1. Treating the outpatient with severe IBD: Case studies Daniel H. Present, MD, MACG Clinical Professor of Medicine The Mount Sinai School of Medicine Russell D. Cohen, MD, FACG, AGAF Professor of Medicine, Pritzker Medical School Co-Director, Inflammatory Bowel Disease Center The University of Chicago Medical Center 1

2. Case 1 : Severe Ulcerative Colitis Russ Cohen 2

3. New Patient Visit 24 yo Black female Moved to Chicago from Maryland to pursue career at Boeing. 1 month ago: developed painless BRBPR with mucus: –Flexible sigmoidoscopy to 60cm: 10cm of proctitis; normal proximal. Biopsies of the affected area revealed active proctitis, crypt abscesses, not much chronicity. Proximal biopsies were normal. 3

4. What Would YOU Do? 1.Any additional workup at this time? a.Full colonoscopy? b.Small bowel imaging? c.Upper endoscopy? 2.Therapeutic Options: a.Mesalamine 1g suppositories qhs? b.Mesalamine 4g enemas qhs? c.Topical steroids instead? d.Oral 5-ASA? e.Oral steroids? 4

5. Initial Clinical Course Starts 5-ASA suppositories Initially attains remission Stops suppositories, relapses. Restart suppositories – not responding, now worse. –5 to 6 blood bowel movements, cramping, diarrhea 5

6. What Would YOU Do? 1.Restart 5-ASA 1g suppository; see how she does. 2.Start 5-ASA enema? 3.Start oral 5-ASA? 4.Start oral steroids? 5.Check stool specs. 6.Start nothing; set up for scope 6

7. Your Decision… She underwent flexible sigmoidoscopy (unprepped) in your office: –Limited to 40cm –Showed moderately active UC to 30cm with an abrupt cut-off to normal mucosa 7 L Colon: Sharp demarcation line Rectum: Circumferential, Continuous Inflammation

8. Next Steps: Mesalamine enemas started; patient can’t hold them. Oral mesalamine 4.8g started; patient seemed to worsen. Oral prednisone (20mg po bid) started; patient still without obvious improvement. 8

9. Why Aren’t the Steroids Working? 1.? Too sick 2.? Infected (ie. C diff) 3.? Wrong Diagnosis 4.They are working for his colitis; diarrhea is of other origin. –Celiac? –5-ASA diarrhea? –IBS? –Dietary 9

10. Acute, Severe Colitis…. Typically Abrupt Onset. –Often can identify a “trigger”: Infection, antibiotic, major life stress –“Get Over” the acute insult. Often Early in Disease Course: –10% of fulminant colitics – initial presentation. –Median Age  early- mid 30’s –Disease Duration: median 4-7 years Cohen RD et al. Am J Gastroenterol 1999;94:1587-92. Stack WA et al. Aliment Pharmacol Ther 1998;12:973-8 Wenzl HH et al. Z Gastroenterol 1998;36:287-93. D’Haens G et al. Gastroenterology 2001;120:1323-9 Hyde GM et al. Eur J Gastroenterol Hepatol 1998;10:411-3. 10

11. Options for Severe Colitis If responsive to oral steroids: –Immunomodulators (aza, 6MP) with gradual taper of steroids –Infliximab –Adalimumab 11

12. Azathioprine or 6-MP in UC AZA Placebo AZA/6-MP Steroid-Dependent Active UC Maintenance of Remission in UC Response Rate Relapse Rate Placebo 1) Jewell DP, Truelove SC. Br Med J. 1974;4:627-630. 2) Hawthorne AB, et al. Br Med J. 1992;305:20-22. 3) Ardizzone S, et al. Gut. 2006;55:47-53. 4) Mantzaris et al. Am J Gastroenterol. 2004;99:1122-1128. 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 1.5-2.0 mg/kg/d 1 100 mg/d 2 0% 10% 20% 30% 40% 50% 60% 70%80% 2.0 mg/kg/d 3 2.2mg/k/d 4 AZA: azathioprine. 6-MP: 6-mercaptopurine

13. UC – Maintenance Therapy n=83 George J et al. Amer J Gastroenterol 1996; 91:1711 Probability of Remission Maintenance Months 1.0.8.6.4.2 0 0 20 40 60 6-MP Maintenance in UC

14. Infliximab in UC: Clinical Remission † † † † P .002 vs placebo ‡ P .003 vs placebo † ‡ ‡ ‡ ‡ ACT 1 ACT 2 Rutgeerts P et al. N Engl J Med. 2005;353:2462-2476.

