Crohn’s DiseaseOverview

Etiology of Crohn’s Disease

Nonspecific inflammationNonspecific inflammationTissue injuryTissue injury

Restitution and repairRestitution and repair

Genetic Susceptibility

Environmental Factors

Host (Immune response)

Several Theories Exist

Elson CO et al. In: Proceedings of V International Symposium on Inflammatory Bowel Diseases. 1998. In Press.

Evidence of the Role of TNF in IBD

Mucosal production of TNF is greater in patients with IBD than in controls in most, but not all reports1,2

The number of cells producing TNF is greater

in patients with IBD than in controls2,3

TNF is increased throughout the intestinal mucosa in patients with UC and throughout both the mucosa and submucosa of patients with CD1

1. Murch SH et al. Gut. 1993;34:1705-1709.2. Reinecker H-C et al. Clin Exp Immunol. 1993;94:174-181.3. Breese ES et al. Gastroenterology. 1994;106:1455-1466.

Evidence of the Role of TNF in IBD

Increased concentrations of TNF have been detected in the stools of children with active disease1

Serum levels of soluble TNF receptors are increased in patients with CD as a result of T-cell activation2

1. Braegger CP et al. Lancet. 1992;339:89-91.2. Stronkhorst A et al. Gastroenterology. 1994;106(Suppl 4):A779. Abstract.

Yang H, Rotter JI. In: Inflammatory Bowel Disease. From Bench to Bedside. 1993:32-64.

Genetic Influence in IBD

Racial and ethnic differences in incidence

Increased incidence among monozygotic twins (primarily in patients with CD)

Association with certain genetic syndromes

Familial Patterns of Inheritance

Approximately 10% of patients have positive family history

2%–10% risk if first-degreerelatives affected

50–100-fold increase in prevalence for children of patients with IBD

Yang H, Rotter JI. In: Inflammatory Bowel Disease. From Bench to Bedside. 1993:32-64.

Microbial Mucosal Immune Interactions

Animal models support the view that IBD is caused by genetically determined dysregulation in mucosal immune response to normal gut microflora (luminal antigens)

Intestinal mucosa relatively free of adherent bacteria

Microbial Mucosal Immune Interactions

IBD patients have increased numbers of diverse bacterial antigens within the mucosa

– Farrell and LaMont Gastro Clin NA 2002;31:41.

Increased numbers of specific species (Bacteroides, Fusobacteria) may be a determinant of post-op recurrence

– Neut et al. Am JGastroenterol 2002;97:939.

Mucosa associated E coli strains alter permeability in IEC monlayers

– Rocha et al. Surgery 2001;130:65.

Pathogenesis of Crohn’s Disease

Podolsky, DK NEJM 2002;347:417-29.

C D 4

C D 4

IL-12IL-18

bacteria Lum en

antigenpresenting

cell

IFN

TNF

IL-10

C D 4

regulatory T ce ll

Tobacco Smoking and IBD

Smoking shown to be protective in UC and has adverse effect on clinical course of CD

Inverse association in UC and CD likely reflective of differences in pathogenesis

Natural History: What Do We Know ?

Complications increase with time and depend on location and behavior

Predictable post-operative recurrence

Negative impact of smoking and NSAIDs

Effect of Disease Location on Behavior of CD in Females

Freeman H. J. Clin Gastroenterology 2003:37, 3: 216-219

0

5

10

15

20

25

30

35

40

Ileum Colon Ileocolon

Nu

mb

er o

f P

atie

nts

Nonstenosing / Nonpenetrating

Stenosing

Penetrating

Chron’s Disease Activity IndexCDAI

Chron’s Disease

Endoscopic Index Severity

CDEIS

Crohn’s Disease Activity Index

Scoring– Maximum score 600– Remission < 150– Moderate activity 200 – 450– Severe activity > 450

Best WR et al. Gastroenterology. 1976;70:439-444.

Crohn’s Disease Endoscopic Index of Severity: Variables

Disease location– Rectum– Sigmoid and left

colon– Transverse colon– Right colon– Ileum

Depth of lesion(s)– Superficial– Deep

Mary JY, Modigliani R. Gut. 1989;30:983-989.

