Review IgG4-RelatedHypertrophicPachymeningitis … · 2020. 12. 17. · IgG4Loc 4.09 3.91 4.02 Abbreviations:CSF,cerebrospinalfluid;Loc,localimmunoglobulinsynthesis …

Copyright 2014 American Medical Association. All rights reserved.

IgG4-Related Hypertrophic PachymeningitisClinical Features, Diagnostic Criteria, and TreatmentLucy X. Lu, PhD; Emanuel Della-Torre, MD; John H. Stone, MD, MPH; Stephen W. Clark, MD, PhD

IMPORTANCE IgG4-related hypertrophic pachymeningitis (IgG4-RHP) is an increasinglyrecognized manifestation of IgG4-related disease, a fibroinflammatory condition that canaffect virtually any organ. It is estimated that IgG4-RHP may account for a high proportion ofcases of hypertrophic pachymeningitis once considered idiopathic.

OBJECTIVE To summarize the current knowledge on IgG4-RHP including its pathological,clinical, and radiological presentations. Particular emphasis is placed on diagnostic andtherapeutic implications.

EVIDENCE REVIEW This review is based on 21 reports published in the English medicalliterature since 2009. PubMed was searched with the following terms: IgG4, pachymeningitis,IgG4-related pachymeningitis, IgG4-related disease, IgG4-related, and IgG4 meningitis. Onlycases with biopsy-proven IgG4-RHP were considered and included in this review.

FINDINGS Little is known with certainty regarding the pathogenesis of IgG4-RHP. Thepresence of oligoclonally restricted IgG4-positive plasma cells within inflammatory meningealniches strongly suggests a specific response against a still unknown antigen. Clinicalpresentation of IgG4-RHP is not distinguishable from other forms of hypertrophicpachymeningitis and reflects mechanical compression of vascular or nerve structures, leadingto functional deficits. Signs of systemic IgG4-related disease may concomitantly be present.Diagnostic process should rely primarily on magnetic resonance imaging, cerebrospinal fluidanalysis, and meningeal biopsy. In particular, hallmark histopathological features of IgG4-RHPare a lymphoplasmacytic infiltration of IgG4-positive plasma cells, storiform fibrosis, andobliterative phlebitis. High-dose glucocorticoids are still the treatment of choice for IgG4-RHPbecause immunosuppressive agents have shown variable efficacy in reducing the meningealhypertrophy. Rituximab is a promising therapeutic approach but experience with B-celldepletion strategies remains limited.

CONCLUSIONS AND RELEVANCE IgG4-related disease accounts for an increasing proportion ofcases of idiopathic hypertrophic pachymeningitis. Clinicians should become familiar with thisalternative differential diagnosis because a prompt, specific therapeutic approach may avoidlong-term neurological complications.

JAMA Neurol. 2014;71(6):785-793. doi:10.1001/jamaneurol.2014.243Published online April 14, 2014.

Supplemental content atjamaneurology.com

Author Affiliations: VanderbiltUniversity School of Medicine,Nashville, Tennessee (Lu, Clark); Unitof Medicine and Clinical Immunology,Università Vita-Salute San Raffaele,San Raffaele Scientific Institute,Milan, Italy (Della-Torre); Division ofRheumatology, Allergy, andImmunology, Massachusetts GeneralHospital, Harvard Medical School,Boston (Stone); Department ofNeurology, Vanderbilt UniversitySchool of Medicine, Nashville,Tennessee (Clark).

Corresponding Author: Stephen W.Clark, MD, PhD, Department ofNeurology, Vanderbilt University,1161 21st Ave, Nashville, TN 37232([email protected]).

Section Editor: David E. Pleasure, MD.

