the production ofvarious autoantibodies (D’Cruz et al., 2007).Different organ systems are involved, with theresult that morbidity and mortality are significant.Gastrointestinal (GI) manifestations are commonin SLE patients due to the disease itself or due toaggressive treatment regimens (Sultan et al., 1999).However, they are seldom reported, probablybecause they are often masked by other morerelevant clinical features such as renal or centralnervous system involvement. The incidence of GImanifestations attributable to the disease itselfvaries widely and ranges from 1.3 to 27.5% in theliterature. These manifestations appear to be morefrequent in patients of Oriental ethnicity. In thischapter, we present the different GI manifestationsof SLE patients.

2. General symptoms

Almost half of all SLE patients suffer fromanorexia, nausea, and vomiting. These symptomscan be caused by the disease itself, by uraemia in the

context of renal failure, and by cytostatic therapiessuch as azathioprine and intravenous pulses ofcyclophosphamide or the more recently usedimmunosuppressive drug, mycophenolate mofetil.

Serositis—pleuritis, pericarditis, and less fre-quently, ascites—is a well-known diagnostic crite-rion of SLE. It is present in 8–11% of patients withSLE and can be differentiated as inflammatory—true serositis—or non-inflammatory, due mainly tohypoalbuminemia (nephrotic syndrome, liver cir-rhosis, protein-losing enteropathy) (Mok, 2005).

3. Oral cavity, oesophagus, and gastric

abnormalities

Oral ulcers are frequent in patients with SLE andaffect between 6 and 52% of patients (Sultan et al.,1999). They are usually painless and involve thehard palate, nasal cavity, and pharyngeal wall. Thefact that most SLE patients receive immunosup-pressive therapy means that infection as a cause oforal ulcers should not be overlooked. Candidiasis,herpes virus, and oral leucoplakia can be recog-nized as oral ulcers or plaque-like lesions.

The presence of a secondary sicca syndromewith dry mouth and dry eyes is not uncommon inSLE patients; almost 20% of cases develop thismanifestation (Andonopoulos et al., 1990). Drymouth favours periodontal disease and aphthousulcers, erythema, haemorrhage, and gingival over-growth. Treatment with cyclosporine A usuallyexacerbates gingival hypertrophy. Tissue biopsyE-mail address: [email protected]


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might show lupus-specific histopathology similarto that of the skin. The histology and immuno-pathology of oral lesions in these patients includean inflammatory perivascular lymphohistiocyticinfiltrate, spongiosis, hyperkeratosis, and IgG/IgM, complement, and fibrinogen deposition atthe dermal–epidermal junction. These lesions aresometimes difficult to distinguish from lichenplanus or leucoplakia.

Anti-malarials (chloroquine and hydroxychloro-quine) and topical corticosteroids are the treatmentof choice. Systemic steroids and/or azathioprine aregenerally used in severe cases. Thalidomide andcyclosporine A in Europe and methotrexate in theUSA are also used as second-line agents in the mostrefractory cases. To date, there are no evidence-based guides to systemic therapy of oral lesions inSLE patients. Sugar-free gum, artificial saliva, andsystemic therapy with pylocarpine hydrochloride toincrease salivation can be useful in cases ofsecondary Sjogren syndrome.

Oesophageal symptoms in SLE patients includedysphagia and heartburn, but it is difficult toassume that these are due to the disease and notthe therapy. The introduction of proton pumpinhibitors has lessened the relevance of oesopha-geal symptoms. Manometry abnormalities, espe-cially hypoperistalsis in the upper one-third, havebeen reported in almost two-thirds of patients—even in asymptomatic patients—and can beassociated with chronic intestinal pseudo-obstruc-tion (CIPO), an uncommon GI complicationexamined below. Involvement of the lower oeso-phageal sphincter is rare, and oesophageal symp-toms do not seem to correlate well withmanometry results. Conventional and sympto-matic therapy—proton pump inhibitors and smalland frequent meals—is probably a better approachthan immunosuppressive or anti-inflammatorytreatment. Nevertheless, if vasculitis or inflamma-tion is documented by biopsy studies, treatment oflupus itself is warranted, especially if serologicallyand clinically systemic disease is recognized.

Gastric disease is more frequently related totreatment complications [non-steroidal anti-inflammatory drugs (NSAID) and corticosteroids]than to the disease itself. Therefore, patients onlong-term NSAIDs may need to be maintained on

a gastroprotective agent such as a proton pumpinhibitor. Cytomegalovirus infection of gastricmucosa should be borne in mind, particularly inSLE patients receiving long-term treatment withmycophenolate mofetil, as is well known in renaltransplantation (Mathew, 1998). Gastric antralvascular ectasia, the so-called watermelon sto-mach, is a rare vascular malformation which hasbeen described in SLE. It can cause acute orchronic bleeding which in turn leads to persistentiron deficiency anaemia. Moderate doses of pre-dnisone are recommended, although transendo-scopic treatment or antrectomy may occasionallybe needed (Hallegua and Wallace, 2000). Apossible protective role for Helicobacter pylori

against the development of SLE has recentlybeen reported in some ethnic groups (Sawalhaet al., 2004).

4. Main gastrointestinal syndromes

4.1. Abdominal pain

Abdominal pain is usually a non-specific symptombut can be particularly important in SLE patients.It is not an uncommon complaint in patients withlupus (Mok, 2005), or in children (Richer et al.,2007). Acute abdomen is always a challengingdiagnostic and therapeutic problem—even more soin SLE (Kishimoto et al., 2007)—and abdominalpain in these patients could also be caused bycomplications of therapy and of the disease itself(Table 1). Immunosuppressive treatment andcorticosteroids are the usual medications in SLEpatients and mainly serve to mask the classicalmanifestations of perforation and ischemia, two ofthe main causes of acute abdomen. Non-steroidalanti-inflammatory drugs, azathioprine, calcineurinantagonists such as cyclosporine and tacrolimus,and mycophenolate mofetil, can all cause abdom-inal pain to a greater or lesser extent. Evaluationof the activity of the disease by means of theSLEDAI (Systemic Lupus Erythematosus DiseaseActivity Index) helps physicians to decide thecorrect approach. It seems that intra-abdominalvasculitis and mesenteric thrombosis—both severe

M. Vilardell-Tarres et al.32

abdominal SLE complications—are clearly asso-ciated with a higher SLEDAI. Radiologicalexplorations such as ultrasound and CT scanningare essential to achieve a correct diagnosis,although in some cases—especially acute abdomenwith active SLE and when the clinical presentationis severe—early laparotomy is preferred becausethe mortality in this subgroup is very high (Medinaet al., 1997).

Middle serositis, small bowel bacterial over-growth, and non-SLE-related causes are the mostfrequent manifestations in outpatients.

Mesenteric insufficiency (Mok, 2005), the so-called intestinal angina, deserves special attention.It is well known that SLE patients are proneto premature atherosclerosis which can affectdifferent territories. Besides cerebral and coronaryvessels, splanchnic arteries may also be involved,causing chronic intermittent abdominal painwhich should not be overlooked. Symptomsusually start after lunch and persist for 1–3 h.Weight loss and fear of eating are usually reportedin patients with mesenteric insufficiency. Conven-tional angiography is the gold standard for acorrect diagnosis, but MRI or abdominal CT scanwith angiography is also useful and less invasive.Long-standing disease, renal insufficiency, long-term corticosteroid therapy, and the presence ofclassical cardiovascular risk factors such as hyper-tension, smoking, hyperlipidemia, and diabetesfavour the development and progression of athero-sclerosis, also in SLE patients. Healthy habits anddrugs (statins) to control or minimize these factors

are strongly recommended. Therapeutic optionsinclude surgical revascularization or, in selectedcases, percutaneous transluminal mesentericangioplasty with or without stent placement.Platelet antiaggregants with aspirin and/or clopi-dogrel or anticoagulation therapy must be chosenon an individual basis.

4.2. Lupus enteritis (gastrointestinalvasculitis)

Lupus enteritis, also called gastrointestinal vascu-litis due to the characteristic histopathologicalfindings in nearly all the cases studied, is one ofthe most serious complications of SLE (Lee et al.,2002). Although some authors believe that thepresence of antiphospholipid antibodies (aPL) isassociated with lupus enteritis, most are of theopinion that these antibodies are largely related toarterial or venous thrombotic events, but not tovasculitis. Thus, there seems to be a link betweenmesenteric thrombosis and aPL, but not betweenvasculitis and aPL. Lupus enteritis is generallyaccompanied by bowel ischemia, and the CT scanshows dilated bowel, focal or diffuse bowelthickening with bowel wall enhancement, mesen-teric oedema, and ascites (Ko et al., 1997). Never-theless, it is known that most of these signs arehighly non-specific. A clue to the diagnosis ofintestinal vasculitis is the involvement of severaldifferent vessels simultaneously. The anatomicalareas most frequently involved are the jejunum and

Table 1

Abdominal pain in systemic lupus erythematosus

SLE related Treatment related Non-SLE causes

Renal vein thrombosis Gastritis, duodenitis Appendicitis

Mesenteric thrombosis Pancreatitis (azathioprine) Viral hepatitis

Acalculous cholecystitis Sepsis Biliary pancreatitis

Bowel perforation Peptic ulcer Diverticulitis

Vasculitis Perforation Surgical adhesions

Ectopic pregnancy Enterocolitis

Pancreatitis Salmonella infection

Serositis

Splenic infarction

Ischemic bowel disease

Angioedema

Systemic Lupus Erythematosus 33

ileum, whereas rectal involvement is fairly uncom-mon, even though this area is well supplied withblood. Improvement after intravenous glucocorti-coid therapy (pulses of 1 gr/d of prednisolone forthree days) may favour a diagnosis of reversibleischemic bowel disease caused by intestinal vascu-litis. A differential diagnosis with inflammatorybowel disease is sometimes required.

Besides abdominal pain, there is usually evidenceof active disease in other organs, with fever andacute-phase proteins, occult blood in stool, or evenfrank GI haemorrhage. Glucocorticoids remainthe therapy of choice and can be combined withimmunosuppressive agents such as cyclophos-phamide. Surgery is recommended when the generalcondition deteriorates (Grimbacher et al., 1998).

4.3. Intestinal pseudo-obstruction

This is a rare and poorly understood GI complica-tion of SLE. It has been defined as the presenceof clinical features of intestinal obstructionwithout an identifiable organic obstructive lesion

(Mok et al., 2000). CIPO reflects a dysfunction ofthe visceral smooth muscle or the visceral auto-nomic nervous system. Ureterohydronephrosisand biliary tract involvement have been reportedwith CIPO, which indicates the existence of asmooth muscle motility problem (Pardos-Geaet al., 2005) (Figs. 1 and 2). Nearly half of thepatients described are Oriental, which implies agenetic component, although studies to identify aspecific HLA have not been carried out.

Clinical presentation is subacute, with slightabdominal pain and abdominal distension accom-panied by very sluggish or absent peristalsis.Rebound tenderness is uncommon. CIPO can bethe first manifestation of SLE in some patients, butit usually represents a GI complication whichappears during the course of the disease. Mortalityis not related to CIPO itself but to sepsis fromimmunosuppressive treatment or other majororgan involvement attributed to SLE. Mostpatients have an undulant course with recurrentattacks and GI clinical relapses. The small bowel ismore commonly involved than the large bowel(Narvaez et al., 2003).

Figure 1. Abdominal magnetic resonance imaging with dilated urinary pelvicaliceal system and bilateral ureterohydronephrosis.


Radiological examination—mainly ultrasono-graphy and enhanced contrast abdominal CTscan—frequently reveals bilateral ureteral dilata-tion with a reduced urinary bladder capacity.Chronic interstitial cystitis, a condition associatedwith immune complex deposition and a well-recognized complication of SLE, has been docu-mented in some cases of CIPO (Kim and Park,1996; Narvaez et al., 2003). Clinical suspicion istypically confirmed by antroduodenal manometry,which generally demonstrates oesophageal aper-istalsis and intestinal hypomotility that maybe neurogenic or myogenic. Immune complex-mediated vasculitis or a common autoantibodyagainst the enteric nervous system or the smoothmuscle could be responsible for CIPO manifesta-tions. Serositis, vasculitis, and bowel wall fibrosis

have occasionally been reported as histopatholo-gical findings. No specific autoantibodies havebeen regularly associated with CIPO, even thoughmost of these patients had positive antinuclearantibodies, serology suggestive of active diseaseand anti-Ro antibodies. Nevertheless, antibodiesagainst the proliferative cell nuclear antigen havebeen reported in two SLE patients with chronicCIPO (Nojima et al., 1996), although the clinicalvalue of this finding remains elusive.

Treatment of CIPO includes high doses ofintravenous prednisone, considered the treatmentof choice for this rare GI complication inSLE patients. Other immunosuppressive agents—azathioprine, cyclosporine A, and cyclophosphamide—have been successfully used as initialtreatment and for maintenance therapy in

Figure 2. Magnetic resonance cholangiopancreatography showing dilatation of the extra hepatic common biliary tract and the

pancreatic duct without extrinsic or intrinsic obstruction.


non-responders. Broad-spectrum antibiotics emplo-yed to diminish bacterial overgrowth or promotilitydrugs such as erythromycin are usually effectivewhen combined with the immunosuppressive regi-men. Octreotide, a long-acting somatostatin analo-gue, and rituximab, an anti-CD20 monoclonalantibody, have been used successfully in isolatedcases and may prove useful for refractory orseverely ill patients.

Early recognition of this GI manifestation isimportant because of the reversibility of thecondition with immunosuppressive agents. Surgeryshould be avoided whenever possible.

4.4. Protein-losing gastroenteropathy

Protein-losing gastroenteropathy (PLGE) is aclinical syndrome characterized by hypoalbumine-mia due to a loss of protein from the GI tract inthe absence of a significant loss of protein from thekidneys, reduced protein intake, malnutrition, orsevere liver disease (Mok, 2005). Therefore, adiagnosis of PLGE relies mainly on the exclusionof other conditions. Moreover, it should not beregarded as a final diagnosis, because several GIalterations, e.g. intestinal lymphoma, lymphaticobstruction or lymphangiectasia, or malabsorp-tion, could be responsible for a loss of protein.The main symptoms of this disorder includegeneralized oedema, abdominal pain, and severediarrhoea. It is a well-known, but uncommon,manifestation of SLE and can be the initialmanifestation of the disease. Moreover, as CIPOis also more frequent in Oriental patients, specificgenetic or environmental factors may play a role(Meulders et al., 1992). The pathogenesis of PLGEis not well known. Mesenteric vasculitis could be alikely mechanism, but it has not been found inmucosal biopsies. Although no specific autoanti-bodies have been associated with this GI manifes-tation, it seems that an increase in mucosalcapillary permeability as a result of complementdeposition or cytokine-mediated damage couldplay a role in the pathogenesis of PLGE (Yaziciet al., 2002).

Diagnosis of PLGE must be confirmed by com-plementary explorations. Technetium 99m-labelled

human serum albumin scanning is the goldstandard and best quantitative study. Otherexplorations such as endoscopy, barium studies,abdominal CT scan, or the absorption test(D-xylose) may be necessary. Most PLGE patientsrespond well to corticosteroid therapy, althoughintravenous pulse cyclophosphamide might benecessary in refractory cases. Recently, the combi-nation of prednisolone and azathioprine hasproven to be effective and well tolerated in thetreatment and outcome of PLGE in SLE patients(Mok et al., 2006).

4.5. Pneumatosis cystoides intestinalis

Pneumatosis cystoides intestinalis is an uncommonbut important condition in which gas is found in alinear or cystic form in the submucosa or subserosaof the bowel wall (Heng et al., 1995). The left colonand the ileum are the segments of the bowel mostlikely to be involved. There are few reports ofpneumatosis cystoides intestinalis in adult patientswith systemic autoimmune diseases, especiallysystemic sclerosis and dermatomyositis, but it hasbeen described in SLE patients (Cabrera et al.,1994). Several mechanisms have been proposed forits development, including breaks in the intestinalmucosa, infection, and ischemia due to vasculitis.Pneumatosis cystoides intestinalis is often asymp-tomatic and may occur with pneumoperitoneum,which is sterile and must be distinguished from aperforated viscus. It should be considered as a sign,not a disease; therefore, its relevance should beinterpreted within the whole clinical context.Differentiation between the benign variety, inwhich no intervention is indicated, and the life-threatening form, in which immediate surgery isnecessary, is extremely important and sometimeschallenging for the clinician. Radiology—mainlycontrast-enhanced CT scan of the abdomen—usually assists diagnosis. Bowel biopsies are notindicated as a rule, given the benignancy of thepicture, although ischemic necrosis of the bowelwall due to vasculitis or thrombosis due to aPL hasbeen reported in SLE patients (Alcocer-Gouyonnetet al., 2000). Once life-threatening illnesses such asbowel necrosis, perforation, and infections are


excluded, patients whose symptoms are due to thecysts themselves may be treated with oxygen and/or antibiotics. Because reports of treatment ofpneumatosis cystoides intestinalis are at bestanecdotal, the decision to treat and the treatmentchosen should be carefully balanced againstthe risks. In the absence of sepsis or peritonitis,treatment remains highly conservative (Boerneret al., 1996).

5. Lupus-associated pancreatitis

This is a rare complication of SLE. In the generalpopulation, common causes of pancreatitis includecholedocholithiasis, alcohol intake, and certaindrugs. Nevertheless, some SLE patients developpancreatitis of uncertain origin, which can beattributed to the disease itself. The clinicalapproach to a patient with SLE-associated pan-creatitis includes a first step in order to rule out themost common causes, which may explain half ofall cases (Pascual-Ramos et al., 2004). Therelationship between azathioprine and corticoster-oids, which can cause drug-induced pancreatitis, isdifficult to prove and remains elusive. AlthoughSLE-associated pancreatitis can be the presentingsymptom of SLE, this is usually a complication ofthe disease and is mostly related to SLE activity.Its aetiology is unknown, but different causes havebeen suggested and include an autoimmune origin,vasculitis, aPL-related thrombosis, or exocrino-pathy when sicca syndrome accompanies SLE.Autopsy reports favour inflammation of possibleautoimmune origin as the most frequent aetiology,but it is difficult to draw definite conclusionsbecause data are scarce. Clinical manifestationsare standard, with severe abdominal pain, nauseaand vomiting, but mortality appears to be higherthan in non-SLE-associated pancreatitis (Nesheret al., 2006). Some authors have used serumimmunoreactive cationic trypsinogen to identify asubclinical pancreatic dysfunction in children withSLE. The clinical relevance of this finding remainselusive (Eberhard et al., 1992). Treatment withsteroids combined with supportive measures seemsto improve the prognosis of these patients.

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2000. Acute abdomen and lupus enteritis: thrombocytope-

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Andonopoulos, A., Skopouli, F., Dimou, G., Drosos, A.,

Moutsopoulos, H. 1990. Sjogren’s syndrome in systemic

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Cabrera, G.E., Scopelitis, E., Cuellar, M.L., Silveira, L.H.,

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Grimbacher, B., Huber, M., von Kempis, J., et al. 1998.

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Hallegua, D.S., Wallace, D.J. 2000. Gastrointestinal manifesta-

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Kim, H.J., Park, M.H. 1996. Obstructive uropathy due to

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Kishimoto, M., Nasir, A., Mor, A., Belmont, H.M. 2007. Acute

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lupus erythematosus. Lupus 16, 137–141.

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Lupus 11, 119–123.





CHAPTER 4

Antiphospholipid Syndrome

Gerard Espinosa, Ricard Cervera�

Department of Autoimmune Diseases, Hospital Clınic, Villarroel 170, 0836 Barcelona, Catalonia, Spain

1. Introduction

The antiphospholipid syndrome (APS) is anautoimmune prothrombotic condition character-ized by venous and/or arterial thrombosis andpregnancy morbidity in the presence of antipho-spholipid antibodies (aPL) [positive lupus anti-coagulant (LA) test, anticardiolipin antibodies(aCL) and/or anti-b2-glycoprotein-I antibodies](Miyakis et al., 2006). This syndrome is consideredprimary if it is not associated with any otherunderlying disease (Asherson et al., 1989), but itcan appear in association with other autoimmunedisorders, mainly systemic lupus erythematosus(SLE) (Font et al., 1989).

It is known that aPL are directed againstphospholipid binding proteins expressed on, orbound to, the surface of vascular endothelial cellsor platelets (Roubey, 1996). The main proteinassociated with aCL activity is b2-glycoprotein-I(b2GPI) bound to phospholipids (Galli et al., 1990;Matsuura et al., 1990; McNeil et al., 1990).

Despite the strong association between aPL andthrombosis, the pathogenic role of aPL in thedevelopment of thrombosis has not been fullyelucidated. Several pathogenic mechanisms havebeen proposed, including inhibition of endothelialrelease of prostacyclin, alterations in proteinC–protein S pathway, a direct procoagulanteffect on platelets, and impairment of fibrinolysis

(Espinosa et al., 2003) The aPL appear to play adirect pathogenic role, and the APS is nowwidely accepted as an example of an autoanti-body-mediated disease. Given the heterogeneity ofclinical manifestations in APS, it is likely thatmore than one pathophysiological process mayplay a role.

The classic clinical picture of the APS ischaracterized by venous and arterial thromboses,fetal losses, and thrombocytopenia, in the presenceof aPL. Single-vessel involvement or multiplevascular occlusions may give rise to a wide varietyof presentations. Deep venous thrombosis, some-times accompanied by pulmonary embolism, is themost frequently reported manifestation (38.9%),followed by cerebrovascular accidents, eitherstroke (19.8%) or transient ischemic attacks(11.1%).

Early fetal loss (35.4%), late fetal loss (16.9%),premature birth (10.6%), and pre-eclampsia(9.5%) are the most frequent fetal and obstetricmanifestations. However, several other manifesta-tions are also frequently found, including thrombo-cytopenia (29.6%), livedo reticularis (24.1%),heart valve lesions (14.3%), hemolytic anemia(9.7%), epilepsy (7.0%), leg ulcers (5.5%), myo-cardial infarction (5.5%), and amaurosis fugax(5.4%), among others (Cervera et al., 2002).

Long-term oral anticoagulation was identified asthe best treatment for prevention of recurrentthrombosis in patients with classic APS (Bertolacciniand Khamashta, 2006).

A minority of APS patients develop life-threaten-ing multiple organ thromboses, which has beenrecognized as catastrophic APS (Cervera et al., 2006).E-mail address: [email protected]


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In 2003, the eponym ‘Asherson’s syndrome’ wasattached to the condition (Piette et al., 2003) Thisis a condition characterized by multiple vascularocclusive events, usually affecting small vessels,presenting over a short period of time, and poorprognosis (almost 50% mortality) despite multi-modal treatment (Bucciarelli et al., 2006). Incontrast to the classic APS, single venous orarterial medium-to-large blood vessel occlusionsare uncommon. Due to the diversity of the clinicaland serological presentations, an internationalconsensus on classification criteria for catastrophicAPS has been developed (Asherson et al., 2003).

Combined treatment with anticoagulants pluscorticosteroids plus plasma exchange and/or intra-venous immunoglobulins has been associated witha higher recovery rate. In contrast, concomitanttreatment with cyclophosphamide did not demon-strate additional benefit (Bucciarelli et al., 2006).

2. Digestive involvement in APS

The digestive manifestations of the APS havereceived scarce attention. In this sense, the APSpresenting with digestive involvement has beenrarely reported and very often has a poor outcome(Von Landerberg et al., 2002). Furthermore, it hasbecome obvious that there is an inordinately highfrequency of digestive involvement in catastro-phic APS, which is not seen with the simple or‘classic’ APS (Erkan et al., 2003) (Table 1). Incatastrophic APS, severe multiple organ dysfunc-tion characterized by diffuse small-vessel ischemiaand thromboses predominantly affecting the paren-chymal organs dominates the clinical picture(Meroni et al., 2000). This fact may explain thehigher frequency of digestive involvement thatappears in patients with catastrophic APS.

3. Gastrointestinal involvement

3.1. Gastrointestinal ischemia

The esophageal and gastric involvement has beeninfrequently reported in patients with aPL. Until

now, only two cases have been published (Cappell,1994; Kalman et al., 1996); both were patients withknown APS (prior venous and arterial throm-boses). The former suffered from esophagealnecrosis and perforation (Cappell, 1994) and thelatter from giant gastric ulceration (Kalman et al.,1996). The histopathological studies in the twocases revealed organized thrombi in esophagealand gastric vessels, respectively, with no choleste-rol plaques or evidence of vasculitis.

The true incidence of intestinal ischemia andinfarction associated with classic APS may beunderestimated because of a lack of generalawareness of bowel complications in patientswith classic APS. Presentation may vary fromsymptoms of acute bowel infarction to chronicmesenteric angina, including gastrointestinalbleeding. Ischemia may involve any part ofintestine, including duodenum, jejunoileum, andcolon.

In a recent paper, 97 APS patients (37 patientswith classic APS and 60 with catastrophic APS)were retrospectively reviewed for the evidence ofintestinal involvement (Cervera et al., 2007). Theprevalence of abdominal pain as the presentingmanifestation of intestinal ischemia was higher inpatients with classic APS compared with those withcatastrophic APS (76 versus 37%; Po0.005). Otherclinical manifestations present in patients withclassic APS were nausea or vomiting (16%),gastrointestinal hemorrhage (14%), abdominal dis-tension (11%), weight loss (8%), diarrhea (8%),

Table 1

Digestive involvement in patients with classic and catastrophic

APS

Type of digestive

involvement

Classic APSa

(n=1000), n (%)

Catastrophic APSb

(n=255), n (%)

Gastrointestinal

involvement

15 (1.5) 60 (23.5)

Splenic involvement 11 (1.1) 48 (18.8)

Hepatic involvement 7 (0.7) 85 (33.3)

Pancreatic involvement 5 (0.5) 19 (7.5)

a Data from ‘Europhospholipid’ cohort (Cervera et al., 2002).b Data from ‘Catastrophic Antiphospholipid Syndrome

(CAPS) Registry’ (Bucciarelli et al., 2006) including clinical

features and findings of autopsy when described.

G. Espinosa, R. Cervera40

and chronic intestinal angina (5%). More than ahalf of patients with classic APS had an acuteclinical presentation of intestinal ischemia, whereas14% had subacute, and 22% had chronic. Theprevalence of patients without abdominal clinicalsymptoms was higher in the group of catastrophicAPS compared with those with classic APS (38versus 14%; Po0.02). In the latter, the diagnosisof intestinal involvement was made during adiagnostic procedure for nephrotic syndrome,splenomegaly, fever of unknown origin, kidneytransplantation, and postsurgical control of gastricperforation due to a gastric ulcer.

With regard to the type of vessel involved, therate of venous involvement was higher in patientswith classic APS (43 versus 7%; Po0.002).Furthermore, the prevalence of large-to-medium-vessel (both venous and arterial) involvement washigher in patients with classic APS compared withthose with catastrophic APS (81 versus 30%;Po0.0005).

The main difference in the histopathologicalfindings between the two groups was the higherrate of microthrombosis in patients with cata-strophic APS (75 versus 4%; Po0.0005). Infact, microthrombosis is the histopathologicalhallmark encountered in these patients (Bucciarelliet al., 2006). This is one of the features thatdifferentiate classic APS from catastrophicAPS. As we indicated above, this fact mayexplain the higher frequency of intestinal involve-ment that we found in patients with catastrophicAPS.

Anticoagulation (usually heparin followed byoral anticoagulation) was the most frequenttreatment. Independent of medical management,67% of patients with classic APS were treated withabdominal surgery. The mortality rate was higherin patients with catastrophic APS (55 versus 17%;Po0.0005), septic shock being the major cause ofdeath in both groups.

In the light of the results of this study, itis necessary to consider that intestinal involve-ment, although infrequent, is an important com-plication in patients with APS, especially inthose with catastrophic APS. This wouldsupport the need for systematic screening foraPL in all cases of mesenteric thrombosis or

ischemic colitis without clear underlying predis-posing factors.

Another cause of intestinal ischemia is themesenteric inflammatory veno-occlusive disease(MIVOD). The mesenteric veins can becomeoccluded from causes other than venous throm-bosis, such as phlebitis and venulitis, which haveoccasionally been described in association withSLE (Bando et al., 2003). This term has recentlybeen used to describe ischemic injury resultingfrom phlebitis or venulitis affecting either thebowel or the mesentery, without any evidence ofcoexisting arterial inflammatory involvement oran obvious predisposing cause. At present, onecase of APS associated with MIVOD has beendescribed (Gul et al., 1996). This was a 24-year-oldCaucasian man with gangrene of small bowelsand intestinal resection due to MIVOD, who laterdeveloped deep vein thrombosis in his left leg.An IgG aCL titer above 60GPLunit/mL andthrombocytopenia confirmed the diagnosis ofprimary APS.

3.2. Inflammatory bowel disease

Patients with inflammatory bowel disease (IBD)rarely experience vascular complications. Whenpresent, these mainly take the form of thromboem-bolic disease (Solem et al., 2004). The reportedprevalence of thromboembolic disease in IBDpatients ranges from 1 to 8% (Koutroubakis,2000). At present, the pathogenic mechanism ofthe development of thrombosis is not fullyknown. Recent studies have investigated thepossible role of aPL in the thrombotic manifesta-tions of IBD (Koutroubakis et al., 1998;Aichbichler et al., 1999; Guedon et al., 2001). Inmost of them, aCL titers were significantlyincreased in patients with IBD, but their levels areassociated neither with the pathogenesis of throm-boembolic events nor with clinical activity of thedisease (Koutroubakis et al., 1998; Aichbichleret al., 1999). Therefore, the presence of aPL inIBD patients would be secondary solely to localinflammation, and they are only markers ofendothelial lesions in IBD.

Antiphospholipid Syndrome 41

4. Hepatic involvement

4.1. Budd-Chiari syndrome

Budd-Chiari syndrome (BCS) is characterized bystructural and functional abnormalities of theliver, caused by obstruction to the outflow ofhepatic venous blood (Dilawari et al., 1994).The consequent liver dysfunction depends onthe extension and velocity of instauration of theobstruction. BCS is clinically characterized byabdominal pain, hepatomegaly, and ascites, andthe clinical presentation may range from nearlyasymptomatic to fulminant liver failure (Hadengueet al., 1994; Blum et al., 1995). The etiology isunknown in a limited proportion of patients, andseveral myeloproliferative disorders and hyperco-agulable states have been implicated, includingpolycythemia vera, essential thrombocythemia,paroxysmal nocturnal hemoglobinuria, antithrom-bin, protein C and protein S deficiency, resistanceto activated protein C, factor V Leiden, G20210Afactor II gene mutation, use of oral contraceptives,pregnancy, and postpartum state (Denninger et al.,2000). In some studies (Pomeroy et al., 1984;Shimizu et al., 1993), a relationship between BCSand elevated levels of aPL has been suggested.However, according to other authors, the patho-genic role of these antibodies is controversial(Aggarwal et al., 1998). Some authors suggest thatthe liver abnormalities caused by the venousoutflow obstruction could be involved in theproduction of these antibodies, which would thenbe just an epiphenomenon secondary to the liverdamage (Aggarwal et al., 1998). However, in somecases aPL were detected before the onset of BCS;this strongly suggests that the production of aPLwas not a consequence of the liver abnormalities.At present, APS is considered to be the secondleading cause of non-tumor-related BCS, aftermyeloproliferative syndromes (Zeitoun et al.,1999; Braham et al., 2001).

Recently, the clinical and immunologic chara-cteristics of 43 previously reported patients withBCS and APS (from 1983 through September2000) have been described (Espinosa et al., 2001).Sixty-seven per cent of patients were female and33% were male. Mean age at presentation of BCS

was 30.8712.3 years. Thirty-two (74%) patientshad primary APS, and eight (19%) had definedSLE. In more than half of patients, BCS was thefirst clinical manifestation of APS, whereas 23%patients had a previous history of major vascularocclusion, and spontaneous fetal losses hadoccurred in 35% of the female patients. Anti-coagulation was the most frequent treatment,followed by steroids. Different types of surgicalderivative procedures were performed in a third ofpatients, and percutaneous transluminal angio-plasty in 11%. Interestingly, of nine patients whopresented with vascular occlusions before thedevelopment of BCS, only one was on prolongedanticoagulant treatment. Of seven patients whodid not receive prolonged anticoagulant therapyafter being diagnosed with BCS, four had newthrombotic events. Nineteen of 25 (76%) patientswith prolonged anticoagulant therapy were ingood health at a mean follow-up of 24 months(range, 1–96 months).

The results of this review stress the clinicalimportance of searching for the presence of LAand aCL in all patients with hepatic veinthrombosis. In these patients, long-term high-intensity anticoagulation is mandatory to preventrecurrent thrombosis. At least 20 new patients withBCS associated with APS have been describedsince the publication of this review.

4.2. Hepatic sinusoidal obstructionsyndrome

Hepatic sinusoidal obstruction syndrome (HSOS)is the new name given to hepatic veno-occlusivedisease (HVOD), an unusual disorder of the liverthat presents classically with tender hepatomegaly,hyperbilirubinemia, and ascites (DeLeve et al.,2002). The most frequent cause of HSOS inWestern Europe and the United States is the useof high-dose chemotherapy in recipients of hema-topoietic stem cell transplantation (Kumar et al.,2003), a procedure used to manage solid tumors,hematologic diseases, and autoimmune disorders(Praprotnik et al., 2005). In this setting, HSOS iscaused by toxicity from high-dose chemotherapy


regimens, with or without total-body irradiation(conditioning therapy), and is responsible forconsiderable morbidity and mortality (Wadleighet al., 2003). Endothelial damage due to pretrans-plant chemo-radiation and activation of hemosta-sis are considered to be early events in thedevelopment of HVOD with the end result beingfibrous obliteration of hepatic vessels.

At present, very few cases with aPL as a possiblecausative agent for HVOD have been described(Hughes et al., 1984; Pappas et al., 1984; Morioet al., 1991). As an example, in one of them, a37-year-old man with acute myeloblastic leukemiain first remission underwent a bone marrowtransplant following conditioning with high-dosecytarabine and total-body irradiation. The donorwas an HLA-identical brother. Graft rejectionoccurred, and a second bone marrow transplantwas performed from the same donor followingconditioning with cyclophosphamide. Engraftmentwas achieved, but the patient developed severejaundice and died of respiratory failure on Day 46after the second transplant. Liver biopsy revealedluminal narrowing of the central veins, and adiagnosis of HVOD was made. The coagulationstudies showed a LA, which may have contributedto HVOD (Morio et al., 1991). Recently, thecausal association between aPL and HVODfollowing bone marrow transplantation has notbeen confirmed (Fastenau et al., 1998). Theseauthors have demonstrated that the incidence ofaPL before conditioning was not greater inpatients who developed HVOD following bonemarrow transplantation.

4.3. Hepatic infarction

The rarity of hepatic infarction has been explainedby the protection from ischemia provided by thedouble arterial and portal inflow. In this sense,only few cases have been described in patients with‘classic’ APS (Mor et al., 1989; Kaplan et al.,1995), and histopathological features of hepaticinfarction have been described in 16% of patientswith catastrophic APS (Bucciarelli et al., 2006). Ofa series of 42 ‘classic’ APS patients with abdominal

thrombotic and ischemic manifestations evaluatedwith computed tomography, only one patient hadhepatic infarction (Kaushik et al., 2001), and inone study of the computed tomographic appear-ance of hepatic infarctions in 10 patients, one hadAPS. She was a 43-year-old-woman with APSassociated with SLE, who complained of acutesevere abdominal pain. She had celiac, commonhepatic, proper hepatic, and splenic arteriesthrombosis.

Moreover, a high prevalence of hepatic infarc-tions has been described during pregnancy asso-ciated with APS in the context of HELLP(hemolysis, elevated liver enzymes, low platelets)syndrome. In a review of 28 patients who had 30pregnancies with concomitant hepatic infarction,aPL were assessed in 16 patients, 15 out of whomwere found to be positive (Pauzner et al., 2003).APS was diagnosed prior to infarction in ninepregnancies. Clinically, all the patients presentedwith right abdominal pain, abnormal liver func-tion tests, usually accompanied by fever, andhypertension. Even though many of these patientswith hepatic infarction suffer from a disease thatresembles HELLP syndrome, they do not fulfill theclassification criteria for HELLP. In a retro-spective analysis of 16 episodes of HELLPsyndrome complicating APS in 15 women, Le ThiThuong et al. (2005) did not find any case of liverinfarction.

4.4. Nodular regenerative hyperplasia ofthe liver

Nodular regenerative hyperplasia (NRH) of theliver is a local hyperplastic response of hepato-cytes, probably due to vascular abnormalities. It ischaracterized by transformation of the hepaticparenchyma into hyperplastic nodules withoutsignificant fibrosis. NRH has been describedassociated with hematologic (Al-Mukhaizeemet al., 2004) and autoimmune disorders (Abrahamet al., 2004; Sekiya et al., 1997) including patientswith APS (Perez Ruiz et al., 1991). The possiblerelationship between NRH and aPL was demon-strated by Klein et al. (2003). These authors tested


the sera from 13 patients with histologicallydefined NRH for aPL. Patients with serologicallyand histologically defined primary biliary cirrhosis(PBC) and autoimmune hepatitis and healthyblood donors were used as controls. The preva-lence of aCL was significantly higher in patientswith NRH compared with patients with autoim-mune liver diseases and blood donors (77% versus14%; po0.05). The pathophysiology of NRH isbelieved to result from altered vascular flowthrough the liver, leading to relative sublethalischemia, with subsequent reactive hepatocytehyperplasia and nodule formation. This theorywould explain that subclinical thromboses in thehepatic microcirculation, as a consequence ofacquired thrombophilia in the form of APS,should provide the stimulus for NRH production.At present, up to 10 patients with NRH associatedwith aPL have been described (Cancado et al.,2006; Gaya et al., 2005; Austin et al., 2004; Kleinet al., 2003; Morla et al., 1999; Cadranel et al.,1996; Keegan et al., 1994; Perez Ruiz et al., 1991).

4.5. Portal hypertension

Portal hypertension has been described in threecases of post-sinusoidal hepatic blood flowobstruction as the main feature of APS (Velascoet al., 1993). Clinically, these patients developedjaundice, malaise, ascites, and hepatomegaly.Doppler ultrasonography and hepatic venographyshowed small hepatic vein disease in two patientsand partial occlusion in the suprahepatic segmentof inferior vena cava in the remaining patients. Inall, aCL were positive and activated partialthromboplastin time was prolonged. Other casesof portal hypertension secondary to APS asso-ciated with SLE (Inagaki et al., 2000; Takahashiet al., 1995) and rheumatoid arthritis (Hirohataet al., 2001) were reported. In the former, theauthors suggested that the portal hypertensioncould have been caused by microthrombosis atthe level of the portal vein radicles causingstenosis and obstruction. Recently, 36 patientswith portal vein thrombosis have been screenedfor occult myeloproliferative disorders and classic

prothrombotic disorders including protein C,protein S, and antithrombin deficiency, factor VLeiden, factor II mutation, and aPL. Patients witha tumorous obstruction and patients with cirrhosiswere excluded. aPL were found in four (11.1%)patients (Denninger et al., 2000). All these casessuggest that aPL should be investigated in patientswith portal vein thrombosis of unexplained etiology.

Only a few reports in the literature describe APS(primary and associated with SLE) coexistent withthe combination of pulmonary and portal hyper-tension (Mackworth-Young et al., 1984; De Clercket al., 1991; Bayraktar et al., 2001).

4.6. Autoimmune hepatitis and autoimmunecholestatic liver diseases

Recently, 24 patients with well-defined autoim-mune hepatitis were investigated for the presenceof aPL and for a correlation with clinical, biologic,or histological characteristics (Branger et al.,2007). The frequency of aPL was 70.8% in thisseries, and four patients had well-defined APS.Seven patients had SLE in the aPL group whereasnone in the aPL negative group. There was nocorrelation between hypergammaglobulinemia andthe presence or the isotype of aPL. Clinicalpresentation and outcome as biologic and histolo-gical parameters were similar between patientswith aPL compared with those without aPL.Although the frequency of aPL in autoimmunehepatitis patients was high, the authors were notable to find clinical, biologic, or histologicalcorrelation with the presence of aPL. These resultsare in accordance with those described by Liaskoset al. (2005).

With regard to autoimmune cholestatic liverdiseases (PBC and primary sclerosing cholangitis),Zachou et al. (2006) demonstrated a significantlyhigher prevalence of aCL in both compared toother liver diseases and healthy individuals. More-over, aCL were associated with more severedisease in PBC and biochemical activity in primarysclerosing cholangitis, but they are co-factor-(b2GPI) independent. The same conclusion inpatients with PBC was achieved by von


Landerberg et al. (2005). These authors demon-strated that aPL were present in PBC patients witha higher level of the disease or more intense liverdamage than in patients without aPL. Furtherstudies on larger cohorts should clarify theassociation between aPL and autoimmune hepati-tis and whether aCL in autoimmune cholestaticliver diseases may contribute to APS developmentor the progression of hepatic disease.

4.7. Antiphospholipid antibodies andcirrhosis

The results of the studies that have analyzed therelationship between cirrhosis, aPL, and thrombo-tic events are contradictory. On the one hand, thereare studies that do not support a causal relationshipbetween them. Mangia et al. (1999) found that aCLwere more frequent in patients with an advancedcirrhosis, mainly due to alcohol abuse, comparedwith healthy controls. However, they were notassociated with thrombotic complications. Forthese authors, in patients with non-autoimmuneliver disease, aCL production was an epiphenome-non of liver damage. The same conclusion wasachieved by Gervais et al. (1996). These authorsdescribed a high prevalence of aCL in patients withalcohol cirrhosis, mainly related to the degree ofliver failure but not to portal obstruction. In thestudy of Amitrano et al. (2004), aPL were notrelated either to the portal thrombosis in spite oftheir high prevalence [IgG aCLW10U/mL (39%)and IgM aCLW10U/mL (13%)].

On the other hand, Violi et al. (1994) andQuintarelli et al. (1994) described a significantassociation between aPL and previous venousthrombotic events in patients with cirrhosis. Thesame result was described in patients with hepa-tocellular carcinoma due to cirrhosis related withchronic hepatitis B virus infection (Elefsiniotiset al., 2003). Recent studies have supported thecausal relationship between aPL and portal veinthrombosis in cirrhotic patients (Oksuzoglu et al.,2003; Romero Gomez et al., 2000).

Therefore, patients with cirrhosis have a highprevalence of aPL. Whether it is a primary or a

secondary phenomenon and its role in the deve-lopment of portal vein thrombosis need furtherevaluation.

The association between hepatitis C virusinfection and APS is controversial (Ramos-Casalsand Font, 2005), and is extensively reviewed inanother chapter.

5. Splenic involvement

5.1. Splenic infarction

Although rare, and usually not isolated, splenicinfarction is described in patients with aPL in SLEand in non-SLE settings (Arnold and Schrieber,1988; Obarski et al., 1989; Cappell et al., 1993;Salcedo et al., 2000; Choi et al., 2002; Kara andAyden, 2004). This does not usually seem to occurin classic APS but is generally described in patientswith catastrophic APS (Table 1).

5.2. Autosplenectomy or functional asplenia

Functional asplenia or autosplenectomy is a rarebut well-recognized complication in patientswith SLE and exposes these patients to the riskof life-threatening infections. At present, only twocases of functional asplenia have been reportedin association with APS (Pettersson and Julkunen,1992; Santilli et al., 2003). The former was awoman with APS associated with SLE, whopresented with an unexplained thrombocytosis,and schystocytes, ovalocytes, burr cells, andHowell-Jolly bodies in the red blood cell smear.The second was an SLE patient, who presentedwith cutaneous vasculitis and an unexpectedthrombocytosis that resulted from autosplenect-omy. Subsequently, she developed full-blown APS.Unfortunately, in the other reports of patientswith asplenia and SLE, the aPL status was notreported (Santilli et al., 2003). The authorshypothesize that the coagulopathy related to aPLcould lead to repeated splenic microthromboticevents.


6. Pancreatic involvement

As we have described above in the splenicinvolvement, pancreatic involvement does notusually seem to occur in classic APS but isgenerally described in patients with catastrophicAPS (Table 1). Unlike SLE, where the primaryabnormality is vasculitis, in APS, vascular occlu-sion is due to thromboembolism. In this sense, thepost-mortem pathological examination of pan-creatitis due to APS showed generalized arterialthrombi within the pancreas (Bird et al., 1987;Wang et al., 1992). At present, three cases ofpancreatitis associated with classic APS have beendescribed (Yeh et al., 1993; Gaspari et al., 1995;Spencer, 2004). Two of them suffered fromprimary APS and the third was associated withSLE. In addition, two of them had a good recoverywith anticoagulant treatment (Gaspari et al., 1995;Spencer, 2004). It has been suggested that theinvestigation of patients with idiopathic pancrea-titis should include checking for aPL (Spencer,2004).

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CHAPTER 5

Gastrointestinal Involvement in Systemic Sclerosis

Dinesh Khanna�

Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, 1000 Veterans Avenue,

Rm 32-59, Rehabilitation Building, Los Angeles, CA 90095, USA

Disease of the gastrointestinal tract (GIT) occursin approximately 90% of patients with systemicsclerosis (SSc) (Sjogren, 1996; Sallam et al., 2006)and has a major impact on their quality of life.Every part of the GIT can be involved in SSc,including the mouth (xerostomia), esophagus(dysmotility, acid reflux), stomach (vascularectasia, gastroparesis), intestines (vascular lesions,hypomotility, bacterial overgrowth, toxic mega-colon), and anorectal system (fecal incontinence)(Sjogren, 1996; Sallam et al., 2006). This chapterprovides practical guidance in the diagnosis andtreatment of SSc-associated GIT involvement.

1. Pathogenesis of GIT dysmotility

Although different GI organ systems may manifestGIT involvement in a variety of ways, the under-lying pathophysiology is the same (Clements et al.,2003). Dysmotility of the smooth muscles of theGIT is the primary abnormality. Different hypo-theses have been put forward to explain thepathophysiology of GIT involvement.

1.1. Vascular hypothesis

Sjogren (1994) proposed that the initial GIT lesionin SSc is neural dysfunction, which is caused byarteriolar changes in the vaso nervosum or bycollagen deposits. During this phase, the smoothmuscle is still functional; patients are generallyasymptomatic and respond to prokinetic agents. Inthe second phase, there is atrophy of the smoothmuscle, which results in GIT-related symptomswith some response to prokinetic agents. The lastphase consists of complete muscle fibrosis, and thesmooth muscle does not respond to prokineticagents.

1.2. Autoimmune hypothesis

A second possibility is autoimmune-mediatedinjury. In one study, high-titer antibodies directedagainst myenteric neurons were detected in 19of 41 patients with SSc, but not in patientswith idiopathic gastrointestinal dysmotility (Howeet al., 1994). In another study, rats were immu-nized with purified immunoglobulin G from theserum of patients with SSc who had anti-myentericneuronal antibodies, and intestinal motility effectsin rats were assessed (Eaker et al., 1999). Passiveimmunization led to the prolongation and disrup-tion of rat intestinal myoelectric activity; there wasno effect on the myoelectric activity when the ratswere immunized by immunoglobulin G of normalhealthy controls.E-mail address: [email protected]


Tel.: (310) 825-3061; Fax: (310) 206-8606


DOI: 10.1016/S1571-5078(07)00005-0

dx.doi.org/10.1016/S1571-5078(07)00005-0.3d

2. Esophagus

Esophageal involvement occurs in 50–90% ofpatients with SSc (Sjogren, 1994). Esophagealdysmotility in SSc is caused by a decrease in, orcomplete absence of, lower esophageal sphincter(LES) pressures, and by decreased amplitudeof distal esophageal peristalsis (Sjogren, 1996),resulting in gastroesophageal reflux disease(GERD). SSc primarily affects the distal two-thirds of the esophagus; the motility of theesophageal sphincter and proximal esophagus isgenerally normal.

2.1. Gastroesophageal reflux disease

Although heartburn is the most common symptomof GERD, other symptoms may include odyno-phagia, mouth ulcers, substernal chest pain,chronic laryngitis, chronic nocturnal cough, andasthma (Weinstein and Kadell, 2004). In addition,an association between GERD and interstitial lungdisease has been proposed in SSc (Troshinskyet al., 1994; Lock et al., 1998; Marie et al., 2001a).The goals of GERD treatment include (1) relievingsymptoms, (2) preventing distal esophageal scar-ring, and (3) reducing the incidence of Barrett’sesophagus.

2.1.1. Treatment approachTreatment consists of anti-reflux measures andmedications as detailed in Tables 1 and 2. I usuallystart empirical therapy with a proton-pumpinhibitor (PPI) twice a day (Sjogren, 1994) andthen sequentially increase the dose (Table 2)(Sallam et al., 2006; Hendel et al., 1992). The goalof the therapy is to completely eliminate thesymptoms of GERD. If the symptoms continueon high doses of PPI, I add a prokinetic agent30–60min before each meal and a histamine type-2receptor blocker at bedtime. If the patient con-tinues to complain of heartburn and other GERD-related symptoms after 2–3 weeks, I do a completeevaluation, such as a barium swallow (Fig. 1) andupper endoscopy, to assess for strictures and rule

out other causes of esophagitis (Hendel et al.,1988). Some authors have suggested barium radio-graphy and upper endoscopy as a baseline testbefore treatment is initiated (Weinstein andKadell, 2004). Esophageal manometry can docu-ment hypomotility but is usually not performedroutinely since a barium swallow has a goodcorrelation with manometry (Clements et al.,1979). In addition, many structural abnormalitiesnot demonstrated by manometry are identified bybarium radiography. Manometry is helpful inpatients who are considering surgery for intrac-table GERD symptoms or patients undergoingevaluation for a heart–lung transplant foradvanced lung involvement. Similarly, although24-h pH monitoring is helpful to document theGERD, it is cumbersome for the patient and istechnically difficult to do. It can be used to assess ifthere is complete suppression of acid productionon therapy before elective surgery is considered.In addition, 24-h pH monitoring is helpful to assessif there is a correlation between acid reflux andcontinuing symptoms in patients receiving max-imum therapy for their GERD (Weinstein andKadell, 2004). Reflux (pHo4) for greater than4% of the 24-h period is considered abnormal(Weinstein and Kadell, 2004).

2.2. Barrett’s esophagus

Barrett’s esophagus is a complication of long-standingGERD (Chang andKatzka, 2004; Shaheenand Ransohoff, 2002) and was present in approxi-mately 13% of 110 consecutive patients withSSc (Wipff et al., 2005) receiving chronic therapywith PPI (an incidence similar to that seen inpatients with GERD) (Chang and Katzka, 2004;Shaheen and Ransohoff, 2002). Barrett’s esopha-gus is associated with adenocarcinoma in SSc(Recht et al., 1988). In a large retrospective studyof 110 patients with SSc (Wipff et al., 2005), therewere no clinical or biological differences in patientswho developed Barrett’s esophagus vs. those whodid not. The American College of Gastroenterol-ogy (Chang and Katzka, 2004; Sampliner, 2002)has developed guidelines for the management of

D. Khanna52

Table 1

GIT involvement with recommended testing and treatment

Problem Test Treatment

Gastroesophageal reflux

disease

Barium swallow, upper endoscopy,

esophageal manometrya, 24-h pH

monitoringa

Anti-reflux measures

Head of the bed elevated using wooden blocks under

the feet at the head of bed or using wedge pillow.

Take frequent small meals (5–6 per day).

Avoid eating or drinking fluids 2 h before bedtime.

Stop smoking (if currently smoking).

Avoid or minimize acid producing foods (fat,

chocolate, and coffee).

Do not wear tight belts as they put pressure on the

abdomen and the lower esophageal pressure

sphincter.

Medications

Anti-secretory

Proton-pump inhibitors (may require 2–4 times

the FDA-approved doses), H2 blockers

Promotility (take 30–60min before meals)

Metoclopramide, erythromycin, domperidoneb,

cisapridec

Surgical procedures

Endoscopic dilatation of strictures,

fundoplication

Gastroparesis Gastric radionuclide emptying study,

upper endoscopyaAnti-reflux measures

Take frequent small meals (5–6 per day).

Avoid eating or drinking fluids 2 h before bedtime.

Medications

Anti-secretory and promotility agents (see GERD

section)

Gastric electric stimulationd, jejunal feeding tube

Watermelon stomach

(iron deficiency anemia)

Upper endoscopy, colonoscopya, push

enteroscopya, radiolabeled red blood

scana, video capsule endoscopya

Medications

Anti-secretory agents

Endosocopic procedures

Argon laser ablation, argon plasma coagulation,

Nd:YAG laser

Surgical

Antrectomy

Bacterial overgrowth

syndrome

Serum iron, calcium, magnesium, alkaline

phosphatase, serum carotene, vitamin B12

and methylmalonic acid, vitamin D, and

prothrombin time, bone density

measurement, glucose hydrogen breath

testa, lactulose hydrogen breath testa,

14C-D-xylose breath testa, fecal fat

quantificationa, bacterial and fungal

culture from jejunal aspiratea

Medications

Antibiotic therapy

Amoxicillin, ciprofloxacin, metronidazole,

doxycycline, neomycine, rifaximine (monthly

rotating, intermittent, or continuous therapy)

Vitamins

Adequate calcium/vitamin D daily

Intestinal pseudo-

obstruction

Plain radiographs of the chest (to rule out

free air) and abdomen, CT of the

abdomen

Bowel rest and intravenous nutrition support, total

parenteral nutrition

Medications

Promotility agents

Octreotide, metoclopramide, erythromycin,

domperidoneb, cisapridec

Gastrointestinal Involvement in Systemic Sclerosis 53

Table 1 (continued )

Problem Test Treatment

Constipation Plain radiographs of the abdomen Medications

Stimulant laxatives

Senna, lactulose, bisacodyl, polyethylene glycol

(Golytelys)

Diarrhea Work-up as recommended for bacterial

overgrowth syndrome

Medications

Bulking agents

Citrucel

Antidiarrheal agents

Loperamide

Rectal incontinence Anorectal manometry, endoscopic

ultrasoundaMedications

Bulking agents

Citrucel

Antidiarrheal agents

Loperamide

Other modalities

Biofeedback

Sacral nerve stimulation

Surgery

Repair for rectal prolapse

Adapted from (Sallam et al., 2006; Jaovisidha et al., 2005; Khanna and Furst, 2007).a Recommended only if symptoms do not improve after initial treatment.b Not FDA-approved in US.c Available in US on compassionate basis (call 1-800-JANSSEN).d Not approved/studied for SSc.eMinimal systemic absorption.

Table 2

Proton pump inhibitors, prokinetic agents used in the treatment of GIT involvement

Generic name Oral dose Dose adjustment

Proton pump inhibitorsa

Esomeprazole 20–80mg per dayb Severe hepatic impairment

Lansoprazole 15–60mg per dayb,c Severe hepatic impairment

Omeprazole 20–80mg per day Caution during severe hepatic impairment

Pantoprazole 40–80mg per dayb No adjustment for renal or hepatic disease

Raberprazole 20–40mg per day Caution during severe hepatic impairment

Prokinetic agentsd

Cisapridee 10–20mg, 4 times a day Decrease dosage in hepatic impairment

Domperidonef 10–20mg, 4 times a day Decrease dosage in renal impairment

Erythromycinb,g 250mg, 3 times a day Decrease dosage in renal impairment

Metoclopramideb 5–10mg, 4 times a day Decrease dosage in renal impairment

Octreotideb,h 50mg, 1–2 times a day Decrease dosage in renal impairment

a All administered daily before breakfast. Second dose, if necessary, should be given before evening meal.b Available for intravenous therapy.c Available as soluble tablet.d 30 to 60min before each meal and at bedtime.e Available in US on compassionate basis (1-800-JANSSEN).f Not available in US.g Available for intravenous and intramuscular use.h Usually given subcutaneously.

D. Khanna54

Barrett’s esophagus: In patients with Barrett’sesophagus with no dysplasia on biopsy, surveil-lance endoscopy is recommended every 3 years; inpatients with low-grade dysplasia, surveillanceendoscopy is recommended every 1 year; and inpatients with high-grade dysplasia, surveillanceendoscopy is recommended every 3 months, alongwith an esophagectomy or endoscopic ablation.

3. Stomach

3.1. Gastroparesis

Like the esophagus, the stomach is also affected bySSc. Alterations in gastric motility, myoelectricactivity, and gastric emptying have been

demonstrated in patients with SSc (Sjogren,1994). In a study of 22 consecutive patients withSSc, gastric impairment was seen in approximately80% of patients on electrogastrography, and 50%had delayed gastric emptying (Marie et al., 2001b).As a result, patients with SSc develop clinicalsymptoms of gastroparesis, including bloating,nausea and vomiting, abdominal pain, and exces-sive flatulence; these symptoms may contribute tosignificant weight loss.

3.1.1. Treatment approachIn addition to advising patients to take smallmeals and avoid lactose-containing products (e.g.milk), I initiate prokinetic therapy (Table 2).Based on small studies, different authors recom-mend metoclopramide and erythromycin asinitial prokinetic agents (Sallam et al., 2006);octreotide inhibits antral motility and is nothelpful for gastric dysmotilty (Sallam et al.,2006). I start empirical treatment, although aninitial gastric emptying study can be performedbecause symptoms of gastroparesis and smallbowel bacterial overgrowth overlap. In patientswho continue to have symptoms on prokinetictherapy, I perform a gastric emptying study toconfirm the diagnosis. If the gastric emptyingstudy is normal or near normal on prokinetics,further work-up to assess small bowel involve-ment is done (detailed in the next section). Someexperts do a baseline gastric emptying study(before initiating prokinetic therapy) to docu-ment gastroparesis, and repeat the procedure ifsymptoms do not improve after treatment(Daniel E. Furst, MD, personal communication).For patients who do not improve with prokinetictherapy but have acceptable intestinal transit, ajejunal tube may be an option. Gastric electricstimulation is a novel therapy for refractorysymptoms. A recent systematic review (Zhangand Chen, 2006) showed the beneficial effects ofgastric electric stimulation (Enterra Therapys)for upper GIT symptoms, including reducednausea/vomiting, decreased duration of gastro-paresis-related hospitalizations, and improvedquality of life in patients with diabetes, surgery,or gastroparesis due to idiopathic causes. Gastric

Figure 1. Barium swallow showing characteristic patulous

esophagus.


electric stimulation has not been evaluated inSSc. Some data support the use of acupuncture(Sallam et al., 2007).

3.2. Gastric antral vascular ectasia(watermelon stomach)

Gastric antral vascular ectasia (GAVE) is animportant cause of iron deficiency anemia inpatients with SSc. Because its characteristicappearance on the upper endoscopy resembles thestripes of a watermelon, it is also termed ‘water-melon’ stomach (Fig. 2). The prevalence of GAVEin SSc ranges from 9 to 14% in different publishedseries (Marie et al., 2001b; Gostout et al., 1992;Duchini and Sessoms, 1998), with a higher like-lihood in patients with limited disease (Marieet al., 2001b). The presenting symptoms may befatigue and tiredness, and a complete blood countmay show moderate-to-severe iron deficiencyanemia. In some patients, repeated blood transfu-sions are necessary (Elkayam et al., 2000).

3.2.1. Treatment approachTreatment consists of endoscopic therapy withargon plasma coagulation, argon laser, or Nd:YAG

laser (Sebastian et al., 2003), the choice of therapydepending on the person performing the endo-scopy (Calamia et al., 2000; Sebastian et al., 2004).Most of the patients require more than onesession, and long-term outcomes are generallygood. If everything else fails, an antrectomy maybe necessary (Sherman et al., 2003).

4. Small bowel

Intestinal dysmotility has been reported in40–88% of patients with SSc (Sallam et al., 2006;Clements et al., 2003). The dysmotility can lead tobacterial overgrowth syndrome, intestinal pseudo-obstruction, and pneumatosis cystoides intestinalis(Sallam et al., 2006).

4.1. Bacterial overgrowth syndrome

Bacterial overgrowth syndrome is caused by stasisof the intestinal contents, resulting in migrationand colonization of bacteria from the colon(Sjogren, 1994). The symptoms include bloating,nausea, vomiting, abdominal pain, diarrhea (withpale, greasy, voluminous, foul-smelling stools),excessive flatulence, and inability to gain or

Figure 2. Gastric antral venous ectasia or ‘‘watermelon’’ stomach on upper endoscopy.

D. Khanna56

maintain body weight with good oral intake; thesymptoms overlap with that of gastroparesis. Lowserum carotene, a marker of vitamin A absorption,is associated with bacterial overgrowth and can beused as a screening test (Clements et al., 2003;Weinstein and Kadell, 2004). Since bacterial over-growth syndrome can cause deficiency of fat-soluble vitamins, vitamin B12, and iron, I getserum B12, methylmalonic acid, iron, calcium,magnesium, albumin, vitamin D, alkaline phos-phatase, and prothrombin time baseline readings.Because bacterial overgrowth is associated withlow bone mineral density when compared to age-and sex-matched controls (Di Stefano et al., 2001;Stotzer et al., 2003), a bone density scan can bedone to get a baseline value.

4.1.1. Treatment approachMy treatment approach includes an empirical trialof a broad-spectrum antibiotic (Table 1) for 2–4weeks to assess the improvement in symptoms,especially of bloating and diarrhea (Attar et al.,1999). I choose this approach rather than doing abreath test because the sensitivity and specificity ofthe lactulose hydrogen breath test in detectingbacterial overgrowth are only 68 and 44%,respectively, and for the glucose breath test only62 and 83%, respectively (Romagnuolo et al.,2002; Corazza et al., 1990). If there is a subjectiveimprovement in the symptoms, the patients can befollowed closely to see if the symptoms reoccur (inthe majority they do), or can continue cyclicantibiotic therapy for 2 weeks on and then 2–4weeks off. Some physicians use different antibio-tics to prevent bacterial resistance. All patientsshould receive standard doses of a multivitamin,1500mg/day of calcium and 800 IU of vitamin D.Additional replacement of multivitamins isguided by the laboratory tests described above.Probiotic therapy may have a role in the treatmentof bacterial overgrowth syndrome, but there is alack of well-designed trials. I recommend yogurtwith live-active cultures to be taken everydaybecause it provides 15–20% of daily requiredcalcium and lacks side-effects. Total parenteralnutrition is required if weight loss continuesdespite therapy.

If patients show no symptomatic improvementwith antibiotic therapy, they should get a completework-up to assess gastric and small intestinedysmotility as detailed in Table 1.

4.2. Intestinal pseudo-obstruction

Intestinal pseudo-obstruction is common in patientswith SSc and usually presents as abdominal painand distention, nausea, vomiting, and inability topass flatulence.

4.2.1. Treatment approachI usually admit patients to the hospital, and all ofthem undergo plain radiographs of the abdomen, abarium radiographic study, and a computertomography scan of the abdomen to rule outmechanical obstruction. The initial treatmentincludes bowel rest, intravenous fluids, and correc-tion of electrolyte imbalances. In addition, Iprescribe prokinetic therapy and broad-spectrumantibiotics to decrease the bacterial load in thesmall intestine. Different case series have reportedthe effectiveness of metoclopramide, cisapride, anddomperidone in relieving pseudo-obstruction; ery-thromycin has no effect on intestinal dysmotility inpatients with SSc (reviewed in Sallam et al., 2006).Octreotide, a somatostatin analogue, improvesintestinal motility and has been studied in SSc-related pseudo-obstruction with favorable results(Soudah et al., 1991; Perlemuter et al., 1999; Marieet al., 2007). I start with octreotide at 50 mg sub-cutaneously twice a day during an acute attack,and clinical improvement (apparent by the presenceof bowel sounds, passing of flatulence, anddecreasing abdominal pain) is usually seen within48–72 h. The dose is increased up to 200 mg if asatisfactory response is not observed. It is impera-tive to rule out bowel obstruction, as a trial ofoctreotide may lead to perforation. Total paren-teral nutrition is usually required while the patientis recovering. For patients with recurrent episodesof pseudo-obstruction, 50mg of octreotide at bedtimeis usually therapeutic and depot octreotide is avail-able that can be prescribed on a monthly basis. Acombination of octreotide and erythromycin can betried in resistant cases (Verne et al., 1995). Surgery


should be avoided but may be needed for venting(decompression to relieve symptoms) and feeding,and to exclude intestinal obstruction.

4.3. Pneumatosis cystoides intestinalis

Pneumatosis cystoides intestinalis, or air in thebowel wall, has been reported in SSc. It is usuallyof no consequence, but rarely the air-filled cysts inthe bowel may rupture, leading to benign pneu-moperitoneum (Weinstein and Kadell, 2004). Asthe cysts do not require surgery, physicians shouldbe aware of this.

5. Colon and anorectal disorders

Colonic involvement is seen in 20–50% of patientswith SSc and usually presents as constipation ordiarrhea. Colonic contractions are usually reducedor absent in patients with SSc, resulting inprolonged colonic transit (Sallam et al., 2006)which can cause pseudo-sacculations (Fig. 3) andsymptoms of constipation. Diarrhea usually resultsfrom bacterial overgrowth syndrome or fecalincontinence seen with anorectal involvement.

Anorectal involvement is common and reportedin 50–70% of patients with SSc. The patientspresent with chronic diarrhea, fecal incontinence,

Figure 3. Barium study showing pseudo-sacculations.

D. Khanna58

and rectal prolapse. The most common mano-metric abnormality is an absent or diminishedrectoanal inhibitory reflex (Massone et al., 2002;Hamel-Roy et al., 1985). The response of theinternal anal sphincter is diminished or absent, andthe response of the external sphincter is eithernormal or increased.

5.1. Treatment approach

For patients with constipation, I avoid a high-fiberdiet and bulk-forming laxatives since these canmake the constipation worse. I recommend liberalingestion of fluids and use stimulant and osmoticlaxatives such as senna, lactulose, bisacodyl, andpolyethylene glycol (Golytelys). These laxativesexert their effects primarily via alteration ofelectrolyte transport by the intestinal mucosa, andby increasing intestinal motor activity. There is noconvincing evidence that chronic use of stimulantlaxatives causes structural or functional impair-ment of the colon, nor do they increase the riskfor colorectal tumors (Weinstein and Kadell,2004; Wald, 2003). I advise patients to take theirlaxatives every 2–3 days to maintain a healthybowel regimen.

Patients with diarrhea are treated with anti-biotics (for bacterial overgrowth syndrome) andwith judicious use of anti-diarrheal agents. Foranorectal involvement, biofeedback therapy hasbeen used. Sacral nerve stimulation has beensuccessful in people with fecal incontinence (Keneficket al., 2002; Hetzer et al., 2007); it requires in-sertion of an implantable pulse generator underlocal anesthesia by a surgeon. The short- and long-term effects have been very encouraging, with adecrease in episodes of fecal incontinence andmarked improvement in quality of life (Keneficket al., 2002; Hetzer et al., 2007), and the procedureis associated with minimal morbidity. A surgicalprocedure is usually required for rectal prolapse.

6. Patient-reported outcome measure

The majority of patients with SSc have multipletypes of GIT involvement with overlapping

symptoms, making quantification of GIT in SScextremely challenging. In addition, the correlationbetween histological or physiological severity andGIT symptoms has been poor in recent studies(Sallam et al., 2006; Sjogren, 1994; Marie et al.,2001b), stressing the need for a validated patient-reported instrument.

Our group recently developed a patient-reportedoutcome measure, the Scleroderma Gastrointes-tinal Tract 1.0 (SSC-GIT 1.0) instrument (Khannaet al., 2007), to capture GIT involvementin patients with SSc. SSC-GIT 1.0 is a 52-itemself-administered instrument that is specificallydeveloped for people with SSc and GIT involve-ment. SSC-GIT 1.0 is feasible—the 52-item instru-ment takes approximately 11min to complete andcovers the whole range of GIT involvement. SSC-GIT 1.0 has six scales—reflux/indigestion, diar-rhea, constipation, pain, emotional well-being, andsocial functioning—that measure different aspectsof GIT involvement. In a cross-sectional study of88 subjects with SSc and GIT involvement, theinstrument showed acceptable test–retest reliabil-ity, internal consistency reliability, and constructvalidity. SSC-GIT 1.0 was able to dis-criminate between GIT severity; participants whorated their GIT disease as ‘mild’ had the highestscores (indicating better health) on all of the sixscales, whereas participants who rated their GIT as‘severe’ had the lowest scores (indicating poorhealth). The instrument is available free of chargefrom the author ([email protected]).

7. Conclusion

GIT involvement in SSc is very common and has amajor impact on quality of life (Nietert et al., 2005).A proactive approach is suggested (Weinsteinand Kadell, 2004). The cornerstones of GITexamination are imaging studies and laboratorytests; physical examination of the GIT systemyields little information (Weinstein and Kadell,2004). For motility disorders, a barium contraststudy is the preferred radiographic procedure, andfor assessment of mucosal disease, endoscopy isthe preferred test.


Acknowledgment

Dr. Khanna was supported by the SclerodermaFoundation (New Investigator Award) and aNational Institutes of Health Award (NIAMSK23 ARO53858-01A1).

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CHAPTER 6

Inflammatory Myopathies

Lara Dani�, Ingrid E. Lundberg

Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna,

Karolinska Institutet, SE-171 76 Stockholm, Sweden

1. Introduction

Polymyositis and dermatomyositis are autoim-mune inflammatory connective tissue diseases thatare characterized by chronic inflammation ofstriated muscle and, in the case of dermatomyositis,also by skin involvement. They are rare diseaseswith an annual incidence of 5–10 new cases permillion people (Medsger et al., 1970). The peak ageat onset of polymyositis or dermatomyositis inadults is between 50 and 60 years. Both polymyositisand dermatomyositis are more frequent in womenthan in men (women:men, 2:1). Dermatomyositis,but rarely polymyositis, also occurs in children, inwhich case it is called juvenile dermatomyositis(Klippel and Dieppe, 2000). The disease mechanismsthat cause muscle weakness are not fully under-stood, but both immune-mediated muscle fibernecrosis as well as non-immune mechanisms arelikely to be involved, such as cytokine-mediatedmuscle weakness, endoplasmic stress that couldlead to an acquired metabolic myopathy (Grundtmanet al., 2007). Moreover, disuse of muscle as well asglucocorticoids treatment may lead to muscleatrophy.

The most important clinical signs commonlyseen in both polymyositis and dermatomyositisare proximal, symmetrical, and often painlessprogressive muscle weakness and reduced muscle

endurance. The muscle groups mainly involved arethe shoulder and pelvic girdles, but neck flexorweakness and thoracic and pharyngeal muscleweakness can also occur. The onset of muscleimpairment is typically insidious over weeks tomonths. In dermatomyositis the skin involvementresults most often in a heliotrope rash of eyelidsand in Gottron’s papulae, which are erythematousplaques over dorsal aspects of joints. Extramus-cular symptoms besides skin rash are common inpolymyositis and dermatomyositis, such as fever,weight loss, arthritis, arthralgia, pulmonary symp-toms due to thoracic muscle weakness, interstitiallung disease or aspiration pneumonia, and cardiacsymptoms such as atrioventricular conductiondefects, myocarditis, and more rarely congestiveheart failure. In children with juvenile dermato-myositis calcinosis in skin, subcutaneous tissue ormuscle may impose a particular problem.

Laboratory abnormalities including elevatedlevels of serum muscle enzymes (especially creatinekinase) are present in most patients, and abnormalelectromyography is frequent (fibrillation potentialsin 90% of patients). Muscle biopsy findings thatsupport polymyositis or dermatomyositis diagnosisare endomysial and/or perivascular infiltrates ofmononuclear inflammatory cells and signs ofmyopathy including muscle fiber degeneration andnecrosis of myofibrils and expression of majorhistocompatibility complex (MHC) class I inmuscle fibers. The inflammatory infiltrates aremainly characterized by T lymphocytes andmacrophages. A muscle biopsy is also importantin the diagnostic evaluation to exclude otherE-mail address: [email protected]


Tel.: +46-8-5177-3020; Fax: +46-8-5177-3080


DOI: 10.1016/S1571-5078(07)00006-2

dx.doi.org/10.1016/S1571-5078(07)00006-2.3d

myopathies. Autoantibodies are common andpresent in approximately 60–70% of the patients.Some autoantibodies are specific for myositis,so-called myositis-specific autoantibodies, themost frequent being anti-Jo-1 autoantibodiespresent in 20–30%, and anti-Mi-2 present in 6%(Hengstman et al., 2002). Myositis-associatedautoantibodies include anti-PM-Scl and anti-RNPautoantibodies that are often present in overlapsyndromes where two inflammatory systemicdiseases coexist in the same patient, especiallypolymyositis and systemic sclerosis with anti-PM-Scland mixed connective tissue disease (MCTD) withanti-RNP antibodies. None of these autoanti-bodies have been reported to confer risk to developinvolvement of the gastrointestinal (GI) tract.

Inclusion body myositis (IBM) is a specialsubtype of myositis, which is characterized byvacuoles and intranuclear and intracytoplasmaticinclusions in muscle fibers in addition to inflamma-tory infiltrates resembling polymyositis. Clinicallydistinct features are slowly progressive onset, overmonths to years, weakness in both proximal anddistal muscle often together with evident muscleatrophy, and furthermore, usually resistance toglucocorticoid and other immunosuppressivetreatment.

The most often recommended therapy today forpatients with polymyositis or dermatomyositis isbased on a combination of high-dose glucocorti-coids (0.75–1mg/kg/day) with another immuno-suppressive drug like azathioprine or methotrexate.There are anecdotal reports that cyclosporine A,mycophenolite mofetile, or cyclophosphamidemay be effective, but controlled trials are missing.There is conflicting data as to whether high-doseintravenous globulin is effective in polymyositisand dermatomyositis (Dalakas, 2006; BarbassoHelmers et al., 2007). Despite the use of theseimmunosuppressive therapies, many patients areleft with muscle impairment and some do notrespond at all. Thus, there is a need for improvedtherapy. The overall prognosis is hard to estimatebecause of the rarity of the disease, but nowadaysthe expected survival with the use of glucocorti-coids in combination with immunosuppressivedrugs, excluding paraneoplastic polymyositis/dermatomyositis, is over 90% five-year survival

(Klippel and Dieppe, 2000). Factors associatedwith poorer survival are dysphagia with aspirationpneumonia, lung or heart involvement, and sideeffects of treatment.

There are several mechanisms that may causeGI-tract involvement in patients with inflamma-tory myopathies. First, striated muscle in the GItract could be affected by inflammation and couldlead to weakness and cause disturbance of motilityat various levels of the GI tract. The inflammationin dermatomyositis is often perivascular, and inoccasional cases, vasculitis in the GI tract could beseen. The latter has mainly been reported injuvenile dermatomyositis. Other autoimmune reac-tions than muscle inflammation localized to the GItract have been observed in patients with myositis,such as celiac disease and autoimmune hepatitis.Finally, the mucosal membrane may be affecteddue to decreased salivation as a result of asecondary Sjogren’s syndrome. These manifesta-tions are in focus of this review and will bediscussed in relation to different parts of the GItract.

2. Oral cavity

Very few reports about patients with myositisinclude problems of the oral cavity. In one recentretrospective report including 34 Hungarianpatients, several problems of the oral cavity wereobserved, however (Marton et al., 2005). Althoughfacial muscles are rarely involved in myositispatients, weakness of masticatory muscle wasreported as one problem of the oral cavity inmyositis patients (Marton et al., 2005). The mostprominent symptom of the oral cavity was drynessof mouth with objectively reduced saliva flow rateand labial biopsies with fibrosis and interstitialperivascular infiltration (Marton et al., 2005).Increased caries prevalence was also seen com-pared to the general population (Marton et al.,2005). An unusual manifestation of oral cavity ismacroglossia with dysartria, swallowing difficul-ties, and noisy breathing, reported in one patientwith polymyositis. EMG and biopsy confirmedchanges compatible with myositis in the tongue,

L. Dani, I.E. Lundberg64

and no other cause of macroglossia was found.Symptoms resolved quickly with glucocorticoidsand infusions with high-dose intravenous immu-noglobulins (Chauvet et al., 2002).

3. Dysphagia

The most frequently occurring symptom in the GItract in myositis patients is difficulties withswallowing. Difficulty in swallowing has beenreported in 12–54% of patients with polymyositisor dermatomyositis, and it is more frequent in theacute than in the late chronic phase of the disease(Sonies, 1997). In IBM, dysphagia is even moreprevalent and is reported in up to 60% of patients(Litchy and Engel, 1992; Dalakas et al., 1997).However, of the total number of cases withdysphagia, myositis accounts only for approxi-mately 3%. Still, myositis diagnosis is worth to beconsidered since it can be treated with immuno-suppressive medical therapy and not only bysurgery.

The clinical signs of dysphagia range from mildswallowing problems of dry food or reflux-likesymptoms to severe problems that confer risk ofaspiration and may require naso-gastric feeding orparental nutrition. A number of patients complainof difficulties when starting to swallow. Nasalregurgitations may also occur. One consequence ofdysphagia could be malnutrition and weight loss.The presence of dysphagia is associated withpoorer prognosis because of risk of aspirationpneumonia, septicemia, and cachexia (Klippel andDieppe, 2000).

The explanation for dysphagia in myositis isinflammation of striated muscle in the GI–tract,leading to dysmotility of both oropharyngealstructures and esophagus (Dietz et al., 1980).Muscle biopsy specimen from the cricopharyngealmuscle has confirmed inflammatory changes.Moreover, disturbed motility was demonstratedin a Turkish study including 19 patients withpolymyositis or dermatomyositis and dysphagiawith 1–10 month duration. The patients wereinvestigated by electrophysiological methods ana-lyzing oropharyngeal muscles: The pharyngeal

transit time of the bolus from the oral cavity tothe upper esophageal sphincter was significantlyprolonged (Ertekin et al., 2004). It had previouslybeen reported that there could be a kind of achalasiain the cricopharyngeal sphincter (Kagen et al., 1985).

In this Turkish study, 50% of the patients alsohad an abnormal cricopharyngeal sphincter acti-vity, some of them had hyper-reflexity (possiblemuscle edema in the acute phase), and some hadhyporeflexity (possibly due to muscle fibrosis inchronic phase and in IBM). Electrophysiologicalinvestigations may differentiate the hyper-reflexity,which is also more suitable to myotomy (Ertekinet al., 2004).

Dysphagia in patients with myositis comparedto neurological diseases and healthy controls wasmore often characterized by more prevalentcricopharyngeal restrictive problems, reducedupper esophageal sphincter opening, and elevatedhypopharyngeal intrabolus pressure when tested withpharyngeo-esophageal videomanometry (Williamset al. 2003). There were other discrepancies alsowhen laboratory findings, EMG, and musclebiopsy data were compared. The mean timebetween dysphagia onset and diagnosis of myositiswas 55 months. Notably in this study, one-thirdof myositis patients did not have any other signs ofmuscle weakness except dysphagia. Only 75% ofmyositis patients had abnormal CPK and EMG,and muscle biopsy was mandatory for myositisdiagnosis. Prognosis was poor with 31% 12-monthmortality due mainly to respiratory complications;despite that, the presence of dysphagia madeimmunosuppressive therapy mandatory. The factthat only two-third of the patients with dysphagiahad other muscle involvement induces the hypo-thesis that there might be a local involvement ofcricopharyngeal muscles with a chronic inflamma-tion that reduces the cricopharyngeal compliancewith time (Shapiro et al., 1996; Williams et al.,2003). This study also reported an unexpected highprevalence of Zenker’s diverticula in myositispatients. Zenker’s diverticula is associated with arestrictive disorder of the cricopharyngeal secon-dary to myonecrosis and fibrous tissue replace-ment. The fibrous replacement in myositis cantherefore lead to Zenker’s diverticula in susceptiblepatients with myositis.

Inflammatory Myopathies 65

In clinical practice, the easiest way to investigatecomplaints of dysphagia is an esophagus radio-graphy with bolus contrast, but in doubtful cases,investigations can be completed with videoradio-graphy or manometric measures such as videoma-nometry. Treatment of dysphagia in myositis isbased on conventional immunosuppressive treat-ment as for the skeletal muscle weakness in generaland, in addition, on symptomatic drugs when thedisease still allows a normal nutrition (mainlyproton pump inhibitors). A more definitive treat-ment is surgical by cricopharyngeal disruption.This could be done either by dilatation or bymyotomy (Venkovsky et al., 1988). Of these, thecricopharyngeal myotomy is the only validatedmethod for treatment of severe dysphagia inpatients with IBM (Verma et al., 1992). There isno clear evidence that immunosuppressive treat-ment could improve dysphagia and finally avoidsurgery in IBM cases. Interestingly, in a small caseseries including four patients with life-threateningdysphagia in IBM, swallowing problems inpatients dramatically improved after the adminis-tration of high-dose intravenous immunoglobulinin combination with glucocorticoids (Cherin et al.,2002). Two other patients who were affected byIBM were successfully treated with injection ofbotulinum toxin A (Liu et al., 2004).

