1. Immunomodulators and Biologics Maria T. Abreu, MD University of Miami Miller School of Medicine Miami, Florida

2. Management of Post-Operative Recurrence of IBD David T. Rubin, MD, AGAF Associate Professor of Medicine Co-Director, Inflammatory Bowel Disease Center University of Chicago Medicine

3. Learning Objectives At the conclusion of this presentation, learners will: 1.Develop an approach to the pro-active assessment of post-operative recurrence of IBD, including Crohn’s disease and ulcerative colitis. 2.Incorporate the emerging understanding regarding pathogenesis of post-operative recurrence into treatment algorithms, and the development of an individualized prevention strategy for their patients. 3.Critically appraise the available information about treatment of post-operative recurrence in IBD. 4.Understand the current literature regarding risks of peri- operative immune suppression in IBD.

4. IBD Induction of remission Maintenance of remission off steroids and/or Mucosal healing (histology) Maintenance of remission

5. What do we know: Guiding principles  Combination therapy is better than monotherapy  Early therapy is better than late therapy (esp Crohn’s disease)  Well timed surgery is ok

6. Indications for Surgery  Crohn’s disease:  Obstruction  Medically refractory disease  Hemorrhage/transfusion requirements  High grade dysplasia or cancer  Growth delay  Fistula/abscess  Ulcerative colitis:  Medically refractory disease/fulminant disease  High grade dysplasia or cancer  Hemorrhage/transfusion requirements  Perforation

7. Chimeric monoclonal antibody (75% human IgG 1 isotype) Infliximab IgG 1 Mouse Human PEG, polyethylene glycol. Humanized Fab’ fragment (95% human IgG 1 isotype) Certolizumab PegolPEG PEG VHVL CH1CH1CH1CH1 No Fc Human recombinant antibody (100% human IgG 1 isotype) Adalimumab IgG 1 First-line Biologic Agents for the Treatment of CD

8. SONIC Moderate-to-severe CD in patients with no prior exposure to biologic agents or immunomodulators Excluded intermediate TPMT activity Average disease duration 2.3 years 1° endpoint: Induction + maintenance of steroid-free remission 2° endpoint: Mucosal healing AZA 2.5mg/kgIFX 5mg/kgIFX + AZA

9. Clinical Remission Without Corticosteroids at Week 26 SONIC 9 Primary Endpoint 30 45 57 0 20 40 60 80 100 Proportion of Patients (%) AZA + placeboIFX + placeboIFX+ AZA p<0.001 p=0.009p=0.022 52/17075/16996/169 Colombel, J.F., et al., N Engl J Med. 362(15): p. 1383-95.

10. Cumulative Probability of Surgery in Crohn’s Disease Mekhjian HS et al. Gastroenterol. 1979;77(4 pt 2):907-913. Patients* (%) 0 20 40 60 80 100 05101520253035 Years After Onset

11. Preoperative Corticosteroids Increase Risk of Postoperative Complications in IBD Minor Complications Major Complications* CS3.69 (1.24–10.97)5.54 (1.12–27.26) CS <20 mg2.56 (0.68–9.61)6.28 (0.97–40.36) CS 30–40 mg3.12 (0.93–10.49)5.87 (0.90–38.23) CS >409.16 (1.51–55.42)18.94 (1.72–207.34) 6-MP/AZA1.68 (0.65–4.27)1.2 (0.37–3.94) 6-MP <1.5 mg/kg1.49 (0.56–3.98)1.12 (0.32–3.93) 6-MP>1.5 mg/kg4.50 (0.46–44.51)1.89 (0.32–3.93) 159 IBD patients (71 UC, 88 CD) undergoing elective bowel surgery Aberra FN et al. Gastroenterology. 2003;125:320. *Major complications include sepsis, pneumonia, peritonitis, abscess, wound infection CS, corticosteroids; 6-MP, 6-mercaptopurine; AZA, azathioprine