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I gG4-related hypertrophic pachymeningitis (IgG4-RHP) is an in-creasingly recognized manifestation of IgG4-related disease(IgG4-RD), a fibroinflammatory condition that can affect vir-

tually any organ. The 3 hallmark histopathological features ofIgG4-RD are a lymphoplasmacytic infiltration of IgG4-positive plasmacells, storiform fibrosis, and obliterative phlebitis.1

Full recognition of IgG4-RD has emerged only since 2001, whena seminal observation described elevated serum IgG4 concentra-tions in patients with sclerosing pancreatitis, a condition known nowas type 1 (IgG4-related) autoimmune pancreatitis.2 Over the next de-cade, the characteristic pathology was identified not only in the pan-creas, but also in the lung, thyroid, lacrimal and salivary glands, lymphnodes, extrapancreatic bile ducts, retroperitoneum, and aorta.3 Cu-riously, IgG4-RD in the brain parenchyma or spinal cord has neverbeen reported and central nervous system (CNS) involvement wasdemonstrated only in the form of hypophysitis. More recently, hy-pertrophic pachymeningitis (HP) has also been recognized as a clini-cal manifestation of IgG4-RD, which may account for a substantialpercentage of cases previously regarded as idiopathic. Indeed, HPis a potential manifestation of many different conditions includinginfectious diseases (eg, neurosyphilis, tuberculosis, bacterial men-ingitis, and fungal meningitis), inflammatory disorders (eg, granu-lomatosis with polyangiitis [formerly Wegener], giant-cell arteritis,rheumatoid arthritis, and neurosarcoidosis), and malignant neo-plasms (eg, dural carcinomatosis, metastasis spreading from adja-cent skull bone or brain, lymphomas, and meningioma).

To date, IgG4-RHP has been described in a number of case re-ports and series but consensus about the optimal diagnostic andtherapeutic approach is lacking. This review summarizes the cur-

rent knowledge on IgG4-RHP including its clinical and radiologicalpresentations, its pathology and epidemiology, and a proposal fordiagnosis and treatment.

MethodsA review of the literature from PubMed with the following searchterms: IgG4, pachymeningitis, IgG4-related pachymeningitis, IgG4-related disease, IgG4-related, and IgG4 meningitis) revealed 21reports, all published since 2009 (eTable and eReferences inSupplement provide the references for these reports). The 21reports include a total of 33 patients with histologically confirmedIgG4-RHP. Among these 33 patients, 21 (64%) were men and 12(36%) were women, with a mean age at diagnosis of 53 years(range, 32-82 years). Both the tendency of IgG4-RHP to affect menand the predilection for individuals who are middle-aged or olderare concordant with the known disease epidemiology.4 To ourknowledge, no data on the incidence and prevalence of IgG4-RHPand IgG4-RD have been reported to date for specific racial, geo-graphic, or ethnic groups.

ResultsPathogenesis of IgG4-RHPThe meninges consist of 3 membrane layers that envelop andprotect the CNS. They consist of the dura mater (also known aspachymeninges), the arachnoid, and the pia mater (known

Figure 1. Pathogenic Model of IgG4-Related Hypertrophic Pachymeningitis

Plasma cell

B

Plasma cell

Eosinophil

Macrophage

Fibroblast

Th2/Treg

IL-4IL-10

pM

HC

IL-4Il-10TGFβ

pMHC

pM

HC

IL-13

Fab-arm exchange

+

+

Activated T-helper and T-regulatory cells produce interleukins (ILs) that recruiteosinophils and macrophages and activate fibroblasts. Interleukin 4 and IL-10drive class switching of autoreactive B cells to IgG4 and IgE and induce thedifferentiation and expansion of IgG4+ plasma cells. Heavy chains are inserted

from different IgG4 molecules and separate and recombine randomly (Fab-armexchange), thereby generating asymmetric bispecific antibodies. pMHCindicates peptide major histocompatibility complex; TGFβ, transforming growthfactor β; Th2, type 2 helper T cell; and Treg, regulatory helper T cell.