Size of lesion(s)– Measured in

centimeters Presence of stenoses

– Ulcerated– Nonulcerated

Crohn’s Disease Endoscopic Index of Severity: CDEIS

Index construction and calculation

CDEIS = Sum of 12 x ISRCF (deep ulceration)

+ 6 x ISRCF (superficial ulceration)

+ ASSD (segmented surface disease)

+ ASSU (segmented surface ulcerated)

+ 3 x PRES (ulcerated stenosis)

+ 3 x PRES (nonulcerated stenosis)

Mary JY, Modigliani R. Gut. 1989;30:983-989.

ISRCF, individual segmental rectocolonic frequency; ASSD, average segmental surfaces involved by disease; ASSU, average segmental surfaces involved by ulceration;PRES, present.

Therapeutic Endpoints of Acute Therapy for CD

CDAI score < 150 (absence of inflammatory symptoms)

Endoscopic evidence of mucosal response (reduction in CDEIS score) – Highest score = 14.9 – Lowest score = 0

Corticosteroid withdrawal Improved quality of life

Goals of Therapy

Inducing remission Maintaining remission Healing mucosa Restore and maintain nutrition Maintain quality of life For those requiring surgery, select

optimal timing for surgical intervention

Current “Step-Up” Approach to Crohn’s Disease (CD) Therapy

AZA/6-MP/ MTX

Infliximab

Corticosteroids

Aminosalicylates

Surgery

Antibiotics

Bowel Rest

Severe

Moderate

Mild

Budesonide

Prednisone

??

“It’s not just inducing remission that

counts; the trick is holding on to it.”

Sachar DB. Inflamm Bowel Dis. 2000;6:329.

Potential Maintenance of Remission Therapies for Crohn’s Disease

Sulfasalazine Mesalamine Antibiotics Corticosteroids Budesonide Azathioprine, 6-Mercaptopurine Methotrexate InfliximabInfliximab

±, questionable; +, weak; ++, moderate; +++, strong; –, none.

Long-term Maintenance of Remission in CD

Oral aminosalicylates ±

Topical aminosalicylates –

Systemic corticosteroids –

Corticosteroids with low systemic bioavailability (budesonide) +

Immunosuppressants

Cyclosporine –

Methotrexate –

Azathioprine/6-mercaptopurine +++

Risk Difference 95% CI

-0.5 -0.4 -0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5

Favors Treatment Favors Control

19957- Arber

199710- De Franchis

19979- Sutherland

19968- Modigliani

19956- Thomson

19945- Bresci

19934- Gendre

19923- Brignola

19922- Prantera

19901- Thomson

DateStudy

Overall: 1371

Mesalamine in Medically Induced Remission

Camma C et al. Gastroenterol 1997;113:1465-73.

Risk Difference 95% CI

-0.5 -0.4 -0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5

Favors Treatment Favors Control

19934- Sutherland

19923- Brignola

19922- McLeod

19901- Caprilli

DateStudy

OverallIncluding Lochs (2000), excluding Caprilli (1994, #1 above)

Overall : 411

Mesalamine in Surgically Induced Remission

Camma C et al. Gastroenterol 1997;113: 1465-73.Camma C et al. Gastroenterol 1997;113: 1465-73.

Azathioprine Maintenance of Steroid- Induced Remission for Crohn’s Disease

100

0

20

40

60

80

0 1 3 5 7 9 11 13 15

Duration of trial (months)

Azathioprine

Placebo

% O

n tr

ial

Candy S. et al. Gut 1995, 37:674-8.

63 patients with active disease

Prednisolone tapering schedule (1 mg/kg–0/12 weeks)

Randomized 2.5 mg/kg azathioprine vs placebo

Outcome treatment success (induction and maintenance of remission)

Six controlled trials have evaluated the efficacy of AZA or 6-MP for maintenance of remission

Five of these studies were included in a meta-analysis*

– The overall rate of remission maintenance was higher in patients receiving AZA or 6-MP compared to placebo (67% vs. 52%)

– Maintenance of remission was dose-dependent

– In studies that evaluated steroid use, patients receiving 2.5 mg/kg/day AZA were significantly more likely to reduce steroid consumption (87% vs. 53%)

AZA & 6-MP: Maintenance of Remission

¨*Pearson et al. Ann Intern Med 1995; 123:132-42.

AZA and 6-MP: Questions ?

How long ?

Combined therapy with infliximab ?

Bouhnik et al. Lancet 1996;347:215-9.

