Treating the outpatient with severe IBD: Case studies

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

2. Case 1 : Severe Ulcerative Colitis • Russ Cohen

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.

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

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

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

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 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.

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

10. 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 Acute, Severe Colitis…. 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.

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

12. Azathioprine or 6-MP in UC 80% 70% 60% 50% 40% 30% 20% 10% 0% Maintenance of Remission in UC Steroid-Dependent Active UC 90% AZA AZA/6-MP 80% Placebo Placebo 70% 60% Response Rate 50% Relapse Rate 40% 30% 20% 10% 0% 2.0 mg/kg/d3 2.2mg/k/d4 100 mg/d2 1.5-2.0 mg/kg/d1 100 mg/d2 AZA:azathioprine. 6-MP: 6-mercaptopurine 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.

13. 6-MP Maintenance in UC UC – Maintenance Therapy n=83 1.0 .8 .6 .4 .2 0 Probability of Remission Maintenance 0 20 40 60 Months George J et al. Amer J Gastroenterol 1996; 91:1711

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

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

16. Infliximab in UC Corticosteroid Discontinuation at Week 30 ACT 1 ACT 2 ‡ † ‡ †P=.030 vs placebo‡P.010 vs placebo 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” Randomization of Patients AZA + PBO (2.5 mg/kg) (n=79) IFX (5 mg/kg) + PBO (n=78) IFX+AZA(n=80) Visits Week 0 Week 2 Week 6 Possible escape* (blinded) Week 8 Week 14 Primary Evaluation Week 16 *Subjects not achieving ≥1 point improvement in partial Mayo score Infusions ABSTRACT ONLY Panaccione et al. DDW 2011 Abstract #835

18. Infliximab, Azathioprine, or Infliximab + Azathioprine for the Treatment of Moderate to Severe Ulcerative Colitis:“UC SUCCESS Trial” P = 0.032 vs. AZA P = 0.017 vs. IFX * Total Mayo score < 2, no subscore >1, no steroids. ABSTRACT ONLY Panaccione et al. DDW 2011 Abstract #835

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 < 2; no subscore >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) Week 8: Remission * p=0.019 vs. placebo. Clinical Remission • 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) ABSTRACT ONLY Sandborn W et al. DDW 2011, abstract #744.

22. Adalimumab: Mucosal Healing in Moderate to Severe UC (DDW 2011) Week 8 *p=0.032 Clinical Remission • 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. ABSTRACT ONLY Sandborn W et al. DDW 2011, abstract #744.

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.

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

25. New Patient Appointment • 30 yo W Male • 10- yr history of vague crampyabd 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.

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…

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

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”

29. Now, What Would YOU Do? • Mesalamine 4g • Budesonide CIR 9mg • Prednisone 40mg • 6MP initiation • Anti-TNF • Natalizumab • Surgery

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

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

32. What Would YOU Do? • Switch from budesonide to prednisone 40mg • 6MP dose increase • Anti-TNF • Natalizumab • Surgery

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

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

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.

36. What Would YOU Do? • Switch from budesonide to prednisone 40mg • 6MP dose increase • Switch Anti-TNF • Natalizumab • Surgery

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

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

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

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

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.

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

43. When do you order… • Imaging? CT? MRI? Dynamic proctography? 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

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

46. What You Gonna Do? • Continue 5-ASA ? • Continue Steroids ? • Start antibiotics? • Start 6MP/ Azathioprine? • Start MTX? • Start anti-TNF? • Start natalizumab?

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

48. When do you stop therapy?