Clinical Review & Education Review IgG4-Related Hypertrophic Pachymeningitis

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together as leptomeninges). The dura mater anchors the brainand the spinal cord to the bones of the skull and vertebrae,envelops the underlying arachnoid, and surrounds the duralsinuses. The dura mater is the chief meningeal layer involved inIgG4-RD but concurrent leptomeningeal disease may beunderestimated.5,6

Little is known with certainty regarding the initiating ofpathogenic events of IgG4-RD and, consequently, of IgG4-RHP. Ingeneral theory, the inflammatory infiltrate—mainly consisting of Band T lymphocytes, eosinophils, and scattered macrophages—activates fibroblasts and induces collagen deposition, leading totissue hypertrophy and increased dural thickness. Recent datasupport the concept that IgG4-RD is an antigen-driven diseaseinvolving collaboration between CD4+ T cells and activated,somatically hypermutated oligoclonal IgG4+ B cells.7 According to

this hypothesis, B-cell–dependent activation of pathogenicCD4+ T cells mediates inflammation and fibroblast activation(Figure 1).4 Recent work has demonstrated the intrathecal

Figure 2. Oligoclonal Bands in IgG4-Related Hypertrophic Pachymeningitis

A

C

B

D

Before Treatment

After Treatment

IgG IgG4

CSF Serum CSF Serum

IgG IgG4

CSF Serum CSF Serum

Magnetic resonance imaging ofa patient with IgG4-relatedhypertrophic pachymeningitis(arrowheads) (A) showing resolutionof dural thickness after therapy (C).Concomitant cerebrospinal fluid(CSF) analysis findings demonstrateIgG and IgG4 oligoclonal bands(arrowheads) (B) that disappearafter treatment (D).

Table 1. Common Presenting Neurological Features of 33 PatientsWith IgG4-Related Hypertrophic Pachymeningitis

Symptoms and Signs No. (%)Headache 22 (67)

Cranial nerve palsies 11 (33)

Vision problems 7 (21)

Motor weakness 5 (15)

Limb numbness 4 (12)

Hearing loss 3 (9)

Seizures 2 (6)

Cognitive decline 1 (3)

IgG4-Related Hypertrophic Pachymeningitis Review Clinical Review & Education

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production of IgG4 oligoclonal bands in the cerebrospinalfluid (CSF) of patients with active IgG4-RHP and has confirmedthe disappearance of these bands during remission (Figure 2).8

Oligoclonal bands signify the compartmentalization within theCNS of a highly restricted number of antigen-specific B-cellclones that have been transformed, after affinity maturation,into immunoglobulin-secreting plasma cells. The presence ofoligoclonally restricted IgG4-positive plasma cells within inflam-matory niches in the meninges strongly supports a patho-genetic model in which the fibroinflammatory immune reactionis triggered by a specific response against a still unknownantigen.

Table 2. Associated Common Systemic Features in 33 PatientsWith IgG4-Related Hypertrophic Pachymeningitis

Organ-System Involvement No. (%)None 10 (30)

Unknown 9 (27)

Bone 4 (12)

Salivary glands 3 (9)

Lung 3 (9)

Kidney 2 (6)

Orbital pseudotumor 2 (6)

Retroperitoneal fibrosis 2 (6)

Figure 3. Radiological Features of IgG4-Related Hypertrophic Pachymeningitis

A

D

G H I

E F

B C

T1-weighted magnetic resonance (MR) imaging, showing hyperintense lineardural thickening (arrowheads) overlying the supratentorial hemispheres (A andB) and the tentorium cerebelli (C) as well as nodular pachymeningealenhancement along the clivus (D and E). Dural thickening appears hypointenseon the T2-weighted MR image (F, asterisks). Pachymeningitis involving the

cranial nerves’ canals (arrowheads) shown by gadolinium-enhancedT1-weighted MR imaging (G) and positron-emission tomography (H). Duralthickening is seen throughout the cervical spine with focal nodularity at theC2-3 and C6-7 levels (arrowheads) (I).