Relapse Rate After Azathioprine Withdrawal According to Duration of Remission on

Azathioprine

0

20

40

60

80

0-1 1 to 2 2 to 3 3 to 4 4 to 5 >5

% o

f R

elap

se a

t 2

yr

MaintainStopped

1501509999 5757 3535

24241212

77

1313

77

66

44

**

***

***

***

n.s.

n.s.

Duration of Remission on Azathioprine (years)

CH3

CH2

CH1

VH

VL

Ck

Mouse

Human IgG1 – Fc

CH2

CH3

Rh p75 TNFR

Human IgG1 – Fc

Rh p75 TNF Receptor

Infliximab: chimeric mouse monoclonal anti-TNF human

IgG1 protein

Etanercept: recombinant human p75 TNF receptor Fc

fusion protein.

TNF Neutralizing Drugs

Membranebound TNF

Soluble TNF

p75 TNF receptor

extracellular

intracellularTACE

p55 TNF receptor

Death domain(TRADD)

TRAF2

TNF Metabolism

Sandborn et al. Gastroenterology 2001

Infliximab but Not Etanercept Is Effective in Crohn’s Disease

0

20

40

60

0 2 4 8

Clin

ica

l Re

sp

on

se

(%

)

Placebo Etanercept

0

10

20

30

0 2 4 8

Clin

ica

l Re

mis

sio

n (

%)

Placebo Etanercept

Etanercept and Infliximab Neutralize Recombinant Human TNF Effectively

0

0

20

40

60

80

0.1 1 10 100

Infliximab (µg/ml)

NF

-kB

-dri

ven

GF

P E

xpre

ssio

n

(co

un

ts)

0

0

25

50

75

2525 x10 -5 25 x10 -3 25 x10 -1

NF

-kB

-dri

ven

GF

P E

xpre

ssio

n(c

ou

nts

)

Etanercept (µg/ml)

medium infliximab c17-1aetanercept

GaH-FITC

Co

un

ts

24

48

Only infliximab Binds memTNF on Activated Peripheral Lymphocytes

0

10

20

30

40

50

60

Me

an

Flu

ore

sc

en

t In

ten

sit

y

Medium Infliximab Etanercept c17-1a

48

C17-1a

0 12 24 36

0

10

20

30

40

50 IMDM

Time (hrs)

Ap

oto

tic

cell

s (%

)

Only Infliximab Induces Apoptosis in Activated Lymphocytes

IMDMInfliximab

0 12 24 36 48

Time (hrs)

0

10

20

30

40

50

Ap

oto

tic

cell

s (%

) } p<0.01

0 12 24 36 48

0

10

20

30

40

50 IMDMEtanercept

Time (hrs)

Ap

oto

tic

cell

s (%

)

Infliximab Activates Caspase 3, Etanercept Does Not.

InfliximabEtanerceptC171A

- -- - - - -+ +- -- + + - -- -- -- - - + +- -

24 48 24 48 24 48 24 48

caspase3active

0

actin

0

1

2

3

4

5

6

7

24 48

Time (hrs)

Ca

sp

as

e 3

Ac

tiv

ati

on

(R

ela

tiv

e t

o 0

hrs

.)

Medium

Infliximab

Etanercept

c17-1A

ACCENT I & II: Baseline Patient Characteristics

ACCENT I ACCENT II

Group I Group II Group III Group I Group II

Patients 188 192 193 143 139

Age 36 35 35 38 38

Disease duration 7.5 7.5 8.7 12.0 10.7

Previous resection 51% 52% 50% 56% 55%

IBDQ 126 126 131 167 155

CRP mg/dL 0.6 0.8 0.9 0.7 0.7

Steroids 51% 51% 51% 29% 29%

Immunomodulators 32% 21% 23% 35% 34%

All values are median

Baseline Patient Characteristics

Typical Crohn’s disease population with moderately to severely active disease

– Median CDAI (range): 297 (193 - 488)

– Median IBDQ (range): 127 (56 - 200)

– Patients receiving corticosteroids: 62%

– Patients receiving immunomodulators: 29%

Patients were well balanced for other parameters

ACCENT I & II Endpoint Definitions

ACCENT I Clinical response: reduction of 25% and 70 points in CDAI

Loss of response: CDAI 175, increased by 35%, 70 points higher than qualifying CDAI

Clinical remission: CDAI < 150

ACCENT II Fistula response: 50% reduction from baseline in the number of draining fistulas

Loss of fistula response: < 50% reduction in the number of draining fistula from baseline over 4 weeks