4. Bowel

Already in 1982 there was a suggestion of anassociation between celiac disease and myositisdue to increased levels of anti-gluten autoantibo-dies (in patients with inflammatory myopathies)(Henriksson et al., 1982). Recently, this wasconfirmed, as 31% of myositis patients werepositive for IgA-class anti-gliadin (AGA) auto-antibodies, especially patients with IBM. Onlyfew patients underwent confirming biopsy, butsome of them had villous atrophy and crypthyperplasia representing 6% of all myositispatients (Selva-O’Callaghan et al., 2007). Mucosalrecovery occurred in all biopsy positive patientsafter three months with gluten-free diet, but theirmuscle symptoms did not improve.

Theoretically also, the lower level of GI tractcould be involved, e.g. the sphincter anus being astriated muscle. However, in the literature we onlyfound one case report with a dermatomyositispatient who presented with rectal incontinence dueto external sphincter myositis (Vitali et al., 1991).

Muscle disorders in patients with inflammatorybowel disease are rare, but there are some reportedcases that have either ulcerative colitis or Crohn’sdisease and myositis (Leibowitz et al., 1994; Chughet al., 1993; Kaneoka et al., 1990; Kulkarni et al.,1997). All patients had involvement of the colon,and it is already known that patients with colonicinvolvement have more extraintestinal manifesta-tions. Some patients did not have any clinicalmuscle symptoms that indicated myositis but hadelevated creatine kinase values. One importantobservation is that patients with inflammatorybowel diseases are often treated with high doses ofglucocorticoids that by themselves can lead to amyopathy that clinically resembles polymyositis,namely steroid myopathy. Muscle biopsy is some-times helpful in differentiating these two entities,as in glucocorticoid-induced myopathy there is nosign of inflammation, which is typically seen inmyositis patients. Moreover, they respond indifferent ways to tapering of glucocorticoids, assteroid myopathy will improve by tapering theglucocorticoid dose.

5. Liver

Liver involvement is unusual in myositis patients.In the literature, there are a few reports referringto an association between polymyositis andprimary biliary cirrhosis (PBC) (Bondeson et al.,1998; Ahn et al., 1993; Rain et al., 1996; Boki andDourakis, 1995; Yasuda et al., 1993). However,one of these reports refers to a patient alreadyaffected by PBC, who developed polymyositis aftertreatment with D-penicillamine. As it is knownthat this drug may cause polymyositis, an associa-tion between PBC and myositis in this particularcase is uncertain. In a review of the literature, 10more cases were found with an associationbetween proven diagnosis of both PBC and


polymyositis/dermatomyositis. This raises thehypothesis of a possible mitochondrial dysfunctionalso in the muscles and makes mitochondrialdysfunction a possible inducing factor for poly-myositis and dermatomyositis patients. On theother hand, an immunological study comparingdifferent rheumatic diseases for presence of anti-mitochondrial antibodies found that they wereoften present in patients with Sjogrenus syndrome,systemic lupus erythematosus, systemic sclerosisand rheumatoid arthritis, whereas none of thepolymyositis/dermatomyositis patients were posi-tive in that study (Zurgil et al., 1992).

One interesting case report tells about a patientwho had Crohn’s disease and within a period of sixyears developed a series of autoimmune diseases,starting with sclerosing cholangitis, then alopeciauniversalis, and finally polymyositis. Polymyositisimproved with glucocorticoids and azathioprinetreatment. In this case it seems more likely that theliver disease was associated with Crohn’s diseaserather than with polymyositis (Seibold et al.,1996).

6. Juvenile dermatomyositis

Particular attention must be paid to juveniledermatomyositis, which is also characterized byproximal muscle weakness and rash, and incontrast to adult dermatomyositis, it is notassociated with malignancy. Juvenile dermato-myositis has more frequent digestive tractinvolvement compared to dermatomyositis orpolymyositis in adults. In juvenile dermatomyo-sitis, the GI-tract manifestations range from dys-phagia to life-threatening ulceration, perforation,and hemorrhage of the whole GI tract as aconsequence of vasculitis or thromboses. A parti-cularly serious situation is a late diagnosis of distalduodenum perforations (Schullinger et al., 1985).Vasculitis can also cause pancreatitis, hepatitis,and renal vessel occlusion. There are a fewreported cases including children with diagnosedjuvenile dermatomyositis and rare digestive com-plications of the disease. Two children presentedwith bowel vasculitis together with pancreatitis,

and one of them also had hepatitis (See et al.,1997); one of them had a good response fromtreatment with high-dose glucocorticoids, theother responded only after immunosuppressivedrugs and plasmapheresis. Their good response toglucocorticoids in some cases is interesting becauseduring the 1950s and 1960s, cortisone was considereda potential cause of pancreatitis (Riemenschneideret al., 1968). Pancreatitis itself has to be treatedurgently because of the risk of cardiovascularcollapse, respiratory distress, or renal failure.

Three cases of juvenile dermatomyositis andcholestasis were reported (Russo et al., 2001). Theyall developed a biopsy-verified cholestasis duringthe first months of disease, and two of themimproved with glucocorticoids. The third patientwas treated from the beginning with glucocorti-coids and cyclophosphamide but died from apulmonary infection. The potential relationshipbetween juvenile dermatomyositis and cholestasisis still uncertain as the reported cases are few.Children with dermatomyositis may also developmalabsorbtion, probably because of inflammatoryinfiltration of the intestinal mucosa (Pachman,1995; Laskin et al., 1999).

7. Summary

In summary, the whole GI tract may be involvedin patients with inflammatory myopathies. Inparticular, dysphagia is common and may, insome patients, become severe and life threatening.However, there are only a few studies in whichGI-tract involvement has been systematicallyinvestigated in myositis patients; thus, the trueprevalence of GI-tract involvement and likewisehow it affects prognosis and health-related qualityof life are uncertain.

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CHAPTER 7

Digestive Involvement in Primary Sjogren’s Syndrome

Manuel Ramos-Casalsa,�, Elke Theanderb, Athanasios G. Tzioufasc, Claudio Vitalid

aLaboratory of Autoimmune diseases ‘‘Josep Font’’, ‘‘Instituto de Investigaciones Biomedicas August Pi I

Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona, SpainbDepartment of Rheumatology, Malmo University Hospital, Malmo, Sweden

cDepartment of Pathophysiology, School of Medicine, University of Athens, GreecedDepartment of Internal Medicine and Rheumatology, Ospedale Villamaria, Piombino, Italy

Sjogren’s syndrome (SS) is a systemic autoimmunedisease that mainly affects the exocrine glands andusually presents as persistent dryness of the mouthand eyes due to functional impairment of thesalivary and lacrimal glands (Fox, 2005). Thehistological hallmark is a focal lymphocyticinfiltration of the exocrine glands, and thespectrum of the disease extends from an organ-specific autoimmune disease (autoimmune exocri-nopathy) (Kassan and Moutsopoulos, 2004) to asystemic process with diverse extraglandular man-ifestations (Ramos-Casals et al., 2005d).

An estimated 2–4 million persons in the UnitedStates have SS, of whom approximately 1 millionhave an established diagnosis (Kassan and Moutso-poulos, 2004). The prevalence in Europeancountries ranges between 0.60 (Dafni et al., 1997)and 3.3% (Thomas et al., 1998). The incidence ofSS has been calculated as 4 cases per 100,000(Pillemer et al., 2001). SS primarily affects whiteperimenopausal women, with a female–male ratioranging from 14:1 (Garcia-Carrasco et al., 2002) to24:1 (Skopouli et al., 2000) in the largest reportedseries. The disease may occur at all ages buttypically has its onset in the fourth–sixth decadesof life, although some cases are detected in younger

female patients, especially in mothers of babies withcongenital heart block (Haga et al., 2005). Whensicca symptoms appear in a previously healthyperson, the syndrome is classified as primary SS.When sicca features are found in association withanother systemic autoimmune disease, most com-monly rheumatoid arthritis (RA), systemic sclerosis(SSc) or systemic lupus erythematosus (SLE), it isclassified as associated SS.

The variability in the presentation of SS maypartially explain delays in diagnosis of up to nineyears from the onset of symptoms (Fox, 2005).Although most patients present with sicca symp-toms, various clinical and analytical features mayindicate an undiagnosed SS. In addition, SS is adisease that may be expressed in many guises,depending on the specific epidemiological, clinicalor immunologic features. Epidemiologically, alower immunologic expression is observed in maleSS patients and those with an older onset (Garcia-Carrasco et al., 2002). Clinically, two mainpatterns of disease expression are observed:patients with only glandular involvement (sicca-limited disease), who have a low frequency ofimmunologic abnormalities and extraglandularfeatures, and patients with a predominant ‘sys-temic’ expression in addition to the siccainvolvement (Garcia-Carrasco et al., 2002).Patients with positive immunologic features needa closer follow-up, paying special attention to theE-mail address: [email protected]


Tel.: +34-93-2275774; Fax: +34-93-2275774


DOI: 10.1016/S1571-5078(07)00007-4

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development of extraglandular manifestations.The therapeutic management of SS is mainlycentered on the control of sicca features, usingsubstitutive and oral muscarinic agents, whilecorticosteroids and immunosuppressive agentsplay a key role in the treatment of extraglandularfeatures.

Gastrointestinal involvement has been littlestudied in primary SS and may include alteredesophageal motility, gastroesophageal reflux(GER), chronic gastritis and, less frequently,malabsorption. More clinical data are availableon pancreatic and liver involvement, which werefirst reported to be part of the extraglandularexpression of SS by Bloch et al. (1965).

1. Esophageal involvement

Recent studies have analyzed esophageal involve-ment in patients with primary SS. Becauseadequate pharyngoesophageal transfer of thealimentary bolus requires saliva (Helm, 1989), itslack might contribute to the development ofdysphagia in SS. However, Anselmino et al.(1997) observed no differences in salivary flowrates of primary SS patients with and withoutdysphagia, while Grande et al. (1993) found norelationship between dysphagia and the parotidsaliva flow rate. Dysphagia has also been asso-ciated with esophageal motor dysfunction andupper esophageal webs (Volter et al., 2004). Thus,Rosztoczy et al. (2001) described decreased peri-staltic velocity in the esophageal body of 11 (44%)out of 25 patients with primary SS. However, themajority of studies have found that SS patientswith and without dysphagia have similar function(Anselmino et al., 1997; Grande et al., 1993;Volter et al., 2004; Tsianos et al., 1985) and thatdysphagia is independent of esophageal dysmoti-lity (Grande et al., 1993; Kjellen et al., 1986; Palmaet al., 1994). Although patients with primary SSmay have altered manometric studies, to date,studies have failed to describe any consistentpattern of esophageal dysfunction, and the motordisorders that some patients may present do notcorrelate with the presence of dysphagia.

A recent study investigated the prevalence andclinical significance of GER in patients with primarySS, and its possible association with esophagealdysmotility (Volter et al., 2004), and found abnorm-alities in motility in 21 patients with SS, which wasassociated with GER. The study found slow acidclearance in the esophagus of SS patients with GER,suggesting a prolonged duration of reflux. Thisextended exposure of the esophagus to refluxed acidmay result either from defective acid neutralizationby salivary bicarbonates or from altered esophagealmotility (Kahrilas et al., 1986; Schowengerdt, 2001;Geatti et al., 1991; Fitzgerald and Triadafilopoulos,1997). Ho et al. (2002) described a high frequencyof tertiary waves in patients with markedlyabnormal pH that were significantly associatedwith the total reflux time, suggesting a relationshipbetween these contractions and prolonged exposureof the esophageal mucosa to low pH values.

2. Gastric involvement

2.1. Chronic gastritis

Although earlier reports described chronic gastricinflammation with mucosal atrophy in nearly 80%of patients with SS (Buchanan et al., 1966; Kilpiet al., 1983; Maury et al., 1985), the prevalence ofchronic gastritis has not been evaluated in recentseries. In clinical practice, patients frequentlycomplain of gastric pain, although gastroscopicstudies often show only mild gastric abnormalities.

Two recent studies have analyzed the prevalenceand clinical significance of anti-parietal cell gastricantibodies (anti-PCA) in primary SS. Nardi et al.(2006) found positive anti-PCA antibodies in 90(27%) out of 335 patients. These patients showed ahigher prevalence of thyroiditis and autoimmuneliver involvement, but not gastrointestinal involve-ment. El Miedany et al. (2005) found anti-PCAantibodies in one-third of SS patients and controls.However, all SS patients with anti-PCA antibodieshad Helicobacter pylori infection, in comparisonwith less than half of the autoantibody-positive controls. Likewise, only 22% of theautoantibody-positive controls had atrophicchanges in gastric mucosa compared with 86% of

M. Ramos-Casals et al.72

those with SS. This study found a close associationbetween anti-PCA antibodies and H. pylori infec-tion, suggesting that this bacterium may induce alocal hyperreactive/autoimmune response thatmight facilitate the induction of autoantibodiesagainst the gastric mucosa of SS patients.

Although anti-PCA antibodies have been asso-ciated with chronic atrophic gastritis and perni-cious anemia, the two processes are only rarelydescribed in patients with primary SS. Two caseswere described in a recent review of hematologicmanifestations in a cohort of 380 SS patients(Ramos-Casals et al., 2002), with only four addi-tional cases being reported (Pedro-Botet et al., 1993;Wegelious et al., 1970; Williamson et al., 1970),suggesting that chronic atrophic gastritis andpernicious anemia are very infrequent in primary SS.

2.2. Helicobacter pylori infection

A number of studies have analyzed the prevalenceand clinical significance of H. Pylori infection inprimary SS, searching for a possible associationwith dyspepsia, gastritis, gastric ulcers or lym-phoma, with controversial results. Theander et al.(2001) found that SS patients have a similarH. pylori seroprevalence rate to controls, whileCollin et al. (1997) found that the seroprevalenceof H. pylori infection in dyspeptic SS patients wassimilar to that of dyspeptic patients without SS.In contrast, other studies have described a higherprevalence of H. pylori antibodies in primary SScompared with controls (De Vita et al., 1996;Ostuni et al., 1993; Sugaya et al., 1995). ElMiedany et al. (2005) found both a significantlyhigher prevalence and higher serum titers of IgGand IgM anti-H. pylori antibodies in SS patientscompared with both patients with other auto-immune diseases without sicca syndrome andhealthy controls. This might reflect geographicdifferences in the prevalence of H. pylori infection,which is reported to be lower in Sweden than inother countries. Moreover, a recent study has shownthat H. pylori was detected in gastric biopsies in71% of Italian SS patients in comparison with 31%of Scandinavian patients (Theander et al., 2001).

Histologically, the severity of gastritis has beenclosely associated with the presence of H. pylori inprimary SS. However, a recent study showed thateradication of H. pylori caused a significantregression of gastric MALT and atrophy in controlsbut not in SS patients (Witteman et al., 1995). Inaddition, dyspepsia did not improve followingbacterial eradication in the majority of SS patients,suggesting that H. pylori does not seem to play arole in the dyspeptic symptoms found in SS.

A possible relationship between H. pylori andgastric lymphomagenesis in SS has recently beenpostulated. Lymphoid accumulation in the gastricmucosa is common in SS, but full evidence for anantigen-driven B-cell expansion has not beendemonstrated. De Vita et al. (1996) described alow-grade gastric lymphoma concomitantlywith H. pylori infection in a patient with SS. AfterH. pylori eradication, a dramatic regression ofgastric lymphoma into chronic gastritis wasobserved, but no amelioration occurred in theparotid and nodal involvement. Multiple molecu-lar analyses showed the expansion of the sameB-cell clone in synchronous and metachronouslymph node, parotid and gastric lesions before andafter H. pylori eradication. Ferraccioli et al. (1996)studied the gastric tissue in SS in order to definewhether the presence of MALT in the stomach isassociated with several infectious agents, andshowed that H. pylori infection is not more frequentamong patient with SS than in controls and that theabnormal accumulation of MALT may occur in thestomach even in the absence of H. pylori infection.Other studies performed on a limited number ofSS patients with simple dyspepsia indicate thatclonality may persist for up to six months after theeradication of H. pylori (Al-Saleem, 1993). Thus,although H. pylori may play a crucial role in thelocal boosting of B-cell lymphoproliferation, theunderlying B-cell disorder seems to be a nonmalig-nant process (De Vita et al., 1996).

3. Intestinal involvement

Intestinal involvement should be considered as oneof the less-frequent extraglandular manifestations

Digestive Involvement in Primary Sjogren’s Syndrome 73

of primary SS, with isolated cases of malabsorptionor vasculitis being reported. However, recentstudies have analyzed the association of celiacdisease (CD) in small series of patients withprimary SS. Iltanen et al. (1999) found that 5(15%) out of 34 SS patients had CD, whileSzodoray et al. (2004) diagnosed CD in 5 (4.5%)out of 111 patients with SS, whereas the prevalenceof CD is estimated to be 0.45% in the generalpopulation. In contrast, Lazarus and Isenberg(2005) found 1 (0.9%) out of 114 patients withprimary SS, and no case was found in a seriesincluding 400 patients (Garcia-Carrasco et al.,2002). In contrast with the opinion of other authors(Roblin et al., 2004), these data suggest that CDshould not be routinely evaluated in patients withprimary SS. However, the close association of CDwith other processes that may also be observed inprimary SS, such as primary biliary cirrhosis (PBC)or IgA deficiency, suggests that these patientsshould be tested for antiendomysial antibodies dueto the increased risk of small bowel adenocarcino-mas and lymphomas in patients with CD.

In patients with primary SS, systemic vasculitisonly rarely involves the gastrointestinal tract. Of19 reports of SS patients with systemic necrotizingvasculitis (Ramos-Casals et al., 2004), 13 hadgastrointestinal tract involvement (Table 1). Inaddition, of the 19 reported deaths of SS patientsdue to vasculitis, the two main causes were CNSinvolvement in six and gastrointestinal perforationin five. Cryoglobulins were determined in 12 ofthese patients and were positive in 10 (83%) cases.In spite of its rarity, gastrointestinal vasculitis,often related to cryoglobulinemia, should beconsidered as a life-threatening situation inpatients with primary SS.

4. Pancreatic involvement

In patients with primary SS, pancreatic involvementis usually asymptomatic and is demonstrated byaltered pancreatic function tests, althoughsome patients may present chronic pancreatitis. Theprevalence of altered pancreatic function tests varieswidely according to the tests used (Table 2). Fenster

et al. (1964) found a prevalence of altered secretin/cholecystokinin test of 52% and Hradsky et al.(1967) a prevalence of 36%, while Gobelet et al.(1983) described a prevalence of 35% using theNBT-PABA test and Coll et al. (1989) a prevalenceof 63% using NBT-PABA test, serum immuno-reactive trypsin levels and stool fat measurement.All these studies, mainly performed in the 1970sand 1980s, suggested a high frequency of alteredpancreatic function in primary SS, although no datawere presented on the clinical impact of thesealtered tests in patients with primary SS. Incontrast, the frequency of chronic pancreatitis is

Table 1

Previous reported cases of vasculitis involving the gastro-

intestinal tract in patients with primary Sjogren syndrome

(Ramos-Casals et al., 2004)

Number

of cases

Histology Site of vasculitic involvement

1 Necrotizing Ileum

2 Necrotizing Gallbladder, spleen

3 Necrotizing CNS, GI, kidney, pancreas

4 Necrotizing Bowel

5 Necrotizing Colonic ulcers

6 Necrotizing Muscle, kidney, CNS, GI

7 Necrotizing Muscle, parotid, bowel

8 Necrotizing Colon ulcers

9 Leukocytoclastic Rectum

10 Leukocytoclastic Bowel

11 Leukocytoclastic Ileum

12 Leukocytoclastic Bowel

13 Leukocytoclastic Gallbladder, appendix,

mesentery

CNS: central nervous system, GI: gastrointestinal.

Table 2

Prevalence of altered functional pancreatic tests in patients

with SS

Author Pancreatic tests Prevalence of

altered tests

Fenster et al. (1964) Secretin 52%

Hradsky et al. (1967) Secretin-cholecystokinin 36%

Gobelet et al. (1983) N-Benzoyl-L-tyrosyl para-

amino-benzoic acid (NBT

PABA) test, radio-

immunoassay trypsinemia

35%

Coll et al. (1989) NBT PABA test, radio-

immunoassay trypsinemia,

and stool fat measurements

63%


very low in large series of patients with primary SS(lower than 2%), although some patients maypresent with a cluster of autoimmune diseasesincluding chronic pancreatitis, thyroiditis andsclerosing cholangitis (SC) (Fukui et al., 2005;Montefusco et al., 1984; Nieminen et al., 1997).

Autoimmune pancreatitis has recently beenconsidered as an IgG4-related autoimmune dis-ease, a novel group of diseases that includes otherorgan-specific autoimmune diseases such asRiedel’s thyroiditis or tubulointerstitial nephritis(Kamisawa, 2006; Takeda et al., 2004). Recentstudies have described some Japanese patients withMikulicz’s disease (MD), a disease closely relatedto SS (Kamisawa et al., 2003; Tsubota et al., 2000).These patients showed a higher frequency ofmales, higher levels of serum IgG4, lower titersof ANA, negative anti-Ro and anti-La antibodies,a predominance of IgG4+ cells in the salivaryglands and a close association with autoimmunepancreatitis in more than 50% of cases. The lackof reported cases outside Japan suggests that theassociation between MD and autoimmune pan-creatitis might be related to local genetic orenvironmental factors.

5. Liver involvement

Liver involvement was one of the first reportedextraglandular manifestations of the systemicexpression of SS, although new developments inthe field of hepatic diseases have changed thediagnostic approach significantly. In the firststudies on SS patients in the 1960s, liver involve-ment was evaluated by the presence of hepatome-galy, with a prevalence of 20%. In 1965,Bloch et al. found a 27% prevalence of liverinvolvement (hepatomegaly and/or raisedalkaline phosphatase) in the first well-describedseries of patients with SS. In 1970, Golding et al.reported a higher frequency of sicca syndrome inpatients with diverse liver diseases includingchronic active hepatitis, PBC or cryptogeneticcirrhosis. Antimitochondrial antibodies (AMA)were included as a marker of liver disease in SSpatients in the 1970s, with later studies finding a

closer association between SS and PBC than withother types of autoimmune liver disease (Alarcon-Segovia et al., 1973; Tsianos et al., 1990).However, it not was until the 1990s when thespectrum of liver disease in patients with primarySS, included the evaluation of clinical signs of liverdisease, liver function and a complete panelof autoantibodies (Lindgren et al., 1994; Skopouliet al., 1994).

Recent studies have shown that liver functiontests may be altered in 10–20% of patients withprimary SS (Csepregi et al., 2002). After discardingpotentially hepatotoxic drugs, the main causeswere chronic HCV infection (especially in geo-graphic areas with a high prevalence) and PBC(Ramos-Casals et al., 2005b; Abraham et al.,2004). Some SS patients may present positiveAMA with no clinical or analytical evidence ofliver involvement, probably reflecting an earlyasymptomatic stage of PBC (Ramos-Casals et al.,2006). Less frequently, SS patients may presenttype 1 autoimmune hepatitis (AIH) and, evenmore rarely, autoimmune or SC.

5.1. Chronic viral hepatitis

Chronic viral liver diseases have recently emergedas an additional cause of liver involvement inpatients with SS (especially in some geographicareas), broadening the spectrum of hepatopathiesthat may affect these patients (Ramos-Casalset al., 2005b). In a recent study, chronic HCVinfection was the main cause of liver involvementin patients with SS, with a prevalence of 13%,nearly threefold greater than that observed forautoimmune liver involvement (Ramos-Casalset al., 2006). This underlines the importance ofchronic HCV infection as a cause of liverdisease in SS patients from regions such as theMediterranean, with higher prevalence of HCVinfection in the general population. Recent experi-mental (De Vita et al., 1995; Koike et al., 1997),virological (Arrieta et al., 2001; Toussirot et al.,2002) and clinical evidence (De Vita et al., 2002;Jorgensen et al., 1996; Ramos-Casals et al., 2001a)has revealed a close association between HCV and


SS and, in a recent large multicenter study(Ramos-Casals et al., 2005b), SS-HCV was indis-tinguishable in most cases from the primary formusing the most recent sets of classification criteria.Two-thirds of SS-HCV patients presented cryo-globulinemia, which may be considered the keyimmunologic marker of SS associated with HCVand the main cause of vasculitis in these patients.How then should this SS be classified? Currentevidence suggests that chronic HCV infectionshould be considered an exclusion criterion forthe classification of primary SS, not because itmimics primary SS, but because it seems to bedirectly responsible for the development of SS in aspecific subset of HCV patients (Ramos-Casalset al., 2005b). SS-HCV patients should be con-sidered as a separate subset from the primaryform, and it would be more appropriate to classifythese patients as having a ‘SS associated withHCV’. The term ‘SS secondary to HCV’ mightbe used in those cases in which infection ofsalivary gland epithelium by HCV is directlydemonstrated.

The association between SS and other types ofchronic viral hepatitis is very infrequent. Only onecase of chronic HBV infection was found in475 SS patients, in comparison with 63 patientswith chronic HCV infection (Ramos-Casals et al.,2006). Three additional cases (Aprosin et al., 1993;Iakimtchouk et al., 1999; Toussirot et al., 2000) ofHBV-related SS have been reported (one associatedwith HBV vaccination), compared with more than300 cases of HCV-related SS (Ramos-Casals et al.,2005c). Similarly, chronic HGV infection also playsan insignificant role in liver disease in SS patients.The predominant etiopathogenic role of HCV isprobably due to its specific lymphotropism andsialotropism (De Vita et al., 1995; Ramos-Casalset al., 2001b), which means it can infect and repli-cate in both circulating lymphocytes and epithelialcells from the salivary glands (Ramos-Casals andFont, 2005).

5.2. Primary biliary cirrhosis

After discarding HCV infection, PBC should beconsidered as the main cause of liver disease in

patients with primary SS (Lindgren et al., 1994;Ramos-Casals et al., 2006; Skopouli et al., 1994).Although historically these patients have beenconsidered as having a ‘secondary’ SS, it seemsmore rational to use the term ‘SS associated withPBC’, due to the clinical-based evidence that SS isassociated with (and not secondary to) otherautoimmune diseases. The inclusion of AMA inthe routine immunologic follow-up of SS patientsshould be recommended, independently of whetherthe analytical liver profile is altered or not, due tothe strong association between AMA and thedevelopment of PBC.

Several studies have analyzed the prevalence ofAMA in patients with primary SS. Csepregi et al.(2002) studied 180 patients and found five AMApositive patients (two of whom developed sympto-matic PBC), three patients with AIH and one withautoimmune cholangitis, while Kaplan (1993)found abnormal liver tests in 29/59 (49%) patients,including five patients with positive AMA and onewith AIH. Nardi et al. (2006) found a prevalenceof 8% of AMA, although only 50% of theseSS-AMA positive patients had clinical or analy-tical evidence of liver involvement, suggesting theexistence of an incipient or incomplete PBC insome patients with primary SS. A recent study hasconfirmed the broad spectrum of abnormalities inthe analytical liver profile of SS patients withAMA-M2, including three patients with no clinicalor analytical data suggestive of liver disease(Ramos-Casals et al., 2006), as has been reportedin five previous cases (Csepregi et al., 2002;Lindgren et al., 1994; Skopouli et al., 1994).Previous studies on non-SS patients have shownthat AMA-M2 patients with any clinical oranalytical sign of liver involvement have a highrisk of developing symptomatic PBC (Prince et al.,2004), underlining the key role of AMA-M2 as anearly immunologic marker of PBC (Abrahamet al., 2004). Although there are no therapeuticguidelines for these asymptomatic patients, earlyuse of ursodeoxycholic acid may be considered,since some studies on non-SS patients with mildanalytical abnormalities have suggested that treat-ment with ursodeoxycholic acid might prevent apossible evolution to liver cirrhosis (Beswick et al.,1985).


5.3. Autoimmune hepatitis

AIH was another autoimmune liver disease foundin SS patients, although less frequently than PBC.There are 51 reported cases of AIH in patientswith primary SS (Table 3) and all are type 1 AIH(Coll et al., 2003). An additional characteristic ofthe AIH associated with primary SS is that most ofthe reported cases (33 out of 51, 65%) are fromoriental countries. There are no reported cases oftype 2 AIH in patients with primary SS, a factconsistent with the lack of positive anti-LKM-1antibodies in SS. The prevalence of anti-LKM-1antibodies has recently been evaluated in a largeseries of patients with primary SS, and none ofthe 335 patients tested had these autoantibodies(Nardi et al., 2006).

5.4. Other autoimmune liver diseases

Other autoimmune liver diseases have infrequentlybeen described in patients with primary SS(Table 4), including 13 cases of SC, 7 cases of

autoimmune cholangitis and 1 case of nodularregenerative hyperplasia of the liver (Ramos-Casalset al., 2006). Some characteristics of patients withSS and associated SC should be highlighted: aspecific pattern of clinical features at presentationof SC (mainly abdominal pain, jaundice anddiarrhea), an overwhelming association withchronic pancreatitis in all but one case (withpancreatic masses demonstrated by CT abdominalscan) and an association with other autoimmuneprocesses such as retroperitoneal fibrosis. Thesespecific features may aid earlier diagnosis of thisrare disease in patients with primary SS.

5.5. Evaluation of altered liver profile inpatients with SS

Detection of an altered liver profile in a patientwith SS requires a sequential diagnosis (Fig. 1). Thefirst step is to discard processes not associatedwith SS, mainly the chronic use of potentially

Table 3

Autoimmune hepatitis and SS: reported cases (Ramos-Casals

et al., 2006)

Number of cases Year Country

1 1991 Japan

2 1993 France

3–9 1995 Japan

10–11 1997 France

12 1997 Italy

13 1998 India

14–19 1998 China

20 1999 Japan

21 2000 Japan

22 2001 Spain

23 2001 Korea

24 2001 Japan

25 2002 Japan

26–28 2002 Hungary

29 2003 Japan

30 2003 France

31 2003 Korea

32–34 2004 Japan

35–42 2005 Japan

43–51 2006 Spain

Table 4

Other autoimmune liver disease associated with SS (Ramos-

Casals et al., 2006)

Liver disease Year Country

Sclerosing cholangitis 1975 UK

Sclerosing cholangitis 1975 UK

Sclerosing cholangitis 1984 USA

Sclerosing cholangitis 1986 France

Sclerosing cholangitis 1989 Peru

Sclerosing cholangitis 1989 Japan

Autoimmune cholangitis 1989 Spain

Sclerosing cholangitis 1991 Spain

Nodular regenerative hyperplasia

of the liver

1994 Spain

Autoimmune cholangitis 1995 Greece

Autoimmune cholangitis 1995 Japan


Sclerosing cholangitis 1997 Finland

Autoimmune cholangitis 1998 Korea

Autoimmune cholangitis 2001 Korea


Autoimmune cholangitis 2002 Hungary

Autoimmune cholangitis 2002 Rumania

Sclerosing cholangitis 2003 Switzerland

Sclerosing cholangitis 2004 Germany



hepatotoxic drugs, steatosis and congestive heartfailure, all of which are frequently found in theelderly. The second step is to differentiate betweenautoimmune and viral liver disease. Evaluation ofepidemiological factors may be helpful. For exam-ple, HCV infection is more frequently found in SSpatients from the Mediterranean area than in thosefrom North Europe (Ramos-Casals et al., 2005a).Likewise, HCV diagnosis is more frequent in olderand male SS patients, while younger and female SSpatients are more likely to have an associatedautoimmune liver disease. The third step is theanalytical liver profile, although in a recentstudy, this was not useful in differentiating betweenHCV- and autoimmune-related liver diseases(Ramos-Casals et al., 2006). The fourth step is theimmunologic profile, which plays a key role indifferentiating between the main etiologies: Patientswith chronic HCV infection have a higher fre-quency of cryoglobulins and hypocomplemente-mia, while those with autoimmune liver disease

present hypergammaglobulinemia and autoanti-bodies (ANA, SMA, Ro and La) more frequently.In SS patients with a suspected autoimmune liverdisease, the existence of AMA with a specific M2pattern indicates PBC, while high titers of ANAand anti-SMA suggest type 1 AIH. The differentialdiagnosis of liver disease in patients with primarySS (viral versus autoimmune) is clinically impor-tant, since the two processes have a differenttherapeutic approach and prognosis.

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Altered liver profile

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CHAPTER 8

Gastrointestinal Involvement in Systemic Vasculitis

Salvatore De Vitaa,�, Luca Quartuccioa, Elisa Gremeseb, Gianfranco Ferracciolib

aRheumatology Clinic, Azienda Ospedaliero-Universitaria ‘‘S. Maria della Misericordia’’, DPMSC,

University of Udine, Udine, ItalybDivision of Rheumatology, School of Medicine, Catholic University of the Sacred Heart, Rome, Italy

1. Introduction

Gastrointestinal (GI) manifestations of systemicvasculitides (SVs) are a challenge for the cliniciandue to the variety and severity of individualvasculitis ranging from isolated involvement (e.g.,small mucosal lesions) to life-threatening diseaserelated to massive intestinal disease (e.g., acutemesenteric ischaemia or infarction) (Table 1)(Mosley et al., 1990). When considering thedifferential diagnosis, it is first necessary todistinguish between primary and secondary vascu-litis (Muller-Ladner, 2001).

Generally, acute intestinal vasculitis presents asrapidly evolving disease with intensive abdominalpain, followed by signs of peritonitis and ileus, andmay progress into a life-threatening shock syn-drome with high mortality. At the emergencydepartment admission, it is quite difficult todistinguish between vasculitis-related mesentericischaemia from embolic or thrombotic disease ina patient with an acute abdomen presentation.More importantly, the first step, after a carefulclinical history collection and physical examina-tion, is to evaluate serum concentrations for lactateand coagulation parameters, as well as specificmarkers of systemic inflammatory disease. Then,when the hypothesis of abdominal ischaemia is

highly probable, abdominal X-ray and multislicethree-dimensional computed tomography (CT)scan and ultrasound Doppler imaging of themesenteric arteries are mandatory for the diagnosisof ileus, intestinal oedema or perforation. Angio-graphy and surgical intervention may be thesubsequent diagnostic and therapeutic step, whichshould be coordinated with radiologists andvascular surgeons (Muller-Ladner, 2001).

Chronic vascular diseases are related to arterio-sclerosis in more than 90% of patients, and in theremaining 10% of patients, they may be due tovarious chronic intestinal vasculitides. However,chronic vascular diseases can mimic all types of GIdisorders; thus, a diagnostic workup should beperformed starting from patient’s history. In thisregard, abdominal pain 30–60min after the meal isone of the predominant symptoms. Abdominal

Table 1

Gastrointestinal involvement in systemic vasculitis

Type of vasculitis Frequency of

gastrointestinal

vasculitis

Polyarteritis nodosa 30–50%

Churg-Strauss syndrome 25–50%

Wegener’s granulomatosis 5–10%

Takayasu’s arteritis up to 50%

Giant cell arteritis 11%

Schonlein-Henoch purpura 50–90%

Vasculitis in systemic lupus erythematosus up to 50%

Rheumatoid arthritis vasculitis up to 10%

Mixed type II cryoglobulinemia RareE-mail address: [email protected]


Tel.: 0039 0432 559800; 0039 0432 559808;

Fax: 0039 0432 559472


DOI: 10.1016/S1571-5078(07)00008-6

dx.doi.org/10.1016/S1571-5078(07)00008-6.3d

bruits due to incomplete stenosis of one of themajor abdominal arterial vessels are oftenrecorded at physical examination, also in thelack of ultrasound alterations. Gastroscopy andcolonoscopy sometimes reveal signs of colitis ormultiple petechiae or small mucosal ulcers.Chronic intestinal vasculitides are associated withimportant morbidity and mortality. In this settinga rare complication, amyloidosis, occurs in thecourse of hypersensitivity vasculitis, leading tointestinal pseudo-obstruction (Hiramatsu et al.,1998).

2. Large-vessel vasculitis

SVs, by nature, can affect any organ or apparatus,and the GI tract falls into the rule. When examiningcarefully the data of the literature on organinvolvement in the various types of systemic vasculi-tides, the GI tract appears especially affected whenthe small- and medium-size vessels are involved andmuch less affected when the large vessels areinvolved (Tables 1–3), even though we must

recognize that no vessel size can be, by definition,ruled out in any of the commonly classifiedinflammatory vasculitides (Ferraccioli et al., 1998).

3. Takayasu’s arteritis

Takayasu’s arteritis (TA) is an acute arteritisaffecting the large and medium vessels (aorta andpulmonary arteries in particular) and is character-ized by signs and symptoms of stenosis of aorticbranches. The typical sign is the pulseless diseasethat affects young women more than men (60–90are women). The incidence is 1.2–2.6 cases/1,000,000o40 years. Prognosis is essentially linkedto the occurrence of catastrophic neurologic eventsdue to hypertension, aneurysms and aortic insuffi-ciency. Progression of inflammation leads tostenotic occlusion of the involved arteries and toaneurysmatic lesions of ascending aorta, aorticarch, descending aorta and bilateral commoncarotid arteries. GI symptoms (abdominal pain,cramps, diarrhoea) are among the most frequentmanifestations of the disease (Tables 2 and 3).

3.1. Pathogenesis

An infectious origin has been hypothesized fromthe fairly common association with previousmycobacterial infection (tuberculosis) (Lupi-Herrera et al., 1977). An autoimmune origin wassuggested by the association described with otherautoimmune diseases (Crohn’s disease, anchylos-ing spondylitis, systemic lupus erythematosus)and by the association with HLAB5 and moreparticularly with B52. Moreover, besides anhigher expression of HLA class I and II antigens,an higher expression of heat shock protein 65(HSP-65) was seen in Takayasu’s arteritic lesions,suggesting a possible pathogenetic role of gd�Tcells (especially Vd1+) cells as well as ab�T cellsactivated by infectious events and infiltrating thearterial wall (Seko, 2000; Kerr et al., 1994).Human studies suggesting endothelial cell activa-tion have demonstrated increased expression ofintercellular adhesion molecule-1 (ICAM-1) andvascular cell adhesion molecule-1 (VCAM-1) in

Table 2

Frequency of the major clinical manifestations of Takayasu’s

arteritis (TA)

%

Fever 35

Asthenia 50

Pulseless 50–96

Hypertension 33–76

Carotidodynia 32

Headache 20–42

Ischemic retinopathy 37–52

Gastrointestinal (clinical/X-ray) 47

Table 3

Frequencies (approximate %) of GI organ involvement in large-

vessel vasculitides

TA GCA Chronic

peri-aortitis

Imaging and/or clinical

gastrointestinal (GI) tract

involvement

47 11 80

S. De Vita et al.84

patients with TA. Humoral immunity is alsobelieved to be involved in this disease; antiaortaantibodies and antiendothelial cell antibodies havebeen found in patients with TA. ImmunoglobulinG, immunoglobulin M and properdin are found inlesions from pathologic specimens.

3.2. Pathology

Macroscopically, the aorta appears rigid, thick-ened and fibrotic. Stenotic lesions can be observedframed with fully normal traits. Microscopically,mononuclear infiltration of the adventitia occursearly in the course of the disease, with cuffing ofthe vasa vasorum. Granulomatous changes may beobserved in the tunica media with Langerhans cellsand central necrosis of elastic fibres and smoothmuscle cells. A panarteritis with infiltrates oflymphocytes, plasma cells, histiocytes and giantcells is present. Later, fibrosis of the media and acellular thickening of the intima compromise thevessel lumen. Wrinkling of the intima is visible ongross examination. In chronic phases, the intimapresents calcifications.

3.3. Diagnosis

Age less than 40, claudication of the extremities,pulselessness in one brachial artery and a pulsepressure difference of more than 10mmHgbetween the upper limbs, clearcut bruits over asubclavian artery, arteriographic lesions of theproximal aortic branches, not linked to artero-sclerotic lesions: The presence of three or morecriteria suggests the diagnosis with a sensitivity of90.5% and a specificity of 97.8%. The arterio-graphic study allows to distinguish among the fivetypes of the disease (class I to IIa and IIb:ascending aorta; class III: thoracic and abdominalaorta; class IV: abdominal aorta and renal arteries;class V: class IIb and III).

3.4. Therapy

No controlled therapeutic trial is available.Corticosteroids are the mainstay of therapy(0.7–1mg/kg/day for 1 month, then tapered

down slowly). In patients who show persistentactivity despite 15mg/day of prednisone, immu-nosuppressive agents should be employed (Cyclo-phosphamide, Azathioprine, Methotrexate,Mycophenolate Mofetil). A 12-month treatmentis generally necessary before reaching a full controlof disease activity. A small series (15 patients)showed that TNF inhibition using etanercept orinfliximab was successful in inducing clinicalremission and permitting corticosteroid taper inpatients who are steroid dependent. The role ofTNF inhibition in treating initial disease orrelapses is yet to be established, but use of theseagents and immunosuppressants, such as myco-phenolate or methotrexate (0.3mg/kg/wk), antici-pate regimens in which disease is controlled whileminimizing morbidity from steroid. Some veryresistant cases to conventional therapies can leadto percutaneous balloon angioplasty and endovas-cular stenting revascularization. Aneurysm forma-tion occurs in 27% of the cases. While the 5-yearsurvival rates exceed 90%, the disease has a highincidence of residual morbidity (Arend et al., 1990;Arora et al., 1997; Baumgartner et al., 2005;Daina et al., 1999; de Leeuw et al., 2004; DellaRossa et al., 2005; Haberhauer et al., 2001;Hoffman et al., 1994, 2004).

4. Giant cell arteritis

Giant cell arteritis (GCA) is a chronic, systemicvasculitis with a distinct localization in large- andmedium-sized arteries (aorta and its extracranialbranches). The incidence is 9–29 cases/100,000 inpatients W50 years, according to geographicalstudies. Symptoms include headache, jaw claudi-cation, scalp tenderness, muscle aches, weight loss,fatigue, fever and visual complaints. The mostserious complications of GCA are persistent andpermanent visual loss or neurologic damage.Prognosis depends upon its major localizations.While the prevalence of myocardial infarction isunknown, the risk of abdominal aneurysm is2.4%, and cerebral infarction has been reportedin 7% of consecutive patients with biopsy-provenGCA (Small and Brisson, 1991; Phelan et al., 1993;

Gastrointestinal Involvement in Systemic Vasculitis 85

Burke et al., 1995; Srigley and Gardiner, 1980;Smith et al., 1988; Krant and Ross, 1992; Hassanand Daymond, 1993; Trimble and Weisz, 2002;Evans et al., 1995). Abdominal complaints arefrequent and strictly related to the ischaemicnecrotic lesions occurring in various parts of thevascular net of the GI tract (Table 3).

4.1. Pathogenesis

The granulomatous histopathology of GCA hassuggested the presence of an antigen-driven diseasewith local T-cell and macrophage activation in ornear elastic tissue in the arterial walls with animportant role of the proinflammatory cytokines.Some familial accumulation and the associationwith HLA-DR4 suggest a clear immunologicalgenetic predisposition. The CD4+T cells appearto be central in the pathogenesis. In fact, clonalexpansion of CD4+T cells presenting identical Agreceptors has been isolated from arteritic lesions.These T cells are thought to derive from vasavasorum, under the influence of chemokines suchas CCL19 and CCL21 produced by dendritic cellspresent in the adventitia. Data suggest thatendothelial cells and dendritic cells are activatedbefore T-cell recruitment (Weyand and Goronzy,2003; Nordborg and Nordborg, 2003).

4.2. Pathology

Biopsy demonstrates a vasculitis with mononuc-lear cell infiltrates. Collections of lymphocytes areconfined to the region of the internal or externalelastic lamina or adventitia in early cases orregions of arteries with minimal involvement.Intimal thickening, with prominent cellular infil-tration, is typically present. In late cases or regionsof arteries with marked involvement, there arewidespread areas of necrosis of portions of thearterial wall. The elastic laminae are usuallyinvolved, and granulomas containing multinu-cleated histiocytic and foreign body giant cells,histiocytes, predominantly helper T-cell lympho-cytes, and some plasma cells and fibroblasts areusually present. Eosinophils may be seen in thespecimen section, but polymorphonuclear (PMN)

leukocytes are rare. Thrombosis may develop atthe sites of active inflammation. These areas withthrombosis may recanalize later. It has beenobserved that the inflammatory process is usuallymost marked in the inner portion of the mediaadjacent to the internal elastic lamina.

4.3. Diagnosis

The American College of Rheumatology criteria(1990) for the diagnosis of GCA are as follows:

� Age of 50 years at onset� New headache� Abnormalities of the temporal arteries� Erythrocyte sedimentation rate (ESR) of50mm/h� Positive results of a temporal artery biopsy(vasculitis characterized by a predominance ofmononuclear infiltrates or granulomas, usuallywith multinucleated giant cells) (Table 4).

4.4. Therapy

Corticosteroids are central in the therapeuticapproach to GCA treatment. The initial dose inthe case of impeding visual loss requires bolusesof corticosteroids (1 g of 6-methylprednisolonefor 3 days) followed by prednisone equivalentsof 1mg/kg/day for 1 month and gradual, slow

Table 4

Characteristics of GCA and TA

Findings Giant cell arteritis Takayasu’s arteritis

Female-to-male ratio 3:2 7:1

Age at onset W50 years o40 years

Ethnic ancestry European Asian

Histopathology Granulomatous

inflammation

Granulomatous

inflammation

Primary vessels

involved

External carotid

artery branches

Aorta and branches

Abdominal pain Rare Common

Renovascular

hypertension

Rare Common

HLA association HLA-DR4 HLA-Bw52

Course Self-limited Chronic

Response to

corticosteroids

Excellent Excellent

S. De Vita et al.86

tapering afterwards. The objective should be todecrease or even stop the steroid as soon aspossible in order to avoid all the side effects thatoccur during a long-term treatment especially inelderly patients. Of crucial importance, no studieshave addressed the issue of how to taper thecorticosteroids in patients with GCA. One possibleapproach is to reduce the daily dose of prednisoneby 10mg every month until a dose of 25mg hasbeen reached, then the daily dose may be decreasedby 2.5mg each month until the patients takes10mg/day and then reduce by 2.5mg on alternatedays every 2wks. These regimens would result infull steroid withdrawal after 13–14 months. How-ever, disease exacerbation is frequent and abdom-inal symptoms are among the manifestations ofrecurrence. Of note, abdominal as well as thoracicaneurysms are among the late complications of apoorly controlled GCA and can develop in nearly20% of the patients (Evans et al., 1995).

5. Chronic periaortitis (Index case)

A 16-year-old boy, in perfect shape, suddenlydeveloped cramping abdominal pain, and fever

a few hours later. The abdominal pain wasunusually (for the age) located in the periumbilicaland left upper quadrant of the abdomen anddid not vanish with spasmolytic drugs nor withparacetamol. The patient at the emergency roomof the local hospital underwent a plain abdominalX-ray and an ultrasound examination thatrevealed a dilated small and large intestine,with large bowel loops and decreased bowelmovements, without any sign of paralysis of theintestine. The acute-phase reactants were elevatedand the abdomen CT scan showed multiple fluid-and gas-filled loops of the small bowel withouta definite point of obstruction. No appendixor pancreatic or kidney lesions were demonstrated.A suspicion of thickening of the abdominal aortawas raised (aortitis?), and the patients wassent to our unit, where a new CT angiographyscan showed periaortitis of the aortic arc, of theabdominal aorta below and above the renalartery, and of the superior mesenteric artery(Figs. 1 and 2). This patient was affected byperiaortitis of the supradiaphragmatic and sub-diaphragmatic aorta, presenting as abdominalpain. This case underlines once again that large-vessel arteritides can present with manifestationsat the GI tract level.

Figure 1. Aorta abdominal tract showing thickening of the wall of 2.8mm.


5.1. Characteristics of the disease

Chronic periaortitis is thought to be the mostaggressive manifestation of inflammatory athero-sclerosis, and is probably an autoimmune process.The estimated annual incidence is 0.2–0.5 per100,000 persons. It affects middle-aged to elderlymen more commonly than females (ratio 2:1–3:1).

5.2. Pathology

The key features are represented by chronicinflammatory infiltrates in the aortic adventitia,medial thinning in dilated or undilated aorta withdifferent degrees of periaortal fibrosis, extendinginto the adjacent structures. The striking inflamma-tory reaction in the adventitia consists of plasmacells, many B cells but few T cells, and macrophages.Occasionally, small granulomas and giant cells canbe observed (Parums, 1990; Pasquinelli et al., 1993).

5.3. Diagnosis

Abdominal (or back) pain is the most commonpresentation (80%). Fever, weight loss, vomiting,malaise, and also testicular pain, ureteral colic andclaudication, have been often described. Symp-toms and elevated acute-phase reactants raise thesuspicion that can be confirmed by contrast-enhanced CT scanning (or MRI). These investiga-tions reveal the periaortic tissue mass as a ring ofabnormal inflammatory (or fibrous tissue) aroundthe aorta and often involving other branches(Hellmann et al., 2007; Jois et al., 2004).

5.4. Therapy

Even though the relative role of corticosteroidsis still undefined, they remain the basic therapeuticapproach in this entity. However, there is nostandard for dose and duration of steroid treatment.

Figure 2. Aorta abdominal tract above and below the renal artery, showing thickening of the wall.

S. De Vita et al.88

When the response is incomplete, azathioprine,methotrexate, mycophenolate mofetil, tamoxifen andcyclophosphamide have all been described as effec-tive in selected case reports or small series (Kardaret al., 2002; Warnatz et al., 2005; Grotz et al., 1998;Marcolongo et al., 2004; Bourouma et al., 1997).

6. Medium-sized vessel vasculitis

Polyarteritis nodosa (PAN) and Kawasaki disease(KD) are the two major forms of medium-sizedvessel vasculitis (MVV), characterized by necrotiz-ing arteritis (Jennette et al., 1994). Patients withnecrotizing arteritis fall into two broad categories:those with vasculitis affecting arteries versus thosewith vasculitis affecting not only arteries but alsovessels smaller than arteries, such as venules andcapillaries. The former includes PAN and KD, thelatter includes several forms of small-sized vesselvasculitis (SVV) (Hunder et al., 1990).

6.1. Polyarteritis nodosa

According to the Chapel Hill Consensus Con-ference (CHCC), PAN is a necrotizing inflamma-tion of small- and medium-sized arteries withoutglomerulonephritis or arteritis in arterioles, capil-laries or venules (1). PAN is a rare form ofsystemic vasculitis, but there are also organ-limitedvarieties of PAN, cutaneous PAN being the bestrecognized. In 1970, Trepo and Thivolet reportedon the association of PAN with hepatitis B virus(HBV) infection. HBV infection is included as adiagnostic criterion in the ACR 1990 classification,but in the 2006 classification proposal for child-hood vasculitis, HBV-PAN is classified as separatefrom idiopathic PAN (Ozen et al., 2006). Theincidence of the disease is rather low, rangingfrom 5 to 10 per million. The pathologic hall-marks of PAN are transmural fibrinoid necrosisand inflammation, which is initially characte-rized by neutrophil infiltration, but later bymonocytes, macrophages and lymphocytes. Thisnecrotizing inflammation results in aneurysms(pseudoaneurysms), the arterial nodules thatprompted the term ‘nodosa’. Biopsy of target

organ hardly allows the differentiation betweenMVV (e.g., PAN) and SVV; thus, the diagnosis ofPAN should be done only after a reasonablesearch for clinical and pathologic evidence forSVV is negative, especially including absence ofglomerulonephritis or pulmonary capillaritis, whileskin and peripheral nerves represent the mostfrequent involvement (Guillevin and Lhote, 1995a).

GI vasculitis is found in up to 25–63% of thepatients and may be present at PAN onset (Stone,2002; Guillevin et al., 1995b). Patients morefrequently present with subacute disease onsetover many weeks or months (Levine et al., 2002).GI involvement may also present as a perforationof the stomach, small or large bowel; infarction ofthe stomach, small or large bowel; vasculiticappendicitis; gallbladder infarction and vasculiticcholecystitis; haemorrhagic pancreatitis; nauseaand vomiting; bloody and non-bloody diarrhoea;melaena; occult or massive intestinal bleeding andrupture of splenic, hepatic or renal arteries. Thediagnosis of PAN is suggested by an angiographicfinding of aneurysms up to 1 cm in diameter withinthe mesenteric and hepatic vasculature. However,this finding is not always pathognomonic forPAN, because it is also seen in necrotizing angiitisassociated with drug abuse (Halpern and Citro,1971), Wegener’s granulomatosis (WG) and sys-temic lupus erythematosus (Travers et al., 1979).Based on a prospective study, the French Vascu-litis Study Group determined that the followingfive factors (five-factor score) had significantlyworse prognostic value in PAN and Churg-Strausssyndrome (CSS): proteinuriaW1 g/day, creatinine-miaW158mg/dl, cardiomyopathy, GI tract invol-vement and central nervous system involvement.

Since 1950s, the introduction of corticosteroidshas dramatically improved the outcome, from87% of a 5-year mortality to 50%, and recentlong-term follow-up studies have described 5-yearsurvival of up to 85%. GI tract involvement, HBVinfection and ageW65 years are associated withincreased mortality (Gayraud et al., 2001). Clinicaltrials of therapeutic strategies over the last 10 yearshave optimized the use of cyclophosphamideand the best administration (continuous oralversus pulsed intravenous) or treatment duration(Guillevin et al., 2003).


6.2. Kawasaki’s disease

KD is a MVV affecting children. This is a febrileillness of childhood that usually occurs before 5years. The most definite feature is the mucocuta-neous lymph node syndrome, which includes fever,polymorphous erythematous skin rash, orophar-yngeal erythema, redness or fissuring of the lips,indurative oedema of the extremities, desquama-tion, conjunctivitis and nonsuppurative lymphade-nopathy. Coronary arteries are often involved andrepresent the most important involvement affect-ing the morbidity and mortality in this setting.

Pathologically, the arteritis of KD shows lessfibrinoid necrosis than that observed in PAN andmore medial oedema.

Involvement of the bowel or gallbladder isrelatively uncommon (Falcini et al., 2002). Thereported GI manifestations comprise surgicallyacute abdomen caused by paralytic ileus, vasculiticappendicitis, haemorrhagic duodenitis, or bloodyor non-bloody diarrhoea.

A course of intravenous immunoglobulins(2 g/kg in total) given in the first 10 days inaddition to aspirin (50–80mg/kg) led to a fasterresolution of fever and clinical signs and to ashorter hospitalization (Newburger et al., 1991).Corticosteroids may be useful in patients whofailed intravenous immunoglobulins (Hashinoet al., 2001). Recently, a randomized trial failedto demonstrate an advantage when a single pulseddose of intravenous methylprednisolone wasadded to conventional intravenous immunoglobu-lin therapy for the routine primary treatment ofchildren with KD (Newburger et al., 2007).

7. Small-sized vessels vasculitis

Small-sized vessels vasculitis (SVV) has a predilec-tion for capillaries and venules, but arterioles andsmall arteries may be involved. SVV can be dividedin two immunopathologic categories: immunecomplex-mediated vasculitis, such as Henoch-Schonlein purpura (HSP) and cryoglobulinemia,and pauci-immune SVV, such as ANCA-associatedvasculitis.

7.1. Henoch-Schonlein purpura andleukocytoclastic vasculitis

HSP is a vasculitis of small vessels, secondary toan immune process that generates circulatingimmune complexes containing significant amountsof IgA, which precipitate in the skin, joints,kidneys and bowel. In fact, clinical features includea palpable purpura, arthritis, acute glomerulone-phritis and abdominal pain. The typical histologiclesion in the skin biopsy is leukocytoclastic angiitisaffecting postcapillary venules, capillaries andarterioles. The most specific pathologic finding forHSP, which can differentiate HSP from otherleukocytoclastic vasculitis, such as cryoglobuline-mia, WG, CSS or micropolyangiitis, is the deposi-tion of IgA-dominant immune complexes in vesselwalls (Baart de la Faille-Kuyper et al., 1973).Although the aetiology is unknown, immuniza-tion, insect bites, medications and infections mayplay a role in its development. HSP occurspredominantly in younger patients, but it can alsoaffect the adult patients. In a Spanish study, morethan 30% of children with HSP presented withabdominal pain alone or in association with othermanifestations, and during the follow-up, 70.5%developed bowel angina and about 31% GIbleeding (Calvino et al., 2001). There is a widespectrum of involvement of the bowel in HSP, GImanifestations having been related to oedema andintramural haemorrhage. GI haemorrhage ismostly confined to the mucosa and submucosa,while full-thickness necrosis and perforation of abowel loop is rare.

The GI findings described in the course of HSPinclude intussusception (2–5%, the most seriouscomplication), bowel ischaemia and infarction,intestinal perforation, fistula formation, acuteappendicitis, massive upper GI haemorrhage,pancreatitis, hydrops of the gallbladder andpseudomembranous colitis. Non-characteristicradiological findings are seen, although upper GIbarium studies as well as CT scans are useful toidentify mural thickening, thickened folds andulcerations (Siskind et al., 1985).

Treatment for HSP has been essentially suppor-tive, a benign course being the most frequentoutcome. Corticosteroids have been widely and

S. De Vita et al.90

successfully used in the acute phase of the diseaseto treat abdominal pain and arthralgias/arthritis inchildren (Rosenblum and Winter, 1987). In refrac-tory cases, intravenous immunoglobulins, plasmaexchange, immunosuppressive treatment (mainlyin leukocytoclastic vasculitis other than HSP) andtonsillectomy have been utilized in open-labelstudy, but the results are controversial.

Isolated localized GI vasculitis is a rare entitythat is very difficult to distinguish from HSP, andit can occur in association with HSP. The absenceof IgA deposits on intestinal biopsy specimenin the context of a leukocytoclastic vasculitis iscrucial for the diagnosis. The course of this diseaseappears more aggressive and difficult to treat thanthat observed in HSP, requiring immunosuppres-sors or surgical intervention (Garcia-Porrua et al.,2006).

7.2. ANCA-associated small-vesselvasculitis

The antineutrophil cytoplasmic autoantibody(ANCA)-associated small-vessel vasculitides(ASV) comprise a group of disorders characterizedby necrotizing small-vessel vasculitis with a pau-city of immune deposits, in conjunction withautoantibodies directed against neutrophil cyto-plasmic constituents, in particular proteinase 3(PR3) and myeloperoxidase (MPO). A commonfeature is glomerulonephritis with crescent forma-tion and fibrinoid necrosis (Jennette and Falk,1997; Bosch et al., 2006).

The ASV include WG, microscopic polyangiitisand CSS. ANCA positivity is often observedin WG patients, usually PR3-ANCA, and mostpatients with microscopic angiitis display MPO-ANCA, while only 35–50% of CSS patientsare positive for ANCA, generally MPO-ANCA(Sinico et al., 2005). These findings, togetherwith substantial clinical, histologic and biologicdifferences between these three entities, haveopened some debate when considering WG, CSSand microscopic angiitis either as three distinctdisorders or, more generally, as different aspectsof a unique type of vasculitis. A putative roleof ANCA, in particular MPO-ANCA, in the

pathogenesis of ASV represents the basis ofthe hypothesis of an ANCA-associated vasculiticsyndrome and the rationale of novel B-cell deple-tion treatment (Falk and Hoffmann, 2007).

The ASV often present with malaise, myalgias,arthralgias, fever, rash and neuropathy. WG andmicroscopic angiitis commonly present with acuterenal and pulmonary disease. A hypereosinophiliaand history of asthma characterize CSS, while theupper respiratory tract (typically ear, nose, throat)is the common target of WG and the granuloma-tous inflammation is the pathologic hallmark(Jennette and Falk, 2007).

GI involvement in the course of CSS is frequent,more common than in the remaining ASV, rangingfrom 25 to 50%. In a recent French study, about30% of CSS patients had GI symptoms duringthe course of their disease and 2/23 died due tomesenteric infarct (Bligny et al., 2004). Otherdocumented manifestations include melaena, hae-matemesis, oesophageal gastric, small intestine andcolonic perforation, cholecystitis, bowel ischaemia,ischaemic colitis and omental haematoma. In somepatients, several of the intestinal vessels can beaffected causing life-threatening organ failures(Boggi et al., 1997). Recently, an Italian studygroup retrospectively followed 75 patients afterdiagnosis: 36 with WG, 23 with CSS, and 16with microscopic polyangiitis. GI involvement wasassociated with an increased risk of relapse, mainlyin patients with CSS, whereas renal diseaseand perinuclear antineutrophil cytoplasmic anti-body positivity were correlated with a lower riskof relapse. Older age, renal and hepatic involve-ment, ESRZ100mm/h and serum creatininelevelsZ1.5mg/dl were all related to higher risk ofdeath in univariate analysis. However, only cere-bral and hepatic involvement and serum creatininelevelZ1.5mg/dl were independently correlatedwith an unfavorable prognosis for survival (Pavoneet al., 2006). Similarly, French groups found thatGI involvement represents a poor prognostic signin CSS or PAN patients, in particular in thosepatients with bleeding, perforation, infarction orpancreatitis (Guillevin et al., 1996).

Interestingly, microscopic polyangiitis resemblesCSS in many aspects, showing a similar spectrumof GI symptoms.


GI involvement in WG appears to be a rareevent, usually resulting in granulomatous colitisand gastritis. WG case reports with bowel infarc-tion, oesophageal ulceration, cholecystitis, gall-bladder infarction, pancreatitis and pancreaticmass, bloody diarrhoea, small and large bowelperforation and spontaneous splenic haemorrhageare recorded in the literature. Isolated intestinalvasculitis sometimes occurred as the only manifes-tation, and with a severe course (Chang and Kerr,2000).

The introduction of cyclophosphamide andcorticosteroids in combination has drasticallyimproved the overall survival in ASV, especiallyin WG, with 85% of patients achieving temporal orpersistent remission. Cyclophosphamide, metho-trexate, azathioprine and glucocorticoids all have arole in the treatment of ASV. However, despitestrong immunosuppressive regimen, many patientsdo not reach remission and up to 50% relapse; inaddition, these regimens may result in high rate ofmorbidity and mortality. Thus, several randomizedcontrolled trials have been recently published or arenow ongoing to optimize the use of immunosup-pressants both in the remission induction and in themaintenance regimen. Novel treatment with biolo-gical agents, such as TNF alpha blocking agents,as well as anti-CD20 therapy (rituximab), are nowunder study in randomized controlled trials, afterpreliminary good results coming from open trials(Kallenberg, 2007). In particular, in one referencestudy, rituximab induced remission in all patientswith active, severe ASV, with resistance or intole-rance to cyclophosphamide, allowing steroid taper-ing (Keogh et al., 2006). A large controlled trial(RAVE) with rituximab in ASV was then started.By contrast, etanercept, a soluble receptor of TNF,proved to be ineffective in the WG etanercept trial(WGET), in addition to the immunosuppressivestandard regimen (Wegener’s GranulomatosisEtanercept Trial (WGET) research group, 2005),increasing the risk of cancer (Seo et al., 2005).Finally, more aggressive treatments, such aslymphocyte depletion with anti-thymocyte globulinor alemtuzumab (CAMPATH 1-H), or autologousstem cell transplantation, have been used in veryrefractory and life-threatening diseases (Jayne,2007).

8. Mixed cryoglobulinemia, HCV infection

and gastrointestinal involvement

The cryoglobulinemic vasculitis or syndrome is asystemic vasculitis usually associated with hepatitisC virus (HCV) infection and characterized bynon-neoplastic B-cell lymphoproliferation in thelarge majority of cases, but with an increased riskof B-cell lymphoma development (Gorevic et al.,1980; De Vita et al., 2000a; Dispenzieri, 2000).Among the HCV-negative cryoglobulinemic syn-drome group, many cases with type II serum mixedcryoglobulinemia (MC) also present Sjogren’ssyndrome, an autoimmune and lymphoprolifera-tive disorder primarily involving the salivary andlachrymal glands, leading to glandular damage,dysfunction and sicca syndrome (Johnssonet al., 2005; Tzioufas et al., 1996; De Vita et al.,2001).

MC syndrome may rarely complicate with life-threatening abdominal vasculitis, possibly involvingthe stomach and the small and the large bowel(Gorevic et al., 1980; Baxter et al., 1988; Cacoubet al., 2001; Ferri et al., 2004; Ramos-Casals et al.,2006). Vague and diffuse abdominal complaintsmay be referred at first. Thus, this organ manifesta-tion must be primarily suspected and specificallyinvestigated in its early stages. In a panarteritis-likesubset of MC syndrome, necrotizing vasculitis maylead to the small aneurysm findings (mesenteric,coeliac, hepatic, as well as renal) by abdomenarteriography (Cacoub et al., 2001; Costedoat-Chalumeau et al., 2002), as seen in classicalpanarteritis nodosa, while colic mucosa biopsy mayshow non-specific pathologic findings. A picture ofacute abdomen and bowel infarctual lesions maythen follow, though it may also develop ab initio.Finally, colitis pseudomembranosa may superim-pose if the patient has been treated with large-spectrum antibiotics in our experience, and thisfurther complicates the diagnostic and treatmentapproach. Although rare, such severe intestinalvasculitic complications of MC syndrome must bediagnosed and treated promptly, and mortality ishigh in any case. Therapy includes high-dosesteroids and cyclophosphamide. We also protectthe patient from superimposed infections withantibiotic plus antifungal therapy in the period

S. De Vita et al.92

of high-to-medium-dose steroids combined withcyclophosphamide, and periodically assess Clostri-dium difficile infection. Plasmapheresis is anothertreatment option as an induction therapy, whilerituximab is currently not recommended for abdo-men vasculitis in MC syndrome, as well as inANCA-associated vasculitis. In fact, the latencyfor clinical efficacy of rituximab may be toolong, usually more than 1 month, despite the usualearly B-cell depletion (Zaja et al., 2003; Quartuccioet al., 2006). In addition, MC cases with verydelayed B-cell clinical response (W3 months afterthe first drug infusion) or with late B-cell depletionhave been observed (De Vita, S., personal commu-nication). However, rituximab may also proveeffective in MC-related intestinal vasculitis basedon personal preliminary experience, either in thecontext of induction polytherapy or as mainte-nance therapy. Thus, additional investigation isrequired.

GI bleeding due to peptic ulcer, MC-unrelated,or due to oesophageal varices associated withportal hypertension in HCV-related cirrhosis(Gorevic et al., 1980) should always be consideredin the differential diagnosis. The association ofprotein-losing enteropathy and cryoglobulinemiawas recently reported in one patient (Samarkos etal., 2003). A 79-year-old woman with HCV-relatedMC syndrome diagnosed in 2001 was successfullytreated by our group with combined standardantiviral therapy, with subsequent virus RNA(genotype 5a) clearance from serum and disap-pearance of systemic vasculitis features and bonemarrow low-grade B-cell lymphoma by morpho-logic analyses. Interferon and ribavirin werehowever suspended after 1 year, since they wereno longer tolerated. Two months after suspensionof antiviral therapy, while still HCV RNA-negative, the patient was then admitted to ourclinic for the onset of chronic diarrhoea inassociation with fever. She developed an intract-able wasting syndrome concomitantly with MCsyndrome reactivation including active nephritisand cutaneous vasculitis. Infectious diseases,lymphoproliferative intestinal diseases and coeliacdisease were all excluded by tissue biopsies andradiological studies. High-dose steroid therapywas ineffective and the patient worsened

developing hepatic failure and, finally, diedbecause of multiorgan failure syndrome. Anotherpatient with MC syndrome and chronic diarrhoea,possibly due to intestinal vasculitis, has beenreported (Jones et al., 1991). Of note, intestinalvasculitis also developed during interferon plusribavirin therapy (Pompili et al., 2005).

Abnormal acquisition of MALT (mucosa-associated lymphoid tissue) in the gastric mucosarepresents an additional and much more frequentclinical manifestation both in HCV-related MCsyndrome and in chronic HCV infection withoutMC, as well as in Sjogren’s syndrome with orwithout MC. This gastric MALT accumulationmay lead to different pictures of chronic gastritislymphoid infiltration, i.e., sparse, follicular orlymphoepithelial lesions (Ferraccioli et al., 1996;De Vita et al., 2000b), and might favour gastriclymphoproliferation and eventually the develop-ment of low-grade gastric B-cell lymphoma ofMALT. Such a subset of MALT lymphoma isusually linked with Helicobacter pylori infection,but in the case of MC syndrome and Sjogren’ssyndrome H. pylori infection likely represents onlya possible pathogenetic co-factor. By contrast,the ‘background’ of lymphoproliferation is likelylinked to the underlying autoimmune disease(De Vita et al., 1996; De Vita et al., 2000b, 2001)(Fig. 3).

As a first issue, HCV may localize in the gastricmucosa, both in HCV-infected individuals withoutMC and in HCV-related MC syndrome. HCVgastric localization was shown by strong andunequivocal reactivity of the cytoplasm of glandu-lar cells by immunohistochemistry, while the nucleiwere completely negative. Results were concordantwith the viral findings obtained by PCR in wholeRNA from the same samples, while HCV in situhybridization could not be employed (De Vitaet al., 2000b). When also considering the possiblecontribution of autoimmunity in chronic gastritis(Hussell et al., 1993; Negrini et al., 1996) and theevidence of intragastric clonal B-cell expansion inSjogren’s syndrome also in the absence of H. pylori

infection (Ferraccioli et al., 1996), the role ofother gastric local triggers (including HCV) andco-factors in the predisposed individual can behypothesized.


Secondly, HCV infection appears to increase therisk of gastric lymphoma, since the rate of HCVinfection was increased in unselected cases ofgastric lymphomas and in HCV-related lympho-mas in Sjogren’s syndrome (De Vita et al., 1998;Luppi et al., 1996; Ramos-Casals et al., 2007). Thisincreased occurrence of HCV-positive cases was

also found for what concerns primary hepatic andmajor salivary gland B-cell lymphomas (De Vitaet al., 1998). Strikingly, HCV shows a tropism notonly for the liver, but also for the salivaryepithelium (De Vita et al., 1995), and a role ofHCV as a trigger of MALT lymphoproliferation inthe local microenvironment has been hypothesized

Figure 3. Low-grade gastric B-cell lymphoma of MALT, H. pylori positive (panel A) occurring in a patient with Sjogren’s syndrome,

persistent parotid swelling due to myoepithelial sialadenitis, and non-malignant lymphadenopathy. Gastric lymphoma regressed to

chronic gastritis after H. pylori eradication with antibiotics (panel B). However, as shown in panel C (agarose gel stained with ethidium

bromide showing VDJ-PCR products) and as confirmed by DNA sequencing, the same B-cell clone Sjogren’s syndrome-related, as

detected in the gastric fundus (F0), lymph node (L0) and parotid (P0) at baseline (monoclonal single band), was still present in the gastric

fundus chronic gastritis (F1) and in non-malignant lymph node (L1) in repeated biopsies after H. pylori eradication (De Vita et al.,

1996). The patient developed a gastric high-grade B-cell lymphoma, H. pylori-negative, in subsequent follow-up. Lanes A0 and A1 in

panel C show a polyclonal pattern in the patient’s gastric antrum uninvolved by lymphoma, and in control reactive lymph node from

another case (lane R). Lane B: positive control with amplified B-cell leukaemia DNA; lane M: molecular weight markers; lane N:

negative PCR control without DNA. (See Colour Plate Section.)

S. De Vita et al.94

(De Vita et al., 2002). Gene sequence analyses werealso consistent with an antigen-driven B-cellproliferation in HCV-positive cases of lymphoma(De Vita et al., 2000b; De Re et al., 2000) inanalogy with H. pylori-related gastric B-cell pro-liferation of MALT.

Thirdly, gastric low-grade B-cell lymphomadid not regress despite eradication of localH. pylori infection, as assessed by repeated metha-cronous gastric biopsies after effective antibiotictherapy, while HCV-RNA was detected by sensi-tive PCR analyses in the same tissue lesions. Ofnote, HCV localization in the cytoplasm of theresidual glandular epithelium was shown by insitu studies within the lymphomatous lesion, withno substantial differences in staining intensity ifcompared to results obtained in chronic gastritisin HCV-positive individuals. Frequently, positivecells could be observed within the centre andthe invasion front of the tumour, and positiveresidual glandular cells were found within thehomogeneously HCV-negative lymphoma cells.Of note, sequence analyses of the immunoglobulinrearranged genes of the neoplastic B-cell clonein the gastric lymphoma sample obtained afterH. pylori eradication still showed the presenceof intraclonal heterogeneity, indicating thepersistence of antigenic stimulation in the gastricmucosa (De Vita et al., 2000b). This also arguesagainst a fully deregulated B-cell neoplastic pro-liferation.

Lastly, gastric B-cell lymphoproliferation inHCV-related Sjogren’s syndrome and in MCsyndrome showed significant deduced amino acidsequence homology both with immunoglobulinsequences encoding for rheumatoid factors (RF)and with sequences encoding for anti-HCV anti-bodies, i.e., antibodies related to HCV infection(De Vita et al., 2000a, b; De Re et al., 2000). Theseearly results led to subsequent studies by ourgroup that better explained a relevant mechanismby which HCV infection may preferentially favourthe proliferation of RF-positive B-cell clones, i.e.,HCV linking to RF B-cell receptor itself (De Reet al., 2006).

For what concerns the acquisition of gastricMALT and vasculitis in HCV-unrelated MCsyndrome and Sjogren’s syndrome, it should be

noticed that among the many extraglandularfeatures that may be observed in the course ofSjogren’s syndrome, MC occurs in a minorityof cases (Tzioufas et al., 1996; De Vita et al., 2001),but has been consistently associated with the deve-lopment of a B-cell lymphoma (Tzioufas et al.,1996), which is in turn a well-known complica-tion in MC syndrome secondary to HCV infection.

By integrated clinical, pathologic and molecularstudies, we recently highlighted that MC has adifferent biologic background in Sjogren’s syn-drome if compared to chronic HCV infection(De Vita, S., personal presentation and manuscriptin preparation). MC is polyclonal in the bonemarrow and is associated with salivary MALTlymphoma in SS, consistent with the primary roleof salivary MALT chronic inflammation andlymphoproliferation as a predisposing factor tolymphoma in this disease, which is rarely asso-ciated with HCV infection. By contrast, MC in thecourse of HCV infection is primarilly a liver andbone marrow autoimmune and lymphoprolifera-tive disorder, and malignant lymphoprolifera-tion of salivary MALT is rarer in this setting.Overlapping features of Sjogren’s syndrome andMC vasculitis may however occur in HCV-positivepatients. Interestingly, as reported above, abnor-mal acquisition of gastric MALT may occur bothin Sjogren’s syndrome and in MC syndrome. Thus,the study of the gastric microenvironment, inconjunction with that of the bone marrow, liverand salivary glands, may be relevant for futureresearch aimed to clarify the mechanisms leadingto preferential RF-positive B-cell expansion inthese diseases, and, in general, to better explain thevarious components of gastric lymphomagenesis.The therapeutic value of targeting the local triggerof chronic inflammation, autoimmunity andlymphoproliferation versus other biologic targetsshould be better explored as well (Quartuccioet al., 2006; De Vita and Quartuccio, 2006).

Besides local antigenic stimulation, the mecha-nisms by which HCV infection and other localtriggers may favour gastric acquisition of MALTand, more generally, chronic inflammation andB-cell expansion, remain elusive. With regard tothis issue, local cytokine networks are likelyimplicated. Recent results pointed out the role of


HCV infection in upregulating the expression ofBAFF (Fabris et al., 2007), a relevant growthfactor implicated in autoimmunity and B-celllymphoproliferation.

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CHAPTER 9

Mixed Connective Tissue Disease

Juanita Romero-Dıaz, Jorge Sanchez-Guerrero�

Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador

Zubiran, Mexico City, Mexico

Mixed connective tissue disease (MCTD) was firstdescribed in 1972 by Sharp et al. as a disease withoverlapping features of systemic lupus erythemato-sus, systemic sclerosis, and polymyositis associatedwith high titers of hemagglutinating antibody to theribonuclease sensitive component (RNP-ribonucleo-protein) of extractable nuclear antigen (ENA). Thecombination of these features may occur simulta-neously or in sequence (Piirainen and Kurki, 1990),and the diagnosis is based on clinical, pathological,and serological criteria. Three sets of criteria for theclassification and diagnosis of MCTD have beenproposed with a high correlation among them(Alarcon-Segovia and Cardiel, 1989a, b).

Recognition of gastrointestinal manifestation inpatients with MCTD is important because theymay have special diagnostic, therapeutic, andprognostic implications that require considerationfor appropriate management (Pope, 2005). For along time, this entity had not gained widespreadrecognition despite having distinct clinical, serolo-gical, and immunoregulatory profiles (Alarcon-Segovia and Cardiel, 1991; Sharp, 2002; Vanables,2006). This may explain the scarcity of studiesfocused on clinical manifestations, particularlygastrointestinal in MCTD patients.

The initial descriptions of the disease included asone of its main clinical characteristics an abnormalesophageal motility, similar to that found in

scleroderma; however, a notable difference withscleroderma esophageal dismotility is the potentialbenefit of corticosteroids in MCTD (Burdt et al.,1999). Subsequent studies included descriptionsof sialoadenitis, malabsorption, colonic, andsmall bowel perforations due to vasculitis, chronicactive hepatitis, acute pancreatitis, protein-loosingenteropathy, and acute pneumatosis intestinalis(PI), reflecting that any area of the gastrointestinaltract may be affected in MCTD. On the otherhand, some gastrointestinal manifestations mayovershadow other aspects of the disease, becausethey may derive from complications of the initialsymptoms or adverse effects of medication (e.g.,esophageal structure).

1. Are gastrointestinal features a common

manifestation of mixed connective tissue

disease?

Involvement of the gastrointestinal tract has beenreported in most of the rheumatic diseases.Concerning MCTD, radiological evidence ofesophageal dysmotility has been recognized as afeature in more than 50% of the patients. Thefollow-up period, important in a disease withmanifestations that tend to drift over time, and thesensitivity of the different tests used vary con-siderably from report to report, contributing to thevariation of the clinical manifestations (Table 1).

Gastrointestinal symptoms are common, affect-ing 66–74% of the patients (Burdt, Marshall, andE-mail address: [email protected]


Tel.: +5487-0900 x 2600 y 2601; Fax: +56-55-10-76


DOI: 10.1016/S1571-5078(07)00009-8

dx.doi.org/10.1016/S1571-5078(07)00009-8.3d

Doria). The most frequently reported, heartburnin 48% and dysphagia in 38% of the patients,result from esophageal involvement (Table 2).

A review of 80 patients from our departmentrevealed a high frequency of diarrhea (36%) andmalabsorption (20%), and in two patients occlu-sive episodes were observed (Alarcon-Segovia andCardiel, 1989a, b).

2. Oral manifestations

As in other connective tissue disease, Sjogren’ssyndrome may be present in MCTD. According to

Alarcon-Segovia (1976), 12 out of 25 patients withMCTD had xerostomia and/or ocular symptomsof keratoconjunctivitis sicca. Setty et al. (2002)determined longitudinally the prevalence ofclinical and serological features of Sjogren’ssyndrome in a cohort of MCTD patients. Thisstudy summarized the clinical and serologicalfeatures of 55 patients followed during 30 yearswho fulfilled criteria for MCTD of whom 23(42%) had sicca symptoms; no association wasfound with anti-SSA/Ro antibodies.

From 19 patients with MCTD, 17 had focalsialoadenitis determined on clinical manifesta-tions, unstimulated and stimulated whole saliva,and minor salivary gland biopsy. Sixty-one percent

Table 1

Cumulative gastrointestinal findings according to length of disease evolutiona

Reference Esophageal dysmotility

At onset At diagnosis Cumulative (years of follow-up)

Burdt et al. (1999) 9 47 66 (15)

Sharp et al. (1972); Nimelstein et al. (1980) 57 – 43 (8)b

Tiddens et al. (1993) – – 100 (9.3)

a The values are presented as percentage of patients.b In this study, evidence of esophageal dysmotility was slightly less frequent. The authors thought that this might be explained by lack

of radiographic or manometric studies on reevaluation.

Table 2

Gastrointestinal symptoms in patients with mixed connective tissue disease

Features Gutierrez et al.

(1982)

Marshall et al.

(1990)

Doria et al.

(1991)

Tiddens et al.

(1993)

Number of patients 17 61 21 14b

Mean of follow-up (years) 8 6.3 7.7 9.3

Dysphagia (%) 53 38 19 40

Heartburn or regurgitation 59 48 23.8 20

Dyspepsia 65 20 – –

Vomiting – 2 – –

Esophageal dysmotility (abnormal esophageal

manometry)

91a 60 85 100

Diarrhea – 5 – –

Constipation – 3 – –

Malabsorption – –

Other conditions

Pancreatitis – 1 – –

Chronic active hepatitis – 1 – –

Spontaneous perforations associated with vasculitis – 1 – –

a Ten of 11 patients studied had abnormal results.b Patients with juvenile onset of MCTD.

J. Romero-Dıaz, J. Sanchez-Guerrero102

had decreased salivary secretion and 74% had oralsymptoms. The mean duration of the disease at thestudy was 10.6 years and only 11 (58%) patientshad positive anti-RNP autoantibodies (Heleniuset al., 2001).

