Treatment of inflammatory bowel disease

1. Treatment of inflammatory bowel disease

2. Goals of treatment

3. Goals of Treatment

5. Asacol® AZO-COMPOUNDS Stomach Small Intestine Large Intestine Mesalamine w/ eudragit-S Azo bond Oral 5-ASA Release Sites Pentasa® Mesalamine in microgranules

6. Aminosalicylate • Well established role in induction and maintaining remission in UC • Dose –related effect in UC • Long term safety established • Efficacy in crohn’s disease is controversial due to absence of rigorous evidence and preponderance of negative studies

7. Steroids

9. Steroids

10. Definitions • Corticosteroid refractory disease • Patients who have active disease despite prednisolone up to 0.75 mg/kg/day over a period of four weeks. • Corticosteroid dependent disease; Patients who are either • (a) unable to reduce corticosteroids below the equivalent of prednisolone 10 mg/day (or budesonide below 3 mg/day) within three months of starting corticosteroids, without recurrent active disease, or • (b) who have a relapse within three months of stopping corticosteroids. The aim should be to withdraw corticosteroids completely. E F Stange, S P L Travis; ECCO Consensus on the diag&Mang of CD”Gut 2006;55(Suppl I.)

11. Steroids • Crohn’s disease: 50% of patients will require treatment with steroids. • Of those 28% will become steroid dependent • Ulcerative colitis: 34% of patients will require treatment with steroids. • Of those 22% will become steroid dependent

12. Steroid • Effective for the short-term control of symptoms of Crohn's disease but are neither effective nor safe for long-term maintenance of response. • In patients with disease that is refractory to or dependent on glucocorticoids, steroid-sparing strategies should be considered, including immune modulators or surgery.

13. Principles of steroid use in IBD

14. Steroid adverse effects

15. Immunomodulators: azathioprine and 6 -mercaptopurine

16. Indications of immunosuppressant

17. Safety and tolerability • Flu like symptoms occuring after 2-3 weeks and resolve on discontinuation of RX (20%) • Hepatotoxicity and pancreatitis(<5%) • Leukopenia(<3%) • Good long term tolerance • Can be given during pregnancy • ? ↑ risk of neoplasm

18. Methotrexate

19. Cyclosporine • Competetively binds to and inhibit calmodulin dependent calcineurin, leading to suppression of T-cell and IG E receptor signaling pathways. • IV Cyclosporine has a rapid onset of action • Neither intravenous nor oral low-dose cyclosporine has proven efficacy in patients with luminal CD. • High toxicity limiting its use

20. Biologic treatment

21. Treatment

22. Treatment of ulcerative colitis

23. Disease location

24. Topical treatment

25. Advantage of topical therapy

26. Mild to moderate distal colitis: induction of remission • Topical 5 –ASA is more effective than topical steroid and oral 5-ASA • Combination of oral and topical 5-ASA is more effective than either alone • Patient unresponsive to topical therapy: po steroids

27. Mild to moderate distal colitis: maintenance of remission • Topical and oral 5-ASA :Effective in maintainaing remission • Combination of oral and topical 5-ASA is more effective than oral 5-ASA alone • Topical and oral steroid: no role

28. Mild to moderate extensive colitis: induction of remission • Oral 5-ASA is the first line of therapy • Oral steroids are reserved for: - refractory patients to PO +/- topical 5-ASA - troubling sxs requiring rapid improvement

29. Mild to moderate extensive colitis: maintenance of remission • All 5 –ASA are effective in preventing relapse • Azathioprine or 6-MP may be used: -steroid sparing agent in steroid dependent patients -steroid refractory patients who are not acutely ill -remission not adequately maintained on 5-ASA

30. Management of severe colitis • Patients with severe colitis refractory to maximal oral prednisone, oral 5-ASA and topical RX, or presents with toxicity should be hospitalized for IV steroids • Patients not responding within 7-10 days of maximal medical therapy should be offered alternative treatment: -biologic treatment -cyclosporin- surgery

31. Cyclosporine • Cyclosporine has a rapid onset of action (more rapid than AZA, 6-MP, or methotrexate) and when administered intravenously has been shown to be effective in the management of patients with severe UC. • It often demonstrates clinical efficacy within 1 week when administered intravenously. • Oral cyclosporine has a possible role in the induction of a clinical response in UC and short term in the maintenance of an intravenous cyclosporine-induced response, allowing time for the slow-acting purine analogues to become effective.