Complete fistula response: absence of any draining fistula

CDAI remission CDAI < 150

ACCENT I: Study Design

Infusion

All Patients (N=573)

Infliximab 5mg/kg

Responders at Week 2 N=335 (58%)

Non-Responders at Week 2 N=238 (42%)

Week 0

Single Dose Group Placebo

N=1885mg/kg

N=19210mg/kg

N=193

3 Dose Induction Group

Crossover to 5mg/kg

Crossover to 10mg/kg

Crossover to 15mg/kg

Evaluation

Week 46

Week 54

Week 38

Week 30

Week 22

Week 14

Week 6

Week 2

10 mg/kg

All Patients (N=573) Clinical Response Through Week 10

Single Dose vs 3-Dose Induction

0

10

20

30

40

50

60

70

80

0 2 4 6 8 10

Pe

rcen

t o

f P

ati

ents

Single infusion (N=188) 3-Dose induction (N=385)

Infusions

Weeks

P=0.035

65

52

Response to Infliximab Therapy Among Randomized Patients

58.5%

22.5%18.0%

0%

20%

40%

60%

80%

Rapid Responders(N=385)

DelayedResponders

(N=135)

Non-responders(N=103)

% o

f P

atie

nts

(N=573)

CSR: 1849.

Patients Who Crossed Over

49%

30%26%

0%

10%

20%

30%

40%

50%

60%

Group I Group II Group III

% o

f P

atie

nts

(N=188) (N=192) (N=193)

MS: 10.

ACCENT I: Patients in Clinical Response Through Week 54

0

20

40

60

80

100

Weeks

Pe

rce

nt

in R

es

po

ns

e

Responders All Randomized

14 18 22 26 30 34 38 42 46 50 54

Group I (N=110)

Group II (N=113)

Group III (N=112)

0

20

40

60

80

100

Weeks

Pe

rce

nt

in R

es

po

ns

e

14 18 22 26 30 34 38 42 46 50 54

Group I (N=175)

Group II (N=183)

Group III (N=183)

ACCENT I: Patients in Clinical Remission

0

10

20

30

40

50

60

Weeks

Pe

rce

nt

in R

em

iss

ion

Responders All Randomized

14 18 22 26 30 34 38 42 46 50 54

Group I (N=110)

Group II (N=113)

Group III (N=112)

0

10

20

30

40

50

60

Weeks

Pe

rce

nt

in R

em

iss

ion

14 18 22 26 30 34 38 42 46 50 54

Group I (N=175)

Group II (N=183)

Group III (N=183)

ACCENT I: CDAI Was Lower With Infliximab Maintenance Therapy

Responders All Randomized

0 2 6 10 14 18 22 26 30 34 5438 42 46 50 0 2 6 10 14 22 30 5438 46

Group I (n=110)

Group II (n=113)

Group III (n=112)

Med

ian

CD

AI

Med

ian

CD

AI

130

350

200

250

300

130

350

200

250

300

WeekWeek

Group I (n=188)

Group II (n=192)

Group III (n=193)

ACCENT I: Average Daily Corticosteroid Dose Through Week 54

0

5

10

15

20

0 6 10 14 22 30 38 46 54

Weeks

Med

ian

Co

rtic

ost

ero

id D

ose

Group I (N=89)Group II (N=95)Group III (N=95)

2 4

Rubenstein JH et al. J Clin Gastroenterol, 2002;35:151.

Reduction of Hospitalizations/ Surgeries with Infliximab

-11-9

-18

-38-40

-30

-20

-10

0Hospitalization* Hospitalized Days All Surgeries GI Surgeries

% In

cid

en

ce

s

P=0.14P=0.06

P<0.01

P<0.05

Rubenstein JH. J Clin Gastroenterol 2002;35(2):151-6.

Rubenstein JH et al. J Clin Gastroenterol, 2002;35:151.

Reduction in ER Visits/Procedures with Infliximab

-66

-43

-13-12

-70

-60

-50

-40

-30

-20

-10

0ER Visits Endoscopies

All RadiologyExams

Non-Plain FilmExams

% In

cid

en

ce

s

P≤0.01 for all endpoints

Rubenstein JH. J Clin Gastroenterol 2002;35(2):151-6.