Konttinen and colleagues (1990) described thesigns and symptoms in the masticatory system. Allthe 10 patients with MCTD included showedclinical dysfunction, and 7 had additional radio-graphic changes of the temporomandibular joints.Sialopenia was observed in 70% of the patients andsialoadenitis with a focus score >1 in the labialsalivary gland biopsy of nine patients. Only onepatient had clinically detectable mucosal lesion. In83% of patients with normal appearing mucosa,histological examination revealed chronic inflam-mation. The authors concluded that as it occurs inother connective tissue disease, MCTD patientsshould be treated on a multidisciplinary basis(Alfaro-Giner et al., 1992).

3. Esophageal dysfunction

Despite the heterogeneity of the rheumatic diseasesin terms of symptoms and prognosis, most of themshare some gastrointestinal manifestations.According to these observations, several investiga-tors have thought that the features in MCTD aresimilar to those found in scleroderma but of milderdegree. Nonetheless, it is clear that esophagealdysfunction is a much more common feature inscleroderma and MCTD than in the other con-nective tissue disease (92 and 88%, respectively)(Marshall et al., 1990). The motor disordersaffecting the esophagus are found not only insystemic sclerosis, but also in systemic lupus

erythematosus and other connective tissue diseases.The simultaneous involvement of the esophagealbody and the lower esophageal sphincter (LES) isdiscriminant between scleroderma, MCTD, poly-myositis and undifferentiated connective tissuedisease, and SLE (Lapadula et al., 1994; Kotajimaet al., 1996).

A study of esophageal motility in 37 patientswith progressive systemic sclerosis, 12 patients withMCTD, and 40 healthy controls without rheuma-tologic symptoms reported that MCTD patientswere similar to PSS patients. Half of the MCTDpatients had dysphagia, four patients had abnor-mal motility, and in only two patients motility wasnormal. LES pressure was low in seven patients,and in only one patient the pressure was similar tothat of the controls. Involvement of the upperesophagus was unusual (Dantas et al., 1985).

Manometry and radiological examinations havealso been used to evaluate the esophageal disorders.Lapadula and colleagues studied the performanceof these methods in the evaluation of esophagealmotility; their data showed a higher sensitivity ofesophageal manometry (EM) over the usual radio-graphic examination of the esophagus (ERE)—72.7vs. 40.7. Manometry was able to detect earlymotility disorders, such as a lower LES pressureand reductions in peristaltic waves amplitude,which are difficult to recognize by ERE (Table 3).

Dinsmore et al. (1966) described the presence ofair on conventional chest roentgenograms withinthe intrathoracic portion of the esophagus in 12out of 16 patients with systemic sclerosis, propos-ing that an air esophagogram is strongly suggestiveof systemic sclerosis. In 1998, Lock et al. assessedsystematically the diagnostic significance of an airesophagogram in 51 patients with connective tissuediseases and esophageal involvement, and 47

Table 3

Esophageal involvement studied by esophageal radiographic examination (ERE) and esophageal manometry (EM)

Reference Patients with abnormal ERE (%) Patients with abnormal EM (%)

Lapadula et al. (1994) 70.6 88.2

Lock et al. (1998) 31.4 45.1

Stacher et al. (2000) – 83.3

Doria et al. (1991) – 71

Gutierrez et al. (1982) – 94

Mixed Connective Tissue Disease 103

controls by comparing the findings in chestroentgenogram with EM as the gold standard ofesophageal motility testing. The presence of air inone or more esophageal segments had a sensitivityof 52% and a specificity of 68% for esophagealdysfunction compared to EM. They concludedthat the radiological sign of air in the esophago-gram is neither sensitive nor specific enough toomit esophageal motility studies in patients withconnective tissue diseases.

Regarding the pathophysiology of esophagealdysmotility, Stevens and colleagues (1994) demon-strated the association between Raynaud’s phe-nomenon (RP) and aperistalsis, suggesting that theesophageal dysfunction may result from anabnormality of the autonomous nervous system,rather than sclerosis of the esophagus. On thecontrary, Lapadula et al.’s (1994) study did notdemonstrate a consistent correlation betweenesophageal motility disorders and RP in 150patients evaluated, suggesting that esophagealdysfunction and RP do not have the sameneurogenic origin. They proposed that RP con-stitutes a parallel but independent phenomenon.

4. Bowel manifestations

PI, an uncommon manifestation in scleroderma,has also been reported in patients with MCTD.These reports included patients between 18 and 77years of age and variable length of the disease(Lynn et al., 1984; Gessner et al., 2001; Essalahand Eddy, 1999; Wakamatsu et al., 1995; Gouletet al., 1988; Samach et al., 1978).

In patients with systemic lupus erythematosus,PI is thought to result from isquemic necrosis ofthe bowel wall due to vasculitis; however, insystemic sclerosis and MCTD, the mechanism ofthis manifestation is poorly understood. It isthought that an increase of the intraluminalpressure allows the passing of air within theintestinal wall. The usual clinical manifestationsare abdominal pain and diarrhea, but patients canalso be asymptomatic. Radiographs show acollection of air within the intestinal wall thatdelineates it longitudinally and intraperitoneal air

can also be seen. The authors concluded that PIshould be suspected in those patients known tohave systemic sclerosis-type involvement of theesophagus and the small bowel, and who presentwith abdominal distension. It may not only occurearly in the course of the disease and resolverapidly through medical intervention, but also hasbeen associated with poor survival. No surgicaltreatment is recommended unless the condition iscomplicated by perforation.

Malabsorption is another symptom observed inscleroderma and less frequent in MCTD. Some-times it may constitute a major managementproblem; several mechanisms have been proposedfor its occurrence, but intestinal stasis with second-ary bacterial overgrowth appears to be the mainfactor (Alarcon-Segovia and Cardiel, 1989a, b).

Protein-loosing enteropathy is a rare manifesta-tion, and there is only one case report of thiscondition associated to MCTD (Nosho et al.,1998). Protein-loosing enteropathy should besuspected when diarrhea and severe hypoalbumi-nemia without proteinuria are found. Histologicalfindings include atrophy of villi, polymorpho-nuclear infiltrate, and edema of the submucosa inthe absence of vasculitis. The increased protein lossfrom the bowel can be documented by an increaseof fecal excretion with intravenous radiolabeledalbumin. Diagnosis is important because mostpatients improve with corticosteroids therapy.

Megacolon is another rare manifestationand is typically manifested radiografically aswide-mouthed diverticular saculations. Symptomssecondary to this complication are rare butoccasionally serious, such as impactation ofbarium or feces (Ferreiro et al., 1986).

Spontaneous perforation associated with vascu-litis has also been reported. The gastrointestinalbleeding may be due to fibrinoid necrosis of bloodvessels of the small and large intestine (Cooke andLurie, 1977; Hirose et al., 1993).

5. Other conditions

In the group of MCTD patients described byMarshall et al. (1990), only one of them had


identifiable pancreatic disease with subsequentpseudocyst and abscess formation. MCTD waspresumed to be the cause of the pancreatitis,although a medication-related etiology could notbe completely excluded. Also, one patient withchronic active hepatitis is the only instance ofclinically significant liver disease in the same seriesof patients.

6. Therapeutic considerations

In contrast to scleroderma, esophageal dysfunc-tion was noted to improve following corticosteroidtherapy in MCTD patients (Lundberg, 2005). Theresults from manometry studies carried out in 10patients before and after treatment suggest thatesophageal dysfunction in MCTD may be respon-sive to corticosteroids. These patients had receiveda mean of 67wk of steroid therapy (range44–154wk) at the time when the follow-upmanometry was performed. Initially, most of thepatients received 1mg/kg of prednisone and theaverage dose during the course of their treatmentwas 25mg/day. The improvement in the LESpressure was statistically significant (po0.05). Nodifferences in distal and proximal esophagealperistaltic pressures were found; however, animprovement in upper esophageal sphincter hypo-tension and a reduction in the frequencyof associated aspiration events were observed(Marshall et al., 1990). Similar results were notdemonstrated by Gutierrez et al. (1982). Theystudied 14 MCTD patients who had receivedsteroids for a mean of 6.9 years (range 1–11 years),and esophageal peristalsis was abnormal in all ofthem; however, this study did not include anevaluation before the corticosteroid treatment.Probably the two series included patients withdifferent degrees of severity of the disease, andprobably in patients with less severe diseaseand predominantly inflammatory reaction in theesophageal muscles, steroids may reverse theinflammatory reaction, while in patients withfibrosis this response is not possible.

According to these results, a course of steroidtherapy (15–30mg/day) may be considered in

some cases of esophageal dysfunction that arerefractory to conventional treatment and have ashort disease evolution.

The conventional treatment consists of proton-pump inhibitors, H2 receptor antagonists, anta-cids, and lifestyle modifications. Esophageal pHmonitoring in patients who have persistent refluxsymptoms to determine if high-dose therapy isneeded, endoscopic dilatations in severe cases ofdysphagia related to structures, and fluids, fiber,and exercise in some cases of constipation shouldbe considered. Severe manifestations such aspseudo-obstruction and PI may require hospitali-zation for bowel rest (Kim and Grossman, 2005).A surgical approach is not recommended since it isassociated to a bad prognosis.

In some MCTD patients with diarrhea, the causeof this symptom may be unclear and symptomatictreatment may be indicated. Patients with malab-sorption may require cyclic broad-spectrum anti-biotic treatment to control colonic bacterialovergrowth (Alarcon-Segovia and Cardiel, 1991).

Among 62 patients (46 systemic sclerosis, 8MCTD, and 8 polymyositis and systemic sclerosisoverlap), 12 (19%) required total parenteral orenteral nutrition. This may reflect severe gastric orintestinal involvement in systemic sclerosis andrelated disorders; however, the possibility oftertiary referral bias because the patients needednutritional support may partially explain theseresults (Weston et al., 1998).

7. Discussion

According to the information available, almostany segment of the gastrointestinal tract can beinvolved in patients with MCTD, particularly theesophagus. Up to now, few studies have evaluatedthe gastrointestinal manifestations in this disease.Unfortunately, the few studies available differ insome characteristics that may influence the resultsas follows: number of patients included, length ofdisease duration, diagnostic criteria used, etc.

Proof of this is that the largest study (Marshallet al., 1990), which included 61 patients, is the onewhere rare gastrointestinal manifestations such as


pancreatitis, chronic active hepatitis, andspontaneous perforations due to vasculitis weredescribed. The single study that assessed gastro-intestinal manifestations at varying periods ofdisease evolution showed the variability in theirprevalence (Burdt et al., 1999). Also, although thefour sets of criteria available (Sharp, 1987;Kasukawa et al., 1987; Alarcon-Segovia andVillarreal, 1987; Kahn and Appeboom, 1991criteria) identify most, MCTD patients, in 80MCTD patients evaluated in our department, theformer three sets of criteria ruled out MCTDin most patients with other connective tissuedisease except the criteria for possible MCTDincluded as part of Sharp’s set of criteria thatidentified as such 10 patients with SLE, 36 withscleroderma, 13 with polymyositis/dermatomyositis,and 2 with Sjogren’s syndrome (Alarcon-Segoviaand Cardiel, 1989a, b).

8. Summary

Gastrointestinal manifestations in patients withMCTD are frequent, especially those related toesophageal symptoms due to dysmotility describedas hypomotility or aperistalsis. The most affectedstructures are two-thirds of the esophageal bodyand the LES, as it is seen with high frequency insystemic sclerosis (Marshall et al., 1990).

Autoimmune hepatitis, pancreatitis, and gastro-intestinal vasculitis have been reported. Somepatients with PI and protein-loosing enteropathyhave also been informed.

To evaluate esophageal dysfunction, manometryis a more sensitive and specific test than chestX-ray.

The initial therapeutic approach includes con-ventional treatments such as proton-pump inhibi-tors, H2 receptor antagonists, antacids, lifestylemodifications, and esophageal pH monitoring inpatients who have persistent reflux symptoms. Acourse of steroid therapy (15–30mg/day) may beconsidered in some cases of esophageal dysfunc-tion that are refractory to conventional treatmentand have a short-time disease evolution.

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CHAPTER 10

Gastrointestinal Manifestations of Rheumatoid Arthritis

John M. Cafardia, Herbert Rakatanskyb, Graciela S. Alarcona,�aDepartment of Medicine, Division of Clinical Immunology and Rheumatology, 510 20th Street South,

FOT 830, The University of Alabama at Birmingham, Birmingham, AL 35294, USAbDepartment of Medicine, Division of Gastroenterology, Warren Alpert School of Medicine,

Brown University Providence, Rhode Island, USA

In this review, the gastrointestinal (GI) pathologyand associated clinical manifestations in patientswith rheumatoid arthritis (RA) will be examined(Sales, 1970). First, some manifestations describedas a direct result of RA will be discussed; this willbe followed by the GI manifestations that com-monly occur as a complication of RA therapy.Finally, diseases that can mimic the presentationof RA in the GI system will be covered. Thisoutline is depicted in Table 1.

1. Manifestations directly due

to rheumatoid arthritis

RA is a chronic, systemic, and progressiveinflammatory condition, mediated by self-reactiveT and B lymphocytes. RA occurs worldwide andaffects approximately 1% of the North Americanand European population (Firestein, 2005; Alamanosand Drosos, 2005; Edwards and Cambridge, 2006;Martinez-Gamboa et al., 2006). It is characterizedby inflammation of the synovium and surroundingstructures, which may lead to significant jointdestruction. The disease is not limited to the joints,however; there are many non-articular complica-tions that are also mediated by the inflammatory

process (O’Dell, 2004; Muller-Ladner et al., 2005;Huber et al., 2006). RA leads to a predominance ofthe CD4+ T-helper lymphocyte subset 1 (TH1)-typeimmune response, with most cytokines secretedfrom this class type, i.e. TNF-a, IFN-g, and IL-1(Choy and Panayi, 2001; Smith and Haynes, 2002).

Systemic manifestations of RA such as rheuma-toid vasculitis and Felty’s syndrome are understoodnow to originate from progressive inflammation,such as that of large and small vessels. Sustainedarticular and extra-articular inflammation may befollowed by premature or accelerated atherosclero-sis. In turn, accelerated atherosclerosis leads to anincreased morbidity and mortality from cardiovas-cular and cerebrovascular disease (Roman et al.,2006; Kremers and Gabriel, 2006; Gonzalez-Gayet al., 2005). Other GI manifestations such asamyloidosis, secondary Sjogren’s syndrome, andliver dysfunction are also present in RA, but theexact pathophysiology is poorly understood(Editorial, 1973; Fleming et al., 1976; Turesson andJacobsson, 2004). An overview of GI disease in RAand its pathophysiology can be found in Table 2.

Rheumatoid vasculitis, though observed lessfrequently at this time than in the past, is a non-articular manifestation of RA in which micro-vascular lesions develop throughout the bodyand the GI tract, predominating in the smallbowel (Schneider et al., 2006). It can present asupper or lower GI bleeding, ulceration, ischemiaor infarction, or intestinal perforation (BabianE-mail address: [email protected]


Tel.: 205-934-2799; Fax: 205-934-4602


DOI: 10.1016/S1571-5078(07)00010-4

dx.doi.org/10.1016/S1571-5078(07)00010-4.3d

et al., 1998; Achkar et al., 1995). Rheumatoidvasculitis, whether involving the GI tract or not, isnot a common presentation of RA; instead, it isfrequently associated with a protracted course anda long history of erosive arthritis (Voskuyl et al.,1993). It is less frequent in patients who have hadearlier or more intensive therapeutic interventions;flares of rheumatoid vasculitis, however, tend toaccompany a more quiescent phase of articulardisease (Cruickshank, 1954; Glass et al., 1976).

Felty’s syndrome is a recognized complication ofRA. The syndrome’s triad consists of spleno-megaly, leucopenia in the setting of seropositive,and nodular and destructive RA (Balint and Balint,2004). As with rheumatoid vasculitis, it is rarelyseen nowadays. Portal hypertension with gastro-esophageal varices (DeCoux and Achord, 1980;Reisman et al., 1977) and hepatic fibrotic disease(Thorne et al., 1982) such as nodular regenerativehyperplasia (Cohen et al., 1982) can occur assecondary manifestations of this rare syndrome.

Secondary amlyoidosis usually occurs in thesetting of chronic inflammatory conditions such asRA, which leads to the progressive deposition of

protein fibrils of serum amyloid A (SAA) (Falket al., 1997). These fibrils are deposited throughoutthe body, but have the most obvious clinicalconsequences when deposited in renal, GI, orcardiac tissues (Cunnane and Whitehead, 1999;Cunnane, 2001). The distribution of secondaryamyloidosis in the context of RA varies world-wide; the majority of cases have been described notin North America or Europe, but rather in otherparts of the world such as Central and East Asia(Shimoyama et al., 2003; Alishiri et al., 2006).Secondary amyloidosis of the GI tract may havedifferent clinical presentations such as localizedulcerations, achalasia-type dysmotility, or a pro-tein-wasting enteropathy (Schneider et al., 2006).

Although Sjogren’s syndrome is more com-monly recognized in its primary form, it can alsooccur secondary to a pre-existing auto-immunedisease, and it is likely that 13 of the 19 patientsthat Sjogren included in his original case-seriesdefinition had secondary disease due to RA (Fox,2005). Primary or secondary Sjogren’s syndromeinvolves lymphocytic infiltration and damage ofexocrine glands; it has classically been recognizedas involving the ocular and salivary glands butGI, cutaneous, renal, vascular, neurologic, andrespiratory involvement is also well documented(Mavragani et al., 2006). Pancreatic exocrinedeficiency has been noted, but is an uncommoncomplication (Kauppi et al., 2001). Severe siccamanifestations may be observed with secondarySjogren’s syndrome, leading to problems with deg-lutition and overall patient comfort (Moutsopouloset al., 1980), while both Sjogren’s-associated andprimary-RA-associated esophageal disease can

Table 1

The gastrointestinal system in rheumatoid arthritis (RA):

chapter outline

Mechanisms of injury in the GI tract

Secondary syndromes and how they can injure the GI tract:

Amyloidosis

Sjogren’s Syndrome

Felty’s Syndrome

GI toxicities of medications used to treat RA

Mimics of GI-RA involvement

Table 2

Secondary GI syndromes in RA: manifestations and pathogenesis

Disease manifestation Pathogenesis

Ulceration of the stomach (peptic ulcer disease), small intestine

and colon, with perforation as a possible sequela

Luminal injury as a result of drug toxicity, such as NSAIDs or

glucocorticoids, or as a consequence of rheumatoid vasculitis

Dysmotility of the esophagus and lower esophageal sphincter Secondary Sjogren’s syndrome

Chronic diarrhea and protein-wasting enteropathy Secondary amyloidosis (SAA) of the small intestine

Hepatic disease––nodular regenerative hyperplasia Felty’s syndrome

Pancreatic exocrine insufficiency and sicca syndrome Secondary Sjogren’s syndrome

J.M. Cafardi et al.110

range from primary dysmotility to lower-esophagealsphincter dysfunction (Bassotti et al., 1988; Volteret al., 2004).

Primary RA hepatotoxicity, unrelated to anytherapeutic intervention, has been noted moreoften in past years rather than in the currentliterature. It was often described as a functionalpathology, with steatosis and evidence of hepato-cellular degeneration and elevated serum transa-minase levels, with some cases progressing toimpaired synthetic function (Sullivan et al., 1978;Lefkovits and Farrow, 1955; Whaley et al., 1970).Overall, such cases are seen less frequently now,with therapeutic interventions currently occurringearlier in the course of the disease.

2. Gastrointestinal disease resulting

from rheumatoid arthritis therapeutics

Both glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs) are frequently usedin the management of inflammation and thesymptoms associated with it, pain in particular.Although these drugs are useful for analgesia andimprovement of function in cases of significantsynovitis, NSAIDs have a limited role in alteringthe course of the disease whereas low-doseglucocorticoids have been recognized to have asignificant disease-modifying effect (Kirwan,1995). Both glucocorticoids and NSAIDs can leadto significant GI toxicity.

GI toxicity in the NSAID-treated patient is aserious problem, with the risk of serious GIcomplications estimated in one study at 13 per1000 RA patients treated with these drugs (Singhand Triadafilopoulos, 1999). Of the subset ofpatients who are hospitalized with upper GIbleeding, secondary to NSAID ulceration, morta-lity is calculated at 5.6% (Lanas et al., 2005). Anestimated 16,500 deaths have occurred each year inNorth America, secondary to GI toxicity since themid-1990s (Singh, 1998).

NSAIDs act through either the selective (iso-enzyme 2) or the non-selective (iso-enzymes 1 and 2)inhibition of cyclooxygenase (COX), leading toeither a total inhibition of synthesis of prostanoids

(PGD2, PGE2, PGH2, PGI2, and TxA2) withthe non-selective COX inhibitors or a selectivedecrement in PGE2 with the COX-2 inhibitors(Steinmeyer, 2000). Although it was originallybelieved that this selective inhibition would lead toequal analgesic efficacy and reduced risk for gastrictoxicity, this original model has been challenged byclinical trial results showing little to no improvementin the rates of gastric ulceration, an increase in therates of cardiovascular complications, compared tonon-selective COX inhibitors, and a loss of any GIprotective effects if concurrent aspirin therapy isused (Psaty and Furberg, 2005; Drazen, 2005;Garcia Rodriguez and Barreales Tolosa, 2007).

The mechanism for the GI toxicity of bothselective and non-selective NSAIDs is incomple-tely understood, but there is consensus on the basicprinciples. In the inhibition of the eicosanoidprecursors transformed into prostaglandins (theend products of the arachadonic acid pathway),the protective prostaglandin––PGI2––amongothers inhibited, is thought to be inhibited by onlynon-selective NSAIDs, while the pro-inflamma-tory prostaglandin PGE2 is inhibited by both.Additionally, inhibition of the COX enzymesappears to have an as-yet-uncharacterized effecton wound healing that prevents already developedulcers from healing (Newberry et al., 1999).Overall, treatment with NSAIDs increases the riskof developing gastritis and peptic ulcer disease,with the subsequent risks of bleeding and perfora-tion (Wolfe et al., 1999; Raskin, 1999), asmentioned above.

Glucocorticoids have multiple, complex mecha-nisms of action, but are currently understood toact at both the transcriptional level (NF-kB) andthrough protein–protein inhibitory interactionssuch as IkB-NF-kB and functional inactivationof cytosolic phospholipase A2 (cPlA2). All of theseprocesses lead to decrease in the production ofpro-inflammatory cytokines and consequentlyreduction of inflammation (Rhen and Cidlowski,2005). Additionally, glucocorticoids are associatedwith gastritis, peptic ulcer disease, and GI bleed-ing, although not to the same degree as NSAIDs(Messer et al., 1983).

Methotrexate is a disease-modifying anti-rheumatic drug (DMARD), which is frequently

Gastrointestinal Manifestations of Rheumatoid Arthritis 111

prescribed as initial therapy for RA. The mecha-nism of methotrexate is irreversible inhibitionof dihydrofolate reductase (DHFR), preventingthe formation of reduced folate metabolitesand inhibiting the de novo synthesis of purines(Cronstein, 1996, 1997; Furst, 1997). The thera-peutic value of methotrexate, however, is oftenhampered by its various systemic toxicities; we willdiscuss the hepatic toxicity here. Other drug-related toxicities, including pulmonary fibrosis andhematopoietic abnormalities, while not discussedhere are understood to have as a common under-lying mechanism the intracellular accumulationof polyglutaminated methotrexate aggregates(Chabner et al., 1985). Specific methotrexatehepatotoxicity can result in histological patternsincluding steatosis, stellate cell hypertrophy, ani-sonucleosis, and hepatic fibrosis (West, 1997;Farrell, 1997). Exposure to other hepatotoxic drugs,alcohol, and intercurrent hepatic infections canincrease the risk of methotrexate liver damage,although the risk for cirrhosis resulting frommethotrexate is small (Kremer et al., 1989;Richard et al., 2000). The American College ofRheumatology has published guidelines for themonitoring of patients with RA receiving metho-trexate therapy that are designed to minimize therisk of toxicity (Kremer et al., 1994).

A newer and less commonly used DMARD isleflunomide, the inactive oral prodrug of the activemetabolite A77-1726 (Fox et al., 1999). A77-1726acts as a non-competitive inhibitor of dihydro-orotate dehydrogenase, thus inhibiting the de novosynthesis of pyrimidines (Herrmann et al., 2000;Sanders and Harisdangkul, 2002). It is brought toattention here because of concerns of hepatotoxi-city. The European Union Medicines ControlAgency (EUMCA) undertook a study of lefluno-mide hepatotoxicity and found 296 total and 129serious events among patients taking leflunomideover 104,000 patient-years. Of those 129 seriousevents, 101 (78%) occurred in patients who weretaking ‘other hepatotoxic medications’ (not speci-fically defined). Among the conclusions reachedwas that although confounding factors exist, acausal relationship could not be excluded, and theuse of leflunomide in patients with pre-existingliver disease was contraindicated. Additionally, the

use of this agent with other potentially hepatotoxicmedicines is discouraged, and the commissionurges its use to be restricted to experiencedspecialists (Products EAftEoM, 2001). The vastmajority of patients who had presumed lefluno-mide-associated hepatotoxicity had previouslyreceived hepatotoxic regimens, including metho-trexate. As such, the biochemical and histologicalpatterns of injury that have been documented havebeen difficult to assign to this single agent. TheFood and Drug Administration and the profes-sional rheumatologic societies in North Americaand Europe have not endorsed these recommenda-tions and have not introduced a black box warningon this product.

The mechanism and side-effects of various RAtherapeutics modalities are summarized in Table 3.

3. Mimics of gastrointestinal disease

in rheumatoid arthritis

Although one of the most common associationsof bowel disease and inflammatory arthritis orspondylitis is found in inflammatory bowel dis-ease, it will not be discussed in this chapter becausethere is a separate chapter in this volume devotedentirely to this topic.

Reactive or post-infectious arthritis may have asimilar presentation to that of RA GI disease(Toivanen and Toivanen, 2000). Dysentery result-ing from infectious agents such as Yersinia

enterocolitica, Yersinia pseudotuberculosis, andChlamydophila spp. (formerly Chlamydia spp.) isassociated with reactive arthritis (Hannu et al.,2003, 2006; Taccetti et al., 1994). If the clinicaltimeline is uncertain, the bloody stools may beseen as a later part of the patients’ illness, ratherthan the precipitating event. Delineation of thepatient’s history can often determine if the under-lying issue is primarily GI or rheumatologic innature.

A more complicated, although admittedly rare,disease is Whipple’s disease; although first des-cribed over 70 years ago, it is still very difficult todiagnose. It consists of progressive wasting,chronic diarrhea, and polyarticular arthritis,


Table 3

GI toxicities of medications used to treat rheumatoid arthritis

Drug or drug class Mechanism Manifestations References

NSAIDs Differential inhibition of

cyclooxygenase isoforms;

downregulation of cytoprotective

prostaglandins and impaired

healing of mucosal ulcerations.

Development and progression of

gastric and enteric ulcers. An

enhanced likelihood of

progression to perforation with

frank hemorrhage or infection.

Armstrong and Blower (1987)

Singh (1998)

Newberry et al. (1999)

Wolfe et al. (1999)

Steinmeyer (2000)

Glucocorticoids Pleiotropic actions, including

indirect inhibition of the

transcription factor NF-kB,cytosolic phospholipase A2a(cPLA2a) and mitogen-activated

protein kinase (MAPK), through

several pathways. They are anti-

inflammatory/immunosuppressive.

Development and progression of

gastric and enteric ulcers.

Messer et al. (1983)

Kirwan (1995)

Methotrexate Polyglutamation of intracellular

methotrexate. Accumulation can

result in toxicity.

Hepatocellular steatosis, fibrosis,

and rarely, cirrhosis.

Chabner et al. (1985)

Gispen et al. (1987)

Kremer et al. (1989)

Sulfasalazine Potent inhibitor of the

transcription factor NF-kB, withresulting anti-inflammatory

actions.

Common nausea, vomiting and

diarrhea, with uncommon,

idiosyncratic hypersensitivity

hepatitis. Rechallenge must not

be attempted.

Box and Pullar (1997)

Smedegard and Bjork (1995)

Wahl et al. (1998)

Hydroxychloroquine Neutralization of acidic lysosomes;

modification of innate immune

response through TLR interaction.

Frequent GI disturbance due to

muscular contractions caused by

drugs; infrequent hepatocellular

damage, which may be worsened

in the setting of pre-existing viral

hepatitis.

Kyburz et al. (2006)

Gladman et al. (1998)

Scherbel et al. (1958)

Mok et al. (2000)

Gold saltsa Exact mechanism uncertain; it may

involve dissociation of antigen-

MHC complexes.

Gold preparations rarely cause

enterocolitis, with parenteral

preparations causing more severe

disease than enteral compounds.

Gold salts can also cause rare

cholestatic jaundice and

pancreatitis.

Fam et al. (1980)

Eisemann et al. (1989)

Conaghan and Brooks (1995)

d-Penicillaminea Exact mechanism uncertain; it may

involve interruption of

T-cell– antigen-presenting cell

interaction. It also complexes with

circulating IgM rheumatoid factor.

Nausea and vomiting are

common side-effects. Dysgeusia,

gingivostomatitis, and the

re-activation of pre-existing

ulcers are also a potential.

Stein et al. (1980)

Fries et al. (1993)

anti-TNF compounds Varies by agent; etanercept consists

of a soluble p75 TNFaR:Ig fusion

molecule that binds to and

inactivates free TNFa. Bothinfliximab and adalimumab are

mAb directed against TNFaR(p55 and p75). They differ in Fc and

route of administration. Infliximab

is human-murine chimeric and is

administered IV; adalimumab is a

human mAb and is administered

subcutaneous.

Etanercept has shown little

significant GI toxicity. Infliximab

has the risk of liver damage, with

several cases of idiosyncratic

hepatitis reported. Adalimumab

has shown potential to cause a

hypersensitivity reaction that can

affect the GI tract, with the liver

most commonly involved.

Menghini and Arora (2001)

Michel et al. (2003)

REMICADEs PI (Centocor,

2006)

HUMIRAs PI (Abbot

Laboratories, 2006)


followed by neurologic deterioration and, ifuntreated, death (Fenollar et al., 2007). Long-termtreatment with trimethoprim-sulfa appears to becurative, with little risk of a relapse. The etiologicorganism Tropheryma whipplei has only beenrecently identified, while seropositivity and car-riage of the organism appear to be frequent(O’Duffy et al., 1999). The prevalence of Whipple’sdisease has been reported as very low, with onlyapproximately 1000 cases reported to date and anautopsy prevalence of less than 0.1%. Due to thewide variability in symptoms, the large seroposi-tive or carrier population, and the difficulty inculturing the organism, the true prevalence of thedisease is unknown at this time. It is known thatmisdiagnosis of Whipple’s disease for RA andtreatment with corticosteroids can lead to anaccelerated course and progression of GI diseaseand a potentially fatal outcome (Mahnel et al.,2005).

4. Summary and conclusions

In summary, GI disease in RA can take on manyforms, although the primary cause of GI manifes-tations at this time is iatrogenic. Physicians shouldbe vigilant in their prescribing habits and carefullymonitor patients on NSAIDs and DMARDs.

In addition to this, healthcare providers shouldremain aware that RA is a chronic, multisystemicdisease that does not manifest itself only in thearticular surfaces. Bleeding, infarction, and per-foration from primarily affected bowel sites shouldbe considered on the differential diagnosis in thecare of patients with RA, while hepatotoxicity andesophageal varices and dysmotility can occureither directly as a result of RA or as manifesta-tions of rheumatic syndromes such as Felty’s andSjogren’s, secondary to RA.

Finally, it should be remembered that numerousdiseases affect the GI tract and articular surfacesin close temporal relationship, and a carefulhistory remains essential.

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PART III:

Autoimmune Liver Diseases





CHAPTER 11

Immunopathogenesis of Autoimmune Liver Damage

Albert J. Czaja�

Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW,

Rochester, MN 55905, USA

Autoimmune liver damage implies that an immuneattack has been misdirected against self (Czaja,2001). This loss of self-tolerance may reflectdeficiencies in the mechanisms by which immuno-cytes distinguish self-antigens from foreign anti-gens and perturbations in the regulatory networksthat influence immunocyte activation, differentia-tion, proliferation, and disposal (Czaja, 2002).The predisposing factors can be extrinsic to theindividual and represent indigenous environmen-tal, toxic or infectious agents that overwhelmself-tolerance by their absolute number or theirrepetitive stimulation (Vergani et al., 2002). Theymay also be intrinsic to the individual andrepresent genetic or hormonal predispositions thatfavor protracted or exaggerated immune responsesto the triggering antigen (Czaja et al., 1998).

Excess antigenic stimulation can relate to themagnitude of antigens with homologous epitopesthat bombard the individual, the frequency ofantigenic exposure, the responsiveness of theindividual to a given antigen, or any combinationof these factors (Czaja, 2001; Vergani et al., 2002).Multiple viruses and drugs have been implicated astriggers for autoimmune liver disease, and thesereports imply that diverse antigenic stimuli canproduce the same clinical result (Czaja, 2001).These diverse antigenic stimuli must have sharedpeptide sequences that stimulate immune reactivity(molecular mimicry) since the CD4 and CD8 T

lymphocytes implicated in the pathogenesis ofautoimmune liver disease possess few antigenrecognition sites (Ichiki et al., 2005). The frequentconcurrence of other autoimmune manifestationsin patients with autoimmune liver disease alsosuggests that the antigen recognition sites on theactivated immunocytes are imprecise (Czaja, 2001;Vergani et al., 2002). This imprecision can extendthe range of targets to tissues anatomicallydifferent and distant from the liver (promiscuousactivity) (Vergani et al., 2002; Doherty et al.,1998). The key epitope triggering autoimmuneliver disease is likely to be a commonly shared,easily mimicked amino acid sequence that canactivate immunocytes with promiscuous activity(Czaja, 2001). The long time lag between the onsetof the disease and its clinical detection can obscurethe initiating event.

Host-dependent, rather than disease-specific,factors may also override self-tolerance (Czajaand Donaldson, 2000). Genetic predisposition maynaturally select individuals from the generalpopulation and favor the development of disease.Genetic risk factors for autoimmune hepatitis(Donaldson et al., 1991; Strettell et al., 1997),primary biliary cirrhosis (PBC) (Gores et al., 1987;Manns et al., 1991a, b; Onishi et al., 1994; Jonesand Donaldson, 2003; Donaldson et al., 2006), andprimary sclerosing cholangitis (PSC) (Donaldsonand Norris, 2001, 2002) have been described,and certain genetic factors may also offer protec-tion from these diseases (Doherty et al., 1994;Strettell et al., 1997; Donaldson and Norris,2002; Donaldson et al., 2006). Autoimmune liverE-mail address: [email protected]


Tel.: +507-284-8118; Fax: +507-284-0538


DOI: 10.1016/S1571-5078(07)00011-6

dx.doi.org/10.1016/S1571-5078(07)00011-6.3d

diseases are polygenic disorders, and complexalterations in the counter-regulatory networksof immune activation that are based on geneticfactors or gender differences may create a complexmilieu that promotes or prevents these diseases(Donaldson, 1996, 2002, 2004; Donaldson andCzaja, 2002). In this context, the components ofthe milieu may vary greatly between individualsdespite producing the same clinical consequence.Single disturbances in a highly coordinated,interactive immune system may change order tochaos, and the ability of subtle effects to bemagnified into a disease state may explain thedifficulty in identifying the core defect in auto-immune liver disease.

In this review, the multi-factorial nature ofautoimmune liver disease is emphasized, and thevarious theoretical bases for its occurrence arepresented. Disturbances in antigen recognition,deficiencies in the regulatory networks that controlimmune reactivity, and differences in the geneticand gender predispositions for autoimmune liverdisease are discussed. These diverse factors areinteractive and the degree of their involvement canvary among individuals and modify the clinicalexpression and behavior of the disease.

1. Disturbances in antigen recognition

The limited number of antigen recognition sitesin CD4 and CD8 T lymphocytes suggests thatautoimmune liver disease can be triggered by onlya few antigens or that the triggering antigenicsequence is shared by multiple peptides (molecularmimicry) (Vergani et al., 2002; Ichiki et al., 2005).Furthermore, the diversity of immune manifesta-tions in individuals with autoimmune liver diseasesuggests that the activated immunocytes haveimprecise antigen recognition sites and are capableof targeting diverse cell populations (promiscuousactivity) (Doherty et al., 1998). Molecular mimicryand promiscuous activity by the activated immu-nocytes are important pathogenic mechanisms thathave been implicated in autoimmune liver disease(Table 1).

1.1. Molecular mimicry

Molecular mimicry implies that multiple antigenictargets have the same or similar epitopes againstwhich activated lymphocytes with imprecise

Table 1

Disturbances in antigen recognition

Immune disturbance Pathogenic mechanism Consequences

Molecular mimicry Multiple antigenic targets have same or similar

peptide sequences or conformational epitopes.

Different etiologic agents with homologous

epitopes produce same immune response.

Foreign and self antigens are indistinguishable. Anatomically different and distant organs can be

targeted in the same individual.

Recognition of

cryptic self-antigens

or neo-antigens

New antigens are uncovered during primary

immune reactions that generate additional

immune responses.

Collateral immune responses escalate the primary

immune reaction and its outcome.

Loss of self-tolerance Protracted or repeated exposure to foreign

antigens that resemble self-antigens generates

cross-reacting humoral and cellular immune

responses.

Self-perpetuating immune attack is directed

against homologous epitopes in own tissue

(autoimmunity).

Promiscuous

immunocyte activity

T cell antigen receptor of activated immunocyte

has imprecise antigen recognition.

Consequences of molecular mimicry are

enhanced.

Immunocyte is unable to distinguish between

closely homologous epitopes in different

antigens.

Immune attack is extended against similar self-

antigens in diverse tissues favoring development

of multiple immune diseases in same individual.

A.J. Czaja122

antigen recognition sites (promiscuous activity)can be directed (Vergani et al., 2002) (Table 1).Molecular mimicry explains autoreactivity(Bogdanos et al., 2001), but it has been difficultto prove in human disease (Albert and Inman,1999). Humoral cross-reactivity has been welldescribed in autoimmune conditions (Choudhuriet al., 1998; Bogdanos and Vergani, 2006), butcellular cross-reactivity has been difficult todemonstrate (Kammer et al., 1999).

Molecular mimicry can occur when there arehomologous amino acid sequences within peptidesor similar conformational epitopes in structurallydissimilar peptides (Bogdanos et al., 2001; Verganiet al., 2002). The uncovering of cryptic self-antigens or the recognition of neo-antigens canescalate the autoreactive response (Table 1).Molecular mimicry explains how different envi-ronmental agents, drugs, and viruses may producethe same disease and how autoimmune hepatitiscan recur or develop de novo after liver transplan-tation (Czaja, 2002). Molecular mimicry alsopredicts that anatomically distant organs can betargeted in the same individual and that immunediseases involving different organs can occur inthe same patient (Vergani et al., 2002). A murinemodel of autoimmune hepatitis based on DNAimmunization against self-antigens has providedstrong support for its pathogenic role (Lapierreet al., 2004).

In this model, immunized mice developedhepatitis after plasmid injections containing theantigenic regions of human CYP2D6 and humanformiminotransferase cyclodeaminase (Lapierreet al., 2004). Affected mice developed antibodiesagainst the human peptides, and cytotoxic Tlymphocytes were found within the liver that weresensitized against the antigens in the plasmidconstructs. DNA immunization against humanantigens appeared to break self-tolerance in thismodel, and liver injury developed because ofmolecular mimicry between foreign- and self-antigens that resulted in cross-reacting humoraland cellular responses.

Homologies between various viral genomes(hepatitis C virus, cytomegalovirus, and herpessimplex type 1 virus) and recombinant CYP2D6suggest that multiple exposures to viruses

mimicking self may be a mechanism by whichto break self-tolerance and induce autoimmuneliver disease (Manns et al., 1991a, b; Kerkar et al.,2003). Cross-reactivity has also been demonstratedbetween HCV antigens and host-derived smoothmuscle and nuclear antigens (Gregorio et al.,2003). Furthermore, HLA B51 has been associatedwith cross-reactive immune responses betweenviral and microsomal antigens (Bogdanos et al.,2004). Geographic differences in the occurrence ofcertain indigenous viral agents or the frequenciesof exposure to structurally similar viruses mayexplain regional differences in the expression ofcertain autoantibodies and disease types.

Various cytosolic enzymes other than the mono-oxygenase, CYP2D6, have been implicated asautoantigens in autoimmune hepatitis. Theyinclude uridine triphosphate glucuronosyltransfer-ase (Manns and Obermayer-Straub, 1997), glu-tathione S-transferase (Aguilera et al., 2001),formiminotransferase cyclodeaminase (Muratoriet al., 2001; Lapierre et al., 2004), and the trans-fer ribonucleoprotein complex, tRNP(Ser)Sec (Costaet al., 2000). Each candidate has the potentialto generate cross-reacting humoral and cellularimmune responses that may overcome self-tolerance. Homologies between these moleculeshave not been investigated, nor have homologiesbetween these candidate autoantigens and variousviral agents been demonstrated.

1.2. Promiscuous immunocyte activity

The ability of molecular mimicry to generate anautoreactive response depends in part on thepromiscuous activity of the sensitized immuno-cytes (Table 1). Promiscuous immunocyte reacti-vity implies that the T cell antigen receptor (TCR)of the immunocyte is imprecise in its targeting andthat the immunocyte cannot distinguish betweenclosely homologous epitopes in different antigens(Doherty et al., 1998). This deficiency promotesand may perpetuate an immune attack against self-antigens that resemble foreign antigens throughmolecular mimicry.

Immunopathogenesis of Autoimmune Liver Damage 123

Antigenic peptides are displayed in the antigen-binding groove of class II molecules of the majorhistocompatibility complex (MHC) (Czaja et al.,2002a). These peptides are selected for presenta-tion by the amino acid sequences within thepeptide that interact with residues within theantigen-binding groove. Peptide binding to classII MHC molecules is highly degenerate in thateach MHC molecule can bind a variety of peptideswith varying affinities. Different MHC moleculesshow a strong bias for particular types of aminoacids that are present at peptide positions P1, P4,P6, P7, and P9 from the N-terminal anchorposition (Doherty et al., 1998; Corper et al., 2000).

The critical contacts that take place betweena TCR and its ligand involve residues of theantigenic peptide, the a-helical region of the classII MHC molecule, and the complementarity-determining regions (CDR) of the a- and b-chainsof the TCR (Penzotti et al., 1996; Garboczi et al.,1996; Garcia et al., 1996). The three variable CDRloops of the a-chain and CDR3 of the b-chain arepredicted to contact the a-helix of the MHCmolecule. The CDR1 and CDR3 loops of boththe a- and b-chains contact the bound peptide, butCDR3 displays the greatest degree of diversitywithin the TCR and it may respond to diversehomologous peptides in the antigen-bindinggroove. The TCR of liver-infiltrating immunocytestend to be restricted (Hoshino et al., 1995; Arenzet al., 1997, 1998, 2001) and clonally differentamong various liver diseases (Shimizu et al., 1997;Arenz et al., 1998), but their limited clonal diversitysuggests that they are each directed against multi-ple similar target antigens (Yoshizawa et al., 1999).Since multiple similar peptides can be presentedby the same class II MHC molecules and multipleclass II MHC molecules can present the same orsimilar peptides, there is ample opportunity toactivate immunocytes against multiple similarpeptides and promote molecular mimicry andpromiscuous activity (Doherty et al., 1998; Czajaet al., 2002a). Furthermore, this pluri-potentialreactivity may be affected by germline polymor-phisms that affect the structure of the TCR(Manabe et al., 1994). Homozygosity for the10-kb Bgl II polymorphism of the TCR constant

b gene occurs more commonly in patients with

autoimmune hepatitis than in normal subjects,especially in patients without HLA DRB1*03 andDRB1*04. In patients aged less than 30 years whohave HLA DRB1*03, the occurrence of thispolymorphism is significantly reduced (Manabeet al., 1994). These observations suggest thatsusceptibility to autoimmune liver disease mayrelate to the lack of antigenic specificity of theTCR of the effector cells and to intrinsic host-specific genetic factors that subtly modify TCRstructure (TCR polymorphisms) and antigen pre-sentation (class II MHC molecules).

2. Deficiencies in regulatory networks

The immune response is tightly controlled bycounter-regulatory molecules that influence immu-nocyte activation, cytokine pathways that affectimmunocyte differentiation and proliferation, andprograms of cell death (apoptosis) that determinethe duration of immunocyte reactivity (Czaja, 2001)(Table 2). Deficiencies in these regulatory pathwayshave been demonstrated in autoimmune liverdisease, and they may contribute to its occurrenceand behavior. Host-specific genetic factors havebeen implicated in disturbing this homeostasis, andthere are undoubtedly many yet unrecognizedinteractive genetic polymorphisms inside and out-side the MHC that work individually, in clusters, orin synergy (epistasis) with the principal drivers ofthe disease to modify its clinical phenotype andoutcome. The completion of the human genomeproject and the availability of gene microarraytechnology and genome-wide DNA microsatelliteassessments will undoubtedly clarify the diversityand importance of these interactions.

2.1. Perturbations in activation signals

Uncommitted CD4 T helper cells are activated bybinding with the antigen-presenting class II MHCcomplexes on the surface of antigen-presentingcells (APC) (first co-stimulatory signal) and afterligation of the CD28 molecules on their surfacewith B7-1 (CD80) or B7-2 (CD86) on the APC

A.J. Czaja124

surface (second co-stimulatory signal) (Czaja andDonaldson, 2000; Czaja, 2001; Czaja et al., 2002a;Vergani et al., 2002). Cytotoxic T lymphocyteantigen-4 (CTLA-4) is expressed on the surface ofactivated CD4 T helper cells, and it competes withCD28 for the B7 ligands. CTLA-4 can dampen theactivation of CD4 T helper cells by inhibiting thesecond co-stimulatory signal.

In white North American and northernEuropeans with autoimmune hepatitis, a poly-morphism of the CTLA-4 gene appears to favordisease occurrence (Agarwal et al., 2000a; Djilali-Saiah et al., 2001) (Table 2). The substitution of aguanine for an adenine at position 49 in the firstexon of the CTLA-4 gene results in a threonine foralanine substitution in the expressed protein, andthis variation in the gene product may be sufficientto impair its function (Agarwal et al., 2000a).The same polymorphism of the CTLA-4 genedescribed in autoimmune hepatitis has been foundin PBC, and it may be one of several autoimmunepromoter genes that are outside the MHC and notdisease specific (Agarwal et al., 2000b).

The CTLA-4 gene polymorphism described inwhite North American and northern European

patients has not been found in South Americanpatients (Bittencourt et al., 2003). Autoimmunehepatitis has a global occurrence, but its manifes-tations can vary by geographic region and ethnicgroup. These phenotypic differences can reflectdiverse etiologic factors, triggering antigens,genetic predispositions, and pathogenic mecha-nisms (Czaja et al., 2002b). Observations made inhomogenous white populations of North Americaand northern Europe may not apply to the samedisease in another region, and there must bewariness in ‘universalizing’ the findings.

The CTLA-4 polymorphism may be only oneexample of the type of genetic factors that caninfluence disease occurrence in different regionsand ethnic groups. The existence and variety ofthese genetic determinants have been underscoredby studies in murine models of autoimmunehepatitis in which mouse strains with differentgenes inside and outside the MHC have respondeddifferently to the same recipe for the induction ofexperimental hepatitis (Lapierre et al., 2006).Polymorphisms of the vitamin D receptor (VDR)gene (Vogel et al., 2002), point mutation of thetyrosine phosphatase CD45 gene (Vogel et al., 2003;

Table 2

Deficiencies in regulatory networks

Immune deficiency Pathogenic mechanism Consequences

Down-regulation of

activation signal

Polymorphism of CTLA-4 gene generates

product that fails to compete with CD28 for the

B7 ligands on the antigen-presenting cell.

Vigorous or excessive immunocyte activation.

Plethora of interactive

polymorphic

autoimmune promoters

Polymorphisms outside the major

histocompatibility complex work alone or in

synergy (epistasis).

Constellations of polymorphic promoters

individualize the disease by affecting the clinical

phenotype, disease severity and outcome.

Cytokine imbalance

favoring type 1 response

Polymorphism of tumor necrosis factor-a gene

(TNFA*2) is associated with high levels of TNF-aand HLA DRB1*03.

Increased levels of TNF-a favor clonal expansion

of liver-infiltrating cytotoxic T cells.

Impaired regulation of

apoptosis

Polymorphism of Fas gene promoter at �670

associated with autoimmune hepatitis.

Fas gene polymorphism facilitates the early

development of cirrhosis.

Bcl-2 is over-expressed on liver-infiltrating CD4

lymphocytes.

Liver-infiltrating immunocytes escape apoptosis

and extend autoimmune hepatitis.

Deficiencies in

regulatory cells with

suppressor function

Regulatory CD4+CD25+ T cells (T-reg cells)

that suppress proliferation of CD8 lymphocytes

are decreased in number and function.

Intrahepatic natural killer T cells are decreased in

autoimmune hepatitis.

Liver-infiltrating CD8 T lymphocytes can

proliferate and enhance liver injury.

Immune-mediated liver injury is promoted.


Esteghamat et al., 2005), polymorphisms of theFas gene [tumor necrosis factor receptor super

family (TNFRSF)] (Hirade et al., 2005; Agarwalet al., 2007), mutations of the autoimmune

regulator (AIRE) gene (Lankisch et al., 2005), andpolymorphisms of the interleukin (IL)-1, IL-6,

and IL-10 promoter genes (Fan et al., 2005) areexamples of other genetic factors outside the MHCthat are not disease specific but are capable ofinfluencing the occurrence and manifestations ofautoimmune liver disease.

2.2. Perturbations in the cytokine network

Cytokines govern differentiation and proliferationof immunocytes through cross-regulatory actions.IL-2, IFN-g, and TNF-a constitute the type 1(Th1) cytokine pathway that regulates cellularimmune mechanisms by facilitating clonal expan-sion of cytotoxic T lymphocytes (Lucey et al.,1996; Peters, 1996). IL-4, IL-5, IL-6, IL-8, IL-10,and IL-13 constitute the type 2 (Th2) cytokinepathway, and they influence the humoral immuneresponse by activating B cells and stimulatingautoantibody production (Lucey et al., 1996;Peters, 1996). The type 1 cytokine responsefavors liver injury by expanding sensitized, tissue-infiltrating, cytotoxic T cells and inducing cell-mediated cytotoxicity, and the type 2 cytokineresponse favors liver cell injury by generatingimmunoglobulin that can complex with normalconstituents of the hepatocyte membrane andbe targeted by natural killer (NK) cells in anantibody-dependent, cell-mediated form of cyto-toxicity. The type 2 cytokine response also hasanti-inflammatory effects that counter the type 1cytokine response.

The type 1 and type 2 cytokine pathwaysconstitute a regulatory network that is character-ized by redundant action and extensive cross-inhibition (Lucey et al., 1996; Peters, 1996)(Table 2). Both cytokine pathways are interactivein autoimmune liver disease and important inmodulating disease activity, but neither patterncharacterizes a particular autoimmune liver disease(Tilg et al., 1992; Al-Wabel et al., 1993; Schlaak

et al., 1993; Lohr et al., 1994; Maggiore et al.,1995; Trautwein and Manns, 1995; Cacciarelliet al., 1996; Bertoletti et al., 1997). Serum determi-nations of the cytokine profile in white NorthAmerican and northern European adults withautoimmune hepatitis show mixed patterns (Czajaet al., 2000). These cytokine patterns changeduring the course and treatment of the disease.Type 1 cytokines may prevail during periods ofactive inflammation, and type 2 cytokines mayprevail during intervals of quiescence. HLADRB1*03 and the A1-B8-DRB1*03 phenotypeoccur more commonly in white North Americanpatients with autoimmune hepatitis and mixedtype 1 and type 2 cytokine profiles than in whitepatients with pure type 2 cytokine profiles (Czajaet al., 2000). This finding suggests that a geneticpredisposition associated with HLA DRB1*03,possibly a genetic polymorphism of the tumor

necrosis factor-a gene (Cookson et al., 1999; Czajaet al., 1999), may influence the cytokine milieu andpromote clonal proliferation of liver-infiltrating,cytotoxic T cells in white North Americanpatients.

Polymorphisms of genes responsible for cyto-kine production may modify the cytokine milieu insome individuals to favor an autoimmune response(Table 2). The TNFA*2 allele is carried on the 8.1ancestral haplotype of white northern Europeans,and this linkage disequilibrium with HLADRB1*03 may modulate the cytokine milieu tofavor a cytotoxic immune response. The substitu-tion of an adenine for a guanine at position �308of the TNF-A gene is associated with highinducible and constitutive levels of TNF-a, andincreased levels of this cytokine directs a type 1cytokine response (Cookson et al., 1999). Thepolymorphism occurs mainly in young patientswith autoimmune hepatitis, especially those whorespond less well to corticosteroid therapy (Czajaet al., 1999). These findings suggest that geneticpolymorphisms that affect the cytokine responsemay work in synergy (epistasis) with HLADRB1*03 to affect disease severity. IL-2, IL-4,IL-6, IFN-g (Fan et al., 2005) and transforming

growth factor-b (TGF-b) (Bayer et al., 1998;Schramm et al., 2003) are also under geneticcontrol, and their role in the occurrence and

A.J. Czaja126

behavior of autoimmune liver disease requiresfurther study.

2.3. Perturbations in the apoptoticpathways

Programmed cell death (apoptosis) is the principalmode of liver cell loss in autoimmune liver disease,and it is also the principal mechanism by whichautoreactive immunocytes are eliminated (Foxet al., 2001). Two overlapping signal pathwaysthat stimulate apoptosis affect the extent and theduration of the autoreactive response throughintrinsic and extrinsic mechanisms (Bai and Odin,2003). Perturbations in each pathway have beenimplicated in the pathogenesis of autoimmuneliver disease (Table 2).

The intrinsic pathway is characterized bymitochondrial dysfunction that results mainlyfrom oxidative stress and damage to the innermitochondrial membrane (Bai and Odin, 2003).This injury releases cytochrome c and apoptosis-inducing factor (AIF). Caspases are then activatedand other factors are released (endo G), whichcleave chromosomal DNA and induce cell death.The intrinsic apoptotic pathway is modulated bycounter-regulatory proteins that prevent apoptosis(bcl-2) or enhance it (bax, bad). IL-4, IL-7, andIL-15 up-regulate the expression of bcl-2, and theyhave anti-apoptotic actions. In autoimmune hepa-titis, the persistence of activated lymphocytesexpressing CD95 (Fas/APO-1) suggests that theintrinsic apoptotic pathway for immunocyte dele-tion is defective (Ogawa et al., 2000). Activatedlymphocytes expressing CD95 (Fas/APO-1) fail todown-regulate the expression of the anti-apoptoticprotein, bcl-2, and high concentrations of bcl-2have been demonstrated in liver-infiltrating lym-phocytes. Apoptosis of the activated effector cellsis inhibited and their persistence within the liver isenhanced.

The extrinsic pathway of apoptosis is mediatedby the cell surface receptors, Fas and TNF-areceptor-1 (TNF-R1), and by the release ofperforin and granzyme B from activated cytotoxicT cells (Bai and Odin, 2003). FasL on the surface

of the cytotoxic T cells and TNF-a in the cytokinemilieu activate the death signals on hepatocytes bybinding with their respective ligands, FasL andTNF-a, whereas granzyme B enters the hepatocytevia a membrane pore formed by perforin. The Fasand TNF-R1 complexes cleave procaspase 8 intoits active form leading to activation of otherdownstream caspases, and granzyme B directlycleaves proteins necessary for cell survival. Theactivated caspases induce cell death directly bycleaving cell proteins or indirectly by releasingcytochrome c from mitochondria. In this fashion,the intrinsic and extrinsic apoptotic pathways caninteract in autoimmune liver disease. The cleavageof cell proteins and the fragmentation of DNA canexpand the number of autoantigens available toperpetuate the autoimmune response or enlargethe spectrum of autoantibodies associated with thedisease.

The human Fas gene is a member of theTNFRSF, and it is located on chromosome10q24.1 (Hirade et al., 2005). Twenty distinctpolymorphisms have been described over a span of26 kb, and four have been associated with theoccurrence of autoimmune hepatitis in Japan(Hirade et al., 2005). In white North Americanand northern European patients with autoimmunehepatitis, an adenosine to guanine single-nucleo-tide polymorphism in the Fas gene promoter atposition �670 (TNFRSF6) has been associatedwith the early development of cirrhosis (Agarwalet al., 2007). Cirrhosis is more common atpresentation in patients with the adenosine/adenosine or adenosine/guanine genotypes thanin those with the guanine/guanine genotype(29 versus 6%, p=0.006; odds ratio=6.4). Thesefindings suggest that genetic factors can influencedisease progression in autoimmune liver diseasethrough modulation of receptor-mediated pro-grammed cell death (Table 2).

Liver-infiltrating CD4 T lymphocytes in patientswith autoimmune hepatitis are distinguished bytheir expression of CD28 and the anti-apoptoticprotein, bcl-2 (Kurokohchi et al., 2006). In thisfashion, the CD4 helper T lymphocytes mayescape apoptosis and provide cognate help for theinduction of cytotoxic T lymphocytes. Theseobservations highlight the capability of effector


cells to undergo special modifications that evadeapoptosis and promote autoimmune liver disease.

2.4. Deficiencies in regulatory cells withsuppressor functions

Counter-regulatory cells have recently been identi-fied that are likely to reduce the autoreactiveresponse by dampening cytokine pathways thatpromote the proliferation of cytotoxic T lympho-cytes (Table 2). The functions of these cellularregulators have been incompletely described, butthey have largely suppressive actions on thepathogenic pathways. Unexplained deficiencies intheir number and function have been identifiedin autoimmune hepatitis, and these deficienciesmay in turn enhance the development and severityof the liver disease.

Regulatory CD4+CD25+ T cells (T-reg cells)modulate CD8 T cell proliferation by exertinga direct suppressive effect on the production ofIFN-g while increasing secretion of IL-4, IL-10,and TGF-b (Longhi et al., 2005, 2006; Lan et al.,2006). These cells are decreased in number andfunction in autoimmune hepatitis, and their failureto modulate CD8 T cell proliferation and cytokineproduction may facilitate the liver injury (Table 2).T-reg cells do not affect target cell apoptosis,but they exert a direct suppressive effect on theimmune response by modifying the cytokinemilieu. Recent studies demonstrating deficientT-reg cell function in the siblings and children ofpatients with PBC suggest that the suppressoractivity of this subset may be modulated by geneticfactors (Lan et al., 2006). Corticosteroid therapycan re-constitute T-reg cell function and attenuatethe cell-mediated cytotoxic response in autoim-mune hepatitis (Longhi et al., 2005).

Natural killer T (NKT) cells are lymphoid cellsderived from the bone marrow, and they areabundant in the liver (Lalazar et al., 2006; Zhanget al., 2006). These cells express surface markersfound on monocytes, granulocytes, and lympho-cytes, and their co-expression of a TCR characte-ristic of lymphocytes and a NK1.1 lectincharacteristic of NK cells has justified their

designation as NKT cells. The NKT cells producecytokines, including IFN-g and IL-4, that can havepro-inflammatory and anti-inflammatory effects(Table 2).

NKT cells are activated by glycolipids that arebound to or presented by the CD1d on APCs orhepatocytes (Lalazar et al., 2006). CD1d-deficientmice lack NKT cells, and they are highly resistantto experimental hepatitis induced by the intrave-nous injection of concanavalin (Con) A (Takedaet al., 2000). Sensitivity to Con-A-induced liverinjury is restored after adoptive transfer of hepaticNKT cells isolated from wild-type mice. In thismodel, the wild-type hepatic NKT cells rapidlyup-regulate cell surface expression of FasL andinduce FasL-mediated cytotoxicity before disap-pearance from the liver by apoptosis. In Con-A-induced liver disease, NKT cells appear to havedeleterious actions (Takeda et al., 2000).

Conversely, NKT cells may have a protectivefunction in autoimmune liver disease (Table 2).Recent studies have indicated that the number ofintrahepatic NKT cells in autoimmune hepatitisis less than in patients with PBC and that thelevels of mRNA encoding soluble CD1d are alsolower in these individuals (Takahashi et al., 2006).Patients without intrahepatic NKT cells havehigher serum aminotransferase and immunoglo-bulin G levels and lower mRNA levels for solubleCD1d than patients with intrahepatic NKT cells.These findings indicate that NKT cells can preventliver injury in autoimmune liver disease. Theirdifferentiation as protectors or effectors of liverinjury may depend on the type of liver disease andhost-dependent co-factors, such as CD1d expres-sion and the natural occurrence of glycolipids.Further characterization of the T-reg cells andNKT cells may afford opportunities to increasetheir suppressor functions in autoimmune liverdisease by medication or adaptive transfer.

3. Genetic and gender predispositions

Host-dependent factors clearly influence the natureand severity of autoimmune liver disease (Czajaet al., 1998). Genetic factors have already been

A.J. Czaja128

implicated in modulating the CTLA-4 pathway ofimmunocyte activation (Agarwal et al., 2000a, b),altering the structure of the TCR of activatedimmunocytes (Manabe et al., 1994), enhancing thetype 1 cytokine pathway (Cookson et al., 1999;Czaja et al., 1999; Fan et al., 2005), altering theapoptosis of liver cells and immunocytes (Hiradeet al., 2005; Agarwal et al., 2007), and possiblyaffecting the number of T-reg cells in PBC (Lanet al., 2006). The female predisposition for auto-immune hepatitis and PBC as well as autoimmunedisease in general is well recognized, and thefemale gender may be the strongest, single, host-specific risk factor for autoimmunity (Czaja et al.,1998).

Earlier examples of genetic factors influencingthe occurrence and phenotype of autoimmuneliver disease consisted mainly of polymorphismsthat were outside the MHC, not disease specific,and unlikely to be the primary drivers of theautoimmune response. Much has been learned

regarding the principal susceptibility factors forautoimmune liver disease, and these insights havegenerated compelling hypotheses regarding thepathogenesis of these disorders. Furthermore,the clarification of the immune-modulating effectsof the various sex hormones, especially estrogen,has allowed speculation as to how gender maycontribute to susceptibility.

3.1. Principal genetic risk factors

The principal susceptibility alleles for autoimmunehepatitis in white North American and northernEuropean patients reside on the DRB1 gene, andthey are DRB1*0301 and DRB1*0401 (Strettellet al., 1997) (Table 3). In contrast, DRB1*1501

has been associated with protection from thedisease (Doherty et al., 1994; Strettell et al.,1997). The key genetic risk factors for PSC are

Table 3

Genetic predispositions

Genetic component Genetic predispositions Consequences

Principal genetic risk

factors

DRB1*0301 and DRB1*0401 in autoimmune

hepatitis.

Susceptibility alleles encode the antigen-binding

groove of the class II molecule of the major

histocompatibility complex to favor presentation

of disease-specific triggering antigens.

DRB3*0101–DRB1*0301 and DRB3*0101–

DRB1*1301 in primary sclerosing cholangitis.

DRB1*0801–DQB1*0402 in primary biliary

cirrhosis.

Shared antigen-

binding motif

LLEQKR encoded at positions DRb67-72 and

lysine at DRBb71 are key factors in autoimmune

hepatitis.

Multiple alleles can encode the same or similar

amino acid motif in the antigen-presenting

molecule and affect disease occurrence similarly.

Arginine is encoded by DRB1*0404 and

DRB1*0405 at DRBb71 and similar to lysine.

DRB3*0101 and DRB5*0101 encode a leucine at

position DRb38 in primary sclerosing

cholangitis.

Region-specific

genetic risk factors

DRB1*1301 is associated with autoimmune

hepatitis in South America.

DRB1*07 is associated with antibodies to liver/

Genetic susceptibilities favor indigenous

triggering antigens in different geographical

regions and ethnic groups.

kidney microsome type 1 in northern Europe. Multiple alleles in a single disease may affect

different aspects of its clinical phenotype.DQB1*0201 is associated with type 2

autoimmune hepatitis.

Gene dose effects Multiple alleles can encode the same antigen

recognition sites.

Multiple antigen recognition sites increase

immunocyte activation.


DRB3*0101–DRB1*0301 and DRB3*0101–

DRB1*1301, and the haplotype containingDRB1*04–DQB1*0501 has been associated withprotection from the disease (Farrant et al., 1992;Donaldson and Norris, 2001, 2002) (Table 3).DRB1*0801 has been weakly associated with PBCin white North American and northern Europeanpatients (Gores et al., 1987; Manns et al., 1991a, b;Donaldson et al., 2006), and DRB1*0803 has beenassociated with PBC in Japan (Onishi et al., 1994)(Table 3). The DRB1*08–DQB1*0402 haplotypemay extend weakly to the DPB1*0301 allele inBritain and to the DPB1*0501 allele in Japan(Underhill et al., 1995), whereas HLA DRB1*11and DRB1*13 may be protective against PBC indiverse ethnic populations (Donaldson et al.,2006). The genetic associations in PBC are withinthe chromosomes 6p21.3 and 2q, and they includethe HLA DRB1*08 haplotypes as well as poly-morphisms that may alter the autoimmune response,such as CTLA-4 (Jones and Donaldson, 2003).

The alleles of the MHC are the principal driversof autoimmune liver disease, whereas polymor-phisms outside the MHC modify the clinicalphenotype and affect disease severity. The MHCalleles encode the amino acid sequences within theantigen-binding groove of the class II MHCmolecules that are responsible for antigen pre-sentation and immunocyte activation (Czaja andDonaldson, 2000; Czaja et al., 2002a). In thisfashion, they directly affect antigen selection andthe immune response. Analyses of amino acidsequence variations encoded by the susceptibilityalleles associated with autoimmune hepatitis inwhite North American and northern Europeanpatients indicate that the core susceptibilitymotif is a six amino acid sequence, LLEQKR, atpositions DRb67–72 of the antigen-binding grooveof the class II MHC molecule (Doherty et al.,1994; Strettell et al., 1997) (Table 3). Lysine (K) atposition DRb71 is at the lip of the antigen-bindinggroove, and it is at a critical contact point betweenthe antigen, the class II MHC molecule, and theTCR. In white North American and northernEuropean patients with autoimmune hepatitis, theoptimal presentation of antigens by the class IIMHC molecules depends on lysine at positionDRb71 (Doherty et al., 1994; Strettell et al., 1997).

Both DRB1*0301 and DRB1*0401 encodeidentical sequences at positions DRb67–72(Doherty et al., 1994; Donaldson and Czaja,2002). DRB1*0301 is in strong linkage disequili-brium with DRB3*0101, which also encodes alysine at DRb71, whereas DRB1*0401 is in stronglinkage disequilibrium with DRB4*0103, whichencodes an arginine at DRb71. Patients withDRB1*0301 have two lysine-encoding DRB allelesper haplotype, whereas those with DRB1*0401 haveone. The reduced density of antigen-presentingmolecules with lysine at DRb71 in patients withDRB1*0401 may attenuate the immune responseand lessen the severity of the disease (Czaja et al.,1997a, b; Strettell et al., 1997). The diversity ofclass II MHC molecules in patients withDRB1*0401 may confer responsiveness to multipleliver and non-liver antigens. This diversitymay in turn favor a more varied clinical pheno-type (Czaja and Donaldson, 2002). Clinical studieshave supported these concepts by indicatingthat patients with DRB1*0301 have more severedisease than those with DRB1*0401, whereaspatients with DRB1*0401 are more commonlywomen and they have a higher frequency ofconcurrent immune diseases than those withDRB1*0301 (Czaja et al., 1993, 1997a, b; Czajaand Donaldson, 2002).

Arginine (R) is a polar amino acid that isstructurally similar to lysine, and its substitutionfor lysine at position DRb71 would not greatlyalter the steric and electrostatic properties ofthe class II MHC molecule (Strettell et al., 1997;Czaja and Donaldson, 2000; Czaja et al., 2002a;Donaldson, 2002; Donaldson and Czaja, 2002).Arginine at DRBb71 has been associated withautoimmune hepatitis in Japan (Seki et al., 1992;Yoshizawa et al., 2005), Mexico (Vazquez-Garciaet al., 1998), and mainland China (Qiu and Ma,2003) where the susceptibility alleles, DRB1*0404

and DRB1*0405, encode an arginine (R) forlysine (K) at the DRb71 position. In contrast,DRB1*1501 protects against type 1 autoimmunehepatitis in white North Americans and northernEuropeans, and this allele encodes an isoleucine (I)for leucine (L) at position DRb67 and an alanine(A) for lysine (K) at position DRb71 (Dohertyet al., 1994; Strettell et al., 1997). Alanine is a

A.J. Czaja130

neutral, nonpolar amino acid whose substitutionfor lysine would greatly affect antigen presentationand immunocyte activation. The substitution ofa single amino acid at a critical location in theantigen-binding groove of the class II MHCmolecule may affect disease occurrence by alteringantigen recognition.

In PSC, susceptibility and protection relate toamino acid substitutions at position DRb38(Farrant et al., 1992). Both DRB3*0101 andDRB5*0101 encode a leucine at position DRb38,whereas the DRB4*0101 allele, which encodesDRw53 and may be protective against PSC,encodes an alanine at this position. Maximumrelative risk for PSC relates to leucine at positionDRb38, and minimum relative risk relates toalanine at DRb38 (Farrant et al., 1992).

Multiple alleles of the MHC in addition to theprincipal susceptibility factors can encode thesame critical amino acids at positions DRb71 inautoimmune hepatitis and DRb38 in PSC(Doherty et al., 1994; Strettell et al., 1997). Thesealleles may increase susceptibility to the disease byenhancing the number of class II MHC moleculeswith critical amino acids at key positions withinthe antigen-binding groove to optimize autoanti-gen presentation (Czaja et al., 1997a, b; Strettellet al., 1997). Alternatively, they may be sufficientto favor development of the disease in the absenceof the principal MHC alleles (Czaja et al., 2006;Montano-Loza et al., 2006). The commonality ofsusceptibility alleles for autoimmune hepatitis indifferent ethnic regions has generated a ‘sharedmotif hypothesis’ of pathogenesis. The ‘sharedmotif hypothesis’ predicts that disease risk relatesto amino acid sequences in the antigen-bindinggroove of the DR molecule and that multiplealleles can encode the same or similar sequenceand affect susceptibility similarly (Czaja andDonaldson, 2000, 2002). The various implicatedsusceptibility alleles for autoimmune hepatitis indifferent ethnic groups, including the Japanese,mainland Chinese, and Mexicans, each encodea similar six amino acid sequence betweenpositions 67 and 72 of the DRb chain. Theonly exception has been the association ofHLA DRB1*13 with autoimmune hepatitis inSouth America (Fainboim et al., 1994; Pando

et al., 1999; Bittencourt et al., 1999; Goldberget al., 2001).

3.2. Region-specific genetic risk factors

Autoimmune liver disease in different geographicregions may have genetic risk factors that arecharacteristic of that region or ethnic group(Fainboim et al., 1994; Pando et al., 1999;Bittencourt et al., 1999; Goldberg et al., 2001).These susceptibility alleles do not encode similaramino acid sequences within class II MHCmolecules and affect susceptibility similarly.Instead, they may encode sequences that favor thepresentation of indigenous triggering antigens thatin turn cause the disease by protracted exposureand molecular mimicry (Fainboim et al., 2001).The ‘molecular footprint hypothesis’ holds thatdifferent individuals within a population havealleles that render them particularly susceptibleto an indigenous, region-specific, etiologic agentthat selects them to develop autoimmune liverdisease (Donaldson, 2002, 2004; Donaldson andCzaja, 2002). By using the susceptibility alleleas a ‘footprint’, it may be possible to deduce theregion-specific, etiologic trigger for the disease.

DRB1*1301 is associated with autoimmunehepatitis in Argentine children (Fainboim et al.,1994; Pando et al., 1999) and Brazilian patients(Bittencourt et al., 1999; Goldberg et al., 2001),and it encodes ILEDER at positions DRb67–72(Czaja et al., 2002a; Donaldson, 2002; Donaldsonand Czaja, 2002) (Table 3). Glutamic acid (E),aspartic acid (D), and glutamic acid (E) are atpositions DRb69, 70, and 71 in the class II MHCmolecules, and these negatively charged aminoacid residues favor presentation of antigensdifferent from those accommodated within classII MHC molecules encoded by DRB1*0301 andDRB1*0401. DRB1*1301 is associated with pro-tracted hepatitis A virus infection (Fainboim et al.,2001), and hepatitis A virus has been associatedwith the development of autoimmune hepatitis(Vento et al., 1991; Huppertz et al., 1995; Tanakaet al., 2005). South Americans, especially children,with DRB1*1301 may be selected to have


prolonged exposure to viral and hepatic antigensand thereby overcome self-tolerance (Tapia-Conyer et al., 1999; Fainboim et al., 2001). Othergeographic regions may have other susceptibilityalleles for the same disease based on the indige-nous antigens that can trigger their disease.

Type 2 autoimmune hepatitis is characterizedby antibodies to liver/kidney microsome type 1(anti-LKM1), and it has been described mainlyin European children (Homberg et al., 1987).Susceptibility to type 2 autoimmune hepatitishas been associated with DRB1*07 in Brazil(Bittencourt et al., 1999), Britain (Ma et al.,2006), and Germany (Czaja et al., 1997a, b) andwith DRB1*03 in Spain (Jurado et al., 1997).DQB1*0201 is in strong linkage disequilibriumwith DRB1*07 and DRB1*03, and it has beenproposed as the principal genetic determinantof the disease (Djilali-Saiah et al., 2006). Theassociation of a single disease with multiple allelessuggests that there may be different determinantsfor various aspects of the condition.

DRB1*07 has been associated with the expres-sion of anti-LKM1 in children with type 2autoimmune hepatitis (Bittencourt et al., 1999;Djilali-Saiah et al., 2006) and in Italian patientswith chronic hepatitis C (Muratori et al., 2007). Incontrast, antibodies to liver cytosol type 1 (anti-LC1) are associated with DRB1*03 (Djilali-Saiahet al., 2006). Both anti-LKM1 and anti-LC1 occurin type 2 autoimmune hepatitis, and each hasgenetic associations distinct from each other butoccurring in the same disease. This disease in turnis driven mainly by DQB1*0201 (Djilali-Saiahet al., 2006). These findings suggest that theexpression of nonpathogenic autoantibodies con-trolled by the HLA DR locus in type 2 auto-immune hepatitis and the occurrence of the diseasecontrolled by the HLA DQ locus can be variablyassociated. The implication is that nonpathogenicantibodies can be expressed in diverse conditions ifthe host has a suitable haplotype and antigenicstimulus. A corollary to this observation is that theinability to detect certain antibodies in patientswith the same disease may reflect the rarity of thepredisposing haplotype in that population. Thiscorollary has been invoked to explain in part thelow occurrence of anti-LKM1 in North American

patients with autoimmune hepatitis (Czaja et al.,1992) or chronic hepatitis C (Reddy et al., 1995;Muratori et al., 2007).

3.3. ‘Gene dose’ effects

The number of susceptibility alleles that canencode the same critical amino acid sequencewithin the binding groove of the class II MHCmolecules (‘gene dose’) determines the density ofthe antigen-binding complexes on the surface ofthe APC (Czaja and Donaldson, 2000; Czaja et al.,2002a; Donaldson and Czaja, 2002). This densityin turn influences the vigor of immunocyteactivation by favoring simultaneous activation ofmultiple antigen recognition sites within the CD4T helper cells.

The clinical phenotype and severity of auto-immune hepatitis in North American and northernEuropean patients with autoimmune hepatitis areassociated with the number of alleles that encodelysine at position DRb71 (Czaja and Donaldson,2000; Czaja et al., 2002a; Donaldson and Czaja,2002) (Table 3). This ‘gene dose’ can be variableamong individuals with the same principal sus-ceptibility alleles since the critical motif at positionDRb71 can be encoded by other alleles within thehaplotype. The ability of multiple alleles to encodethe same critical motif may also account for theoccurrence of autoimmune hepatitis in individualsfrom the same geographic region who lackDRB1*0301 and DRB1*0401 (Czaja et al., 2006;Montano-Loza et al., 2006).

In type 2 autoimmune hepatitis, the proliferativeT cell response to the target antigen, CYP2D6,is against multiple antigenic regions (Ma et al.,2006). These antigenic regions differ in patientswith and without DRB1*07, presumably becauseof differences in the peptide-binding affinity of theclass II MHC molecules. T and B cell responsescan be induced by the same overlapping antigenicsequences, and disease activity relates to thenumber of epitopes involved in the T and Bcell responses and the amount of cytokinesproduced from these responses (Ma et al., 2006).Gene dosing and its impact on the density of

A.J. Czaja132

antigen-presenting MHC molecules is probably animportant factor that affects the occurrence andseverity of autoimmune liver disease.

3.4. Gender effects

The strong female predilection for autoimmuneliver disease is unexplained (Czaja et al., 1998), butit is an important association that might provideclues to regulatory mechanisms controlled bysex-linked genes or gender-specific hormones(McFarlane and Heneghan, 2004). Immune cellshave two estrogen receptors, and the activationof these receptors relate to the concentrations ofestrogen in the microenvironment (Fox et al.,1991; Muller et al., 1995). High estrogen levels, asin pregnancy, inhibit the type 1 cytokine responsethat favors the proliferation of cytotoxic T cells,and they promote a type 2 cytokine responsethat favors antibody production and antibody-dependent pathogenic pathways. Low estrogenlevels favor a type 1 cytokine response andpromote cell-mediated pathogenic pathways(Whitacre et al., 1999). Because the female pre-dilection for autoimmune hepatitis is apparentamong children (Gregorio et al., 1997) and theelderly (Wang and Czaja, 1989; Czaja andCarpenter, 2006), fluctuations in estrogen levelsare insufficient to account for all cases of thedisease.

Pituitary hormones, such as prolactin andgrowth hormone (Reber, 1993; Paavonen, 1994),and other sex hormones, such as progesterone andtestosterone (Chao et al., 1995; Kimura et al.,1995), counter-regulate the immune response,probably by altering the cytokine milieu andestrogen receptor expression. Interactions betweengrowth hormone, prolactin, testosterone, andestrogen may constitute a changing hormonalmilieu that affects immune responsiveness differ-ently at various ages and favors certain antigensduring different stages of maturation. The femalegender may be the critical determinant affectingthe hormonal blend of this interactive networkat each age.

Women may also be exposed to unique trigger-ing antigens that enhance their susceptibility toautoimmune disease or have attributes that favoroptimal antigen presentation. Pregnancy is aunique female experience, and fetal cells in thematernal circulation have been associated withthe initiation and exacerbation of autoimmunedisease. Microchimerism can persist for years afterpregnancy, and it may compromise self-tolerancelate in life by promoting cross-reactivities in thehumoral and cellular immune responses (Nelson,1999; Lambert et al., 2000). Its importance inautoimmune liver disease has not been established(Tanaka et al., 2000), and the female propensitymay better reflect gender-related attributes inantigen presentation and the activation of CD4 Thelper cells.

White North American women with autoim-mune hepatitis have HLA DRB1*04 more com-monly than men with the same disease (Czajaet al., 1993, 1997a, b; Czaja and Donaldson, 2002),and they have a greater diversity of HLADRB1*04 alleles (Czaja and Donaldson, 2002).This diversity of HLA DRB1*04 alleles in womenimplies that they are able to present a greatervariety of antigens to CD4 T helper cells than men.This propensity may enhance their ability totrigger an autoimmune response as well as targetanatomically distant organs. HLA DRB1*04 hasbeen associated with autoimmune hepatitis andwith the concurrence of other immune diseases inthe same individual (Czaja et al., 1993, 1997a, b;Czaja and Donaldson, 2002). The mechanisms bywhich the female gender enables autoreactivity arelargely conjectural, but the female predilection forthis response across all age groups underscores theimportance of host-related predispositions, geneticand otherwise, in the occurrence of autoimmuneliver disease.

One X-chromosome is normally inactivated inwomen in a random fashion to achieve equivalentX-linked gene products in each gender. In primarybiliary cirrhosis, X-chromosome loss occurs morefrequently than in normal women or diseasecontrols, and the inactivation is not random(Miozzo et al., 2007). Genes crucial for immunetolerance are on the X-chromosome, and varia-tions in their inactivation may favor the loss of


self-tolerance. The preferential X-chromosome lossmay be acquired and a basis for the female predi-lection in some autoimmune diseases.

4. Summary

Autoimmune liver disease is the net consequenceof an interactive network of stimulatory andinhibitory immune responses that are activatedby diverse antigens that probably have a homo-logous epitope (Czaja, 2001; Vergani et al., 2002).The final product of these convergent modifiersis dependent on the genetic and hormonal compo-sition of the host (Czaja and Donaldson, 2002;Czaja et al., 2002a). Cell-mediated and antibody-dependent cytotoxic mechanisms initiate and extendthe injury pattern, and flaws in the apoptoticpathways that deplete autoreactive T cells or preventexcessive hepatocyte loss perpetuate the disease.

