2013.05.09.

1

Inflammatory Bowel diseases

LAKATOS Péter László

Semmelweis University, 1st Department of Medicine

Inflammatory bowel diseases (IBD)

Colitis of known origin

– Infectious colitis (Salmonellas, Shigella, Campylobacter jejuni,

Yershinia, amoeba)

– Pseudomembranous – antibiotic associated colitis (Clostridium

difficile)

– Ischaemic colitis

– Collagen colitis

– Irradiation colitis

– Microscopic colitis, lymphocytic colitis

– Diverticulitis

Colitis of unkown origin

– Ulcerative colitis

– Crohn’s disease

IBD epidemiology

UC incidencie: 0,5-20/100 000

CD incidencie: 0,1-11/100 000

UC prevalence: 50-200/100 000

CD prevalence: 20-100/100 000

UC/CD ratio is decreasing (from 4-5:1 to

2:1)

Incidence in North America vs Europe

No Difference!

Logan RFA Gut 1998;42:309

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Current trends

Current incidence in North America

Stabilizing?

Loftus EV Jr Inflamm Bowel Dis 2007;13:254-61.

Current studies in Western and Northern Europe:

Differences evolution of UC and CD incidence?

Molinie F Gut 2004;53:843-48

Current studies in Western and Northern Europe:

Still increasing numbers?

Vind I Am J GE 2006;101:1272-82.

Jacobsen BA EJGH 2006;18:601-6.

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IBD epidemiolology

More prevalent in „Western” developed

countries

West to East greadient?

Urbanization and „western type diet”

Higher education

IBD epidemiology in Hungary

IBD epidemiolology

Gender: both sexes are affected almost equally

(CD slight female predominance, UC slight male

predominance)

Age at onset: late adolescence, early adulthood

Ethnic differences: determined by genetics

and/or environmental factors

Perinatal events, „hygene”, „Oversheltered

child”

IBD etiopatogenezise

I. Genetics

II. Environmental factors

Luminar antigens? Microbes? Diet?

Pszichosomatic disturbance?

III. Epithelial factors

IV. Immunological factors

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IBD pathogenesis

Genetic predisposition, various environmental

and host factors (e.g. genetic-, epithelial-,

immune and non-immune) play a major role in

the pathogenesis of IBD

Genetics in the pathogenesis of IBD

Poligenic disease

Several loci and susceptibility genes have been

identifed

Some genes are associated with CD or UC, while

other are predicting disease phenotype or

progression

IBD locus Chromosome Identified genes Disease

IBD1 16q13 NOD2/CARD15 CD

IBD2 12q14 Not known

(VDR, NRAMp2, MMP18,

b2-integrin)

UC

IBD3 6p Not known

(HLA, TNF)

IBD

IBD4 14q11-12 Not known

(TCR, LTB4 receptor)

CD

IBD5 5q31-33 SLC22A4/A5

(IRGM, IL-4,6, CD14)

CD

IBD6 19p13 Not known

(ICAM1, C3, TBXA2)

IBD

IBD7 1p36 Not known

(TNF-R family, IL-23R)

IBD

IBD8 16p12 Not known CD

IBD9 3p26 Not known

(CCR5, CCR9, hMLH1)

IBD

10q23 DLG5 IBD

2q37 ATG16L1 CD

7q32 IRF5? IBD

Modifed from Lakatos PL Curr Genom 2006

Pattern recognition receptors (PRRs)

Important role in innate immunity

Recognition and response against Gram-negative bacteria

Extracellular – membrane bound, Toll Like Receptors (TLR)

Intracellular – in the cytosol, NOD2/CARD15

Some mutations predispose to bacterial infections, others to immune mediated diseases

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NOD2/CARD15 as a

Pattern recognition receptor (PRR) NOD2/CARD15 mutations

„Major” NOD2/CARD15 mutation

– Missense: R702W (SNP8)

– Missense: 908R (SNP12)

– Frameshift-insertion ( C): 3020insC (SNP13)

Risk for CD

Heterozygous: 2-4x

Homozygous or compound: 20-40x

Ahmad T Gastroenterology 2002;122:854-66.

Satsangi J. Best Pract Reas Clin Gastroenterol 2003;17:3-18

Chamaillard M PNAS 2003;100:3455-60.