32. Biologic treatment • Infliximab is the only FDA approved treatment for patients with moderate-severe ulcerative colitis • ACT 1 study: treatment with infliximab can prevent hospitalizations and surgery for UC patients in the first year of treatment

33. Ulcerative Colitis: Mild to Moderate Acute flare Exclude entericpathogen Extensive Left side Oral 5-ASA Patient willing totake rectal therapy Patient unwilling to take rectal therapy Consider rectal therapy(5-ASA and/or steroid) Maintain Maintainoral 5-ASA Oral steroid Responseadequate Responseinadequate Response adequate Considerincreased dose Response inadequate Oral 5-ASA Responseinadequate Responseadequate Response inadequate

34. Ulcerative Colitis: Moderate to Severe Moderate Severe Infliximab IV Steroid ConsiderCyA Oral steroid 6MP/AZA Taper Success Colectomy Successful Maintain on5-ASA and observe Maintaininfliximab Maintain6-MP/AZA Inadequate response Inadequate response Adequate response Response Unsuccessful No response Failure No response Response

35. Therapeutic Pyramid for Active UC Severe Surgery Cyclosporine Infliximab Moderate Systemic Corticosteroids AZA/6-MP Oral Steroids Mild Aminosalicylates

36. Indication for surgery • Total colectomy with ileoanal pouch anastomosis is the procedure of choice for patients with UC:

37. Indications for surgery in UC Analysis of 917 UC patients at Heidelberg University between 1982 and 2001 Perforation 6% Toxic uc 10% Colorectal ca 7% Dysplasia 3% Failure of medical therapy 74% Hoffmann et al. Chronisch-Entzündliche Darmerkrankungen. Thieme 2004

38. Potential Complications of UC Surgery • 3-10 stools/24 hrs 1 • Decrease in female fertility (38-54%)3-5 • Pouchitis (10-60%)1 • Small bowel obstruction (20%)1 • Abscesses & fistulae (5-12%)6 • Pouch-vaginal fistula (4%)1 • Long-term continence problems (15%)6 • Impotence (1.5%)2 1Sagar PM, Pemberton JH. In Satsangi J, Sutherland L, et al, eds. Inflammatory Bowel Diseases. Spain: Elsevier Limited; 2003:491 511. 2Pemberton JH, et al. Ann. Surg. 1987;206(4):504-513. 3Olsen, KO, et al. Gastroenterology. 2002;122:15-19. 4Johnson P, et al. Dis Colon Rectum. 2004;47;1119–1126. 5Gorgun E, et al. Surgery. 2004;136(4):795–803. 6Stange et al. Colitis ulcerosa – Morbus Crohn.Uni-Med Verlag AG 1999.

39. Pouchitis • Idiopathic inflammation of “pouch” after ileoanal pouch anastomosis

40. Treatment of crohn’s disease

41. Mild to moderate luminal active disease • Despite the use of oral mesalamine treatment in the past, new evidence suggests that this approach is minimally effective as compared with placebo and less effective than budesonideor conventional corticosteroids

42. 5-ASA in crohn’s disease • No mesalamine product has been FDA approved for either induction or maintenance of remission • Not effective in maintaining post-operative remission.

43. Mild to moderate luminal active disease • Oral budesonide is more effective than placebo, or 5-ASA and have similar efficacy to conventional po steroids for the treatment of mild-moderate active CD involving distal ileum and/or right colon. • Budesonide is recommended for use as primary therapy for patients with mild to moderate active CD localized to ileum and/or right colon

44. Moderate to severe luminal disease • Prednisone (40 -60 mg/day) until resolution of symptoms • Infection or abscess requires antibiotic therapy or drainage • Azathioprine and 6-MP are effective in maintaining a steroid-induced remission • Parenteralmethotrexate (25 mg/week) :effective for steroid-dependent and steroid-refractory CD

46. Biologic treatment • Anti TNF monoclonal Ab : infliximab, adalimunab and cetrolizumab are effective for: -moderate- severely active CD not responding despite complete and adequate therapy with a steroids or immunosuppressive agent -as alternative to steroid therapy in selected patients in whom steroid is contraindicated • The anti-alpha 4 integrinAb : natalizumab, is effective for patients with moderate to severely active disease who had an inadequate response to anti TNF AB or unable to tolerate it

48. Therapeutic Strategies:Step up Sequential escalation based upon symptoms, usually starting with the efficacysafest medication but with the least Most prevalent strategy Advantages: minimize risks of adverse drugs effects Disadvantages: risk of inadequate treatment, not targeting the underlying process, i.e. the inflammation and the potential complications

49. Therapeutic pyramid for treatment of luminal non fistulizing crohn’s disease Severe Mild

50. Therapeutic Strategies:Top down Therapy with a potent agent since the beginning Advantages: strong suppression of inflammation from diagnosis Disadvantages: Expensive, treats all patients as if they have identical risk and lead to unnecessary exposure to adverse drug effects