12. TNF Use Prior to Surgery Postoperative infections –CD 1 : Mayo Clinic 52 IFX vs 218 no IFX OR 0.9 (95% CI 0.4–1.9) 1 –UC 2 : Mayo Clinic 47 IFX vs. 254 no IFX OR 2.7 (95% CI 1.1–6.7) –UC 3 : Cleveland Clinic Pelvic sepsis 46 IFX vs. 46 no IFX OR 13.8 (1.8–105) 1. Colombel JF et al. 1. Colombel JF et al. Am J Gastroenterol. 2004;99:878. Selvasekar CR et al. J Am Coll Surg. 2007;204:956. 2. Selvasekar CR et al. J Am Coll Surg. 2007;204:956. 3. Mor IJ. Dis Col Rectum. 2008;51:1202. CD UC ? IFX, infliximab; OR, odds ratio; CI, confidence interval

13. Immediate and Long-term Outcomes of Corticosteroid Therapy in Adult CD Complete Response 58% Partial Response 26% Faubion WA Jr et al. Gastroenterol. 2001;121:255. No Response 16% Prolonged Response 32% Steroid- dependent 28% Surgery 38% N=74

14. Role of Bacteria in Post-op Recurrence in Crohn’s Disease Unknown Possibilities –Loss of the ileocecal valve exposes the neo-terminal ileum to colonic bacteria –Bacteria associated with post-op recurrence may have increased adherence and penetrance Evidence –Diversion leads to “durable” remission –Antibiotics studied to prevent recurrence –Probiotics? Ahmed T et al. Gut 2011;60:553-562

15. Disability Post-op Ileocecectomy is the Perfect Opportunity for Prevention! Disease Prevention Prevention of Symptomatic Disease Prevention of Complications Prevention of Relapse Health Subclinical Inflammation Symptomatic Inflammation Complications

16. Recurrence After Surgery in Crohn’s Disease Rutgeerts P et al. Gastroenterol. 1990;99(4):956-963. Years Patients (%) Survival without surgery 0 20 40 60 80 100 012345678 Survival without symptoms Survival without laboratory recurrence Survival without endoscopic lesions N=89

17. Risk Stratification for Recurrence in Post-operative Crohn’s disease  Smoking  Perforating-type of disease  Small bowel disease  Ileocolonic disease  Perianal fistulas  Duration of disease  Age  ? Clear margins  ? Length of resection  ?Type of anastomosis Greenstein AJ et al. Gut. 1988;29(5):588-592. Bernell O et al. Ann Surg. 2000;231(1):38-45. Bernell O et al. Br J Surg. 2000;87(12):1697-1701. D'Haens GR et al. Gut. 1995;36(5):715-717. Lautenbach E et al. Gastroenterol.1998;115(2):259-267. Moskovitz D et al. Int J Colorectal Dis. 1999;14(4- 5):224-226. Kono T et al. Dis Colon Rectum 2011 May;54(5):586-92.

18. The Neo-TI: The Rutgeerts’ Score Patients should be scoped 6 months after surgery to re-stratify risk Normal ileal mucosa Rutgeerts 0 <5 aphthous ulcers Rutgeerts 1 >5 aphthous ulcers, normal intervening mucosa Rutgeerts 2 Ulceration without normal intervening mucosa Severe ulceration with nodules, cobblestoning, or stricture Rutgeerts 3Rutgeerts 4

19. The neo-terminal ileum is not the anastomosis! Suture-related trauma Marginal ulcerations/ischemia

20. Symptoms after Crohn’s Surgery are Not Always Inflammatory! Symptom/CauseTreatments Post-operative painLimited analgesia, regional anesthesia when possible Post-resection “diarrhesis” (rapid transit due to absence of obstruction and muscular hypertrophy) Anti-diarrheals Bile saltsBile acid sequestrant Narcotic bowelNO narcotics! Bacterial overgrowthantibiotics

21. Clinical RecurrenceEndoscopic recurrence Placebo25% – 77%53% - 79% 5 ASA24% - 58%63% - 66% Budesonide19% - 32%52% - 57% Nitroimidazole7% - 8%52% - 54% AZA/6MP34% – 50%42 – 44% Infliximab0%9.1% Regueiro M. Inflamm Bowel Dis. 2009 Oct;15(10):1583-90. Medical Prevention of Clinical and Endoscopic Recurrence of Crohn’s Disease

