Crohn’s diseasethe new challenge

Dr .Nahla A Azzam (MRCP)GI/ Medicine Consultant

KKUH

Objectives

-overview on the pathogenesis of CD

-Treatment options

-CD management approach

-Prevalence of CD in Saudi Arabia

-KKUH experience

Pathogenesis

Genetic SusceptibilityChromosome 1, 3, 7, 12, 16Chromosome 1, 3, 7, 12, 16

Polygenic traitPolygenic trait

EnvironmentalTriggers & Modifiers

Gut bacteriaGut bacteriaSmoking/nicotineSmoking/nicotine

Epithelial dysfunctionEpithelial dysfunction

IncreasedIncreasedImmune ResponseImmune Response

Innate & autoimmune Innate & autoimmune Macrophage activationMacrophage activation

T cell activationT cell activationCytokine/adhesion moleculeCytokine/adhesion molecule

expressionexpression

Current Model: Pathogenesis of Crohn’s Disease

Genetics

NOD2 geneNOD2 gene involved in NF-involved in NF-B activationB activation

--CARD: caspase-activation recruitment domainCARD: caspase-activation recruitment domainNBD: nucleotide-binding domainNBD: nucleotide-binding domainExpressed in monocyteExpressed in monocyte

--Leucine rich region (LRR) interacts with Leucine rich region (LRR) interacts with bacterial LPS to activate NF-kBbacterial LPS to activate NF-kB

1 28 124 220 273 577577 744 1044LRRCARD CARD NBD

Genotype relative risks (RR)Genotype relative risks (RR) for three major associated for three major associated NOD2NOD2 variants variants

Heterozygous RR : 1.5 - 4.0Heterozygous RR : 1.5 - 4.0

Homozygous RR : 15 - 40Homozygous RR : 15 - 40

Disease penetrance < 10% for homozygotesDisease penetrance < 10% for homozygotes

and compound heterozygotesand compound heterozygotes

NOD2NOD2 Population attributable risk for Population attributable risk for ilealileal disease ,Younger ,fibrostenoticdisease ,Younger ,fibrostenotic

New gene in IBD:IL23R

Encodes a subunit of the IL-23 receptor

IL-23 is required for colitis in mice models

Expressed in colon and TI

Mutations associated with

both CD and UC

Duerr RH et al. Science, 26 Oct 2006.

CD management

Unmet Needs in Crohn’s Disease Management

Accurate predictors of response to therapies

therapies or approaches change the natural history of IBD

Surgery

Hospitalization

Disability

Uncertain risk/benefit of combined therapies

*Kaplan-Meier analysis.Mekhjian HS, et al. Gastroenterology. 1979;77:907-913.

% o

f P

ati

en

ts20

40

60

80

100

5 10 15 20 25 30

Years After Onset

Cumulative Probability* of Surgery in Crohn’s Disease

CD therapeutic pyramid

SurgerySurgeryCyACyA

InfliximabInfliximabMTXMTX

AZA/6-MPAZA/6-MPSystemic Systemic

CorticosteroidsCorticosteroids

SurgerySurgeryCyACyA

InfliximabInfliximabMTXMTX

AZA/6-MPAZA/6-MPSystemic Systemic

CorticosteroidsCorticosteroids

AntibioticsAntibiotics5-ASA5-ASA

AntibioticsAntibiotics5-ASA5-ASA

Mild to ModerateMild to ModerateDiseaseDisease

Moderate to SevereModerate to SevereDiseaseDisease

BudesonideBudesonide

Hanauer SB, Sandborn W. Hanauer SB, Sandborn W. Am J Gastroenterol.Am J Gastroenterol. 2001;96:635–643. 2001;96:635–643.

Systemic circulation

10-20%

70% absorbed in ileum

Budesonide absorption & bioavailability

CD limited to small bowel

5ASA????

budesonide

prednisone

6MP/AZA

MTX

infliximab

Others: CyA, thalid… ,.

NPO + TPN

CD limited to colon

5ASA: Asacol, Colazal… ,

Abx: cipro, metro… ,

prednisone

6MP/AZA

MTX

infliximab

Others: CyA, thalid… ,.

NPO + TPN

ileostomy

Infliximab Indications:

-Mod to severe CD not responded to conventional therapy

-Fistulizing CD with drainage EC fistula

-Fistulizing CD that responded to induction infliximab

-steroid dependant CD that fail to attempt to taper the steroid

RemicadeContraindications

Absolute Class III/IV CH

Active bacterial infection

RelativeElderly

Severe co-morbidities

Bowel stricture?