15. Infliximab in UC: Mucosal Healing † † †† † P<.001 vs placebo ‡ P .009 vs placebo ACT 1 ACT 2 ‡ ‡ ‡ ‡ Mucosal healing = endoscopic subscore of 0 or 1 Rutgeerts P et al. N Engl J Med. 2005;353:2462-2476.

16. Infliximab in UC Corticosteroid Discontinuation at Week 30 † † P=.030 vs placebo ‡ P .010 vs placebo ‡ ‡ ACT 1 ACT 2 Rutgeerts P et al. N Engl J Med. 2005;353:2462-2476.

17. Infliximab, Azathioprine, or Infliximab + Azathioprine for the Treatment of Moderate to Severe Ulcerative Colitis: “UC SUCCESS Trial” Panaccione et al. DDW 2011 Abstract #835 Possible escape* (blinded) IFX (5 mg/kg) + PBO (n=78) AZA + PBO (2.5 mg/kg) (n=79) IFX+AZA (n=80) Randomization of Patients Visits Week 0 Week 2 Week 6 Primary Evaluation Infusions Week 16 Week 14 *Subjects not achieving ≥1 point improvement in partial Mayo score Week 8 ABSTRACT ONLY

18. * Total Mayo score 1, no steroids. P = 0.032 vs. AZA P = 0.017 vs. IFX Infliximab, Azathioprine, or Infliximab + Azathioprine for the Treatment of Moderate to Severe Ulcerative Colitis: “UC SUCCESS Trial” Panaccione et al. DDW 2011 Abstract #835 ABSTRACT ONLY

19. Co-administration of Immunosuppressants: Dramatically Lower anti-Infliximab antibody rates “SONIC” Crohn’s Disease Trial: Infliximab alone: 14% anti-Infix antibodies Infliximab + Aza: 1% anti-Infix antibodies “UC-Success” Ulcerative Colitis Trial: Infliximab alone: 14% anti-Infix antibodies Infliximab + Aza: 1% anti-Infix antibodies

20. Adalimumab in Moderate to Severe UC 8 week trial: Doses given weeks 0,2,6. Primary endpoint: Clinical Remission (Mayo score 1). * p=0.031 vs. placebo. SAE: 7.6%, 3.8%, 4.0% respectively. 2 malignancies: both in placebo (basal cell; breast) * Reinisch W et al. Gut ;2011 (online Jan 5, 2011: 10.1136/gut.2010.221127)

21. Adalimumab: Induction of Clinical Remission in Moderate to Severe UC (DDW 2011) 8 week endpoint (52 week trial): Doses given weeks 0,2,6. 494 Patients: moderate to severe UC Primary endpoints: Clinical Remission at weeks 8 and 52. Response rates: 34.6% placebo vs. 50.4% ADA (p<0.001) Clinical Remission * p=0.019 vs. placebo. Sandborn W et al. DDW 2011, abstract #744. ABSTRACT ONLY Week 8: Remission

22. Adalimumab: Mucosal Healing in Moderate to Severe UC (DDW 2011) 8 week endpoint (52 week trial): Doses given weeks 0,2,6. 494 Patients: moderate to severe UC Primary endpoints: Clinical Remission at weeks 8 and 52. Clinical Remission * p=0.032 Sandborn W et al. DDW 2011, abstract #744. ABSTRACT ONLY Week 8

23. Back to the case: Patient started on infliximab and azathioprine. Initially also on topical therapies. Steady response; steroids successfully tapered. Subsequent colonoscopy revealed no active disease, although chronic mucosal changes and pseudopolyps characterized rectum – to –distal L colon. 23

24. Case #2: Severe Crohn’s Disease Dan Present 24

25. New Patient Appointment 30 yo W Male 10- yr history of vague crampy abd pain, intermittent but became more persistent. Recalls going to the local ER about 8 years ago while in college and subsequently having “intestine xrays where I had to drink barium” which suggested possible Crohn’s disease. Thinks he had a colonoscopy and “didn’t show anything” but didn’t know if the ileum was intubated. 25

26. Current Symptoms Post-prandial watery bowel movements. Admits that he has lost about 20lbs in the past few months due to “it hurts when I eat too much.” Fatigued. Vague joint pains. Asks if he can step outside to smoke a cigarrette… 26