The signal for B-cell class to switch to IgG4 remains unclear, butmany cytokines that stimulate IgE production also promote IgG4 pro-duction. The immunoregulatory cytokine interleukin (IL)–10 isthought to divert classic Th2-type immunity away from IL-4– and IL-13–induced IgE responses in favor of IgG4.9 Indeed, IL-10 has beenshown to trigger a modified Th2 response by inducing the differen-tiation of IgG4+ B cells. In the presence of IL-4, IL-10 directs B cellsto undergo antibody class switching and secrete IgG4.10

IgG4 comprises only 1% to 4% of the total IgG population inhealthy individuals. In contrast with other IgG subclasses, IgG4 hasa limited ability to activate immune responses because of its low af-finity for both Fc receptors and the C1 complement molecule.4 IgG4is also unique in its ability to undergo half-antibody exchange, a pro-cess where the IgG4 heavy chains dissociate from each other andreassociate randomly with other nonsymmetrical antibody halves.As a consequence of the half-antibody exchange, IgG4 moleculesbecome functionally bispecific (capable of binding 2 antigens, nei-ther tightly) and rarely associate with each other to form large im-mune complexes (Figure 1).4 In view of this noninflammatory na-ture of IgG4, its elevated concentrations in IgG4-RD probably do notrepresent the primary disease driver but rather signify a secondaryprocess designed to dampen ongoing immune activation or, ulti-mately, an epiphenomenon.4

Clinical FeaturesPresentationThe neurological presentations of patients with IgG4-RHP typi-cally reflect mechanical compression of vascular or nerve struc-tures, leading to functional deficits. These presentations are notdistinguishable from those of patients with other forms of HP, butclinical manifestations of IgG4-RD beyond the meninges (eg, inthe orbits, lungs, and retroperitoneum) may yield important cluesto the underlying cause. Local dural involvement of the periorbitalareas, vestibular structures, and the clivus, brainstem, or spinalnerve roots typically causes focal signs such as visual or hearingimpairment, cranial or spinal motor nerve palsies, and sensoryalterations. In contrast, more diffuse symptoms, such as head-ache, neck stiffness, and seizures, occur if meningeal inflamma-tion spreads along the hemispheric and basal dura or the tento-rium cerebelli.

Table 1 summarizes the most common presenting neurologi-cal symptoms in patients with IgG4-RHP. Among the 33 cases re-ported to date, 22 (67%) presented with headache, 11 (33%) withcranial nerve palsies, 7 (21%) with vision problems (typically doublevision or decreased visual acuity), 5 (15%) with motor weakness, 4(12%) with limb numbness, 3 (9%) with sensorineural hearing loss,and 2 (6%) with seizures. Impairment of cranial nerves IX, X, and XIIis of particular concern given the importance of these nerves in co-ordinating airway protection during deglutition.

Patients with IgG4-RHP may also present with signs of sys-temic disease, namely, constitutional features such as weight lossand malaise, thyroid dysfunction (eg, from Riedel thyroiditis), ab-dominal pain caused by autoimmune pancreatitis, flank or back painassociated with retroperitoneal fibrosis or periaortitis, facial or neckswelling due to lacrimal or salivary gland enlargement, proptosiscaused by orbital disease, and pulmonary manifestations such as in-terstitial pneumonia or tracheobronchial stenosis (Table 2). Con-stellations of several of these other forms of organ involvement

strongly suggest IgG4-RD and offer the possibility of confirming thediagnosis underlying idiopathic HP without necessarily requiring ameningeal biopsy.