Lakatos PL World J GE 2005;11:1495

Peptidoglycan (G+) Lipoprotein Lipoarabinomannan (Mycobacterial) LPS (Leotosopia) LPS (Porphyromonas) GPI (Trypanosoma cruzi) Zymosan Yeast)

LPS (G-) Lipoteichoic acids (G+) RSV F Protein 9q32

dsRNA

Flagellin

Unmethylated CpG DNA

TLR9 TLR5 TLR3 TLR4 CD14 TLR1 TLR2 TLR6

MD-2

Toll-Like Receptor Ligands:

Recognition of Pathogen

associated molecular patterns

(PAMP)

NOD2/CARD15 mutations

+

a-defensin

lysosim

Pattern

recognition

receptorok

(PRRs)

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Environmental factors Bacteria, viral factors?

bacteria (Diplostreptococcus, E. coli,

Proteus, Yershinia, Clostridium, Shigella)

Mycobacterium paratuberculosis

viruses (rotavirus, Norwalk)

Measles

fungi (Saccharomyces cerevisiae)

Smoking

Lakatos PL World J GE 2007

Diet Dietary factors:

– Brest feeding - protective

– Increased glucose intake in CD

– Lower fruit, vegetable intake

– The deleterious effect of certain proteins (e.g lactose) could not be proven)

No dietary factors were proven to play an important role in the pathogenesis

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IBD pathogenesis

Conclusion Clinical symptoms in IBD

• Ulcerative colitis

Frequently typical

– Bloody/mucous diarrhea

– Tenesmus

– Symptoms of general

disease only in severe

cases: anaemia, weight

loss

• Crohn’s disease

Frequently atypical

– Non bloody diarrhea

– Abdominal pain

– Weight loss

– Palpable abdominal mass

– Fistula

– Malabsorption, anaemia

– Extraintestinalis

symptoms

IBD diagnostics

• Diagnosis

– Clinical picture

– Imaging: endoscopy, radiology, histology

• Differential diagnosis

– Other inflammaotry colitis cases, malignancy

– Irritable bowel syndrome

– Deifferentiation between UC and CD

IBD diagnosis

Complaints, symptoms

Stoll culture studies

Laboratory tests

Endoscopy

Imaging

X-ray- follow though

Enterography

UH

CT, MRI

Leukocyta scintigraphy

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Serologic markers in IBD

Antibody Directed against CD UC

ASCA Mannose of Saccharomyces

cerevisiae

+ (40-60%) -

pANCA Neutrophils +

(UC-like CD)

+

(40-60%)

PAB Pancreas + (15-30%) +

Omp (C) Outer Membrane porin + (20-40%) +

I2 Pseudomonas fluorescens + (20-40%) -

cBir1 flagellin + (20-50%) -

ACCA glycan (Chitobioside) + (20-40%) -

ALCA glycan (Laminaribioside) + (20-40%) -

Papp M World J GE 2007

UC and CD clinical symptoms UC CD

Weight loss (+) ++

Abdominal pain (+) ++

diarrhoea +++ ++

Bloody stool +++ (+)

Tenesmus ++ (+)

Palpable mass - ++

fever (+) ++

mucus +++ (+)

Perianal lesions - ++

+++ typical ++ frequent + sometimes (+) rarely - none

Satsangi J Gut 2006;55:749-53.

Classification of Crohn’s disease

Vienna vs. Montreal Crohn’s disease stenosis

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Crohn’s disease - fistula

Satsangi J Gut 2006;55:749-53.

Classification of ulcerative colitis

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

240 228 216 204 192 180 168 156 144 132 120 108 96 84 72 60 48 36 24 12 0

0

10

20

30

40

50

60

70

80

90

100

Cu

mu

lati

ve

Pro

bab

ilit

y (

%)

Patients at risk: Months

2002 552 229 95 37 N =

Penetrating

Stricturing Inflammatory

Long-term evolution of disease

behaviour in Crohn’s Disease

Lakatos PL Hepatogastroenterology 2005;52:817-22..

Long-term evolution of disease

behaviour in Crohn’s Disease

0

10

20

30

40

50

60

ileal colonic ileocolonic upper GI

%

<10 years

>10 years

0

10

20

30

40

50

60

inflammatory stricturing penetrating

%

<10 years

>10 years

P =0.03 P =0.0001

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Natural History of Ulcerative Colitis*

Langholz E et al. Gastroenterology. 1994;107:3.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 2 4 6 8 10 12 14 16 18 20 22 24

Years After Diagnosis

Percen

t o

f P

ati

en

ts

Colectomy

Disease activity

Remission

Status at any given timepoint

Most patients with UC have an

intermittent course of disease activity

Langholz E et al. Gastroenterology. 1994;107:3-11

Cumulative probability of completely relapse free course was

18% at 5 years and 11% at 25 years

1161 patients followed up to 25 years

The nature of intermittant disease

600 patients in years 3 – 7 after diagnosis

Langholz E et al. Gastroenterology. 1994;107:3-11.