Multiple sclerosis

Anti-TNF Biologic Agents Indications, Route of Administration, and Dosing

Infliximab (infusion)Induction dose:5 mg/kg IV at 0, 2, and 6 weeks

Maintenance dose:5 mg/kg IV q 8 weeks

Adalimumab (SQ, pre-filled syringe, injectable pen)

significant efficacy in phase III studies in CD

Loading dose:160 mg at week 0; 80 mg at week 2

Maintenance dose:40 mg SQ weekly or every other week

Certolizumab pegol (subcutaneous)

significant efficacy in phase III studies in CD

Loading dose:400 mg SQ at weeks 0, 2, 4

Maintenance dose:400 mg SQ q 4 weeks

Major Clinical Trials With TNF Antagonists in Crohn’s Disease

AgentStudy NameReferenceAim of Study

Infliximab

—Targan et al.N Engl J Med 1997Induction

—Present et al.N Engl J Med 1999Induction (F)

—Rutgeerts et al. Gastroenterology 1999

Maintenance

ACCENT IHanauer et al.Lancet 2002Maintenance

ACCENT IISands et al.N Engl J Med 2004

Lichtenstein et al.Gastroenterol 2005Maintenance (F)

REACHHyams et al.DDW 2006Induction &Maintenance (P)

Adalimumab

CLASSIC IHanauer et al.Gastroenterol 2006Induction

CLASSIC IISandborn et al.UEGW 2005Maintenance

CHARMColombel et al.DDW 2006Maintenance

Certolizumab

—Schreiber et al.Gastroenterol 2005Induction

PRECiSE 1Sandborn et al.DDW 2006Induction &Maintenance

PRECiSE 2Schreiber et al.UEGW 2005Maintenance

F = fistulas; P = pediatric.

ACCENT II: Number of Crohn’s Disease-Related Hospitalizations per 100 Patients Through Week 54

Rutgeerts P, et al. Gastroenterology. 2004;126:402–413.

Episodic Strategy

5 mg/kg Scheduled

Strategy

10 mg/kg Scheduled

Strategy

Combined Scheduled

Strategy

Ho

spit

aliz

atio

ns

per

100

Pat

ien

ts

p = 0.047 p = 0.023 p = 0.014

0

10

20

30

40

50

N = 188 192 193 385

ACCENT II: Cumulative Number of Surgeries Over Time in RespondersC

um

ula

tive

Nu

mb

er

of

Su

rger

ies

& P

roce

du

res

Weeks

Randomization

Infliximab 5 mg/kg maintenance (n = 96) Placebo maintenance (n = 99)

Lichtenstein GR, et al. Gastroenterology. 2005;128:862–869.

0

25

50

75

100

125

0 2 6 14 22 30 38 46 54

Major Clinical Trials With TNF Antagonists in Crohn’s Disease

AgentStudy NameReferenceAim of Study

Infliximab

—Targan et al.N Engl J Med 1997Induction

—Present et al.N Engl J Med 1999Induction (F)

—Rutgeerts et al. Gastroenterology 1999

Maintenance

ACCENT IHanauer et al.Lancet 2002Maintenance

ACCENT IISands et al.N Engl J Med 2004

Lichtenstein et al.Gastroenterol 2005Maintenance (F)

REACHHyams et al.DDW 2006Induction &Maintenance (P)

Adalimumab

CLASSIC IHanauer et al.Gastroenterol 2006Induction

CLASSIC IISandborn et al.UEGW 2005Maintenance

CHARMColombel et al.DDW 2006Maintenance

Certolizumab

—Schreiber et al.Gastroenterol 2005Induction

PRECiSE 1Sandborn et al.DDW 2006Induction &Maintenance

PRECiSE 2Schreiber et al.UEGW 2005Maintenance

F = fistulas; P = pediatric.

CLASSIC 1 trial

CHARM: Clinical Remission of CD Over Time With Adalimumab

Randomized Responders (n = 499)

* *

* **

* * * *

*

**

* * * * **

†

% o

f P

atie

nts

Weeks

47

40

41

36

1712

*p < 0.001 vs placebo; †p = 0.005 vs placebo.Colombel JF, et al. DDW 2006, Abstract 686d.

