Inflammatory Bowel Diseases - Mucosal Immunology...2 Definition of Inflammatory Bowel Diseases (IBD) Chronic relapsing inflammatory diseases involving : - The whole GI tract Crohn‘s

1

Wednesday Feb. 25th 2015 8:15 – 9:00 Master's Course in Gastroenterology Universitätsklinik für Viszerale Chirurgie und Medizin Inselspital, Bern

Source: MGH Crohn’s and colitis center

Inflammatory Bowel Diseases

Dr. med. P. Juillerat, MSc Oberarzt I Head of IBD clinical studies

Source: medicaldaily.com

2

Definition of Inflammatory Bowel Diseases (IBD) Chronic relapsing inflammatory diseases involving : - The whole GI tract

Crohn‘s disease

11% : unclassified = undeterminate / unspecified colitis

- Colon and Rectum Ulcerative colitis

3

Crohn‘s disease ulcerative colitis

segmental continuous

diarrhea, abd. pain, rectal bleeding malabsorption, ... urgencies

All GI-tract only colon

transmural superficial

fistula, abscess, stenosis toxic megacolon, perforation Hoffmann JC et al. DGVS Leitlinien Z Gastroenterol 2008; 46: 1094–1146 Sands BE et al. Gastroenterology 2004;126:1518–1532

4

Prof. M. Neurath, Nature reviews 2014 ; vol. 14 : 329- 42

genes and environnment

The intestinal barrier is impaired

immune deficiency

Inappropriate «overreaction» of the immune system

Pathogenesis of IBD I

5

N= 14,763 CD, 10,920 UC and 15,977 controls Æ 193 suceptibility loci, among 71 new

Lees CW, Satsangi J. et al, Gut. 2011;60(12):1739-53. Jostins, et al nature 2012

Genetic of IBD (based on GWAS) Nature 2001

6

Pathogenesis of Inflammatory Bowel Diseases

Æ10 years ago

The Th1/Th2 paradigm. from Romagnani S. TH1/TH2 Cells. Inflamm Bowel Dis 1999;5:285–294.

7

Source: Baumgart et al. Lancet 2012

Anti-TNF alpha

Other Cytokines

Anti- integrin

ÆNOW !

8

Pathogenesis IBD II Microbiom «Dysbiosis»

Sokol H, Curr . Op .Gastro . 2010 . Round JL, Nat. Rev. Immunol. 2009

• ↓ Diversity of Bacteroidetes

• ↓ Firmicutes (e.g. Clostridium)

• ↑ Proteobacteria

• ↓ „good“ bacteries („Symbionts“ e.g. F. prausnitzii)

R. Navus F.Nucleatus Ecoli AIEC

F. prausznitzii R. intestinalis A. muciniphyla

9

HOW FREQUENT ?? Do you know people with IBD???

?

10

One Study on prevalence in Canton de Vaud � 1/500 individual has inflammatory bowel disease (IBD) In Switzerland : (Vaud is very similar to Switzerland for age and gender)

12’000 IBD patients (6100 CD; 5900 UC)

Juillerat et al. Journal of Crohn's and Colitis (2008) 2, 131–141

11

Switzerland compared to Europe

USA + Canada

Sud de l’Europe et Europe de l’Est

Nord de l’Europe

et Grande-Bretagne

Juillerat et al. Journal of Crohn's and Colitis (2008) 2, 131–141

12

First peak of prevalence between 20 and 40 years old

2nd peak of prevalence Around 60-70 years old But 20 – 30% of the patients are < 20 years old

Juillerat et al. Journal of Crohn's and Colitis (2008) 2, 131–141

13

Paradoxal effect of SMOKING

Deleterious for Crohn’s disease (OR >2), but protective for ulcerative colitis !! (OR 0.5)

however … no reason to smoke !

Cosnes J et al. Best Pract Res Clin Gastroenterol. 2004;18:481-496.

14

Crohn

Smoking and IBD Diagnosis

05

1015202530354045 UC Smoking cessation

Jahren

Cosnes J et al. Clin Gastroenterol Hepatol 2004; 2: 41-48

N= 1784 IBD, 1096 UC , 688 Crohn

279 (61%)

52 (12%)

15

Crohn’s Disease

16

Crohn‘s disease ILEITIS and COLITIS

17

Diagnosis: Endoscopy Æ HISTOLOGY

Hoffmann JC et al. DGVS Leitlinien Z Gastroenterol 2008; 46: 1094–1146 Sands BE et al. Gastroenterology 2004;126:1518–1532

Segmental focal inflammation of the whole intestinal wall : 1) Destruction / modification of the architectures oft the crypts 2) Infiltration of Lymphocytes and Plasmocytes 3) epitheloid Granuloma (20–40 %) 4) Reduction of gobelet cells Macroscopically : microerosions, fissures, ulcerations

Crohn‘s disease Normal

18

Crohn‘s disease lesions

• Most frequent : terminal ileum & caecum

• Upper GI : rare

• rectum : rare and mostly associated with fistula

Harrisons Gastroenterologie und Hepatologie, 1. Auflage; Martin Zeitz, Hartmut H.-J. Schmidt, Christian Bojarski (Hrsg.); ABW Wissenschaftsverlag, 2011.