3 years 28%

< 3 years 29%

IBD complications

Intestinal

Severe bleeding

Toxic megacolon

Perforation

Stenosis- ileus

abscess

Fistula

Malignancy (tumor surveillance !)

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IBD complications contd.

Extraintestinal

Hepatobiliar (PSC, steatosis,

CAH)

Joint (sacroileitis, polyarthritis,

spondylarthritis)

Occular (episcleritis, uveitis,

iridocyclitis)

Skin (erythema nodosum,

pyoderma gangraenosum)

Haematological (anaemia,

thrombosis, haemolysis)

Treating systemic disease: extra-intestinal

manifestations common in CD patients

Ocular inflammation 2-13%

Oral ulceration 20-30%

Satsangi et al. (ed.) Inflammatory Bowel Diseases, Churchill Livingstone, 669-684 (2003)

Lakatos L World J GE 2003;10:2300-7.

Ankylosing spondylitis 1-6%

Peripheral arthritis 10-20%

Erythema nodosum 6-15%

Pyoderma gangrenosum 0.5-2%

Erythema nodosum in IBD Pyoderma gangraenosum in IBD

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Endoscopy in ulcerative colitis Endoscopic picrute of Crohn’s disease

Inflemmatory mass in CD on CT scan

Jobb flexura

Crohn’s disease - fistula

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Crohn’s disease- progressive fistulas

Crohn’s disease – stenosis – X-ray

irrigoscopy

•Atrophy

Crohn histology

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• A: ulcer and almost normal mucosa

• B: non-regenerative hyperplasia. pseudopolyp

Crohn histology

A B

• C: Transmural inflammation, epitheloid granuloma

• D: Hyperplasia of the myenteric plexus, typical for CD

C D

Crohn histology

UC and CRC

First case was described by

Crohn and Rosenberg (UC

and rectal tumor) in 1925

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Background: Pathogenesis

Rhodes JM Trend in Mol Med 2002; 10-16

Rutter M, Gastroenterology 2004;126:451-459

Lakatos PL LAM 2006;16: 121-9.

long standing inflammation?

environmental factors?

predisposed host?

Background: Pathogenesis-genetics

Lakatos PL Orv Hetil 2006;147:363-9.

Fleisher AS Cancer Res 2000;60:4464-8.

Background: UC and CRC

IBD has been widely recognised to be associated

with an increased risk for CRC

accounts for approximately 10-15% of all deaths

in IBD

accounts for 1–2% of all CRC cases

Munkholm P. Aliment Pharmacol Ther 2003;18(suppl2):1-5.

Langholz E, et al. Gastroenterology 1992; 103: 1444–51.

Lennard-Jones JE, et al. Lancet 1983 ii:149-152. Loftus EV Jr Gastroenterol Clin N Am 2006

„Patients with UC are at increased risk of CRC, but a series of population-

based studies published within the past 5 years suggest that this risk has

decreased over time. The crude annual incidence rate of CRC in UC ranges

from approximately 1 in 500 to 1 in 1600.”

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IBD: therapy

Medical treatment

Surgical treatment

Supportive care

IBD treatment

The ultimate cause of the disease is not

known

There is no cure just care

Goal is achive and maintain of „remission”

A good doctor-patient relationship is needed

to achieve high compliance

Treatment starts at anamnesis

Detailed clinical history

Exclusion of other diseases

Assessement of IBD

Type

Location

Severity

The outcome of previous treatment options

Others (e.g. age, pregnancy, concomittant diseases)

ASSESSMENT of UC activity

(Truelove, Witts B M J 1955;2:1041)

mild moderate severe

Stool no <4 >6 >10

Haematochesia intermittant Frequent continuous

temperature Normal >37,5 >37,5

Pulse Normal >90 >90

Haemoglobin Normal <75 % Needs transfusion

We <30 >30 >30

Plain abd x-ray - Oedema, air in the

bowels

dilatation

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Clinical Activity Index in UC (CAI) Rachmilewitz D. Br M J 1989;298:82

Stool no/week

Bloody stool no/week

General assessement

Abdominal pain

Fever

Extraintestinal symptoms

We, Hb alteration

mild: < 6

moderate: 6-12

severe: >12

Harvey-Bradshow „simple” CD activity

index Harvey RF. Brawshaw JM. Lancet 1980;1:514

General well being 0- 4

Abdominal pain 0- 3

Lose stools/day

Plapable abd mass 0- 3

Extraintestinal manifestations (No)

4-5 HB ~ Best index 150

Endoscopic Activity Index in UC (EAI) Rachmilewitz D. Br M J 1989;298:82

Granulation

Vessel signs

Contact mucosal injury

Mucosal lesions (mucus, erosion, ulcus)

– mild: <5

– moderate: 5-8

– severe: >8

Apoptosis of lymph.

