1. Crohn’s disease the new challenge Dr.Nahla A Azzam (MRCP) GI/ Medicine Consultant KKUH

2. Objectives - overview on the pathogenesis of CD - Treatment options -CD management approach - Prevalence of CD in Saudi Arabia - KKUH experience

3. Pathogenesis

4. Genetic Susceptibility Chromosome 1, 3, 7, 12, 16 Polygenic trait Environmental Triggers & Modifiers Gut bacteria Smoking/nicotine Epithelial dysfunction Increased Immune Response Innate & autoimmune Macrophage activation T cell activation Cytokine/adhesion molecule expression Current Model: Pathogenesis of Crohn’s Disease

6. Genetics

8. NOD2 gene involved in NF-  B activation -CARD: caspase-activation recruitment domain NBD: nucleotide-binding domain Expressed in monocyte -Leucine rich region (LRR) interacts with bacterial LPS to activate NF-kB 128124220273 577 744 1044 LRRCARD NBD

11. Genotype relative risks (RR) for three major associated NOD2 variants Heterozygous RR : 1.5 - 4.0 Homozygous RR : 15 - 40 Disease penetrance < 10% for homozygotes and compound heterozygotes NOD2 Population attributable risk for ileal disease,Younger,fibrostenotic

12. 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.

14. CD management

15. 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. % of Patients 20 40 60 80 100 51015202530 Years After Onset Cumulative Probability* of Surgery in Crohn’s Disease

16. CD therapeutic pyramid SurgeryCyAInfliximabMTXAZA/6-MP Systemic Corticosteroids SurgeryCyAInfliximabMTXAZA/6-MP Antibiotics5-ASAAntibiotics5-ASA Mild to Moderate Disease Moderate to Severe Moderate to SevereDisease Budesonide Hanauer SB, Sandborn W. Am J Gastroenterol. 2001;96:635–643.

21. Systemic circulation 10-20% 70% absorbed in ileum Budesonide absorption & bioavailability

24. CD limited to small bowel 5ASA ???? budesonide prednisone 6MP/AZA MTX infliximab Others: CyA, thalid., … NPO + TPN

25. CD limited to colon 5ASA: Asacol, Colazal, … Abx: cipro, metro, … prednisone 6MP/AZA MTX infliximab Others: CyA, thalid., … NPO + TPN ileostomy

26. 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

27. Remicade Contraindications Absolute Class III/IV CH Active bacterial infection RelativeElderly Severe co-morbidities Bowel stricture? Multiple sclerosis

28. 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

29. Major Clinical Trials With TNF Antagonists in Crohn’s Disease Agent Study NameReference Aim 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 II Sands et al.N Engl J Med 2004 Lichtenstein et al.Gastroenterol 2005 Maintenance (F) REACHHyams et al.DDW 2006 Induction & 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 2006 Induction & Maintenance PRECiSE 2Schreiber et al.UEGW 2005Maintenance F = fistulas; P = pediatric.

30. 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 Hospitalizations per 100 Patients p = 0.047 p = 0.023 p = 0.014 0 10 20 30 40 50 N =188192193385

31. ACCENT II: Cumulative Number of Surgeries Over Time in Responders Cumulative Number of Surgeries & Procedures 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 026142230384654

33. Major Clinical Trials With TNF Antagonists in Crohn’s Disease Agent Study NameReference Aim 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 II Sands et al.N Engl J Med 2004 Lichtenstein et al.Gastroenterol 2005 Maintenance (F) REACHHyams et al.DDW 2006 Induction & 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 2006 Induction & Maintenance PRECiSE 2Schreiber et al.UEGW 2005Maintenance F = fistulas; P = pediatric.

34. CLASSIC 1 trial

35. CHARM: Clinical Remission of CD Over Time With Adalimumab Randomized Responders (n = 499) * * * * * * * * * * * * * * * * * * † % of Patients Weeks 47 40 41 36 17 12 *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 0102030405060 PlaceboAdalimumab 40 mg EOWAdalimumab 40 mg weekly 26 56

36. 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 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 % of Patients Step-up Top-down * 0 20 40 60 80 100 020406080100 Co-primary endpoints 6 & 12 months † * * P < 0.01; † P <0.05

37. Top-Down Versus Step-Up Trial Clinical 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 % of Patients 88 71 47 30 p < 0.001 0 20 40 60 80 100 ReductionDisappearance Step-up Top-down Weeks % of Patients Patients Receiving Infliximab 0 50 100 020406080100 Step-up Top-down 0 50 100 % of Patients Patients Receiving Immunosuppressants

38. 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?

40. 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

41. 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

42. 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

44. 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

45. 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.

46. Clinical features of CD patients Age26.5 y Male18 (42%) Female24 (58%) Duration since diagnosis 3 Y Family HX of IBD3 (7%) Saudi92%

47. Presenting symptoms Abdominal Pain41(97%) Diarrhoea40(95%) Bleeding P/R21(50%) Vomiting14(33%) Fever7(16%) WT loss21(50%)

48. Disease location

49. CD types

50. 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.

51. 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