Autoimmune liver disease has pathogenicmechanisms that are shared by other autoimmunediseases (HLA predispositions and genetic poly-morphisms) (Czaja et al., 2001; Alarcon-Segovia,2005), and its distinction from these other diseasesmust reflect unique antigenic triggers and aconstellation of host-dependent modifiers thatshape the clinical phenotype. Autoimmune liverdisease is a human model of autoimmunity, and ithas the potential to provide insight into themechanisms and treatment of other similar condi-tions. Major strides have already been made inunderstanding target autoantigens and geneticpredispositions that trigger the autoreactiveresponse and perpetuate the disease. A confidentanimal model of the human disease is necessary toclarify the critical pathogenic mechanisms and toassess emerging pharmacological agents and mole-cular interventions that will improve treatmentstrategies.

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CHAPTER 12

Primary Biliary Cirrhosis

Rupert Abdalian, Jenny Heathcote�

Division of Gastroenterology, Department of Medicine, Toronto Western Hospital, University Health

Network, Toronto, Ont., Canada

1. Introduction

Primary biliary cirrhosis (PBC) is an autoimmuneliver disease characterized by the chronic progressiveloss of interlobular bile ducts. An immune-mediateddestruction of the bile duct epithelium is thoughtto mediate its pathogenesis. It is a disease thatprimarily affects middle-aged women of all races.Histologically, it is characterized by portal inflam-mation comprising aggregates of lymphoid cells and/or granulomas, which invade and destroy biliaryepithelial cells (Fig. 1). This causes secondary ductloss, decreased bile secretion, and cholestasis whichpromotes hepatic fibrosis, cirrhosis, and, eventually,liver failure. Serologically, the diagnostic hallmarkfinding is antimitochondrial antibody (AMA).

PBC was first described in 1851 by Addison andGull (1851), and subsequently in 1952 the con-firmation of an association with hyperlipidemiaand cutaneous xanothomas led to the initialdescription of ‘xanothomatous biliary cirrhosis’(McCabe and Thompson, 1952). The label of‘Primary Biliary Cirrhosis’ was adopted a yearlater at the Rockefeller Institute, despite opposi-tion from those who argued that not all patientspresent with cirrhosis at diagnosis. The laterdescription of ‘chronic non-suppurative destruc-tive cholangitis’ was deemed more plausible

clinically, yet it never grew to replace the morepopular designation of PBC.

2. Epidemiological highlights

Initial studies published between 1974 and 1985described annual incidence rates for PBC rangingbetween 0.6 and 13.7 cases per million population(Hamlyn and Sherlock, 1974; Lofgren et al., 1985).Subsequent studies from Europe reported incidencerates ranging from 0.7 to 48 cases per million. InNorth America, the incidence rate of 27 cases permillion population with prevalence rates between160 and 402 cases per million have been reportedwithin specific regions (Kim et al., 2000; Hurlburtet al., 2002). The age- and gender-adjusted pre-valence per 100,000 persons was 65.4 for womenand 12.1 for men in a well-defined population fromMinnesota (Kim et al., 2000). The concept of a‘north-south’ gradient as in other autoimmuneconditions can also be postulated in PBC. Thehighest incidence and prevalence rates have beenreported in the United Kingdom, Scandinavia,Canada, and the United States, whereas the lowestin Australia. Notably high rates have been reportedin clusters of populations such as one large FirstNations family near Vancouver Canada (Arbouret al., 2004) as well as a group of individualsliving in close proximity to the Nagasaki atomicbomb explosion site in Japan (Ohba et al., 2001).A selection bias as well as variable diagnosticcriteria may account for this geographic variability.E-mail address: [email protected]


Tel.: (416) 603-5914; Fax: (416) 603-6281


DOI: 10.1016/S1571-5078(07)00012-8

dx.doi.org/10.1016/S1571-5078(07)00012-8.3d

The absence of population-based standardizedmethodology limits the reliability of these findings.As more sophisticated testing for AMA are deve-loped and diagnostic criteria further refined anduniversally applied, more cases may be identified.

Little information is available regarding thecontribution of race and ethnicity to the patho-genesis of PBC. In a recent report from Australia,the prevalence rates in migrants from Great Britain(41 cases per million), Italy (200 cases per million),and Greece (208 cases per million) were signifi-cantly higher when compared to the local indige-nous population surveyed (Sood et al., 2004). Inwomen older than 40 years, the PBC prevalence inBritish-born immigrants to Victoria was signifi-cantly higher than that of Australian-born women.With our current knowledge of genetic suscepti-bility in PBC, it is difficult to delineate the trueinteraction between the environment and the host.An interesting case report described developmentof PBC in a daughter, her mother, and a closeunrelated friend who had nursed the daughterthrough her terminal illness (Douglas and Finlayson,1979). This suggests that host susceptibility plays asignificant role in the development of PBC.

The peak incidence of PBC occurs in the fifthdecade of life, and it is uncommon under the age of

25 years. The onset is usually between the ages of30 and 65, but it has been reported in women asyoung as 15 and as old as 93. A 90% femalepreponderance is observed. A familial predisposi-tion is now well recognized as well. Relatives ofpatients with PBC are more likely to exhibitimmune system derangements. Various reportshave estimated prevalence rates of PBC amongfirst-degree relatives ranging between 5 and 6%(Jones et al., 1999). This correlation is the strongestamong sisters and daughters who are younger atdiagnosis compared to index cases (Tsuji et al.,1999). It is noteworthy to mention, however, thatfamily clustering may reflect ascertainment biasand shared environmental factors. To this day,specific HLA associations with PBC have beenonly weak at best, and reports of specific inheritedalleles altering immune responsiveness have failedto convincingly highlight any disease-specific asso-ciations (Milkiewicz et al., 2006).

3. Pathophysiological insights

An immune-mediated destruction of bile ductepithelial cells is thought to drive the pathogenesisof PBC. Chronic inflammation and repeated injury

Figure 1. Typical bile duct lesion of primary biliary cirrhosis (center). (See Colour Plate Section.)

R. Abdalian, J. Heathcote142

to the small ducts promote a repair mechanismthat involves expansion of portal tracts withproliferating bile ductules. The ensuing myofibro-blastic response results in the net accumulation ofcollagen matrix, which, with time, expands toadjacent portal areas, leading to the typical biliarypattern of fibrosis and eventually of cirrhosis.Inflammatory responses likely stem from recogni-tion of aberrant expression of mitochondrialself-antigens and/or breakdown of immunologictolerance, resulting in the generation of specific Tand B lymphocytes that mediate production ofproinflammatory cytokines and autoantibodies(Kita et al., 2003).

The mechanisms that mediate the fibrogenicresponse to bile duct injury have been recentlysubjected to considerable investigation. Immaturecholangiocytes have been shown to generate auto-crine growth factors (e.g., hepatocyte growthfactor, epidermal growth factor) as well as cyto-kines (e.g., platelet-derived growth factor b) thatare believed to mediate the proliferation ofmyofibroblastic cells (Omenetti et al., 2007). There-fore, signaling between biliary epithelial cells andstromal cells may modulate the mechanismwhereby bile ducts are damaged. The Hedgehogfamily of ligands has recently been shown topromote the growth of both of these cell types(Sicklick et al., 2006). They function as viabilityfactors for many types of progenitors, and havebeen shown to play a pivotal role in tissuemorphogenesis during embryological development(Deutsch et al., 2001). They mediate the signalingbetween mesenchymal and epithelial cells and thusmodulate remodeling responses after injury duringadult life (Sicklick et al., 2006). Using immunohis-tochemistry, Jung et al. (2007) demonstrated thatproliferating bile ductular cells are a rich source ofHedgehog ligands, further supporting the hypo-thesis that an epithelial–mesenchymal ‘cross-talk’promotes the fibroproliferative response to bileduct injury via autocrine and/or paracrine regula-tion of hepatic progenitor cell populations. Aninappropriate upregulation of connective tissueelements in bile-duct-ligated mice with a geneticdefect limiting downregulation of the Hedgehogpathway activity has been reported as well, furthersupporting this hypothesis (Omenetti et al., 2007).

A more concerted research effort in unraveling theHedgehog pathway intricacies and that of othersystems that modulate progenitor cell proliferation,apoptosis, and differentiation may shed furtherlight into the complex pathogenesis of PBC.

PBC is considered an organ-specific autoimmunedisease associated with the presence of well-characterized antimitochondrial antibodies. Thesetarget at least three components of the M2 familyof mitochondrial antigens: the E2 subunit ofpyruvate dehydrogenase complex (PDC-E2), the2-oxoglutarate dehydrogenase complex (OGDC),and branched-chain 2 oxo-acid dehydrogenasecomplex (BCOADC). Additional targets such asthe keto-glutaric acid dehydrogenase complex andthe dihydrolipoamide dehydrogenase binding pro-tein have been described (Gershwin et al., 2000).Marked homology exists between these differentantigenic targets, all share a lipoic acid moiety andare involved in oxidative phosphorylation. They arelocated on the inner mitochondrial matrix and playa critical role in the metabolism of keto-acidsubstrates. These antimitochondrial antibodies aredetected in the sera of at least 95% of affectedindividuals, and have been validated as highlysensitive and specific tools in the diagnosis of PBC(Kaplan and Gershwin, 2005).

PBC seems to be the only disease in whichautoreactive T cells and B cells responding to thePDC-E2 are detected. Autoantibodies directed atnuclear antigens have been described in approxi-mately 50% of patients PBC, and often in patientswho possess antimitochondrial antibodies (Kaplanand Gershwin, 2005). Their pathogenic role isfurther supported by reports demonstrating secre-tory IgA autoantibodies against PDC in the saliva,bile, and urine specimens of patients with PBC(Reynoso-Paz et al., 2000; Tanaka et al., 2000).Examples of antinuclear antibodies include thoseagainst the nuclear pore proteins gp210 and p62,both of which are believed to be associated withmore active and severe disease (Nakamura et al.,2007). The nuclear body protein sp100 is anotheridentified target. The nuclear-rim and nuclear-dotantinuclear patterns of these are highly specific forthe disease (Worman and Courvalin, 2003).

The main paradox in the above hypothesis,however, is the fact that mitochondrial proteins are

Primary Biliary Cirrhosis 143

present in all nucleated cells, yet the targets ofautoimmune injury are the biliary epithelium andsalivary duct cells. It is believed that cellularapoptosis can increase the exposure of PDC-E2domain to the immune system via modification ofits lysine-lipoyl moiety by glutathione (Odin et al.,2001). The immunoreactivity is decreased by gluta-thionylation, whereas it is sustained by inhibitionof glutathionylation. It is speculated that thisintricate control of immune expressivity is impairedin cells involved in the pathogenesis of PBC.Cellular apoptosis itself can cause aberrant expres-sion of PDC-E2 on cell surface, which leads to thefailure of attachment of this key regulatoryglutathione group (Odin et al., 2001). In vitrocaspase cleavage of PDC-E2 has been shown togenerate immunologically active protein fragments(Macdonald et al., 2004). In addition, specificxenobiotic modifications of the inner lysine-lipoyldomain of the PDC-E2 are immunoreactive whentested with the serum of patients with PBC, furthersupporting this mechanism (Amano et al., 2005).Markers of ongoing apoptosis have been reportedwithin affected portal tracts, including down-regulation of the antiapoptotic protein bcl-2(Matsumura et al., 2002).

The T-cell mitochondrial responses also contri-bute to bile duct injury in PBC. PDC-E2-specificCD4+ and CD8+ T cells have been identified inthe peripheral blood and liver of PBC patients,mostly during early disease states (Palmer et al.,1999; Kita et al., 2002). Epitope mapping studieshave identified the HLADR4�0101-restricted T-cellepitope that spans amino acid residues 163 through176 of the PDC-E2 domain. Also, CD8+ T cellsfrom livers of patients with PBC demonstratecytotoxicity against PDC-E2 159–167 pulsed auto-logous cells (Palmer et al., 1999).

Recently, a mouse model for PBC has beendescribed. Irie et al. (2006) demonstrated that theNOD.c3c4 mice congenically derived from a non-obese diabetic strain develop an autoimmunebiliary disease that models human PBC. Thesemice develop antibodies to PDC-E2 that are specificfor the inner lipoyl domain. The affected biliaryepithelium is infiltrated with CD3+, CD4+, andCD8+ T cells, and treatment with monoclonalantibody to CD3 protects further bile duct injury.

Histological analysis reveals destructive cholangitis,granuloma, and eosinophilic infiltration as seen inPBC; although, unlike PBC, the extrahepatic biliaryducts are also affected. These have been reports oftwo other mouse models that are associated withAMA and chronic biliary disease—both havedeficient T regulatory cells (Wakabayashi et al.,2006; Oertelt et al., 2006).

Potential associations between specific environ-mental exposures and the development of PBChave shed some light into its pathogenesis. Mole-cular mimicry is the most widely proposed mecha-nism for the initiation of autoimmunity (Selmi andGershwin, 2004). Its underlying concept is that ofcross-reactivity with self-antigens from circulatingantibodies developed in response to infection.Several causative culprits have been identified,including bacteria, viruses, and environmentalpollutants. Examples of bacterial pathogens linkedto PBC are Escherichia coli, Pseudomonas aerugi-

nosa, Helicobacter pylori, Chlamydia pneumoniae,and Haemophilus influenza. The most intriguingassociation is Novosphingobium aromaticivorans, aubiquitous pathogen, whose own PDC-E2 domaincontains 12 of 13 contiguous amino acids sequenceidentical to human PDC-E2 (Selmi and Gershwin,2004). Two case-control studies describe a greaterthan expected frequency of previous urinary tractinfection in patients with PBC (Gershwin et al.,2005; Howel et al., 2000). There is a report of ahuman b retrovirus resembling mouse mammary-tumor virus (MMTC) in patients with PBC(Mason et al., 2004), although this work hasnot been reproduced. The potential role of micro-organisms in triggering PBC via their interactionwith the innate immune system has been proposed(Hartmann and Krieg, 2000). A recent investigationdescribed the association between PBC and resi-dency near superfund toxic waste sites in New Yorkcity (Ala et al., 2006). Whether these findings aremere coincidental associations or etiologicallyrelevant is a matter of ongoing debate.

It has been suggested that pregnancy is a riskfactor for PBC. Persistence of fetal cells in thematernal circulation may play a role in thepathogenesis of PBC. However, existing data fromclinical investigations are quite disparate on thisissue (Corpechot et al., 2000a; Schoniger-Hekele


et al., 2002). The association between oral contra-ceptive use and PBC is weak, but recent datasuggest that current or prior use of hormonereplacement therapy is observed at higher thanexpected rates in patients with PBC compared tounaffected controls (Parikh-Patel et al., 2001). Lesswell investigated are the impact of diet and lifestyle.Past smoking history was observed in 76% ofpatients with PBC surveyed in one series from theUnited Kingdom, compared to 57% of unaffectedcontrols (Howel et al., 2000). A greater than 20pack-year history of smoking was associated witheven a higher prevalence rate of PBC. Such anassociation is biologically plausible, as toxiccompounds found in cigarette smoke activate Tlymphocyte cytokine responses that could play arole in the pathogenesis of PBC.

The older literature reports a higher frequency ofextrahepatic autoimmune diseases among patientswith PBC supports the autoimmune basis of thecondition (Culp et al., 1982). However, studiesdocumenting prevalence rates for specific associa-tions have reported divergent data. Both rheumatoidarthritis and thyroid disease were reported as oftenin PBC as in unaffected controls in one series, where-as the risk of Sjogren syndrome and Raynaud’sphenomenon was approximately fourfold higher(Watt et al., 2004). Classic rheumatoid arthritisdevelops in 5–10% of patients and approximately40–65% have symptoms of Sjogren syndrome,including keratoconjunctivitis and/or xerostomia.Clonal expansion of T cells bearing a specific betachain variable region (TCRBV3) has been demon-strated in some of these patients, suggesting thatpatients with PBC and CREST may have a distinctdisorder (Mayo et al., 1999). The significance ofsystemic lupus erythematosus (SLE) as risk factorfor PBC was also recently confirmed by multivariateanalysis (Watt et al., 2004). These associationsfurther support the hypothesis of genetic suscept-ibility as a predisposing factor for PBC.

4. Clinical presentations

PBC is diagnosed much earlier now than pre-viously. Nearly 60% are asymptomatic at diagnosisand underlying liver disease is often identified justby an elevation in serum ALP in an asymptomatic

individual. This may be accompanied by two- tofourfold rise in serum aminotranferases levels(Prince et al., 2004). Fatigue and pruritus are themost common presenting complaints (Witt-Sullivanet al., 1990). Fatigue itself has been a reportedcomplaint in up to 78% of patients and can be acause for significant disability (Forton et al., 2005).The cause of this fatigue, which is not refreshed bysleep, remains elusive. Recent data suggest apossible association between the fatigue of PBCwith altered autonomic control and daytimesomnolence (Newton et al., 2006). It is notnecessarily improved by liver transplantation(Goldblatt et al., 2002) and is not associated withliver disease severity (Cauch-Dudek et al., 1998).

The pruritus of PBC, whether local or diffuse,can also be severely distressing at times. It mayinterfere with sleep, as it is usually worst at night.Its onset often precedes the onset of jaundice andlessens with progression of the disease! The precisemechanism that promotes pruritus in chroniccholestasis remains uncertain, but as partial biliarydiversion and plasmapheresis alleviate this symp-tom the pruritigen is obviously present in both bileand blood (Ng et al., 2000; Cohen et al., 1985).Unexplained intermittent right upper quadrantpain is noted in approximately 10% of patients.The severity of liver disease may be discordantfrom the severity of symptoms. Overt symptomaticdisease develops within 2–4 years in the majority ofinitially asymptomatic patients, although nearlyone-third of patients will remain symptom-free formany years (Prince et al., 2004).

Additional findings in PBC include hyperlipide-mia, hypothyroidism, metabolic bone disease (withadvanced liver disease), and coexisting autoim-mune disease such as Sjogren’s syndrome andscleroderma (Watt et al., 2004). Portal hyper-tension and related complications may occurearly in the course of illness due to obliteration ofthe portal venous radicals probably secondary tothe inflammatory response within the portal triadscausing nodular regeneration hyperplasia (Colinaet al., 1992). Once cirrhotic, patients present withascites, hepatic encephalopathy, and/or esophagealvariceal hemorrhage. Fat-soluble vitamin defi-ciency, malabsorption, and steatorrhea occur onlyonce jaundice is present. With longstanding,


histologically advanced PBC, the risk of hepato-cellular carcinoma is significantly elevated (Nijhawanet al., 1999).

The physical examination is usually normal inpatients with asymptomatic PBC. As in all chroniccholestatic diseases increased melanin pigmenta-tion of the skin develops with time, made worseby chronic excoriation caused by pruritus. Xanthe-lasma are seen in a minority of patients, and xan-thomas are rare. Hepatosplenomegaly is anotherfeature predominant in a few. Jaundice is nowrarely noted (likely due to current therapy), butascites and edema suggest onset of liver failure(Prince et al., 2002).

Histologically, PBC is divided into four distinctstages. However, the liver is not always uniformlyinvolved, and a single biopsy may demonstrate thepresence of all four stages simultaneously. Thecharacteristic lesion of PBC is the asymmetricdestruction of the bile ducts within portal triads.Stage 1 is defined by portal inflammation. Stage 2 isdefined by extension of this inflammation beyondportal tracts into the surrounding parenchyma withor without associated duct loss. In stage 3, fibroussepta link adjacent portal triads. Stage 4 representsend-stage liver disease, characterized by frankcirrhosis within regenerative nodules.

The diagnosis of PBC is, therefore, based on aconstellation of findings. Current criteria requirethe presence of detectable AMA, abnormal liverenzymes (mostly alkaline phosphatase) for morethan 6 months, and histological findings in the liverthat are compatible with the PBC to make a‘definite’ diagnosis. A ‘possible’ diagnosis is made ifany two of these findings are present. Liver biopsyallows the severity of disease to be clarified andmay indicate the need for specific therapeuticregimens. As many as 10% of patients are AMAnegative, but their disease course seems identical tothat in patients with classic PBC (Michieletti et al.,1994) (Table 1).

5. Natural history and prognostic

considerations

Historically, the first case descriptions of PBCwere almost uniformly described in patients who

had presented with jaundice with or without end-stage liver disease. Access to routine screening ofliver chemistries has since generated a large cohortof asymptomatic patients. Asymptomatic PBCaccounts for over 60% of newly diagnosed cases(Prince et al., 2002). In a population-based cohortof 469 patients with asymptomatic PBC, thecumulative 1-year incidence rates for developingfatigue, pruritus, and complications from portalhypertension were 15, 13, and 5%, respectively(Prince et al., 2004). However, 10 years later, only20% continued to remain asymptomatic.

Despite refined diagnostic and clinical tools,unfortunately not all patients with PBC receivetheir diagnosis when the disease is still in an earlyhistological stage. In a study of 262 patients withPBC, the probability of succumbing to liver failureor requiring a liver transplant in those withadvanced disease, as compared with a healthy age-and sex-matched population, was significantlyincreased despite UDCA therapy (relative risk2.2) (Corpechot et al., 2005). In a large cohort of770 patients from northern England, the mediantime until death or liver transplant referral wasonly 9.3 years (Prince et al., 2002). Patients whowere asymptomatic at diagnosis did not live longerthan their symptomatic counterparts in starkcontrast to other studies ascribing a clear survivaladvantage to those with early and asymptomaticdisease (Pares et al., 2000). This difference is likelyrelated to age—the cohort from the studies inthe north of England being at least one decadeolder at the time of initial diagnosis. Of note, there

Table 1

AMA-negative PBC vs. AMA-positive PBC

Clinical picture AMA negative

(17)

AMA positive

(17)

Female:male 14:3 14:3

Age at diagnosis (mean) 51.1 55.0

Jaundice 3 3

Fatigue 8 7

Pruritus 9 11

Hypothyroidism 3 3

Polyarthralgias 5 3

Sicca syndrome 3 7

Raynaud’s 2 4

Michieletti et al. (1994).


is no distinguishing feature that helps predictwhich patients will remain asymptomatic indefi-nitely (Springer et al., 1999). Neither the presencenor the AMA titer affects risk of disease progres-sion, survival, or treatment responsiveness (VanNorstrand et al., 1997). But recent data suggestthat presence of anti-gp210 antibodies, and parti-cularly when in high titer, may predict thosepatients with poor outcome (Nakamura et al.,2007). Prospective cohort studies with long follow-up periods and serial clinical, biochemical, andhistological data will prove invaluable in unravel-ing markers of disease progression in PBC.

For symptomatic PBC, advanced age, elevatedINR, jaundice, low serum albumin, edema, ascites,and advanced histological stage are stronglycorrelated with median survival rates less than 5years from the time of diagnosis. Serum totalbilirubin remains the most reliable clinical variablefor survival estimates and is a key component incurrent mathematical predictive models of PBC(Dickson et al., 1989). Liver failure remains thepredominant cause of death in patients with PBC.A 60% mortality from liver-related causes isreported in symptomatic patients (Prince et al.,2002). Thirty percent of initially asymptomaticpatients will succumb to liver failure as well (Princeet al., 2004). Such numbers, however, are derivedfrom studies in large tertiary referral centers priorto the widespread use of UDCA, and thus findingsmay not reflect the more current and contemporaryexperience of PBC therapy. Liver failure hasbeen described in patients without cirrhosis butwith severe cholestasis and marked ductopenia(Vleggaar et al., 2001). Non-liver-related mortalityrisk is nearly doubled in patients with asympto-matic disease (Prince et al., 2002), an observationthat may stem from a surveillance bias during theevaluation of more significant medical comorbidi-ties, although cigarette smoking is more common inpatients with PBC than the general population(Parikh-Patel et al., 2001).

6. Treatment considerations

The Food and Drug administration has approvedUDCA at 13–15mg/kg body weight as the

preferred pharmacological agent of choice for thetreatment of PBC. UDCA is an epimer of cheno-deoxycholic acid, and comprises 2% of human bileacids. It functions as a choleretic agent. It decreasesserum levels of bilirubin, alkaline phosphatase,alanine aminotransferase, aspartate aminotransfer-ase, cholesterol, and IgM. In a study that combineddata from three controlled trials, UDCA 13–15mg/kg/day was found to decrease likelihood of livertransplantation and death after 4 years (Pouponet al., 1997). However, the clinical use and thera-peutic benefits of UDCA in PBC remain contro-versial. Two separate meta-analyses highlighted noclear survival difference between UDCA-treatedand placebo-treated patients (Goulis et al., 1999;Gong et al., 2007). However, the surveyed rando-mized trials had questionable validity, as markeddifferences in follow-up periods and UDCA doses(at times suboptimal) may have flawed the results.However, no difference was observed even if short-duration trials were analyzed separately thanlonger-duration ones. A third meta-analysis featur-ing data from more methodologically sound trialsdemonstrated that the risk of death and livertransplantation was 32% lower in the UDCA-treated group (Corpechot et al., 2005), but the mostrecent meta-analysis of randomized clinical trialsusing Bayesian approach indicated no benefit ofUDCA on morbidity, mortality, and need for livertransplantation (Gong et al., 2007). The lifeexpectancy of patients treated with and respondingto UDCA was similar to that of age- and sex-matched healthy controls for up to 20 years inanother survey; nevertheless, detailed histologicalstudies indicate that UDCA slows disease progres-sion particularly in those with early-stage histolo-gical involvement (Angulo et al., 1999; Corpechotet al., 2000b), but no disease regression is observed.

The last three decades have seen a variety ofadjuvant medications that have been used alone orin combination with UDCA in patients with anincomplete response to UDCA monotherapy.These include systemic corticosteroids, budesonide,azathioprine, mycophenolate mofetil, metho-trexate, colchicine, silymarin, and bezafibrate.Neither the larger trials nor the pilot studies haveindicated any survival benefit from their agents.Now that serum bilirubin levels remain normal for


so many years there is no surrogate markeravailable as an indirect measure of outcome.Hence, therapeutic trials in early PBC are verydifficult to conduct as patients are intolerant ofprolonged trials and the costs of running same areprohibitive. At the present time, UDCA incombination with various other adjuvant productsis not recommended outside of research protocols.

7. Conclusion

There is still ongoing debate about the pathophy-siology of PBC since its original description in 1851.With the advent of sensitive diagnostic and researchtools, it has become a liver disease, which is well-recognized worldwide; thus, the majority of patientsare now diagnosed at an early asymptomatic stage.Epidemiological data indicate that geographicclustering occurs, implicating both genetic andenvironmental influences in its pathogenesis. Givena genetically primed host both xenobiotics and viralinfections could promote the development of PBC.The recent description of mice models for PBC isexciting and will surely guide further geneticresearch. The pathophysiological basis of PBCseems to lie in the demonstrated defects in immunetolerance that results in the activation and expan-sion of self-antigen-specific T and B lymphocyteclones and the production of circulating autoanti-bodies, cytokines, and other inflammatory media-tors. Larger prospective cohort studies withlongitudinal clinical, serological, genetical, andhistological data will prove invaluable in unravelingnew associations, and perhaps highlighting markersof disease progression. The true impact of UDCAon disease course and natural history needs moredefinitive scrutiny. Its inadequate efficacy in causingdisease regression gives impetus to further studiesof the pathogenetic mechanisms of the disease anddrives the endless search for new therapies.

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CHAPTER 13

Autoimmune Hepatitis

Diego Vergani�, Giorgina Mieli-Vergani

Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, Denmark

Hill, London SE5 9RS, UK

1. Definition

Autoimmune hepatitis (AIH) is a progressiveinflammatory liver disorder, preferentially affectingfemales, characterized histologically by interfacehepatitis (Fig. 1), and serologically by high levels oftransaminases and immunoglobulin G (IgG) andpresence of autoantibodies, in the absence of aknown aetiology. AIH is divided into two maintypes according to the autoantibody profile: type 1is positive for anti-nuclear antibody (ANA) and/oranti-smooth muscle antibody (SMA); type 2 ispositive for anti-liver/kidney microsomal type 1antibody (anti-LKM-1). AIH responds satisfacto-rily to immunosuppressive treatment.

2. History and epidemiology

AIH is a recently recognized disease having beenfirst described by Waldenstrom in 1950. Seroposi-tivity for ANA, the hallmark of systemic lupuserythematosus, led Mackay to call it ‘lupoidhepatitis’ (Mackay et al., 1956), a term no longerused. Since the disease frequently presents acutely,similarly obsolete is the term ‘chronic activehepatitis’, which implied that the disease shouldbe chronic, i.e. of at least six months duration,before institution of immunosuppression. Before

the efficacy of immunosuppression was established,untreated severe AIH had a mortality of 50% at5 years and 90% at 10 years (Soloway et al.,1972; Murray-Lyon et al., 1973). The prevalence of

Figure 1. Portal and periportal lymphocyte and plasma cell

infiltrate, extending to and disrupting the parenchymal limiting

plate (interface hepatitis). Swollen hepatocytes, pyknotic

necroses and acinar inflammation are present. Haematoxylin

and eosin staining. (Picture kindly provided by Dr. Alberto

Quaglia.) (See Colour Plate Section.)E-mail address: [email protected]


Tel.:+44-(0)-20-3299-3305; Fax:+44-(0)-20-3299-3700


DOI: 10.1016/S1571-5078(07)00013-X

dx.doi.org/10.1016/S1571-5078(07)00013-X.3d

AIH is unknown. Prevalences varying from 1/200,000in the US general population (Manns et al.,1998) to 20/100,000 in females over 14 years ofage in Spain (Primo et al., 2004) have beenreported, though probably both figures are under-estimates.

3. Clinical features

The diagnosis of AIH is based on the presence ofpositive autoantibodies, elevated transaminase andIgG levels, and interface hepatitis on liver biopsy.The latter is required to confirm the diagnosis andto evaluate the severity of liver damage. The levelsof transaminases and of IgG do not reflect theextent of the histological inflammatory activity,nor indicate presence or absence of cirrhosis.Other hepatic disorders that may share some ofthe above features need to be considered in thedifferential diagnosis. These include viral hepati-tides (in particular B and C), Wilson disease anddrug-induced liver disease (minocycline, nitrofur-antoin, isoniazid, propylthiouracil, diclofenac,pemoline, atovastatin and alpha-methyldopa).Female patients outnumber male patients (3:1). Afamily history of autoimmune diseases is present insome 40% of the patients. Associated autoimmunedisorders are present at diagnosis or develop duringfollow-up in at least one-fifth of the patientsand include thyroiditis, ulcerative colitis, insulin-dependent diabetes, vitiligo, nephrotic syndrome,hypoparathyroidism and Addison’s disease, thelast two being observed in particular in anti-LKM-1 positive patients or in patients with auto-immune polyendocrinopathy-candidiasis-ectodermaldystrophy (APECED), a monogenic disorder witha variable phenotype that includes AIH in some20% of the cases. Typically, AIH responds toimmunosuppressive treatment, which should beinstituted as soon as diagnosis is made. The onsetof AIH is often ill defined, and it frequently mimicsacute hepatitis, particularly in young patients. Twomain types of AIH are recognized, according to thepresence of SMA and/or ANA or anti-LKM-1(Fig. 2). Major targets of SMA are the microfila-ments (MFs) of smooth muscle, whereas the

molecular target of anti-LKM-1 is cytochromeP4502D6 (CYP2D6). The distinction in type 1 andtype 2 AIH is particularly relevant in paediatrics,since anti-LKM-1 positive disease is quite rare, butnot absent, in adults. In paediatrics, anti-LKM-1positive AIH represents one-third of all cases andhas a clinical course similar to ANA/SMA-positiveAIH, though anti-LKM-1 positive children presentat a younger age, more often with an acute onset,including fulminant hepatitis, and have associatedIgA deficiency (Gregorio et al., 1997). There arethree main patterns of disease presentation: anacute onset, characterized by non-specific symp-toms of malaise, nausea/vomiting, anorexia, andabdominal pain, followed by jaundice, dark urine,and pale stools; an insidious onset, with an illnesscharacterized by progressive fatigue, relapsingjaundice, headache, anorexia, and weight loss; andfinally a presentation with complications of portalhypertension, such as haematemesis from oesopha-geal varices, bleeding diathesis, chronic diarrhoea,weight loss, and vomiting. The mode of presenta-tion of AIH is therefore variable, and the diseaseshould be suspected and excluded in all patientspresenting with symptoms and signs of prolon-ged or severe liver disease. Some patients, however,are completely asymptomatic and are diagno-sed after incidental discovery of abnormal liverfunction tests. The course of disease can befluctuating, with flares and spontaneous remis-sions, a pattern which may result in delayed referraland diagnosis. The majority of the patients,however, on physical examination have clinicalsigns of an underlying chronic liver disease, i.e.cutaneous stigmata (spider nevi, palmar erythema,leukonikia, striae), firm liver and splenomegaly; atultrasound the liver parenchyma is often nodularand heterogenous.

4. Diagnosis and laboratory findings

Diagnosis of AIH is based on a series of positiveand negative criteria (Johnson and McFarlane,1993; Alvarez et al., 1999). Liver biopsy is necessaryto establish the diagnosis, the typical histolo-gical picture including the following: a dense

D. Vergani, G. Mieli-Vergani154

mononuclear and plasma cell infiltration of theportal areas, which expands into the liver lobule;destruction of the hepatocytes at the periphery ofthe lobule with erosion of the limiting plate(‘interface hepatitis’); connective tissue collapseresulting from hepatocytes death and expandingfrom the portal area into the lobule (‘bridgingcollapse’); and hepatic regeneration with ‘rosette’formation (Fig. 1). In addition to the typical histo-logy, other positive criteria include elevated serumtransaminase and IgG/gammaglobulin levels, andpresence of ANA, SMA or anti-LKM-1. Thediagnosis of AIH has been advanced by the criteriadeveloped by the International Autoimmune Hepa-titis Group (IAIHG) (Johnson and McFarlane,1993; Vergani et al., 2004), where negative criteriasuch as evidence of infection with hepatitis B or Cvirus or Wilson disease, alcohol, etc are taken intoaccount in addition to the positive criteria men-tioned above. IAIHG has provided a scoringsystem for the diagnosis of AIH, mainly used forresearch purposes (Table 1).

4.1. Autoantibodies

A key component of the criteria developed by theIAIHG (Johnson and McFarlane, 1993; Alvarezet al., 1999; Vergani et al., 2004) is detection byindirect immunofluorescence of autoantibodies toconstituents of the nuclei (ANA), smooth muscle(SMA) and liver kidney microsome type 1 (anti-LKM-1). Autoantibody detection not only assistsin the diagnosis, but also allows differentiation ofAIH types. ANA and SMA that characterize type1 AIH and anti-LKM-1 that defines type 2 AIHare practically mutually exclusive; in those rareinstances when they are present simultaneously,the clinical course is similar to that of AIH type 2.Recognition and interpretation of the immuno-fluorescence patterns is not always straightforward(Vergani et al., 2004). The operator dependency ofthe technique and the relative rarity of AIHexplain the non-infrequent occurrence of errorsin reporting, particularly of less frequent specifi-cities such as anti-LKM-1. Problems do exist

SMA ANA LKM

Figure 2. Immunofluorescence appearance of smooth muscle (SMA), anti-nuclear (ANA) and anti-liver/kidney microsomal type 1

(anti-LKM-1) autoantibodies on renal and liver rodent sections. SMA stains the small artery and the glomeruli in a renal section, ANA

the nuclei in a liver section and anti-LKM-1 the cytoplasm of hepatocytes and proximal renal tubules. SMA and/or ANA are the

markers of autoimmune hepatitis type 1: Their molecular targets are still unknown. Anti-LKM-1 characterizes autoimmune hepatitis

type 2 and its target is cytochrome P4502D6. (See Colour Plate Section.)

Autoimmune Hepatitis 155

between laboratory reporting and clinical inter-pretation of the results that are partly dependenton insufficient standardization of the tests, butalso partly dependent on a degree of unfamiliarityof some clinicians with the disease spectrum ofAIH. With regard to standardization, guidelineshave been given by the IAIHG serology committee(Vergani et al., 2004). The basic technique for theroutine testing of autoantibodies relevant to AIHis indirect immunofluorescence on a freshly pre-pared rodent substrate that should include kidney,liver and stomach to allow the detection of ANA,SMA, anti-LKM-1 as well as anti-liver cytosoltype 1 (anti-LC-1), but also of anti-mitochondrialantibody (AMA), the serological hallmark of pri-mary biliary cirrhosis. Commercially availablesections are of variable quality because, tolengthen shelf-life, they are treated with fixatives(acetone, ethanol or methanol), which readilyresult in enhanced background staining that mayhinder the recognition of diagnostic autoantibo-dies, especially when these are present at low titre.Since healthy adults may show reactivity at theconventional starting serum dilution of 1/10, thearbitrary dilution of 1/40 has been consideredclinically significant by the IAIHG. In contrast, inhealthy children, autoantibody reactivity is infre-quent, so that titres of 1/20 for ANA and SMAand 1/10 for anti-LKM-1 are clinically relevant.Positive sera should be titrated to extinction. Thelaboratory should report any level of positivityfrom 1/10 in children to 1/40 in adults, and theattending physician should interpret the resultwithin the clinical context.

ANA is readily detectable as a nuclear stainingin kidney, stomach and liver. On the liver, inparticular, the ANA pattern may be detected ashomogeneous, or coarsely or finely speckled. Inmost cases of AIH, but not in all, the pattern ishomogeneous. To obtain a much clearer and easierdefinition of the nuclear pattern, HEp2 cells thathave prominent nuclei should be used. HEp2 cells,however, should not be used for screening pur-poses, because nuclear reactivity to these cells isfrequent at low serum dilution (1/40) in the normalpopulation (Tan et al., 1997). For ANA, likelymolecular targets include nuclear chromatin and

Table 1

IAIHG scoring system for the diagnosis of autoimmune

hepatitis

Parameter Feature Score

Principal parameters

Sex Female +2

ALP:AST (or ALT) ratio W3 �2

1.5–3 0

o1.5 +2

Serum globulins or IgG (times

above normal)

W2.0 +3

1.5–2.0 +2

1.0–1.5 +1

o1.0 0

ANA, SMA or anti-LKM-1 titresa W1:80 +3

1:80 +2

1:40 +1

o1:40 0

AMA Positive �4

Viral markers of active infection Positive �3

Negative +3

Hepatotoxic drug history Yes �4

No +1

Average alcohol o25 g/day +2

W60 g/day �2

Histological features Interface hepatitis +3

Plasma cells +1

Rosettes +1

None of above �5

Biliary changesb �3

Atypical changesc �3

Optional additional parameters

Seropositivity for other defined

autoantibodies

Anti-SLA/LP, actin,

LC1, ASGPR, pANCA

+2

HLA DR3 or DR4 +1

Response to therapy Remission +2

Relapse +3

Interpretation of aggregate scores

Pre-treatment

Definite AIH W15

Probable AIH 10–15

Post treatment

Definite AIH W17

Probable AIH 12–17

IAIHG, International Autoimmune Hepatitis Group; ALP,

alkaline phosphatase; AST, aspartate aminotransferase; ALT,

alanine aminotransferase; IgG, immunoglobulin G; ANA, anti-

nuclear antibody; SMA, smooth muscle antibody; LKM-1, liver

kidney microsomal antibody type 1; AMA, anti-mitochondrial

antibody; SLA/LP, soluble liver antigen/liver pancreas; LC1,

liver cytosol type 1; ASGPR, asialoglycoprotein receptor;

pANCA, perinuclear anti-neutrophil cytoplasmic antibody;

HLA, human leukocyte antigen; AIH, autoimmune hepatitis.a In children, significant titres are 1:20 for ANA and SMA,

and 1:10 for anti-LKM-1.b Including granulomatous cholangitis, concentric periductal

fibrosis, ductopaenia, marginal bile duct proliferation with

cholangiolitis.c Any other prominent feature suggesting a different aetiology.

Modified from Alvarez et al. (1999).


histones, akin to lupus, but there are probablyseveral others. The advent of new techniques usingrecombinant nuclear antigens and immunoassayswill enable a better definition of ANA targetantigens, an assessment of their specificity fordiagnosis and their possible role in the pathogen-esis of AIH type 1.

SMA is detected on kidney, stomach and liver,where it stains the walls of the arteries. In thestomach it also stains the muscularis mucosa andthe lamina propria. On the renal substrate, it ispossible to visualize the V, G and T patterns; Vrefers to vessels, G to glomeruli, and T to tubules(Bottazzo et al., 1976). The V pattern is presentalso in non-autoimmune inflammatory liver dis-ease, in autoimmune diseases not affecting the liverand in viral infections, but the VG and VGTpatterns are more specific for AIH. The VGTpattern corresponds to the so-called F actin orMF pattern observed using cultured fibroblasts assubstrate. Neither the VGT nor the anti-MFpatterns are, however, entirely specific for thediagnosis of AIH type 1. Though the VGT-MFpattern has been suggested to be due to a specificantibody uniquely found in AIH type 1, it may justreflect high-titre SMA. The molecular target of theMF reactivity that is observed in AIH type 1remains to be identified. Though ‘anti-actin’reactivity is strongly associated with AIH type 1,some 20% of SMA-positive AIH type 1 patients donot have the F-actin/VGT pattern. The absence,therefore, of anti-actin SMA does not exclude thediagnosis of AIH (Muratori et al., 2002).

Anti-LKM-1 stains brightly the liver cell cyto-plasm and the P3 portion of the renal tubules, butdoes not stain gastric parietal cells. Anti-LKM-1 isoften confused with AMA, since both autoantibo-dies stain liver and kidney. Compared to anti-LKM-1, AMA stains the liver more faintly and therenal tubules more diffusely with an accentuation ofthe small distal ones. In contrast to anti-LKM-1,AMA also stains the gastric parietal cells. In thecontext of AIH, there can be positivity for AMA inrare cases (Gregorio et al., 1997). The identificationof the molecular targets of anti-LKM-1, i.e.cytochrome P4502D6 (CYP2D6), and of AMA,i.e. enzymes of the 2-oxo-acid dehydrogenase

complexes, has led to the establishment of immu-noassays based on the use of the recombinant orpurified antigens (Vergani et al., 2004). Commer-cially available ELISAs are accurate for detection ofanti-LKM-1, at least in the context of AIH type 2,and reasonably accurate for the detection of AMA.Therefore, if a doubt remains after examination byimmunofluorescence, this can be resolved by the useof molecularly based immunoassays.

Other autoantibodies less commonly tested butof diagnostic importance include anti-LC-1, anti–neutrophil cytoplasm antibody (ANCA) and solu-ble liver antigen (SLA). Anti-LC-1, which can bepresent on its own, but frequently occurs inassociation with anti-LKM-1, is an additionalmarker for AIH type 2 and targets formimino-transferase cyclodeaminase (FTCD) (Lapierreet al., 1999). ANCA can also be positive in AIH(Gregorio et al., 1997; Vergani et al., 2004). Thereare three types of ANCA, namely cytoplasmic(cANCA), perinuclear (pANCA) and atypicalperinuclear, the target of which is a peripheralnuclear and not cytoplasmic perinuclear antigen(hence the suggested name of pANNA, i.e.peripheral anti-nuclear neutrophil antibody). Thetype found in AIH type 1 is pANNA, which is alsofound in inflammatory bowel disease and scleros-ing cholangitis, while it is virtually absent in type 2AIH. Anti-SLA that was originally described as thehallmark of a third type of AIH in humans (Mannset al., 1987) is also found in some 50% of patientswith type 1 and type 2 AIH, where it defines amore severe course (Ma et al., 2002). Screening ofcDNA expression libraries using high-titre anti-SLA serum has allowed to identify the moleculartarget antigen as UGA tRNA suppressor asso-ciated antigenic protein (tRNP(Ser)Sec) (Wieset al., 2000; Costa et al., 2000). Molecularly baseddiagnostic assays have become available, but theirfull evaluation is still under way.

After assessment of all the specificities describedabove, there is a small proportion of patients withAIH without detectable autoantibodies. Thiscondition, which responds to immunosuppressionlike the seropositive form, represents seronegativeAIH, and its prevalence and clinical characteristicsremain to be defined.


5. Pathophysiology

5.1. Genetics

AIH is a ‘complex trait’ disease, i.e. a condition notinherited in a Mendelian autosomal dominant,autosomal recessive or sex-linked fashion. Themode of inheritance of a complex trait disorder isunknown and involves one or more genes, operatingalone or in concert, to increase or reduce the risk ofthe trait, and interacting with environmentalfactors.

Susceptibility to AIH is imparted by geneswithin the histocompatibility lymphocyte antigen(HLA) region on the short arm of chromosome 6,especially those encoding DRB1 alleles. These classII major histocompatibility complex (MHC) mole-cules are involved in peptide antigen presentationto CD4 T cells, suggesting the participation ofMHC class II antigen presentation and T cellactivation in the pathogenesis of AIH.

In Europe and North America, susceptibility toAIH type 1 is conferred by the possession of HLADR3 (DRB1�0301) and DR4 (DRB1�0401), bothheterodimers containing a lysine residue at position71 of the DRB1 polypeptide and the hexamericamino acid sequence LLEQKR at positions 67–72(Donaldson, 2002, 2004). In Japan, Argentina andMexico, susceptibility is linked to DRB1�0405

and DRB1�0404, alleles encoding arginine ratherthan lysine at position 71, but sharing the motifLLEQ-R with DRB1�0401 and DRB1�0301

(Czaja and Donaldson, 2000). Thus, K or R atposition 71 in the context of LLEQ-R may becritical for susceptibility to AIH, favouring thebinding of autoantigenic peptides complementaryto this hexameric sequence.

The lysine-71 and other models for AIH type 1cannot explain the disease completely, since forexample in European and North Americanpatients, presence of lysine-71 is associated with asevere, mainly juvenile, disease in DRB1�0301-positive patients, but with a mild, late-onset,disease in DRB1�0401-positive patients. Othergenes within or/and without the MHC are, there-fore, likely to be involved in determining thephenotype. Possible candidates are the MHC-encoded complement and tumour necrosis factor

alpha (TNF-a) genes, mapping to the class IIIMCH region, and the MHC class I chain-related Aand B genes. Patients with AIH, whether anti-LKM-1 or ANA/SMA positive, have isolatedpartial deficiency of the HLA class III complementcomponent C4, which is genetically determined(Vergani et al., 1985; Doherty et al., 1994).

Susceptibility to AIH type 2 is conferred by thepossession of HLA DR7 (DRB1�0701) and DR3(DRB1�0301), patients positive for DRB1�0701

having a more aggressive disease and severeprognosis (Ma et al., 2006).

A form of AIH resembling AIH type 2 affectssome 20% of patients with APECED, a conditionalso known as autoimmune polyendocrine syn-drome 1. APECED is a monogenic autosomalrecessive disorder caused by homozygous muta-tions in the AIRE1 gene and characterized by avariety of organ-specific autoimmune diseases, themost common of which are hypoparathyroidismand primary adrenocortical failure, accompaniedby chronic mucocutaneous candidiasis (Simmondsand Gough, 2004; Liston et al., 2005). The AIRE1

gene sequence consists of 14 exons containing 45different mutations, with a 13bp deletion atnucleotide 964 in exon 8 accounting for more than70% of APECED alleles in the UK (Simmondsand Gough, 2004). The protein predicted to beencoded by AIRE1 is a transcription factor. AIRE1

is highly expressed in medullary epithelial cells andother stromal cells in the thymus involved in clonaldeletion of self-reactive T cells. Studies in a murinemodel indicate that the gene inhibits organ-specificautoimmunity by inducing thymic expression ofperipheral antigens in the medulla leading tocentral deletion of autoreactive T cells. Interest-ingly, APECED has a high level of variability insymptoms, especially between populations. Sincevarious gene mutations have the same effect onthymic transcription of ectopic genes in animalmodels, it is likely that the clinical variability acrosshuman populations relates to environmental orgenetic modifiers. Of the various genetic modifiers,perhaps the most likely to synergize with AIRE

mutations are polymorphisms in the HLA region.HLA molecules are not only highly variable andstrongly associated with multiple autoimmunediseases, but are also able to affect thymic


repertoire selection of autoreactive T cell clones.Carriers of a single AIRE mutation do not developAPECED. However, although the inheritancepattern of APECED indicates a strictly recessivedisorder, there are anecdotal data of mutations in asingle copy of AIRE being associated with humanautoimmunity of a less severe form than classicallydefined APECED (Simmonds and Gough, 2004;Liston et al., 2005). The role of AIRE1 hetero-zygote state in the development of AIH remains tobe established.

5.2. Immune mechanisms

The typical histological picture of AIH, interfacehepatitis, is characterized by a dense mononuclearcell infiltrate eroding the limiting plate and invad-ing the parenchyma (De Groote et al., 1968;Scheuer, 1973). Immunocytochemical studies haveidentified the phenotype of the infiltrating cells. Tlymphocytes mounting the alpha/beta T-cell recep-tor predominate. Among the T cells, a majority arepositive for the CD4 helper/inducer phenotype,and a sizable minority are positive for the CD8cytotoxic phenotype. Lymphocytes of non–T-celllineage are fewer and include (in decreasing orderof frequency) natural killer cells (CD16/CD56positive), macrophages and B lymphocytes (Senaldiet al., 1992). The recently described natural killer Tcells, which express simultaneously markers ofboth natural killer (CD56) and T cells (CD3), areinvolved in liver damage in an animal model ofAIH (Takeda et al., 2000).

A powerful stimulus must be promoting theformation of the massive inflammatory cell infil-trate present at diagnosis. Whatever the initialtrigger, it is most probable that such a high numberof activated inflammatory cells cause liver damage.

There are different possible pathways that anautoimmune attack can follow to inflict damage onhepatocytes (Fig. 3). It is believed that liver damageis orchestrated by CD4+ T lymphocytes recogniz-ing a self-antigenic peptide on hepatocytes. Totrigger an autoimmune response, the peptide mustbe embraced by an HLA class II molecule andpresented to uncommitted (naıve) CD4+ T helper(Th0) cells by professional antigen-presenting cells

(APC), with the co-stimulation of ligand–ligand(CD28+ on Th0, CD80+ on APC) fosteringinteraction between the two cells. Th0 cells becomeactivated, differentiate into functional phenotypesaccording to the cytokines prevailing in the micro-environment and the nature of the antigen, andinitiate a cascade of immune reactions determinedby the cytokines these activated T cells produce.Th1 cells, arising in the presence of the macro-phage-produced interleukin 12 (IL-12), secretemainly IL-2 and interferon gamma (IFN-g), whichactivate macrophages, enhance expression of HLAclass I antigens (increasing liver cell vulnerabilityto a CD8+ T cell cytotoxic attack) and induceexpression of HLA class II molecules on hepato-cytes. Th2 cells, which differentiate from Th0 if themicroenvironment is rich in IL-4, produce mainlyIL-4, IL-10 and IL-13 which favour autoantibodyproduction by B lymphocytes. Physiologically, Th1and Th2 antagonize each other. Th17 cells, arecently described population (Weaver et al., 2006;Steinman, 2007), arise in the presence of trans-forming growth factor beta (TGF-b) and IL-6 andappear to have an important effector role ininflammation and autoimmunity. The process ofautoantigen recognition is strictly controlled byregulatory mechanisms, such as those exerted byCD4+CD25+ regulatory T cells, which are derivedfrom Th0 in the presence of TGF-b, but in theabsence of IL-6. If regulatory mechanisms fail, theautoimmune attack is perpetuated.

Over the past three decades, different aspectsof the above pathogenic scenario have beeninvestigated.

5.2.1. T regulatory cellsAutoimmunity arises on the background of defec-tive immunoregulation and this has been repeat-edly reported in AIH. Early studies showed thatpatients with AIH had low levels of circulating Tcells expressing the CD8+ marker, and impairedsuppressor cell function which segregates with thepossession of the disease-predisposing HLA hap-lotype B�08/DRB1�03 (formerly B8/DR3) and iscorrectable by therapeutic doses of corticosteroids(Nouri-Aria et al., 1985; Nouri-Aria et al., 1982).It is possible, though not formally tested, thatthese early characterized CD8+ T cells with a


suppressor function represent the recently definedCD8+CD28� suppressor T cells (Cortesini et al.,2001). Furthermore, patients with AIH were shownto have a defect in a subpopulation of T cellscontrolling the immune response to liver-specificmembrane antigens (Vento et al., 1984). Novelexperimental evidence confirms an impairment ofthe immunoregulatory function in AIH. Amongstrecently defined T cell subsets with potentialimmunosuppressive function, CD4+ T cells con-stitutively expressing the IL-2 receptor alpha chain(CD25) [T regulatory cells (T-regs)] have emerged

as the dominant immunoregulatory subset oflymphocytes (Shevach et al., 2001). These cells,which represent some 5% of the total population ofperipheral CD4+ T cells in health, control innateand adaptive immune responses by preventingproliferation and effector function of autoreactiveT cells. In patients with AIH, T-regs are defectivein number and function compared to normalcontrols, and this impairment relates to the stageof disease, being more evident at diagnosis thanduring drug-induced remission (Longhi et al., 2004;Longhi et al., 2005; Longhi et al., 2006). The

Class I

B

APC

P

Tc

Th2

cellLiver

Th1Tr

IL-4

NKIL-17

IL-6Th17

IL-17

TGF-β

Th0

IL-4

IL-2

IL-12

IL-1

M

Co-stimuli

IFN-γ

IFN-γ

TNF-α

Class IIPeptide

IL-10IL-13

Class II

Figure 3. Autoimmune attack to the liver cell. A specific autoantigenic peptide is presented to an uncommitted T helper (Th0)

lymphocyte within the HLA class II molecule of an antigen-presenting cell (APC). Th0 cells become activated and, according to the

presence in the microenvironment of interleukin (IL)-12 or -IL4 and the nature of the antigen, differentiate into Th1 or Th2 and initiate

a series of immune reactions determined by the cytokines they produce: Th2 secrete mainly IL-4, IL-10 and IL-13, and direct

autoantibody production by B lymphocytes; Th1 secrete IL-2 and IFN-g, which stimulate T cytotoxic (Tc) lymphocytes, enhance

expression of class I and induce expression of class II HLA molecules on hepatocytes and activate macrophages; activated macrophages

release IL-1 and TNF-a. If T regulatory cells (T-regs) do not oppose, a variety of effector mechanisms are triggered: Liver cell

destruction could derive from the action of Tc lymphocytes; cytokines released by Th1 and recruited macrophages; complement

activation or engagement of Fc receptor-bearing cells such as natural killer (NK) lymphocytes by the autoantibody bound to the

hepatocyte surface. The role of the recently described Th17 cells, which arise in the presence of transforming growth factor beta (TGF-b)and IL-6 is under investigation.


percentage of T-regs inversely correlates withmarkers of disease severity, such as anti-SLA andanti-LKM-1 autoantibody titres, suggesting that areduction in regulatory T cells favours the serolo-gical expressions of autoimmune liver disease. Ifloss of immunoregulation is central to the patho-genesis of AIH, treatment should concentrate onrestoring T-regs’ ability to expand, with consequentincrease in their number and function. This is atleast partially achieved by standard immunosup-pression, since numbers of T-regs increase duringremission (Longhi et al., 2004, 2005, 2006).

5.2.2. Autoreactive T cellsAs mentioned above, to trigger an autoimmuneresponse, a peptide embraced by an HLA class IImolecule must be presented to uncommitted Thelper (Th0) cells by professional APCs (Fig. 3).Given the impaired regulatory function describedabove, it is suspected that in AIH an autoantigenicpeptide is indeed presented to the helper/inducer Tcells, leading to their sustained activation. There isdirect, albeit limited, evidence that an autoanti-genic peptide is presented and recognized in AIHtype 2 (Ma et al., 2006). Activation of T helper cellshas been documented in earlier studies on AIH,both in the liver and in the peripheral blood(Senaldi et al., 1992; Lobo-Yeo et al., 1987). Theseactivated cells are mainly of the CD4 phenotype,and their numbers are highest in the most activestages of AIH.

Advances in the study of T cells have occurred inAIH type 2, since the knowledge that CYP2D6 isthe main autoantigen has enabled the characteriza-tion of both CD4 and CD8 T cells targeting thiscytochrome. One study has shown that CD4 T cellsfrom patients with type 2 AIH positive for thepredisposing HLA allele DRB1�0701 recognizeseven regions of CYP2D6 (Ma et al., 2006), fiveof which have later been shown to be alsorecognized by CD8 T cells (Longhi et al., 2007).High numbers of IFN-g-producing CD4 T cellsand CD8 T cells are associated with biochemicalevidence of liver damage, suggesting a combinedcellular immune attack.

What triggers the immune system to react to anautoantigen is unknown. A lesson may be learnedby the study of humoral autoimmune responses

during viral infections. Thus, recent studies aimedat determining the specificity of the anti-LKM-1,present in both the juvenile form of AIH and insome patients with chronic HCV infection, haveshown a high amino acid sequence homologybetween the HCV polyprotein and CYP2D6, themolecular target of anti-LKM-1, implicating amechanism of molecular mimicry as a trigger forthe production of anti-LKM-1 in HCV infection(Manns et al., 1991; Vento et al., 1997; Kerkaret al., 2003). It is therefore conceivable that an asyet unknown virus infection may be at the originof the autoimmune attack in AIH.

Titres of antibodies to liver-specific lipoprotein,a macromolecular complex present on the hepato-cyte membrane, and to its well-characterizedcomponent asialoglycoprotein receptor, correlatewith the biochemical and histological severity ofAIH (Jensen et al., 1978; McFarlane et al., 1986).Antibodies to alcohol dehydrogenase, a secondwell-defined component of liver-specific lipopro-tein, have been described in patients with AIH(Ma et al., 1997). Immunofluorescence studies onmonodispersed suspensions of liver cells obtainedfrom patients with AIH showed that these cells arecoated with antibodies in vivo (Vergani et al.,1987). A pathogenic role for these autoantibodieshas been indicated by cytotoxicity assays showingthat autoantibody-coated hepatocytes frompatients with AIH are killed when incubated withautologous (Mieli-Vergani et al., 1979) lympho-cytes. The effector cell was identified as an Fcreceptor–positive mononuclear cell (Mieli-Verganiet al., 1979). T cell clones obtained from liverbiopsies of patients with AIH and expressing thegamma/delta T cell receptor have been shown to becytotoxic to a variety of targets but to preferen-tially kill liver-derived cells as opposed to cell linesderived from other organs (Wen et al., 2001).

The establishment of cell lines and clones hasenabled Wen and colleagues (Wen et al., 1990,2001), and Lohr and colleagues (Lohr et al., 1991;Lohr et al., 1992) to show that the majority of Tcell clones obtained from the peripheral blood anda proportion of those from the liver of patientswith AIH are CD4 positive and use the conven-tional alpha/beta T cell receptor. Some of theseCD4 positive clones were further characterized and


were found to react with partially purified antigens,such as crude preparations of liver cell membraneor liver-specific lipoprotein (Wen et al., 1990),and with purified asialoglycoprotein receptor (Wenet al., 1990; Lohr et al., 1992) or recombinantCYP2D6 (Lohr et al., 1991) and to be restricted byHLA class II molecules in their response. BecauseCD4 is the phenotype of Th cells, both Wen andcolleagues (1990) and Lohr and colleagues (1992)investigated whether these clones were able to helpautologous B lymphocytes in the production ofimmunoglobulin in vitro and found that theircoculture with B lymphocytes resulted in a dra-matic increase in autoantibody production. All ofthe above experimental evidence suggests thatcellular immune responses are involved in the liverdamage of AIH even though the evidence that thetrigger is an autoantigen is still incomplete.

6. Management and prognosis

Three small controlled clinical trials in the early1970s have provided the basis for the currentimmunosuppressive regimens, collectively suggest-ing that treatment with prednisolone improves liverfunction tests, ameliorates symptoms and prolongssurvival (Johnson, 1997; Czaja and Freese, 2002).Though azathioprine was not able to induceremission when used on its own, it did allow main-taining remission in association with a significantlyreduced dose of steroids. In the 1980s and 1990s, anumber of studies addressed two important ques-tions: Whether immunosuppression could be safelywithdrawn after obtaining remission and whethersteroid-free maintenance could be achieved(Johnson, 1997; Czaja and Freese, 2002). It wasshown that the great majority of cases relapserapidly upon immunosuppression withdrawal, butthat steroid-free maintenance could be achievedwith azathioprine alone provided that its dose isincreased to 2mg/kg/day.

There is no doubt that immunosuppressivetreatment is beneficial in patients with severesymptomatic disease and it should be started assoon as possible, without waiting for six months assuggested in early studies. Most patients, includingthose with cirrhosis (Czaja and Freese, 2002), will

achieve remission on 30mg prednisolone daily forone month, after which azathioprine can be intro-duced at 1mg/kg/day and the dose of prednisolonereduced to 5–15mg/day to maintain the amino-transferase activity within the normal range.Though some authors define remission as trans-aminase levels up to twice the upper limit ofnormal, a better outcome has been reported whennormal transaminase levels are attained and main-tained (Seela et al., 2005). If the patient developssteroid side effects, the dose of azathioprine can beincreased to 2mg/kg/day and a complete with-drawal of steroids can be considered. The optimalduration of treatment is unknown. It is prudent notto attempt withdrawal of immunosuppressionwithin two years of diagnosis. During withdrawalattempts, it is essential to closely monitor the liverfunction tests since relapse may be severe and evenfatal. Patients who have successfully stoppedimmunosuppression should be followed up forlong term, since relapse may occur even 10 yearslater. Nonadherence to treatment is common,particularly in adolescents and young adults, andis one of the most important causes of relapse(Kerkar et al., 2006).

A question frequently asked is whether treat-ment can be safely continued during pregnancy.Although the experience is limited, there does notappear to be adverse events for mother and baby(Heneghan et al., 2001). In particular, no terato-genic effects have been described with azathioprinein humans, though for women concerned aboutits use, treatment with steroids alone can beconsidered.

It is now clear that there are patients with amilder form of the disease who may be asympto-matic or pauci-symptomatic and are detectedincidentally, during routine check-ups. For thesepatients the approach to treatment is less clear. Thebenefit of therapy is undefined and it may be so lowthat the risk of corticosteroid side effects isunjustified. This is particularly relevant to post-menopausal women and elderly patients. Thelatter, however, frequently have severe disease thatneeds active management to achieve normal lifeexpectancy (Al-Chalabi et al., 2006).

The most common side effect of steroid treat-ment is cushingoid changes which affect most


patients after prolonged treatment. Less common,but severe, side effects include osteoporosis,vertebral collapse, diabetes, cataract, hypertensionand psychosis. Only 13% of treated patientsdevelop complications that necessitate dose reduc-tion or premature drug withdrawal, the mostcommon reasons for treatment withdrawal beingcosmetic changes or obesity, osteopaenia withvertebral collapse, and brittle diabetes (Czaja andFreese, 2002).

Side effects of azathioprine are uncommonaffecting less than 10% of the patients and includecholestatic hepatitis, veno-occlusive disease, pan-creatitis, nausea and vomiting, rash, and bonemarrow suppression. Usually these complicationssubside upon drug withdrawal (Czaja and Freese,2002).

A theoretical long-term complication of contin-uous immunosuppressive therapy is the develop-ment of malignancies. The risk of extra-hepaticcancer in AIH has been reported to be 1.4-foldhigher than that of an age- and sex-matched normalpopulation (Wang et al., 1989). Akin to otherchronic liver diseases, the risk of primary hepato-cellular cancer is related mainly to the presence ofcirrhosis and is generally reported to be uncommon.

When the standard treatment fails, other drugsthat have been tried, which include cyclosporin,ursodeoxycholic acid, budesonide, and mycophe-nolate mofetil. Though encouraging results aredescribed, these reports are anecdotal.

Liver transplantation is the ultimate treatment formost patients who present with fulminant hepaticfailure and those who reach end-stage chronic liverdisease. Transplantation in AIH has an excellentprognosis, with a five-year patient and graft survivalbetween 80 and 90%. Before transplantation isconsidered, however, it is important to rememberthat even patients presenting with decompensatedcirrhosis can respond to immunosuppressive treat-ment and avoid surgery for a long time (Czaja andFreese, 2002). AIH may recur after transplant.

7. Recurrence of AIH after transplant

Recurrence of AIH after liver transplant has beenshown in several studies (Vergani andMieli-Vergani,

2002). The diagnosis is based on reappearance ofclinical symptoms and signs, histological features ofperiportal hepatitis, elevation of transaminases,circulating autoantibodies and elevated IgG, asso-ciated to response to steroids and azathioprine.Possession of the HLA DR3 allele appears toconfer predisposition to disease recurrence, as itdoes to the original AIH, though this has not beenuniversally confirmed. Recurrence has been notedin both adult and paediatric series, and though therate of this complication increases with the post-transplant interval, it may appear as early as onemonth post-surgery. Most transplant recipientswith recurrent AIH respond to an increase in thedose of corticosteroids and azathioprine, but, in afew, recurrence can lead to graft failure and to theneed for re-transplantation. Caution should betaken in weaning immunosuppression in patientswho undergo transplantation for AIH since dis-continuation of corticosteroid therapy may increasethe risk for recurrent disease.

8. De novo AIH after transplant

Tissue autoantibodies after liver transplantation, inparticular ANA and SMA, are common also inpatients transplanted for non-autoimmune liverdisease (Vergani and Mieli-Vergani, 2002). Anti-LKM-1 is the third most frequently reportedantibody, but its fluorescence pattern is at timesatypical, staining preferentially the renal tubulesand sparing the liver. The described prevalence ofpost-liver-transplant autoantibodies is variable,probably reflecting different techniques used fortheir detection, the cut-off point above which theautoantibodies are considered positive, the timepost-transplant at which they are tested, the natureof the clinical condition leading to transplantation,and the presence or absence of post-transplantcomplications. In the late 1990s, it was observedthat AIH can arise de novo after liver transplanta-tion in patients who had not been transplanted forautoimmune liver disease (Kerkar et al., 1998).After the original report in children, de novo AIHafter liver transplant has been confirmed by severalstudies in both adult and paediatric patients(Vergani and Mieli-Vergani, 2002; Mieli-Vergani


and Vergani, 2004). More importantly, treatmentwith prednisolone and azathioprine, using the sameschedule for classical AIH, is also effective inde novo AIH leading to excellent graft and patientsurvival. It is of interest that these patients do notrespond satisfactorily to standard anti-rejectiontreatment, making it essential to reach an earlydiagnosis to avoid graft loss.

Recurrence of AIH post transplant can bereadily explained. The recipient’s immune systemis sensitized to species-specific antigens and has apool of memory cells, which are re-stimulated andre-expanded when the target antigens, ‘auto anti-gens’, are presented to the recipient’s immunesystem either by recipient’s APC repopulating thegrafted liver or by donor’s APC sharing histocom-patibility antigens with the recipient. In contrast,akin to autoimmune liver disease outside trans-plantation, the pathogenesis of post-transplantde novo AIH remains to be defined. There are severalnon-mutually-exclusive explanations: In additionto release of autoantigens from damaged tissue, apossible mechanism is molecular mimicry, wherebyexposure to viruses sharing amino acid sequenceswith autoantigens leads to cross-reactive immunity(Vergani et al., 2002). Viral infections, which arefrequent post transplant, may lead to autoimmu-nity also through other mechanisms, includingpolyclonal stimulation, enhancement and inductionof membrane expression of MHC class I and IIantigens and/or interference with immunoregula-tory cells. Another possible mechanism is suggestedby animal experiments showing that the use ofcalcineurin inhibitors predisposes to autoimmunityand autoimmune disease, possibly by interferingwith the maturation of T lymphocytes or with thefunction of regulatory T cells, with consequentemergence and activation of autoaggressive T cellclones (Mieli-Vergani and Vergani, 2004). Anotherproposed mechanism stems from observations byAguilera et al. (2001), who reported that anantibody directed to glutathione-S-transferase T1(GSTT1) characterized their patients with de novoAIH (Aguilera et al., 2001, 2004, 2005). Since thegene encoding this protein is defective in a fifth ofcaucasoid subjects and the encoded enzyme wasabsent in patients experiencing de novo AIH, theauthors speculated that graft dysfunction resulted

from recognition as foreign of GSTT1 acquiredwith the graft. We have been, however, unable toconfirm this observation, having investigatedsequentially on 60 occasions the reactivity againstGSTT1 in 20 patients with post-liver-transplantde novo AIH (Komorowski et al., unpublished data).

That allogeneic transplantation of a solid organcan lead to the development of autoimmunity hasbeen unequivocally demonstrated in a murinemodel of heart allograft (Fedoseyeva et al., 1996,1999); heart transplant from an allogeneic donorresulted not only in signs of rejection, but also inthe production of antibodies and CD4+ T cellsdirected against cardiac myosin in the recipient.The relative importance of autoantigenic andallogeneic stimuli in the development of de novoAIH post liver transplant remains to be elucidated.

9. Conclusion

With immunosuppressive treatment, prognosis ofAIH is excellent with symptom-free long-termsurvival in the majority of patients. Over the pastthree decades, several pathogenic aspects of AIHhave been elucidated, including predisposinggenetic factors and disease-specific humoral andcellular immune responses. Tasks for the futureinclude further elucidation of its pathogenesis andthe establishment of novel treatments aimed atarresting specifically liver autoaggression or, ideally,at reinstating tolerance to liver antigens.

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CHAPTER 14

Primary Sclerosing Cholangitis

Roger Chapman�

Department of Gastroenterology, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK

Primary sclerosing cholangitis (PSC) is a chroniccholestatic liver disease caused by a diffuse inflam-mation and fibrosis that can involve the entirebiliary tree. The progressive pathological processobliterates intra- and extrahepatic bile ducts in ulti-mately leading to biliary cirrhosis, portal hyper-tension and eventually hepatic failure. In addition,cholangiocarcinoma develops in about 10–30% ofpatients during the course of the disease.

The generally accepted diagnostic PSC are asfollows:

� generalized beading and stenosis of the biliarysystem on cholangiography (Fig. 1)� absence of choledocholithiasis (or history ofbile duct surgery)� exclusion of bile duct cancer, usually byprolonged follow-up

The term ‘secondary sclerosing cholangitis’ is usedto describe the typical bile duct changes describedabove when a clear predisposing factor to ductfibrosis can be identified. The causes of secondarysclerosing cholangitis are shown in Table 1.

1. Aetiology

A number of causative agents have been impli-cated in the pathogenesis of PSC, but no single

hypothesis has provided a unifying explanation forall the clinical and pathological features of thisdisease.

Any hypothesis has to integrate the closeassociation of PSC with inflammatory boweldisease (IBD); the majority (65–86%) of patientswith PSC have coexistent ulcerative colitis (UC)whilst a minority of patients have Crohn’s colitis.The prevalence of PSC in UC populations isbetween 2 and 6% (Schrumpf et al., 1982; Shepherdet al., 1983; Chapman et al., 1983). In a patientwith UC, abnormal liver function tests, particu-larly an elevated serum alkaline phosphatase, maybe the first indication of this insidious condition.

The precise aetiology and pathogenesis of PSCis still not completely understood. Evidencesuggests that immune mechanisms play a key rolein the development of the disease.

1.1. Autoimmunity

The 2:1 male-to-female gender ratio of patientswith PSC and the relatively poor response of thedisease to immunosuppression suggest that PSC isnot a classical autoimmune disease. PSC patientsdo have an increased frequency of the HLA B8DR3 DQ2 haplotype, however, in common with anumber of organ-specific autoimmune diseasessuch as lupoid chronic active hepatitis, type 1diabetes mellitus, myasthenia gravis and thyrotoxi-cosis (Schrumpf et al., 1982; Shepherd et al., 1983;Chapman et al., 1983). PSC is also independentlyassociated with a range of autoimmune diseases,E-mail address: [email protected]


Tel.: 44-1865-228756; Fax: 44-1865-771100


DOI: 10.1016/S1571-5078(07)00014-1

dx.doi.org/10.1016/S1571-5078(07)00014-1.3d

diabetes mellitus and Graves’ disease being themost common. Saarinen et al. (2000) found that25% of patients with PSC had one or moreautoimmune disease, compared to 9% of patientswith IBD alone.

1.2. Autoantibodies

A wide range of autoantibodies can be detected inthe serum of patients with PSC, clearly indicating

an altered state of immune responsiveness orimmune regulation. Although a few studies havedemonstrated some correlation between particularclinical parameters and the presence of autoanti-bodies, there is presently insufficient evidence tomake use of any of them in determining prognosis.Most are present at low prevalence rates and atrelatively low titres (Table 2).

Anti-neutrophil-specific antibodies are a fairlyconsistent feature of PSC, occurring in up to 88%of patients. The anti-neutrophil antibodies asso-ciated with PSC are distinct from c-ANCA andclassical p-ANCA that are commonly used as diag-nostic and therapeutic seromarkers for Wegener’sgranulomatosis and microscopic polyangiitis,respectively. PSC, UC and autoimmune hepatitisare associated with ‘atypical p-ANCA’ which has adistinct staining pattern on indirect immunofluo-rescence microscopy. The prevalence of atypicalp-ANCA in PSC, UC and autoimmune hepatitis is33–88%, 40–87% and 50–96%, respectively. Work

Figure 1. Endoscopic retrograde cholangiogram showing the characteristic changes of primary sclerosing cholangitis. There is severe

stricturing and dilatation of both intra- and extrahepatic bile ducts.

Table 1

Causes of secondary sclerosing cholangitis

Previous bile duct surgery with stricturing and cholangitis

Bile duct stones causing cholangitis

AIDS––probably infective as a result of cytomegalovirus or

cryptosporidium

Intra-hepatic arterial infusion of 5-fluorodeoxyuridine

Insertion of formalin into hepatic hydatid cysts

R. Chapman170

by Terjung and Worman (2001) has demonstratedthat the target antigen for atypical p-ANCAappears to be localized to the nuclear periphery,and it has been suggested that the anti-neutrophilantibody in PSC therefore be renamed p-ANNA(anti-neutrophil nuclear antibody). The specifictarget antigen of this antibody remains to beclarified, but Terjung’s group has demonstratedthat about 90% of p-ANNA from individuals withPSC reacted with a neutrophil-specific nuclearenvelope protein with a molecular mass ofapproximately 50 kDa. The molecular identity ofthis nuclear envelope protein remains unknown,however.

The importance of autoantibodies in the deve-lopment of PSC remains unclear. To date there isno convincing model of the pathogenesis of PSC,UC or autoimmune hepatitis that implicates anti-neutrophil antibodies, and it may be that theseantibodies are simply a marker for an as yetundetermined immune dysregulation. There is,however, some evidence that a monoclonal anti-body to a colonic epithelial protein in patients withUC cross-reacts with epithelial cells lining theextrahepatic bile ducts of PSC patients with UC,suggesting that the pathogenesis of these twoconditions might be associated with a commonantigen (Mandal et al., 1994). An interesting paperby Xu et al. has demonstrated the presence ofautoantibodies to surface antigens expressed onbiliary epithelial cells (BECs) in PSC. This studyalso showed that these autoantibodies inducedincreased expression of CD44 on the BEC,

demonstrating that the BEC may be the candidateepithelial cell in PSC (Xu et al., 2002). More workis needed in this area to clarify if this might bemechanism of action of autoantibodies in thedevelopment of the clinical disease.

1.3. MHC genes

The major histocompatibility complex on the shortarm of chromosome 6 encodes the HLA moleculeswhich have a central role in T cell response and arehighly polymorphic. The MHC class I and class IIregions encode the classical transplantation anti-gens of the HLA A, B, Cw, and DR, DQ and DPfamilies. The class III region encodes a range ofimmune response genes, including those encodingtumour necrosis factor-alpha and -beta (TNF-aand -b), the heat shock protein family (HSP-70),complement proteins C2, C4A, C4B and Bf, andthe genes encoding the MHC class I chain-relatedproteins, MICa and b (MICA and MICB).

Early studies based on HLA serotyping foundan increased frequency of the HLA B8 DR3haplotype in PSC patients compared to controls.More recently, serotyping has been replaced bythe more detailed technique (Donaldson, 2003)(Table 2).

The technique of molecular genotyping haselucidated five key HLA haplotypes associatedwith PSC (Spurkland et al., 1999). It is not yetclear whether there is a single primary suscept-ibility allele on each of these haplotypes, althoughMICA�008 (mapping to the HLA class I/class IIIboundary between B8 and TNFA) occurs on twoof the key haplotypes (Table 3).

Studies of genes encoding the key proteins in theimmune system have contributed towards ourunderstanding of the influence of the immunesystem on the development and progression ofPSC.

PSC appears to be a ‘complex’ disease in that itis not attributable to a single gene locus. Suscep-tibility to PSC is probably acquired throughinheriting one of a number of patterns of geneticpolymorphisms which together cause a predisposi-tion to development of the disease.

Table 2

Prevalence of autoantibodies in primary sclerosing cholangitis

Antibody Prevalence

Anti-nuclear antibody (ANA) 7–77%

Anti-smooth muscle antibody (ASMA) 13–20%

Anti-endothelial cell antibody (AECA) 35%

Anti-cardiolipin antibody 4–66%

Thyroperoxidase 7–16%

Thyroglobulin 4%

Rheumatoid factor 15%

NB Antimitochondrial antibody is only rarely detected in

PSC (o10%). This is useful in differentiating PSC from

primary biliary cirrhosis (PBC).

Primary Sclerosing Cholangitis 171

1.4. Non-MHC immunoregulatorygenes in PSC

A range of non-MHC immunoregulatory geneshas been studied in relation to PSC. Cytotoxiclymphocyte antigen-4 (CTLA-4, CD152) is one ofthe differentiation antigens exclusively expressedon activated CD4+ and CD8+ T cells. It acts bybinding to B7, the same ligand as CD28, therebydisrupting the crucial CD28–B7 interaction, one ofthe key costimulatory events in the initiation andprogression of the T cell immune response. Anamino acid changing single-nucleotide polymor-phism (snp) in codon 17 of the leader peptide ofCTLA-4 has been associated with susceptibility toautoimmune thyroid disease, insulin-dependentdiabetes mellitus, AIH and PBC. The role of thispolymorphism in PSC, however, is controversialand to date results have been conflicting.

After antigen presentation, the next step in theadaptive immune response is the release ofcytokines and chemokines at the site of inflamma-tion. One polymorphism in TNF-a, as discussedabove, is associated with PSC but this appears tobe related to the extended HLA B8 DR3 DQ2haplotype rather than being an independent effect(Bernal et al., 1999; Mitchell et al., 2001a, b).Polymorphisms have also been studied in IL-1 andIL-10 and chemokine CCR-5 to assess a relation-ship to PSC (Donaldson et al., 2000). So far these

studies have been negative or controversial and noclear association has emerged.

The end result of inflammation in PSC is peri-ductal fibrosis. Genes involved in the regulation ofthe production and destruction of extracellularmatrix are therefore also good candidate genes forstudy. One such family of genes is that comprisingthe matrix metalloproteinases. A functional poly-morphism of MMP-3 (stromelysin) has beenshown to be associated with both susceptibilityto PSC and progression to portal hypertension in aBritish population (Satsangi et al., 2001).

1.5. Cellular immune abnormalities

The initiation and maintenance of the immunecascade is determined not only by MHC recogni-tion but also by the presence of accessory cells andmolecules to provide costimulatory signals and theproduction of cytokines to amplify or modify theimmune response.

Studies of circulating lymphocyte subsets in PSChave produced rather conflicting results, althoughthere does seem to be some consensus on thefinding that there is a fall in CD8+ T cells as thedisease progresses (Lindor et al., 1987). The factthat this change occurs only in advanced disease,however, means that it is unlikely to be significantin the pathogenesis of the disease.

The cellular infiltrate at the site of tissue injury isprobably more relevant than the circulating popu-lation. Although it is clear that there is a T cellpredominant portal tract infiltrate in PSC, there isstill some uncertainty regarding the relative impor-tance of CD4+ and CD8+ cells in this infiltrate.The hypothesis that these T lymphocytes areinvolved in the pathogenesis of the disease (ratherthan simply being markers for its presence) issupported by evidence that these cells are func-tional. This evidence comes from studies of surfacemarkers expressed on activated and memory T cells.

1.6. T cell receptor

Most T cells carry a T cell receptor (TCR) consis-ting of two disulphide-linked polypeptides, termed

Table 3

Key HLA haplotypes associated with primary sclerosing

cholangitis

Haplotype Significance in PSC

B8-TNF�2-DRB3�0101-DRB1�0301-DQA1�0501-DQB1�0201

Strong association with

disease susceptibility

DRB3�0101-DRB1�1301-DQA1�0103-DQB1�0603



DRB5�0101-DRB1�1501-DQA1�0102-DQB1�0602

Weak association with


DRB4�0103-DRB1�0401-DQA1�03-DQB1�0302


protection against disease

MICA �008 Strong association with


R. Chapman172

a and b. A group of T cells carrying an alternativereceptor, termed gd, has been identified over thepast 13 years. These cells appear to be involved inautoimmunity, although their exact function isnot clear (Hayday and Geng, 1997). An increasein the number of gd T cells has been found in theperipheral blood and portal infiltrates of patientswith both PSC and AIH compared with controls(Martins et al., 1996). There was no concentrationof the gd cells in the areas of bile ducts or inter-face hepatitis, however, and the predominantcell type was still ab. The significance of gd cellsin the pathogenesis of PSC is therefore not clearalthough they might function by modulating abT cell activation or regulating antibody or auto-antibody production from B cells.