RadiologyImaging studies in IgG4-RHP are used to identify fibrotic menin-geal lesions, assess the potential for damage to neighboring struc-tures, provide clues about specific clinical manifestations, andmonitor disease activity. On computed tomography (CT) scansand magnetic resonance (MR) imaging studies, IgG4-RHP mayappear either as a linear dural thickening or as a bulging mass(Figure 3). Meningeal disease can be confined to localized areassuch as the meninges overlying the supratentorial hemispheres,skull base, or spinal cord. Alternatively, it can involve a combina-tion of these sites. In general, MR imaging offers certain advan-tages over CT in the anatomical evaluation of the optic chiasm,nerve roots, brainstem, and skull base. On T2-weighted MRimaging, fibrotic HP is thickened and relatively hypointense, withoccasional scattered foci of hyperintensity suggestive of inflam-mation. Gadolinium-enhanced T1-weighted MR imaging studiesmay offer superior spatial resolution and facilitate the identifica-tion of active inflammation along the dural edges. Conversely,CT scans are more useful in the assessment of concomitantbone involvement. Dural lesions typically appear thickened andhyperdense on CT studies and enhance after administration ofiodinated contrast.

Nuclear imaging in the form of positron emission tomographyscans with fludeoxyglucose F 18 has potential for use in assessingthe degree of active inflammation within the meninges and in iden-tifying extracranial meningeal involvement, as well as disease, inother organs.11 For the evaluation of intracranial meningeal lesions,carbon 11–labeled methionine is preferred because of its lowuptake in the normal brain.12

DiagnosisSerologySerological findings in IgG4-RHP may depend on the extent of dis-ease in both the meninges and extrameningeal organs. Acute-phase reactants, such as the erythrocyte sedimentation rate andC-reactive protein, are usually (but not always) elevated to a mod-erate degree. Increased levels of serum IgE also occur in some pa-tients. No specific antinuclear antibody and no cases of IgG4-RD as-sociated with high titers of anti-Ro/Sjögren syndrome antigen A oranti-La/Sjögren syndrome antigen B antibodies or antineutrophil cy-toplasmic antibodies have been reported to date. Although somepatients with IgG4-RD have low-titer–positive antinuclear anti-body assay results, the identification of a specific autoantibody usu-ally implicates another disease.

Elevated serum IgG4 levels are consistent with IgG4-RD andare present in 70% to 90% of patients with this condition. The dra-matic serum IgG4 elevations observed in some patients with thiscondition correlate with multiorgan involvement. Other IgG sub-classes, particularly IgG1, are frequently elevated in IgG4-RD aswell, although generally not to the extent of IgG4. However, mea-surements of both IgG4 and total IgG lack sufficient sensitivity andspecificity for the purpose of diagnosis.13 In addition, IgG4-RHP dif-fers from systemic disease in that the fibroinflammatory processoccurs in close proximity to the blood-brain barrier and the CSF.






The serum IgG4 concentrations in the periphery may remain nor-mal even as they increase in the CNS, particularly if the meningesare the only site of disease. The presence of an elevated serumIgG4 concentration in patients with IgG4-RHP generally implicatesextrameningeal disease.

Cerebrospinal FluidLumbar puncture provides essential information, the primary valueof which is the exclusion of CNS infections and malignancies. Cere-brospinal fluid evaluations in patients with IgG4-RHP generally re-veal clear fluid with normal glucose concentrations, normal to mildlyincreased protein levels, and a variable degree of lymphocytic pleo-cytosis (Table 3). Evaluations of the blood-brain barrier derived fromcomparing measurements of analytes in the CSF with those sameanalytes in serum typically exhibit pathological values of permeabil-ity indices, and (as noted) isoelectric focusing may reveal intrathe-cal synthesis of oligoclonal bands. These data support either mod-erate to severe damage to the blood-brain barrier or an inflammatoryinsult to the meninges. However, such findings are nonspecific andcannot differentiate IgG4-RHP from other forms of inflammatorypachymeningitis.