Upper GI : 4% Ileum & colon 40-55% Ileum only 30-40% Colon only 15-25%

19

Silverberg MS, et al. Can J Gastroenterol 2005; 19:5–36. Quelle: Baumgart et al. Lancet 2012

Montréal classification of Crohn‘s disease

20

MRI-example : inflammation type B1

1 year later

21 21

Complication of the behavior of Crohn‘s disease: ulcerations Æ Stenosis – stricturing Type -

Courtesy of Prof. Dr. med. R. Ehehalt

ulcerations stenosis

22

Crohn disease after resection

Wall thickening Stricture

– stricturing type - B2 -

23

Complication of the behavior of Crohn‘s disease: Perforations Æ Fistula – penetrating type - B3 - fistulizing perianal - +P -

24

Crohn disease : evolution

Cosnes J, et al. Gastroenterology 2011 ;140 (6):1785–1794

25

Progression of digestive damage and inflammatory activity in a theoretical patient with CD Pre-clinical Clinical

Inflamm

atory Activity

(CD

AI, CD

EIS, PCR)

Surgery

Stricture

Stricture

Fistula/abscess

Disease onset

Diagnosis Early disease

Dig

estiv

e D

amag

e

Progression of digestive disease damage (Lémann score) and inflammation

Pariente B et al. Inflamm Bowel Dis 2011;17(6):1415-22

Typ B1

Typ B2 Typ B3

TREATMENT

26

Therapeutical Arsenal

« Optimizing» therapy means currently: Æ An « accelerated» step –up ! OR …

27

Evolution of the need for surgery in CD since the 1930's and impact of medications

1930 1940 1950 1960 1970 1980 1990 2000 2010 2020 2030 0

10% 20% 30% 40% 50% 60% 70% 80% 90%

100% Probability of receiving biologics at 5 years Probability of receiving immunosuppressants at 5 years

Rate of surgery at 5 years

Disease duration before introduction of biologics (yr)

3-5 7-8 1-2

0 10% 20% 30% 40% 50% 60% 70%

Population-based studies (within 5 yr)

Randomised controlled trials (at 1 yr)

Referral centre trials (within 5 yr)

Before the era of biologics In the era of biologics

44.4

29

9.1 3.7

23.6 21.4

Courtesy LPB Bouguen and Peyrin-Biroulet, Gut 2011

28

New concepts

Early : changing the course of disease

Mucosal Healing and deep remission

Long term use

before after

Van Dullemen HM et al. Gastroenterology 1995;109:129-135

29

« Mucosal Healing » = best prognosis

• longer period of steroid free remission

• ↓ hospitalizations

• ↓ intestinale resections (Crohn’s disease) or less colectomies (ulcerative colitis)

• ↓ neoplasia (↓ inflammation; UC)

80 vs 27% (Baert et al, 2010)

19 vs 28% ( Rutgeerts 2006) (Schnitzler IBD 2009) (Froslie, Gastroenterology + Am J Gastro 2007; Sjoberg

Gut 2008 [Abstract])

(Rutter 2004, Rubin 2006, Gupta 2007)

Congrès de l’ASPE, 12 sept. 2013 - Dr P. Juillerat MSc. Hôpital de l’île. Berne

30

CONCEPT of deep remission

J.F. Colombel, Adalimumab EXTEND trial

clinical and biological remission

Endoscopical remission

Clinical flare CRP

Endoscopic flare, ev. calprotectin ↑

Transmural flare Æ Only at MRI

DEEP remission

Remission

31

ulcerative colitis

32

Colitis ulcerosa – Befallsmuster

32

Harrisons Gastroenterologie und Hepatologie, 1. Auflage; Martin Zeitz, Hartmut H.-J. Schmidt, Christian Bojarski (Hrsg.); ABW Wissenschaftsverlag, 2011.

•Proctitis (40–50 %)

• rectal pain, urgency • stool incontinence • blood - mucus

Left sided colitis (30–40 %)

• bloody diarrhea • obstipation

Pancolitis (20 %)

• weight loss • fever • severe bleeding • abdominal pain

Backwash-Ileitis (10–20 % of patients with Pancolitis)

Montréal classification for ulcerative colitis E1 E2 E3

33

Mayo clinic (Rochester, USA) classification

Mayo 1 = mild - erythema + -↓ partial loss of vascular pattern

Mayo 2 = moderate - Erythema ++ - complete loss of vascularity - contact bleeding - Erosionen

Mayo 3 = hochgradig - Spontaneous bleeding - ulcerations Rutgeerts P, et al.. N Engl J Med. 2005 Dec 8;353(23):2462-76.