Although TCR gene rearrangements serve togenerate genetic diversity, a particular Vab genesegment can play a dominant role in recognition ofcertain peptide–MHC complexes. Expanded T cellpopulations using restricted sets of TCR V genesegments have been identified in areas of inflam-mation in diseases such as rheumatoid arthritisand Sjogren’s disease. This suggests the presence ofa specific antigen with the capacity of driving theproduction of T cells with this restricted Vabsegment product (Sumida et al., 1992; Imbertiet al., 1993). Studies from Broome et al. (1997)indicated that the hepatic, but not peripheral,T cells in PSC preferentially have Vb3 T cellrepertoires. An oligoclonal expansion was notdemonstrated in this study, but oligoclonal TCRwhich proliferate in culture with enterocytes andare cytotoxic to enterocyte cell lines in vitro havealso been reported in PSC (Probert et al., 1997).

1.7. Cytokines

Most studies in the context of PSC have looked atcytokine secretion from peripheral, rather thanliver-derived, lymphocytes. This work has not beenconclusive. There are some preliminary data(published only in abstract form to date) thatshow an increased expression of both Th1 and Th2cytokines within the liver of PSC patients comparedwith healthy controls (Mitchell et al., 1997a, b).Downregulation of IL-10 mRNA expression in

PSC and PBC was also demonstrated. These changeswere reversed after treatment with ursodeoxy-cholic acid (UDCA) (Mitchell et al., 1997a, b).

An abnormal cytokine repertoire and the highexpression of cytokine mRNA in the early stagesof PSC suggest that Th1 and Th2 cytokines mayplay a role in the pathogenesis of the disease.Cytokines could have an influence on manyaspects of the progression of PSC including thecytotoxic T cell development, aberrant expressionof class II MHC molecules on BECs, and matrixmetalloproteinase gene expression in fibroblasts(Mitchell and Chapman, 2000). Their true role inthe development and progression of PSC has yet tobe clearly defined.

1.8. Biliary epithelial cells

The BEC is the target of immune attack in PSC,whilst at the same time appearing to be an activeparticipant in the immune response. Aberrantexpression of HLA molecules on target cells isimportant in the pathogenesis of autoimmunediseases. Normal BECs express only HLA class I,and not class II, antigens. However, the HLA classII antigens HLA DR, DQ and DP have all beenfound to be expressed by the BECs of patients withPSC (Chapman et al., 1988; Broome et al., 1990).These antigens have the potential to initiate animmune response by binding autoantigens orexogenous antigens and presenting the peptidesto class II restricted T lymphocytes.

‘Professional’ antigen-presenting cells (APC)also express cell-surface costimulatory moleculessuch as CD54 (ICAM-1) and members of the B7family (CD80 and CD84) which are required forT cell activation. These co-stimulatory moleculesappear to be lacking on the BECs in PSC, andthis observation has cast doubt upon the theorythat BECs act as APC (Leon et al., 1996).Aberrant expression of CD54 (ICAM-1), however,has recently been demonstrated as occurring inpatients with end-stage PSC. This finding couldnot be replicated in patients with earlier stagedisease (Adams et al., 1992; Broome et al., 1993).Recently, Cruickshank et al. (1999) have alsodemonstrated that CD44, the lymphocyte homing


receptor, is highly expressed on BECs in a rangeof inflammatory liver diseases including PSC. Thisphenomenon may occur as a function of biliarycell response to stress or damage and, through theability of CD44 to bind chemokines and growthfactors, might mediate local inflammatory res-ponses. BECs, therefore, may act as APC althoughthey seem to be less active in this role thandendritic cells or macrophages.

1.9. Role of bacteria in theaetiopathogenesis of PSC

The coexistence of inflammatory colitis in around75% of Northern European patients with PSC hasled to the hypothesis that the initiating step in thisdisease is the access of intestinal bacteria throughan inflamed and leaky bowel wall, to the portalcirculation. An abnormal immune response tobacterial antigens (possibly acting as molecularmimics for autoantigens) in an immunogeneticallysusceptible host might be sufficient to precipitatethe cascade of immune reactions detailed above.

Investigation of bacterial growth from humantissue is confounded by the bacterial contamina-tion caused by intubation of the bile duct atERCP. Several animal models, however, have beenused to investigate this proposal. Wistar andSprague–Dawley rats develop a pattern of hepaticinjury somewhat similar to human PSC afterartificially induced small bowel bacterial overgrowth(Lichtman et al., 1990). Rat models have alsodemonstrated that bacterial peptides instilled intothe rectum of rats with a chemically induced colitisappear very quickly in the bile and will initiate asmall duct cholangitis, although no extrahepaticstrictures are produced (Yamada et al., 1994).

1.10. Hypotheses for the aetiopathogenesisof PSC

A plausible unifying hypothesis for the aetio-pathogenesis of PSC has been put forward byVierling (1998). This suggests that the initial insultis the reaction of an immunogenetically susceptible

host to bacterial cell wall products entering theportal circulation through a permeable gut walleither due to colitis or possibly during episodes ofintestinal infection. The resulting Kuppfer cell(hepatic macrophage) activation would result inperibiliary cytokine and chemokine secretion attract-ing activated neutrophils, monocyte/macrophages,lymphocytes and fibroblasts to the site of infection.The resultant concentric fibrosis around the bileducts could then lead to ischaemia and thenatrophy of the BEC. The bile duct loss wouldthen lead to progressive cholestasis, fibrosis andsecondary biliary cirrhosis. This hypothesis doesnot explain why there is a relative paucity ofpatients with PSC and underlying Crohn’s colitis,nor the association of PSC with stricturing of thepancreatic duct.

More recently, Grant et al. have proposedthe existence of an enterohepatic circulation oflymphocytes, whereby some mucosal lymphocytesproduced in the gut during active inflammationpersist as memory cells capable of recirculationthrough the liver (Grant et al., 2002). Undercertain circumstances, these gut-derived lympho-cytes might become activated resulting in hepaticinflammation. This hypothesis is supported by thefinding that some lymphocyte homing receptorsare shared by the liver and gut. This concept ofdual homing lymphocytes helps to explain theobservation that PSC runs a course independent ofinflammation in the bowel and indeed can developeven after proctocolectomy.

In conclusion, current evidence suggests that PSCis an immune-mediated, rather than a classical,autoimmune disease. The association with inflam-matory colitis suggests that an abnormal immuneresponse may be initiated in an immunogeneticallysusceptible host by the access of bacterial antigen,through a permeable gut wall, to the portal cir-culation. This bacterial antigen might then act as amolecular mimic of an autoantigen precipitating animmune cascade which results in structuring andscarring of the intra- and extrahepatic bile ducts,peribiliary fibrosis and ultimately, cirrhosis. Thereare difficulties in determining which of the widerange of immune abnormalities identified in thesepatients are causal and which are the consequencesof tissue injury.

R. Chapman174

2. Diagnosis

Serum biochemical tests usually show a cholestaticpattern, often in asymptomatic patients with IBD.Although ERCP remains the gold standard for thediagnosis of PSC, it is an invasive technique thatcarries a small but significant risk of morbidity andmortality.

Magnetic resonance cholangiography (MRC)is a relatively new non-invasive technique, andincreasing data exist on its performance relativeto ERCP. In one recent study (Angulo et al.,2000), the ERCP and MRC of patients with asuspected diagnosis of PSC were independentlyevaluated, and MRC was as sensitive and specificas either ERCP or percutaneous hepatic cholan-giography. Current evidence suggests that MRCPshould be used in place of ERCP to establish thediagnosis of PSC.

Liver biopsy changes are only diagnostic inapproximately one-third of patients who show thecharacteristic changes of concentric ‘onion skin’fibrosis, although there is usually histologicalevidence of cholestasis. Therefore, liver biopsy isnot normally required to establish the diagnosisin patients with PSC with diagnostic cholangio-graphic changes.

3. Small duct PSC

There are a group of patients with cholestatic liverfunction tests and diagnostic features of PSC onliver histology who have normal cholangiography;the term ‘small duct PSC’ has been coined to applyto such patients. Approximately 6–16% of thePSC population have small duct PSC. In general,they follow a benign course and have a favourableprognosis. Only 25% of patients will develop largeduct disease, and to date no patients with smallduct PSC have developed cholangiocarcinoma.

4. Autoimmune pancreatitis (AIP)

Patients with the multisystem disease, AIP, havebeen reported to have biliary strictures similar to

PSC. Serum IgG4 levels are increased in approxi-mately 75% of AIP patients, whereas elevatedIgG4 levels are found in 9% of PSC patients.Unlike adult PSC, biliary strictures improve withcorticosteroid therapy. The relationship betweenPSC and AIH remains to be determined.

5. Prognosis

The clinical course of PSC is quite variable; thedisease is indolent in some patients and morerapidly progressive in others. The natural historyof PSC is described in a number of retrospectivestudies with the median survival time fromdiagnosis to death or orthotopic liver transplanta-tion (OLT) reported between 12 and 21 years(Broome et al., 1996; Wiesner et al., 1989; Farrantet al., 1991; Helzberg et al., 1987). Differences insurvival estimations may reflect the variation inthe definition of onset and outcome. As there isno reliable marker of early disease in PSC, theonset is difficult to identify clearly. Whether theonset is defined as the occurrence of the firstsymptoms consistent with PSC, as the time ofthe first abnormal liver function test or as thetime of diagnosis by ERCP will result in differ-ences in survival estimates. In retrospectivestudies, details of distant events may be sparseand there is likely to be failure to recognize earlysigns and symptoms. Patients with late-stagedisease may predominate, whilst patients whodie from rapidly progressive disease may bemissed.

The ideal study of prognosis is prospective andfollows patients from a defined point in the diseaseprocess, usually diagnosis. There have been nostudies using such an inception cohort in PSCbecause the disease is rare and its slow progressionmakes a prospective study impractical. A largeretrospective study published by Broome et al.(1996) did include a high proportion (46%) ofpatients with early (stage I and II) disease. Forty-four percent of patients were asymptomatic atdiagnosis, and these patients exhibited longersurvival than symptomatic patients. The estimatedmedian survival for the whole PSC group was 144


months. For patients with symptoms at the timeof diagnosis, the estimated median survival wassignificantly less, at 112 months. Over one-fifthof the asymptomatic patients became symp-tomatic during the median follow-up period of63 months. From these studies a number ofprognostic models have been developed, mainlyusing parameters defined at diagnosis (Tables 4and 5). Perhaps the most controversial prognosticfactor is HLA DR4. Studies from Oxford (Mehalet al., 1994) and the Mayo Clinic (Aguilar et al.,1994) suggest that HLA DR4 is associated withpoor prognosis, whilst studies from London(Maloney et al., 1996) were unable to confirm thisassociation. Although these models successfullypredict the natural history of the disease in acohort of PSC patients, they are less successfulwhen applied to individual patients. The con-founding factor is the development of hepatobi-liary or colonic cancer.

Cholangiocarcinoma is difficult to diagnose(Miros et al., 1991), is associated with poorprognosis (Kornfield et al., 1997) and precludesOLT (Herbener et al., 1988). In Broome et al.’sstudy (1996) cholangiocarcinoma was found in8% of patients with PSC but occurred in 30% of

the 79 patients who died or underwent OLT. Inthis and other studies, none of the investigatedclinical or laboratory parameters could identifythose patients who would subsequently develop

Table 4

Studies of prognosis in primary sclerosing cholangitis: multivariate analysis

Study Number of patients % asymptomatic Median survival (year) Independent prognostic factors

Helzberg et al. (1987) 53 25 a Hepatomegaly

Serum bilirubin

W1.5mg/day at onset of disease

Wiesner et al. (1989) 174 21 11.9 Age

Serum bilirubin

Blood hemoglobin conc.

Presence of IBD

Histological stage

Farrant et al. (1991) 126 16 12.0 Hepatomegaly

Splenomegaly

Serum alkaline phosphatase

Histological stage

Age

Broome et al. (1996) 305 44 12.0 Age

Serum bilirubin

Histological stage

a 5% survival=9 years.

Table 5

Studies of prognosis in primary sclerosing cholangitis:

univariate analysis

Study Number of

patients

Prognostic

indicator

Comments

Craig et al.

(1991)

129 Disease assessment

by cholangiography

Intrahepatic

disease worse than

extrahepatic

Mehal et al.

(1994)

83 HLA DR4 HLA DR4

associated with

poor prognosis

Olsson et al.

(1995a, b)

94 Disease assessment

by cholangiography

High grade

intrahepatic

strictures indicate

early jaundice and

short survival

Maloney,

1996

120 HLA DR4 HLA DR4 not

associated with

poor prognosis but

confers resistance

to developing PSC

R. Chapman176

cholangiocarcinoma, although PSC patients withcoexistent UC have a three- to fourfold higher riskof developing cholangiocarcinoma. A recent case-control study has suggested that long duration ofUC and smoking are independent risk factorsassociated with the development of hepatobiliarymalignancy in PSC (Bergquist et al., 1998).

Two studies have shown that biliary dysplasiaseen on liver biopsy can antedate the develop-ment of cholangiocarcinoma by at least two years,and may be an indication for early liver trans-plantation. Patients with UC and PSC are alsoconsidered to be at higher risk of developingcolonic dysplasia and carcinoma (D’Haens et al.,1993). Early studies (Loftus et al., 1996; Marchesaet al., 1997) investigating this risk gave conflictingresults due to the different methodologies employed,small numbers, design flaws and different end-points (Ahnen, 1996). However, a recent study ofa retrospectively defined inception cohort (Lashneret al., 1998) has shown that the risk of develo-ping colonic dysplasia or cancer is significantlyincreased in UC patients with PSC compared withpatients with UC alone. A high proportion ofright-sided cancers was noted in the PSC patients,consistent with the hypothesis that these cancersarise due to exposure to carcinogenic bile acids(Marchesa et al., 1997). Consensus has emergedthat PSC definitely predisposes to colonic dysplasiaand cancer. Recent studies have shown thatpatients treated with UDCA have a 30% reductionin the incidence of colonic dysplasia or carcinoma(Pardi et al., 2003). PSC patients with UC remain atrisk of developing colon cancer or dysplasia evenafter they have undergone OLT (Bleday et al.,1993).

The evidence is that physicians can only providetheir PSC patients with a tentative survivalestimate using the variables derived from prog-nostic models. The development of cholangiocar-cinoma is often insidious and unpredictable.Although a significant impact of screening onmortality is unproven, we recommend that PSCpatients with UC should immediately enter ayearly colonoscopic surveillance programme, incontrast to the two yearly surveillance programmeafter eight years of colitis that is recommendedfor UC patients without PSC.

5.1. Management of complications

As PSC slowly progresses to biliary cirrhosis andportal hypertension, complications may arise fromchronic cholestasis or chronic liver failure (as inPBC and other liver diseases) or complicationsspecific to PSC such as biliary strictures and thedevelopment of cholangiocarcinoma. The generalmanagement of the complications of cholestasiswill not be discussed here.

5.1.1. Management of the complications ofchronic liver diseaseThe complications of end-stage chronic liverdisease, namely oesophageal varices, ascites andporto-systemic encephalopathy, are equally obser-ved in the later stages of PSC. The managementof these complications is common to all advancedliver disease and warrants no further discussionhere. Special mention should be made of the pro-blem of bleeding from peristomal varices whichoccur as a consequence of portal hypertensionin PSC patients who have undergone proctocolec-tomy for underlying IBD and have an ileal stoma.Peristomal variceal bleeding can be severe anddifficult to treat. Local measures such as injectionof sclerosant, venous ligation and ileostomy revi-sion are usually unsuccessful and associated withrecurrent bleeding. Porto-systemic shunts, i.e.TIPPS, can control severe bleeding episodes, butsuch patients may ultimately require hepatictransplantation.

Ideally, patients with PSC who require aproctocolectomy for control of their UC shouldhave ileal pouch-anal anastomosis so as to avoidthe formation of an ileal stoma and the problem ofperistomal varices. With the recognition that PSCpatients with UC have a greater risk of developingcolonic dysplasia or DNA aneuploidy comparedwith patients with UC alone (Broome et al., 1995),surveillance of the anastomosis is required.Although there is no direct evidence, there isconsensus that patients with UC with an intactcolon should undergo annual surveillance colono-scopy with multiple biopsies The incidence ofpouchitis is also increased in patients with an ileal


pouch anal anastomosis and coexistent PSC(Penna et al., 1996).

5.1.2. Management of complicationsspecific to PSCPSC is characterized by multiple small annularstrictures in the biliary tree seen at ERCP. Tightbiliary strictures, particularly in the extrahepaticbiliary tree, may interrupt the indolent course ofdisease and cause deterioration of liver functionwith more rapid progression to biliary cirrhosis.Such benign dominant biliary strictures cannot bereliably differentiated from cholangiocarcinomaby cholangiographic appearance. In one study ofpatients awaiting OLT, ultrasound-guided biopsyof a dominant biliary stricture accurately demon-strated cholangiocarcinoma complicating PSCin 75% of cases (Mirza et al., 1994). Exfoliativebrush cytology of strictures at ERCP has a highspecificity and positive predictive value for thediagnosis of cholangiocarcinoma but low sensiti-vity and negative predictive value (Ferrunior et al.,1994). Despite the relatively low sensitivity, endo-scopic bile duct brush cytology may be diagnosticfor malignancy or reveal high-grade dysplasia (Leeet al., 1995a, b). No single serum marker accuratelypredicts the development of cholangiocarcinoma,but an index combining two serum markers, CA19-9and CEA, may be useful to identify PSC patientswith occult tumours (Ramage et al., 1995). Thisfinding has not been confirmed by other investiga-tors (Bjornsson et al., 1999).

Dominant strictures may be treated endoscopi-cally or surgically. Endoscopic treatment involvesballoon dilatation of the stricture and/or place-ment of a biliary stent. Surgical procedures aim tobypass the obstruction and drain the biliary systeminto the gut. Unfortunately, there are no controlledtrials which examine the validity of either approachand guide future management. Since biliarymanipulation increases the risk of stricturing andbacterial cholangitis and may jeopardize futureOLT, endoscopic and surgical intervention in PSCis as a rule best avoided for as long as possible.

Selected non-cirrhotic PSC patients with domi-nant extrahepatic strictures may benefit from a bilio-enteric bypass (Hepburgh, 1994). A non-randomized

retrospective study of endoscopic interventionincluding dilatation or stenting of strictures, place-ment of nasobiliary drainage and extraction ofstones in PSC suggested that 77% of the patientsshowed improvements of their clinical symptoms,liver function tests or cholangiograms (Lee et al.,1995a, b). A report from Amsterdam described 32patients with dominant strictures treated with short-term endoscopic stenting for a mean of 11 days.Primary endpoints were improvements in symp-toms and cholestasis which were seen in all patients,and which were maintained for several years.Seven transient procedure-related complicationsoccurred in 45 therapeutic procedures (Ponsioenet al., 1999). Where OLT is precluded, as in biliaryobstruction due to cholangiocarcinoma, endoscopicstenting is undoubtedly the best option for moredistal lesions.

5.2. Medical therapy: the prevention ofdisease progression

In both PBC and PSC, the primary site of inflam-mation and damage is the biliary epithelium. Whenseverely damaged or destroyed, the bile ducts do nothave the capacity to regenerate like hepatocyteswhich are the primary target for injury in variousparenchymal liver diseases. Given the finite numberof bile ducts in the liver, the natural history of PSC,like PBC, is that of progressive loss of functioningintrahepatic bile ducts (ductopenia). This ductope-nia leads to a progressive and irreversible failure ofhepatic biliary excretion. To delay and reverse thisprocess, physicians have tried a variety of agents,but in PSC, in contrast to PBC, few randomizedcontrolled trials have been performed.

5.2.1. D-penicillamineIncreased hepatic copper levels are detected in allpatients with prolonged cholestasis includingthose with PSC. This observation provided therationale for the controlled trial of the cupruretic,D-pencillamine, performed by the Mayo Clinic(LaRusso et al., 1988). Seventy patients wererandomized to either D-pencillamine or placebofor 36 months. No improvement was observed on

R. Chapman178

disease progression or overall survival in thetreatment group. Major adverse effects includingpan-cytopenia and proteinuria led to the perma-nent discontinuation of penicillamine in 21% ofthe treated patients.

5.2.2. CorticosteroidsIt is surprising that there have been no long-termstudies of the effect of corticosteroid therapyon histological progression and survival in PSC,especially as the disease may be immune mediated.This may reflect concerns about the long-termadverse effect profile of corticosteroids. Systemicand topical corticosteroid therapy has beenevaluated in a number of small, often uncon-trolled, trials (Sivak et al., 1981; Burgert et al.,1984). In one such study, 10 patients diagnosedby ERCP and liver biopsy with early PSC(elevated serum alkaline phosphatase, but nonewith biliary cirrhosis) were treated with prednisonewithout a significant response (Sivak et al., 1981).In another uncontrolled pilot study, 10 patientswith PSC, selected because they had elevatedaminotransferases, were given prednisolone, andthe majority responded with improvement in theirbiochemistry (Burgert et al., 1984). In a subse-quent study, Lindor et al. (1991) were unable toconfirm these optimistic results. They treated 12patients with a combination of low-dose predni-sone (10mg daily) and colchicine (0.6mg twicedaily). The clinical course of the treated patientswas compared with a control group, but the studywas not randomized. After two years, no signifi-cant differences in the biochemistry and liverhistology were detected between the two groups.In this study, treatment did not alter the rate ofdisease progression or improve survival. Theabsence of a beneficial response, and the suspicionthat corticosteroid therapy enhanced cortical boneloss and hence the risk of developing compressionfractures of the spine even in young male patients,led the authors to advise against empiricalcorticosteroid therapy in these patients. Thisconclusion was strengthened by the observationthat spontaneous fractures in patients who haveundergone liver transplantation occur almostexclusively in PSC patients who are already

osteopenic at the time of transplantation (Poraykoet al., 1991).

Topical corticosteroids are usually administeredthrough a nasobiliary drain left in situ followingERCP. Three anecdotal studies (Grijm et al.,1986; Jeffrey et al., 1990; Craig et al., 1990) havereported benefit. The only controlled trial ofnasobiliary lavage with corticosteroids from theRoyal Free Hospital (Allison et al., 1986) showedno benefit when compared with a placebo group.Although the numbers were small, the bile of allthe treated patients became rapidly colonized withenteric bacteria and a higher incidence of bacterialcholangitis was recorded in the treatment group.

More recent clinical trials have studied thepossible benefit of budesonide, a second-generationcorticosteroid with a high first-pass metabolismand minimal systemic availability. Unfortunately,preliminary results both alone (Angulo et al.,1999a, b) and in combination with UDCA (vanHoogstraten et al., 2000) have been disappointing.

There is no direct evidence to suggest thateither oral or topical corticosteroids are beneficialin PSC. Indeed, when PSC patients with coexistentUC are given courses of corticosteroids to treattheir UC, this treatment appears to have littleinfluence on the behaviour of their liver disease.It may be difficult to justify a trial usingcorticosteroids as monotherapy, but a large con-trolled trial could clarify their role in combinationwith a choleretic agent. Potentially serious adverseeffects may be reduced by new agents suchas biphosphonates which prevent cortical boneloss.

5.2.3. MethotrexateAfter demonstrating a promising response to low-dose oral pulse methotrexate in an open study(Knox and Kaplan, 1991) involving 10 PSCpatients without evidence of portal hypertension,Knox and Kaplan (1994) performed a double-blind, randomized placebo controlled trial of oralpulse methotrexate at a dose of 15mg/wk. Twelvepatients with PSC were entered into each group.Although each patient was monitored with bothliver biopsy and ERCP (at baseline and yearly)and biochemical tests, the only significant change


was a fall in the serum alkaline phosphatase by31% in those receiving methotrexate.

There were no significant improvements in liverhistology, treatment failure or mortality rates. Theonly toxicity attributed to methotrexate during thestudy was a transient decrease in the white cellcount related to a bout of bacterial cholangitis andCampylobacter enterocolitis in a single patient.

The study was too small in terms of numbers ofpatients and of too short duration to haveadequate power to detect a significant benefit inpatients with early disease, should such a benefitexist. Nevertheless, with the negative results of thiscontrolled trial and more recent reports of thetoxicity of pulse methotrexate in patients withPBC (interstitial pneumonitis, severe lung damage,hepatotoxicity), it would be difficult to justify alarger controlled trial of methotrexate therapy atpresent. In a pilot study, Lindor et al. (1996) foundthat methotrexate given in combination withursodeoxycholic acid (UDCA) to 19 PSC patientswas associated with toxicity (alopecia, pulmonarycomplications) but showed no additional improve-ment in liver biochemistries compared to a controlgroup of nine patients treated with UDCA alone.

5.2.4. Other immunosuppressantsDespite the evidence that PSC may be an immune-mediated disease, there have been few randomizedcontrolled trials of immunosuppressive agentscontaining sufficient numbers of patients withearly disease. Immunosuppression is unlikely tobe effective in patients with advanced liver diseaseand irreversible bile duct loss, and this mayaccount for the disappointing results so far seenin PSC with these agents. No controlled trials ofazathioprine in PSC have been reported. In onecase report (Javett, 1971), two patients improvedclinically on azathioprine, but in another thepatient deteriorated (Wagner, 1971). The use ofcyclosporin in PSC has been evaluated in arandomized controlled trial from the Mayo Clinic(Kyokane et al., 1994) involving 34 patients withPSC and, in the majority, coexistent UC. Treat-ment with cyclosporin reduced the symptoms ofUC (Sandborn et al., 1993) but had no effect onthe course or prognosis of PSC. Follow-up liver

histology after two years of treatment revealedprogression in 9/10 of the placebo group, but only11/20 of the cyclosporin-treated group.

This was not reflected by any beneficial effect onthe biochemical tests. The prevalence of adverseeffects was low; serious renal complications werenot reported. A combination of cyclosporin andprednisolone elicited a beneficial response in a65-year-old man with PSC accompanied by pan-creatic duct abnormalities (Kyokane et al., 1994).

Tacrolimus (FK 506), an immunosuppressivemacrolide antibiotic, has been used to treat 10patients with PSC in an open study (Van Thielet al., 1995). After one year of treatment with atwice daily oral regimen, all patients experiencedan improvement in their liver biochemical tests.For example, the median serum bilirubin level wasreduced by 75% and the serum alkaline phospha-tase was reduced by 70%. No major adverse eventswere reported in this initial study in PSC. Arandomized controlled trial is required to confirmthese encouraging preliminary results.

Cladribine, a nucleoside analogue with specificantilymphocyte properties, has been used to treat avariety of autoimmune disorders. In a recent pilotstudy on PSC, six patients with early disease weretreated for six months and followed for two years.Whilst significant decreases were seen in peripheraland hepatic lymphocyte counts, no significantchanges were observed in symptom scores, liverfunction tests or cholangiograms (Duchini et al.,2000).

The hepatobiliary injury which occurs in ratswith experimental bacterial overgrowth is said toresult from peptidoglycan-polysaccharide-mediatedactivation of Kupffer cells which in turn releasecytokines such as tumour necrosis factor-alpha(TNF-a). In rats the liver injury can be preventedby pentoxifylline. In an open pilot study, 20patients with PSC were treated with pentoxifylline400mg qid for one year. In this dose, pentoxifyl-line did not improve symptoms or liver tests(Bharucha et al., 2000).

5.2.5. Anti-fibrogenic agentsIn the light of initial reports which suggested apositive trend of the anti-fibrogenic agent

R. Chapman180

colchicine on survival in PBC and other types ofcirrhosis, a randomized trial from Sweden (Olssonet al., 1995a, b) compared colchicine in a dose of1mg daily by mouth in 44 patients with PSC witha matched placebo group of 40 patients. At three-year follow-up, there were no differences in clinicalsymptoms, serum biochemistry, liver histology orsurvival between the two groups. The onlyrecorded adverse effect attributable to colchicinewas diarrhoea in a single patient. The absence inthis study of any proven effect of colchicineon disease progression, outcome or survival is inkeeping with more recent long-term studies ofcolchicine in PBC and other chronic liver diseaseswhich have failed to confirm the initial reportedsurvival benefits.

5.2.6. Ursodeoxycholic acidThis hydrophilic bile acid has become widely usedin the treatment of cholestatic liver of all causes.UDCA appears to exert a number of effects all ofwhich may be beneficial in chronic cholestasis:a choleretic effect by increasing bile flow, a directcytoprotective effect, an indirect cytoprotectiveeffect by displacement of the more hepatotoxicendogenous hydrophobic bile acids from the bileacid pool, an immunomodulatory effect and finallyan inhibitory effect on apoptosis.

Using a labelled bile acid analogue, Jazrawiet al. (1994) demonstrated a defect in hepatic bileacid excretion but not in uptake in patients withPBC and PSC, resulting in bile acid retention.They observed an improvement of hepatic excre-tory function with UDCA in patients with PBCbut only a trend towards improvement in the smallnumber of patients with PSC. Not only is hepaticbile acid excretion affected by UDCA but so isileal reabsorption of endogenous bile acids. Thenet result is enrichment of the bile acid pool withUDCA. Hydrophobic bile acids are more toxicthan UDCA which can protect and stabilizemembranes.

Studies have demonstrated that long-term treat-ment with UDCA decreases aberrant expression ofHLA class I on hepatocytes and reduces levels ofsoluble cell adhesion molecules (sICAM) in PBCpatients. In vitro studies have shown that UDCA

may alter cytokine production by human peri-pheral mononuclear cells. In PSC, one study hasshown that UDCA has been shown to decreaseaberrant HLA DR expression on bile ducts(Lo et al., 1992). However, a more recent studycould not demonstrate any alteration in expressionof either HLA class I and II or ICAM-1 on eitherBECs or hepatocytes (van Milligen de Wit et al.,1999). The body of evidence suggests that UDCAdoes have some modulatory effects on immunefunction, but how important these are remainsunclear.

Numerous studies have attempted to address theclinical efficacy of UDCA treatment in PSC. Themajority have been uncontrolled studies in smallnumbers of patients. In a pilot study, O’Brien et al.(1991) treated 12 patients with UDCA on an openbasis over 30 months. They documented improve-ment in fatigue, pruritis and diarrhoea andsignificant improvement of all liver biochemicaltests, particularly alkaline phosphatase during thetwo UDCA treatment periods. Symptoms andliver biochemistry relapsed during a six-monthwithdrawal period between treatment phases.During UDCA treatment, the amount of cholicacid declined slightly but the levels of otherrelatively hydrophobic bile acids did not changesignificantly.

In the first randomized double-blind controlledtrial of UDCA in PSC, Beuers et al. (1992)compared over a 12-month period six patientswho received UDCA 13–15mg/kg body weightwith eight patients who received placebo (Table 6).The majority of patients had early disease (Ludwigclassification stages I and II). After six months, asignificant reduction in alkaline phosphatase andaminotransferases was achieved in the treatmentgroup. A significant fall in bilirubin was only notedafter 12 months. Using a multiparametric score,the UDCA-treated group showed significantimprovement in their liver histology, mainlyattributed to decreased portal and parenchymalinflammation. Unfortunately, treatment did notameliorate their symptoms. UDCA-induced diar-rhoea was the only important side effect requiringa patient to withdraw.

Similar results were obtained by Stiehl et al.(1994) who randomized 20 patients to either 750mg


Table 6

Controlled trials of ursodeoxycholic acid in PSC

Author Patient

numbers

Study type Dose Study duration LFTs improved Symptoms

improved

Liver

histology

improved

Proportion

with early

diseaseaAlk P GGT Bili AT

Beuers et al.

(1992)

14 DBPC 13–15mg/kg

daily

12 months Yes Yes Yes Yes No Yes 57%

Lo et al. (1992) 23 DBPC 10mg/kg daily 24 months Trend Trend No Trend No No 74%

Stiehl et al.

(1994)

20 DBPC,

Unc

750mg daily Controlled for

three months,

uncontrolled up

to four years

Yes Yes No Yes No Yes 35%

Mitchell et al.

(2001a, b)

26 DBPC 20–25mg/kg

daily

12 months Yes Yes No No No Yes 30%

van Hoogstraten

et al. (1998)

48 DB 10mg/kg daily in

single (Group1)

or three (Group

2) doses

24 months Yes Yes No Yes No NA NA

Lindor (1997) 105 DBPC 13–15mg/kg

daily

Mean 2.9 years Yes Yes Yes Yes No No NA

Key: Unc=uncontrolled, DB=Double blinded trial, PC=Placebo-controlled trial; Alk P=alkaline phosphatase, GGT=gglutamyltranspeptidase, Bili=Bilirubin;

NA=Data not available.a Proportion with early disease, i.e. stages I and II.

R.

Ch

ap

ma

n182

daily of UDCA or placebo (Table 6). How-ever, in a larger randomized placebo-controlledtrial of UDCA in PSC by Lindor (1997). No benefitwas demonstrated. In this trial, 105 patients wererandomized to treatment with UDCA in conven-tional doses, viz. 13–15mg/kg body weight daily, orplacebo and followed up for up to six years (mean2.9 years). Treatment with UDCA had no effectupon the time until treatment failure defined asdeath, liver transplantation, the development ofcirrhosis, quadrupling of bilirubin, marked relapseof symptoms or the development of signs of chronicliver disease. Furthermore, the significant improve-ment in liver biochemical tests seen in the treatedgroup was not reflected by any beneficial changesin liver histology. On the contrary, there was asuggestion that the liver histology of patients onUDCA showed a greater tendency to progresstowards fibrosis. However, this could also beexplained by sampling variability between serialliver biopsies (Olsson et al., 1995a, b).

The failure of standard doses of UDCA toprovide clinical benefit led our group to considerthe use of higher doses. Our rationale is that withincreasing cholestasis, there is decreasing enrich-ment of the bile acid pool with UDCA and higherdoses are required to achieve the same level ofenrichment (Stiehl et al., 1995). Furthermore the invitro immunomodulatory effects of UDCA areenhanced with increasing UDCA concentrations(Hirano et al., 1996). In a pilot study we evaluated26 patients with PSC who were randomized toeither high-dose (20–25mg/kg) UDCA or placebo(Mitchell et al., 2001a, b) for two years. High-doseUDCA had no effect on symptoms, but asexpected, there was a significant improvement inliver biochemistry. More importantly, we found asignificant reduction in cholangiographic appear-ances and liver fibrosis. In the treatment group,bile acid saturation with UDCA W70% confirmedpatient compliance. No significant adverse effectswere reported, in particular no worsening of colitiswas seen. Similar encouraging results wereobtained in an open study on 30 patients withPSC treated for one year (Harnois et al., 2001).When compared to historical controls, a signifi-cant improvement in projected survival using theMayo risk score was observed with high dose but

not with the conventional dose (13–15mg/kg/day)of UDCA.

In the light of these promising results, a largecontrolled trial of high-dose UDCA has beencompleted in Scandanavia. The results have shownno significant differences between the two groups,although there was a strong trend in favour ofimproved survival in the UDCA group. Moreover,the study was probably underpowered to show apositive result, as the endpoints of death ortransplant were lower than expected in bothgroups (Ollson et al., 2006).

Whilst it is established that hydrophilic bile acidUDCA inhibits injury by hydrophobic bile acids,hepatocyte cell death from bile acid inducedtoxicity occurs more frequently from apoptosisthan from necrosis. It has been demonstrated thatUDCA inhibits deoxycholic acid induced apopto-sis by modulating mitochondrial transmembranepotential and reactive oxygen species production(Rodrigues et al., 1998). Moreover, UDCA inhi-bited in vitro deoxycholic acid stimulated growthin several tumour cell lines including colon cancer(Martinez et al., 1998). This has led to thesuggestion that UDCA may reduce the risk ofdysplasia and cancer in the biliary tree and/orthe colon. Tung et al. (2001) studied 59 patientswith PSC and UC followed with three yearlysurveillance colonoscopy. Colonic dysplasia wassignificantly less common in those patients treatedwith UDCA. However, these results were notconfirmed in a study of 120 patients followed withtwo yearly colonoscopic surveillance (Wolf et al.,2001). The recent study of Pardi et al. (2003) hasconfirmed the chemopreventive effect of UDCA.To date, there is only anecdotal evidence that thehigh rate of bile duct cancer is reduced by UDCAtherapy.

5.2.7. Miscellaneous treatmentsIn keeping with UC, there is a strong inverserelationship between PSC and cigarette smoking.This led Angulo et al. (1999a, b) to test the hypo-thesis that oral nicotine might have a beneficialeffect in PSC. Eight non-smoking patients withPSC were treated with nicotine 6mg qid for up toone year. Adverse effects were frequent requiring


cessation in three patients and no beneficial effectswere seen.

5.2.8. Combined therapyIn an important pilot study, the potential ofcombination therapy was explored by Schrammet al. (1999), who treated 15 patients with PSC. Allpatients received low-dose UDCA (500–750mgdaily), prednisolone 1mg/kg daily and azathioprine1–1.5mg/kg daily. After a median follow-upperiod of 41 months, all patients had a significantimprovement in liver function tests. Seven patientshad been previously treated with UDCA, but liverenzymes improved only after immunosuppressivetherapy was added. More importantly, 6 of 10 withfollow-up biopsies showed histological improve-ment, and significant radiological deteriorationwas only seen in 1 of 10 patients who hadendoscopic retrograde cholangiography.

In a 13-year prospective study, Stiehl et al.(1997, 2002) studied the survival of 106 patientswith PSC treated with 750mg UDCA daily and byendoscopic balloon dilatation of major dominantstenoses whenever necessary. Ten patients had adominant stricture at entry, and over a medianfollow-up of five years another 43 developed adominant stenosis. This was not prevented by low-dose UDCA treatment but was successfully treatedby balloon dilatation in the majority, only fiverequiring temporary stenting. This combinedapproach of UDCA and endoscopic interventionsignificantly improved the survival compared withpredicted survival rates. This was an uncontrolledstudy which provides only relatively weak evidencethat UDCA and/or endoscopic therapy prolongedsurvival, although the results are promising.

5.2.9. Orthotopic liver transplantationFor patients with advanced PSC, orthotopic livertransplantation (OLT) is the only therapeuticoption. A number of centres report a five-yearsurvival rate in excess of 75% (Gow and Chapman,2000). Farges et al. (1995) advocate assessment forOLT earlier in the course of the disease to reducethe operative risk and to prevent the development

of hepatobiliary malignancy. Against this appro-ach is the recognition that PSC may recur in thegraft (Graziadei et al., 1999) and that colon canceris the most frequent cause of death in PSC patientsafter OLT (Vera et al., 2003). A recent study hasshown that PSC recurrence is commoner in maleIBD patients who have an intact colon. Five-yearsurvival rates are also improved in colectomizedpatients. In absence of prognostic models capableof predicting the course of disease or the onset ofcomplications in individual patients, the timing ofOLT continues to be controversial (Brandsaeteret al., 2003). A recent report suggests that priortreatment with UDCA is associated with a betteroutcome after transplantation (van Hoogstratenet al., 1998).

6. Conclusion

There is no established effective medical treatmentfor PSC. Recent studies suggest that high-doseUDCA may have a role in at least slowing diseaseprogression, although the results of larger long-term randomized trials are awaited. Randomizedcontrolled trials of immunosuppressive agents inearly PSC are needed, possibly in combination withhigh-dose UDCA. With the identification of T cellsubsets involved in PSC and the cytokines theyproduce, it may be possible to use particularrecombinant cytokines or antibodies to specificcytokines such as anti-TNF antibody (infliximab)to manipulate the immune response in PSC andalter disease progression. Greater insight into thepathogenetic mechanisms involved in PSC wouldenable therapy to be targeted more specifically atthe area of initial damage, namely the biliaryepithelium. Liver transplantation remains the main-stay of treatment for patients with end-stage diseasebut the disease will recur in at least 30% of patients.

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R. Chapman188

PART IV:

Autoimmunity and Viral Hepatitis





CHAPTER 15

Systemic and Autoimmune Manifestations of Hepatitis B VirusInfection

Christian Pagnoux�, Loıc Guillevin

Department of Internal Medicine, National Referral Center for Necrotizing Vasculitides and Systemic

Sclerosis, Hopital Cochin, Universite Paris 5 – Rene Descartes, 27 rue du faubourg Saint-Jacques, 75679 Paris

cedex 14, France

1. Introduction

Effective vaccination campaigns, more stringentblood donor selection, and effective viral inacti-vation procedures have greatly decreased theincidence of hepatitis B virus (HBV) infectionin industrialized countries, yet it remains a majorpublic health problem, especially in developingcountries. In endemic countries, more than 10%of the population may have chronic infection,with HBV remaining among the leading causesof cirrhosis and liver cancer. Indeed, an estimated350–400 million people worldwide are chroni-cally infected with HBV and up to 1 million dieannually because of HBV-related complications(Lavanchy, 2004; Van Damme and Van Herck,2007).

In non-vaccinated people, acute HBV infectionoften remains clinically undetectable or is res-ponsible for only transient icterus in 10–30% ofcases. Conversely, in approximately 1% of newlyinfected adult patients, acute and fulminanthepatitis can develop, and in another 5–10%, thevirus remains. Indeed, chronic infection is definedas the persistence of HBV surface antigens (HBsAg) 6 months after acute hepatitis. One-third of

these chronically infected patients are asympto-matic chronic carriers, whereas chronic hepatitisdevelops in the remaining two-thirds, then hepaticcirrhosis in 20%, and eventually hepatocellu-lar carcinoma in 20% of the latter group ofpatients with cirrhosis (Krastev, 2006; Yim andLok, 2006).

Besides all these potential hepatic manifesta-tions of HBV infection, some extra-hepatic sys-temic and/or autoimmune manifestations mayoccur with both acute and chronic viral infections,usually independently of hepatic involvement. Themost common extra-hepatic manifestation is theprodromal pre-icteric flu-like syndrome witharthralgias and sometimes urticarian cutaneousrash, observed in some patients with acute infec-tion. Other extra-hepatic manifestations, such asHBV-related glomerulonephritis or polyarteritisnodosa (HBV-PAN), have become very rare inparallel with the decreased incidence of HBVinfection.

However, the extra-hepatic HBV-related mani-festations we review here, such as those associatedwith chronic hepatitis C virus (HCV) infectionreceiving much attention in recent years, are still inevidence and must be acknowledged by physicians.In addition, such manifestations were the first toillustrate that some infectious agent may beresponsible for, or at least trigger, systemicdiseases, with clear epidemiological and physio-pathological evidence.E-mail address: [email protected]


Tel.: +33-1-58-41-14-61; Fax: +33-1-58-41-29-68


DOI: 10.1016/S1571-5078(07)00015-3

dx.doi.org/10.1016/S1571-5078(07)00015-3.3d

2. Hepatitis B virus infection

2.1. Virus characteristics

HBV, a member of the hepadnavirus family, is acircular and partially double-stranded DNA virusof 3200 base pairs. The HBV particle consists of anenvelope with three related surface proteins—the S(small), M (medium), and L (large) HBs Agsharing some common epitopes, primarily the ‘a’dominant epitope, a main target of anti-HBsantibodies (Ab)—enclosing an icosahedral nucleo-capsid of approximately 30 nm in diameter con-taining core protein C, and, finally, the viral DNAgenome and DNA polymerase-reverse transcrip-tase. The eight different HBV genotypes (A–H)identified at present differ by more than 8% insequence and show differences in their worldwidegeographical distribution and clinical outcome(Kidd-Ljunggren et al., 2004; Schaefer, 2007). InEurope, genotypes A and D are predominant,whereas in Asia, genotypes B and C are morefrequent, and in the Middle East, genotype D.Genotype E seems restricted to Africa. GenotypeF is found largely in Central and South Americaand Alaska. All eight HBV genotypes are found inthe United States, genotypes A and C being themost common (Chu et al., 2003; Kramvis andKew, 2005). Indeed, these genotypes can now bedivided into at least 24 subgenotypes, differing byat least 4% in sequence and with distinctiveepidemiological properties. Notably, because ofthe high replication capacity of HBV—with arelease of up to 1000 viral particles per day viareverse transcription of RNA intermediates—mutations and additional recombinations continu-ously occur in chronic infection. Furthermore,superinfection with a different genotype that mayalso favor recombinations has been reported tooccur in up to 17.5% of patients (Schaefer, 2007).

The HBV genome has four open-reading framesencoding for the pre-S/S gene, which codes for theenvelope proteins, the C gene for the core proteins,the P gene for the DNA polymerase-reversetranscriptase, and the X gene for the X protein.The C gene includes a core and a pre-core regionand codes for two mRNAs with slightly differentstarts, ends, and lengths. The shorter of the

mRNAs encodes for a protein that assembles toform structural nucleocapsid particles, named HBcAg. The longer mRNA encodes for the so-calledpre-core protein, which is consequently cleaved ofits C-terminal region into HBe Ag, a secretory,non-structural, and non-particulated viral product,used as a seromarker for high viral replication.Notably, disruption of the conformational particlesdefining HBc Ag results in a loss of HBc anti-genicity and the appearance of HBe antigenicity(Schlicht and Wasenauer, 1991; Schodel et al.,1993).

Pre-core mutants are the most common mutantviruses, with pre-core mutations responsible for thedecrease or non-production of HBe Ag. Moreover,such mutations often occur at the time of serocon-version from HBe Ag to anti-HBe Ab (Bozkayaet al., 1996; Miyakawa et al., 1997). Because theselective advantage of the wild-type virus decreasesduring chronic infection in patients with both thewild-type and pre-core mutant virus, HBe Ag-negative chronic hepatitis now predominates. Somestudies have found patients negative for HBe Agtending to be older, male, have lower HBV-DNAand transaminase levels, with disease that morefrequently progresses to cirrhosis (Zarski et al.,1994, 2006).

Finally, the X protein is a non-structuralregulatory protein whose precise functions are notyet fully elucidated, but is required for efficientviral replication. It acts as a positive transcriptionalcoregulator and was recently shown to increase theactivity of androgen-receptor-mediated transcrip-tional activity (Chiu et al., 2007; Miyakawa et al.,1997), and the gene expression and transcriptionalactivity of sterol regulatory element binding pro-tein 1 (SREBP1) and peroxisome proliferator-activated receptor-gamma (PPAR-g), implicatedin hepatic lipid accumulation (Kim et al., 2007).

2.2. Natural history of infection

HBV is transmitted only on a human-to-humanbasis, even though a virus reservoir in certain apesmay exist. Although HBs Ag does not reveal thewhole infective HBV particle, it can be detected inall kinds of human secretions, including blood,

C. Pagnoux, L. Guillevin192

serum, saliva, tears, sweat, urine, stool, semen,vaginal secretions, and maternal milk. HBV is veryresistant and can persist on surfaces out of the bodyfor up to 7 days. It can be transmitted by tight andrepeated contact with chronic-infected subjects(horizontal transmission, probably prevalent inAfrica), especially in families or institutions, butthe three main and clearly identifiable routes areparenteral (blood transfusion, needle sharingamong injection drug users, needlestick injury,tattooing and piercing, acupuncture), sexual, andperinatal, mainly during delivery, particularly inMediterranean, Asian, and developing countries(Abdool Karim et al., 1991; Botha et al., 1984).Transplacental transmission accounts for less than2% of all the perinatal transmissions (Shepardet al., 2005). However, the source and/or route ofinfection remains unidentifiable in nearly one-thirdof patients (Custer et al., 2004; Guillevin et al.,2005; McMahon, 2005; Trepo and Guillevin, 2001).

The mean time of incubation of HBV is 60–90days and the range 45–180 days. Icterus occurs inapproximately one-third of adult patients but inless than 10% of children younger than 5 years.Fulminant hepatitis and death occur in less than1% of patients. Chronic infections develop in2–10% of adult patients but in 30–90% of children,especially those infected as newborns. HBV has adynamic natural history, since disease can fluctuatebetween periods of active replication and/or liverinflammation and periods of inactivity, with less ortransiently no viral replication, sometimes withdelayed spontaneous seroconversion.

Disease progression is influenced by variousfactors, including viral genotype, specific muta-tions, demographic features, duration of disease,concurrent viral infections, and/or social and envi-ronmental factors (McMahon, 2005). Although theclinical relevance is not absolute, genotype A seemsto have better outcome in Europe, whereas in Asia,genotype B, especially Bj, is associated with a lowerrisk of cirrhosis and hepatocellular carcinoma(Kramvis and Kew, 2005). In up to 25% ofchildren and older children with chronic HBVinfection, HBV-related cirrhosis or hepatocellularcarcinoma eventually develops, at a rate of 5% perdecade of adulthood for the latter complication(Shepard et al., 2005).

The clinical significance and impact of coinfec-tion with hepatitis D virus (HDV), especiallygenotype I HDV (Su et al., 2006), HCV, and/orhuman immunodeficiency virus (HIV) amongpatients with HBV chronic hepatitis, has emergedas a major issue (Shukla and Poles, 2004). Approxi-mately 5% of the global HBV carriers arecoinfected with HDV (Hsieh et al., 2006). Theprevalence of chronic HBV infection among HIV-infected individuals has been reported to be 6–10%in Western countries and up to 20% in Asia (Shenget al., 2004); a recent cross-sectional study of HBV-infected patients in French departments of internalmedicine found 53% coinfected with HIV (Seneet al., 2007). Occult HBV infection, defined by thepresence of HBV DNA in the serum or liver in theabsence of HBs Ag, was found in 45% of HCV-infected injection-drug users in the United States(Torbenson et al., 2004).

2.3. Immunopathophysiology and biologicaldiagnosis

HBV has a tropism for hepatic cells, but does nothave cytopathogenic effects per se. Indeed, hepaticcell necrosis is caused by physiological immuneresponses to viral antigens, mainly involving cyto-toxic CD8+ T lymphocytes, which may be exces-sive in symptomatic infection and/or persistent inchronic infection.

Notably, HBV DNA sequences have been foundin circulating leukocytes (Hadchouel et al., 1988),predominantly lymphocytes and especially CD4+but also CD8+ T lymphocytes (Calmus et al.,1994), as well as in lymph nodes, but withoutevidence of replicative forms of HBV (Umeda et al.,2005). Such sequences have been found to a lesserdegree in endothelial cells or stromal fibroblasts, inspleen, small bowel, gonads, thyroid gland, kidneys,pancreas, and adrenal glands, during both acuteand chronic infection (Mason et al., 2005; Yoffeet al., 1990).

Diagnosis and management of HBV infectionnow relies on both the standard serologic markersbut also, largely for chronic infection, on tests toquantify HBV load and study the virus genotypeand possible mutations. In acute infection, viral

Systemic and Autoimmune Manifestations of Hepatitis B Virus Infection 193

replication can first be evidenced by the detectionof HBV-DNA and HBs Ag in sera. Next appearsanti-HBc Ab, of IgM then Ig G isotypes, then anti-HBs Ab, which testify to the effective clearance ofthe virus and are protective. In chronic infection,anti-HBc Ab is adequately produced, but the non-clearance of the virus leads to persistent detectionof HBV-DNA, at least during the initial andreplicative phases, and HBs Ag without anti-HBsAb. HBe Ag is associated with viral replicationand therefore detectable early during acute infec-tion and during the initial and reactivation phasesin chronic infection. With the wild-type virus, theseroconversion to anti-HBe Ab theoreticallyoccurs concomitantly toward the end of virusreplication, but in up to 5% of chronic infectioncases (Yim and Lok, 2006; McMahon et al., 2001;Lok et al., 1987), reversion may still occur in theyear following seroconversion. Most importantly,HBV replication can continue in HBe Ag-negativepatients, because of the frequent pre-core muta-tions that can occur during chronic infection, asdescribed above, especially during seroconversionof HBe Ag to anti-HBe Ab itself, occurringspontaneously and/or under antiviral therapy(Yim and Lok, 2006).

3. Extra-hepatic manifestations of HBV

infection

Most of the described and clinically overt extra-hepatic manifestations of HBV infection occurwith acute infection or within the months follow-ing initial infection. In some cases, especially forpatients with the most severe and sometimes life-threatening manifestations, that is, those withHBV-related PAN, antiviral therapy is required.Such a situation is highly unique, because antiviralagents were developed and are approved officiallyfor HBV infection to treat only chronic hepatitis.With the exception of glomerulonephritis, extra-hepatic manifestations during chronic infection aregenerally less pronounced, and therefore haverarely been emphasized in hepatology trials ortextbooks on HBV infection, as compared withHCV infection (Amarapurkar and Amarapurkar,

2002; Han, 2004). Nonetheless, extra-hepaticclinical or biological manifestations have beenreported to occur in up to 16% of patients withchronic infection (Cacoub et al., 2005).

Case reports and the few studies available showthat in both acute and chronic settings, extra-hepatic manifestations do not seem to be linked to aspecific HBV genotype. However, such manifesta-tions differ in geographical distribution, and extra-hepatic biological manifestations might be morefrequent in patients infected with pre-core mutantvirus (Cacoub et al., 2005). Indeed, HBV-PAN wasmore frequently reported among European, Medi-terranean, and North American adult patients,whereas glomerulonephritis is more frequent inchildren in endemic regions of the world, such asAsia or South America, where HBV transmission ischiefly perinatal or horizontal and leads morecommonly to chronic infection (Han, 2004).

These manifestations are suggested to resultfrom the formation and deposition of HBV Agand anti-HBV Ab immune complexes, then theirinappropriate persistence leading to excessiveactivation of the complement cascade. The preciseidentification of causative HBV Ag remains con-troversial. Notably, a direct role of HBV virusthrough its continuous replication in some extra-hepatic tissues is not totally excluded, even thoughno overt cytopathogenic effects have been unveiledin these tissue cells (Mason et al., 2005).

3.1. Prodromal pre-icteric syndrome

In up to 30% of adult patients and fewer children,symptoms of acute HBV infection develop. Afterthe incubation period, a prodromal pre-ictericsyndrome may occur, with non-specific symptomssuch as nausea, asthenia, and anorexia but alsofever, arthralgias mainly involving the neck andspine, and/or arthritis, myalgias, and sometimesurticarian skin rash. Glomerulonephritis, especiallyin children, and/or central and/or peripheralnervous-system involvement may also occur. Thissyndrome is usually transient, and symptomsspontaneously resolve after 3–7 days, whereasicterus appears 1–3wk later. The symptoms are


likely to correspond to a serum-sickness disease inthe context of high viral replication and immuneresponse with formation of immune complexes. Atthis stage, HBs Ag and HBV-DNA are alreadydetectable, whereas anti-HBc Ag IgM appears atthe beginning of symptoms, then anti-HBc Ag IgGand HBe Ag a few days before icterus onset.Prodromic syndrome is not predictive of fulminanthepatitis or chronic infection (Krugman et al.,1979). However, arthralgias and/or arthritis mayoccasionally persist for longer, without jointdestruction (Han, 2004; Trepo and Guillevin,2001), possibly, but not always, reflecting thetransition to chronic infection.

3.2. HBV-related polyarteritis nodosa

3.2.1. EpidemiologyPolyarteritis nodosa (PAN) is a systemic necroti-zing vasculitis predominantly involving medium-sized arteries that can affect most of the body’sorgans. First described by Kussmaul and Maier(1866), PAN is rare. It can affect all racial groups.Estimates of the annual incidence of PAN in thegeneral population range from 4.6 per 1,000,000inhabitants in England (Scott et al., 1982) to 77 per1,000,000 in Alaska, an HBV-hyperendemic region(McMahon et al., 1989). During the 1970s, abouthalf of the patients with PAN were indeed infectedwith HBV, which therefore appeared to be theleading identifiable cause of PAN (Prince andTrepo, 1971; Trepo and Thivolet, 1970). However,the frequency of HBV-PAN among all the cases ofPAN has declined from 38.5% during 1972–1976to 17.4% during 1997–2002, with a peak of 48.8%between 1982 and 1986 (Guillevin et al., 2005;Mahr et al., 2004). The main reduction is explainedby donor selections reinforced, with systematicblood testing for Hbs Ag, anti-HBc Ab andtransaminase (GPT) level, and widespread vaccina-tion campaigns organized for teenagers and peopleat risk. Similarly, in the United States, theincidence of acute HBV infection in children andadolescents has decreased by 89% (CDC, 2004),and with the possible exception of China, manyAsian countries have now become intermediate-prevalence areas (Custer et al., 2004). Indeed, most

of the recent HBV-PAN patients we have seencame from countries with no vaccination policy,were intravenous drug addicts, or were at risk forsexually transmitted diseases. Strikingly, since2002, the overall incidence of PAN, related toHBV or not, has decreased, which further sup-ports, albeit indirectly, the hypothesis of a potentialexogenous and/or infectious cause of PAN (HBVand/or another yet unidentified agent(s)). Conver-sely, the incidence of some other systemic vasculi-tides, such as microscopic polyangiitis, Wegener’sgranulomatosis, and Churg–Strauss syndrome, isincreasing (Mahr et al., 2004, 2006).

3.2.2. PathogenesisThe immunopathogenic mechanisms leading tovascular injury in PAN and HBV-PAN areprobably comparable but heterogeneous. Themechanism of vascular inflammation implicatedmost often is an immune-complex–induced lesion(Guillevin et al., 1990; Lambert et al., 1980; Trepoand Thivolet, 1970), like for the prodromal pre-icteric syndrome, but with more severe and longerlasting clinical presentation because of morepersistent infection and viral replication. Indeed,almost all cases of HBV-PAN are associated withwild-type HBV and high virus replication with HBeantigenemia, which suggest that lesions could resultfrom the deposition of soluble viral Ag–Abcomplexes in Ag excess. However, the preciseidentification of this latter Ag remains controver-sial, since all the three HBs, HBc, and HBe Ag havebeen suspected. Notably, cases of PAN occurringafter anti-HBV vaccination—a controversial topic,especially in Europe, and out of the scope of thischapter—are extremely infrequent and lack epide-miological confirmation and/or strong imputabilityproof (Degos, 2006). These circulating immunecomplexes would deposit in the vessel walls,although only rarely histologically proven (Goweret al., 1978; Prince and Trepo, 1971; Trepo andThivolet, 1970), and, in turn, would activate thecomplement cascade, then neutrophils, resulting inendothelial injury. Although theoretically possible,HBV-PAN occurring during chronic infection as aviral recombination or superinfection with adifferent HBV genotype has not been reported,


and published cases of HBV-PAN with mutantpre-core virus are extremely rare to date (Miguelezet al., 1998). However, no published results ofPAN-HBV patients have described a systematicanalysis of the HBV genotype.

Notably, some other viruses have been reportedto engender PAN features, although more rarelythan HBV; examples include HCV, GB virus-C(Servant et al., 1998), parvovirus B19 (Cormanand Dolson, 1992), some members of the Herpes

viridae family (Rodriguez-Pereira et al., 1997), andHIV (Gisselbrecht et al., 1997; Pagnoux et al.,2006a). Conversely and to date, no case ofsuperinfection with HDV causing PAN has beenreported in HBV-infected patients.

3.2.3. HistologyVasculitic lesions have a segmental distributionpattern, with a predilection for arterial bifurcations.Early inflammatory infiltrates of and/or around thevessel walls contain lymphocytes, plasmocytes,histiocytes, and some neutrophils. Fibrinoid necro-sis predominates in the internal layer of the arterialmedia, thereby supporting thrombosis develop-ment (Fig. 1). Segmental necrosis of medium-sized

vessel walls may actually give rise to microaneu-risms, detectable on angiography (Fig. 2), mainly onrenal and celio-mesenteric arteries, which usuallyregress or disappear with effective treatment(Darras-Joly et al., 1995).

3.2.4. Clinical manifestations and diagnosisIn HBV-PAN, symptoms of most cases developedless than 6 months (range, 30–1695 days) followinginfection (Guillevin et al., 2005). Symptoms arelisted in Table 1 (Guillevin et al., 2005). HBV-PANpatients are usually younger than 40 years. Mainmanifestations are those described for PAN notrelated to HBV: weight loss, fever, myalgias,arthralgias, asthenia, cutaneous lesions (livedo,cutaneous nodules, and/or necrosis), peripheralneuropathy, especially mononeuritis multiplex(Moore, 1995), gastrointestinal tract involvement,and/or cardiac failure. Abdominal manifestations(53%), and especially those requiring emergencysurgery, such as gastrointestinal tract infarctions,perforations, and/or necrotizing pancreatitis,are frequent, and represent the leading cause ofdeath (Guillevin et al., 2005; McMahon et al.,1989; Pagnoux et al., 2005; Sergent et al., 1976).

Figure 1. Muscle biopsy of a patient with polyarteritis nodosa showing leukocyte infiltrates in the wall of a medium-sized artery (blank

arrow), with fibrinoid necrosis (plain arrow), and thrombosis in the vessel lumen (asterisk). (See Colour Plate Section.)


Hypertension and/or renal impairment are alsoamong the most frequent symptoms and areincluded in the classification criteria established in1990 by the American College of Rheumatology(Table 2—Lightfoot et al., 1990); they result fromrenal artery involvement with consecutive renalischemia and some infarction, but not fromglomerulonephritis, which is more characteristicof small-sized vessel vasculitides such as micro-scopic polyangiitis or Wegener’s granulomatosis.Only very rare cases of glomerulonephritis occur-ring in PAN or HBV-PAN patients have beenreported. Hence, kidney biopsy is not part of theusual diagnostic and/or initial investigations inpatients with suspected or established PAN.When it is performed, if there are no renalmicroaneurisms seen on angiography that would

contra-indicate the biopsy, the presence of glome-rulonephritis should primarily lead to reconsiderthe diagnosis. Notably, HBV-PAN patients lessfrequently tend to have malignant hypertension(5%), renal infarction, and/or orchiepididymitis(25%) than those with PAN not linked to HBVinfection.

Hepatitis habitually remains silent before theonset of PAN symptoms, which can be the firstmanifestations of HBV infection. Transamine(GPT and GOT) levels are usually only moderatelyelevated and even remain at normal levels in one-third of patients (Guillevin et al., 2005), whereascholestasis is usually absent or minor. Liverbiopsy, when performed, frequently reveals signsof chronic hepatitis, even when taken just a fewmonths after HBV infection, which further sug-gests that pathogenic mechanisms differ betweenliver disease in HBV-PAN and that in acutehepatitis. Notably, hepatic biopsy must not beperformed for diagnosis of HBV-PAN becausevasculitis is rarely seen on histology and the biopsyitself can be hazardous because of the possibletraumatic injury of microaneurisms with subse-quent and potentially life-threatening bleeding.

The diagnosis of HBV-PAN ideally relies onthe combination of clinical symptoms; radiolo-gical investigations, especially angiography, whenpatients have abdominal pain resembling mesentericischemia; biopsy of an affected tissue, especiallynerve and muscle in case of neuropathy, but alsosometimes of skin lesions; and, of course, thedetection of replicative HBV infection. Patientsmust of course be tested for other possible co-infections, such as HCV or HIV. As alreadyemphasized, kidney and/or liver biopsies shouldtheoretically not be performed in patients withPAN, regardless of relation to HBV or not, becausethey may be dangerous and because PAN is amedium-sized vessel vasculitides, usually withoutevidence of vasculitis in the liver parenchyma orglomerular involvement. Moreover, angiography ismandatory before any kidney or liver biopsy in therare HBV-PAN patient for whom it is indicated,that is, with suspected glomerulonephritis, usuallyinfrequent, or possible liver dysfunction resultingfrom another associated liver disease, such asautoimmune hepatitis or cancer.

Figure 2. Renal angiogram showing artery stenoses (arrow-

heads) and microaneurisms (arrows) in a female patient with

polyarteritis nodosa. (See Colour Plate Section.)


3.2.5. TreatmentFor HBV-related PAN, conventional treatmentwith corticosteroids and cyclophosphamide is notrecommended because it favors virus replicationand, hence, facilitates evolution to chronic infec-tion. Therefore, a combination strategy has beendevised (Guillevin et al., 2005; Gupta et al., 2001):

� to rapidly control the most severe and poten-tially life-threatening manifestations, initial andshort treatment with corticosteroids (1–2wk ata 1mg/kg/day equivalent dosage of predni-sone), then their abrupt discontinuation toenhance immunological clearance of theHBV-infected hepatocytes and favor serocon-version of HBe Ag to anti-HBe Ab;� to clear circulating immune complexes andcontrol the course of the disease, plasmaexchange (60ml/kg 3–4 times/wk for 3wk, then2–3 times/wk for 2wk, progressively taperedand discontinued when anti-HBe Ab isdetected to avoid the clearance of the newlysynthesized immunoglobulins);� antiviral agents for several months, at leastuntil virologic response with seroconversionand complete remission are achieved.

Table 1

Characteristics of the 115 HBV-PAN patients reported by the

French vasculitis study group (adapted from Guillevin et al.,

2005)

Patient characteristics

Age (years, mean7SD) 51.1717

Sex ratio M:F 1.8

Interval between HBV infection and

the first manifestation(s) of PAN

[available for 12 patients] (days,

mean7SD(range))

5967628 (30–1695)

Delay between first symptom(s) and

diagnosis (days, mean7SD)

84784

Clinical manifestations at diagnosis (%)

General symptoms 96.5

Fever 68.7

Weight loss >5kg 87

Myalgia 47.5

Arthralgia 55.7

Neurological involvement

Mononeuritis multiplex 83.5

Superficial peroneal nerve

involvement

71.3

Deep peroneal nerve involvement 40

Radial involvement 10.4

Ulnar involvement 21.7

Bilateral neuropathy 72.5

Central nervous system

involvement

9.6

Renal and urological involvement 38.3

Proteinuria/hematuria 18.3

Renal vasculitis 29.6

Dialysis/anuria at diagnosis 3.5

Orchitis 25.3

Recent hypertension 31.3

Malignant hypertension 5.2

Skin manifestations (except edema) 31.3

Nodules 8.7

Purpura 16.5

Livedo reticularis 10.4

Ankle edema 15.7

Gastrointestinal manifestations 53.0

Abdominal pain 51.3

Bleeding 2.6

Small intestine perforation/

ischemia

2.6

Cholecystitis 5.2

Appendicitis 1.7

Pancreatitis 6.1

Cardio-vascular signs 30.7

Raynaud phenomenon 2.6

Cardiac insufficiency 12.2


Myocardial infarction 0.9

Pericarditis 5.2

Retinal vasculitis 1.7

Disease scoring

BVAS (mean7SD) 17.878.2

FFS (% of patients)

>1 61.7

>2 31.3

Radiology (%)

Microaneurisms on angiography

(performed in 67 patients)

68.6

Renal infarcts 28.3

Outcome

Follow-up (months, mean7SD) 697135.8

Remission (%) 80.9

HBe Ag to anti-HBe Ab

seroconversion

36.0

Relapses 9.7

Deaths (including those who died

after achieving complete remission)

35.7


Immunosuppressants should only be given topatients with worsening PANmanifestations despitewell-conducted therapy as recommended above.The efficacy of this antiviral strategy was confirmedin a series of 115 HBV-PAN patients (Guillevinet al., 2005): among the 80 who were treatedwith the antiviral strategy, 73 (91%) exhibited

remission, 4 (5%) relapse and 24 (30%) died ascompared with 20 (57%) remissions, 5 (14%)relapses, and 17 (49%) deaths (not significant)among the remaining 35 who received corticosteroidsalone or in combination with cyclophosphamideand/or plasma exchange but no antiviral agents.Moreover, seroconversion rates for HBe Ag toanti-HBe Ab for the two groups were 49% and15%, respectively (po0.001). The antiviral agentsand their dosages for these patients are similar tothose prescribed for chronic HBV hepatitis, andincluded vidarabine for the first patients, theninterferon (IFN)-alpha or lamivudine. Indeed,vidarabine is no longer used because of its highand frequent occurrence of neurological andhematological toxicity. Lamivudine has been shownto increase seroconversion rate in up to 60% ofpatients (Guillevin et al., 2005), but was not able toimprove survival rate at 18 months as comparedwith conventional treatment without antiviraldrugs (mortality rate at 18 months was 28% withconventional immunosuppressive therapy vs. 18%with combined antiviral therapy, p=0.46). Othercombination strategies, including Pegylated IFN-alpha-2 and/or lamivudine and/or newer agents,such as entecavir, emtricitabine, or adefovirdipivoxil, are probably at least as effective as IFN-alpha-2 or lamivudine alone and may be preferen-tially prescribed in the future. They might be moreeffective in controlling HBV replication in thosepatients in whom vasculitis resolved but HBVinfection persisted (Krastev, 2006). Because of therarity of HBV-PAN at present, a trial investigatingthis therapeutic issue is unlikely, but advances inthe treatment of chronic HBV hepatitis must beconsidered for the antiviral treatment of HBV-PAN, in combination with plasma exchange andthe short initial corticosteroid course.

3.2.6. OutcomeHBV-PAN is an acute disease that can be severeinitially, but the outcome is excellent in most caseswith the timely application of adequate treatment.Localized forms, such as those limited to cutaneousmanifestations or muscle involvement describedfor PAN not related to HBV, are exceptional inHBV-PAN. With the application of the effective,

Table 2

1990 ACR criteria for the classification of polyarteritis nodosa

(adapted from Lightfoot et al., 1990)

Criterion Definition

1. Weight loss >4kg Loss of 4 kg or more of body

weight since illness began, not

due to dieting or other factors

2. Livedo reticularis Mottled reticular pattern over

the skin of portions of the

extremities or torso

3. Testicular pain or

tenderness

Pain or tenderness of the

testicles, not due to infection,

trauma, or other causes

4. Myalgias, weakness,

or polyneuropathy

Diffuse myalgias (excluding

shoulder and hip girdle) or

weakness of muscles or

tenderness of leg muscles

5. Mononeuropathy

or polyneuropathy

Development of

mononeuropathy, multiple

mononeuropathies, or

polyneuropathy

6. Diastolic blood

pressure

>90mmHg

Development of hypertension

with the diastolic blood

pressure higher than 90mmHg

7. Elevated blood urea

nitrogen or

creatinine

Elevation of blood urea

nitrogen >40mg/dl

(14.3 mmol/L) or creatinine

>1.5mg/dl (132 mmol/L), not

due to deshydratation or

obstruction

8. Hepatitis B virus Presence of HBs Ag or anti-

HBs Ab in serum

9. Arteriographic

abnormality

Arteriogram showing

aneurysms or occlusions of the

visceral arteries, not due to

arteriosclerosis, fibromuscular

dysplasia, or noninflammatory

causes

10. Biopsy of small- or

medium-sized artery

containing

polymorphonuclear

neutrophils

Histologic changes showing

the presence of granulocytes

or mixed leukocytes infiltrate

in the artery wall

A patient with vasculitis can be classified as having

polyarteritis nodosa if at least 3 of these 10 criteria are present.

The presence of any three or more criteria yields a sensitivity of

82.2% and a specificity of 86.6%.


precise combined antiviral strategy defined above,the prognosis of HBV-PAN has improved and theoverall survival rate increased to between 64 and70% (Guillevin et al., 2005). Seroconversionusually parallels recovery. Once remission has beenobtained, PAN tends not to recur, unlike othersystemic vasculitides such as Wegener’s granulo-matosis or microscopic polyangiitis. Indeed, only8–12% of HBV-related PAN and 19–32% of non–HBV-related PAN tend to relapse, with a meantime to first relapse of 37 and 29 months,respectively (Gayraud et al., 2001; Pagnoux et al.,2006b). Notably, HBV-PAN relapses occur almostexclusively in patients with continued active virusreplication despite treatment. In these rare cases,the clinical pattern of relapse does not necessarilyrepeat the original presentation. However, evenafter disease cure, sequelae such as vascularnephropathy or peripheral neuropathy may persistfor years or sometimes indefinitely.

3.3. HBV-related glomerulonephritis

Besides ischemic renal vasculopathy seen in HBV-PAN, different forms of renal disease have beendescribed with HBV infection: membranous neph-ropathy, membranoproliferative glomerulonephri-tis, mesangial proliferative glomerulonephritis,and, more rarely, minimal change disease, IgAnephropathy, or focal segmental glomerulosclerosis(Bhimma and Coovadia, 2004). Although rare inNorth America and the other Asian countries,HBV-related or, more cautiously, HBV-associatedglomerulonephritis remains among the most com-mon causes of glomerulonephritis in children inendemic countries such as China (Bhimma andCoovadia, 2004). Indeed, glomerulopathy wasdiagnosed in 5% of adult patients with chronicHBV infection in a French cross-sectional study(Cacoub et al., 2005), but it has also been reportedduring acute HBV infection. The potential causa-tive role of HBV in these renal diseases is supportedby their decreased incidence following vaccinationcampaigns (Sun et al., 2003) and by the resultsof a Chinese study revealing that HBV-infectedpeople with diabetes were significantly moreprone to develop end-stage renal disease than their

HBV-negative counterparts (8.7% vs. 6.4%), aftercontrolling for potential confounding factors suchas age or glycemic control (Cheng et al., 2006).Biologically, HBV Ag was found expressed inkidney tissue in some studies, as was HBV-DNAin the nucleus and cytoplasm of epithelial cells ofrenal tubules, which correlates with the duration ofproteinuria (Xin et al., 1998). In some patients withchronic HBV infection, especially those positive forHBV-DNA, serum showed the in vitro ability topromote apoptosis in renal tubular cells through aFas/Fas-ligand pathway (Deng et al., 2006).

A direct cytopathogenic role of HBV in thekidney cannot be excluded. However, the morefrequently invoked mechanism for glomerular injuryin HBV infection is, once again, the formationof immune complexes of viral Ag and anti-HBVAb, with their subsequent subendothelial and/ormesangial deposition in the kidneys. Indeed, theexpression of HBV-DNA could persist in renaltissues, leading to the continuous expression ofviral Ag. Earlier studies suggested that HBe Agwas the most likely HBV Ag responsible, butcontroversies further emerged concerning thispoint, because all types of glomerular depositions,with HBs Ag, HBc Ag, and/or HBe Ag, have beenreported (Lin, 1990). Finally, why nephropathydevelops only in some individuals with chronicHBV infection remains unknown, and underlyinggenetic and/or socio-environmental factors and/ora predisposing host immunological abnormality,especially concerning HBV-specific cellular immuneresponse, may therefore also play a role (Bhimmaand Coovadia, 2004).

The main symptoms of these HBV-relatedglomerulopathies are proteinuria and nephroticsyndrome, occurring predominantly in males,especially children. As for HBV-PAN, liver func-tions are generally spared, and most patients withrenal involvement are chronic ‘asymptomatic’carriers and do not have chronic hepatitis. HBV-related membranous nephropathy is the mostfrequent form and resolves spontaneously in mostchildren, usually in parallel with HBe Ag clearance,whereas progression to renal failure may occur inup to one-third of adults (Lai et al., 1991).Corticosteroids do not have any beneficial effectand can induce virus replication. Antiviral


treatment, with IFN-alpha and/or other, newerantiviral drugs and/or combinations, can be moreefficiently used. In the study by Lin (1995), completeresolution of proteinuria was obtained in all 40patients treated with IFN-alpha, and seroconver-sion of HBe Ag to anti-HBe Ab was achieved in 16as compared with none of the 20 patients receivingonly supportive treatment, for both parameters.

3.4. Gianotti–Crosti syndrome

Gianotti–Crosti syndrome, also named infantilepapular acrodermatitis, is characterized by anacral, self-limiting, symmetrical, papular skin rashin children. It is preferentially located on the dorsalfaces of hands and feet (Fig. 3—Brandt et al., 2006;Gianotti, 1973), but it can also affect, althoughrarely, the face and/or buttocks. Diagnostic criteriainclude three positive clinical features (at leasta 10-day duration of symmetrical papules or

papulovesicles; 1–10mm in diameter; on at leastthree of the following four sites—cheeks, buttocks,extensor surfaces of the forearms, and extensorsurfaces of legs) and two negative features (exten-sive truncal lesions and scaly lesions) (Chuh, 2001).The syndrome can occur during acute HBVinfection and was reported in a non-negligiblenumber of cases in conjunction with superinfectionwith measles or after a concomitant vaccinationagainst both these latter viruses (Andiran et al.,2002). It has also been observed after vaccinationagainst HBV (Karakas et al., 2007). The cutaneouslesions spontaneously resolve within a few weeks,usually in parallel to the clearance of HBs Ag, andhence do not warrant any specific therapy.

The underlying mechanisms remain elusive, eventhough the syndrome might also be related to theformation of immune complexes during the acutephase of the infection, in a particular genetic andenvironmental setting. In earlier papers, HBVserotypes ayw, adr and adw were preferentially

Figure 3. Gianotti–Crosti syndrome (infantile papular acrodermatitis). Pseudo-urticarian rash on the dorsum of the hands and on the

calves. (See Colour Plate Section.)


associated with this syndrome. No HBV genotypestudy has been performed since, largely because ofthe rarity of the syndrome. Some single case-reportdescriptions have suggested that HBV genotype Dmight be more frequently associated with thesyndrome (Michitaka et al., 2004). Of note, thesyndrome is not specific to HBV, because it wasalso reported with Epstein Barr Virus, RespiratorySyncytial Virus, enterovirus or Human HerpesVirus 6 (Caputo et al., 1992; Draelos et al., 1986),and some bacterial infections (Khan et al., 2007)or after vaccination against hepatitis A virus(Monastirli et al., 2007). However, the syndromeis a very rare HBV-associated manifestation, whosefrequency has decreased during the past decades,for some not completely explainable reasons.

3.5. Porphyria cutanea tarda

Porphyria cutanea tarda is a relatively rare disease,with an estimated overall prevalence of approxi-mately 1/25,000 inhabitants in the United Kingdom.Two forms exist: the familial form and the sporadicform, which accounts for 80–90% of cases. Thedisorder is characterized by skin lesions and liverdamage in most cases, especially in the familialform, in relation to a metabolic disorder caused byreduced hepatic uroporphyrinogen decarboxylaseactivity (Roux et al., 1996). Skin lesions includefragile skin, subepidermal bullae, pigmentation insun-exposed areas such as the dorsal faces of thehands, and hypertrichosis, particularly on the fore-head and upper cheeks. Patients do not haveincreased risk of acute neurological manifestationsas compared with those affected by variegateporphyria or hereditary coproporphyria, who mighthave similar skin lesions.

In the sporadic form, etiological and/or asso-ciated factors include alcohol and estrogen use,iron overload, and toxins such as hexachloroben-zene but also HCV and/or HBV infection(s) (Vallset al., 1986). Indeed, serologic markers of chronicinfection with HCV or HBV were detected in 91and 41%, respectively, of 34 patients in one study,with viral genomes of HCV or HBV detected in 65and 40%, respectively (Navas et al., 1995). How-ever, available data are not all in concordance, and

in another study of 66 patients, the frequency ofHBV or HCV infection was somewhat lower, 21%for each, and one-third of infected patients hadboth infections (Stransky et al., 2000). The truthprobably lies somewhere between these values, withchronic HCV infection probably more frequentthan chronic HBV infection (Gisbert et al., 2003).No specific treatment is recommended, except forusual skin care and avoidance of sunlight, alcoholand, possibly, estrogen therapy (Thadani et al.,2000). Antiviral treatment is indicated only forchronic HBV hepatitis, when necessary, withinsufficient data to predict its effect, if any, on thisparticular cutaneous manifestation.

3.6. Diabetes mellitus

An association of diabetes mellitus and both HBVand/or HCV infection(s) has been suggested bysome study results, especially those conducted inregions with high HBV and HCV prevalence.Indeed, diabetes mellitus was significantly morefrequent in a study of Asian Americans with HBVinfection (65% vs. 27.5% for HBV-negative con-trols), as well as in patients infected with HCV orboth HBV and HCV (Li-Ng et al., 2007). In a studyin Niger, 9% of patients with diabetes showed HBsAg in sera as compared with 2.9% of non-diabeticcontrols (Oli and Okafor, 1980). Patients withdiabetes may have greater exposure to the virusthrough poor hygiene practice in insulin injectionsand/or the use of finger sticks (Khan et al., 2002).Indeed, in a European study, HBV markers weremore frequently detected in diabetic patientstreated with insulin than in those treated orally(Hasslacher et al., 1977). As well, a subsequentseries in the same regions showed a decline or evendisappearance in frequency of HBV Ab amongdiabetic patients (Onyekwere et al., 2002), perhapsdue to improved hygienic measures.