ACCENT II: Study DesignAll Patients (N = 306)

Infliximab 5 mg/kg

PlaceboPlaceboMaintenance (N=143)Maintenance (N=143)

Infliximab Maintenance 5 mg/kg (N= 139)

Responders(N = 99)

Non-responders(N = 44)

Responders(N = 96)

Non-responders(N = 43)

Week 22

Week 30

Week 38

Week 46

Week 54Evaluation

Crossoverto 5 mg/kg

Crossoverto 5 mg/kg

Crossoverto 10 mg/kg

Crossoverto 10 mg/kg

NotRandomized

(N = 24)

InfusionWeek 0Week 2Week 6

Week 14

ACCENT II: Baseline Patient Characteristics

ACCENT IIGroup I Group II

Patients 143 139

Age 38 38

Disease duration 12.0 10.7

Previous resection 56% 55%

IBDQ 167 155

CRP mg/dL 0.7 0.7

Steroids 29% 29%

Immunomodulators 35% 34%

All values are median

ACCENT II Endpoint Definitions

ACCENT II Fistula response: 50% reduction from baseline in the

number of draining fistulas

Loss of fistula response: < 50% reduction in the number of draining fistula from baseline over 4 weeks

Complete fistula response: absence of any draining fistula

CDAI remission CDAI < 150

ACCENT II: Patients in Fistula Response & Complete Fistula Response

0

20

40

60

80

100

Weeks

Pe

rce

nt

of

Pa

tie

nts

Group I (N=99)Group II (N=96)

Fistula Response

14 18 22 26 30 34 38 42 46 50 54

0

20

40

60

80

100

Weeks

Pe

rce

nt

of

Pa

tie

nts

Placebo (N=99)Infliximab 5 mg/kg (N=96)

Complete Fistula Response

14 18 22 26 30 34 38 42 46 50 54

Duration of Infliximab Maintenance vs. Episodic Treatment

23.1

39.7

0

10

20

30

40

50

60

Group I Group II

Du

rati

on

of

Re

sp

on

se

(W

ee

ks

)

(n=133) (n=125)

19

38

54

0

10

20

30

40

50

60

Group I Group II Group III

Du

rati

on

of

Re

sp

on

se

(W

ee

ks

)

(n=146) (n=154) (n=193)

ACCENT I ACCENT II

ACCENT I: Endoscopic Substudy

Patients– N=99– 25 European sites– 2-week responders and recipients of

episodic retreatment Endoscopic Assessment

– CDEIS Weeks 0,10, and 54 Definition of healing:

– Mucosal ulceration at Week 0 and no mucosal ulceration at follow-up colonoscopies

Evaluations CDAI scores were calculated at baseline and

Weeks 2, 6, 10, 14, 22, 30, 38, 46, 54 Data regarding lesions were calculated by endoscopic

examination of the rectum, sigmoid and left colon, transverse colon, right colon, cecum, and ileum at baseline, Week 10, and Week 54

Reduction of ulcerations was also assessed using the CDEIS (higher CDEIS scores indicate greater disease activity)

Mucosal healing was defined as presence of mucosal ulceration (aphthoid, superficial or shallow, deep, or ulcerated stenosis) at Week 0 and absence at follow-up visits

Rutgeerts et al, DDW 2002: Abstract W1367.

Patients Demonstrating Mucosal Healing

-6

-5

-4

-3

-2

-1

0

Infliximab5 mg/kg

Infliximab10 mg/kg Placebo

-6

-5

-4

-3

-2

-1

0

Combined Infliximab Placebo

CDEIS Median Chg from BL to Week 54CDEIS Median Chg from BL to Week 10

Rutgeerts et al, DDW 2002: Abstract W1367.

Maintenance Infliximab vs Episodic Therapy: Patients with Healed Mucosa

7%

46%

31%

53%

0

10

20

30

40

50

60

70

0%

P=0.01

P=0.026

P=0.007

Week 10 Week 54N=17 N=32 N=14 N=11 N=15

Single Infusion Infliximab 5 mg/kg Infliximab 10 mg/kg

Week 2 Responders

% o

f P

atie

nts

Rutgeerts et al, DDW 2002: Abstract W1367.

Endoscopic Findings for a 5 mg/kg Infliximab Maintenance Patient

Baseline Week 10 Week 54

Rutgeerts et al, DDW 2002: Abstract W1367.