22. N=60 Rutgeerts P et al. Gastroenterol. 1995;108(6):1617-1621. Metronidazole Post-op Prophylaxis in Crohn’s Disease P=NS Endoscopic at 3 Months Clinical Recurrence (%) P=.09 P=.02 P≤.044 P=NS 30% 26% 4% 13% 52% 50% 43% 25% 43% 75% 0 20 40 60 80 100 AnySevere12 Months24 Months36 Months Metronidazole Placebo

23. EndoscopicClinical Thiopurines for the prevention of postoperative recurrence in Crohn’s disease: meta-analysis Peyrin-Biroulet L et al. Am J Gastroenterol. 2009 Aug;104(8):2089-96.

24. Metronidazole/azathioprine combination therapy for post-operative recurrence –High risk pts (n=81) = (age <30, smokers, steroids <3 months, second resection, perforated/abscess) –N=40 metronidazole 250 mg TID 3 months + AZA 2–3 tabs –N=41 metronidazole 250 mg TID 3 months + placebo D'Haens GR et al. Gastroenterology. 2008 Oct;135(4):1123-9. % patients with endoscopic recurrence (>i2) post surgery

25. Infliximab vs placebo p=0.0006 Endoscopic Recurrence defined as endoscopic scores of i2, i3, or i4. Regueiro M et al. 2009 Feb;136(2):441-50.e1; quiz 716. 1/1111/13 Post-operative Endoscopic Recurrence Infliximab vs. Placebo

26. Assess risk of recurrence Low Moderate High Don’t Know Therapy? Start therapy ? ? Thiopurine + MTX TNF + IMM Colonoscopy at 6 months Colonoscopy at 3-6 months Metronidazole at discharge i0-i1 i2-i4 i0-i1 i2-i4 i0-i1 i2-i4 Follow up Treatment Escalate Rx Change dose/ optimization 4 weeks Metronidazole at discharge Proposed Algorithm for Prevention of Post-Op Recurrence in Crohn’s

27. What to do in Follow-up after 6 Months? Clinical follow-up only? Repeat colonoscopy in 6 months or 12 months? Less invasive disease monitoring? –Fecal calprotectin –MR enterography –Ultrasound –Capsule endoscopy Rutgeerts P. Aliment Pharmacol Ther. 2006;24 Suppl 3:29-32. Calabrese E et al. J Crohns Colitis. 2012 Feb 23. Jensen MD et al. Clin Gastroenterol Hepatol. 2011 Feb;9(2):124-9.

28. Ulcerative colitis

29. Early mucosal healing a favorable prognostic factor in UC Infliximab-treated patients P<0.0001 Patients in Corticosteroid-free remission % Week 8 endoscopic score ACT 1 and ACT 2 Colombel JF et al. Gastroenterology. 2011 Jun 29. [Epub ahead of print]. Week 8 endoscopy

30. Can Surgery for UC be Prevented? Mucosal Healing and Time to Colectomy in Infliximab-Treated Patients 1 = MILD2 = MODERATE3 = SEVERE0 = NORMAL Colombel JF, Rutgeerts P, Reinisch W, et al. Gastroenterology. 2011 Oct;141(4):1194-201

31. The Challenges of Surgery in Crohn’s Disease It is still required It is often done when all else has failed - but should be embraced as an effective treatment option earlier Ongoing issues and concerns –Issues with peri-operative immune suppression –Issues with misinterpretation of “failure of medical therapy” –Distinction between fibrostenosis and true medically refractory disease

32. The Significance and Rate of Post- operative Recurrence in IBD Ulcerative colitis: –Medically refractory disease: End ileostomy  no recurrence IPAA  risks of pouchitis, cuffitis, pre-pouch ileitis, Crohn’s disease Crohn’s disease: –Disease of the colon and terminal ileum: End ileostomy  recurrence in small bowel very low Resection and primary anastomosis  recurrence at anastomosis high –Disease of the proximal small bowel: Resection and primary anastomosis  recurrence at anastomosis probably high (not studied well)

