1. End points in IBD treatment Mucosal healing Vs Symptom relief Jose Francis Lakeshore Hospital Kochi

2. Introduction No cure for IBD No end points available!!

3. Treatment goals * Maintenance of remission * Maintenance of QOL * SYMPTOM RELIEF

4. Additional goals!! * Disease modification * Mucosal healing * Pharmacoeconomics * Disease prevention! * MUCOSAL HEALING

5. New therapeutic goals in IBD Clinical Induction & maintenance of remission off steroids Closure of fistulas Bowel Mucosal & maintenance of healing Healing of fistula tracks Long term Avoidance of complications, hospitalizations, surgeries & mortality

6. Definition - mucosal healing Clinician will say - “I know it when I see it” * Intact bowel mucosa Clinical trials - secondary endpoint Remember!! - Normal mucosa when biopsied * Granulomas (ileum/colon) * Focal enhancing gastritis (antrum) * Lymphocytic infiltration (rectum)

7. Key question Does healing of mucosa * Improves the outcome? Unfortunately treatments that heal * Do not cure When one stops Rx, the disease will recur

8. Not uncommon situation Patient feels fine –Physicians say “you’re better now, let’s just keep doing what we’re doing” Colonoscopy – activity Physicians do not say “The fact that you are better now and we’ve achieved this level of mucosal healing through therapy escalation likely means that you’ll be in better shape in 10 years’’

9. Clinical endpoints- Assessment CDAI ( Remission <150) CAI Difficulty in evaluation - Assess symptom relief only - Non specific & non sensitive - Inconsistencies in the way symptoms are reported, collected and understood, and symptom-based indices are limited when it comes to predicting how patients will fare (CDAI) - Disease-focused, but not disease specific - Symptom-based index has little to no prognostic value

10. Surrogates for Mucosal Healing ESR CRP Calprotectin Lactoferrin Imaging (MRE, CT,USG) Endoscopy – MAYO, CDEI Histopathology Difficulty in evaluation - Invasive tests - the incidence of procedures & cost - Compliance (when pt. is feeling fine) - No standardization

11. What’s Wrong with Using Clinical Endpoints Rather Than Mucosal Healing? Crohn’s disease * No correlation with endoscopic findings * Patients treated to clinical endpoints - Have progression of disease Ulcerative colitis * Complete clinical remission & mucosal healing (score of 0) - good prognosis * No escalation for mild residual symptoms

12. Mucosal healing as a surrogate for longer term outcomes Associated with * Better quality of life * Fewer hospitalizations * Fewer surgeries * Longer time to clinical relapse * Reduction in dysplasia/cancer

13. Why is mucosal healing an important treatment endpoint? Mucosal healing - Measure of the underlying inflammation Clinical symptoms - Secondary surrogate Clinical symptoms are important, but treating the underlying inflammatory condition is likely the more critical factor

14. To attain mucosal healing Escalating dose Adequate & Maintenance dose Switching over Combination Efficacy of anti-TNF drug are trough levels Adherence to treatment

15. Escalating dose 3 weeks, mucosal healing –65% with moderately active UC (4.8 g/d) –58% of patients 2.4 g/d (P=.219) After 6 weeks, mucosal healing –80% compared with 68%(P=.012) Am J Gastroenterol. 2005;100:2478-2485 Aliment Pharmacol Ther. 2005;21:133-140. Can J Gastroenterol. 2007;21:827-834. Clin Gastroenterol Hepatol. 2007;5:95-102 Aliment Pharmacol Ther. 2011;33:672-678 Am J Gastroenterol. 2005;100:2478-2485 Aliment Pharmacol Ther. 2005;21:133-140. Can J Gastroenterol. 2007;21:827-834. Clin Gastroenterol Hepatol. 2007;5:95-102 Aliment Pharmacol Ther. 2011;33:672-678

16. Infliximab Dose Dose escalation - Decrease of the interval between infusions - Dose increase to 10 mg/kg ACCENT I study - 90% who lose response can be rescued ACCENT II study - Fistulizing disease - Successful in 60%

17. Adequate dose ASA Steroids Azathiopurine Biologic agents

18. Maintenance dose

19. 5-ASA switching Few studies Granulated mesalamine 1.5 g once daily or placebo Maintained remission after 6 months of treatment 78% vs 59%; P<.001 Relapse-free at 6 months (77% vs 50%; P<.001). Am J Gastroenterol. 2008;103(Suppl 1):A429-A430