One study compared the CSF IgG subclass profiles frompatients with IgG4-RHP with those of patients with other forms ofinfectious, neoplastic, and inflammatory pachymeningitis.14 Inaddition to measuring the concentrations of IgG4 and other IgGsubclasses, the investigators calculated the IgG4 index and theIgG4Loc values to assess the degree of blood-brain barrier perme-ability and intrathecal production of total IgG and IgG subclasses.Compared with healthy control individuals and patients with other

forms of pachymeningitis, patients with IgG4-RHP demonstratedhigher CSF IgG4 concentrations as well as higher IgG4 indices andIgG4Loc values. The IgG4Loc value, which calculates and integratesserum and CSF IgG4 concentrations in relation to the blood-CSFbarrier, demonstrated the best diagnostic performance in differen-tiating the 2 groups. In one study, IgG4Loc values greater than 0.47had both a sensitivity and specificity of 100% in differentiatingIgG4-RHP from other causes of inflammatory pachymeningitis.11

Studies of larger numbers of CSF samples from patients withIgG4-RD and other conditions are required to confirm and extendthese findings.

PathologyBiopsy material from the meninges is the gold standard for thediagnosis of IgG4-RHP. Healthy dura mater consists of a thick,monotonous layer of dense fibrous connective tissue, includingmostly layered collagen with only scattered fibroblasts (Figure 4A).IgG4-RHP disrupts this ordered structure and leads to a character-istic pattern of fibrosis within the meninges, namely, a swirling,fibroinflammatory response that enmeshes the lymphoplasma-cytic infiltrate in tendrils of collagen (Figure 4B). The fibrosis, whichhas a basketweave pattern, is known as storiform fibrosis(Figure 5A and B). Hematoxylin-eosin staining displays dense baso-philic lymphocytic infiltrates comprising both T and B cells(Figure 5C). T lymphocytes, primarily CD4+ cells, are identifiedprominently within IgG4-RD tissues and are arrayed diffuselythroughout the tissues. In contrast, B cells tend to be locatedwithin lymphoid aggregates or even frank germinal centers. Eosin-ophils, macrophages, and even histiocytes are often observed.

Table 3. Features of Lumbar Puncture in IgG4-Related Hypertrophic Pachymeningitis

Parametera

Sourceb

Moss et al,2012

Tajimaet al, 2012

Yamashitaet al, 2012

Shapiroet al, 2012

Wallace et al,2013

Liptonet al, 2013

Hyun et al,2013

Della-Torre et al,2012 and 2013

Appearance Colorless,clear

Colorless,clear

Colorless,clear

Colorless,clear

Colorless,clear

Protein, mg/dL 42, 45 260 83 135, 22 71 44 76 82

Glucose, mg/dL 30, 40 51 59 42 73

White blood cell count,μL (lymphocytes %)

4 (44),12 (95)

14 25 (86) 23 112 (94),4 (88)

24 (93) 2 (100) 32 (100) 1 (100)

Cytologyc Neg Neg Neg Neg Neg Neg Neg Neg

Microbiologyd Neg Neg Neg Neg Neg

Oligoclonal bands Present Present Present

CSF IgG, mg/dL 38 8.7 17.4 18.8

IgG index 1.8 0.8 1.8

IgGLoc 5.5 1 12.4

CSF IgG4, mg/dL 4.94 5.36 5.17

IgG4 index 3.16 3.21 3.07

IgG4Loc 4.09 3.91 4.02

Abbreviations: CSF, cerebrospinal fluid; Loc, local immunoglobulin synthesis(according to the Reiber/Felgenhauer formula); Neg, negative.

SI conversion factors: To convert glucose to millimoles per liter, multiply by0.0555; IgG to grams per liter, multiply by 0.01; lymphocytes to ×109 per liter,multiply by 0.001.a Reference ranges are as follows: normal values for protein = 12-60 mg/dL,

glucose = 40-80 mg/dL, white blood cell count = 0-1/μL, ogliclonalbands = absent, CSF IgG = 0.8-3.8, IgG index = <0.7, IgGLoc = 0,

CSF Ig4 = 0.01-0.33 mg/dL, IgG4 index = 0.25-2.11, and IgG4Loc = 0.b See eReferences in Supplement.c Morphological and flow cytometry analysis for malignant cells.d Bacterial, fungal, and mycobacterial cultures as well as Venereal Disease

Research Laboratory test, polymerase chain reaction for herpes simplex virus,and cryptococcal antigen.