33. Assessment of Risk of Post-Operative Recurrence Should Occur Pre-operatively Know your patient Discuss the available options Manage medical therapies Communicate with the surgeons –Clarify type, extent and severity of disease –Discuss plans for immune suppression Be proactive! Institute prevention strategies

34. Ulcerative Colitis: Ileo-pouch Anal Anastomosis Colectomy J pouch Cuff/Anal Transition zone

35. Better Outcomes at High Volume Hospitals OR = 1.18 (0.99–1.41) Kaplan GG et al. Gastroenterology. 2008;134:680. Percent 50 40 30 20 10 0 35.4 25.6 OR = 2.42 (1.26–4.63) 4.0 0.7 Mortality Complications Low volume High volume

36. “Complications” of the Ileal Pouch Compliments of Bo Shen, MD Surgical/ Mechanical Surgical/ Mechanical Inflammatory/ Infectious Inflammatory/ Infectious Functional Dysplasia/ Neoplasia Dysplasia/ Neoplasia Systemic/ Metabolic Systemic/ Metabolic - Afferent limb syn. - Efferent limb syn. - Strictures - Leaks - Fistulae - Sinuses - Abscess - Adhesions - Re-operation - Afferent limb syn. - Efferent limb syn. - Strictures - Leaks - Fistulae - Sinuses - Abscess - Adhesions - Re-operation -Pouchitis -Crohn’s dis. -Cuffitis -Small bowel bacterial overgrowth -CMV -C. difficile -Polyps -Pouchitis -Crohn’s dis. -Cuffitis -Small bowel bacterial overgrowth -CMV -C. difficile -Polyps - Irritable pouch syn. - Pelvic floor dysfunction - Poor pouch compliance - Pseudo- obstruction - Irritable pouch syn. - Pelvic floor dysfunction - Poor pouch compliance - Pseudo- obstruction - Anemia - Osteoporosis - Vitamin B12 deficiency - Malnutrition - Fertility - Sexuality - Anemia - Osteoporosis - Vitamin B12 deficiency - Malnutrition - Fertility - Sexuality - Dysplasia - Cancer - Dysplasia - Cancer

37. Risk Factors for Pouchitis Extensive UC Backwash ileitis Primary sclerosing cholangitis p-ANCA NOD2/ IL-1 receptor antagonist polymorphisms Ex-smoker NSAIDs Arthralgias Family history of Crohn’s disease Fazio VW et al. Ann Surg. 1995 August; 222(2): 120–127; Schmidt CM et al. Ann Surg. 1998 May; 227(5): 654–665; J L Lohmuller et al. Ann Surg. 1990 May; 211(5): 622–629; Fleshner P et al. Clin Gastroenterol Hepatol. 2007 Aug;5(8):952-8; quiz 887; Achkar JP et al.Clin Gastroenterol Hepatol. 2005 Jan;3(1):60-6; Shen B et al. Am J Gastroenterol. 2005 Jan;100(1):93-101; Le Q et al. Inflamm Bowel Dis. 2012 Mar 29 [Epub ahead of print]

38. Tips to the Appropriate Pouchoscopy Examination Upper endoscope Sedation optional Prep varies- single enema in the morning Identify: –Pouch –Pouch inlet –Afferent limb of ileum –Cuff/anal transition zone (hand sewn or stapled) Biopsy normal and abnormal areas to assist in pathological assessment

39. Figure: http://www.webmd.com accessed May, 2012.http://www.webmd.com

40. Endoscopy Is the Most Valuable Tool for the Diagnosis of Pouchitis HistologyEndoscopySymptom PouchitisNo Pouchitis P < 0.001 Shen B, Achkar JP, Lasher BA, et al. Gastroenterology 2002;121(2):261-7

