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IBD: clinics and pathogenesis

Prof. Dr. Frank SeiboldGastroenterologie

Spital Netz Bern Tiefenau undInselspital Bern

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IBD: heterogeneous diseases

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Befallsmuster bei M. Crohn

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Intestinal involvement in CD

• Everywhere in the GIT

• Transmural• Segmental• Luminal, stenosing,

fistulizing

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IBD Clinics

• Ulcerative colitis– continuous– Inflammation starts in

the rectum– blood– mucosa– No fistula– Extraintestinal

manifestations

• Crohn‘s– segmental– ileocoecal– Not frequently blood– Transmural– Fistula– Extraintestinal

manifestations

– stenosing

In 10-30% differential diagnosis CD - UC not possible:Colitis indeterminata.

Both diseases: Fatique, fever, abdominal pain, cramps, diarrhea. From first symptoms till diagnosis >2 years

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Granuloma in Crohn‘s disease

• Found in max. 50% of pts with CD• Frequency: Small intestine 1: colon 6:

rectum 18: anus 36• Patients with multiple

granuloma in colon withmild course of diseaseChambers, Gut 1979

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Diagnostic relevance of antibodies to differentiate CD - UC (105 patients)

Marker status Serological diagnosis

Clinical diagnosis

Positive pre-dictive value

ASCA+, PAB+N=25

CD CD =25 100%

ASCA +N=30

CD CD=29UC=1

96%

PAB+N=6

CD CD=6 100%

pANCA+, ASCA+N=8

CD CD= 7UC=1

87%

pANCA+N=36

UC UC=32CD=4

89%

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Extraintestinal manifestations in IBD

• Indicates that IBD is a systemic disease• Arthritis (15%), Spondylitis, • hepatic: PSC• ocular: Episkleritis/Iridozyklitis• dermal: Erythema nodosum, Pyoderma

gangrenosum• Pankreas• lung, kidney, heart??

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Complications in IBD• bleeding• Stenosis• Ileus• Kachexia• Folic acid and Vit. B 12 deficiency• Short bowel• Stoma• Abszess • Fistula• Extraintestinal Manifestations• Colon carzinoma

10Cosnes J et al. Inflamm Bowel Dis. 2002;8:244.

240228216204192180168156144132120108968472604836241200

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20

30

40

50

60

70

80

90

100

PatientenMonate

2002 552 229 95 37N =

Penetrating

Stenosinginflammatory

Kum

ulat

ive

Häu

figke

it (%

)

Natural course in Crohn‘s

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Pathogenesis of IBD• Questions:

– tasks of the intestine?– challenges of the intestinal immune system?

• Epidemiology• Environmental factors• Genetics• immunology

Postsurgical Recurrence of CD

McLeod RS, et al. Gastroenterology. 1997;113:1823-1827.

Rising Incidence of CD

Courtesy of S. Schreiber.

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Nord-Süd-Gefälle in EuropaAktuell: Zunahme der Inzidenz in Nordafrika

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Epidemiologie IBD

• CH: IBD ca.: 2/1000 inhabitants• More frequently in agglomerations compared to

country• North-south gradient• Danmark: Incidence of pediatric Crohn-cases

1998-2000 in comparison to 1996 10-fold elevated

• Arabs are less diagnozed with CD than Jews

» UEGW 2003

Impact of Smoking Cessationon Crohn’s Disease Outcome

Gastroenterology 2001

p<0.001

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1435

21

37

0 12 24 36 48

Months after inclusion

20

40

60

80

100

Prob

abili

ty o

f Fla

re-u

p (%

)

6

0

QuittersContinuous smokersNon-smokers

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Further environmental factors

• No proven relationship to food intake• Appendectomy: AE protects from UC• Role of infection: association between

acute gastroenteritis and the development of IBD

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IBD Genetics• First-degree relatives of IBD: 3-20x risk to

develop disease• Twin studies• Concordance in the location and type of CD• Mouse studies• More than 40 mutations detected that are

involved in human IBD• Gen variants lead to a disturbed innate

immunity: autophagy, phagocytosis

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Genetic Complexity in IBD

‘Significant' Linkage

‘'Suggestive’ Linkage*

Replicated

Non=replicated

Non-replicated

Replicated

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16

IL-4 rec

CD10

CD11

E-cadherin

α 1-integrin

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VDR

NRAMP2

STAT6

MMP 18

α5-integrin

Interferon γ

β7-integrin

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TCR α and δ

Proteosome cluster

Leukotriene B4 rec 19

ICAM1

C3

TBXA2

LTB4H

IL 3-5,13

CSF 2

13 4

5 6

HLA Class I-III

MICA

NFκB

IFN-γR

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MUC 3

EGFR

HGF

CCR5

GNAI2

Cytokine cluster

hMLH1IL-2 gene

TGF-β2

TGF-β4

E2G

TNF-R family

HSPG2

UBE1L

IL12A

Satsangi et al. Best Pract Res Gastro 2003:17;3.