0

10

20

30

40

50

60

0 10 20 30 40 50 60

Placebo Adalimumab 40 mg EOW Adalimumab 40 mg weekly

26 56

Top-Down Versus Step-Up Strategies in CD

• Newly diagnosed CD of < 4 years’ duration (N = 129)

• Naive to immunomodulators and biologics

Step-up (n = 64)

Steroids

+ IFX

+ AZA MTX

Steroids

Steroids

Top-down(n = 65)IFX (Wk 0, 2, 6)

+ AZA

IFX + AZA

+ (episodic) IFX

Steroids

Hommes D, et al. DDW 2006, Abstract 749.

CDAI < 150 Points AND No Steroids AND No Surgery

Weeks

% o

f P

atie

nts

Step-upTop-down

*

0

20

40

60

80

100

0 20 40 60 80 100

Co-primary endpoints6 & 12 months

†*

* P < 0.01; † P <0.05

Top-Down Versus Step-Up TrialClinical Results at 2 Years

Hommes D, et al. DDW 2006, Abstract 749.; D’Haens GR, et al. DDW 2006. Abstract 764.

Reduction and Disappearance of Ulcers

% o

f P

atie

nts

88

71

47

30

p < 0.001

p < 0.001

0

20

40

60

80

100

Reduction Disappearance

Step-upTop-down

Weeks

% o

f P

atie

nts

Patients Receiving Infliximab

0

50

100

0 20 40 60 80 100

Step-upTop-down

0

50

100

% o

f P

atie

nts

Patients Receiving Immunosuppressants

Unanswered Questions About Biologic Therapy in IBD

Do biologics change long-term outcomes in IBD ?

Economic burden ,safety

immunosuppressives beneficial indefinitely or just early?

Where should biologic therapy fit in our treatment algorithm?“Top down” approach?

Before 1982, Kirsner and shorter observed that inflammatory bowel disease was rare or non existent in Saudi Arabia Kirsner JB, Shorter RG. Recent developments in non-specificinflammatory bowel disease .

N Engl J Med 1982; 306: 837-848

Mokhtar and his group from King Abdul- Aziz University in Jeddah reported the first two

cases of Crohn’s disease in Saudi’s 1982

Mokhtar A, Khan MA. Crohn’s disease in Saudi Arabia. Saudi Med J 1982; 3: 207-208

Epidemiology and outcome of Crohn’s disease in a teaching hospital in Riyadh

Abdullah S. Al-Ghamdi, Ibrahim A. Al-Mofleh, Rashed S. Al-Rashed, Saleh M. Al-Amri, Abdulrahman M. Aljebreen, World J Gastroenterol 2004;10(9):1341-1344

retrospective analysis of 77 patients of crohn’s seen for 20 years (between 1983

and 2002) .

Abdullah S. Al-Ghamdi, Ibrahim A. Al-Mofleh, Rashed S. Al-Rashed, Saleh M. Al-Amri, Abdulrahman M. Aljebreen, World J Gastroenterol 2004;10(9):1341-1344

Emerge of Crohn’s Disease Incidence in Saudi Arabia; Tertiary

Care Centre Experience

Azzam N et al Abstract in the 9th GI &liver conference Abha , SA 7-10 may 2007

METHODS

Retrospective analysis of 42 CD patients diagnosed (between 2003 and 2005) was performed.

Individual case records were reviewed with regard to history, clinical findings, the disease extent, location, clinical pattern, treatment and outcome.

Clinical features of CD patients

Age26.5 y

Male 18) 42%(

Female 24) 58%(

Duration since diagnosis

3 Y

Family HX of IBD3) 7%(

Saudi92%

Presenting symptoms

Abdominal Pain41)97%(

Diarrhoea 40)95%(

Bleeding P/R21)50%(

Vomiting14)33%(

Fever7)16%(

WT loss21)50%(

Disease location

0%

5%

10%

15%

20%

25%

30%

35%

40%

Diseaselocations

ileal

colonic

ilocolonic

duodenal

CD types

0%

10%

20%

30%

40%

50%

60%

70%

C D types

C D types

inflammatory

fistulizing

fibrostenotic

Result

Forty -Two patients with Crohn's disease were reviewed .

The incidence of the CD was increased significant in KKUH from 77 patients diagnosed as Crohn’s disease from (1983-2002) to 42 new patients with CD within

(2003-2005) The patients had more severe disease and

more colonic involvement .

Conclusion

-This study shows an increase in the incidence of CD in Saudi population in tertiary centre especially in the last 3 years

-National data registry is needed for the true prevalence of crohn’s diasease in Saudi Arabia