0 = Remission

34

Ulcerative colitis : Chronic lesions (pseudopolyps)

Initial inflammation Æ Pseudopolyps

35

activity mild - moderate severe

Number stool/ d < or = 5 > 5

Blood in the stool few a lot

Temperatur < 37,5°C > = 37,5°C

Puls < 90/min > = 90

BSR < 30 mm/h > = 30mm/h

Hemoglobin > 10g/dl < = 10g/dl

Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. BMJ 1955;4947:1041–8

Fulminante or toxic colitis:

• > 10 Stool/d, continously with blood loss, Abdominal tenderness • Radiological wall thickening and potential dilatation of the proximal colon (megacolon)

Ulcerative colitis : evaluation of severity / TW criteria

36

Ulcerative colitis : fulminant colitis Æ colectomy

Source : Wikipedia

37

FDG-PET Courtesy of Prof. Neurath

ulcerative colitis – treatment paradigm

Anti-TNFs

38

Treatment algorithm for mild to moderate UC.

from Rogler, Dig Dis 2009;27:542–549

Anti- TNFs

39

Mucosal Healing and : colectomies LOR to infliximab

40

Groupe I: frequent extraintestinal manifestations Rheumatological

Ophtalmological

Dermatological

Hepatological

Peripheral arthritis

Typ I / II

Spondylarthritis

Uveitis (Epi)Scleritis

Stomatitis

Pyoderma gangrenosum Erythema nodosum

PSC

Vavricka SR, et al. Am J Gastroenterol 2011; Su & Lichtenstein Gastroenterol Clin N Am 2002

IBD Patients >35%

41

Dermatologische Stomatitis

Pyoderma gangrenosum

Erythema nodosum

15% IBD patients

Vavricka SR, et al. Am J Gastroenterol 2011; Su & Lichtenstein Gastroenterol Clin N Am 2002

42

Groupe II: Extraintestinale complications ! Æ Associated with bowel dysfunction / malabsorption

• Osteopenia/ porosis • Osteonecrosis

(could be steroid-associated)

• Gallstones •Choledocholithiasis • Leberabscesses • Portal vein thrombosis

Urological: • Renal stones

Hematological : • Anemia • coagulopathy

Pancreas: • Crohn of the papilla

Vavricka SR, et al. Am J Gastroenterol 2011; Su & Lichtenstein Gastroenterol Clin N Am 2002

43

Hypertrophic Osteoarthropathies Polychondritis

• Pyostomatitis vegetans • Psoriasis • Erythema multiformis • Epidermolysis bullosa • Vasculitis • Sweet Syndrome • Cutaneous Crohn

Harnwege: • Amyloidose • Obstructive Uropathie • Fisteln

Hematological, HNT, CNS,

pulmonary and cardiac manifestations

Groupe III: rare EI manifestations and associated diseases

• Pericholangitis • cirrhosis • Steatosis • Granulomatous Hepatitis • Autoimmune Hepatitis

Pancreas: • Granulomatous Pancreatitis

Vavricka SR, et al. Am J Gastroenterol 2011; Su & Lichtenstein Gastroenterol Clin N Am 2002

44

Terzic, Gastroenterology 2010

Ulcerative colitis associated colorectal carcinoma

45

Recommendations for colitis (Crohn or UC) colorectal cancer screening

• Based on disease duration and extension: 8–10 Jahre (pancolitis) 15-20 Jahre (left –sided colitis) • then, controls (in particular with pancolitis)

every 2–3 years after 20 y. dis. duration every 1-2 years after 30 y., 40 y., ...

• CAVE: every year with the diag. of primary sclerosing cholangitis

Farraye AGA Technical review GE 2010, Josh Korzenik MGH , Boston

46

! !

Wang, Loftus et al. Am J Gastro 2013; 108:444-9

47 Farray. AGA Medical Position Statement and Technical Review, Gastroenterology 2010

High grade Dysplasia

DALM: Dysplasia-Associated Lesion or Mass Adenoma-like DALM Non-Adenoma-like DALM

Low grade Dysplasia

3-6 Mo

48

Chromoendoscopy • Dye: Indigocarmin (or methylen blue) vial of 5 ml, with 20 ml NaCl [Spritze] (or 10 ml/50 ml) Æ Spray – catheter => use oft at least 40 ml

49

Lausanne

Genève

Zürich

Basel

St-Gallen

Bern

Æ From November 2006 till now

SWISSIBDcohort study

[email protected]

www.ibdcohort.ch