41. Infrequent Relapse Infrequent Relapse Frequent Relapse Frequent Relapse Antbx-dependent Pouchitis Antbx-dependent Pouchitis Antbx-responsive Pouchitis Antbx-responsive Pouchitis Responded Not Responded Cipro or Metronidazole x 2 more wks Responded Not Responded Cipro+ Metronidazole or Rifaximin or Tinidazole x 4 wks Cipro+ Metronidazole or Rifaximin or Tinidazole x 4 wks Antbx-refractory Pouchitis Antbx-refractory Pouchitis Not Responded 5-ASA/steroids/ Immunomodulators/Infliximab? 5-ASA/steroids/ Immunomodulators/Infliximab? Antibiotics prn Probiotics or Antibiotics Probiotics or Antibiotics Cipro or Metronidazole x 2 wks Pouchitis Management of Pouchitis (endoscopic confirmation is preferred)

42. Can Pouchitis be Prevented? Frequency of Pouchitis with Probiotic Prophylaxis Gionchetti P et al. Gastroenterol 2003 May;124(5):1202-9. N = 20 6 grams QD x 12 months N = 20 P < 0.05 % cases with flare-up

43. Franke A et al. Nat Genet. 2010 Dec;42(12):1118-25. Anderson CA et al. 2011 Mar;43(3):246-52. Emergence of genome-wide association study (GWAS) platforms 120 100 80 60 40 20 0 20002001200220032004200520062007200820092010 IBD CD UC Shared loci 99 71 48 20 44 36 11 34 32 5 3 2 12 5 3 2 Shared Genetic Loci in IBD May Explain Varying Phenotypes Based on Anatomy

44. What about Peri-operative Immune Suppression? Can be associated with post-operative complications; distinction between CD and UC Most studies suggest not Don’t stack immune suppression Steroids are the worst offenders Staged approach is appropriate for at-risk patients Ali T et al. World J Gastroenterol 2012 January 21; 18(3): 197-204

45. Summary: Management of Post- operative Recurrence in IBD Embrace surgery as an appropriate treatment option at the right time. Understand your patient’s risks for complications or recurrence. Weigh risks and benefits of long-term treatment based on risks of disease recurrence. Employ preventive strategies: –Stratify follow-up based on risk- don’t wait for symptoms! –Perform colonoscopy/pouchoscopy when treatment options will be adjusted because of the findings. In Crohn’s disease, treat to prevent- timing does matter! Post-operative prevention in UC is less well-defined, but early intervention and confirmation of inflammation is also essential.

46. Key Take Home Messages

47. IBD Stratify patients for disease severity & potential long-term complications Combination therapy better than monotherapy for sick patients naïve to both Low Absolute risk of IS or Biologic therapy Vaccines, DXAs and other health maintenance issues will eventually be used to measure quality

48. Risks of IBD Therapy Non-melanoma skin cancer (NMSC) associated with current or past IS therapy No other solid tumors show clear association with IS or anti-TNF therapy No clear signal that combination therapy leads to higher risk than monotherapy HSTCL occurs AFTER 2 years of thiopurine exposure Risk of PML after 2 years on natalizumab about 1 in 100 exposed patients

49. Management of Post-operative Recurrence in IBD Know patient’s risk of recurrence Confirm endoscopic disease Ulcerative colitis –Mucosal healing reduces risk of colectomy –Assess risk of pouchitis –Distinguish pouchitis/Crohn’s/pre-pouch ileitis Crohn’s disease (ileo-colonic anastomosis) –Assess colonoscopic recurrence @ 6 months –Prophylaxis vs re-treatment based on risks and treatment history –Subsequent clinical/endoscopic f/u not defined

50. Microscopic colitis Incidence appears to have stabilized Consider celiac disease if steatorrhea or weight loss Consider drug-induced MC Treat with bismuth or budesonide – -Right dose and right duration Maintenance therapy with budesonide is effective

51. Gut microbiota and IBS Microbiota in IBS: –Differs from health & may contribute to pathogenesis –May lead novel diagnostic tests for IBS –May select or predict response to IBS treatments treatments –Provide potential target in IBS Antibiotics, Probiotics, Therapeutic foods