20. Infliximab - switching Switching to another biologic agent Adalimumab Certolizumab

21. ASA - Oral/rectal combination therapy Decrease in CAI scores Decrease in no. of relapses Am J Gastroenterol. 1997;92:1867-1871 Am J Gastroenterol. 1997;92:1143-1147 Am J Gastroenterol. 1997;92:1867-1871 Am J Gastroenterol. 1997;92:1143-1147

22. Infliximab/Azathioprine combination

23. Mesalamine for postsurgical maintenance in Crohn’s disease? Preventing relapse (OR, 0.68; 95% CI 0.52 to 0.90) Gastroenterology. 2000;118:264-273. Cochrane Database Syst Rev. 2011:CD008414 Gastroenterology. 2000;118:264-273. Cochrane Database Syst Rev. 2011:CD008414

24. Infliximab for postsurgical maintenance in Crohn’s disease? 5 mg/kg within 4 weeks of surgery Maintenance for 1 year Endoscopic recurrencefrom 85% to 9% Gastroenterology 2009; 136: 441–50e1

25. Trough levels

26. THIOPURINES - levels Active metabolites 6-thioguanine (6-TGN) 6-methylmercaptopurine nucleotide (6-MMPN) Meta-analysis of 12 studies 6-TGN levels higher among patients in remission - 62% with 6-TGN levels above 230–260 pmol/8 x108 RBC - 36% below this value(P<.001) Gastroenterology. 2006;130:1047-1053.

27. Managing adherence 89% remain in remission over the long term 39% of those who are nonadherent Pill burden Educational intervention Am J Med. 2003;114:39-43. Am J Gastroenterol. 2002;97:1853 Am J Med. 2003;114:39-43. Am J Gastroenterol. 2002;97:1853

28. Infliximab - Antibodies Human antichimeric antibodies (HACAs) - Episodic dosing 37% to 61% - Scheduled infliximab 6% and 16% Similar in adalimumab & certolizumab Detectable trough concentrations had - Higher rates of clinical remission - Lower CRP - Higher rate of endoscopic improvement Lancet. 2002;359:1541-1549 N Engl J Med. 2003;348:601-608 Clin Gastroenterol Hepatol. 2006;4:1248-1254 Lancet. 2002;359:1541-1549 N Engl J Med. 2003;348:601-608 Clin Gastroenterol Hepatol. 2006;4:1248-1254

29. Early Aggressive Biologic Therapy Vs Conventional management of Crohn’s Disease

30. D'Haens G, et al. Lancet 2008;371:660-667 Step Up Vs Top Down Results

31. Step Up Vs Top Down Complete Remission at 2 Years

32. Actuarial analysis of symptomatic recurrence in patients stratified according to severity of endoscopic lesions Rutgeerts P, et al. Gastroenterology. 1990;99:956-963

35. Safety issues  Infections  Reactivation of latent TB  Possible lymphoma risk  Hepatosplenic T-cell lymphoma in young patients on infliximab plus concomittant azathioprine (n = 8)

37. Weighing the Value of Top-Down Therapy Maintenance of remission Improved function and QOL Early promotion of mucosal healing to prevent complications Maintenance of remission Improved function and QOL Early promotion of mucosal healing to prevent complications Side effects Cost Majority of patients may not require more potent treatments initially Under-treatment of most severe patients with episodic strategy? Side effects Cost Majority of patients may not require more potent treatments initially Under-treatment of most severe patients with episodic strategy? Benefits Disadvantages Lichtenstein GR, et al. Inflamm Bowel Dis. 2004;10:S2–S10. Caprilli R, et al. Digestive Liver Dis. 2005;37:973–979.

38. Predictors of More Severe Disease Crohn’s disease Young age of onset (<40 years) Ileal or ileocolonic extent Fistulizing disease at diagnosis Early need for steroids ASCA / other serologies? Genetics? Crohn’s disease Young age of onset (<40 years) Ileal or ileocolonic extent Fistulizing disease at diagnosis Early need for steroids ASCA / other serologies? Genetics? Ulcerative Colitis Extensive colitis Male gender Early need for steroids Early hospitalization Ulcerative Colitis Extensive colitis Male gender Early need for steroids Early hospitalization

39. Mucosal healing Existing evidence Achieve mucosal healing in about 44% Colombel JF et al N Engl J Med 2010: 362: 1383 - 1395

40. SUMMARY There is no “one size fits all” to IBD therapy –Tailored to the individual Current Rx guidelines for CD / UC - Step-up treatment There is insufficient data to universally adopt top-down therapy into clinical practice at the present time There is no “one size fits all” to IBD therapy –Tailored to the individual Current Rx guidelines for CD / UC - Step-up treatment There is insufficient data to universally adopt top-down therapy into clinical practice at the present time

41. Symptom relief Vs Mucosal healing Long way to go!!

42. Thank You