Conversely, a Turkish study revealed a significantdifference in prevalence of HBV markers betweendiabetic patients and controls (51% vs. 25%) notrelated to diabetes duration, patient age, and,more importantly, insulin injections (Khuri et al.,1985), which suggests that other mechanisms mayexplain the possible link between HBV and


diabetes mellitus. Moreover, gestational diabetesmellitus was diagnosed slightly more frequentlyin women with chronic HBV infection than inHBV-negative pregnant women (Lao et al., 2003,2007). Diabetic patients may have impaired abilityfor HBV removal and/or be highly susceptibleto subclinical HBV infection, whereas HBV itself,or some serum constituents of infected patients,may play a causative or participating role inthe development of diabetes mellitus. Potentialpancreatic damage secondary to extra-hepatic viralreplication has been evoked to support this lattertheory.

However, links between HBV and diabetesmellitus remain controversial, as does the respec-tive influence of HBV or HCV, particularly becauseof numerous potential confounding factors. Incontrast to HCV, HBV was indeed not identified asbeing associated with diabetes mellitus in someAsian studies (Chen et al., 2006; Okan et al., 2002),whereas diabetes mellitus was found in 5.6% ofHCV-positive and no HBV-positive Pakistanianpatients without liver disease and with comparablefrequencies of 24.5 and 19.4% in those withchronic liver disease due to HCV or HBV infection,respectively (Qureshi et al., 2002). Conversely, inan Italian study of type 2 diabetes patients(Sangiorgio et al., 2000), the prevalence of HCVand HBV infection was similar (7.6 and 7.1%,respectively), with an overall prevalence of HBVand/or HCV infection of 11%.

3.7. Autoimmunity

3.7.1. Thyroid manifestationsSerum thyroxine level was increased proportionalto transaminase levels in 60% of patients withacute HBV infection, presumably because of therelease of thyroxin-binding globulin into thecirculation from injured hepatocytes (Zafar et al.,1992). The thyroxine level usually returns tonormal after HBV recovery (Gardner et al.,1982). Data on serum triiodothyronine levels areconflicting; levels were reported to increase in 10%of acute HBV cases in one study (Zafar et al.,1992) but decrease in another (Gardner et al.,1982), with a return to normal levels after HBV

recovery in both. Some HBV-infected childrenwere reportedly positive for anti-thyroid Ab.Thyroid hormones were within the normal rangein those latter patients positive for anti-thyroidAb, but thyrotropin-releasing hormone-stimulationtest revealed subclinical hypothyroidism (Kansuet al., 2004). Indeed, thyroid gland dysfunction is aknown complication of INF-alpha therapy inpatients with chronic viral hepatitis (Wong et al.,2002), especially HCV hepatitis. However, anti-thyroid peroxidase Ab and anti-thyroglobulin Abcan be detected in up to 5 and 3% of HBV-infectedpatients, respectively, before any antiviral treat-ment (Fernandez-Soto et al., 1998) and do notappear to be influenced by subsequent IFN-alphatherapy (Gregorio et al., 1996), except in onestudy in which 45% of the patients developedanti-thyroid auto-Ab 4–8 months after beginningIFN-alpha therapy (Mayet et al., 1989). Intrigu-ingly, still unknown is the pathophysiologicalmeaning of thyroxine and triiodothyronine bind-ing sites present on the spherical particles asso-ciated with HBs Ag (Neurath et al., 1975).

3.7.2. Anticardiolipin autoantibodiesAnticardiolipin Ab of IgG, IgM, and/or IgAisotype(s) have been found in 14–21.5% of patientswith HBV infection, especially chronic infection(Elefsiniotis et al., 2003; Mangia et al., 1999;Zachou et al., 2003), but anti-beta2-glycoprotein I(GPI) Ab in only 2% (Zachou et al., 2003), thusarguing for cofactor beta2-GPI independency inmost cases (Guglielmone et al., 2001). Indeed, Abtiters were relatively low and the levels anddistribution of isotypes did not differ much betweenpatients with acute or chronic HBV infection(Guglielmone et al., 2001). Notably, high anti-cardiolipin Ab level might be more frequent amongpatients coinfected with HDV (42.8%) (Zachouet al., 2003). Importantly, the detection of anti-cardiolipin Ab is not associated with clinical featuresof anti-phospholipid syndrome, but perhaps withsome extra-hepatic manifestations such as leucocy-toclastic angiitis or membranoproliferative glome-rulonephritis, and, among patients with HBV-relatedhepatocellular carcinoma, a high risk of venousportal thrombosis (Elefsiniotis et al., 2003).


3.7.3. Other autoantibodiesDiverse other auto-Ab have been reported withchronic viral hepatitis, including HBV infection,and usually occur as an epiphenomenon and atrelatively low titers. About 15% of the HBV-infected patients have at least one detectableauto-Ab, particularly anti-smooth muscle cell Ab(7%), antinuclear Ab (3%), antinucleosome Ab,cryoglobulin, rheumatoid factor, and/or anti-liver–kidney–microsome (anti-LKM) Ab (2% foreach) (Cacoub et al., 2005; Lohse et al., 1995;Mangia et al., 1999). In children, the prevalence ofan auto-Ab, especially anti-smooth muscle cell andantinuclear Ab, can be as high as 34% (Gregorioet al., 1996). Mutant pre-core virus seems to bemore frequently associated with such auto-Ab butonly by univariate analysis; no correlation with anyHBV genotype has been identified (Cacoub et al.,2005). Moreover, as for antithyroid Ab, these otherauto-Ab do not seem to be induced or modified byIFN-alpha therapy (Gregorio et al., 1996). Incontrast to mixed cryoglobulinemia in HCVinfection, clinical expression of these Ab is rare inHBV-infected patients (Czaja, 1997).

3.8. Miscellaneous

During acute HBV infection, other manifestationshave been reported, such as isolated arthralgias,myalgias, or, more rarely, neuropathy, Guillain–Barre-like syndrome (Han, 2004; Trepo andGuillevin, 2001), or epididymitis (Tasar et al., 2005);such manifestations might correspond to a minorprodromal pre-icteric phase or to limited forms ofsystemic HBV-PAN.

Similar concerns relate to other extra-hepaticmanifestations infrequently reported for patientswith chronic HBV infection; examples includepsoriasis skin lesions (1% of patients), skin vascu-litis (1%), pruritus (1%), Raynaud phenomenon(2%), uveitis (2%), myalgias (3%), arthralgias(3%), sicca syndrome (3%), and/or sensory-motorneuropathy (5%) (Cacoub et al., 2005). Thesemanifestations most often occur in the early yearsfollowing infection and possibly correspond to mildand/or localized forms of HBV-PAN or during anacute increase of HBV replication. However, the

precise relation of these manifestations with HBVinfection remains elusive and they might indeedoccur coincidentally.

Isolated acute pancreatitis, a possible feature ofsevere HBV-PAN, has been documented in acuteHBV infection but also in acute exacerbation ofchronic HBV infection (Fournier et al., 1991),sometimes following liver transplantation. Patientswith possible HBV-PAN-related isolated pancrea-titis seem to have a higher mortality rate (80%)than patients with pancreatitis from other causes(12%) or with acute exacerbation of chronic HBVinfection without pancreatitis (2%) (Yuen et al.,2001). In some patients with fatal acute necrotizingpancreatitis, damage of both exocrine and endo-crine epithelial cells with inflammatory responseswas observed on autopsy, whereas immunohisto-chemistry and in situ hybridization of the pancreasrevealed the presence of HBs Ag and HBV-DNA inthe cytoplasm of acinar cells, and electron-micro-scopically showed core-like particles in the nucleusand cytoplasm (Cavallari et al., 1995; Yoshimuraet al., 1981).

HBV-related ophthalmological manifestations,mainly vasculitic retinal ischemia (Akova et al.,1993; Lortholary et al., 1989), are rare but canoccur during HBV-PAN, as in PAN not due toHBV, but also during chronic HBV infection, withconjunctival and perilimbic microcirculationabnormalities, possibly resulting in scleritis, peri-pheral ulcerative keratitis, non-granulomatousuveitis, and/or central retinal artery occlusionand/or optic nerve dysfunctions (Cusnir et al.,1997; Morgan et al., 1986).

Myalgias are frequent during acute prodromalpre-icteric syndrome and in HBV-PAN, as men-tioned previously. HBV serology is therefore oftenincluded in the initial diagnostic investigations forpatients with suspected myositis. However, lessthan 10 cases of polymyositis or dermatomyositissupposedly related to HBV infection have beenreported. However, this association could be justcoincidental because evidence are lacking. Thereportedly simultaneous occurrence of hepatitisand myositis or the worsening of myositis followingexacerbation of hepatitis in those latter 10 chroni-cally infected patients are indeed clearly notsufficient as an argument to support this assoiation


(Nojima et al., 2000). Immunofluorescence of bothmuscle and liver revealed HBs Ag/anti-HBs Abimmune complexes and complement deposits in onlya few patients (Mihas et al., 1978; Pittsley et al.,1978), and in almost all patients, corticosteroidtherapy alone was effective.

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CHAPTER 16

Extrahepatic Manifestations in Patients with Chronic Hepatitis CVirus Infection

Manuel Ramos-Casalsa,�, Xavier Fornsb, Jose-Maria Sanchez-Tapiasb, Juan Rodesb

aLaboratory of Autoimmune Diseases ‘‘Josep Font’’, ‘‘Instituto de Investigaciones Biomedicas August Pi

I Sunyer (IDIBAPS)’’, Hospital Clinic, Barcelona, SpainbLiver Unit, ICMD, Ciberehd, ‘‘Instituto de Investigaciones Biomedicas August Pi I Sunyer (IDIBAPS)’’,

Hospital Clinic, Barcelona, Spain

1. Introduction

Autoimmunity and viral infections are closelyrelated fields, and viruses have been proposed aspossible etiologic or triggering agents of systemicautoimmune diseases (SAD). The hepatitis C virus(HCV), a linear, single-stranded RNA virus identi-fied in 1989 (Choo et al., 1989), is recognized as oneof the viruses most often associated with auto-immune features. A decade ago, various authorsdescribed the association of HCV infection with aheterogeneous group of extrahepatic conditions,such as pulmonary fibrosis, cutaneous vasculitis,glomerulonephritis, Mooren ulcers, porphyria cuta-nea tarda, or lichen planus (Gumber and Chopra,1995), although it is currently accepted that a weakdegree of association exists in some of them(Campisi et al., 2004). More recently, there hasbeen growing interest in the relationship betweenHCV and SAD (Ramos-Casals et al., 2001a). Theclinical association of the different SAD withchronic HCV infection may be analyzed from twodifferent, but complementary, points of view. Firstly,a review of the literature found nearly 500 patientswith coexisting SAD and chronic HCV infection

(Ramos-Casals et al., 2005d), with Sjogren’ssyndrome (SS; 182 cases), rheumatoid arthritis(RA; 94 cases), systemic lupus erythematosus(SLE; 67 cases), and polyarteritis nodosa (PAN;41 cases) being the most frequent SAD described.Secondly, analysis of all references to series ofpatients with SAD tested for HCV shows thehighest prevalences of HCV infection in patientswith SS (17.6%), PAN (14.4%), SLE (9.6%), andRA (5.9%) (Ramos-Casals et al., 2005d). Otherrecent studies have focused on the associa-tion between chronic HCV infection and circulat-ing autoantibodies, organ-specific autoimmunediseases, and lymphoproliferative processes.

2. Autoantibodies and HCV

Circulating autoantibodies are often detected inpatients with chronic HCV infection. Anti-nuclearantibodies, rheumatoid factor, and anti-smoothmuscle antibodies are the most frequently found,while other autoantibodies (such as anti-dsDNA,anti-ENA, AMA, or anti-LKM-1) are infrequent(Fried et al., 1993; Abuaf et al., 1993; Rolachonet al., 1994; Pawlotsky et al., 1994; McFarlaneet al., 1994; Richardet et al., 1994; Borotto et al.,1994; Clifford et al., 1995; Czaja et al., 1995;Cassani et al., 1997; Buskila et al., 1998; RiveraE-mail address: [email protected]


Tel.: +34-93-2275774; Fax: +34-93-2275774


DOI: 10.1016/S1571-5078(07)00016-5

dx.doi.org/10.1016/S1571-5078(07)00016-5.3d

et al., 1999b; Cacoub et al., 2000; Drygiannakiset al., 2001; Stroffolini et al., 2004; Yee et al., 2004)(Table 1). ANA have been detected in 589 (18.6%)out of 3169 unselected HCV patients included in 16studies (Table 1), although the geographic preva-lence varied significantly (Yee et al., 2004). Yee et al.(2004) reported a threefold higher prevalence ofANA in HCV females compared with males, with nocorrelation between ANA and the response to anti-viral therapy, while Stroffolini et al. (2004) foundno correlation between non-organ-specific autoanti-bodies (NOSA) and the main HCV-related epide-miological, biochemical, and histological features, orthe response to anti-viral treatment. This suggeststhat the presence of ANA or NOSA in HCVpatients should not be considered a contraindicationfor anti-viral treatment. In addition a recent studyhas shown that combined anti-viral treatment (IFN-ribavirin) is safe and effective in NOSA-positiveHCV patients, with a similar prevalence of long-termresponse between NOSA-positive and NOSA-negative patients (49 vs. 57%) (Muratori et al., 2005).

With respect to other immunological markers,Watt et al. (2004) found a correlation betweenserum immunoglobulin levels in HCV patients(IgA, IgG, and total Ig) and histological progres-sion to liver fibrosis. These results are consistentwith our findings in 321 patients with HCV-related

cryoglobulinemia, in whom hypergammaglobuli-nemia was observed more frequently in cirrhoticthan in non-cirrhotic patients (Font et al., 2004).

3. Organ-specific autoimmune diseases

and HCV

Recent studies have analyzed the association ofHCV with some organ-specific autoimmune dis-eases such as thyroiditis or diabetes mellitus (DM).

3.1. Thyroiditis

The role of HCV in inducing thyroid autoimmu-nity is still unclear. Bini and Mehandru (2004)described the development of thyroid disease (overtor subclinical) in the 11% of 225 male HCV-infected patients treated with combined anti-viraltherapy, although the thyroid disease respondedwell to specific treatment and was reversible inmost cases. Antonelli et al. (2004c) reported ahigher frequency of hypothyroidism (13%) andanti-thyroid antibodies (21%) in 630 treatment-naıve HCV patients compared with normal con-trols, and also found similar results in a subset ofthese HCV patients with associated mixed cryoglo-bulinemia (MC) (Antonelli et al., 2004a). However,other studies, performed in the same geographicalarea, did not find this close association (Tomer andVillanueva, 2004). Floreani et al. (2006) tested 697Italian subjects for thyroid autoantibodies andanti-HCV antibodies. Of the 71 HCV-positivepatients, 4 (6%) were positive for at least onethyroid autoantibody, compared with 7 (5%) ofthe HCV-negative sex- and age-matched controls.

3.2. Diabetes mellitus and steatosis

Several clinical studies have suggested a possiblelink between chronic hepatitis caused by HCV andthe development of DM. Antonelli et al. (2004b)have also reported that the prevalence of type 2diabetes is higher in patients with MC-HCV thanin controls, with diabetic MC-HCV patients havinga more pronounced autoimmune reactivity than

Table 1

Meta-analysis of the main studies analysing prevalence of

autoantibodies in unselected series of patients with chronic

HCV infection

Autoantibodies HCV patients

tested

Positive

markers

Percentage

(%)

Cryoglobulins 514 204 39.7

Rheumatoid

factor

738 281 38.1

Anti-SMA 2203 481 21.8

Antinuclear

antibodies

3169 589 18.6

Anti-LKM 2193 75 3.4

Anti-dsDNA 606 16 2.6

Anti-ENA 444 11 2.5

AMA 1210 4 0.3

Abbreviations: HCV, hepatitis C virus; SMA, anti-smooth

muscle antibodies; LKM, anti-liver-kidney microsomes anti-

bodies; ENA, anti-extractable nuclear antigens (anti-Ro/SS-A,

anti-La/SS-B, anti-RNP, anti-Sm); AMA, anti-mitochondrial

antibodies.


non-HCV patients with type 2 diabetes. In addi-tion, recent findings suggest that the developmentof liver fibrosis is associated with insulin resistancein HCV-infected patients (Taura et al., 2006) andthat DM may contribute to the presence andseverity of hepatic encephalopathy independent ofthe severity of liver disease.

Metabolic disorders in HCV patients may berelated to the development of steatosis, whoseclinical significance in HCV patients has beenrecently emphasized (Lonardo et al., 2004). Var-ious factors are associated with hepatic steatosis,including obesity, high alcohol consumption, typeII DM, and hyperlipidaemia. These factors maycontribute to steatosis in HCV patients. Indeed,after anti-viral treatment, HCV-related steatosisdisappears (Asselah et al., 2006).

Hepatic inflammation may mediate fibrogenesisin patients with liver steatosis. Leandro et al. (2006)conducted a meta-analysis from 3068 patients withhistologically confirmed chronic hepatitis C. Stea-tosis was present in 1561 patients (51%) and fibrosisin 2688 (88%). Steatosis was independently asso-ciated with genotype 3, fibrosis, diabetes, hepaticinflammation, ongoing alcohol abuse, higher bodymass index, and older age. The association betweensteatosis and fibrosis was invariably dependent on asimultaneous association between steatosis andhepatic inflammation. Control of metabolic factorssuch as overweight by lifestyle adjustments appearsimportant in the management of chronic hepatitis C.

4. Systemic autoimmune diseases and HCV

The association between HCV and SAD has gene-rated growing interest in recent years. The extra-hepatic manifestations often observed in patientswith chronic HCV infection (both clinical andimmunological) may lead to the fulfillment of thecurrent classification criteria for some SAD (Table 2).

4.1. Sjogren’s syndrome

Recent experimental (De Vita et al., 1995; Koikeet al., 1997), virological (Arrieta et al., 2001; Toussirotet al., 2002), and clinical evidence (Jorgensen et al.,

1996; Ramos-Casals et al., 2001c; De Vita et al., 2002)has revealed a close association between HCV andSS. In 2002, we formed the SS-HCV Study Group, amulticenter international collaboration that has, sofar, recruited 137 SS-HCV patients (Ramos-Casalset al., 2005). We found that HCV-associated SS isindistinguishable in most cases from the primary formusing the most recent set of classification criteria, andwe have proposed the term ‘SS secondary to HCV’ inthose HCV patients who fulfill the 2002 ClassificationCriteria (Vitali et al., 2002). Chronic HCV infectionshould be considered an exclusion criterion for theclassification of primary SS, not because it mimicsprimary SS, but because the virus may be implicatedin the development of SS in a specific subset ofpatients (Ramos-Casals et al., 2001b).

Table 2

Different degrees of association between HCV and systemic

autoimmune diseases

Degree of association Extrahepatic HCV features

overlapping with the classification

criteria

High

Sjogren’s syndrome Xerostomia, xerophthalmia, ocular

tests (+), salivary biopsy (+), ANA,

RF

Rheumatoid

arthritis

Arthritis of 3 or more joint areas,

arthritis of hand joints, symmetric

arthritis, RF

Systemic lupus

erythematosus

Articular involvement, renal

involvement, ANA, aPL, cytopenias

Intermediate

Polyarteritis nodosa Weakness, peripheral neuropathy,

elevated creatinine, positive HBV

markers

Anti-phospholipid

syndrome

Positive aPL, atypical thrombotic

events

Sarcoidosis Pulmonary fibrosis

Inflammatory

myopathies

Weakness, elevated GOT, GPT

Low

Systemic sclerosis Pulmonary fibrosis

Wegener

granulomatosis

Renal involvement

Giant cell arteritis Age W50 years

Polymyalgia

rheumatica

–

Ankylosing

spondylitis

–

Extrahepatic Manifestations in Patients with Chronic HCV Infection 211

There is a considerable overlap between Europeandiagnostic criteria for SS and some extrahepaticfeatures of HCV infection (Table 3). Extrapo-lating from the main studies with large series ofHCV patients, xerostomia was observed in 158(18%) of 859 patients, xerophtalmia in 129 (17%)of 769, positive ocular tests in 83 (38%) of 216,positive salivary gland biopsy (grades 3–4 ofChisholm-Mason classification) in 64 (25%) of251, positive ANA in 481 (18%) of 2641, andpositive RF in 357 (40%) of 1117 HCV patients.In contrast, positive anti-Ro/SS-A antibodies weredescribed in only 30 (4%) of 765 HCV patients andanti-La/SS-B in 27 (3%) of 765. These percentagessuggest that a diagnosis of SS could be easily madein HCV patients presenting sicca syndrome,positive ANA, and/or RF. The SS diagnosed inthese HCV patients may be considered as one ofthe extrahepatic manifestations of chronic HCVinfection.

The main differential aspect between primaryand HCV-related SS is the immunological pattern,with a predominance of cryoglobulinemic-relatedmarkers (mixed cryoglobulins, RF, hypocomple-mentemia) over SS-related markers (anti-Ro/SS-Aand anti-La/SS-B autoantibodies) in HCV-relatedSS (Ramos-Casals et al., 2005c). We found athreefold higher prevalence of hypocomplemente-mia in SS-HCV patients compared with patientswith primary SS (Ramos-Casals et al., 2005a).Cryoglobulinemia seems to be the key immunolo-gical marker of SS associated with HCV, having a

close association with RF activity and complementactivation.

A recent study (Ramos-Casals et al., 2007) hasfirstly described the disease characteristics of B-celllymphoma in SS-HCV patients, its treatment,outcome, and survival prognosis. These patientsare clinically characterized by a high frequency ofparotid enlargement and vasculitis, an immunolo-gic pattern overwhelmingly dominated by thepresence of RF and mixed type II cryoglobulins,the predominance of MALT lymphomas and anelevated frequency of primary extranodal involve-ment in organs in which HCV replicates (exocrineglands, liver and stomach). The triple associationbetween SS, HCV and B-cell lymphoma suggestsan important role for associated autoimmune andchronic viral diseases in the pathogenesis of B-celllymphoproliferative disorders and reinforces theidea that autoimmunity, infection and cancer maybe closely related. A careful evaluation and follow-up of HCV patients with associated SS to aidearly diagnosis and treatment of possible B-celllymphoma should be recommended.

4.2. Rheumatoid arthritis

It is understandable that HCV patients withpolyarthritis and positive RF may be clinicallyclassified as having RA. Of the 1988 revised ACRcriteria, there are 4 (arthritis of 3 or more jointareas, arthritis of hand joints, symmetric arthritisand RF) that some HCV patients may present.Rosner et al. (Rosner et al., 2004) reviewed theprevalence and clinical characteristics of the HCV-related arthritis exhaustively, and also analysed thesignificant overlap with RA. The most frequentclinical presentation of HCV-related arthritis ischronic inflammatory polyarthrtis, which may leadto the fulfillment of the ACR classification criteriafor RA in more than 50% of cases. The existence ofmorning stiffness, rheumatoid nodules and erosivearthritis (rarely described in the setting of HCVinfection) (Rivera et al., 1999a; Zuckerman et al.,2000a) may be useful to diagnose a true coexistenceof RA and HCV.

Recent studies have focused on the prevalenceand clinical significance of antibodies to cyclic

Table 3

Prevalence of the 1993 European criteria for SS diagnosis in

large series of patients with chronic HCV infection

1993 European criteria Present feature/

HCV patients

Prevalence

(%)

Xerostomia 158/859 18

Xerophthalmia 129/769 17

Positivite ocular tests 83/216 38

Parotid scintigraphy No data No data

Salivary gland biopsy 64/251 25

Immunological tests

Anti-nuclear antibodies 481/2641 18

Rheumatoid factor 357/1117 40

Ro/SS-A 30/765 4

La/SS-B 27/765 3


citrullinated peptide (CCP) in patients withchronic HCV infection. Wener et al. (2004) foundno anti-CCP antibodies in HCV patients, althoughsome false-positive results were observed inpatients with MC, while Bombardieri et al. (2004)found anti-CCP antibodies in 76% of patients withRA and in 60% of those with coexisting RA andHCV, but not in HCV patients, irrespective of theirarticular involvement. Lienesch et al. (2005) foundanti-CCP antibodies in 1/50 HCV patients with-out arthritis. Sene et al. (2006) investigated thediagnostic reliability of anti-CCP antibodies indistinguishing HCV-associated rheumatologicalmanifestations from RA. Anti-CCP antibodieswere detected in only two HCV infected patientswith articular involvement (6%), in none withoutarthralgia and in 78% of patients with RA. With aspecificity of 93% and a positive predictive value of96%, anti-CCP antibodies were the most specificbiological marker for RA. These studies suggestthat anti-CCP antibodies may be useful in dis-criminating HCV patients with a true RA fromthose with HCV-associated arthropathy.

4.3. Systemic lupus erythematosus

Viruses have been postulated as potential etiologicor triggering agents in the pathogenesis of SLE.Chronic HCV infection can induce clinical andserologic features (arthritis, nephropathy, haemo-cytopenias and low titers of ANA or anti-dsDNA)which, in combination, may meet the ACR 1982criteria for SLE.

In this context of autoimmunity related to HCV,some reports have suggested that HCV infectionmay mimic SLE. Some authors have analysed theprevalence of HCV infection in SLE patients(Cacoub et al., 1992; Kowdley et al., 1997;Marchesoni et al., 1995), and case reports of theirassociation have also been published (Marvisi,1998; Nepveu and Libman, 1996). Cacoub et al.(1992) found anti-HCV antibodies (ELISA-2) in 7(11%) of 62 patients, although RIBA-2 waspositive in only one (2%). Kowdley et al. (1997)found anti-HCV antibodies (ELISA-2) in 5 (12%)of 42 SLE patients, but only 3 (7%) patients werepositive in the immunoblot analysis and 2 (5%)

were PCR positive. None of these patients hadchronic liver disease symptoms, and only one hadabnormal liver test results. We analysed a largeseries of SLE patients and found that HCVinfection was present in 11% of an unselected SLEpopulation (Ramos-Casals et al., 2000). Thisprevalence is significantly higher than the preva-lence of HCV infection found in the control group(1%) and in the general population in Catalonia(1.2%), and suggests a possible link between HCVinfection and SLE. Similar results have beenobtained by Ahmed et al. (2006) in the UnitedStates (10% in SLE patients compared with 1.3%in the general population).

In comparison with patients with idiopathicSLE, SLE-HCV patients have a different patternof clinical and immunologic manifestations, mainlycharacterized by a lower frequency of cutaneousSLE features, a higher prevalence of liver involve-ment, a lower frequency of anti-dsDNA antibodiesand a higher prevalence of hypocomplementemiaand cryoglobulinemia. Thus, it appears that severalSLE criteria are very specific to SLE and are rarelypresent in HCV infection (malar rash, discoidlesions, subacute cutaneous lesions, photosensiti-vity, neurological manifestations, high titers ofANA or anti-dsDNA and presence of anti-Smantibodies). Two differentiated subsets of SLE-HCV patients may be defined: patients with HCVinfection and a ‘true’ SLE, in which HCV might bea concomitant process or, perhaps, might act as atriggering factor, and patients with a ‘lupus-likesyndrome’ possibly caused by HCV infection.

The first group of patients have at least two ofthe following specific SLE features: malar rash,discoid lesions, subacute cutaneous lesions, photo-sensitivity, neurological criteria, ANA Z1/160,anti-dsDNA W15U/mL or anti-Sm antibodies.We believe that this subset of SLE-HCV patientsshould be considered as having a ‘true’ SLE withan associated HCV infection. Although the patho-genic role of HCV infection in these patients isunclear, it is possible that HCV acts, in our geogra-phical area, as a triggering factor in some patientswith a definite genetic background. The secondsubset present a ‘mild’ SLE, mainly characterizedby articular involvement, hematologic features,lower titers of ANA and anti-dsDNA and positive


cryoglobulins in the majority of cases. It is knownthat patients with cryoglobulinemia can showseveral features commonly observed in SLE, suchas arthritis, nephropathy or hypocomplementemia(Perlemuter et al., 2003). In this subset of patients,it is possible that chronic HCV infection (associatedwith cryoglobulinemia in some cases) may producea ‘lupus-like syndrome’, mimicking a ‘true’ SLEaccording to the 1982 revised criteria for SLEclassification. These studies suggest that HCVtesting should be considered in the diagnosis ofSLE, especially in patients without typical SLEcutaneous features and with low titers of autoanti-bodies (ANA and anti-dsDNA), liver involvementor cryoglobulinemia (61). Conversely, patients withchronic HCV infection and extrahepatic featuresmimicking SLE should be tested for the presence ofANA and anti-dsDNA.

4.4. Anti-phospholipid syndrome

Recently, the possible association of anti-phospho-lipid syndrome (APS) with viruses has generatedgrowing interest. Historically, aPL have alwaysbeing closely associated with infectious agents, eversince they were first detected in sera from syphilispatients (Cervera and Asherson, 2003). In a recentreview, Uthman and Gharavi (2002) have analysedthe etiopathogenic role of viruses in APS anddescribed isolated cases associated with viruses suchas cytomegalovirus, varicella zoster, Epstein–Barrvirus and HCV.

We have recently analysed a total of 45 HCVpatients with clinical features related to APS(Ramos-Casals et al., 2004a). In comparison withgeneral APS series, APS-HCV patients had a highermean age and a differentiated clinical spectrum ofthrombotic involvement, with a lower frequency ofthe more typical APS features such as peripheralthrombosis or neurological features and, in con-trast, a higher prevalence of atypical or infrequentAPS features, such as myocardial infarction orintra-abdominal thrombotic events. In addition, ahigher frequency of positive immunological mar-kers that are often detected in chronic HCVinfection, such as ANA, cryoglobulins, hypocom-plementemia, and rheumatoid factor, was observed

in patients with APS-HCV. In addition, the higherpresence of LA (80%) in APS-HCV patients maywell explain the occurrence of thrombotic events inthis subset of HCV patients, since its prevalence inunselected series of HCV patients is extremely low(less than 1%).

Infectious agents may play a diverse etiopatho-genic role in the clinical expression of APS, withbacterial infections probably acting as acute trig-gering agents of a devastating, multiorganic form ofAPS (catastrophic APS), while chronic viral infec-tions (such as HCV and HIV) may trigger aheterogeneous, atypical presentation of APS.

4.5. Cryoglobulinemic vasculitis

Patients with cryoglobulinemia present a verybroad spectrum of clinical features. Although morethan 50% of patients present a relatively benignclinical course with a good prognosis and survival(Ferri et al., 2004), some patients may presentsevere, life-threatening internal organ involvement.Why some cryoglobulinemic patients present thissevere cryoglobulinemic vasculitis remains unclear.Ferri et al. (2004) recently found that 35% of theirpatients with cryoglobulinemic vasculitis had amoderate-severe clinical course, with the prognosisbeing severely affected not only by cryoglobuline-mic involvement but also by associated conditionssuch as HCV-related liver failure.

Two recent studies have analysed the clinicalcharacteristics of HCV-related cryoglobulinemia inlarge series of patients. Sene et al. (2004) studied125 patients with MC retrospectively and foundthat cryoglobulinemic vasculitis was associatedwith advanced age, longer duration of HCVinfection, type II MC, and a higher MC serumlevel. Ferri et al. (2004) analysed demographic,clinical and serologic features and survival in 231patients with MC. One hundred sixty eight patientswere tested for HCV infection, with 155 (92%)being positive. Malignancies were observed in 15%of patients, mainly non-Hodgkin lymphoma(NHL) and hepatocellular carcinoma, and themain causes of death were related to MC (64%),NHL (13%), and liver involvement (13%).


Life-threatening cryoglobulinemia is found in10–15% of patients with cryoglobulinemic syn-drome. The most frequent type of life-threateninginvolvement is renal failure due to cryoglobuline-mic glomerulonephritis. Recent data suggest thatcryoglobulinemic glomerulonephritis significantlyaffects the prognosis and survival. Ferri et al.(2004) described renal failure secondary to cryo-globulinemic glomerulonephritis as the main causeof death in their patients with cryoglobulinemia,with a survival rate of 33% after a mean follow-upof 10 years, while Tarantino et al. (1995) describeda survival rate of 49% at 10 years after renalbiopsy in 105 patients with cryoglobulinemicglomerulonephritis. We found a survival rate of39%, with cryoglobulinemic involvement contri-buting directly to death in only one third of cases,with infection and liver disease being the mostfrequent causes of death (Ramos-Casals et al.,2006). Likewise, Tarantino et al. (1995) found thatthe main causes of death were cardiovasculardisease, hepatopathy, and infection. Cryoglobuli-nemic glomerulonephritis seems to have a poorprognosis in patients with HCV-related cryoglo-bulinemia. Most of our patients with severe renalinvolvement had chronic HCV infection, whileBeddhu et al. (2002) reported that all their patientswhose serum creatinine doubled or who pro-gressed to end-stage renal disease were HCVpositive. Impaired renal function at diagnosis hasalso been related to poor prognosis. Tarantinoet al. (1995) found that patients with an initialserum creatinine level higher than 1.5mg/dL had ahigher risk of end-stage renal disease or death. Inaddition, chronic renal failure may enhanceimmunosuppression and the risk of infectiousprocesses. In fact, four out of the five patientswho died in our series due to infectious processeshad chronic renal failure due to cryoglobulinemicglomerulonephritis (2006). Gastrointestinal vascu-litis and pulmonary hemorrhage are very rare andhad a very poor prognosis in patients withcryoglobulinemia. Of the 33 well-reported cases,26 (80%) died (Ramos-Casals et al., 2006). Thisillustrates the extremely poor prognosis of cryo-globulinemic pulmonary and intestinal involve-ment, with a high mortality at presentation and apoor prognosis in survivors presenting a further

episode. The lack of a therapeutic protocol (due tothe rarity of this type of involvement) togetherwith the high mortality in patients with other typesof vasculitis means that both clinical presentationare one of the main challenges in dealing withpatients with cryoglobulinemia.

4.6. Sarcoidosis

The first association between sarcoidosis and HCVwas reported in 1993 by Blum et al. (1993), andwas directly related to the onset of a-interferontherapy. A recent study have analysed the clinicalcharacteristics and outcome of 68 cases of coex-isting sarcoidosis and chronic HCV infection, innearly 75% of whom sarcoidosis was triggered byanti-viral therapy (Ramos-Casals et al., 2005).Two other patterns of association between sarcoi-dosis and HCV have been described: the coex-istence of both diseases in treatment-naıve HCVpatients, and the reactivation of a pre-existingsarcoidosis in HCV patients subsequently treatedwith anti-HCV therapies.

4.6.1. Sarcoidosis triggered by anti-viraltherapySarcoidosis may be precipitated or exacerbated insome HCV patients receiving anti-viral therapy.Nevertheless, this phenomenon remains uncom-mon. We recorded five cases of sarcoidosis trig-gered by anti-viral therapy from nearly 2000 HCVpatients treated in our Liver Unit (Ramos-Casalset al., 2005e), a prevalence of 0.2%, which is verysimilar to that observed by Leclerc et al. (2003),who described one case out of 1159 HCV patientstreated with a-interferon (0.1%). Thus, a prevalenceof 1–2 cases of sarcoidosis per 1000 HCV patientstreated with anti-viral agents should be postulated.As the estimated prevalence of sarcoidosis rangesfrom 1 to 40 cases per 100,000 population, thefrequency of sarcoidosis seems to be higher in HCVpatients receiving anti-viral therapy than in thegeneral population.

Analysis of 50 cases of sarcoidosis triggered byanti-viral therapy for HCV infection (Ramos-Casalset al., 2005e) has permitted a better definition of the


main clinical manifestations and outcome of thisinduced form of sarcoidosis. It appears predomi-nantly in middle-aged women, of whom a round aquarter had received previous anti-viral courses,with no response in most cases. In two thirds ofthe 50 cases, sarcoidosis was triggered in the first6 months of anti-viral therapy. Although lessfrequent, sarcoidosis may also appear after comple-tion of anti-viral therapy, but in all these cases thedisease emerged in the first 3 months after comple-tion. The cause–effect relationship between inter-feron administration and the development ofsarcoidosis seems to be clear in nearly all cases.However, a possible additional role for ribavirinshould be considered. In 10 out of 12 patients whohad received a-interferon monotherapy before thedevelopment of sarcoidosis, the granulomatouslesion appeared during a second course of treatmentwith interferon and ribavirin and not earlier withinterferon alone. Ribavirin may enhance the Th1response by increasing production and expressionof IL-12 mRNA, by increasing production of IFN-gand tumor necrosis factor-a, and by lowering theTh2 response. Consequently, the enhancement ofa Th1-type immune reaction induced by thecombined therapy might trigger granulomatousreactions more frequently than a-interferon mono-therapy. This might explain the progressively highernumber of cases published in recent years: only 10cases published between 1993 and 1999, while in thelast 4 years, coinciding with the generalized use ofcombined therapy, the number of cases reported hasincreased fourfold.

A specific clinical pattern was observed in HCVpatients with sarcoidosis triggered by the anti-viraltherapy, with a higher prevalence of cutaneous andarticular involvement and a lower frequency ofhilar and extrapulmonary adenopathies in compari-son with unselected HCV-negative patients withsarcoidosis. The lungs are affected in more than90% of all patients with sarcoidosis, while in theHCV patients with sarcoidosis the observedpercentage is 76%. In contrast, while cutaneousinvolvement usually occurs in about 25% of allsarcoidosis patients, the percentage in sarcoidosistriggered by anti-viral therapy is 60%. In addition,cutaneous sarcoidosis was the only clinical featurein six patients (Ramos-Casals et al., 2005e), a

clinical presentation rarely observed in non-HCVpatients. The reasons for this specific predilectionfor cutaneous involvement are not known.Although cutaneous sarcoidosis may occur inisolation, it is more commonly seen as a manifes-tation of systemic disease. Severe sarcoid involve-ment (e.g., progressive pulmonary fibrosis, cardiac,and central nervous system) was observed in lessthan 5% of HCV patients with sarcoidosistriggered by anti-viral therapy (Ramos-Casalset al., 2005e), a similar figure to those reported ingeneral series of sarcoidosis patients (Hunninghakeet al., 1999).

Although the natural history of sarcoidosis ishighly variable, spontaneous remission occurs innearly two-thirds of patients, while the course ischronic and progressive in 10–30% (Hunninghakeet al., 1999). Nearly 85% of cases of sarcoidosistriggered by anti-HCV therapy improved or remittedspontaneously (Ramos-Casals et al., 2005e), withless than 10% of cases having a chronic and stablecourse. Improvement or remission was clearly relatedto discontinuation of anti-viral therapy, with only35% of patients requiring systemic corticosteroids.In most large published series, 30–50% of unselectedpatients with sarcoidosis were treated with corticos-teroids (Hunninghake et al., 1999), although thesymptoms requiring corticosteroid therapy remaincontroversial. In patients with mild disease (mainlyskin), topical steroids may be all that is necessary,while in those with systemic, symptomatic disease,oral corticosteroids are often employed.

Few data are available about the response toanti-viral therapy in HCV-sarcoidosis patients.Near to 50% of our patients treated with IFN/RBV presented a viral response at the end of thetherapy, a similar prevalence to that observed inunselected HCV patients. We have also reviewedthe response to anti-HCV patients in the casespublished in the literature (Ramos-Casals et al.,2005e). The response was detailed in only 23 cases,with a rate of viral response of 48%. According tothese figures, a similar viral response to anti-HCVtherapy seems to be observed in HCV patientswith sarcoidosis compared with the most recentseries of unselected HCV patients.

Some recommendations for the management ofHCV patients with triggered sarcoidosis should be


suggested for the daily clinical practice (Table 4).Firstly, an accurate evaluation of the interferon-related adverse effects (such as arthralgias, fever,myalgyas, or fatigue) should be made, in order toclearly separate these effects from the symptoma-tology originated by the triggered sarcoidosis,discarding the existence of an underlying triggeredsarcoidosis in patients with more severe side effects.Secondly, we suggest a baseline chest X-ray uponstarting anti-viral therapy, with a specific follow-upcentered on the possible development of cutaneousor respiratory symptoms. Thirdly, a differenttherapeutic approach should be considered accord-ing to the severity of the triggered sarcoidosis. Inpatients with mild disease (cutaneous involvement,lymphadenopathy) cessation of anti-viral therapywill probably be sufficient, although continuationmight be considered under close follow-up (espe-cially in patients with isolated cutaneous lesions).In patients with severe disease (diffuse pulmonaryinvolvement, systemic disease) cessation of anti-viral therapy is mandatory, probably together withinitiation of oral corticosteroids (adding immuno-suppressive agents according to the clinical

evolution). In these cases, a close monitoring ofliver function, HCV-RNA levels and cell counts ismandatory. Finally, with respect to the use of anti-viral therapy in HCV patients with previoussarcoidosis, anti-viral therapy in these patientsshould only be indicated with extreme caution andstrict individualized assessment, especially inpatients who received previous anti-viral courses.

4.6.2. Sarcoidosis in treatment-naıvepatientsThe first case of sarcoidosis in treatment-naıve HCVpatient was reported by Belgodere et al. (1999) in1999, and the association of the two diseases wasconsidered casual. Eighteen additional cases havebeen published over the last 4 years, suggesting thatthis situation may be more frequent than previouslysupposed. However, this association should beconsidered as less frequent than that associatedwith anti-HCV treatment. No differences in clinicalfeatures or prognosis being found between treat-ment-naıve HCV patients and sarcoidosis triggeredby anti-HCV therapy. In fact, no study has analysedthe prevalence of HCV infection in large seriesof unselected patients with sarcoidosis, althoughBonnet et al. (2002) have reported a higher preva-lence in a small series of patients with sarcoidosis,detecting HCV infection in 5 out of 32 patients withsarcoidosis. Although a casual coexistence of twoindependent diseases can occur in some of thesepatients, the role of HCV as an etiopathogenicagent for sarcoidosis should be investigated infuture large matched case–control studies.

4.7. Systemic vasculitis

PAN is considered the most-frequent systemicvasculitis associated with chronic HCV infection.More than 60 HCV patients have been reported, insome cases in association with HBV coinfection(Ramos-Casals et al., 2005d). In addition, theprevalence of HCV markers in patients with PANis high, with positive HCV antibodies beingdetected in 25 (14%) of the 173 patients analysed.Several of the 1990 criteria for the classification ofPAN, such as weight loss, myalgias or weakness,peripheral neuropathy, elevated BUN/creatinine,

Table 4

Recommendations for the management of sarcoidosis in

patients with chronic hepatitis C virus infection

Perform baseline chest X-ray upon starting anti-viral therapy

Evaluate IFN-related adverse effects accurately, discarding the

existence of an undiagnosed sarcoidosis in patients with

unexpectedly severe or prolonged IFN-related side effects

Specific follow-up centered on the possible development of

cutaneous or respiratory symptoms suggestive of sarcoidosis

Discontinue anti-viral therapy in patients with mild sarcoidosis

(cutaneous involvement, lymphadenopathy), although

continuation might be considered under close follow-up

In patients with severe sarcoidosis (diffuse pulmonary

involvement, systemic involvement), cessation of anti-viral

therapy is mandatory

When the severity of sarcoid involvement requires treatment

with corticosteroids and/or immunosuppressive agents, a close

monitoring of liver function, HCV-RNA levels, and cell counts

is mandatory

In HCV patients with previous sarcoidosis, anti-viral therapy

should only be indicated with extreme caution and strict

individualized assessment


and positive HBV markers, are often observed inHCV patients. Although cryoglobulinemic vascu-litis could histologically mimic cutaneous or renalinvolvement observed in microscopic polyarteritis,classic PAN shows necrotizing inflammation ofsmall or medium-sized arteries without glomeru-lonephritis or vasculitis in arterioles, capillaries, orvenules. Thus, the main difference between the twotypes of systemic vasculitis most frequently asso-ciated with HCV (PAN and cryoglobulinemia) isthe different size of the vasa involved. The highspecificity of this histologic criterium may beuseful in the differential diagnosis of PAN orHCV-cryoglobulinemic vasculitis.

Other systemic vasculitides are rarely associatedwith chronic HCV infection, such as giant cellarteritis, Takayasu’s arteritis, Wegener granulo-matosis, Churg–Strauss vasculitis, and Henoch–Schonlein purpura (Ramos-Casals et al., 2005b).The 1990 criteria for these vasculitis showed a smalloverlap with the most common extrahepatic fea-tures observed in HCV infection, and the coexis-tence of these vasculitis with HCV infection may beconsidered a chance phenomenon.

4.8. Inflammatory myopathies

The association of HCV with inflammatory myo-pathies is mainly found in isolated case reports, witha total of 36 cases published, of which 21 were poly-myositis (Ramos-Casals et al., 2005b). In contrast,only three studies have analyzed the prevalence ofHCV in series of patients with inflammatorymyopathies and found HCV infection in 12 of 126(9.5%) patients (Ramos-Casals et al., 2005b). Thecriteria of Bohan and Peter show a small degree ofoverlap with HCV infection, since HCV patientsinfrequently present muscle weakness with elevationof muscle enzyme levels or electromyographic evi-dence of a generalized myopathy. Thus, at present,inflammatory myopathies are tenuously associatedwith HCV infection.

4.9. Other systemic autoimmune diseases

Although we have described seven patients withsystemic sclerosis and HCV infection (76), this

association should be considered as very infre-quent. The criteria for the diagnosis of systemicsclerosis are highly specific, since the existence ofcutaneous sclerosis and positive anti-Scl70/anti-centromere antibodies are infrequently describedin HCV patients. Other SAD associated with HCVhave been reported, including Behc-et disease(seven cases), Still disease (one case), ankylosingspondylitis (one case), and mixed connective tissuedisease (one case) (Ramos-Casals et al., 2005d).Herrera et al. (2004) reported a patient withrelapsing polychondritis (RP), HCV, and MC, inwhom treatment with anti-HCV therapy improvedthe symptoms of RP.

5. Hematological diseases and HCV

The specific tropism of HCV for many extrahepa-tic cell types (Table 5), especially for circulatingblood cells, has recently been suggested by severalstudies (Arrieta et al., 2001; Toussirot et al., 2002;Crovatto et al., 2000; De Almeida et al., 2004; DeVita et al., 2000; Authier et al., 2003; Di Muzioet al., 2003; Bonetti et al., 1999; Radkowski et al.,2002; Okabe et al., 1997; Agnello and Abel, 1997;

Table 5

Extrahepatic localizations of the hepatitis C virus infection

References

Circulating blood cells

B-lymphocytes Crovatto et al. (2000),

Ducoulombier et al. (2004)

T-lymphocytes Crovatto et al. (2000)

Monocytes Crovatto et al. (2000)

Neutrophils Crovatto et al. (2000)

Platelets Crovatto et al. (2000)

Extrahepatic tissues

Salivary glands Arrieta et al. (2001),

Toussirot et al. (2002)

Gastric mucous De Vita et al. (2000)

Striate muscle Authier et al. (2003),

Di Muzio et al. (2003)

Peripheral nerve Authier et al. (2003),

Bonetti et al. (1999)

Central nervous sytem Radkowski et al. (2002)

Myocardium Okabe et al. (1997)

Cutaneous lesions Agnello and Abel (1997)


Ducoulombier et al., 2004), providing a clear linkbetween HCV and the development of autoim-mune and neoplasic hematological processes. Thesusceptibility of blood cells to HCV infection mightbe enhanced by coexisting additional chronic viralinfections. Laskus et al. (2004) reported that HIVfacilitates the infection and replication of HCV incirculating blood cells, a fact that might be relatedto the development of severe cytopenias in someHCV-HIV patients (Ramos-Casals et al., 2003).

5.1. Autoimmune cytopenias

Although HCV-related cytopenias are not uncom-mon, they are usually considered as mild labora-tory abnormalities with no clinical significance,especially in patients with hypersplenism. Themost frequent is thrombocytopenia, which has achronic clinical course with severe bleeding beinguncommon. De Almeida et al. (2004) found noassociation between HCV genotypes and throm-bocytopenia, although HCV-RNA was detectedmore frequently in the platelets of thrombocyto-penic patients than in those with a normal plateletcount. Wang et al. (2004) described a 10-foldhigher frequency of thrombocytopenia in HCVpatients compared with HCV-negative controls,and thrombocytopenia correlated with the severityof HCV-related liver disease.

Severe cytopenias are observed in some HCVpatients, related or not to anti-viral therapy.Thrombocytopenia may be severe (o30� 109/L)in treatment-naıve HCV patients, and in some isassociated with concomitant autoimmune diseases,cryoglobulinemia, and HIV coinfection (Ramos-Casals et al., 2003a). Two cases of severe Coombs-positive autoimmune hemolytic anemia (AHA)have recently been reported in patients nottreated with IFN (Elhajj et al., 2004; Etienne,2004). Previously, 17 cases of HCV-related AHAhad been reported (Ramos-Casals et al., 2003),frequently associated with autoimmune diseases,with cryoglobulinemia being the most frequentimmunologic marker. Finally, isolated cases ofpure red-cell aplasia have also been described inHCV patients (Ramos-Casals et al., 2003a;Tanaka et al., 2004).

5.2. Lymphoproliferative diseases

Recent studies have found a higher prevalence oflymphoproliferative disorders in HCV patients(Bianco et al., 2004; Morton et al., 2004; Iwataet al., 2004). Matsuo et al. 2004; Iwata et al., 2004)performed an elegant meta-analysis of 23 epide-miological studies on the association between HCVand NHL, including 4049 NHL patients. Thesummary odds ratio (OR) for NHL in HCVpatients was 5.70, being 5.04 for B-cell, and 2.51for T-cell NHL (Matsuo et al., 2004). A similarmeta-analysis was conducted by Dal Maso andFranceschi (2006) to evaluate the strength and theconsistency of the association between HCV andNHL, including only studies withZ100 cases whichwere also adjusted for sex and age. The pooled RRof all NHL in HCV-positive individuals was 2.5.Nieters et al. (2006) tested for HCV infection serumsamples of 1807 lymphoma cases and 1788 controls,and found HCV infection in 53 (2.9%) lymphomacases and in 41 (2.3%) control subjects (OR, 1.42).When restricted to individuals who tested positivefor HCV-RNA, the OR raised to 1.82.

The prevalence of HCV infection in NHL patientsmay be higher, since Paydas et al. (2004) have des-cribed false negative results in the ELISA detectionof anti-HCV antibodies in 8 (72%) out of 11 patientswith NHL, in whom the presence of HCV-RNA wasconfirmed in paraffin-embedded lymphomatoustissues. This occult HCV infection has also beendescribed in some patients with an altered liverprofile of unknown origin (Castillo et al., 2004), inwhom the virus was isolated from liver tissue andcirculating mononuclear cells, and was not detec-table by ELISA and PCR techniques in serum.

Lymphomagenesis in HCV patients might beinitiated by the chronic stimulation of polyclonal Bcells by the virus (Starkebaum and Sasso, 2004)and the compartmentalization of HCV quasispe-cies in blood mononuclear cells (Di Liberto et al.,2006), with the posterior development of specificB-cell clonal expansions (Sansonno et al., 2004;Vallat et al., 2004) and pro-carcinogenic mutations(Machida et al., 2004; Libra et al., 2004). Vallatet al. (2004) suggested that B-cell clonality in theblood and liver may be a marker of lymphomadevelopment in some HCV patients. Machida et al.


(2004) reported that both acute and chronic HCVinfection caused a 5- to 10-fold increase inmutation frequency in the Ig heavy chain, BCL-6,p53, and beta-catenin genes, while Libra et al.(2004) detected bcl-2 rearrangement in mucosa-associated lymphoid tissue (MALT) lymphomasfrom HCV patients. Rosa et al. (2005) haverecently proposed that CD81-mediated activa-tion of B cells in vitro mimics the effects ofHCV binding to B cell CD81 in vivo and thatpolyclonal proliferation of naive B lymphocytesis a key initiating factor for the development ofHCV-associated B lymphocyte disorders.

The close relationship between autoimmunity,viruses, and cancer is demonstrated by thedescription of patients with HCV infection, SAD,and B-cell lymphoma, who had a high prevalenceof cryoglobulinemia, a high frequency of primaryextranodal NHL involvement, and a poor prog-nosis (Ramos-Casals et al., 2004c). The clearestexample is the development of NHL in patientswith SS-HCV (Ramos-Casals et al., 2002) (Fig. 1).Recently, Ambrosetti et al. (2004) have reportedthat most cases of primary salivary MALT

lymphoma are associated either with SS or HCVinfection. In addition, Arcaini et al. (2007) retro-spectively studied 172 patients with a histologicaldiagnosis of marginal zone B-cell MALT lym-phoma, in whom HCV infection was found in 60patients (35%). HCV-positive patients showedmore frequent skin (35%), salivary glands (25%),and orbit (15%) lymphomatous involvement.

The close relationship between HCV and NHLmight have therapeutic implications (Emens andSulkowski, 2002; Levine et al., 2003), since Tursiet al. (2004) have reported the disappearance ofgastric MALT lymphoma in 13 out of 18 HCVpatients after 6 months of anti-viral therapy. Werecommend a careful evaluation of patients withB-cell NHL in order to detect silent autoimmuneor chronic viral diseases.

6. Therapeutic management of extrahepatic

features

The therapeutic management of HCV-relatedautoimmune features has become a clinical

Figure 1. The triple association between Sjogren’s syndrome, hepatitis C virus, and B-cell lymphoma: etiopathogenic links. (See Colour

Plate Section.)


challenge in HCV patients, in whom chronic liverdisease associated with severe autoimmune featurescontributes to a very poor prognosis (Ramos-Casalset al., 2003b). Both anti-viral and immunosuppres-sive therapies, either alone or in combination, seemlikely to have an important role, although thesetreatments should be individualized according tocost, follow-up, relapses, organ involvement, risk ofexacerbation of autoimmune disease, and thepossible consequences of immunosuppression in thesetting of chronic HCV infection (Vassilopoulosand Calabrese, 2002). In spite of the small numberof patients included in the available reportedstudies, combined anti-viral therapy plus cortico-steroids, and/or immunosuppressive agents mayachieve symptomatic relief and even long-termremission of the cryoglobulinemic syndrome. Insevere, symptomatic cryoglobulinemic vasculitis,plasmapheresis should also be considered. Theoptimum length of treatment remains to beestablished, and severe cases may need long-termor even lifelong therapy. Recent data are availablefor the use of immunosuppressive and biologicalagents in HCV patients with autoimmune orlymphoproliferative manifestations (Table 6).

6.1. Anti-viral therapy

The treatment of HCV infection has progressedsignificantly with the recent introduction of

combined therapy with pegylated interferonalpha and ribavirin. This treatment has provi-ded much better short and long-term results inpatients with HCV-related vasculitis than histori-cally reported with monotherapy with IFNa.In three uncontrolled studies (Zuckerman et al.,2000b; Naarendorp et al., 2001; Cacoub et al.,2002), combination therapy with standard IFNaand ribavirin demonstrated significant efficacy onthe main HCV-related vasculitic manifestations.Two studies reported reduced proteinuria in sus-tained viral responders treated with IFNa plusribavirin (Bruchfeld et al., 2003; Alric et al., 2004).Saadoun et al. (2006) recently studied 72 consecu-tive HCV-MC patients and found that Peg-IFNaplus ribavirin achieved a higher rate of completeclinical response (67 vs. 56%) and virologicalresponse (62 vs. 53%) compared with standardIFNa plus ribavirin, regardless of HCV genotypeand viral load. Early virologic response wasindependently associated with a complete clinicalresponse of MC.

6.2. Mycophenolate mofetil

Recent reports have suggested a promising role formycophenolate mofetil (MMF) in the treatment ofHCV-related autoimmune processes, especiallysevere cytopenias (Ierardi et al., 2003) andcryoglobulinemic vasculitis (Reed et al., 2001;Caponnetto et al., 2001). In addition, Medinaet al. (2004) have reported preliminary results onthe successful use of MMF to treat diffuseproliferative glomerulonephritis in five patientswith HCV-related SLE. The favorable response toMMF in these patients, with no major side effectsand no signs of worsening of HCV infection,suggests that MMF may be used as monotherapyor in association with other drugs in patients withSAD associated with chronic HCV infection.

6.3. Rituximab

In 2003, some studies demonstrated the efficacy ofusing rituximab in cryoglobulinemic vasculitis(Lamprecht et al., 2003; Zaja et al., 2003; Sansonno

Table 6

Use of the new immunosuppressive and biological agents in

patients with autoimmune or lymphoproliferative diseases

associated with chronic HCV infection

Agent Autoimmune disease

Rituximab HCV-related cryoglobulinemia

Coombs+ haemolytic anemia

B-cell lymphoma, SS, and HCV

Anti-TNF RA and HCV

HCV-related cryoglobulinemia

Psoriatic arthritis+HCV

MMF HCV-related cryoglobulinemia

Myasthenia gravis+HCV

HCV-related thrombocytopenia

Coombs+ haemolytic anemia

Abbreviations: MMF, mycophenolate mofetil; anti-TNF,

anti-tumor necrosis factor agents.


et al., 2003). Recent reports have described thesuccessful use of rituximab in HCV patients withcryoglobulinemic glomerulonephritis, although thenephritis relapsed and required a second course ofrituximab in some patients (Roccatello et al., 2004).A recent study by Quartuccio et al. (2006) des-cribed a rapid, sustained renal response in 5 HCVpatients with active, biopsy-proven, cryoglobuline-mic glomerulonephritis. Rituximab also provedeffective against other active cryoglobulinemicmanifestations, no major side-effects occurred andsteroids were not required in the follow-up.

The successful use of rituximab to treat hema-tological processes associated with HCV, such assevere cytopenias or NHL, has also been reported.Etienne et al. (2004) have successfully treated anHCV patient with severe AHA, and we have usedrituximab to treat indolent B-cell lymphoma inpatients with SS and HCV (Ramos-Casals et al.,2004b). In comparison with standard chemothe-rapy regimens, monotherapy with rituximab isgenerally well tolerated and serious adverse effectsare uncommon.

6.4. Anti-TNF agents

Finally, anti-tumor necrosis factor (TNF) agentshave recently been used in some HCV patients withcoexisting systemic and rheumatic diseases. Anti-TNF agents (infliximab or etanercept) have beenused in patients with coexisting RA and HCVinfection (Parke and Reveille, 2004; Peterson et al.,2003; Oniankitan et al., 2004), although few detailson the clinical response of the articular involve-ment were included. Other authors have describedthe use of infliximab in isolated cases of refractorycryoglobulinemic vasculitis (Chandesris et al.,2004) and the use of etanercept in HCV patientswith psoriatic arthritis (Magliocco and Gottlieb,2004). A recent study by Marotte et al. (2007)reports nine patients with HCV-related rheumato-logical manifestations treated with etanercept.Although etanercept appeared to be safe in thesepatients, the effect on the extrahepatic manifesta-tions was heterogeneous and lower than thatobserved in RA. Although these agents seem to

have a reasonable safety profile in the setting ofHCV infection (Calabrese et al., 2004), the avail-able data are still insufficient to evaluate theirclinical efficacy and possible long-term side effectsin patients with chronic HCV infection andautoimmune features.

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2172–2178.


PART V:

Other Conditions





CHAPTER 17

Autoantibodies in Gastrointestinal Autoimmune Diseases

Neophytos P. Papageorgiou, Yehuda Shoenfeld�

Center for Autoimmune Diseases, Department of Medicine B, Chaim Sheba Medical Center

(Affiliated to Tel-Aviv University), Tel-Hashomer 52621, Israel

1. Antibodies in inflammatory bowel

diseases

1.1. Introduction

Crohn’s disease (CD) and ulcerative colitis (UC),also known as inflammatory bowel diseases (IBD),are chronic diseases affecting the intestinal tract.Although the etiology is still unknown, it isbelieved that a combination of environmentalfactors, genetic predisposition and a dysregulatedimmune response to endogenous bacteria in thegastrointestinal tract play significant role in thedevelopment of these diseases (Nakamura et al.,2003).

Several antibodies have been described in thepast that are associated with IBD and have beenfound to be useful for diagnosing and differentiat-ing CD from UC (Nakamura et al., 2003).

The most important and frequently studied areas follows: (a) anti-Saccharomyces cerevisiae anti-bodies (ASCA), (b) atypical perinuclear antineutro-phil cytoplasmic antibodies (pANCA), (c) anti-OmpC(outer membrane porin from Escherichia coli) andmost recently described (d) the antibody to CBir1(anti-CBir1 flagellin) (Nakamura et al., 2003; Israeliet al., 2005; Reumaux et al., 2003; Targan et al.,2005).

1.2. The antibodies

1.2.1. DefinitionsAtypical pANCA are IgG class autoantibodiesdirected against antigens of the inner side of thenuclear membrane of the neutrophil (Nakamuraet al., 2003; Jaskowski et al., 2006). Some studiesshowed that pANCA are produced locally in thecolonic mucosa, suggesting that antigens ofmicrobial agents may be involved in the develop-ment of IBD (Nakamura et al., 2003).

ASCA are antibodies of the IgG and IgA classdirected against mannose sequences of S. cerevisiae

cell wall (Nakamura et al., 2003; Reumaux et al.,2003; Jaskowski et al., 2006). ASCA is a highlyspecific serological marker of CD (Nakamuraet al., 2003).

Anti-OmpC are antibodies directed against theouter membrane porin C of E. coli. Theseantibodies are of IgA and IgG class found to beassociated with both CD and UC (Nakamuraet al., 2003; Reumaux et al., 2003; Jaskowski et al.,2006).

Anti-CBir1 flagellin is an IgG class antibodyagainst the flagellin CBir1, a bacterial antigen firstidentified in a murine model, which is associatedwith IBD, specifically with a subset of CD patients(Targan et al., 2005; Lodes et al., 2004).

1.2.2. Methods of detectionDetection of atypical pANCA IgG is performedusually by indirect immunofluorescence (IIF)E-mail address: [email protected]


Tel.: 972-3-5302652; Fax: 972-3-5352855


DOI: 10.1016/S1571-5078(07)00017-7

dx.doi.org/10.1016/S1571-5078(07)00017-7.3d

technique on ethanol and formalin-fixed neutro-phils. Sera that show a perinuclear pattern onethanol-fixed neutrophils but that are negative onformalin-fixed neutrophils are considered to bepositive for atypical pANCA (Jaskowski et al., 2006).In addition, positive samples marked as atypicalpANCA can be further analyzed by enzyme-linkedimmunosorbent assay (ELISA) for the exclusionof antiproteinase 3 (PR3), antimyeloperoxidase(MPO) and other known autoantibodies (Israeliet al., 2005; Reumaux et al., 2003; Jaskowski et al.,2006).

ASCA IgG and IgA are detected using anELISA assay. A variety of ASCA tests areavailable today showing several sensitivities andspecificities possibly due to different cut-off values(Reumaux et al., 2003).

An ELISA assay is also used for the detectionof IgG and IgA anti-OmpC. Purified antigensisolated from E. coli are used to bind theantibodies (Zholudev et al., 2004).

In the same way, anti-CBir1 IgG detection isperformed by ELISA analysis using the NH2-terminal fragment of CBir1 (147 AA) (Targanet al., 2005).

1.2.3. GeneticsIt has always been questioned if the antibodiesassociated with IBD are genetically determined.Data from several family studies showed anincreased positivity of pANCA in 16–30% ofhealthy first-degree relatives of UC patients(Reumaux et al., 2003; Seibold, 2005). Anotherstudy showed an increased HLA-DR2 expressionin ANCA-positive UC patients (Reumaux et al.,2003). Nevertheless, more studies are needed to bedone to confirm these results.

Concerning ASCA, they have also been demon-strated to be positive in 20–25% of unaffectedfirst-degree relatives of patients with CD (Israeliet al., 2005; Reumaux et al., 2003; Seibold, 2005).This indicates that ASCA may represent a geneticmarker specific for susceptibility to CD.

Data from a recent study showed an increasedfrequency of anti-OmpC in unaffected familymembers of CD patients, raising again the possibilityof a genetic susceptibility to CD (Mei et al., 2006).

In conclusion, a reasonable question is raised,whether these positive asymptomatic family mem-bers will eventually develop the disease and need tobe monitored. Definitely, larger studies need to beperformed with long time period follow-up inorder to obtain more conclusive data.

1.2.4. Pathogenic roleThe mechanisms triggering the development ofIBD still remain unknown. However, severaltheories are proposed trying to illuminate theexact pathophysiologic concepts of these diseasesand the pathogenetic role of the associatedantibodies.

A loss of immune tolerance to endogenousbacteria of the gastrointestinal tract results indysregulation of the immune response and theproduction of antibodies to certain bacterialantigens (Nakamura et al., 2003; Seibold, 2005).Possibly the development of the pANCA is due tocross-reactivity to bacterial antigens (Reumauxet al., 2003; Seibold, 2005). However, none of theASCA, pANCA or anti-OmpC have been shownto play a direct pathogenic role.

On the contrary, CBir1 flagellin has proven toinduce the production of anti-CBir1 antibodies andT helper-1 cell responses to flagellin leading to thedevelopment of colitis in mice. CBir1 flagellinpossibly shows a similar immune response in patientswith CD (Targan et al., 2005; Lodes et al., 2004).

1.2.5. Sensitivity and specificityIt is well known that one of the main character-istics of autoimmune diseases is the presence ofautoantibodies in the sera of patients. Based onthis fact, several serological markers have beenstudied in the recent years and found to behelpful not only in diagnosing IBD but even inpredicting the development of the disease (Hareland Shoenfeld, 2006). Antibody evaluation is alsovery significant in cases of indeterminate colitis(Seibold, 2005).

Many studies in the literature demonstrate a largerange in sensitivity and specificity of serologicalmarkers used in diagnosing CD and UC (Reumauxet al., 2003; Targan et al., 2005) (Table 1).

N.P. Papageorgiou, Y. Shoenfeld232

The prevalence of pANCA is reported to be45–82% in patients with UC and from 2 to 28% inCD patients. The specificity of pANCA-positivetest for UC can reach 94% (Reumaux et al., 2003).

ASCA levels were found to be remarkably higherin CD patients. Sensitivity ranges from 48 to 69%in CD and from 5 to 15% in UC (Reumaux et al.,2003). IgG ASCA is more sensitive than IgAASCA for diagnosing CD (Buckland et al., 2005).Specificity of ASCA is also high, reaching 95%.Combining ASCA and pANCA increases thespecificity and positive predictive value both forCD and UC (Reumaux et al., 2003; Bucklandet al., 2005; Reese et al., 2006).

Definitely, these markers are disease specific, buttheir low sensitivity and the fact that bothantibodies are found also in other autoimmunegastrointestinal diseases make them unsuitable forroutine screening (Reumaux et al., 2003; Seibold,2005; Buckland et al., 2005).

However, a currently available panel thatincludes ASCA (IgG and IgA), pANCA andanti-OmpC together has been shown to exhibitgood sensitivity and very high specificity foridentifying patients with CD and UC. Anti-OmpCused in this panel, despite its low sensitivity, can beuseful because it recognizes a small group of IBDpatients not detectable by the other assays(Zholudev et al., 2004).

Anti-CBir1 flagellin is present in 50–55% ofpatients with CD and in only 6% of patients withUC, making this marker specific for CD. Also, thismarker identifies a unique subgroup of CDpatients who are negative to other serologicalmarkers (Targan et al., 2005).

In cases of patients with indeterminate colitisand positive serological response, positive ASCA/negative pANCA predicts CD in 80% of patientsand negative ASCA/positive pANCA predicts UCin 63.3% (Seibold, 2005). In addition, the fact thatanti-CBir1 is present in 40–44% of positivepANCA CD patients and in only 4% of positivepANCA UC patients makes this marker anadditional tool in assessment of indeterminatecolitis (Targan et al., 2005).

1.3. Discussion and conclusions

IBD are chronic idiopathic inflammatory disorderscharacterized by excessive inflammatory responseof the gastrointestinal tract that results in tissuedamaging and often in the production of severalantibodies (Israeli et al., 2005).

Strong evidence suggests the etiology to bemultifactorial involving genetic factors and dysre-gulated immune reactivity to the microbiota of thegastrointestinal tract (Nakamura et al., 2003).

The presence of specific antibodies in the sera ofIBD patients have always been the focus of intensestudies. Such antibodies that have been shown tobe related with the presence of IBD are theatypical pANCA, ASCA, anti-OmpC and latelythe anti-CBir1 flagellin. These serological markersare highly specific for IBD and when combinedtogether they increase the diagnostic ability.However, because of their low sensitivity, serolo-gical testing is not used as a single test inevaluation of suspected patients.

Some studies suggest that there is a correlationof serological markers with disease phenotype andthat these serological markers can be used topredict not only the course of the disease but alsothe disease itself (Israeli et al., 2005; Zholudevet al., 2004; Harel and Shoenfeld, 2006; Amreet al., 2006; Dubinsky et al., 2006).

Table 1

Sensitivity and specificity of several autoantibodies in IBD and

celiac disease

Autoantibodies Sensitivity (%) Specificity (%)

pANCA in UC 45–82 65–94

ASCA in CD 48–69 86–95

AGA IgG in celiac disease 83–100a 47–94a

57–78b 71–87b

AGA IgA in celiac disease 52–100a 71–100a

55–100b 82–100b

EMA IgA in celiac disease 88–100a 90–100a

86–100b 99–100b

tTG2 IgA in celiac disease 94–100a 90–100a

77–100b 91–100b

CD=Crohn’s disease, UC=Ulcerative colitisa Children population.b Adult population.

Autoantibodies in Gastrointestinal Autoimmune Diseases 233

ASCA positivity and high titers are associatedwith the development of early complications, suchas fistulae and abscesses (Zholudev et al., 2004;Amre et al., 2006; Dubinsky et al., 2006).

The risk of progressing to a more aggressivephenotype is increased in those individuals withimmune reactivity to more than one microbialantigen (Targan et al., 2005; Dubinsky et al.,2006).

Recently, a study demonstrated the presence ofASCA and atypical pANCA in the sera of CDpatients long before the clinical diagnosis, suggest-ing that antibody positivity may precede or evenpredict the development of the disease (Israeliet al., 2005).

This evidence is of great importance because itallows the identification of asymptomatic indivi-duals who are at risk of developing IBD, andtherefore, it might allow several preventive modi-fications (Harel and Shoenfeld, 2006).

Search for the ideal serological test that couldlead to an accurate diagnosis of IBD or even todistinguish CD from UC is the challenge of thenear future.

2. Antibodies in celiac disease

2.1. Introduction

Celiac disease (CD) is an autoimmune diseasetriggered by exposure to gluten, a wheat protein,and is characterized by an infiltration of themucosal epithelium by lymphocytes, villous atro-phy and hyperplastic crypts (Basso et al., 2006;Akbari et al., 2006). The ingestion of gluten ingenetically predisposed patients leads to theoccurrence of disease-specific reactive antibodiesagainst the enzyme tissue transglutaminase type 2(tTG2), against endomysium and against gliadin(Basso et al., 2006; Collin et al., 2005; Hill, 2005).Measurement of such antibodies in serum can helpestablish the diagnosis, but despite their highspecificity and sensitivity, a small bowel biopsyshould be performed to evaluate the histologicalfindings and to confirm the diagnosis (Basso et al.,2006).

2.2. The antibodies

2.2.1. DefinitionsAnti-gliadin antibodies (AGA) are antibodies ofthe IgA and IgG classes found in the sera of CDpatients. These antibodies mainly target gliadin-derived peptides, which are the main proteins ofgluten. AGA are not specific for CD as they arealso found in patients with other gastrointestinaldiseases such as gastritis, gastroenteritis and IBD(Basso et al., 2006; Bizzaro and Tonutti, 2007).

Anti-endomysial antibodies (EMA) are IgAclass autoantibodies directed against endomysium,the collagen matrix of human and monkey tissues(Akbari et al., 2006). The antigen of the endomy-sium is considered to be the enzyme tTG2(van Heel and West, 2006).

Anti-tTG2 are autoantibodies of class IgA andIgG produced by tTG2-specific B cells (Espositoet al., 2002). Specifically, IgA autoantibodiesrecognize the enzyme tTG2, making them specificmarkers for CD (Tonutti and Bizzaro, 2007). tTG2is a calcium-dependent cytosolic protein possessingboth intracellular and extracellular functions, andit appears to play a critical role in controlling celland tissue homeostasis (Caputo et al., 2004).

2.2.2. Methods of detectionIgA endomysial antibodies can be determined byan immunofluorescence test, using either thehuman umbilical cord as antigen or the monkeyesophageal antigen. The test is based on theimmunofluorescence findings of a reticular stainingpattern when the antibody binds to the endomy-sium (Akbari et al., 2006; Collin et al., 2005).

IgA tTG2 can be determined by an indirect non-competitive ELISA assay using either humanrecombinant antigen or guinea pig protein as thesource of tTG2 antigen (Akbari et al., 2006). Thesource of tTG2 used in ELISA has a significantrole as it was shown that the human recombinantbased tTG2 is more sensitive and specific whencompared to the guinea pig protein (Hill, 2005).Another method of measurement of anti-tTG2 isthe immunochemiluminescent assay using humanrecombinant antigen that shows even better sensi-tivity when compared to the second-generation


ELISA (human recombinant antigen) (Basso et al.,2006).

The determination of AGA of the IgA and IgGclasses can be established by immunofluorescenceand ELISA. Because of their low diagnosticaccuracy and the introduction of newer, moreaccurate serological tests, AGA testing is notcommonly used today in the investigation of celiacdisease. However, recent ELISA tests usingsynthetic gliadin peptides show diagnostic accu-racy similar to that of anti-tTG tests (Bizzaro andTonutti, 2007).

2.2.3. Pathogenic roleAlthough it is still unclear whether antibodies playa role in the pathogenesis of celiac disease, severalstudies showed that anti-tTG2 autoantibodies caninhibit the catalytic activity of human tTG2 bothin vitro and in situ (Esposito et al., 2002; Sollidand Jabri, 2005). In addition to this, it was shownthat differentiation of intestinal crypt epithelialcells dependent on transforming growth factor B(TGF-b) can be inhibited by tTG2 autoantibodies(Esposito et al., 2002; Sollid and Jabri, 2005;Guandalini and Gokhale, 2002). It is also pro-posed that the presence of autoantibodies to tTG2is involved in the extraintestinal manifestations ofCD (Sollid and Jabri, 2005). Recently, a studyshowed that a subset of anti-tTG2 autoantibodieshave the ability to increase intestinal permeabilityand activate monocytes through binding with toll-like receptor 4 (TLR4). These antibodies recognizerotavirus protein VP-7, suggesting that molecularmimicry may be a possible mechanism of viralinvolvement in the pathogenesis of the disease(Zanoni et al., 2006).

2.2.4. GeneticsA very high percentage of patients with CDpossess either the HLA-DQ2 heterodimer or theHLA-DQ8 demonstrating the strong genetic rela-tion that is involved in the development of thedisease. More than 97% of CD patients havethe DQ2 and/or DQ8 heterodimer encoded bythe DQA1*0501 and DQB1*0201 genes comparedto one-third of the general population (Basso et al.,

2006; Periolo and Chernavsky, 2006). Also theconcordance rate in the monozygotic twins is 86%,whereas in dizygotic twins it reaches only 20%(Stepniak and Koning, 2006). The observationthat HLA-DQ2 homozygous individuals have atleast fivefold higher risk of developing the diseasethan HLA-DQ2 heterozygous individuals showsclearly the strong HLA-DQ2 gene dose effect(Tonutti and Bizzaro, 2007; Stepniak and Koning,2006). Modification of wheat gluten proteins bytissue transglutaminase into peptides with nega-tively charged amino acids leads to more efficientbinding to the specific and positively chargedHLA-DQ2 or DQ8 receptors (van Heel and West,2006; Periolo and Chernavsky, 2006; Stepniak andKoning, 2006). T-cell activation by gliadin–tTG2complexes presented by HLA-DQ molecules pro-vides the necessary help for production of anti-gliadin and anti-tTG2 antibodies (Sollid and Jabri,2005; Stepniak and Koning, 2006; Hourigan, 2006).

2.2.5. Sensitivity and specificityA number of studies have been conducted toreport the sensitivity and specificity of severalserological tests used commercially for diagnosingCD. A review of these studies report interestingresults. AGA IgG, AGA IgA, EMA IgA and tTG2IgA were evaluated (Hill, 2005) (Table 1).

AGA IgA and AGA IgG are characterized bylow specificity and sensitivity when compared withthe newer serological tests. AGAs should not beused in the evaluation of suspected individualshaving CD (Basso et al., 2006). EMA IgAantibodies have shown good sensitivity andspecificity in both adult and children population.The overall sensitivities ranged from 86 to 100%and specificities ranged from 90 to 100%. A firstlook on results for tTG2 IgA can be misleading,suggesting lower overall sensitivity and specificitycompared with EMA –IgA; however, these studiesused either guinea pig protein or human recombi-nant protein for anti-tTG2 determination. Todayit is well established that anti-guinea–pig tTG2 haslower sensitivity and specificity than recombinantanti-human tTG2 (Basso et al., 2006; Leffler andKelly, 2006). Although EMA IgA and humanrecombinant tTG2 IgA have no significant


differences in recognizing individuals suspected forCD, EMA IgA testing is time and moneyconsuming and operator dependent. This factleads to the conclusion that the use of anti-tTG2IgA using human recombinant antigen is the testof choice today for the detection of people withCD (Basso et al., 2006; van Heel and West, 2006;Tonutti and Bizzaro, 2007). In persons with IgAdeficiency and suspicion of CD, anti-tTG2 IgG isrecommended as the most appropriate test forevaluating these cases (Basso et al., 2006).

2.3. Discussion and conclusion

CD is a multifactorial disease involving bothenvironmental and genetic factors. Gliadin playsa key role in the pathogenesis of CD. Gliadinpeptides, after ingestion and modification by theenzyme tTG2, are more easily recognized by themucosal antigen-presenting cells that express HLA-DQ2 and HLA-DQ8 molecules leading to T-cellactivation and finally to the production of highlydisease specific autoantibodies to tTG2. Tests usinghuman recombinant or human purified tTG2 areconsidered to be highly specific and sensitive andare recommended as the initial test of choice in thediagnostic evaluation of CD. Also anti-tTG2antibody determination can be used for monitoringpatients diagnosed with CD (Basso et al., 2006).

However endoscopy, accompanied by multipleduodenal biopsies, still remains the necessarydiagnostic tool for confirming the diagnosis ofCD (Basso et al., 2006; Caputo et al., 2004). It istoo early to recommend a mass screening for CDin asymptomatic individuals using serological tests(Moritoki et al., 2006).

3. Antibodies in autoimmune liver diseases

3.1. Introduction

Autoimmune liver diseases are chronic diseasesaffecting the liver and are characterized by thepresence of several autoantibodies, some of whichare present in more than one autoimmune disease

whereas others are disease specific (Moritoki et al.,2006). The three most important autoimmune liverdiseases are autoimmune hepatitis (AIH), primarybiliary cirrhosis (PBC) and primary sclerosingcholangitis (PSC).

AIH is a chronic, progressive hepatitis ofunknown etiology occurring in individuals of allages (Krawitt, 2006). Based on the autoantibodyprofile, AIH may be divided into three subtypes(Moritoki et al., 2006; Czaja and Norman, 2003).PBC is a chronic cholostatic liver disease ofunknown cause characterized by female predomi-nance and by the destruction of small intrahepaticbile ducts that leads eventually to cirrhosis andliver failure (Kaplan, 1996). PSC is a fibrosingdisease affecting the large bile ducts that arefrequently associated with inflammatory boweldisease (Cullen and Chapman, 2003).

The presence of autoantibodies in autoimmuneliver diseases reflects immune reactivity and manytimes is helpful in establishing the diagnosis. Theirpresence may have a role in the pathogenesis ofthese diseases, but on the other hand, theirexistence may simply represent the result of liverinjury. The basic autoantibodies used in diagnos-ing autoimmune liver diseases are antinuclearantibodies (ANA), smooth muscle antibodies (SMA),antibodies to liver–kidney microsome type 1 (anti-LKM1), antimitochondrial antibodies (AMA) andatypical perinuclear antineutrophil cytoplasmicantibodies (pANCA). Today more serologicalmarkers are emerging, expanding the diagnosticcapability in diagnosing autoimmune liver diseases(Table 2) (Czaja and Norman, 2003).

3.2. The antibodies

3.2.1. Antinuclear antibodiesANA are autoantibodies directed against nuclearantigens such as ribonucleoproteins, ribonucleo-protein complexes and centromeres. Usually theyare used as serological markers of AIH but arealso present in PBC, PSC and other autoimmunediseases. In addition, the fact that a percentage ofhealthy individuals are ANA positive makes thesemarkers least specific in AIH (Czaja and Norman,


2003). ANA are detected by indirect immuno-fluorescence (IIF) assay using human epithelialcells (HEp-2) or by enzyme-linked immunosorbentassay (ELISA) (Czaja and Norman, 2003;Nishioka and Morshed, 1999). The patterns ofnuclear fluorescence are the homogenous, thespeckled, the peripheral or the rim pattern andthe centromeric pattern. Homogenous andspeckled pattern appear more frequently in AIH.Immune reactivity to several nuclear antigens isassociated with different patterns of immunofluore-scence, but it may also be associated with differentclinical features of the autoimmune liver diseases(Nishioka and Morshed, 1999).