However, findings of either granulomatous inflammation or neu-trophilic infiltrates argue strongly against the diagnosis of IgG4-RD.1

Obliterative phlebitis, a pathology finding nearly unique to IgG4-RD(Figure 5D), appears as obliterated or semiobliterated veins. Theobliteration of the vascular structure is so complete that elastinstains are often required to identify residual vascular tissue. Finally,immunostaining for IgG and IgG4 demonstrates that a dispropor-tionate percentage of plasma cells within the lesion are IgG4+

(Figure 5E and F).

Immunohistochemistry and Diagnostic CriteriaAn international, multidisciplinary group of IgG4-RD expertsdescribed a consensus strategy for the pathology diagnosis ofIgG4-RD including IgG4-RHP.1 Pathology criteria for the diagnosisof IgG4-RD consist of 3 characteristic histological features includingdense lymphoplasmacytic infiltrate, fibrosis with storiform fea-tures, and obliterative phlebitis. The consensus maintains that 2 ofthese 3 histologic features should be fulfilled for a diagnosis ofIgG4-RD. When only 1 of these criteria is met, additional infor-mation—such as an increased serum IgG4 concentration, elevatedIgG4 to IgG ratio within tissue, or multiorgan involvement with typi-cal clinical manifestations of IgG4-RD in different organs—isrequired to support the diagnosis.

A common feature of IgG4-RD is the increased IgG4 to IgGplasma cell ratio on immunohistochemical evaluation. Previousstudies have suggested that an IgG4 to IgG ratio greater than 40%is indicative of IgG4-RD.5 Another important tool to differentiateIgG4-RD is the number of IgG4-positive plasma cells per high-power field (×400). However, no single immunohistochemicalfeature can be diagnostic of IgG4-RD, which requires the charac-teristic histologic findings as well as clinicopathologic correlation.Cutoff values for the number of IgG4+ plasma cells per high-powerfield vary according to the organ involved. In particular, for menin-geal disease, more than 10 cells per high-power field may be con-sidered sufficient for the diagnosis, particularly in biopsies charac-terized by extensive fibrosis, if the clinical scenario is alsocompatible.5

Treatment of IgG4-RHPThere is currently no consensus about treatment for patients withIgG4-RHP. A review of the published reports reveals a preferencefor glucocorticoid treatment on diagnosis, followed by the additionof other immunosuppressive agents in the event of a recurrence.6

A consensus guideline from Japan recommended treating IgG4-related autoimmune pancreatitis with prednisolone (0.6 mg/kg/d)for 4 weeks, followed by a 3- to 6-month taper to a maintenance

Figure 4. Anatomic Pathology of IgG4-Related Hypertrophic Pachymeningitis

A BSubarachnoid space(cerebrospinal fluid)

Skull bone

Pia mater

Dura mater

Arachnoid

A, The IgG4-related disease causes hypertrophic thickening of the dura mater(and likely leptomeninges) with mass effect on neighboring structures. Healthydura mater consists of dense fibrous connective tissue with only scatteredfibroblasts (hematoxylin-eosin, original magnification ×200). B, IgG4-related

hypertrophic pachymeningitis disrupts this ordered structure and leads to acharacteristic pattern of storiform fibrosis (hematoxylin-eosin, originalmagnification ×200).






dose of 2.5 to 5.0 mg/d for up to 3 years.14 The degree to whichthese recommendations can be extrapolated to IgG4-RHP is notclear, but the potential implications of severe neurologic dysfunc-tion caused by IgG4-RHP justify beginning treatment in somepatients with pulse methylprednisolone (eg, 1 g of methylpredniso-lone a day for 3 days) followed by a glucocorticoid taper longerthan those used in autoimmune pancreatitis.11 The doses and dura-tion of glucocorticoid therapy are highly empirical and not specifiedin detail in most published reports.