IBD1-locusIBD1-locus

NOD2/CARD15

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IBD 1: mutations in NOD2

• Susceptibility of ileal CD• NOD2 protein activates NFkB in response

to a fragment of bacterial peptidoglycan (muramyl dipeptid)

• Mutations found in 10-30% of patients with CD, mutation not found in Asia

• NOD2 gene found in macrophages

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IBD genetics• NOD2• IBD5• Il23 R• ATG16L1• Chr 5p13.1• Chr5q33.1• Chr10q21.1• NCF4• TNFSF15

Figure 2. Pathogenesis of Inflammatory Bowel Disease: Induction of Inflammatory Cascade Bacterial antigens inappropriately leak across the intestinal epithelial cell barrier.

Blumberg, R. S. et al. JAMA 2001;285:643-647

Copyright restrictions may apply.

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Mouse models in IBD

• MDR1 -/- altered epithelial barrier• IL10-/- Lack of T reg• SAMP1/YIT epithelial cell defect, expanded B cells• CD4 CD45RBhi decreased T reg• TCRa-/- lack of regulatory B cells• WASP-/- regulatory B cells• CD40L tg increased activated T cells• DSS direct damage to epithelial barrier• TNBS hapten• Muc 2-/- mucus defect• N-cadherin mutant barrier function• IL2-/- decreased CD4 CD25+ cells• NFkB-/- increased IL2 production

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IBD and flora• T cell and humoral response towards the

resident intestinal flora• Special E coli eg LF 82 that adheres to

epithelial cells of the ileum• In animal models specific germs eg

Bacteroides vulgatus were able to induce colitis in IL10-/- mice

• What is the „normal flora“?• IBD: flora is different

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Early lesions of recurrent CD caused by infusion of intestinal contents in excluded ileum

D‘Haens, Gastroenterology 1998, 114: 262

3 patientsInfusions of luminal contentsIn excluded ileum for 8daysFocal infiltration with Mononuclear cellsEosinophils in lamina propria, Vessels, and epithelium

Intestinal contents trigger postoperative recurrence of CD

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Unterschied DarmfloraAfrika vs Europa

• Darmflora durch Ernähung beeinflusst

• Aufbau normaler Darmflora nicht ausreichend bekannt

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Enteric flora in IBD

Arumungam Nature 2012

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Dysbiosis as a predictive factor for relapse in Crohn‘s

disease• 31 Kontrollen und 37 Patienten mit CD zum

Zeitpunkt IFX Stopp• Stuhlproben Monat 0,2,6• 18 Pat. Schub, 19 Remission• PCR Analyse der Bakteriengruppen • Dysbiose Monat 0 mit wenig Firmicutes, F.

prausnitzii• Patienten mit Rezidiv: Dysbiose mehr

ausgeprägt» Rajca, ECCO 2011

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Epithelial barrier

• Mucus• MUC2-/- mice develop colitis• Paneth cell deficiency increases the risk

for CD

Pathogenesis of IBD

Immune systeme

T-cell

Genetic predisposition, NOD2

Exogenous factors

Intestinal flora

Th17

Th2

IL4,IL13, IL10

IL2,γIFN, TNFa

IL1, IL6, IL8, Radicals, Leukotriens, NO Proteases, acute phase proteins

IL12IL4

HomingICAM

Inflammation

TNFa anti-TNFaThalidomid

T reg

Innate immunesystem

Th1

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Treatment of IBD

• Anti-inflammatory: eg. Mesalamin=5-ASA (UC)

• Antibiotics (CD), Probiotics (UC)• Prednisone/ prednisolone• Immunosuppressants: Azathioprin, 6-

mercaptopurine, metothrexate• TNF blocker

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Summary• IBD are heterogeneous diseases• IBD can be treated but not cured• CD: transmural, frequently patchy disease• UC: mucosal disease, always continuous

involvement• Incidence increasing• Pathogenesis: genetic, environmental and

immunologic reasons.• Defects in innate immunity of major importance