ANA are commonly found in PBC in up to 70%of the cases, and in PSC the prevalence rangesfrom 7 to 77% (Cullen and Chapman, 2003;Nishioka and Morshed, 1999).

3.2.2. Smooth muscle antibodiesSMA are autoantibodies directed against actin andnon-actin cytoskeleton components such as vimen-tin, tubulin and desmin, and they are commonlyused for the diagnosis of AIH (Moritoki et al.,2006; Czaja and Norman, 2003).

Detection of these antibodies is done by IIFusing as substrates murine stomach, liver andkidney, demonstrating a variety of staining pat-terns. In type 1 AIH, the most specific SMApattern is the SMA-T. SMA can also be found inother autoimmune liver diseases like celiac diseaseand viral diseases like chronic hepatitis C.Although the prevalence of SMA in type 1 AIH

reaches 80%, they are characterized by lack ofdisease specificity (Selmi et al., 2007). A subset ofSMA, autoantibodies against F-actin, showedeven better specificity than the typical SMA as itwas demonstrated to be common in AIH andabsent in other liver diseases. Also the presenceof anti-actin autoantibodies are associatedwith early age onset of the disease and worseprognosis (Moritoki et al., 2006; Czaja andNorman, 2003).

3.2.3. Antibodies to liver–kidney microsomeAnti–LKM1 are autoantibodies directed againstthe cytochrome monooxygenase P450 IID6(CYP2D6), a significant enzyme system locatedin the cytosol of the liver. The presence of theseantibodies is highly associated with type 2 AIH. In10% of patients with hepatitis C, anti-LKM1 arefound to be positive possibly due to cross-reactivity between CYP2D6 and hepatitis C virus(Moritoki et al., 2006; Czaja and Norman, 2003).The sensitivity of anti-LKM1 is very low (4–20%)and varies among different geographic regions(Czaja and Norman, 2003).

Anti-LKM3 are autoantibodies, first describedin chronic hepatitis D, that target a 55 kDamolecular weight molecule found to be the uridinediphosphate glucuronosyltransferase (UGT).UGTs are enzymes that catalyze the glucuronida-tion of many endogenous and exogenous com-pounds and are located in the endoplasmicreticulum. These serological markers find use inthe diagnosis of type 2 AIH.

Anti-LKM3 are present in 8–19% of patientswith type 2 AIH, and also in 6–13% of patientswith chronic hepatitis D. They are highly specificfor type 2 AIH as they were not detected in the seraof patients with other autoimmune liver diseases.

Anti-LKMs are detected by IIF on murine liverand kidney tissue and subclassification is achievedby Western blotting and ELISA (Fabien et al.,2004). Although LKM3 antibodies recognizemany isoforms of UGT, they exhibit a higherreactivity with UGT1A1, the isoform that isinvolved in bilirubin glucuronidation (Moritokiet al., 2006; Fabien et al., 2004).

Table 2

Autoantibodies in autoimmune liver diseases

AIH PBC PSC

Characteristic

autoantibodies

ANA AMA Atypical pANCA

SMA ANA ANA

Anti-LKM1 Anti-gp210

Anti-LKM3 Anti-p62

Anti-LC1 Anti-lamin B

receptor

Anti-SLA/LP

Anti-ASGPR

Atypical pANCA


3.2.4. Antimitochondrial antibodiesAMA are autoantibodies directed against innermitochondrial membrane proteins which are theE2 subunits of pyruvate dehydrogenase complex(PDC-E2), the branched chain 2-oxo acid dehydro-genase complex (BCOADC-E2), the 2-oxoglutaratedehydrogenase complex (OGDC-E2), the E1a andE1b subunits of PDC and the dehydrogenase-binding protein of the PDC (PDC-E3 BP) (Medinaet al., 2001; Jones, 2000; Invernizzi et al., 2007).These enzymes participate in oxidative phosphor-ylation and have an important role in the glycolyticpathway, tricarboxylic acid cycle and the pathway ofbranched-chain amino acids metabolism (Invernizziet al., 2007). The detection of AMA is significant forthe diagnosis of PBC (Jones, 2000).

The prevalence of AMA in PBC reaches 95%with a specificity of 98% for the disease (Kaplan,1996). AMA show the highest specificity for anautoimmune liver disease among the rest of theserological markers.

AMA are detected by IIF on murine kidney andstomach tissues but immunoblotting and ELISAmay also be used, leading to an increase insensitivity and specificity of the test (Czaja andNorman, 2003; Invernizzi et al., 2007).

3.2.5. Atypical perinuclear antineutrophilcytoplasmic antibodiesAtypical pANCA are autoantibodies against avariety of neutrophil antigens. Although theautoantigen is not clearly defined, it is proposedthat pANCA are directed against several antigenssuch as catalase, enolase, cathepsin G andbacterial permeability increasing protein (BPI)(Czaja and Norman, 2003; Aoki et al., 2005).Some other studies demonstrate that the autoantigenis considered to be a neutrophil-specific 50 kDanuclear envelope protein (Moritoki et al., 2006;Czaja and Norman, 2003). Atypical pANCA arefound in 33–88% of patients with PSC andin 50–96% of patients with AIH (Cullen andChapman, 2003). These autoantibodies are notdisease specific as they are also present in patientswith ulcerative colitis (UC).

3.2.6. Antibodies to liver cytosol type 1(anti-LC1)Anti-LC1 are autoantibodies that recognize theantigen formiminotransferase cyclodeaminase(FTCD), which is a liver-specific enzyme havinga role in converting histidine to glutamic acid(Strassburg and Manns, 2007). These antibodiesare specific for AIH, and frequently express inpatients also positive for anti-LKM1. They arefound in 30–50% of patients with type 2 AIH andhave been shown to be present in 10% of AIHpatients negative to other serological markers(Moritoki et al., 2006; Strassburg and Manns,2007). In addition, it was demonstrated that anti-LC1 are associated with disease activity and mayrepresent markers of residual liver inflammation.IIF and immunodiffusion are the preferablemethods of detection of these autoantibodies(Czaja and Norman, 2003; Strassburg and Manns,2007).

3.2.7. Antibodies to soluble liver antigen/liver pancreas antigen (anti-SLA/LP)Anti-SLA are autoantibodies found to be reactivewith a 50 kDa cytosolic transfer ribonucleoproteincomplex (tRNP), the same autoantigen recognizedby antibodies to the liver/pancreas. Anti-SLA/LPwere shown to be highly specific markers for AIHoccurring in 10–30% of the cases with thespecificity reaching 99%. They are helpful markersin identifying a small group of patients withcryptogenic hepatitis (Czaja and Norman, 2003;Manns, 2000). These autoantibodies are detectedby an ELISA based on recombinant antigen fromprokaryotic and eukaryotic systems (Czaja andNorman, 2003).

3.2.8. Antibodies to asialoglycoproteinreceptor (anti-ASGPR)Anti-ASGPR are autoantibodies directed against aliver-specific lipoprotein located on hepatocytemembranes that have a role in recognition andtransportation of potential antigens (Czaja andNorman, 2003). Anti-ASGPR are expressed in


up to 88% of patients with AIH but are alsopresent in other liver diseases such as PBC,alcoholic liver disease and viral hepatitis (Moritokiet al., 2006; Czaja and Norman, 2003). Also theseantibodies showed a correlation with diseaseactivity and treatment response. Assays used todetect anti-ASGPR are ELISA using human,rabbit or rat ASGPR and radioimmunofiltration(RIFA) using rabbit ASGPR (Czaja and Norman,2003).

3.2.9. Antibodies to nuclear pore complexantigensAntibodies to nuclear pore complex antigens wereshown to be highly associated with the presence ofPBC. Particularly, antibodies to glycoproteingp210 are present in 10–41% of PBC patients withthe specificity reaching over 99%. Also anti-gp210are found in 20–41% of cases with negative AMA,making these antibodies helpful serological mar-kers for establishing a diagnosis in this group ofpatients. The prevalence of anti-p62 antibodies inPBC patients is lower (23–32%) but with highspecificity, similar to anti-gp210. Anti-lamin Breceptor antibodies are also highly specific forPBC, but they are characterized by very lowsensitivity (1–3%). Antibodies to nuclear porecomplex antigens are best identified by IIF usingHEp-2 cells giving a membrane-like pattern ofstaining. The high specificity of these antibodiesfor PBC definitely points out their significance asserological markers for diagnosing patients withPBC (Jones, 2000; Nesher et al., 2001).

3.3. Genetics

Several studies in the literature suggest a geneticsusceptibility to autoimmune liver diseases withspecific genes identified to be associated with AIH,PBC and PSC.

HLA-DRBI*0301DRB3*0101DQA1*0501DQB1*0201 and HLA-DRB1*0401 are commonly asso-ciated with AIH. In addition, different populationshave found to be related with specific alleles. Thus,

in South American populations, the most frequentlyrelated haplotype is HLA-DRB1*1301 and in Japanit is the HLA-DRB1*0405DQB1*0401. Also, HLA-DRB1*03 and HLA-DRB1*13 alleles are morecommon in children populations (Krawitt, 2006).Some studies reported PBC to be more frequent inpatients with an affected family member, suggestinga genetic predisposition to the disease (Selmi et al.,2004). A weak association of PBC with haplotypeHLA-DR8 and DPB1 gene is also reported in theliterature (Kaplan, 1996). In PSC, a strong associa-tion was demonstrated with DRB1*03-DQA1*0501-DQB1*02 haplotype, whereas the HLA-DRB1*04-DQA1*03-DQB1*0302 haplotype is nega-tively associated with the disease (Aoki et al., 2005).

3.4. Pathogenic role

As in many autoimmune diseases that are chara-cterized by the presence of autoantibodies, aquestion is raised whether this presence reflectsthe outcome of the disease itself or has a directpathogenic role in the development of the disease.

The role of autoantibodies in autoimmune liverdiseases still remains unclear. Nevertheless, severalstudies imply involvement of autoantibodies in thepathogenesis of the disease. It is proposed thatdestruction of biliary epithelial cells may bepossible after binding of circulating AMA withthe specific autoantigens expressed on cell surfacemembranes in PBC patients (Medina et al., 2001;Selmi et al., 2004). Also AMA interference withcellular functions after penetration of biliaryepithelial cells could be a possible mechanism(Medina et al., 2001; Jones, 2000). However, thesetheories need to be confirmed. It is well knownthat catalase is an antioxidant enzyme found in thecytosole of hepatocytes and biliary epithelial cellsand its role is to protect cells from damage byoxygen-derived radicals. In PSC patients, impair-ment of catalase antioxidant functions by thepresence of catalase specific pANCA may lead tooxidative stress and biliary epithelial cells destruc-tion (Medina et al., 2001; Aoki et al., 2005). Inaddition, neutrophil binding to bacterial


lipopolysaccharide (LPS) of Gram-negative organ-ism or endotoxins may be inhibited by pANCAautoantibodies targeting BPI (Aoki et al., 2005).Anti-LKM1 autoantibodies were found to inhibitCYP2D6 in vitro and induce liver-infiltratingT-lymphocytes activation, thus suggesting a rolein the development of AIH (Strassburg andManns, 2007).

3.5. Discussion and conclusions

The existence of autoantibodies and their impor-tance in diagnosing autoimmune liver diseases isunquestionable. Their role in the pathogenesis ofautoimmune liver diseases and their diagnosticspecificity is well-studied. The possibility thatautoantibodies contribute to the development andprogression of AIH, PBC and PSC is supported byseveral studies, but more evidence need to comeforward. In addition, some autoantibodies such asanti-LC1 and anti-ASGPR may correlate withdisease activity and treatment response. On theother hand, autoantibody production may be justthe result and not the cause of liver injury,suggesting their non-pathogenic nature (Czaja andNorman, 2003). The ongoing effort of newautoantibody identification that will help to revealnew autoantigens and new immunopathogenicmechanisms and to improve the current diagnostictools is of major significance.

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CHAPTER 18

Gastrointestinal Complications of Anti-Rheumatic Drugs

K.D. Rainsforda, Iain R.L. Keana, Walter F. Keanb,�aBiomedical Research Centre, Sheffield Hallam University, Sheffield S1 1WB, England, UK

bDepartment of Medicine, McMaster University Faculty of Health Sciences, Suite #401, 1 Young Street,

Hamilton, Ont., Canada L8N 1T8

1. Introduction

In this chapter we review (a) the current status fortreating pain and inflammation in chronic arthriticconditions; (b) the occurrence of gastrointestinal(GI)1 adverse reactions during arthritis therapy withnon-steroidal anti-inflammatory drugs (NSAIDs)2

and other drug combinations; (c) the GI reactionsthat occur in patients with autoimmune arthropa-thies; (d) the GI reactions and other adverse eventsthat occur with newer supposedly GI safe NSAIDs,especially the coxibs, with a critical evaluation of theevidence for their claims to have reduced occurrenceof serious and symptomatic GI adverse events;(e) approaches for reducing the development of GIulceration and other adverse reactions; and (f)considerations of prescribing practice for the patientwith rheumatoid arthritis (RA) and related auto-immune arthropathies.

2. The clinical setting

2.1. Populations with musculoskeletal pain

World Health Organisation (WHO) statistics andInternational population studies have demonstratedthat 10–50% of people around the world sufferfrom musculoskeletal disorders requiring treat-ment, including 25% of adults over 65 years(WHO, 2003). In Canada, studies by The ArthritisSociety demonstrate that the number of people withmusculoskeletal disorders will rise from 2.9 millionin 1991 to 6.5 million by 2031 (Badley and Wang,1998), and that this acceleration in new cases,equivalent to 300 new patients per day, will parallelthe increase in prevalence of disability due toarthritis from 2.3% in 1991 to 3.3% by 2031(Badley, 1995). Arthritis with the associated chronicpain process is the main cause of work-related

E-mail address: [email protected]


Tel.: +1-9055210514; Fax: +1-9055282385

1The term GI reactions used here is meant to embrace the

whole range of the entire GI tract. They include ulceration,

haemorrhage, inflammatory bowel diseases (IBD), bowel

perforation and peritonitis, diaphragmatic strictures, ‘water

melon stomach’ (Dulai and Jensen, 2004), digestive malfunction

(‘disorders’), painful symptoms notably associated with indiges-

tion or use of drugs and other symptomologies. This list is by

no means complete. Peptic ulcer disease (PUD) is a clinically

defined condition in which there are ulcers present in the

stomach and/or duodenum (upper GI ulcers) with or without

accompanying haemorrhage.2In this chapter, the terms traditional NSAID (or tNSAID)

and NS-NSAID (non-specific NSAID) are used interchange-

ably. The tNSAIDs denote those NSAIDs that were introduced

in the period of the 1950s–1980s and include aspirin and other

salicylates many of which were discovered prior to this period.

They are separated from the highly cyclo-oxygenase-2 (COX-2)

selective drugs, known as the coxibs that were initially

discovered during the 1990s. Because of their high COX-2

selectivity they are distinguished from less COX-2-specific drugs

(e.g. diclofenac, ibuprofen, and naproxen) which are by

convention termed non-selective NSAIDs (or NS-NSAIDs)

and preferentially selective COX-2 inhibitors (e.g. etodoloac

and nimesulide), which have COX-2 selective with COX-2

activity intermediate between NS-NSAIDs and coxibs.


DOI: 10.1016/S1571-5078(07)00018-9

dx.doi.org/10.1016/S1571-5078(07)00018-9.3d

disability, and its outcome affects all socioeconomicclasses and all age groups (Badley, 1995). In the agegroup 20–89 years, back pain and sciatica havebeen documented to be present in up to 27% ofcases (Lyons et al., 1994), and the majority of thesepeople with musculoskeletal disease will suffer frompain. Up to 65% of rheumatoid patients rank painas the most important symptom which requirestreatment (Anderson et al., 1994), and 55% ofosteoarthritis (OA) patients report pain as the worstaspect of their disease (Office of National Statistics,2002). In a 1993 Welsh community survey on healthstatus, on 1201 randomly selected adults (827 res-pondents) aged 20–89, it was found that 39.3% ofpeople treated by their doctor in the previous 12months had chronic musculoskeletal pain due toarthritis (19.1%) or back pain (20.2%) or sciatica(6.3%) compared to much lower numbers for othersignificant disorders such as hypertension (13.1%),insomnia (10.3%), anxiety (8.8%), depression(6.6%), angina (7.4%), asthma (6.6%), and dia-betes (2.8%). The SF 36 health status instrument,especially in the physical functioning role—physical,and bodily pain domains, demonstrated the sub-stantial health burden of musculoskeletal dis-orders (Lyons et al., 1994). Elliott and colleagues(1999) performed a chronic pain study in Scotlandwith 5000 questionnaires (80% replied). Chronicpain was defined as ‘pain or discomfort thatpersisted continuously or intermittently for longerthan 3 months’. Approximately 50% of the respon-dents reported to have chronic pain, and thisincreased from 33% in those of 25–34 years ageto 66% of those greater than 65 years. Fox andcolleagues (1999) fromMcMaster University identi-fied that the pain prevalence of nursing homeresidents was 49–83%, and that the prevalence ofthis pain was almost entirely due to OA or relateddisorders. There is a wide range of disorders thatconstitute the problem of musculoskeletal pain inthe young and elderly, with OA, back pain, andsciatica as the most common. The prevalence of RAis 1–2% (Kean et al., 1982, 1983; Gabriel, 2000).Crystal diseases such as gout and pseudogout arepresent in 0.5–2.8% of males over 40 years, and theprevalence of all types of reactive arthritis includingReiter’s syndrome, ankylosing spondylitis, psoriaticarthritis, and inflammatory bowel disease is 1–6%

(Felson, 1996). In addition, a small number ofpatients suffer from immune disorders such as sys-temic lupus and polymyalgia rheumatica, and frommyofascial disorders such as fibromyalgia.

Notwithstanding that the overall management ofmusculoskeletal disease is a multidisciplinary pro-blem, and involves collaboration of all the healthand social disciplines, the majority of patients withmusculsoskeletal disorders require analgesic andanti-inflammatory medications for pain relief.Many of these patients especially in the over 50years age group also require aspirin for cardiovas-cular (CV) prophylaxis. NSAIDs are among themost commonly used pharmacologic agents world-wide. They have been calculated to annuallycomprise 70 million prescriptions dispensed in theUnited States (Gabriel et al., 1993), 10 million inCanada (IMS Canada, 1999), and 25 million in theUnited Kingdom (Hawkey, 1990). Estimates showthat a UK general practitioner with an average listof 2000 registered patients has 374 patients withconnective tissue disorder of whom 63 haveformally been diagnosed with OA (Eccles et al.,1998). On this basis, although 1.6 million people inthe United Kingdom have formally been diagnosedwith OA, the total number of dispensed NSAIDprescriptions suggests their much wider use. In theUnited Kingdom, the cost of dispensed prescrip-tions has been reported as d150 million (US$213million), represented by volume, with ibuprofen(26%) and diclofenac (37%) (Eccles et al., 1998).

In the United States, it has been estimated that70% of patients over 65 years or greater takeNSAIDs once per week with an estimated111,400,000 prescriptions annually from September1999 to August 2000 resulting in $4.8 billion ofannual drug costs and $3 billion additional costs onover the counter (OTC) analgesics includingacetaminophen (Laine, 2001). The potential forGI side effects of analgesic and anti-inflammatorymedications is the major limitation to safe manage-ment of musculoskeletal and related pain disorders.

2.2. Burdens of analgesic andanti-inflammatory medication use

Almost all patients with musculoskeletal disorderswill need treatment with analgesic agents, NSAIDs,

K.D. Rainsford et al.244

or steroids (Buchanan and Kean, 2002; Kean andBuchanan, 2005). The incidence of musculoskeletaldisorders increases with age (Elliott et al., 1999), inparallel to the increased risk of adverse effects tothe NSAIDs (Laine, 2003). The major therapeuticlimitations to the successful management of muscu-loskeletal disease and disability are the side effectsfrom the medications, especially the NSAIDsincluding aspirin (Buchanan and Kean, 2002). Theoral and sometimes systemic versions of thesemedications can cause injury or other complica-tions to the GI tract (Wolfe et al., 1999), the kidney(Whelton, 1999), the CV homeostatic mechanisms(Pope et al., 1993; Kean and Buchanan, 2005), theliver, and the skin (Buchanan and Kean, 2002).While concomitant physiological failure results inan increase in renal, CV, and other NSAID adverseresponses especially with age, the most serious sideeffects are due to GI toxicity (Hirschowitz, 1994;Singh and Ramey, 1998; Langman et al., 1999;Buttgereit et al., 2001; Kean and Buchanan, 2005).The majority of GI effects are symptomaticresponses such as bloating, cramping, pain, diar-rhoea, constipation, and acid reflux, but the mostdangerous are erosions, gastric and duodenalulcers, perforations, and bleeds (Hirschowitz,1994; Hawkey et al., 2005, 2007a, b).

When used for primary CV protection, aspirinhas been shown to increase bleeding complicationsby 69% (Sanmuganathan et al., 2001). Yeomansand colleagues (2005) reported in a study of usersof low dose (75–325mg od) of aspirin that the ulcerprevalence was 11% (lesion >3mm with depth)with age and Helicobacter pylori being predictivefactors but warned that symptoms were infrequentand indeed symptoms were more common in thenon-ulcer group in their study. It has been shownthat low and greater doses of aspirin over long termwere associated with a bleeding rate of 2.3 and2.5% respectively compared to 1.4% in placebocontrols in a meta-analysis of 24 randomisedcontrolled trials which included more than 66,000subjects. In a case-controlled study of patientshospitalised with ulcer bleeding, 25.1% of patientswere taking low-dose aspirin (>300mg od) com-pared to only 7.4% of controls. However, it hasbeen identified that the risk of serious GI bleedingis reduced in low-dose aspirin users if anti-secretory

therapy is co-administered (Serrano et al., 2002),and recurrence can be reduced by co-administrationof the proton-pump inhibitor (PPI), lansoprazole,to patients who have had a previous complicatedulcer on low-dose aspirin (Lai et al., 2002). GI sideeffects to NSAIDs have been estimated to occurin approximately 25–40% of patients: 15–20%with gastric ulcers; 5–8% with duodenal ulcers;and 1–3% of users are thought to develop GIbleeding as a consequence, especially when expo-sed to the traditional NSAIDs (tNSAIDs*)(Hirschowitz, 1994; Tannenbaum et al., 1996; Singhand Ramey, 1998; Langman et al., 1999; Buttgereitet al., 2001). Each year, as many as 2000 estimateddeaths in the United Kingdom (Tramer et al.,2000), 7600 deaths and 76,000 hospitalisationsin the United States, and 365 deaths and 3900hospitalisations in Canada (Tamblyn et al., 1997;Tannenbaum et al., 1996) may be attributable toNSAIDs. However, in a review of 74,666 patientsin 12 trials, only 138 deaths and 248 serious GIevents were identified. (Hooper et al., 2004). Thus,reflecting that the exact estimates of GI complica-tions and even estimates of death rate may be verydifficult to assess due to factors such as underreporting, drop-outs not evaluated, and assignmentof the event to other causes. The gastointestinaladverse effects, whether only symptomatic orclinically serious, can significantly affect quality oflife (QoL) (Hawkey et al., 2005), and can result indiscontinuation of treatment for musculoskeletalpain in up to 10% of patients (Hirschowitz, 1994;Singh and Ramey, 1998; Langman et al., 1999;Buttgereit et al., 2001).

Initial studies on the effect of steroids on the GItract did not identify a clear relationship betweenoral steroids and GI complications (Green, 1976;Conn and Poynard, 1994), but Messer and col-leagues (1983) did identify a small risk for pepticulcer disease (PUD) and steroid use. However, it isnow well established the steroids alone convey anincreased risk of upper GI complications and thatrisk markedly increases when the steroids are takenconcomitantly with NSAIDs. Piper and colleaques(1991) identified an odds ratio (OR) of 1.1 (95%confidence interval (CI): 0.5–2.12) for steroid useonly, but 14.6 (95% CI: 6.7–32.0) for steroids plusNSAIDs versus patients on no drugs.

Gastrointestinal Complications of Anti-Rheumatic Drugs 245

Hernandez-Dıaz and Rodrıguez (2001) estimatedthe risk of upper GI complications associated withuse of steroids alone and in combination, using anested case-control analysis which was conductedon the General Practice Research Database fromthe United Kingdom. The authors identified 2105cases of upper GI complications and 11,500controls between 1993 and 1998. The adjusted ORsassociated with current use of oral steroids were 1.8(95% CI: 1.3, 2.4) for upper GI complicationsoverall, 2.4 (95% CI: 1.7, 3.4) for gastric, and 1.2(95% CI: 0.8, 1.9) for duodenal damage. Steroidswere similarly associated with bleeding (OR 1.8;95% CI: 1.3, 2.4) and perforations (OR 1.6; 95%CI: 0.9, 3.1). Simultaneous use of steroids with low-,medium-, and high-NSAID doses, respectively,produced ORs of 4.0 (95% CI: 1.3, 12.0) and 12.7(95% CI: 6.2, 26.1), compared with users of none.

This marked increase in risk for concomitantNSAID and steroid use may be related to impairedulcer healing induced by the steroids (Luo et al.,2004).

2.3. Mechanisms of action of the NSAIDs

Almost all of the original or tNSAIDs are weakacids with a pKa of 3.5–5.0 and thus demonstrateeither hydrophilic (in the ionised state) or lipophi-lic properties (non-ionised state) dependent on thepH of the surrounding milieu. The mechanismsof the serious adverse effects are well established,and are related to a series of actions includinglocal solute effects (Kean and Buchanan, 1987),back diffusion of hydrogen ions (Davenport,1967; Somasundaram et al., 1995; Sigthorssonet al., 2000), and systemic effects on cell migrationand prostaglandin (PG) synthesis (Schoen andVender, 1989; Wolfe, 1996; Cryer and Feldman,1998). Other biochemical effects of importance inthe development of mucosal injury by NSAIDsinclude (a) enhanced production of vasoconstrictorpeptide-leukotrienes and leucoattractant leukotrieneB4 as a consequence of cyclooxygenase inhibition(Rainsford, 1986, 1992, 1997d, 1999a, b) which canalso lead to increased acid-pepsin production;(b) delayed ulcer healing (Halter et al., 1997a, b),(c) reduced production of protective mucus and bio-

carbonate (Rainsford, 1988a, b, 2001); (d) enhancedoxyradicals and in combination with nitric oxide for-mation of tissue destructive peroxynitrite (Rainsford,2001); (e) activation of NFkB signalling pathwayswith consequent production of TNFa, other cyto-kines and metalloproteinases (Rainsford, 2001);(f) reduced ATP and mitochondrial effects leadingto enhanced caspases activation and apoptosis(Rainsford, 2001); and (g) altered cyclic nucleotideproduction affecting control of acid, pepsin andother physiological functions (Rainsford, 2001).

The NSAIDs are a necessary choice in painmanagement because of the integrated role of thecyclo-oxygenase (COX) pathway in the generationof inflammation and in the biochemical recognitionof pain (Bevilacqua, 2002; Dallegri and Ottonello,2002). The inflammatory reaction and tissue injuryresult in cellular release of interleukin-1 (IL-1) andtumour necrosis factor a (TNF-a), which thenstimulate macrophage nuclear factor kappa B toproduce cyclo-oxygenase 2 (COX-2) and hence theproduction of large quantities of prostaglandin E2(PGE2) which facilitates nociceptor recognitionand hence the perception of joint pain.

3. Gastrointestinal reactions in autoimmune

arthropathies

GI reactions are among the most frequently seen inpatients with auto-immune arthropathies (Schneideret al., 2006). These events are more frequent inwomen than in men (Schneider et al., 2006) andthe classical picture of the ‘elderly frail femalerheumatic patient that is under weight’ is probablythe likely candidate for severe GI disorders, mostespecially with ulcers in the upper and lowerGI regions and haemorrhage. Long-term use ofNSAIDs while essential for relief of symptomsof joint pain in patients with auto-immunearthropathies is also accompanied by increasedrisks of GI reactions (Schaffer et al., 2006).Anaemia and subnormal functional GI physiologyleading to subnormal digestive processes and, inthe extreme, protein-loosing enteropathy comprisethe consequences of GI disorders in these elderlypatients (Bjarnason et al., 1991; Hogan et al.,


1994a, b). Modern medical management should,but not always, involve GI evaluation and treat-ment (Schneider et al., 2006) where there aresuspicions of GI disorders such as reduced/subnormal body mass, anaemia, gastric distress,or other GI symptoms. Of course, the elderly frailfemale is not the only ‘category’ of arthritic patientwho suffers GI symptoms, but may presentwith life-threatening symptoms. Moreover, theconsequences of subnormal digestive processesleading to impaired nutrition may have profoundconsequences, e.g. cognitive impairment, decline inthe status of the arthritic disease, and reducedsociality and independence as part of the dete-rioration in QoL (Taha et al., 1993).

3.1. Multiple origins of GI reactions

The origins of these GI reactions are manifold(Table 1), among them are:

a. Use of drugs that are known to cause GIulceration, haemorrhage, or gastric upsets. Theseinclude agents that are well known to causethese effects such as aspirin (Rainsford, 1999b,2004), non-selective COX inhibitory NSAIDs(Hernandez-Diaz and Garcia-Rodriguez, 2000),

the coxib class of NSAIDs (Peng and Duggan,2005), and notably paracetamol (acetamino-phen) (Rainsford and Whitehouse, 2006) givenat high dosages (2–4 g/day) (Table 2) (Garcia-Rodriguez and Hernandez-Diaz, 2001a, b).Low doses of NSAIDs such as in OTCpreparations lead to much lower incidence ofGI effects (Rainsford, 1997c; Rainsford &Powanda, 1997) confirming that there arepronounced dose-response effects in NSAIDassociated GI ulcers and bleeding. It shouldalso be noted that GI reactions are sometimesassociated with the use of disease-modifyinganti-rheumatic drugs (DMARDs), e.g. goldcomplexes, methotrexate (Kelly and Hamilton,2007). Thus, the usual culprits, the NSAIDs,are implicated in gastroduodenal-opathies inauto-immune arthritic conditions and may notalone be the cause of severe GI disorders(ulceration, haemorrhage) or of painful symp-toms (Talley et al., 1995).

b. H. pylori infection of the gastroduodenalregion (Hunt and Tytgat, 1993, 1996) and,although less well-known, pathogenic enter-obacteria strains including Escherichia coli,Clostridium difficile, Campylobacter jejunii,Gastrospirillium spp., and other indigenousenteric flora (Neu, 1985; Sjostedt, 1989). H. pylori

infection like that of many other entericbacteria is commensual and the conditions forthe development of pathogenic strains are notclear, although generalised host populationcharacteristics such as increasing populationdensity, use of antibiotics, and other agentsthat create selection pressure leading to selec-tion of certain strains are likely factors. From aclinical standpoint the identification of theknown pathogenic strains of H. pylori, com-prising CagA+ and VagA+ combinations, israrely undertaken in patients with H. pylori

associated PUD. Thus, the conclusion thatH. pylori infection is responsible for PUD in aparticular patient or group of patients may notbe adequately justified. Likewise, the inferencethat H. pylori infection may contribute to PUDin patients receiving NSAIDs or as popularisedby Hawkey (2000) that NSAIDs may inhibit orprevent the mucosal inflammation attributed to

Table 1

Risk factors for the development of NSAID-associated gastro-

duodenal ulcers

Established risk factor Possible risk factor

Advancing age High alcohol consumption

High-dose NSAID or

paracetamol

Cigarette smoking

Use of more than two NSAIDs Diuretics

Concurrent paracetamol

Concurrent anti-coagulants Anti-hypertensive agents

Concurrent aspirin (even low

dose)

Concurrent corticosteroids

(dose-dependent)

Helicobacter pylori infection

Prior history of peptic ulcer

disease

Rheumatoid arthritis

Note: Modified and with additional information from Wolfe

et al. (1999), Garcia Rodriguez and Hernandez-Diaz (2001a, b),

Laine (2001), and Rainsford (2004).


H. pylori infection may be suspected unless thepathogenicity of the infecting strain is clearlyestablished (Wilcox, 1997). NonethelessCagA+/VagA+ strains of H. pylori are fre-quently found in patient isolates, so that theinfection with this organism must at least beconsidered suspect in many patients with PUDwhere there has been a positive increase orimmuno- (histochemical-) assays employed toidentify the infection. For the other enteric floradiscussed above, there is little if any clinicalevidence to identify their involvement in GIreactions in patients with autoimmune arthro-pathies.

Some in vivo studies in rats have shown thatrepeated oral administration of indomethacin(10mg/kg/day) or the same dose given subcuta-neously resulted in a marked increase in faecalanaerobic and aerobic bacteria coincident withthe development of ileo-caecal ulceration (Benoniet al., 1984; Konaka et al., 1999). Intestinal lesionsfrom indomethacin do not develop in germ-freeanimals (Robert and Asano, 1997) or in thosegiven antibiotics (Rainsford, 1988c), highlightingthe role of enteric bacteria in the development ofintestinal lesions in rats. Indeed it has beensuggested that use of poorly absorbed antibioticssuch as rifaxamin may be useful in preventingintestinal injury in patients taking NSAIDs (Lanasand Scarpignato, 2006).

An increase in the number of gram-negativeintestinal bacteria has been observed with NSAIDs,with bacterial lipopolysaccharide contributing tothe development of intestinal lesions in rats(Hagiwara et al., 2004). Similar implications ofintestinal flora in the pathogenesis of intestinalpathology involving alterations in faecal flora byNSAIDs (Rainsford, 1988c; Uejima et al., 1996).Colonisation of gastric ulcers by enteric bacteriahas been found to impair ulcer healing in rats(Elliott et al., 1998).

Faecal Clostridium perfringens have been foundto be increased by NSAIDs in RA, but not inpatients with OA; in the RA patients this wasparalled by an increase in serum IgA antibody tothe a-toxin of C. perfringens (Dearlove et al., 1992).These results suggest that there may be marked

Table 2

Epidemiological data from General Practice Database (UK) on

peptic ulcer bleeding risks from aspirin and other NSAIDs and

paracetamol and other sources

Drug Usage/factor Relative risk

Aspirin Overall use Users 2.0

cf Non-users 1.0

Recent users 1.5

Past users 1.1

Dose 75–300mg/day 2.1

>400mg/day 3.1

o50mg/day 0.7

Period of use 1–60 days 4.5

61–180 days 2.7

181–730 days 1.0

>730 days 1.6

Concurrent

NSAIDs

Low-medium

dose

2.4

High dose 4.3

Formulation Plain versus

coated, both for

GU and DU

B2.0

Paracetamol o1 g/day 1.0

1–2 g/day 0.9

2–4 g/day 3.4

>4 g/day 6.5

2 g with NSAID 4.2

>2 g with

NSAID

13.5

cf NSAID alone 3.5

NSAIDs Low dose 2.5

High dose 5.0

Duration 1–30 days 4.3

>730 days 3.5

Indication OA

Adjusted 4.3

Crude 3.7

RA

Adjusted 4.7

Crude 5.3

Pain

Adjusted 4.2

Formulation Plasma t1/2

o12 h 4.2

(high dose)

Z12 h 5.4

Slow release 6.2

o12 h 2.4

(low dose)

Z12 h 2.8

Overall slow

release

3.9

Ibuprofen Lowest risk

(dose dependent) B1.0–2.0

Note: From Garcia-Rodriguez and Hernandez-Diaz

(2001a, b) and modified by Rainsford (2004).


changes in faecal flora by NSAIDs especially inpatients with RA and this may contribute to theintestinal pathology seen in this patient group.

Recent studies show that following H. pylori

eradication therapy in patients with gastric or duo-denal ulcers, there is an increase in Klebsiella

and Enterobacter species (Shimbo et al., 2005)suggesting that there may be important conse-quences of eradication therapy on the levels andstatus of GI flora.

The clinical significance of these observations inrelation to ulcer development has not, to ourknowledge, been established in arthritic patients,though it is clearly important to establish if this isthe case.

c. HLA-B27-associated immuno-inflammatoryreactions in the intestinal mucosa, includingthe development of ulcerative colitis (UC),are well established to occur frequently inpatients with ankylosing spondilitis (AS).Moreover, use of NSAIDs in these patientshas been shown to exacerbate symptoms of UC(Hawkey, 2006). Whether upper symptoms,e.g. PUD, develop or are exacerbated inpatients with AS is not known, although theymay be suspected. Exacerbation of GI symp-toms has also been reported in patients withsystemic lupus erythematosis (Khoury, 1989).

d. The systemic consequences of rheumatoid andother seropositive or seronegative arthropa-thies in promoting or potentiating upper GIulcer disease from intake of NSAIDs and otherdrugs have long been suspected with evidencein support of this disease–drug interactionbeing derived from extensive studies in labora-tory animal models (e.g. adjuvant-inducedchronic polyarthritis, acute inflammatory states,physical stress conditions) (Rainsford, 1975,1977a, b, 1978, 1981, 1989b, 1992; Whitehouseand Rainsford, 1977). These studies have shownthat there is marked increase in the develop-ment of mucosal lesions and ulcers in animalswith these inflammatory or stressful statesgiven NSAIDs. It is known that patients withrheumatic disorders experience profoundsocio-psychologic stress (Eich, 2004) so thesestudies in laboratory animal models of

rheumatic disease have particular relevancein highlighting the potential of stress factorsto exacerbate development of GI ulcers inthese patients. Confirmation of these observa-tions has been difficult to establish in rheu-matic patients taking NSAIDs.

Comparisons have been made of the incidence ofulcers, endoscopically observed lesions of the upperGI tract and bleeding episodes or micro-bleeding insubjects receiving different NSAIDs who have RAcompared with OA. Some studies have shown thatthe incidence of these upper GI pathologiesfollowing intake of NSAIDs is greater in patientswith RA compared with OA, but in other studiesthe results have been equivocal. If it is acceptedthat NSAIDs cause more injury to the GI tractin patients with RA than with OA, it would suggestthat the systemic manifestations in RA that leadto mucosal susceptibility to these drugs might involve:(a) altered liver metabolism of the drugs such as toenhance their toxicity, (b) reduced production ofalbumin or other plasma proteins that bind thedrugs in the circulation, (c) enhanced productionof pro-inflammatory cytokines with consequentinflammation in mucosal cells and reduction inmucosal protective mechanisms, impaired diges-tive functions, and in the extreme TNF-a-relatedcachexia. Attractive as these mechanisms mayseem it is equally possible that the debilitatingeffects of sustained joint pain and disability that isevident in OA, with consequent psychologicalstress, may also promote mucosal susceptibilityto NSAIDs and other ulcerogenic drugs. Thus,comparisons of the occurrence and severity ofulcers or mucosal injury in RA with OA patientsmay not provide convincing evidence for systemicmanifestations contributing to susceptibility tothese dugs in patients with RA. The discussionabout the role of systemic, sociopsychological anddisease-manifestation that are evident in autoim-mune and osteo-arthropathies serves to illustratethe potential importance of these states in predis-posing the GI tract to the ulcerogenic effects ofNSAIDs and other ulcerogens.

e. Many middle-aged and elderly patients withautoimmune arthropathies may have other


chronic debilitating conditions (e.g. diabetesmellitus, atherosclerosis, coronary vasculardisease, subnormal, or impaired hepato-renalfunctions) that can have profound conse-quences for vascular functions and drugtoxicities that affect mucosal functions andintegrity. Indeed studies in streptozotoicindiabetic rats (Tashima et al., 2000) or rats withspontaneous hypertension have shown thatthese have markedly enhanced susceptibilityto the ulcerogenic effects of NSAIDs orother gastric irritants (Rainsford, unpublishedstudies; Shichijo et al., 1991). Even subtlealterations of blood glucose influence theulcerogenic effects of NSAIDs (MacDonald,1997).

Another consequence of these concomitantchronic illnesses is that the drugs taken by patientswith these conditions sometimes promote orenhance the development of ulceration or haemor-rhage attributed to NSAIDs. The list of thesedrugs includes diuretics, calcium channel blockers,anti-hypertensive agents, and corticosteroids(Gabriel et al., 1991; Garcia-Rodriguez andHernandez-Diaz, 2001a, b; Peura, 2002; Rainsford,1997b). With some of these drugs, NSAIDs mayaffect their pharmacokinetics or pharmacody-namics, thus contributing to the GI toxicity ofNSAIDs.

3.2. Variation in ulcerogenicity of NSAIDs

It is now well established that individual NSAIDsvary considerably in their propensity to causeulceration and haemorrhage (Carson and Strom,1992; Taha et al., 1994; Cheatham et al., 1999;Lanza et al., 1999; Hunt et al., 2000; Uemura et al.,2003; Lungardon et al., 2004). Evidence in supportof this variability has come from (a) pharmaco-epidemiological studies, (b) case-controlled studiesand clinical trials, (c) endoscopic investigations involunteers, and (d) radiochromium (51Cr)-labelledred cell or other blood-loss investigations involunteers. Data in laboratory animal models havealso contributed valuable information (Rainsford,1981, 1989a, b, 1992, 1997a, b). Often because thisis at variance with the data from human studies,the data from animal studies have been dismissedor downgraded as being unreliable or not of humanrelevance (Rainsford, 1991)! This is a patentlyflawed reasoning particularly as the specific experi-mental conditions in which the studies in animalsand humans as well as important pharmacokineticconsiderations have failed to be considered in thetranslation of animal to human situations and viceversa. These aspects have been reviewed elsewherein extenso (Rainsford, 1988a, b, 1989a, b, 1992,1997a, b, 2006) and the reader should consult thisliterature for further detailed considerations.

Data from epidemiological studies (e.g. as shownin Fig. 1; Henry et al., 1998) typically show that

Figure 1. Estimated relative risk of major gastrointestinal complications with individual drug. (Reproduced with permission from

Henry et al., 1998.)


ibuprofen is among the least ulcerogenic NSAIDs,a feature which is evident in most record-linkage,case-controlled or other epidemiological studies aswell as in endoscopy investigations (Henry et al.,1998).

For consideration of data on the association fordifferent NSAIDs to cause serious GI conditions inpatients with auto-immune diseases, it is necessaryto consult specific pharmaco-epidemiologicaldatabases, case-controlled studies, or GI investiga-tions in patients with rheumatic diseases (Singhet al., 1994; Singh and Ramey, 1998).

4. Coxibs versus non-selective NSAIDs

4.1. Pharmacological rationale fordevelopment of coxibs

By the early 1990s, two forms of the COXenzyme were ‘identified’ using molecular biologicaltechniques. Needleman and Isakson were amongseveral investigators who reported that a constitu-tive isoform, COX-1, was present in most cell typesand maintained a homeostatic function. However,the COX-2 isoform, normally undetectable in mosttissues, was shown to be induced in response toinflammatory mediators, tumour promoters, andgrowth factors (Frolich, 1995; Needleman andIsakson, 1997; Crofford, 1997; Brooks et al., 1999;Hawkey, 1999; Silas and Clegg, 1999). The presentterminology used to describe the cyclo-oxygenasesis to call COX-1 the constitutive isoform andCOX-2 the inducible isoform (Hla and Neilson,1992; Jones et al., 1993; Smith et al., 1996). How-ever, these definitions may be an over simplifica-tion since the enzymes are the expression ofcomplex regulatory mechanisms that govern theirproduction. COX-2 is located in brain and kidneyin the absence of inflammation, and growth factorinduction and developmental regulation of theCOX-1 gene have been reported (Harris et al.,1994; Guan et al., 1997; Komhoff et al., 1997;Yang et al., 1997). The original NSAIDs inhibitboth COX-1 and COX-2 activity, whereas theglucocorticoids inhibit COX-2 expression(Masferrer et al., 1990; Crofford et al., 1994).Experiments by Crofford (1997) and Siegle et al.

(1998) have shown that COX-2 is not expressed innormal joint synovium, but is present in variousdegrees in the synovial fibroblasts, endothelialcells, and macrophages of patients with RA, OA,and other inflammatory joint diseases. Furtherinduction of COX-2 can take place in vitro byaddition of inflammatory cytokines (Crofford,1997; Siegle et al., 1998).

The much heralded introduction slightly lessthan a decade ago of highly selective COX-2inhibitors classed as ‘coxibs’ with claims of beingGI safer than conventional NSAIDs (Bensenet al., 1999; Hawkey, 1999; Langman et al., 1999;Simon et al., 1999, 2001; Bombardier et al., 2000;Goldstein et al., 2001) has proved to have hadmixed outcomes. In essence most if not all thecontrolled investigative studies performed in volun-teers (e.g. radiochromium blood loss or endoscopyobservational studies), observational, and/or endo-scopic investigations in patients with rheumatoidor OA (Feldman and McMahon, 2000) comparingindividual coxibs with NSAIDs have shown thatthere are fewer upper GI ulcers or bleeds in thosesubjects that have received coxibs.

In some patient groups, these controlled studiesextended for up to 6–12 months. Often the rates ofpeptic ulcer bleeds (PUBs) or other indices ofserious GI complications (ulceration) have beensimilar to or slightly above those from placebo orparacetamol and statistically significant and lowerthan the values observed with the NS-NSAIDsgrouped together instead of individually (Langmanet al., 1999; Silverstein et al., 2000; Watson et al.,2001; Hochberg, 2003; VIGOR Study Mamdaniet al., 2002; Singh et al., 2006). The groupingtogether of all NS-NSAIDs is both pharma-cologically and statistically unjustified. On thepharmacological side, drugs such as diclofenac,ibuprofen, and naproxen (which have frequentlybeen used as comparators) have widely differingincidences of upper GI ulceration and haemor-rhage and each has marked differences in pharma-cokinetics and potency as PG synthesis inhibitorsand other anti-inflammatory activities. On thestatistical side grouping of data with data onindividual drugs each with their relative meansvariance or errors that often differ can give anartificial impression of homogeneity and disguise


underlying statistical differences between theNS-NSAIDs and may lead to disguising of whatcould be potential differences between individualNS-NSAIDs and coxib(s). There is an impressionthat the grouping of NS-NSAIDs for comparisonwith coxibs may have been driven by the commer-cial interests that dominate the support of many ofthe clinical studies published on the new coxibs.

Another comparison which has found favour inrecent years is the comparison of coxibs withNS-NSAIDs in combination with PPIs (Chanet al., 2002; Lai et al., 2005). Some of the patientsin these studies were receiving low-dose aspirin forcardioprotection and since this treatment has beenassociated with increased risk of ulcers or bleeding,use of a PPI blocker is justified on the grounds ofpreventing aspirin as well as NSAID injury (Laheijet al., 2003; Laine, 2003; Kimmey and Lanas, 2004).

The results from these studies show that PPIinhibitors taken with an NSAID in H. pylori

negative patients for up to 24 months have loweredrisk of developing GI ulcers and complications andthat this is comparable with that observed inpatients that received celecoxib (Lai et al., 2005).Other studies (Chan et al., see also review byLaine, 2004) show that PPI inhibitors givenwith NS-NSAIDs reduce the occurrence of seriousGI events to that which may be comparable withcoxibs.

Despite evidence from controlled clinical trialsthat coxibs may reduce the risks of developingserious upper GI events compared with that fromNS-NSAIDs, careful re-evaluation of some of thepublished data (Schoenfeld, 2001; Juni et al., 2002),including that from two large-scale studies thatevaluated ulcer complications from celecoxib withthose from diclofenac and ibuprofen in a trialknown as Celecoxib Long-term Arthritis SafetyStudy (CLASS) (Table 3; Silverstein et al., 2000)and the other known as Vioxx GastrointestinalOutcomes Study (VIGOR), has questioned the‘reduced GI risk from coxibs’ (Table 4; Bombardieret al., 2000). It should be noted that both thesestudies were probably the largest GI investigationsthat had been performed up to the early 2000s andundoubtedly set the standard for future studieswith new NSAIDs. Unfortunately, the outcomesfrom these studies were not all that clear and

reflected problems in trying to relate studies fromcontrolled clinical trails in selected patient groupsand translating these results to large patient groupsnearer to the real-world situation. Thus, it hasbecome clear from a number of critical data (re)-evaluations that the relative advantages of thesetwo coxibs in comparison with NSAIDs in relationto serious GI complications, ulcers, or bleeding aremuch lower than originally apparent from thepublished reports. Indeed there have been somehighly critical analyses and commentaries (Bjarnasonand Rainsford, 2001a, b; Ostor and Hazleman,2005; Bjarnason and Thjodleifsson, 2005; Khannaet al., 2005; Halpern, 2005; Rainsford, 2005).

The most critical issue concerns the analysis ofrelative or absolute risk reduction (ARR), numberneeded to treat, and the clinical benefits. Tables 3and 4 summarise these assessments in CLASS andVIGOR studies, which were reported by Schoenfeld(2001). These calculations (Table 5) show thatalthough the percentage of relative risk reduction(RRR) for celecoxib cf NSAIDs (ibuprofen, diclo-fenac) is 61% and for rofecoxib cf naproxen is 60%,the values for ARR are relatively small being 0.7and 0.8% respectively for the two trials. The latter

Table 3

Summary of adverse events in the CLASS study

Event % Celecoxib Diclofenac Ibuprofen

GI 45.6 55.0 46.2

Withdrawal 12.2 16.6a 13.4

Renal 6.8 6.7 10.3a

Withdrawal 1.0 0.6 1.3

CV non-ASA 1.6 1.2 0.4

Hepatic 1.8 6.9a 1.9

Withdrawal 0.3 3.5a 0.3

Note: Based on data published by Silverstein et al. (2000).a Significantly different compared with celecoxib.

Table 4

Summary of the adverse events in the VIGOR study

Event % Rofecoxib Naproxen

GI abdominal pain 9.3a 7.8

CV 1.8 0.7

Renal 0.2 0.002

Hepatic 0.25 0.007

Note: Based on data published by Bombardier et al. (2000).a Significant increase compared with naproxen.


values represent the fact that the percentageincidence of GI complications for the NS-NSAIDas well as for the two coxibs is in the low end rangeof 0.4–1.14% which are very low percentages. Thus,with such small differences calculations of RRRare meaningless and give a false impression ofimproved benefit to the GI tract of the coxibs. Thisapproach of using RRR percentage benefits hasbeen extensively exploited in published data oncoxib trials and must, therefore, be regarded assuspect statistical treatment of data which has littlerelevance clinically. Indeed clinical significance inmany coxib trials has rarely been considered incontrast to statistical significance.

Three other major groups of adverse reactionshave emerged with the coxibs—CV, hepatic, andrenal, and to some extent they may be inter-related(Khanna et al., 2005; Ostor and Hazleman, 2005;Rainsford, 2005). Thus, any consideration ofrelative safety of coxibs compared with NS-NSAIDshas to involve CV and hepato-renal ADRs. Asshown in Tables 4 and 5 these serious ADRs werefrequently reported in the CLASS and VIGORstudies respectively. The CV events amounted tomyocardial infarction and hypertension and werenoted particularly with rofecoxib. They were of

sufficient concern for the company producing thisdrug, Merck Sharp and Dohme, to withdraw it fromthe market. The FDA and other agencies worldwidewere alerted and alarmed about the CV ADRs withrofecoxib such that extensive reviews were under-taken by these agencies worldwide of both coxibsand NSAIDs (Kean and Buchanan, 2005).

From the point of view of GI safety, there mayhave been pathological consequences of hepato-renalADRs and hypertension that contributed to thevascular aetiology of upper GI ulcer disease as wellas the consequences of the diuretics and anti-hypertensive drugs (which as noted earlier increasethe risk for developing ulcers) as well as NSAID–drug interactions that patients with hepato-renalconditions and hypertension received for treatmentof these conditions. In the end what has emergedin the overall safety analysis of the coxibs is sum-marised in Table 6, it is clear that the benefits ofwhat now are classed as ‘first generation’ coxibs(celecoxib, rofecoxib, valdecoxib) may have beenmarginal compared with some conventional NSAIDs,among which etodolac, ibuprofen, nabumetone, and

Table 6

Issues concerning safety and efficacy of coxibs and preferential

COX-2 inhibitors

Cardiovascular (CV) reactions rofecoxiv, valdecoxib, and

celecoxib (twofold increased risk); withdrawal of refecoxib

(VIOXX) 30 September 2004 (marketing and PR disaster!)

FDA, EMEA, and other national agencies instigate review of

coxibs and NSAIDs

Evidence for lack of highly favourable GI safety of celecoxib cf

NSAIDs (Juni et al., 2002, BMJ 324:1287), extensive hepatic

metabolism, drug interactions, and liver reactions with

celecoxib

Delayed gastric ulcer healing—clinically unproven

Skin reactions with valdecoxib

Renal toxicity with rofecoxib, possibly less with celecoxib

Symptomatic ADRs (nausea, abdominal pain, dyspepsia, etc.)

same with coxibs as conventional NSAIDs

Perception that rofecoxib is not a good analgesic

Possibility that rofecoxib may be safe(r) in aspirin-sensitive

asthma compared with other NSAIDs

Cost/benefit cf conventional NSAIDs with low upper GI

effects—ibuprofen, diclofenac but maybe with naproxen

Table 5

Estimation of serious gastrointestinal reactions from rofecoxib

(VIGOR) and celecoxib (CLASS) trials compared with

NSAIDs�

In the VIGOR trial: percentage of patients with serious

NSAID-associated gastrointestinal complications

Rofecoxib=0.6%, naproxen=1.4%

ARR=1.4–0.6=0.8%, NNT=1/0.8%=1/0.008=125

RRR=1.4–0.6/1.4=60%

In the CLASS trial (non-aspirin-using patients only):

percentage of patients with serious NSAID-associated

gastrointestinal complications

Celecoxib=0.44%, diclofenac=0.48% (no statistically

significant difference between diclofenac and celecoxib)

Celecoxib=0.44%, ibuprofen=1.14%

ARR=1.14–0.44=0.7%, NNT=1/0.7%=1/0.007=143

RRR=1.14�0.44/1.14=61%

Note: From Schoenfeld (2001).

ARR, absolute risk reduction; RRR, relative risk reduction;

NNT, number needed to treat.�Results are reported as serious NSAID-associated gastro-

intestinal complications (i.e. gastrointestinal bleeds, perfora-

tions, and obstructions) per 100 patients per year.


possibly diclofenac (although the intestinal ulcerationand hepatotoxicity from this drug limit it beingconsidered to have a favourable safety profile).

The limited value of coxibs compared withNS-NSAIDs is highlighted in data on the adverseevents reported in the French PharmacovigilanceStudy (Lugardon et al., 2004), a summary of whichis shown in Table 7.

5. Potential for impact of arthritic disease

An interesting and possibly important point whichshould be considered is the arthritic condition inthe CLASS and VIGOR as well as other studieswith the coxibs. Patients in the VIGOR only hadRA whereas those in the CLASS Study had bothRA and OA. It has been claimed that there wereno differences in ulcer complications in patientswith OA cf RA. This is in one sense surprisingsince as noted earlier it has been speculated thatpatients with RA may be more susceptible toNSAIDs than those with OA. It could be that theselection criteria for patients entered in the CLASSStudy were such that RA as well as OA patientswere relatively ‘fit’ and without complicating

chronic conditions that inevitably occur in oldermore infirmed patients, especially those with RA.

Indeed the ulcer incidence in the CLASS Studyas well as in the meta-analysis of celecoxib trials byMoore et al. (2005) reveals a remarkably lowincidence in placebo and NSAID groups. Thisgives support to the view that patients selected forinclusion in these studies may have been ofrelatively favourable health. Another issue is thatif there were any real differences in data of ulcercomplications in say a proportion of patients withRA cf those with OA these may have beendisguised in the grouping of data together suchas in the CLASS results.

The data on ulcer complications in the CLASSStudy observed at 6 months showed there weredifferences between celecoxib and NSAIDs. How-ever, as pointed out by Juni et al. (2002) these diffe-rences were not apparent at 12 months, suggestingthere are time-dependent factors that are significantin considering ulcer incidence of both coxibs andNS-NSAIDs. The clinical significance of these datalike that from other long-term studies is that whencoxibs are taken for relatively short periods of time(2–4wk) they are likely to cause less ulcer compli-cations than NS-NSAIDs such as naproxen anddiclofenac than if they are taken for several monthsor longer. There is also the issue of what has beendescribed as ‘channelling’ where patients with ahistory of GI complaints or GI ulcer disease may beprescribed coxibs in the belief they will be ‘gastric-safe’, this may be such that benefits for using thesedugs may be less apparent and the patients mayrequire anti-ulcer co-therapy [e.g. with H2-receptorantagonists (H2RAs) or PPIs]. The cost-benefits ofcoxibs therapy may prove less favourable as notonly are these drugs notably more expensive thanconventional NSAIDs, but also if PPIs or otheranti-ulcer therapies have to be employed they mayas well be given with cheaper NSAIDs, especiallythose with a lower propensity to cause CV compli-cations (e.g. naproxen) or combinations withaspirin for cardioprotection.

As an example of how their cost-benefit analysescan impact decisions on the choice of coxibtherapy, the UK National Institute for ClinicalExcellence (NICE; which advises the UK NationalHealth Service on approved choices for therapies)

Table 7

Adverse drug reaction reporting odds ratio (OR) (with their

95% confidence interval) according to main classes of

non-steroidal anti-inflammatory drugs (NSAIDs) from the

French Pharmacovigilance Database (Lungardon et al., 2004)

Drugs Adjusted ORa (95% CI) Adjusted ORb (95% CI)

Coxibs 4.6 (3.3–6.5)� 14.9 (9.3–23.7)�

Rofecoxib 5.2 (3.1–8.7)� 21.0 (10.6–41.6)�

Celecoxib 3.7 (2.4–5.8)� 11.7 (6.6–20.9)�

Oxicams 12.2 (6.7–22.2)� 25.3 (11.9–53.6)�

Heteroaryl acetic acids

Ibuprofen 4.5 (3.2–8.8)� 7.3 (3.2–16.6)�

Diclofenac 3.9 (2.1–7.2)� 9.2 (3.8–22.2)�

Naproxen 10.6 (4.7–23.7)� 17.9 (6.7–47.6)�

Ketoprofen 8.6 (5.3–13.9)� 19.9 (10.7–37.0)�

�po0.0001.a Adjustment for matching factors (age, gender, period of

occurrence).b Adjustment for matching factors (age, gender, period of

occurrence) and confounding factors (regional pharmacovigi-

lance centre, work place of health professional, and drug

exposure: anti-coagulants, anti-platelet drugs, aspirin, gastro-

protective, and other NSAIDs).


has recommended that celecoxib only be prescribedfor elderly patients at risk of upper GI complica-tions. The question of co-therapy with anti-ulcerdrugs is another issue which has not beensatisfactorily resolved at the time of writing thischapter. Elsewhere in this chapter we consider theconfounding factors in relation to benefits of usinganti-secretory agents in the elderly for protectionagainst NSAID ulcer complications.

In the VIGOR Study performed in RA patients itis possible that the CV ADRs developed in thesepatients because they had rheumatoid disease. It isknown that patients with RA are more prone to CVdiseases and it is possible that rofecoxib ‘triggered’development of myocardial infarction or hyperten-sion in these patients as a result of the actions of theoxidised metabolite of the drug reacting with LDLand elastin molecules in vascular tissues so pre-cipitating or exacerbating atherosclerotic changes inarteriolar vessels that were prone to weakness orobstruction. The renal effects of rofecoxib may alsohave contributed to the hypertension so contribu-ting to further explosive weakness in vessels at risk.Since CV and hypertensive effects of NSAIDs mayplay a role in the development of GI mucosallesions, these CV and renal effects may have contri-buted to the ulcer complications that were observedin RA patients on rofecoxib.

6. GI symptomatic adverse drug reactions

Meta-analysis of the tolerability and adverse eventsfrom a range of trials of celecoxib compared withNS-NSAIDs, paracetamol, and placebo (using datafrom the published and unpublished trials fromPfizer) (Moore et al., 2005) revealed some interes-ting features and trends concerning the occurrence ofGI symptoms notably nausea, dyspepsia, diarrhoea,abdominal pain, vomiting. These constitute mainreasons (other than ulcer/bleeds or other seriousADRs) for withdrawal from therapy, and indeed thedata by Moore et al. confirmed this pattern.

Data in Table 8 show the principal dyspepticsymptoms summarised in the report by Moore et al.(2005). They highlight: (1) the occurrence andrelative risks (RR) of most GI symptoms in patients

receiving celecoxib, rofecoxib, or paracetamol beinggreater than that of placebo, (2) while there aretrends for a lower incidence of some symptoms withlow-dose celecoxib the differences are less distinctwith higher dose celecoxib, and (3) the data on CIsin RRs with most comparisons often overlap to theextent that it is doubtful if any differences, especiallythose favouring celecoxib, have any meaning.

6.1. Individual symptoms

The authors of this study noted that the proportionof patients having dyspepsia was about 7% andthat there were no differences in comparison withplacebo, paracetamol, or rofecoxib, but there weremore patients on NSAIDs. Celecoxib was respon-sible for abdominal pain in about 5% patients therebeing no difference cf placebo or paracetamol butmore patients on NSAIDs and rofecoxib experi-enced this adverse effect. In these and other GIsymptomatic effects as well as overall GI toler-ability there were trends in favour of celecoxib incomparison with the other treatments but the 95%CIs for RR often overlapped those of comparatordrugs. Making much of what are relatively smallvalues for incidence and percentage differences ofsymptomatic GI ADRs like that of clinical ulcersand bleeds in this meta-analysis (Moore et al.,2005), is probably of limited value and meaning.

7. Enter the second-generation coxibs

Merck, Pfizer, and Novartis all had follow-upcoxibs in development around the time that

Table 8

Meta-analysis of dyspepsia events (%) in patients OA (25,903)

or RA and OA (10,470)

Treatments Celecoxib Comparator

Cele versus placebo 6.9 4.8

Cele versus paracetamol (4 g/day) 2.9 2.2

Cele versus rofecoxib (50mg/day) 4.4 4.9

Cele (200–400mg/day) versus NSAIDs 5.7 7.3

Cele versus NSAIDs (all dosages) 8.1 10.7

Note: Cele, celecoxib.

From Moore et al. (2005).


rofecoxib and celecoxib were introduced at the turnof this decade. Clearly, with events surrounding thewithdrawal of rofecoxib and the knock-on effectswith other drugs that followed the investigations ofthis and other coxibs and the NSAIDs in general,development of a second generation of coxibs hasproceeded apace. These developments have beenguided by experience from the ‘coxib disaster’.

In the wake of the issues surrounding with-drawal of rofecoxib the FDA determined thatvaldecoxib (Pfizer) had similar CV risks as well asthe skin reactions that emerged with this drug, ledto its withdrawal in 2005.

Etoricoxib (Arcoxias) developed by MerckSharp and Dohme is probably the most selectiveinhibitor of COX-2 of those drugs that have beendeveloped to date. While long-term investigationsare awaited there are indications that GI and CVevents from etoricoxib may be lower than withtNSAIDs and celexocib (Laine et al., 2007).

Lumiracoxib (Novartis) (now withdrawn inAustralia, Canada and not approved in USA) isnot chemically like that of other coxibs being aderivative of diclofenac. It does not have the highCOX-2 selectivity of etoricoxib or rofecoxib. In alarge-scale multicentre trial of lumiracoxib versusnaproxen and ibuprofen in some 14,000 patientsboth GI and CV complications were lower thanfrom ibuprofen and naproxen. A summary of thecombined GI and CV events is shown in Table 9(Schnitzer et al., 2004). These data show that thehazard ratio is significantly lower for lumiracoxib

than the two NS-NSAIDs although there isconsiderable overlap of the values of the 95% CIs.

The same arguments about the clinical benefitsin relation to GI adverse events from the newersecond-generation coxibs, as considered earlier inrelation to VIGOR and CLASS studies, need to beconsidered (Laine et al., 2007). To quote the oft-used phrase ‘the jury is undoubtedly out’ inassessment of the GI benefits of these new drugs.

8. Strategies to minimise or eliminate

gastrointestinal complications

Over the years, numerous strategies have beendevised to prevent, minimise, and treat GI compli-cations of analgesics, NSAIDs, and steroids. Therehave been many attempts at altering the GIabsorption rate and site of drugs by creatingalterations in route of drug dispensed (e.g. suppo-sitories, injections): changes in formulation withthe use of suspensions and mixtures; and varioustypes of enteric coating (Kean and Buchanan,1987). There has been very little success gainedby these methods in preventing GI complicationsrelated to the drug use. In addition, attemptsat prevention and/or management of analgesic,NSAID, and steroid GI-induced side effects haveincluded the use of antacids, H2RAs, PG analo-gues, and PPIs.

Table 9

Combined incidence of gastrointestinal and cardiovascular events from lumiracoxib, compared with ibuprofen and naproxen, by

substudy (safety population Schnitzer et al., 2004)

Number of patients with events/number at risk (%) Hazard ratio (95% CI) p�

Both substudiesw

Lumiracoxib 89/9117 (98%) 0.65 (0.49–0.84) 0.0014

Non-steroidal anti-inflammatory drugs 133/9127 (1.46%)

Lumiracoxib versus ibuprofen substudy=

Lumiracoxib 30/4376 (0.69%) 0.50 (0.32–0.79) 0.0025

Ibuprofen 56/4397 (1.27%)

Lumiracoxib versus naproxen substudy=

Lumiracoxib 59/4741 (1.24%) 0.75 (0.53–1.05) 0.0961

Naproxen 77/4730 (1.63%)

�Based on Wald w2 statistic for treatment group comparison. Cox proportional-hazards models include, in addition to treatment

group, the factors wsubstudy, low-dose aspirin, and age; and =low-dose aspirin and age.


For over 80 years, the management of musculo-skeletal pain was hampered by NSAID toxicityproblems related to these original or so-calledtNSAIDs, and many clinicians have been reluctantto use the tNSAIDs for pain management becauseof this issue. A 1999 report by IMS health on theCOX-2 inhibitor market indicated that 20% ofcelecoxib use in the United States was in new orincremental patients (IMS Health, 1999), andsimilar increases were identified in Canada (IMSHealth, Canada, 1999). These findings are indirectindicators that a proportion of patients have beendenied the benefits of NSAIDs for management oftheir musculoskeletal pain. This is discussed laterand has been described in detail elsewhere (Wonet al., 2004; Kean and Buchanan, 2005).

8.1. Effects of NSAIDs and H. pylori onacid secretion

The concept that acid secretory status plays a majorrole in the aetiopathogenesis of NSAID- andH. pylori associated PUD has received wide accep-tance (Soll, 1990; Rainsford, 1992; Hunt andTytgat, 1993, 1996). Likewise, the application ofpotent acid anti-secretory agents to control andtreat this condition has undoubtedly been of majortherapeutic benefit (Hunt and Tytgat, 1996).

The rationale for the use of acid-secretoryinhibitors (histamine H2RAs and H-pump block-ers) for the prevention of NSAID-induced gastro-duodenal mucosal injury, especially in patients atrisk (e.g. the elderly or frail rheumatic patients), hasbeen based on evidence that (a) NSAID-inducedinhibition of PG production, especially that ofPGE2, blocks or prevents the auto-regulation ofgastrin secretion (Befrits et al., 1984) which con-trols acid secretion (Levine and Schwartzel, 1984);(b) E-type PGs have been found to inhibit gastricacid secretion in isolated parietal cells in vitro(Choquet et al., 1993) and in human volunteers(Karim et al., 1973; Konturek et al., 1976); (c) thedeficiency in mucosal concentrations of PGs ingastroduodenal ulcers (Wright et al., 1982; Ahlquistet al., 1983; Konturek et al., 1982) may contributeto the pathogenesis of these conditions by

dysregulation of acid secretion as well as affectingother mucosal functions including mucosal protec-tion (Hawkey and Walt, 1986); and (d) the effectsof E-PGs and their analogues in the treatment ofgastroduodenal ulcers in humans are apparent atdoses which exhibit anti(acid)-secretory activity(Hawkey and Walt, 1986).

However, the central issue of whether NSAIDsgiven to humans do, in fact, stimulate acid secre-tion as a consequence of reduced PGs has beendebatable (Rademaker et al.,1995). In many ofthe earlier studies the possibility of controllingH. pylori infection, which causes stimulation ofacid secretion, via enhanced levels of gastrin andpepsinogen (Chittajallu et al., 1991, 1992; Levyet al., 1989) was not considered or feasible to beeliminated or in earlier studies (Rademaker et al.,1995). The growth of H. pylori adjacent to thestomach mucosa is known to depend upon localacid secretion (Lee et al., 1995). The evolution ofdifferent forms of gastritis that is associated withH. pylori infection depends on the state of acidsecretion (Sipponen et al., 1996a, b). Thus, peakacid output stimulated by pentagastrin is greater insubjects with mild or no gastritis than those withsevere chronic gastritis (Sipponen et al., 1996a).There are complex inter-relationships betweenacute effects of H. pylori in stimulating cytokineproduction (Bodger and Crabtree, 1988) that leadsto hypergastrinaemia and stimulation of acidproduction (Chittajallu et al., 1991, 1992; Levyet al., 1989; Beales et al., 1996). EnvironmentalpH clearly influences the growth of H. pylori

(Meyer-Rosberg et al., 1996), so there is a cyclicinter-relationship between influences of the micro-organism on inflammatory reactions and the conse-quent effects on acid secretion leading to acidicpH conditions that favour growth of H. pylori.The persistent inflammatory response driven bychemokines and pro-inflammatory cytokines pre-sumably leads to gastritis, which under chronic

conditions results, paradoxically, in reduced acidsecretion or achlorhydria.

The significance of previous studies on the effectsof NSAIDs on acid secretion and gastrin production(Konturek et al., 1982; Caldara et al., 1978; Sternet al., 1984) should be considered against the possi-bility that some of the patients or volunteers may


have been infected with H. pylori. It does not appearthat the acute response to indomethacin (i.e. overabout 1–3 days) in subjects with unknown H. pylori

status resulted in increased production of basal-,sham-fed-, and histamine-induced acid secretion innormal volunteers. However, the majority of studiesin normal volunteers indicates that basal acidsecretion is unaffected after one or more weeks oftreatment; the effects of histamine on the acidsecretion in normal or arthritic subjects receivingindomethacin for these periods are clearly morevariable. Since healthy elderly subjects haveincreased capacity to produce acid (Goldschmiedtet al., 1991), it is possible that the variable responsein arthritic patients could be related to differences ineffects of gastritis and other health parameters aswell as age in the latter group of patients (Feldmanet al., 1996).

To eliminate the possibility of confoundinginfluences of H. pylori infection, studies wereperformed in proven H. pylori-negative individualswho received indomethacin 50mg t.i.d. for 7 days.It was found that this treatment did not affect 24 hintegrated pH or 2 h meal-stimulated acid secre-tion (Rademaker et al., 1995) under conditionswhich in the early period up to 4 h would haveinhibited mucosal PGs by this drug (Rainsfordet al., 1993).

Hamlet et al. (1998) showed that antral distention-induced stimulation of acid secretion in H. pylori

negative subjects was reduced by 3 days treatmentwith aspirin 2 g/day, but there was no effect ongastrin secretion. These authors also showed thatthe aspirin treatment increased the productionof IL-1b, IL-6, and IL-8 but not of TNF-a orinterferon (IFN)-a, coincident with the develop-ment of an apparent gastritis.

It appears therefore, that NSAIDs vary in theireffects on acid secretion in H. pylori negativenormal subjects depending on the drug, duration oftreatment, and nature of the stimulus for acidsecretion. The drug-associated changes in patternsof pro-inflammatory cytokine production mayinfluence acid secretory responses in part from theeffects of IL-1 and possibly other pro-inflammatorycytokines stimulating production of PGE2. Thiswould be expected to have a negative effect on acidsecretion (Hawkey and Walt, 1986; Bennet et al.,

1973). There may also be influences of stimulatedPGE2 production enhancing bicarbonate secretion(Hogan et al., 1994a, b).

8.2. Acid secretion and gastrin productionin rheumatic patients

When considering the issue of acid secretion inpatients with rheumatic diseases receiving NSAIDsfor long periods of time more complex factors mayprevail. It is, for instance, well known that mucosaladaptation occurs to long-term (3–4wk) afterintake of several NSAIDs manifest by a reduc-tion in lesions or ulcers observed by endoscopy(Graham et al., 1988a; Shorrock and Rees, 1989,1992; Shorrock et al., 1990; Shorrock, 1993,Konturek et al., 1994). The clinical relevance ofthe adaptive response is controversial (Shorrock,1993) but may be related to acid secretion beingsomehow inhibited. It is also possible that mucosalregenerative responses may also be affected bycontinuous intake of NSAIDs. There have been anumber of reports that acid secretion is subnormalin certain patients with arthritic diseases (Edstrom,1939; Henriksson et al., 1986; DeWitte et al., 1979;DiMario et al., 1989; Kanerud et al., 1991) andsome patients, especially the elderly, are achlor-hydric. This situation is, however, complicated bythe observation that plasma gastrin levels areincreased in patients with RA and Sjoegren’sdisease (DeWitte et al., 1979; DiMario et al.,1989; Kanerud et al., 1991; Buchanan et al., 1996;Maury et al., 1985; Rooney et al., 1973, 1976a, b).

The question to be considered, therefore, is thatthe gastrin receptor-mediated control of acidsecretion is somehow affected in the patientsperhaps as a result of downregulation of gastrinreceptors, post-receptor events from the influenceof the disease process. Rowden et al. (1978)postulated that hypergastrinaemia may be asso-ciated with RA, so it is possible this state could beintrinsic to RA. Alternatively, it may be a propertyof the drugs used to treat RA, as the long-term useof anti-rheumatic agents such as auranofin maydifferentially stimulate COX-1-derived mucosalprotective PGs (Yamada et al., 1997), so directly


inhibiting acid secretion via PGE2 receptor activa-tion on parietal cells.

8.3. Why give anti-secretory agentsto rheumatic patients?

Irrespective of the responses to gastrin in rheu-matic patients it is clear that there is reduced acidsecretion in certain patients. This raises the issuewhether anti-ulcer agents that exert their actionsby inhibition of acid secretion should be employedin the prophylaxis of NSAID-associated upper GIulceration and haemorrhage in ‘at risk’ indivi-duals, especially the elderly who often may havesubnormal acid secretion or be achlorhydric?

There are important consequences from the useof anti-secretory agents in the elderly rheumaticpatient. Thus, there may be risks from persistentachlorhydria or subnormal secretion in the elderlyrheumatic patient combined with the effect of ananti-secretory drug that may create conditions forbacterial overgrowth in the stomach, a factor thatis known to promote the development of gastriccancers (Stockbruegger, 1985; Bartsch et al., 1992;Houben and Stockbruegger, 1995). The lack ofacid in the stomach may result in suboptimal orsubnormal pepsin activity and this may lower theprotein nutritional status in the elderly. Finally, itis known that achlorhydria or suppressed acidproduction does not result in reduced propensityfor aspirin-induced GI ulcers (Jazewsky et al.,1989; Janssen et al., 1994), so the benefits ofcreating an anacidic state to reduce the risk of ulcerdevelopment would appear to be very limited.

Of course, it is possible that PPIs such asomeprazole could have effects in controlling thegrowth of H. pylori (Hunt and Tytgat, 1996). Inthose elderly rheumatic patients given this drug toprevent ulcers from the NSAIDs, this may beconsidered a beneficial effect. However, the readyavailability of non-invasive tests for H. pylori

enables the presence of an infection from thesebacteria to be established in the first instance. Thus,good practice would indicate that H. pylori infec-tion should be ruled out or treated as the case maybe. Likewise, in those patients with hypersecretionthe use of anti-secretory agents would, of course, be

justified. Prior investigation is, therefore, importantto establish if the patient with musculoskeletaldisease has H. pylori infection or abnormal acidsecretion before being continued on NSAIDs.

8.4. Risk factors

Several international experts over the years haveattempted to identify the RR of toxicity to theGI tract by analgesics and NSAIDs, in casecontrol and cohort studies (Henry et al., 1996;Garcia-Rodriguez and Hernandez-Diaz, 2001a, b).Unfortunately even the best of these studies stillsuffer from problems of population inclusion bias,and case interpretation and selection bias (Henryet al., 1996).

The risks for a serious GI event are mostcommon in the first 3 months and the majority ofpatients who have a serious GI event are asympto-matic prior to the event. The risk factors forNSAID-associated ulcer complications are welldocumented and include: past complicated ulcer,OR 13.5; multiple NSAIDs including ASA, OR9.0; high-dose NSAID, OR 7.0; anti-coagulantuse, OR 6.4; past uncomplicated ulcer, OR 6.1; age>70 years, OR 5.8; and steroid use, OR 2.2(Gabriel et al., 1991; Garcia Rodrguez and Jick,1994; Silverstein et al., 1995). Thomas et al. (2002)showed that OTC NSAIDs were a significant causeof GI side effects with up to 30% of people havinga GI problem in the previous 30 days andindividual events resulting in GI bleed or ulcer1%: nausea and vomiting, bloating, heartburn,cramping pain in 2–5%, and constipation and/ordiarrhoea in up to 10%. The consumption ofalcohol while taking NSAIDs can double the riskof GI bleeding, and this increases to a fivefoldincrease for people taking OTC drugs (Peura et al.,1997).

8.5. Agents used to control acid

8.5.1. AntacidsAntacids such as calcium carbonate, aluminium,and magnesium hydroxides and combinationsthereof provide a degree of symptomatic relief for


mild dyspepsia and acid reflux by elevating thegastric pH, but are not of value in the prevention orcure of significant GI adverse events.

8.5.2. H2-receptor antagonistsThe H2RAs are competitive inhibitors of histamineat the parietal cell H2 receptor. They block theaction of histamine released from enterochromaffincells, with resultant reduction in acid secretion, andin addition they reduce the promotion of acidsecretion by gastrin and acetylcholine. Over the last30 years, H2-receptor anatagonists have beentraditionally used for the treatment of dyspepsia,acid reflux, and PUD. The most commonly usedare cimetidine, ranitidine, famotidine, and nizati-dine. All are relatively well tolerated but cimetidinewhich has a significant inhibition of the cyto-chrome P450 enzymes can result in increase inplasma and tissue levels of concomitantly useddrugs such as warfarin, Beta blockers, tricyclicanti-depressants, calcium channel blockers, sulpho-nylureas, metronidazole, and alcohol. Cimetidineuse is associated with headache, constipation,diarrhoea, hypotension, dizziness, and is also asso-ciated with gynaecomastia, loss of libido, andimpotence in males. Rostom et al. (2002) showedthat in a pooled analysis of five randomisedcontrolled trials of H2RAs that standard dosesreduced the risk of duodenal ulcers, but not gastriculcers. In three randomised trials it was shown thatdouble the dose of H2RAs were effective againstNSAID-related gastric and duodenal ulcers withthe greatest benefit or effect in patients with priorhistory of ulcers (Hudson et al., 1997; ten Woldeet al., 1996; Taha et al., 1996). Analysis of the studyby Hudson et al. (1997) showed that the majoreffect was in patients with H. pylori infection.

Leonard et al. (2007) in an analysis of 12 studiesevaluating 2948 patients with C. difficile identifiedan increased risk of taking anti-secretory therapyin those infected with C. difficile. In six studieson Salmonella, Campylobacter, and other entericinfections were identified in 11,280 patients, againidentified that there was an increased risk of takingacid suppression in those with enteric infections(OR 2.55; 95% CI: 1.53–4.26).

8.5.3. MisoprostolMisoprostol is a synthetic PGE1 analogue whichhas been shown to be of benefit in the prevention ofNSAID-induced gastric ulceration (Silversteinet al., 1995; Graham et al., 1988b) at a dose of200mg qid. It has also been manufactured as acombined product with the NSAID Diclofenac.While it has been shown to be useful in theprevention of gastric ulceration (Silverstein et al.,1995; Hooper et al., 2004; Elliott et al., 2006), itsuse has been greatly limited by patient intoleranceto the proven effective anti-gastric ulcer dosage of800mg/day (Silverstein et al., 1995). Up to 13% ofpatients can develop diarrhoea often in conjunctionwith bloating, cramping, and flatulence. Thisadverse effect can last for up to 8 days with 2%or greater of patients discontinuing the drug. It hasbeen established in a meta-analysis of 33 rando-mised controlled trials that misoprostol, H2RAs,and PPIs reduce the incidence of NSAID-relatedgastrodudenal ulcers (Rostom et al., 2002). How-ever, only misoprostol at 200mg qid dosage hasbeen shown to reduce the NSAID-related ulcercomplications with a 40% reduction (Silversteinet al., 1995). However, the median dose toleratedwas only 600mg/day. Although misoprostol 200mgqid has been shown to be superior to lansoprazole15 and 30mg/day, for the prevention of gastro-duodenal ulcer at 12wk, with ulcer rates of 15, 43,47 per 100 patients for misoprostol, lansoprazole15 and 30mg respectively, the patients on mis-oprostol had a much higher withdrawal rate(Graham et al., 2002).

A theoretical point of concern for long-term useof PG analogues is the potential for local andmetastatic spread of cancer cells and recent workhas shown that PGE2 promotes tumour progres-sion by inducing myeloid-derived suppressor cells(Sinha et al., 2007).