• Purine analogs

• Infliximab

• Adalimumab

• Visilizumab

Activity of effect.c.

• 5-ASA

• CS

• IL-10

Antigen stimulation

• Probiotics

• Antibiotics

Migration of Leu

• Natalizumab

• Leukoaferesis

Cytokines

• anti IL-12

• Certolizumab

Regulation of T cells

• Trichuris suis

IBD

Therapy of IBD

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Outcome of steroid therapy*

for patients with CD

* Prednisone 1 mg/kg for 1 month

• Munkholm P et al. Gut 1994;35:360

1 Month

Outcomes

(n = 109)

Remission

48%

Improved

32%

No response

20%

Remission

54%

Relapse

46%

Improved

57%

Relapse

43%

12 Month

Outcomes

(n = 87)

Steroid dependent

36%

(n = 39)

Prolonged response

44%

(n = 48)

Steroid resistant

20%

(n = 22)

Summary

Outcomes

(n = 109) 16

38

26

58

32

28

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1 month 1 year

% p

ati

en

ts

Steroids for the treatment of Crohn’s

Disease – benefit for the patient

remission

partial

remission

no

response

prolonged

response

steroid

dependent

surgery

N = 74 N = 73

“positive”

outcome

“negative”

outcome

Faubion WA et al. Gastroenterology. 2001;121:255.

• Candy S et al. Gut 1995;37:674

AZA vs placebo for steroid

withdrawal in CD

80

60

40

20

0

Placebo (n=30)

AZA 2.5 mg/kg per d (n=33) 80

60

40

20

0

Placebo (n=30)

AZA 2.5 mg/kg per d (n=33) 80

60

40

20

0

Placebo (n=30)

AZA 2.5 mg/kg per d (n=33)

% P

ati

en

ts N

ot

Fa

ilin

g T

ria

l

Duration of Trial (Months)

Remission induced by prednisolone; tapered over 12 wk

Safety of purine analogs

Adverse effects of

purine analogs

28% treated

Intolerance Idiosyncrasy

primary toxic effect

- genetic defect

(TPMT 3A)

-drug overdose

• nauzea

• emesis

• abdominal

pain

• hepatitis

•pancreatitis

•systemic

toxoallergic reaction

Myelotoxicity 2%

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Biologic therapy in IBD

• Anti TNF a antibodies

• Infliximab (Centocor, Schering-Plough CEAG)

• Adalimumab (Abbott)

• Certolizumab (UCB-Pharma)

• Selective adhesion molecule inhibitors

• Natalizumab (Protein Design Labs)

• MLN-02 (Pfizer)

• Anti-CD3 antibodies

• Visilizumab (Protein Design Labs)

Anti-TNF-a biologicals

Chimeric

monoclonal

antibody

Humanized

monoclonal

antibody

Human

recombinant

antibody

Humanized

Fab

fragment

Human

recombinant

receptor / Fc

fusion protein

79% human 95% human 100% human 100% human PEG PEG

Side effects of infliximab

• Immunogenicity

• Reactivation of TBC

• Infections

• Lymphoma (hepatoplenic lymphoma risk)

• Malignancy?

How do current treatment options for

Crohn’s Disease address these objectives?

Aminosalicylates

Steroids

Infliximab/biologicals

Immunosuppressants

The classical Step-Up-treatment paradigm

Surgery

Which patients should be

treated with biologicals?

What is optimal treatment

with biologicals?

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Remission

dependent

5-ASA

Oral Steroids

AZA

refractory

Colectomy

Severe Mild

Current treatment algorithm

Mild to Severe UC

ifx to induce remission

ifx to maintain remission Rescue

Colectomy

CsA

IV steroids

Acute Severe

Current treatment algorithm

Acute severe UC

ifx to induce remission

ifx to maintain remission

Indications for surgery in UC

Hoffmann et al. Chronisch-Entzündliche Darmerkrankungen. Thieme 2004

Failure of

medical

therapy

74%

Perforation

6%

Toxic UC

10%

Colorectal

Carcinoma

7%

Dysplasia

3%

Analysis of 917 UC patients at

Heidelberg University between

1982 and 2001

Successful IPAA outcome

Satsangi et al. Inflammatory Bowel Diseases. Churchill Livingstone, 2003

Stool frequency

- by day

- by night

3-9 times (mean 6)

0-1 time (mean 1)

Stool weight 650 g semisolid/d

Fecal seepage

- by day

- by night

33% of women, 14% of men

56% of women, 44% of men

Use of antidiarrheal medication 20% of patients at 1 year

Unable to discriminate gas from stool 30% of patients at 1 year