27. WHAT WOULD YOU DO? 1.Order a colonoscopy? 2.Order small bowel imaging? a.If so, which one? 3.Start mesalamine 4g 4.Start metronidazole 500mg tid? 5.Start anti-TNF? 27

28. Diagnostic Workup SBFT: Multiple strictures of the distal jejunum, mid- and distal ileum, with normal intervening mucosa. Active inflammation. No proximal dilation. Colonoscopy: colon normal; ileum: narrowed; some ulcerations. Bx: Ileum: Ileitis c/w Crohn’s. Colon: normal Diagnosed with “Crohn’s disease” 28

29. Now, What Would YOU Do? 1.Mesalamine 4g 2.Budesonide CIR 9mg 3.Prednisone 40mg 4.6MP initiation 5.Anti-TNF 6.Natalizumab 7.Surgery 29

30. Clinical Course Budesonide 9mg started –Plan is to decrease by 3mg every 3 weeks. 6MP 75mg started (pt weight 75kg) –Increased to 100mg after 2-3 weeks. –(TPMT genotype was wildtype) Although pt felt better on 9mg budesonide, he could not decrease the dose to 6mg without relapse 30

31. At this point WBC 3,500 Polys: 80%, Bands 2% Hgb 12.5 Platelet count: 200,000 LFT’s: normal 6TG: 325 6MMP 5,000 31

32. What Would YOU Do? 1.Switch from budesonide to prednisone 40mg 2.6MP dose increase 3.Anti-TNF 4.Natalizumab 5.Surgery 32

33. You start an anti-TNF: 1.And stop the 6-MP? 2.And decrease dose of the 6-MP? 3.With same dose of 6-MP? 33

34. P<0.001 vs. aza P=0.055 vs. ifx P<0.001 vs. aza P=0.022 vs. ifx Columbel JF et al. N Engl J Med 2010;362:1383-95. Combination Therapy Increases Efficacy

35. Minimal Improvement Is seen on the infliximab Suspecting a need for surgery, you order at CT enterography: inflammation, –Still a substantial amount of SB activity, multiple strictures but none are obviously obstructive. 35

36. What Would YOU Do? 1.Switch from budesonide to prednisone 40mg 2.6MP dose increase 3.Switch Anti-TNF 4.Natalizumab 5.Surgery 36

37. Decide to try Natalizumab JC virus antibody status: negative Patient stops 6MP Starts natalizumab 300mg IV q 28 days Able to slowly wean off of Entocort over 3 months 6 months out: well on natalizumab 37

38. Case 3: Severe Fistulous Crohn’s Disease Russ Cohen and Dan Present 38

39. Presentation To Your Office 45 yo W M with fistulous Crohn’s disease to the perineal area for 10 years. Colonoscopies to the ileum have always showed normal TI, normal colon, other than the distal rectum, which has some small ulcerations, and a anorectal stricture. Now with increased fistula discharge and increased difficulty in passing BM 39

40. Medications Prednisone 25mg po qd Mesalamine 4.8 g qd Previously on short-term antibiotics Had previous fistulotomy 6-years ago 40

41. Physical Exam Abdominal exam: all normal Perianal exam- multiple draining perianal fistulas with mild fluctuance; previous fistula sites seen, as well as previous fistulotomy site. Attempted rectal examination – stricture too tight to allow introduction of finger-tip. 41

42. When do you call… The surgeon? –Trial of antibiotics first? –Trial of immunomodulators first? –Trial of anti-TNF first? 42

43. When do you order… Imaging? CT? MRI? Dynamic proctography? 43 from: radiologyassistant.nl

44. Start antibiotics, sent to surgeon Orders MRI Pelvis to determine if fistulas connected to main cavity. Examination under anesthesia –Dilation of the stricture (Hegar) –Flex sig to 25cm: only distal rectal disease. –Multiple fistulas emanating from a single fistula orifice on each side of the dentate line. Fistulectomy x2, seton placed x2 44

45. Patient now sits in front of you.. With 2 setons coming out their bottom Wanting to know, “What ya gonna do?” 45

46. What You Gonna Do? 1.Continue 5-ASA ? 2.Continue Steroids ? 3.Start antibiotics? 4.Start 6MP/ Azathioprine? 5.Start MTX? 6.Start anti-TNF? 7.Start natalizumab? 46

47. What you did… Patient started on azathioprine and infliximab. Visits back to the surgeon after each induction dose of infliximab to evaluate need for setons (eventually removed). Patient well on azathioprine and infliximab 47

48. When do you stop therapy? 48