8.5.4. Proton-pump inhibitorsPPIs act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme sys-tem (H+/K+ ATP-ase) known as the proton-pump in the gastric parietal cell. The PPIs aremuch more effective than the H2RAs and reduce


acid secretion in the gastric lumen by 99%, withresultant promotion of ulcer healing and reductionin acid-related symptoms. The commonly usedPPIs are omeprazole, lansoprazole, esomeprazole(the active enanatyiomer of omeprazole), panto-prazole, and rabeprazole (Peura et al., 2007). ThePPIs are generally well absorbed with a slightreduction in absorption rate with food. Theplasma half life is approximately 0.5–2 h, but theacid secretion inhibition can be up to 2–3 daysbecause of the irreversible nature of the drugbinding to the proton-pump. The PPIs aregenerally well tolerated with few side effects. Theseinclude headache, nausea, diarrhoea, abdominalpain, constipation, and bloating. Prolonged usecan result in decrease in vitamin B12 absorptionand elemental calcium absorption with concernsregarding the development of osteoporosis andrisk of hip fracture (Yang et al., 2006).

The PPIs are effective and recommended for therelief of upper GI symptoms (Peura et al., 2007)which are common in patients using NSAIDsincluding selective COX-2 inhibitors and may beacid related. The use of the PPI esomeprazole hasbeen assessed for the treatment of upper GIsymptoms in a total of 794 and 848 continuousNSAID users, free of gastroduodenal ulcers,erosive esophagitis, and H. pylori, enrolled intotwo identical, 4 wk, multinational, multicenterdouble-blind studies [Nexium Anti-inflammatorySymptom Amelioration (NASA1), Symptom Pre-vention by Acid Control with Esomeprazole(SPACE1)] (Hawkey et al., 2005). The 608 and556 patients were randomised to receive 4wk ofesomeprazole 20mg, or 40mg, or placebo oncedaily. The primary variable was the patient-reported change in the upper GI symptom (pain,discomfort, or burning in the upper abdomen)score on a 7-graded severity scale (0–6) from the 7days prior to treatment to the last 7 days in thestudy. The results showed that esomeprazole wasassociated with highly significant symptomimprovement compared to placebo. Symptomimprovements were 2.30 mean (SD 1.63) onesomeprazole 20mg and 2.03 (1.56) on esomepra-zole 40mg versus 1.64 (1.57) on placebo in NASA1and 2.17 (1.34) and 2.12 (1.48) versus 1.56 (1.26),

respectively, in SPACE1 (all placebo comparisonsat least po0.001). Esomeprazole-improved symp-toms in patients taking selective COX-2 inhibitors,with changes of 2.21 (1.46) and 1.92 (1.38) versus1.64 (1.46) in NASA1 and 2.20 (1.26) and 2.24(1.62) versus 1.58 (1.37) in SPACE1 (all placebocomparisons at least po0.05), as well as those onnon-selective NSAIDs. Esomeprazole was welltolerated and associated with significant improve-ments in QoL assessments. Thus, it was concludedthat the PPI esomeprazole 20 and 40mg improvedupper GI symptoms associated with continuous,daily NSAID therapy, including selective COX-2inhibitors.

In an extension of the above 4wk studies,Hawkey et al. (2007a, b) assessed the effects ofesomeprazole for maintenance of long-term relieffrom NSAIDs and selective COX-2 inhibitors,induced upper GI symptoms. Six hundred and tenpatients with a chronic musculoskeletal disorderwho required NSAIDs and who had achieved reliefof NSAID-associated symptoms of pain, discom-fort, or burning in the upper abdomen during thetwo previous studies (Hawkey et al., 2005) wereenrolled and randomly assigned into two identical,multicentre, parallel-group, placebo-controlled stu-dies of esomeprazole 20 or 40mg treatment(NASA2 and SPACE2 studies; ClinicalTrials.govidentifiers NCT00241514 and NCT00241553,respectively) performed at various rheumatology,gastroenterology, and primary care clinics. Fourhundred and twenty-six patients completed the6-month treatment period. The primary measurewas the proportion of patients with relapse of upperGI symptoms, recorded in daily diary cards, after 6months. Relapse was defined as moderate-to-severeupper GI symptoms (a score of more than or equalto 3 on a 7-grade scale) for 3 days or more in any7-day period. Esomeprazole was significantly moreeffective than placebo in maintaining relief of upperGI symptoms throughout 6 months of treatment.Life-table estimates (95% CIs) of the proportion ofpatients with relapse at 6 months (pooled popula-tion) were placebo, 39.1% (32.2–46.0%); esome-prazole 20mg, 29.3% (22.3–36.2%) (p=0.006versus placebo); and esomeprazole 40mg, 26.1%(19.4–32.9%) (p=0.001 versus placebo). Patients


on either NSAIDs or selective COX-2 inhibitorsappeared to benefit. The frequency of adverseevents was similar in the three groups. Thus, it wasconcluded that the PPI, esomeprazole maintainsrelief of NSAID-associated upper GI symptoms inpatients taking continuous tNSAIDs or selectiveCOX-2 inhibitors. The same group of investigators(Hawkey et al., 2007a, b) assessed the efficacy ofesomeprazole 20 and 40mg for resolution ofheartburn and acid regurgitation in patients recei-ving continuous NSAIDs. They studied a post hocanalysis of five clinical trials. Two identicallydesigned, placebo-controlled, 4wk studies(NASA1, SPACE1) enrolled non-ulcer, NSAIDs-treated patients with upper abdominal pain, dis-comfort or burning. PLUTO and VENUS wereidentically designed, placebo-controlled, 6-monthstudies that enrolled patients at risk of NSAIDs-induced ulcers. Study 285 was an 8wk comparativestudy with ranitidine (300mg/day) in patientswith NSAIDs-induced gastric ulcers. Resolutionof investigator-assessed heartburn and acid regur-gitation was defined as symptom severity of ‘none’in the last 7 days. The results showed that in theNASA1/SPACE1 trials, heartburn resolved in 61and 62% of patients taking esomeprazole 20 and40mg, respectively (versus 36% on placebo,po0.001), and acid regurgitation resolved in 65 and67% (versus 48%, po0.001). Resolution of bothsymptoms was greater with esomeprazole than withplacebo in the PLUTO/VENUS studies (pr0.001).Resolution of both symptoms was greater for eso-meprazole 20mg versus ranitidine 300mg (po0.05),study 285. It was concluded that while heartburnand regurgitation are common in patients takingNSAIDs, the PPI esomeprazole is effective incontrol of these symptoms.

Scheiman et al. (2006) assessed the PPI esome-prazole for ulcer prevention in at-risk patients (Z60years and/or ulcer history) taking NSAIDs, inclu-ding COX-2 inhibitors in two similar double-blind,placebo-controlled, randomised, multicenter stu-dies; VENUS (United States) and PLUTO (multi-national). A total of 844 and 585 patients requiringdaily NSAIDs, including COX-2 inhibitors, wererandomised to receive esomeprazole (20 or 40mg)or placebo, daily for 6 months. It was identified

that in the VENUS Study, the life-table estimatedproportion of patients who developed ulcers over6 months (primary variable, intent-to-treat popu-lation) was 20.4% on placebo, 5.3% on esomepra-zole 20mg (po0.001), and 4.7% on esomeprazole40mg (po0.0001). In the PLUTO Study, the valueswere 12.3% on placebo, 5.2% with esomeprazole20mg (p=0.018), and 4.4% with esomeprazole40mg (p=0.007). These significant reductionswere observed for users of both non-selectiveNSAIDs and COX-2 inhibitors. Pooled ulcer ratesfor patients using COX-2 inhibitors (n=400) were16.5% on placebo, 0.9% on esomeprazole 20mg(po0.001), and 4.1% on esomeprazole 40mg(p=0.002). Esomeprazole was well tolerated andassociated with better symptom control thanplacebo. They concluded that in at-risk patients,esomeprazole was effective in preventing ulcers inlong-term users of NSAIDs including selectiveCOX-2 inhibitors.

Laheij et al. (2004) reported on the increasedincidence of community-acquired pneumoniathought to be associated with impaired eliminationof pathogenic organisms due to the relativeachlorhydria, and recommeded that high-riskpneumonia patients only receive short courses oflow-dose PPIs.

Leonard et al. (2007) in an analysis of 12 studiesevaluating 2948 patients with C. difficile identifiedan increased risk of taking anti-secretory therapyin those infected with C. difficile (pooled OR 1.94;95% CI: 1.37–2.75). This association was greaterfor PPI use (OR 1.96; 95% CI: 1.28–3.00) compa-red with H2RAs use (OR 1.40; 95% CI: 0.85–2.29).A total of six studies evaluated Salmonella,Campylobacter, and other enteric infections in11,280 patients. Again, it was identified that therewas an increased risk of taking acid suppressionin those with enteric infections (OR 2.55; 95%CI: 1.53–4.26). The association was greater for PPIuse (OR 3.33; 95% CI: 1.84–6.02) compared withH2RAs use (OR 2.03; 95% CI: 1.05–3.92). It wastherefore concluded that there is an associationbetween acid suppression and an increased risk ofenteric infection. Further studies on patients takinglong-term acid suppression are needed to establishwhether this association is causal.


8.6. Evaluation of relative benefits ofanti-secretory therapies

Hooper and associates (2004) have attempted todetermine if there is an effective measure to protectthe GI tract in patients who require NSAIDs. Theyassessed the effectiveness of five gastroprotectivestrategies for people taking NSAIDs: H2RAs plustNSAIDs; PPIs plus tNSAIDs; misoprostol plustNSAIDs; COX-2 selective NSAIDs (etodolac,meloxicam, nabumetone, and nimesulide); or COX-2-specific NSAIDs in reducing serious GI compli-cations, symptomatic ulcers, serious CV or renaldisease, and deaths, and improving QoL. Theyreviewed 112 randomised controlled trials (74,666participants), and identified 138 deaths and 248serious GI events overall. On comparing gastro-protective strategies versus placebo, they found noevidence of effectiveness of H2RAs for any primaryoutcomes. They stated that PPIs might reducethe risk of symptomatic ulcers (RR 0.09; 95% CI:0.02–0.47) and that misoprostol reduced the risk ofserious GI complications (0.57, 0.36–0.91) andsymptomatic ulcers (0.36, 0.20–0.67). For theCOX-2-selective NSAIDs there was a reduced riskof symptomatic ulcers (0.41, 0.26–0.65) and simi-larly the COX-2-specific NSAIDs reduced the riskof symptomatic ulcers (0.49, 0.38–0.62) and possi-bly serious GI complications (0.55, 0.38–0.80). Allstrategies except COX-2 selectives reduced the riskof endoscopic ulcers (at least 3mm in diameter).The authors concluded that misoprostol, COX-2-specific and -selective NSAIDs, and probably PPIssignificantly reduce the risk of symptomatic ulcers,and misoprostol and probably COX-2 specificssignificantly reduce the risk of serious GI complica-tions, but warned that data quality was low. It wasfelt that more data on H2RAs and PPIs wereneeded, in addition to better reporting of rare butimportant outcomes. Effective misoprostol use islimited by diarrhoea, cramping, and bloatingintolerance to the recommended dosage of 800mgod. Subsequent studies have shown that PPIs areeffective at significantly reducing the GI complica-tions of tNSAIDs and COX-2-selective NSAIDsfor symptomatic relief and prevention of symptomsand prevention of gastric ulceration (Hawkey et al.,

2005, 2007a, b; Scheiman et al., 2006). Cost oftherapy is of great importance to financial governingbodies and numerous detailed reports address thispoint. Elliott and colleagues (2006) in their costutility analysis suggest that a tNSAID plus anH2RA was more cost effective than a tNSAIDalone and equally effective and less costly thanselective COX-2 inhibitors and Scheiman andFendrick (2007) stated that it may not be feasibleto recommend the ‘safest’ regime in every circum-stance, but cautioned that cost is ultimately assessedbased on the patient’s underlying risk. The questionof CV risk remains as to whether COX-2-selective drugs should be used (Kean andBuchanan, 2005), and notwithstanding the debatethat there may or may not be a CV risk fromtNSAIDs (McGettigan and Henry, 2006), thefindings are that the risk from tNSAIDs is less.Thus, on the balance as to whether to risk majororgan damage to the stomach or the CV andcerebral system, it is our opinion that use of a PPIwith a tNSAID is the most reasonable strategy toadopt in the prevention of GI symptoms andulceration in patients who require NSAID therapy.

8.7. Modification of analgesics to preventgastric complications

Changes of anti-rheumatic drug formulations suchas the use of topicals, injections, oral suspensions,suppositories and various forms of enteric coating,and attempts at slow-release formulations, all havehad some degree of merit but problems of effective-ness, ease of patient use, and ultimate reduction inGI toxicity result in a need to continue to seekalternative strategies to effectively treat the pain inpatients with musculoskeletal disease while avoidingor minimising gastric and other major organ toxicity.

Some of the issues concerning the developmentof newer NSAIDs and anti-rheumatic drugs havebeen explored elsewhere (Rainsford, 2006, 2007).Many of the newer developments are focussed onachieving disease modification as well as pain reliefin RA (Rainsford, 2007). With increasing focus ondrugs directed at disease modification there may be


coincidently sparing of the GI protective mecha-nisms from the actions of these drugs so leading toreduced risk of GI events. We await detailedstudies in rheumatic patients with these neweragents and especially long-term clinico-epidemio-logical investigations directed at establishing theirrelative safety compared with existing NSAIDs andanti-rheumatic drugs.

Current alternatives to NSAIDs for painrelief include non-narcotic analgesics, acet-aminophen (paracetamol), dipyrone or thenarcotics (codeine, dextropropoxyphene,fentanyl). The use of acetaminophen forpain relief in osteoarthritis A has beenstated in some studies to be equivalent tothat of NSAIDs (Brandt, 1993a, b; Brandtand Bradley, 1993) while in others theresults are equivocal and the issue is highlydebatable (Buchanan and Kean, 2002;Kean and Buchanan, 2005). However, forepisodes of local inflammatory ‘‘flare’’,acetaminophen would probably have limi-ted effects (Dieppe et al., 1993a, b, c;Williams et al., 1993). More recently theweak narcotics (e.g. tramadol, dextro-propoxyphene, fentanyl) have been shownto be effective in controlling rheumatic andother chronic non-cancer pain states(Buchanan and Kean, 2002; Ackermanet al., 2003; Schnitzer et al., 2000). Thesetherapeutic alternatives to NSAIDs may beusefully employed in rheumatic patientsalthough appropriate caution must betaken in the elderly and in patients withconcomitant disease.

The popular use of natural products with claimedbenefits for relieving symptoms of pain and inflam-mation but with possibly low GI adverse effects ismuch debated. Some of these preparations (e.g.St. John’s Wort) have attracted much attention fortheir potential to cause interactions with drugmetabolising systems and thus affect the safety ofsome conventional drugs that may necessarily betaken by rheumatic patients. Other natural

products may be safer but they need investigationto establish their relative safety.

In an attempt to facilitate a uniform approach tothe clinical management of arthritis, academicadvisory bodies, such as the British Society forRheumatology with the Royal College of Physi-cians (UK) and the American College of Rheuma-tology (ACR), developed treatment guidelinesaimed at reducing toxicity while maintainingeffectiveness. One such strategy was used for themanagement of OA (Guidelines, 1993; Hochberget al., 1995a, b). While the UK and the ACRguidelines had good attributes, both advocatedthe use of paracetamol as the drug of first choice inthe treatment of OA based on a study by Bradleyet al. (1991) which had significant methodologicaland reporting bias. It was assumed that parace-tamol would be less toxic on the GI tract butwould provide good analgesia based on the resultsof the Bradley Study. However, it should be notedthat OA is often a painful inflammatory condition,and should therefore respond better to a NSAID(Hungin and Kean, 2001). Although the UK andACR guidelines for the management of OA werewell intentioned, the literature evidence for para-cetamol as a first drug of choice is weak (Hunginand Kean, 2001; Kean and Buchanan, 2005)especially since Bradley et al. (1992b) subsequentlyshowed that it was the anti-inflammatory activityof the S enantiomer of ibuprofen that was theactive compound responsible for the clinical bene-fit in OA of the hip and knee. Neverthelessliterature citations and guidelines (Bradley et al.,1992a; Brandt, 1993a, b; Dieppe, 1993; Dieppeet al., 1993a, b, c; Williams et al., 1993; Creamer,2000; Tannenbaum et al., 1996) with respect tothe first line treatment benefits of paracetamol inOA appear to have influenced a large numberof clinicians around the world into withholding ormodifying the use of NSAIDs in the managementof OA (Won et al., 2004), Won and colleaguesstudied the use of analgesics in 21,380 residentsover age 65 years, in US nursing homes and persis-tent pain was identified in 49% of residents. Thepersistent pain was prevalent in 63% who had ahistory of fracture and 64% who had a history ofsurgery in the last 6 months. One quarter receivedno analgesics. It must be argued that ACR


guidelines of 1995 influenced this practice? It is ofinterest that the most common analgesic adminis-tered to these nursing home patients was parace-tamol (37.2%), followed by propoxyphene (18.2%),hydrocodone (6.8%), and tramadol (5.4%) (Won etal., 2004; Kean and Buchanan, 2005).

In addition, the ACR guidelines also advocatedthe use of short half life NSAIDs in preference tolong half life NSAIDs despite the fact that there isno evidence that the phamacokinetic short half lifeproperty correlates with less toxicity (Hungin andKean, 2001). It is most likely that the ACRcommittee (not properly informed) (Hochberget al., 1995a, b) probably intended there commentsto more correctly refer to rate of plasma or tissueclearance of the drugs, but this also does notcorrelate with reduction in toxicity. The ARAMISdata on toxicity in rheumatoid disease indicatedthat the short half life, rapid clearance drugketoprofen ranked highly for GI toxicity (Frieset al., 1991), and the study by Cryer and Feldman(1998) on gastric mucosal PG inhibition indicatedthat the short half life, rapid clearance drugibuprofen was a potent inhibitor of gastric PGs.

Subsequent studies have shown that paraceta-mol greater than 2000mg od has a significant GItoxicity profile. Garcia-Rodriguez and Hernandezstudied the association between paracetamol andNSAIDs and the risk of upper GI bleed/perfora-tion in a population-based cohort of 958,397persons in the United Kingdom between 1993 and1998. The case-control analysis included 2105 casesand 11,500 controls. RR estimates were adjustedfor several factors known to be associated withupper GI bleed/perforation. Compared with non-users, the users of paracetamol at doses less than2000mg did not have an increased risk of upper GIcomplications. However, the adjusted RR forparacetamol at doses greater than 2000mg thatwere advocated by the ACR Guidelines commi-ttee (Hochberg et al., 1995a, b) was 3.6 (95%CI: 2.6–5.1). The corresponding RRs for low/medium and high doses of NSAIDs were 2.4 (95%CI: 1.9–3.1) and 4.9 (95% CI: 4.1–5.8). The RRwas 3.1 (95% CI: 2.5, 3.8) for short plasma half-life, NSAIDs, 4.5 (95% CI: 3.5–5.9) for longhalf-life, NSAIDs, and 5.4 (95% CI: 4.0–7.1) forslow-release formulations of NSAIDs. Thus, not

only does paracetamol at greater than 2000mg odhave a significant GI toxicity profile, but also havelower analgesic efficacy than NSAIDs, and is thusnot an effective alternative to NSAIDs in any ofthe inflammatory arthritides (Hungin and Kean,2001). Thus, recommendations on the use of para-cetamol at 200mg od or more as an alternative toNSAIDs was an incorrectly conceived concept(Hochberg et al., 1995a, b) and would not theore-tically result in reduced toxicity to the GI tract(Kean and Buchanan, 2005).

8.7.1. COXIBsThe rationale for the use of coxibs has beendiscussed in detail above (see Section 4) and isbriefly summarised in this section on Strategies.

The COX-2 selective inhibitors arrived on theclinical scene with great promise but riding ashallow ‘evidence-based’ wave of clinical abstractsthat ultimately would swallow its advocates.Although there has been a trend to increase usageof COX-2 selective inhibitors based on theirpresumed low GI toxicity, the potential for CVside effects, and the concern that they may not haveless GI toxicity (Simon et al., 2002; Strand andHochberg, 2003; Juni et al., 2002), makes there-evaluation of the use of the tNSAIDs a reason-able consideration.

Laine et al. (2007) reported that the selectiveCOX-2 inhibitor etoricoxib (60 or 90mg od)use was associated with less upper GI clinicalevents than patients who received diclofenac(150mg od) but that this decrease was related touncomplicated events while the risk of complicatedevents was the same in the two groups (Laine et al.,2007).

Juni et al. (2002), in an article in the British

Medical Journal, reviewed reports published forthe so-called CLASS Study which comparedcelecoxib 800mg/day with ibuprofen 2400mg/dayand diclofenac 150mg/day in OA or RA. Theseauthors criticised that only the first 6 months ofthe trial was published, despite the fact that somepatients received treatment for up to 12–15months. While the results of the first 6 monthsdata showed that celecoxib may have less GIadverse reactions than the ibuprofen and thediclofenac, the authors concluded that information


obtained after the 6 months showed that there wasno difference in the incidence of adverse effectsamongst the three drugs, celecoxib, ibuprofen,and diclofenac. They concluded that there maynot be an increased benefit to the use of thisCOX-2-selective NSAID over tNSAIDs, if it hasno advantage in GI protection.

COX-2 inhibitors while having shown somereduction in incidence of upper GI ulcers andbleeding (Hooper et al., 2004) this has not been thefindings of all studies and Laporte et al. (2004) in astudy of upper GI bleeding from a gastric orduodenal ulcer (2813 cases versus 7193 matchedcontrols) showed that greater COX-2 selectiveinhibition did not confer less risk of upper GIbleeding. COX-2 selective inhibitors were notoriginally claimed to reduce symptomatic sideeffects frequently seen with NSAIDs, e.g. dyspep-sia, epigastric pain, nausea. These adverse reactionsare the most frequent reasons for cessation ofNSAID therapy. The question whether or not thehighly selective COX-2 inhibitors (coxibs) havereduced incidence of dyspepsia have yielded mixedresults. In general, dyspepsia is still a frequentoccurrence in patients taking COX-2-selectiveinhibitors and there is evidence that patients stillneed therapy with PPIs or other anti-secretoryagents (Hawkey et al., 2005, 2007a, b).

9. Discussion and conclusions

Clearly, there is a large population worldwide withmusculoskeletal conditions, which requires analge-sic, NSAIDs, and/or steroid treatment for musculo-skeletal disorders, but a serious impairment in QoLand potential for serious GI adverse effects resultsin a significant limitation in the effective manage-ment of these patients. Basic science and clinicalstudies have attempted to establish cause and effectof the analgesics, NSAIDs, and steroids in theiraction on the GI tract. Numerous strategies havebeen attempted to counter the adverse effects of theanalgesics, NSAIDs, and steroids. These strategieshave included changes in drug formulations androute of administration, and the use of pharmaco-logical agents to protect or heal the GI tract. Some

of these interventions may prove to result in feweradverse consequences for the GI tract in patientswith RA and the other arthritides. It is clear thatthe first-generation coxibs, when taken long-term,have proven to have had limited benefits insignificantly reducing the serious GI complicationsnormally seen with tNSAIDs in patients withmusculoskeletal disorders. Whether the newersecond-generation coxibs (etoricoxib, lumiracoxib)will have any significant benefits in the long-term, isan open question until more experience has beengained from extensive use of these drugs. There areclearly cost issues and problems with increased risksof GI events that have to be faced when using thecoxibs with other drugs, especially when low-doseaspirin is required. There may be small benefits tothe GI tract from use of coxibs in the short-term,but for the patient with RA or other chronicmusculoskeletal disorders, because of their require-ment for long-term pain relief, a sustained GIbenefit may not be achieved by the coxibs over theuse of tNSAIDs. As stated above, the issue of CVrisk remains as to whether coxibs should be used atall (Kean and Buchanan, 2005), and notwithstand-ing the debate that there may or may not be a CVrisk from tNSAIDs (McGettigan and Henry, 2006),the findings are that the overall risk to general wellbeing from tNSAIDs is less. Thus on balance, withrespect to the question whether one should riskmajor organ damage to the GI tract, or the CV andcerebral system, it is our opinion that use of a PPIwith a tNSAID is the most reasonable strategy toadopt in patients with musculoskeletal disorderswho require NSAID therapy (Kean and Buchanan,2005).

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Index

A

A77-1726 112

Abdomen arteriography 92

Abdominal films. See Plain abdominal films

Abdominal pain 32–34

treatment 32

A1-B8-DRB1*03 126

A4b1 integrin 4

A4b7 integrin 4

Absolute risk reduction (ARR) 252

Acetaminophen 244, 264

Acid secretion

effects of NSAIDs and H. pylori 257–258

in rheumatic patients 258–259

stimulation of 257

Acid-secretory inhibitors, use of 257

Adaptive immune responses 6

Adrenocortical failure, primary 158

Adventitia

aortic 88

dendritic cells in 86

mononuclear infiltration of 85

and vasa vasorum 85

Adverse drug reactions (ADRs) 253

GI symptomatic 255

Ag receptors 86

AIRE1 gene 158

Air esophagogram 103

Alanine 130–131

effect of CTLA-4 gene on 125

Alcohol dehydrogenase, antibodies to 161

Alemtuzumab (CAMPATH 1-H) 92

Allogeneic transplantation 164

Alopecia universalis 67

Alpha/beta T cell receptors 159, 161

Amaurosis fugax 39

American College of Gastroenterology 52, 55

American College of Rheumatology (ACR) 86, 112, 264

Amino acid sequences 130

homologous 123

Amyloidosis 84, 110

Anaemia 246

Analgesia 111

Analgesic agents 244–245

Analgesic and anti-inflammatory medication use

244–246

Analgesics, modification of 263–265

Anal sphincter 59

ANCA. See Anti-neutrophil cytoplasm antibody

(ANCA)

Anchylosing spondylitis. See Autoimmune diseases

Aneurysms 85

abdominal 87

angiographic finding of 89

necrotizing inflammation effect on 89

thoracic 87

Angiography 83

CT 87

Angioplasty, mesenteric 34

Animal experiments 164

Ankylosing spondilitis (AS) 218, 249

Antacids 105, 259–260

Anti-actin reactivity 157

Antiaorta antibodies 85

Antiapoptotic protein bcl-2 144

Anti-b2-glycoprotein-I antibodies 39Antibiotic therapy 92, 95

Antibodies 9, 132, 123

to asialoglycoprotein receptor (anti-ASGPR)

238–239

in autoimmune liver diseases 236–240

to CBir1 (anti-CBir1 flagellin) 231

in celiac disease 234–236

to glycoprotein (gp210) 239

in inflammatory bowel diseases 231–233

to liver cytosol type 1 (anti-LC1) 238

to liver–kidney microsome (Anti–LKM1) 237

to nuclear pore complex antigens 239

to soluble liver antigen/liver pancreas antigen

(anti-SLA/LP) 238

Anticardiolipin Ab. See Anticardiolipin autoantibodies

Anticardiolipin antibodies (aCL) 39, 42, 44–45

Anticardiolipin autoantibodies 203

Anti-CCP antibodies 213

Anti-CD20 therapy (rituximab) 92

Anticoagulants 40

Anticoagulation 34

Anti-dsDNA 213–214

Anti-ENA 209

Anti-endomysial antibodies (EMA) 234

Antiendothelial cell antibodies 85

Anti-fibrogenic agents 180–181

Antigen

binding groove 124, 132

of the class II MHC 130, 131

individual’s response to 121

presenting class II MHC 124, 125

presenting molecules 130, 131, 133

recognition sites 121

activation of multiple 132

disturbances in 122–124

Antigen formiminotransferase cyclodeaminase (FTCD)

238

Antigenic peptides 124

Antigenic stimulation 95

Antigen-presenting cells (APC) 124–125, 159, 164, 173

Antigens of HLA 171

Antigen 4 (VLA4) 4

Anti-gliadin antibodies (AGA) 234, 235

Anti-HBs antibodies (Ab) 192

Anti-HBV

Ab immune complexes 194

vaccination 195

Anti-HCV antibodies 210, 213

Anti-inflammatory drugs (NSAIDs)

GI toxicity of 250

global usage of 247

half life, short and long 265

long-term use of 246

pain management of 257

risk factors of 259

ulcerogenicity of 250–251

Anti-lamin B receptor antibodies 239

Anti-LC-1 157

Anti-liver cytosol type 1 (anti-LC-1) 156

Anti-liver/kidney microsomal type 1 antibody

(anti-LKM-1). See Anti-LKM-1

Anti- LKM-1 153, 157, 161, 209

charatcterization of 155

molecular target of 154

stains 157

vs. AMA 157

Anti-malarials 32

Antimitochondrial antibody (AMA) 67, 141, 156, 157,

209, 210, 236, 238

and mouse models 144

negative PBC vs. positive PBC 146

role in diagnosis of PBC 146

testing for 142

Antimyeloperoxidase (MPO) 232

Anti-myenteric neuronal antibodies 51

Anti-neutrophil cytoplasm antibody (ANCA) 91,

157

Antineutrophil cytoplasmic autoantibody

(ANCA)-associated small-vessel vasculitides

(ASV) 91–92

Anti-neutrophil-specific antibodies 170

Antinuclear 204

Anti-nuclear antibody (ANA) 143, 209, 210, 214,

236–237

autoantibodies to 155

detection of 156

seropositivity for 153

target antigens 157

Anti-OmpC (outer membrane porin from Escherichia

coli) 231

Anti-p62 antibodies 239

Antiphospholipid antibodies (aPL) 34, 35,

39–46

thrombosis due to 36–37

Anti-phospholipid syndrome (APS) 39–46

as autoantibody-mediated disease 39

catastrophic 214

classic vs. catastrophic 40

digestive involvement in 40

features 214

gastrointestinal involvement in 40–41

immunological markers in 214

infectious agents in 214

Anti-PM-Scl antibodies 64

Antiproteinase 3 (PR3) 232

Antirheumatic drug (DMARD) 111–112

Anti-RNP

antibodies 64

autoantibodies, positive 103

Anti-saccharomyces cerevisiae antibodies (ASCA)

231

Anti-secretory therapies 263

Anti-smooth muscle antibody (SMA) 154, 209

detection of 156, 157

titres of 156, 157

Anti-smooth muscle cell Ab 204

Anti-SSA/Ro antibodies, in MCTD 102

Anti-thymocyte globulin 92

Anti-thyroid Ab 203, 204

antibodies 210

Anti-tTG2 234, 235–236

Anti-tumor necrosis factor (TNF) agents 222

Anti-ulcer co-therapy 254

Anti-viral therapy 194, 215–217

Antrectomy 32, 56

Aorta abdominal tract 87, 88

Index278

APECED. See Autoimmune polyendocrinopathy-

candidiasis-ectodermal dystrophy (APECED)

Aperistalsis 104

APL 214

Apoptosis 6, 124, 127, 128

apoptotic cells 9

cellular 144

extrinsic pathway of 127

of liver cells 129

markers of ongoing 144

Apoptosisinducing factor (AIF) 127

Apoptotic pathways, perturbations in 127–128

ARAMIS data, on toxicity 265

Arginine (R) 130

Argon laser 55, 56

Argon plasma coagulation 56

Arterial

nodules 89

wall 86

Arteriosclerosis 83

Arteritic lesion

giant cell arteritis (GCA) 86

Takayasu’s 84

Arthritic disease, impact of 254–255

Arthritis Society 243

Ascending aorta 84, 85

Ascites 31, 35

Asherson’s syndrome 40

Asialoglycoprotein 161, 162

Aspartic acid (D) 131

Aspirin 34, 90, 245, 247

Aspirin therapy’s role in GI protective effects 111

Atherosclerosis 33, 34

accelerated 109

Atherosclerotic stenosis 19

Atrophy of villi 104

Atypical perinuclear antineutrophil cytoplasmic

antibodies (Atypical pANCA) 170–171, 238

Autoantibodies 7–9, 64, 155–157, 203–204, 209–210

anticardiolipin Ab of, IgG, IgM, and IgA 203

anti-gluten 66

antiliver– kidney–microsome (anti-LKM) Ab 204

antinuclear 204

antinucleosome Ab 204

anti-smooth muscle cell Ab 204

antithyroid Ab 204

cryoglobulin 204

detection 155–156

immunofluorescence of 155, 156

low titers of 213, 214

myositis-associated 64

myositis-specific 64

in PSC 170–171

rheumatoid factor 204

Autoantigen recognition 159

Autoimmune

arthropathies 246–247

cytopenias 219

diseases 84

hemolytic anemia (AHA) 219

injury 144

liver diseases 236–240

pancreatitis (AIP) 175

polyendocrine syndrome 1 158

polyendocrinopathy-candidiasis-ectodermal

dystrophy (APECED) 154, 158, 159

regulator (AIRE) gene 126

Autoimmune hepatitis (AIH)

and alleles encoding for lysine postion 132

cell-mediated cytotoxic response in 128

clinical features of 154

as a complexes trait disease 158

cytosolic enzymes role in 125

deficiencies in 128

development of 131

diagnosis of 154–157

effect of molecular mimicry 123

female predisposition for 129, 133

genetic risk factors for 121

genetics pathophysiology of 158–159

and HLA DRB1*04 133

and HLA DRB1*13 131

IAIHG scoring system for the diagnosis of 156

immune mechanisms of pathophysiology of 159–162

murine model of 123, 125

occurence of 125

persistence of activated lymphocytes expressing

CD95, 127

as polymorphism of the CTLA-4 gene 125

principal susceptibility alleles for 129, 130, 131

recurrence of 163

seronegative 157

treatment of 162–163

type 1 157

type 2 132, 157

Autoimmunity

adaptive immune responses 6

graft-versus-host disease 7

gut-associated 3–6

preventing 9

in PSC 169–170

and self-tolerance 6

Wiskott–Aldrich syndrome 8

Autologous DNA 9

Index 279

Autoreactive response 123

effect of counter-regulatory cells on 128

effect of signal pathways on 127

role of molecular mimicry in 123

Autoreactive T cells 161–162

Azathioprine 31, 32, 67, 162, 180. See also

Immunosuppressive agents

and corticosteroids 37

and prednisolone 36

side effects of 163

B

Bacterial

antigens 174, 232

cholangitis 178, 179

growth 174

overgrowth 174, 180

permeability increasing protein (BPI) 238

Bacterial overgrowth syndrome

diagnosis of 56–57

prothrombin time, in 57

serum carotene, in 56

symptoms 56

treatment 56

Balloon dilatation 178, 184

Barium

studies 15

swallow 52, 55

Barrett’s esophagus

and adenocarcinoma 52

guidelines, for management of 55

treatment 55

Bayesian approach 147

B-cells 4, 6

auto-reactive 7

B-cell-activating factor (BAFF) receptors 6

clonality 219

depletion treatment 91

early 93

expansion 93, 95

late 93

lymphoma 92, 93, 94, 95, 212, 220

lymphoproliferation, gastric 95

lymphoproliferation, non-neoplastic 92

self-reactive 6

tolerance mechanism for auto-reactive 6–7

Bcl-2 127

BCL-2-interacting mediator (BIM) 6–7

BCL-2 proteins 6–7

B7 expression 7

B2–glycoprotein-I (b2GPI) 39

Bile acid, excretion 181

Bile duct 142–144

cancer 183

loss 174, 180

Biliary

epithelial cells (BECs) 141, 143, 171, 173–174, 239

epithelium 178

strictures 175, 178

tract 34, 35

Biliary tree

anatomy of 23

bowel opacification 16

MRC, to depict 23

pathology 16

Biochemical

tests 180, 181

tuning 7–8

Biofeedback therapy 59

Biphosphonates 179

B7 ligands 125

Bloodstream 4

B lymphocytes 159

autologous 162

self-reactive 109

Bone density measurement 57

Botulinum toxin A 66

Bowel

angina 90

biopsies 36–37, 234

diseases, inflammatory 66

ischemia 19, 20, 34

manifestations, in MCTD 104

Bradley Study 264

Branched-chain 2 oxo-acid dehydrogenase complex

(BCOADC) 143

British Medical Journal 265

British Society for Rheumatology 264

Broad-spectrum antibiotic treatment, cyclic 105

Bruits, abdominal 83–84

Budd-Chiari syndrome 19

Bystander activation 9

C

C. difficile infection 260, 262

Calcineurin antagonists 32

Campylobacter 260, 262

Campylobacter enterocolitis 180

Campylobacter pylori 9

Cancer, hepato-cellular 163

Index280

Cardiovascular (CV) prophylaxis 244

Caspases 127

Catalase 239

Catastrophic APS

digestive involvement in 40

gastrointestinal involvement in 40–41

hepatic infarction, in patients with 43

mortality rate, in patients with 41

pancreatic involvement, in patients with 46

rate of microthrombosis, in patients with 41

splenic infarction, in patients with 45

vs. classic APS 40, 41

CD4 T helper cells

activation of 124

effect of CTLA-4 on 125

multiple antigen recognition sites within 132

CD4+ T-helper lymphocyte subset 1 (TH1)- type,

immune response 109

CD4+ T helper (Th0) cells 159

CD4 T lymphocytes 120

antigen recognition sites 122

liver-infiltrating in 127

CD8 T lymphocytes 121

antigen recognition sites in 122

cell proliferation in 128

CD8+ T lymphocytes, cytotoxic 193

Celecoxib 252

cost-befefit analyses of 254

first generation 253

meta-analysis of 254

safety analysis of 253

second generation 255–256

vs. NSAIDs 253–254

Celecoxib Long-term Arthritis Safety Study (CLASS)

252–253, 254

Celiac disease 64

Cell lines, T cell 161

Cellular immune abnormalities 172

Cellular infiltrate 172

Central lymphoid organs 6

Cerebral infarction 85

Cerebrovascular accidents 39

Chapel Hill Consensus Conference (CHCC) 89

Chelates of gadolinium 23

Chemokine receptors 4

Chemokines 86

Chest roentgenogram 103–104

Chlamydia pneumoniae 144

Chlamydophila spp. 112

Chloroquine 32

Cholangiocarcinoma 176–177, 178

Cholangiocytes, immature 143

Choledocholithiasis 37

Choleretic agent 179

Cholestasis 67, 197

Chromosome 10q24.1 127

Chronic

active hepatitis 105, 106, 153

hepatitis 191, 192, 197, 200

inflammation 95–96, 142–143

interstitial cystitis 35

intestinal pseudo-obstruction (CIPO). See Intestinal

pseudo-obstruction

intestinal vasculitides 84

liver diseases 154, 163, 177–178

mucocutaneous candidiasis 158

non-suppurative destructive cholangitis 141

pain 244

periaortitis 87–89

Churg-Strauss syndrome (CSS) 89

Cimetidine 260

Cirrhosis 127, 162, 163

Cladribine 180

Clonal anergy 7

Clones, T cell 161

Clopidogre 34

Clostridium perfringens, faecal 248

Coeliac disease 93

Cognitive impairment 246–247

Colchicine 181

Colic mucosa biopsy 92

Colitis pseudomembranosa 92

Colon cancer 177, 183, 184

Colonoscopy 84

Color dopplers 16, 17

Combined therapy 184

Complementarity-determining regions (CDR) 124

Computed tomography (CT) 16–20

angiogram 18, 19

contrast media, iodinated 19–20

imaging protocols in 16–17

multidetector computed tomography (MDCT) 16–20

multiple X-ray transmission 16

scanners 16

Con-A-induced liver injury 128

Conjunctivitis 90

Constipation 57

Contrast agents

MR 23–24

US 16

Contrast media, iodinated 19–20

vs. contrast agents in MR 23

Index 281

Coronary arteries 90

Corticosteroid

and cyclophosphamide 92

role in chronic periaortitis’s treatment 88

role in giant cell arteritis (GCA) treatment 86–87

role in henoch-schonlein purpura (HSP) treatment 90, 91

role in kawasaki’s disease treatment 90

role in takayasu’s arteritis treatment 85

Corticosteroids 32, 179, 198, 199

and azathioprine 37

Corticosteroid therapy 205

Cortisone 67

Costimulatory molecules 7

Costimuli, limitation of 8–9

COX 111, 243, 251, 253, 256, 261–262

Creatine kinase 63, 66

Crohn’s disease (CD) 66, 67, 231

Cross-reactivity 123

cellular 123

humoral 123

Cryoglobulinemia 210, 214, 215, 219

glomerulonephritis 215

vasculitis 214–215

Crypt hyperplasia 66

Cryptidins 3

Crystal diseases 244

CT. See Computed tomography (CT)

CTLA-4. See Cytotoxic T lymphocyte antigen-4 (CTLA-4)

CTLA-4 gene 125

Cushingoid changes 162–163

CV ADRs 253, 255

Cyclic citrullinated peptide (CCP) 212–213

Cyclo-oxygenase. See COX

Cyclophosphamide 92, 93

clinical trials of 89

and corticosteroid 92

role in chronic periaortitis’s treatment 89

Cyclophosphamide 31, 35–36, 40, 43, 64, 67, 198, 199

Cyclosporin 180

Cyclosporine A 31, 32, 35

CYP2D6 123, 132

Cytochrome c 127

Cytochrome

monooxygenase P450 IID6 (CYP2D6) 237

P4502D6 (CYP2D6) 154, 157, 161

P450 enzymes 260

Cytokines 4– 5, 8, 126, 127, 128, 133, 173, 109, 143, 257

IFN-g 109

IL-1 109

local networks of 95

proinflammatory 86, 111

TNF-a 109

Cytomegalovirus, infection 32

Cytopenias. See Autoimmune cytopenias

Cytoplasm, of grandular cell 93, 95

Cytoskeleton components 237

Cytosolic

enzymes 123

phospholipase A2 (cPlA2) 111

Cytosol type 1 (anti-LC1) 132

Cytostatic therapies 31

Cytotoxicity assays 161

Cytotoxic

T lymphocyte antigen-4 (CTLA-4) 125, 172

T lymphocyte (CTL) 4

D

Defensins 3

Dendritic cells 5, 6, 86

De novo AIH 163–164

Dermatomyositis 63, 67

Desquamation 90

Diabetes mellitus 202–203, 210–211

Diarrhoea 58–59, 90

Dihydrofolate reductase (DHFR), irreversible inhibition

of 112

Dihydrolipoamide dehydrogenase binding protein 143

Disease-modifying anti-rheumatic drugs (DMARDs)

248

DNA

aneuploidy 177

chromosomal 127

fragmentation of 127

immunization 123

Dominant strictures 178

Dopplers 16, 17

D-penicillamine 66, 178–179

DR molecules 131

Drug withdrawal 163

Dry mouth 31–32, 64

Ductopenia 178

Dysentery 112

Dysmotility 51

of esophagus 110–111

Dysphagia 32, 65–66, 103, 105

Dysplasia

biliary 177

colonic 177, 183

E

Edema, of submucosa 104

Effector cell 161

Index282

Eicosanoid, precursors 111

Elastic lamina 86

Elderly frail female 246

Electrogastrography 55

Electromyography 63

ELISA 157

detection 219

ELISA-2 213

EMG 65

Encoding, gene and enzyme 164

Endocytosis 7

Endomysium 234

Endoplasmic stress 63

Endoscopic

ablation 55

dilatations 105

retrograde cholangiography (ERC) 24

treatment, of PSC 178

Endothelial cells 39, 84, 86, 193

Enteric bacteria 179, 248

Enteric flora 248

Enterobacter 248

Enterobacteria strains 248

Enterocytes 3

Enterovirus or human herpes virus 6 202

Enzyme-linked immunosorbent assay (ELISA) 232, 237

Eosinophils 86

Epididymitis 204

Epilepsy 39

Epistasis 124, 126

Epithelial cells 142, 143

Epithelial–mesenchymal ‘cross-talk’ 143

Epithelium

cortical epithelium 7

follicle-associated epithelium 3, 5

intestinal epithelium 5

Epstein Barr Virus 202

ERCP 175, 178, 179

Erythema, oropharyngeal 90

Erythrocyte sedimentation rate (ESR) 86

Erythromycin 55, 57

Escherichia coli 144

Esomeprazole 261–262

Esophageal

disease 110–111

dysfunction 103–104

dysmotility, radiological evidence of 101–102

manometry (EM) 52, 103, 105

motility 103–104

necrosis 40

peristalsis 105

pH monitoring 105

Esophagitis 52

Esophagogram. See Air esophagogram

Esophagus 103–104

Estrogen 133

therapy 202

E2 subunit of pyruvate dehydrogenase complex

(PDC-E2) 143, 144

Etanercept 85, 92, 222

Etoricoxib 256

European Union Medicines Control Agency (EUMCA)

112

External sphincter myositis 66

Extractable nuclear antigen (ENA) 101

Extrahepatic cell types, for HCV 218

Extra-hepatic manifestations 194–205

F

F actin 157

Faecal flora, by NSAIDs 248

Fas gene [tumor necrosis factor receptor super family

(TNFRSF)] 126, 127

FasL 127

mediated cytotoxicity 128

Fatigue 145

Fc receptor–positive mononuclear cell

161

FDA 253, 256

Fecal incontinence 58–59

Felty’s syndrome 110

Ferromagnetic implants 24

Fetal cells, persistence of 14418F-fluorodeoxyglucose ([18F]FDG) 26

Fibrinoid necrosis 89, 90, 91, 196

Fibroblasts 86

Fibrosis 169, 174, 210, 211

bowel wall 35

muscle 64, 65

Fibrous tissue replacement 65

Fine-needle biopsy 19, 20

Fissuring (redness), of the lips 90

Fluoroscopy 19

Focal liver lesions 16, 23

Focal nodular hyperplasia 23–24

Food and Drug Administration

112, 147

Foreign antigens 121, 123

Formiminotransferase cyclodeaminase (FTCD) , 123,

157

French Pharmacovigilance Study 254

French Vasculitis Study Group 89

Fulminant hepatitis 193, 195

Index 283

G

Gadolinium, chelates of 23

Gallbladder 16

Gastric

antral vascular ectasia (GAVE) 32, 56

disease 32

electric stimulation 55–56

lymphomas 94

ulceration 40

Gastrin production 258–259

Gastritis 111, 257, 258

Gastroesophageal reflux disease (GERD) 52

Gastrointestinal (GI)

diseases 112–114, 233, 234

involvement’s in systemic vasculitis 83

ischemia 40–41

manifestations 31

pathology 15

syndromes 32–37

system in rheumatoid arthritis 110

tract 63–67

Gastrointestinal (GI) reactions

in autoimmune arthropathies 246–251

death rate, estimates of 245

multiple origins of 247–250

steroid, effect of 245–246

Gastrointestinal tract (GIT) 5, 59

Gastroparesis 55

Gastroprotective strategies 263

Gastroscopy 84

GB virus-C 196

Gender effects 133–134

Gene

dose effects 132–133

expression 5–7

microarray technology 124

mutations 158

General Practice Research Database 246

Genes encoding 171

Gene sequence, analyses 95

Genetic polymorphisms

effect on cytokine response 126

interactive 124

Genetic predisposition 121, 129

and HLA DRB1*03 126

Genetic risk factors

principal 129–131

region-specific 131–132

Genetic susceptibility

hypothesis of 145

in PBC 143

Genome 6

Germline polymorphisms 124

Gianotti–Crosti syndrome 201–202

Giant cell arteritis (GCA) 85–87

Giant cells 85, 86

GI bleeding 90, 93

due to peptic ulcer 93

GI bleeding and perforation 245–246

GI complications

and steroid 245–246

strategies to minimise 256–266

GI haemorrhage 90

GI side effects, due to NSAIDs 244, 245, 259

GI symptoms 84, 91

GI toxicity 245, 250, 265

Gliadin peptides 235, 236

Glomerulonephritis 89, 90, 91

symptoms 200

treatment 200–201

Glucocorticoid-induced myopathy 66, 67

Glucocorticoids 35, 64, 111, 251

Glucose metabolism 26

Glutamic acid (E) 131

Glutathione 144

Glutathione-S-transferase T1 (GSTT1) 123, 164

Glutathionylation 144

Gluten 234

Gottron’s papulae 63

Graft dysfunction 164

Granulomas 86, 88

Granulomatous colitis 92

Granzyme B 127

Gray scale equipment, high-resolution 15

Growth factor B (TGF-b) 235Growth hormone 133

Guillain– Barre-like syndrome 9, 204

Gut-associated immunity 3–6

H

H. pylori infection. See Helicobacter pylori infection

Haemophilus influenza 144

Haemorrhagic duodenitis 90

Harmonic imaging 16

Hazard ratio 256

HBc Ag 192

HBe Ag 192, 194

HBV

Ag 194, 200

infection vs. HCV infection 194

related cirrhosis 193

surface antigens (HBs Ag) 192–193

Index284

Heartburn 32, 52

Heart valve lesions 39

Heat shock protein 65 (HSP-65) 84

Hedgehog ligands 143

Hedgehog pathway 143

Helicobacter pylori 32, 144, 245

eradication therapy 248

growth of 257, 259

infection 93, 95, 248, 257–258

pathogenic strains of 248

Heliotrope rash, of eyelids 63

Hematological diseases 218–219

Hematopoietic abnormalities 112

Hemolytic anemia 39

Hemorrhage 67

Hemostasis activation 43

Henoch-Schonlein purpura (HSP) 90–91

Hepatic

cell 193

cirrhosis 191

fibrotic disease 110

inflammation 211

tumors 23, 24

Hepatitis

autoimmune 64, 67

A virus 131, 202

B virus (HBV) 89, 192–194

C, chronic 132

Hepatitis C virus (HCV) 202–203, 237

anti, antibodies 95

infection 92–96

lupus-like syndrome, due to 213, 214

metabolic disorders in 211

negative 92, 93, 95

positive 94, 95

RNA 93

and Sjogren’s syndrome (SS) 211

vs. HBV 194

Hepatitis D, chronic 237

Hepatitis D virus (HDV) 196

genotype I HDV 193

Hepatobiliary

contrast agents 23

injury 180

Hepatocellular carcinoma 193, 214

Hepatocytes 23, 127, 128, 161, 183

Hepato-renal ADRs 253

Hepatosplenomegaly 146

Hepatotoxicity 111–112

HEp2 cells 156

Herpes viridae 196

High endothelial venules (HEV) 5

Histamine 257, 258

Histiocytes 85, 86

Histocompatibility lymphocyte antigen (HLA)

158

class I antigens 159

class II molecules 159, 162

haplotypes 171, 172

molecules 171, 173

polymorphisms in 158

possession of 163

predisposing, allele 161

predisposing, haplotype 159

serotyping 171

HLA class I and II antigens 84

Homeostasis

homeostatic proliferation 8

intestinal immune homeostasis 5

Homeostatic proliferation 8

Homing receptors 6, 7

Homologous epitopes 121, 123

Hormone replacement therapy 145

H2-receptor antagonists (H2RAs) 105, 254, 260

Human

epithelial cells (HEp-2) 237

genome project 124

immunodeficiency virus (HIV) 193

Humoral

cross-reactivity 123

immunity 85

Hydroxychloroquine 32

Hyperlipidemia 34

Hyperplasia, nodular regenerative 110

Hyper-reflexity 65

Hypersensitivity vasculitis 84

Hypoalbuminemia 31, 36, 104

Hypoparathyroidism 158

Hypoperistalsis 32

Hypopharyngeal intrabolus pressure 65

Hyporeflexity 65

Hypothyroidism 210

I

IAIHG 155, 156

IBM. See Inclusion body myositis (IBM)

Ibuprofen 261

ICOS 9

Icterus 193

Idiopathic gastrointestinal dysmotility 51

IFN-alpha therapy 203, 204

IFN-g 109

IFN-ribavirin 210

Index 285

IgA 4

autoantibodies 234

endomysial antibodies 234

IgA-class anti-gliadin (AGA) 66

IgA-dominant immune complexes 90

IgG. See Immunoglobulin G (IgG)

IgM 4

IkB kinase-b(IKK-b) 5IkB-NF-kB 111

IL-1 109

Ileal pouch-anal anastomosis 177

Ileus 83

paralytic 90

IL-10 mRNA, downregulation of 173

IL-2 receptor alpha chain (CD25) [T regulatory cells

(T-regs)] 160

Imaging techniques

barium studies. See Barium studies

computed tomography. See Computed tomography

magnetic resonance. See Magnetic resonance (MR)

plain abdominal films. See Plain abdominal films

positron emission tomography. See Positron emission

tomography

technological development of 26

ultrasound. See Ultrasound

Immune attack 121, 123

Immune cells 133

Immune disorders 244

Immunoblotting 238

Immunochemiluminescent 234–235

Immunocytes

activated 121, 122, 124, 129

differentiation and proliferation of 126

elimination of autoreactive 127

liver-infiltrating 126

sensitized 125

Immunodiffusion 238

Immunofluorescence of muscle and liver 205

Immunofluorescence test 234

Immunoglobulins 4, 65, 210

G and M 85

IgA 4

IgM 4

sequence analyses of, rearranged genes 95

Immunoglobulin G (IgG) 51, 151

elevated 163

levels of 154

Immunohistochemistry 143

Immunologic ignorance 6

Immunoreactivity 144

Immunoregulation 159, 161

Immunosuppressants 85, 180, 199

use of 92

Immunosuppression 153, 157, 161, 162, 215, 221

Immunosuppressive agents 85. See also

Immunosuppressive drugs

Immunosuppressive drugs 31, 32, 35, 64

Immunosuppressive therapy 163

IMS health 257

Inclusion body myositis (IBM) 64

dysphagia in 65–66

Indirect immunofluorescence (IIF) 231–232

assay 237

Indomethacin 248, 258

Infarction 114

cerebral 85

gallbladder 89

prevalence of myocardial 85

stomach 89

Infectious agents 112

Infiltration

inflammatory 67

perivascular 63, 64

Inflammation 64, 65, 172, 174, 178

Inflammatory

bowel diseases (IBD) 231–234, 243

cells, mononuclear 63

colitis 174

infiltrates 63

reactions 249, 257

response 257

Inflammatory myopathies 218

bowel involvement in 66


liver involvement in 66–67

oral cavity in 64–65

Infliximab 85, 222

Intercellular adhesion molecule-1 (ICAM-1) 84

Interface hepatitis 153, 154, 155, 159

Interferon 93

a-interferon 215, 216

Interferon gamma (IFN-g) 159Interferon (IFN)-alpha 199

Interleukin, polymorphism of 126

Interleukin-1 (IL-1) 258

Interleukin 12 (IL-12) 159

International Autoimmune Hepatitis Group (IAIHG).

See IAIHG

International population studies 243

Intestinal

angina 33

epithelial cells (IEC) 5

Index286

inflammation 5

ischemia. See Gastrointestinal ischemia

lesions 248

pneumatosis 21

pseudo-obstruction 35–36, 56–59, 84

Intestinal vasculitis

acute 83

isolated 92

MC-related 93

Intima 85, 86

Intramural haemorrhage 90

Iron deficiency anemia 56

Ischaemic necrotic lesions 86

Ischemic bowel disease. See Bowel ischemia

Ischemic bowel disease 35

Isolated acute pancreatitis 204

Isolated arthralgias 204

Isoleucine (I) 130

J

Jejunal tube 55

Joint destruction 110

Juvenile dermatomyositis 67

K

Kawasaki’s disease (KD) 90

Keratoconjunctivitis sicca 102

Keto-acid substrates, metabolism of 143

Keto-glutaric acid dehydrogenase complex 143

Klebsiella 248

Komeda diabetes prone (KDP) rat strain 8

Kupffer cells 6, 23–24, 180

L

Lamivudine 199

Langerhans cells 85

Lansoprazole 245, 260

Laxative stimulants 59

Leflunomide 112

Leg ulcers 39

Leucopenia 110

Leucoplakia 31, 32

Leukocytes. See also Polymorphonuclear (PMN)

leukocytes

in HBV DNA 193

Leukocytoclastic

angiitis 90

vasculitis 90–91

Lichen planus 32

Lipoprotein 161, 162

liver-specific 238

Livedo reticularis 39

Liver biopsy 146, 154–155, 175

biliary dysplasia in 177

Liver cells 161

cytoplasm 157

immunofluorescence studies on 161

Liver disease

drug-induced 154

severity of 145

Liver function tests 162, 175, 178

Liver-infiltrating immunocytes 124

Liver/kidney microsome type 1 (anti-LKM1) 132

Liver MR 24

Liver parenchyma 154

Liver transplantation 123, 145, 147, 163

LLEQKR 130

Lower esophageal sphincter (LES) 52, 103, 110–111

Lumiracoxib 256

Lupoid hepatitis 153

Lupus anticoagulants (LA) 42, 43

test 39

Lupus enteritis (gastrointestinal vasculitis) 34–35

Lymphadenopath, nonsuppurative 90

Lymph nodes 193

external iliac 25

left iliac 20

Lymphocytes 193

activated 122, 123, 127

autologous 161

of B cells 159, 162

CD4+ 193

CD4 helper T 127

CD4 T 121, 122

CD4+ T 159

CD8 T 121, 122

CD8+ T 193

circulation 174

collections of 86

cytotoxic T 123

clonal expansion of 126

induction of 127

proliferation of 128

differentiation and activation 4

clonal anergy and tuning 4, 7–8

clonal deletion 4, 6

extrinsic regulation 4, 8

receptor editing 4, 6

homing receptors 174

immunoregulatory subset of 160

Index 287

infiltrates of 85

liver-infiltrating 127

lymph nodes 193

of non–T-cell lineage 159

persistence of activated 127

portal and periportal 153

self-reactive 6

somatic genome modification 6

of T cells 164

TCR characteristic of 128

V(D)J recombination 6

Lymphoid infiltration, chronic gastritis 93

Lymphoma 19, 25

B-cell 92, 93, 94, 95

gastric 94, 95

HCV-negative cells 95

HCV-positive cases of 95

MALT 93, 95

Lymphomagenesis 95

in HCV 219

Lymphomatous lesion 95

Lymphopenia 8

Lymphoproliferation 93, 95

MALT 94

Lymphoproliferative intestinal diseases 93

Lymphotoxins

lymphotoxin-a1b2 3lymphotoxin-a-deficient 4

Lysine-71 158

Lysine (K) 130

M

Macroglossia 64–65

Macrophage inflammatory protein 3 (MIP3) 5

Macrophages 63, 86, 88, 89, 159

Magnetic resonance cholangiography (MRC) 175

Magnetic resonance cholangiopancreatography (MRC) 21

Magnetic resonance (MR) 20–26

abdominal 21

angiography 21, 23, 26

applications 20–21

cholangiopancreatography 21, 24

contrast agents 23–24

endoscopic retrograde cholangiography (ERC) 24

enteroclysis 24

hydrogen atoms, relaxation properties of 20

implants and devices 24

liver 24

scanners 20

technique 20–23

vs. CT 23

Major histocompatibility complex (MHC) 124

alleles of 131

class II 124

antigen-binding groove of 130, 131, 132

antigen-presenting 124

diversity of 130

effect of arginine 130

peptide-binding affinity 132

genes, in PSC 171–172

molecules and complexes 7

Major histocompatibility complex (MHC), Class II

antigen presentation of 158

molecules 158

Malabsorption 67, 104, 105

Malnutrition 65

MALT. See Mucosaassociated lymphoid tissue

(MALT)

Manometry. See Esophageal manometry

Masticatory

muscle weakness 64

system 103

Matrix metalloproteinases 172

Maximum intensity projection (MIP) 19, 20, 25

M cells 3, 5

MCTD. See Mixed connective tissue disease (MCTD)

MDCT. See Multidetector computed tomography

(MDCT)

MDCT protocols 17

Medium-sized vessel vasculitis (MVV)

kawasaki’s disease (KD) 90

polyarteritis nodosa (PAN) 89

vs. small-sized vessel vasculitis (SVV) 89

Megacolon 104

Merck Sharp and Dohme 253, 256

Mesenchymal cells 143

Mesenteric

insufficiency 32–33

ischemia 19, 20, 83

vasculitis 36

vessels 20

Metabolic myopathy 63

Metastases 16

Methacronous gastric biopsies 95

Methotrexate 62, 111–112, 179–180. See also

Immunosuppressive agents

Metoclopramide 55, 57

MF pattern 157

MHC. See Major histocompatibility complex (MHC)

Microaneurisms 196, 197

Microbubbles 16

Microchimerism 133

Microfilaments (MFs), of smooth muscle 154

Index288

Micropolyangiitis 90

Microscopic angiitis 91

Microthrombosis 41

Microvascular lesions 109

Misoprostol 260, 263

Mitochondria 127

Mitochondrial

dysfunction 67, 127

matrix 143

membrane proteins, inner 238

proteins 143–144

Mixed connective tissue disease (MCTD) 64, 218

bowel manifestations in 104

esophageal dysfunction in 103–104

gastrointestinal tract involvement in 101–102

oral manifestations in 102–103

Sjogren’s syndrome, in MCTD 102

therapeutic considerations for 105

Mixed cryoglobulinemia (MC) 92–96, 210

MMP-3 (stromelysin), polymorphism of 172

Molecular

footprint hypothesis 131

genotyping 171

mimicry 122–123, 144, 164

Monoclonal antibody 171

Monooxygenase 123

Mouse mammarytumor virus (MMTC) 144

MR. See Magnetic resonance

MR angiography. See Magnetic resonance

cholangiopancreatography (MRC)

MRC. See Magnetic resonance

cholangiopancreatography (MRC)

MR contrast agents 23–24

mRNAs encodes, in HBV 192

MR scanners 20

Mucocutaneous lymph node syndrome 90

Mucosaassociated lymphoid tissue (MALT)

93, 95

lymphomas 212, 220

Mucosal

lesion 103

membrane 64

Multidetector computed tomography (MDCT) 16–20

Multiplanar

capacity 21–22

reformations (MPR) 16–18, 20, 22

Multiple X-ray transmission 16

Muscle

atrophy 63, 64

biopsy 63–64

disorders, inflammatory 66

impairment 63, 64

Muscle weakness

cytokine-mediated 63

pharyngeal 63

proximal 67

skeletal 66

thoracic 63

Musculoskeletal pain 243–244

management of 244, 256

in young and elderly 244

Mutant pre-core virus 204

Myalgias 204

Mycobacterial infection 84

Mycophenolate mofetil. See Immunosuppressive agents

Mycophenolate mofetil 31, 32

Mycophenolate mofetil (MMF) 221

Myeloperoxidase (MPO) 91

Myocardial infarction 39

Myofibroblastic cells 143

Myonecrosis 63, 65

Myopathy

glucocorticoid-induced 64

metabolic 63

steroid 66

Myositis 63

autoantibodies associated with 64

in bowel 66


external sphincter 66

in liver 66

oral cavity in 64–65

N

Narcotics 264

Nasal regurgitations 65

National Institute for Clinical Excellence (NICE) 254

Natural killer (NK) cells 126, 159

Natural killer T (NKT) cells 128

Nd:YAG laser 56

Necrosis

of arterial wall 86

of elastic fibres effect on granulomatous changes 85

full-thickness 90

transmural fibrinoid 89

Necrotizing

angiitis 89

arteritis 89

Negative selection, of T cells 7, 8

Neoplastic diseases 19

Nephrotic syndrome 200

Nephrotoxicity, of contrast agents 23

Neurological diseases 65

Index 289

Neuropathy 196, 197, 207

membranous 200

Neutrophil

antigens 238

binding 239–240

Nexium Anti-inflammatory Symptom Amelioration

(NASA1) 261

NF-kB 111

NF-kB (RANK) 5

NF-kB1 activation 7

NF-kB2 activity 8

Nicotine 183

Nicotinic acetylcholine receptor a7 5

NK. See Natural killer (NK) cells

NKT. See Natural killer T (NKT) cells

Nodosa. See Arterial nodules

Non-Hodgkin lymphoma (NHL) 214

odds ratio (OR) for 219

Non-MHC immunoregulatory genes, in PSC 172

Non-organ-specific autoantibodies (NOSA) 210

Non-steroidal antiinflammatory drugs (NSAID)

32, 111

Noradrenergic fibers 5

Novosphingobium aromaticivorans 144

NSAIDs. See Anti-inflammatory drugs; Non-steroidal

antiinflammatory drugs

Nuclear

body protein 143

pore proteins 143

Nutritional support, parenteral and enteral 105

O

Occlusion 19

Octreotide 57

Ocular tests, positive 212

Odds ratio (OR), for NHL 219

Oedema 90

Oesophageal symptoms 32

Oral anticoagulation 41

Oral

cavity 64–65

ulcers 31–32

Oropharyngeal dysphagia 65

Oropharyngeal muscles 65

Orthotopic liver transplantation (OLT) 184

Osteoarthritis (OA) 244

Over the counter (OTC) analgesics 244

Oxidative stress 239

OX40L 9

2-oxoglutarate dehydrogenase complex (OGDC) 143

P

PAN. See Polyarteritis nodosa (PAN)

Panarteritis 85, 92

Pancreatic

ducts 24, 34

exocrine deficiency 110

Pancreatitis 37, 67, 105

Pan-cytopenia 179

P-ANNA (anti-neutrophil nuclear antibody)

171

Paracetamol 87, 247, 255

and NSAIDs 264, 265

use of 265

Paralytic ileus 90

Paraneoplastic phenomenon 64

Parvovirus B19 196

PBC. See Primary biliary cirrhosis (PBC)

PCR, detection 219

PDC-E2. See E2 subunit of pyruvate dehydrogenase

complex (PDC-E2)

PD1 proteins 7

Pentagastrin 257

Pentoxifylline 180

Peptic ulcer

bleeds (PUBs) 251

disease (PUD) 111, 243, 245

Percutaneous transluminal angioplasty 20

Perforation 32, 40, 67, 110, 111

Perforation, spontaneous. See Spontaneous

perforation

Perforin 127

Periaortal fibrosis 88

Periaortic tissue mass 88

Peritonitis 83

Peroxisome proliferatoractivated receptor-gamma

(PPAR-g) 192Persistent reflux 105

Perturbations

in activation signals 124–126

apoptotic pathways 127–128

in the cytokine network 126–127

PET. See Positron emission tomography

Peyer’s patches 3, 5

Phagocytes 6

Phosphatase 7–8

Phospholipids 39

PI. See Pneumatosis intestinalis (PI)

PIM2 8

Pituitary hormones 133

Plain abdominal films 15

Index290

Plasma

cell infiltrate 153

cells 85, 86, 88

exchange 198, 199

Plasmapheresis 67, 93

Platelet antiaggregants 34

PLUTO and VENUS studies 262

PMN. See Polymorphonuclear (PMN) leukocytes

Pneumatosis

cystoides intestinalis 36–37, 58

intestinalis (PI) 104

Pneumoperitoneum. See Pneumatosis cystoides

intestinalis

Polyarteritis nodosa (PAN) 89, 195–204, 217

vs. cryoglobulinemia 218

Polyarthrtis, chronic inflammatory 212

Polymorphonuclear infiltrate 104

Polymorphonuclear (PMN) leukocytes 86

Polymyositis 63–67, 103, 105

Porphyria cutanea tarda 202

Portal hypertension 110, 145, 146, 177

Portal inflammation 146

Porto-systemic shunts 177

Positive selection, of T cells 7

Positron emission tomography (PET) 25–26

Power dopplers 16

PPI. See Proton pump inhibitors

Predilection of female 133–134

Prednisolone 162

Prednisone 32, 35, 85, 86, 87

Pretransplant chemo-radiation 43

Primary biliary cirrhosis (PBC) 66, 121, 133. See also

Autoimmune liver diseases

AMA-negative vs. positive 146

autoimmune hepatitis 125

bacterial pathogens 144

cohort studies of 147

colchicine in 181

diagnosis of 143, 145–146

and DRB1*0801 130

effect of genetic factors 129

fatigue of 145

genetic associations in 130

and HLA 142

methotrexate toxicity in 180

mouse model for 144

and oral contraceptive use 145

population studies on 141–142

pregnancy as a risk factor for 144

pruritus of 145

rheumatoid arthritis and thyroid disease in 145

stages 146

treatment of 147–148

T-reg cell function in patients of 126

ursodeoxycholic acid (UDCA) treatment in 181

Primary sclerosing cholangitis (PSC) 129, 131. See also

Autoimmune liver diseases

cellular immune abnormalities in 172

and cigarette smoking 183

complications management of 178

diagnosis 175

and inflammatory colitis 174

tissue injury in 172, 175

Probiotic therapy 57

Proctocolectomy 174, 177

Prodromal pre-icteric syndrome 194–195

Professional rheumatologic societies 112

Progesterone 133

Programmed cell death. See Apoptosis

Prokinetic agents 51, 54

Prolactin 133

Promiscuous immunocyte activity 123–124

Properdin 85

Prostaglandin E2 (PGE2) 257, 258

Prostaglandin (PG)

analogues 256, 260

production 257

synthesis 246, 251

Prostanoids 111

Proteinase 3 (PR3) 91

Protein-loosing enteropathy 93, 104, 246

Protein-losing gastroenteropathy (PLGE) 36

Proteinuria 179, 200–201

Protocols

abdominal 21

MDCT 17

Proton-pump inhibitor (PPI) 245, 254, 260–261,

262

and NSAID 252

as treatment of upper GI symptoms 261

Proton pump inhibitors 32, 54, 105

Proximal muscle weakness 67

Pruritus 145

PSC. See Primary sclerosing cholangitis (PSC)

Pseudomonas aeruginosa 144

Pseudo-obstruction 105

PSS, patients 103

Pulmonary

embolism 39

fibrosis 112

infection 67

Pulsed dopplers 16

Index 291

Pulseless disease 84, 85

Pulselessness. See Pulseless disease

Pyrimidines 112

R

RA. See Rheumatoid arthritis (RA)

Radioimmunofiltration (RIFA) 239

Radiologist 16

RAVE 92

Raynaud’s phenomenon (RP) 104, 145

Recombination-activating gene (RAG) 6, 7

Rectal

incontinence 66

prolapse 59

Regulatory cells with suppressor functions, deficiencies

in 128

Regulatory networks, deficiencies in 124–128

Relapsing polychondritis (RP) 218

Relative risk reduction (RRR) 252

Renal

ADRs 253

disease 91

failure 215

transplantation 32

vessel occlusion 67

Resistive indices 16

Respiratory syncytial virus 202

Reticuloendothelial contrast agents 23–24

Revascularization, surgical 34

Rheumatic diseases 67, 103

Rheumatoid arthritis (RA) 145, 212–213

associated esophageal disease 110–111

complications of 110

gastrointestinal system in 110

GI manifestations in 107–109

hepatotoxicity 111

hipple’s disease for 114

mechanism and side-effects of therapeutics modalities

of 113–114

NSAIDs treatment for 111

predominance of the CD4+ T-helper lymphocyte

subset 1 109

secondary amyloidosis in context of 110

secondary GI syndromes in 110

systemic manifestations of 109

therapy 109, 112

use of methotrexate in 111

whipple’s disease for 114

Rheumatoid factor (RF) 95, 209, 212

Rheumatoid vasculitis 109, 110

RIBA-2 213

Ribavirin 93, 216

Ribonuclease sensitive component

(RNP-ribonucleoprotein) 101

Ribonucleoprotein complex 123

Rituximab 221–222

Rockefeller Institute 141

Rofecoxib 253, 255–256

Rotavirus protein VP-7, 235

Royal College of Physicians (UK) 264

Royal Free Hospital 179

S

Sacral nerve stimulation 59

Saliva flow rate 64

Salivary gland biopsy 102, 103

positive 212

Salivary secretion, in MCTD 102–103

Salmonella 260

Sarcoidosis 215

by anti-viral therapy 215–217

cutaneous 217

treatment-naıve patients 217

Scanners 16, 20

Scleroderma 103, 104

esophageal dismotility 101

Scleroderma Gastrointestinal Tract 1.0 (SSC-GIT 1.0)

59

Sclerosing cholangitis 67

Self-antigens 121, 123

Self-reactive lymphocytes 6, 8

extrinsic controls of 8

regulation of 9

self-tolerance 6, see also tolerance

Self-reactive receptors 6–7

Self-tolerance 6

effect of antigens on 123

effect of host-dependent factors on 121

effect of microchimerism on 133

effect of multiple exposure to viruses on 123

loss of 121

Sepsis 35

Seroconversion 198–199, 200

Serological markers 232–233

of AIH 236

Serological tests 233, 234, 235

Serositis 31, 33, 35

Serotypes, HBV 201

Serum

biochemical tests 175

carotene 57

creatinine level 91

Index292

determinations 126

IgG4 levels 175

marker 178

muscle enzymes 63

thyroxine, level 203

Serum aminotranferases level 145

Serum amyloid A (SAA) 110

Serum bilirubin 180

levels 147–148

Sex hormones 133

immune-modulating effects of 129

Shared motif hypothesis 131

Sialoadenitis, focal 102

Sialopenia 103

Sicca manifestations 110

Sicca symptoms, in MCTD 102

Single-nucleotide polymorphism (snp) 172

Sjogren’s syndrome (SS) 32, 145, 211–212

associated esophageal disease 110–111

vs. chronic HCV infection 95

in MCTD 102

secondary 62, 64, 65, 67

Skin

biopsy 90

lesions 197, 202

rash 63, 201

polymorphous erythematous 90

SLEDAI (Systemic Lupus Erythematosus Disease

Activity Index) 32–33

Small bowel

anatomy of 24

diseases 24

loops 19, 21

Small-sized vessels vasculitis (SVV) 90–92

Smoking, toxic compounds 145

Smooth muscle antibodies (SMA) 236, 237

Soluble

cell adhesion molecules (sICAM) 181

liver antigen (SLA) 157

Somatic hypermutation 6, 9

Somatostatin analogue 57

Spasmolytic drugs 87

Spectral dopplers 16, 17

Splenomegaly 110

Spontaneous perforation 104

SS-HCV Study Group 211

Steatosis 111, 112, 211

Stem cell transplantation, autologous 92

Stenosis of aortic branches, signs and symptoms

of 84

Stenotic lesions 85

Stent placement 20

Steroids 66, 85, 87

and NSAID 245, 246

oral 245, 246

side effects 162–163

tapering 92

treatment 88, 89, 92

use of 246

Sterol regulatory element binding protein 1 (SREBP1)

192

Still disease 218

Stimuli, autoantigenic and allogeneic 164

Striated muscle, inflammation of 64, 65

Stromal fibroblasts 193

Subepithelial dome 3

Submucosal hemorrhage 19

Superior mesenteric artery (SMA) 21–22

Surgical procedures 178

Surveillance colonoscopy 177, 183

Surveillance endoscopy 55

Symptom Prevention by Acid Control with

Esomeprazole (SPACE1) 261

Synergy. See Epistasis

Synovitis 111

Synovium, inflammation of 109

Systemic autoimmune diseases (SAD) 209, 211,

218

Systemic immunity 5–6

Systemic lupus erythematosus (SLE) 9, 39, 44, 45,

89, 103, 145, 213–214. See also Autoimmune

diseases

diagnostic criterion 31

general symptoms 31

mild 213

patients with 104

true 213

Systemic sclerosis (SSc) 64, 67, 103, 104, 105

anorectal involvement in 58–59

colonic involvement in 58

esophageal involvement in 52–55

Systemic

Churg–Strauss vasculitis 218

cryoglobulinemic vasculitis or syndrome

92

disappearance of, features 93

gastrointestinal (GI) involvement in 83

giant cell arteritis (GCA) 85–87, 218

Henoch–Schonlein purpura 218

polyarteritis nodosa (PAN) 89

steroids 32

Takayasu’s arteritis 218

vasculitides 195, 197, 200

vasculitis 217–218

Index 293

T

TA. See Takayasu’s arteritis (TA)

Tacrolimus (FK 506) 32, 180

Takayasu’s arteritis (TA) 84–86

T cells 158

ab 84

activation 235

auto-reactive 158

and B cells, autoreactive 143

CD4 + 86

cytotoxic 124

gd, role in takayasu’s arteritis 84

immune response 172

self-reactive 158

T cells, autoreactive 7, 9

T cell antigen receptor (TCR) 123

a- and b-chains 124of activated immunocytes 129

characteristic of lymphocytes ,co-expression of 128

degree of diversity within 124

effect of germline polymorphisms 124

of effector cells 124

ligand 124

of liver-infiltrating immunocytes 124

polymorphisms 124

T cell receptor (TCR) 172–173

gene rearrangements 173

polypeptides 173

V gene segments 173

T cells bearing a specific beta chain variable region

(TCRBV3) 145

TCR. See T cell antigen receptor (TCR)

Temporomandibular joints 103

Teslas (T) 20

Testosterone 133

Th1 cells 159

Therapeutic protocol 215

Thrombocytopenia 39, 41, 219

Thromboembolic disease, in IBD patients 41

Thromboembolism 46

Thrombosis 19, 67, 86, 196

arterial 39

splenic arteries thrombosis 43

microthrombosis 41

thromboembolism 46

thromboses, arterial and venous 39, 40

venous

deep venous 39, 41

hepatic vein 42

portal vein 44, 45

Thymic cortical epithelium 7

Thyroid

gland dysfunction, in HCV 203

hormones 203

Thyroiditis 210

Thyrotropin-releasing hormone-stimulation test 203

Thyroxine and triiodothyronine binding 203

Tissue

autoantibodies 163

harmonic imaging 16

transglutaminase type 2 (tTG2) 234

T lymphocytes 63, 159, 172

activation 240

self-reactive 109

TNF

alpha blocking agents 92

etanercept, as receptor of 85, 92

inhibition 85

TNF-a 109

TNF-a receptor-1(TNF-R1) 127

TNFRSF. See Fas gene [tumor necrosis factor receptor

super family (TNFRSF)]

Tolerance mechanisms 6–7. See also Self-tolerance

Toll-like receptors (TLR)

microbial TLR agonist 9

TLR9-induced differentiation 7

TLR ligands 4, 7, 9

Toll-like receptor 4 (TLR4) 235

Tonsillectomy 91

Traditional NSAIDs (tNSAIDs) 245, 256, 263

Transaminases

elevation 154, 155, 163

levels of 154, 162

Transamine (GPT and GOT) levels 197

Transducers 15–16

Transfer ribonucleoprotein complex (tRNP) 238

Transforming growth factor-b(TGF-b) 15, 126, 159T regulatory cells (T regs) 159–161

deficient 144

Trichuris 5

Trimethoprim-sulfa 114

tRNA suppressor associated antigenic protein

(tRNP(Ser)Sec) 157

TRNP(Ser)Sec 123

Tropheryma whipplei 114

Tru-cut biopsies 19

Trypsinogen 37

Tuberculosis. See Mycobacterial infection

Tumor necrosis factor-a 5, 126, 159, 171, 180, 249

Tunica media 85, 86

Tuning. See Biochemical tuning

Type 2 (Th2) cytokine, pathway 126

Tyrosine phosphatase CD45 gene, mutation of 125, 126

Index294

U

Ubiquitin ligases 8

UDCA therapy 146, 147

UGA tRNA 157

Ulceration 67, 110, 111

Ulcerative colitis (UC) 66, 231, 238, 249

Ulcer

bleeding 245, 247

incidence 254

Ultrasonography. See Ultrasound (US)

Ultrasound (US) 15–16

Unmethylated CpG dinucleotides 9

Uraemia 31

Ureterohydronephrosis, bilateral 33, 35

Uridine diphosphate glucuronosyltransferase (UGT)

237

Uridine triphosphate glucuronosyltransferase 123

Ursodeoxycholic acid (UDCA) 181–183

US. See Ultrasound (US)

V

Vagous nerve 5

Valdecoxib 253, 256

Vasa vasorum 85, 86

Vascular

anatomy, visualization of 19–20

cell adhesion molecule-1 (VCAM-1) 84, 85

Vasculature, mesenteric and hepatic 89

Vasculitic

appendicitis 90

lesions, in HBV 196

Vasculitis 64, 67, 104

acute intestinal 83

hypersensitivity 84

necrosis of the bowel wall due to 104

primary and secondary 83

spontaneous perforation associated with 104, 106

Venous thrombosis, deep 39, 41

Venules 89, 90

V gene segments, of TCR 173

VGT-MF pattern 157

VGT patterns 157

Vidarabine 199

Videofluoroscopy 15

Videomanometry 65, 66

Villous atrophy 66

Villus–crypt unit 4

Vioxx Gastrointestinal Outcomes Study (VIGOR)

251–253, 255

Viral hepatitides, B and C 154

Vitamin D receptor (VDR) gene 125

Volume rendering (VR) 20

W

Watermelon stomach. See Gastric antral vascular

ectasia (GAVE)

Wegener’s granulomatosis (WG) 89

Welsh community survey 244

WG etanercept trial (WGET) 92

Whipple’s disease 112, 114

Wilson disease 154, 155

Wiskott-Aldrich syndrome 8

X

Xanothomatous biliary cirrhosis 141

Xanthelasma 146

Xenobiotics 144

Xerophtalmia 212

Xerostomia 102, 212

X protein, in HBV 192

Y

Yersinia enterocolitica 110

Yersinia pseudotuberculosis 110

Z

Zenker’s diverticula 65

Index 295


Digestive Involvement in Systemic Autoimmune Diseases

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