Crohn’s-Related Hospitalization and Surgery Rates and ICU Days by Mucosal Healing

0

50

100

150

200 Hospitalizations/100 patients

ICU days/100 patients

Surgeries/100 patients

No Mucosal

healing

(N=74)

Mucosal healing

at one visit

Mucosal healing

at both visits

(N=16) (N=9)

Infliximab Safety

Infliximab Patient Exposure

PSUR 2 8/00 13,883 76,400

PSUR 3 2/01 26,959 135,693

PSUR 4 8/01 49,948 199,943

PSUR 5 2/02 75,853 271,152

PSUR 6 8/02 103,553 344,117

PSUR 7 2/03 127,577 432,648

Period Ending EU Worldwide

PSUR 1 2/00 4,975 22,032

Cumulative Exposure and Reporting Rates for Tuberculosis

PSUR Expos/ Expos Cases PRR* Cumul PRR*

period Cumul Cases Cumul

1 22,032 34,354 1 0.00% 2 0.01%

2 44,786 79,140 15 0.03% 17 0.02%

3 68,383 147,523 40 0.06% 57 0.04%

4 81,815 229,338 62 0.08% 119 0.05%

5 105,821 335,159 80 0.08% 199 0.06%

6 127,028 462,187 78 0.06% 277 0.06%

*Proportional report rate.

Most Infliximab Associated

Tuberculosis Occurs Early in Tx

PSUR 5: pg. 250.Baker et al. ACR 2001.PSUR 6: pg. 79.

Infusion Number

% o

f P

atie

nts

0

20

40

60

1 2 3 4 5 6 7 8 9 10

Algorithm for TB Testing:European-Based Recommendations

New infliximab patient has office visit

PPD Test PositivePPD Test Positiveand active TBand active TB

Initiate latent TB Initiate latent TB treatmenttreatment

Treat active TB to Treat active TB to resolutionresolution

Initiate infliximabInitiate infliximabInitiate infliximabInitiate infliximab

Administer appropriate TB screening test(PPD skin test + chest x-ray + family history)

Evaluate test results

Test NegativeTest Negative

Initiate infliximabInitiate infliximab

PPD Test PositivePPD Test Positiveand normal CXRand normal CXR

Serious Infusion Reactions Infliximab

ATTRACT Study Report pg.288-289.ACCENT I Study Report pg.262-263. *Patients with evaluable samples.

0.0 0.0 0.00

10

20

30

40

50

Positive*0 / 329

Negative*0 / 1224

Inconclusive*0 / 3092

Antibody-to-Infliximab Status

No serious infusion reactionsNo serious infusion reactionsin ATTRACTin ATTRACT

Pro

po

rtio

n o

f In

fusi

on

s w

ith

Ser

iou

s In

fusi

on

Rea

cti

on

s

ATTRACT ATTRACT through week 102through week 10211

0.4 0.0 0.50

10

20

30

40

50

Pro

po

rtio

n o

f In

fusi

on

s w

ith

Ser

iou

s In

fusi

on

Rea

cti

on

s

Antibody-to-Infliximab Status

Positive*1 / 254

Negative*3 / 656

Inconclusive*0 / 1470

ACCENT I ACCENT I through week 54through week 5422

New Management Trend In Crohn’s Diseases

Inverting the Treatment Pyramid: “Step-Down” Therapy for CD

Corticosteroids 5-ASA

Early

Late

Surgery

AZA/6-MP/MTX

Biologics (eg, infliximab)

5-ASA5-ASA AntibioticsAntibiotics

PrednisonePrednisone BudesonideBudesonide

AZA/6-MPAZA/6-MP MTXMTX

InfliximabInfliximab

SurgerySurgery

DiseaseDisease

SeveritySeverity

Other TNF blockers

Inhibitors of leukocyte migration

The future… Beginning Today ?

Sequential management of

steroid-dependent patients

Chronically active CDChronically active CD

Oui

Failure (12 weeks)Failure (12 weeks)Failure (12 weeks)Failure (12 weeks)

AZA or MTXAZA or MTX

Other OptionsOther Options

Surgery ?Surgery ?

Add Infliximab and maintain Q8 weeksAdd Infliximab and maintain Q8 weeksAdd Infliximab and maintain Q8 weeksAdd Infliximab and maintain Q8 weeks

Reevaluation of Tx Reevaluation of Tx (Dose escalation or reduce frequency)(Dose escalation or reduce frequency)

Reevaluation of Tx Reevaluation of Tx (Dose escalation or reduce frequency)(Dose escalation or reduce frequency)