Steroid-sparing agents have been used following diseaseflares including methotrexate (20 mg/wk), azathioprine (100-200 mg/d), mycophenolate mofetil (1000 mg twice daily), andcyclophosphamide (either oral [100 mg/d] or intravenous [1g/m2/mo]. The efficacy of these treatments has never been con-firmed to be independent of the effects of glucocorticoids, whichare always used concomitantly. To our knoweldge, no randomizedclinical trials of conventional steroid-sparing agents have beenperformed.

The most promising steroid-sparing agent is rituximab, an anti-CD20+ B-cell–depleting agent that appears to be effective for manysystemic manifestations of IgG4-RD, leading to both substantial

reductions of serum IgG4 concentrations and clinical improve-ment.15 However, experience with B-cell–depletion strategies inIgG4-RHP remains limited and with alternate results.6 Indeed, asfor other immunosuppressive agents, the overall efficacy of ritux-imab may depend on both the stage of the fibrosis and the menin-geal layer involved. In fact, dense, well-established, end-stage,pauci-inflammatory fibrosis is likely to be unresponsive to immuno-modulation. On the other hand, capillaries in the leptomeninges, incontrast with those in the dura mater, share many morphologicalsimilarities with intracerebral vessels, composing an element of theblood-brain barrier.16 This, in turn, means that drug concentrationin the leptomeninges may vary according to the chemical andphysical properties of the molecule itself as well as the integrity ofthe blood-brain barrier.

ConclusionsFuture treatment studies are likely to focus on B-cell depletion andthe mechanistic impact of this intervention on both the clinical andimmunological features of IgG4-RD.

Figure 5. Histopathology of IgG4-Related Hypertrophic Pachymeningitis

A B

C D

E F

Dural perivascular lymphoplasma-cytic infiltrate surrounded by stromalfibrosis (hematoxylin-eosin, originalmagnification ×200 [A] and×400 [B]). C, T lymphocytes areinterspersed throughout the tissue,but B cells tend to localize withinlymphoid aggregates or germinalcenters (hematoxylin-eosin, originalmagnification ×300). D, Stain showsobliterative phlebitis(hematoxylin-eosin, originalmagnification ×400).Immunohistochemistry stainingreveals abundant IgG4+ plasma cells(hematoxylin-eosin, originalmagnification ×200 [E] andhematoxylin-eosin, originalmagnification ×400 [F]).






ARTICLE INFORMATION

Accepted for Publication: January 31, 2014.

Published Online: April 14, 2014.doi:10.1001/jamaneurol.2014.243.

Author Contributions: Drs Stone and Clark had fullaccess to all of the data in the study and takeresponsibility for the integrity of the data and theaccuracy of the data analysis. Drs Lu and Della-Torrecontributed equally to this manuscript.Study concept and design: All authors.Acquisition, analysis, or interpretation of data: Allauthors.Drafting of the manuscript: All authors.Critical revision of the manuscript for importantintellectual content: All authors.Statistical analysis: Della-Torre.Administrative, technical, or material support:Della-Torre, Stone.Study supervision: Della-Torre, Stone, Clark.

Conflict of Interest Disclosures: None reported.

Additional Information: Supplemental materialincludes the source of the information for thepresent review, namely, an eTable with the 33 casereports describing histologically provenIgG4-related hypertrophic pachymeningitis and therelative references available in the literature.

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Review IgG4-RelatedHypertrophicPachymeningitis … · 2020. 12. 17. · IgG4Loc 4.09 3.91 4.02 Abbreviations:CSF,cerebrospinalfluid;Loc,localimmunoglobulinsynthesis …

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