1. Treating the Outpatient with Severe IBD: Case Study Alan C. Moss MD, FEBG, FACG, AGAF Associate Professor of Medicine Director of Translational Research

2. Disclosures Consultant; Janssen, Theravance, Bayer, Roche Research Support; Pfizer, NIDDK, Salix, Shire

3. Case - 42 yr old male patient Left-sided ulcerative colitis for 8 years Failed mesalamine 4.8g/day, azathioprine 100mg/day Recurrent flares responsive to prednisone Now steroid-dependent; gets more diarrhea / abdominal pain / fevers when dose lowered to 20mg CRP 56 / ESR 80 / Hct 28 / Stool negative for C.difficile High-grade B-cell lymphoma 3 years ago – now in remission

4. Sigmoidoscopy

5. What would you recommend? A.Colectomy B.Infliximab C.Vedolizumab D.Methotrexate E.Tacrolimus F.Tofacitinib G.Budesonide

6. ‘Knowns & Unknowns’ in IBD Patients DrugEarly “Response” Rate in UC#Lymphoma Risk* Infliximab67% (RCT, all) Similar to IBD Population Vedolizumab49% (RCT, on steroids) None in clinical trials Methotrexate58% (RCT, steroid-dependent) Similar to General Population Tacrolimus60% (OL, refractory) Similar in Transplant Population Tofacitinib53% (RCT, on steroids) Case Reports Lichtenstein, Am J Gastroenterol, 107 (2012), pp. 1409–1422 Mariette X, Blood, 99 (2002), pp. 3909–3915 Caillard S, Transplantation. 2005 Nov 15;80(9):1233-43 Lee B, N Engl J Med. 2014 Jun 19;370(25):2377-86 Sandborn W, N Engl J Med. 2012 Aug 16;367(7):616-24 Boschetti G, Dig Liver Dis. 2014 Oct;46(10):875-80 Mate-Jimenez J, Eur J Gastroenterol Hepatol. 2000 Nov;12(11):1227-33 Feagan B, N Engl J Med. 2013 Aug 22;369(8):699-710 # week 6-8 clinical response * in patients without prior history of lymphoma

7. ECCO Recommendations Few data exist in using immunosuppressants (IS) in IBD patients with prior cancer Recommended “waiting period” before IS starts ; 2 years for invasive cancers 5 years for aggressive cancers (lymphoma, melanoma, breast, sarcomas, urinary tract cancers, and myeloma) Beaugerie L, Dig Dis Vol. 31, No. 2, 2013 Magro F, J Crohns Colitis. 2014 Jan;8(1):31-44

8. Feagan B, N Engl J Med. 2013 Aug 22;369(8):699-710 Vedolizumab - Efficacy in Patients with UC on Steroids

9. Treating the Outpatient with Severe IBD: Case Study Joshua Korzenik, MD Director, BWH Crohn’s and Colitis Center Brigham and Women’s Hospital Boston, MA

10. Disclosures Consultation: Abbvie, Roche, Vithera, Shire Research support: Abbvie, Takeda, Pfizer, Transparency

11. 43 yo woman with Crohn’s Mid-jejunal, ileocolonic Crohn’s dx in 1994 at age 23 Multiple resections: – Ileocolonic in 2001 – Mid-jejunal resection 2003 – Poor response to 6-MP Perianal disease developed post-resection – Responded to infliximab then anaphylaxis – Rectovaginal fistula – Adalimumab- rash – Certolizumab

12. Psoriasis Paradoxical but not rare occurrence Report of 30 patients – Occurs on all anti-TNFs – Nearly half responded to topical therapy – 17/30 no response to topical therapy – 9/30 discontinued anti-TNF due to psoriasis – Eight patients were treated with an alternative anti- TNF with recurrence in two (25%). Cullen et al, IBD Journal, 2011

13. FDA Adverse Event Reporting System (FAERS) 5,432 reports (2004-2011) 1 – Infliximab 1789 – Adalimumab 3475 – Certolizumab 168 British Society for Rheumatology Biologics Register 2 – 9826 anti-TNF-treated – 2880 DMARD-treated patients 25 cases of psoriasis in anti-TNF/ 0 in DMARD-treated 1.04 (95% CI 0.67 to 1.54) per 1000 person years 1) Kip et all, IBD, 2013 2) Harrison, Ann Rheum Dis, 2009

14. Other Auto-Immune Diseases Provoked by Anti-TNF Agents Drug-induced lupus Psoriasis Alopecia areata/totalis Autoimmune hepatitis Sjogren’s syndrome Demylinating diseases Vasculitis IBD

15. Treatment options? A)Surgery B)Methotrexate C)Golimumab D)Ustekinumab E)Cyclosporine

16. Sandborn WJ et al. N Engl J Med 2012;367:1519-28 CERTIFI: Ustekinumab Phase IIb for Response Induction in CD

17. CASE #2

18. Crohn’s disease 27 yo man with a hx of ileocolonic Crohn’s disease for 6 years 6-MP partial response, infliximab added Sustained remission for 4 years on dual therapy He wants to discontinue all medications CRP/ESR normal All other routine labs are normal

19. You recommend: A)Discontinue 6-MP B)Discontinue Infliximab C)Discontinue both D)Colonoscopy or imaging 1) If normal: a. Discontinue 6-MP b. Discontinue Infliximab c. Discontinue both 2) If not normal: a. Discontinue 6-MP b. Discontinue Infliximab

20. “STORI”: What happens when IFX is withdrawn? Prospective multi-center study: GETAID Patients with luminal CD, >17 y.o., who received at least 1 year of IFX plus AZA/6-MP/MTX At least 2 infusions of IFX administered in preceding 6 months. Final IFX no more than 2 weeks after accrual. Outcome: Steroid-free remission >6 months, CDAI <150. CDAI at recruitment: 37 (19-61) Louis E et al. Gastroenterology 2012; 142 (1): 63-70.

21. “STORI”: What happens when IFX is withdrawn?

22. What do these data mean for this patient? Low-to-Intermediate risk of relapse –Male, no previous surgery –On immunomodulator –Normal CRP, hemoglobin Options: –Stop IFX, continue 6-MP –Continue 6-MP, then stop IFX Louis et al.: Re-treatment with IFX induced remission in 36/40 (96%)

23. Treating the Outpatient with Severe IBD: Case Studies Corey A. Siegel, MD, MS Geisel School of Medicine at Dartmouth Dartmouth-Hitchcock Medical Center CCFA Advances December 5th, 2014

24. Case: 67 year old gentleman with UC 67 year old gentleman with recent onset of diarrhea with bleeding 10-12x/day, up at night Stool studies (including C. diff) negative Colonoscopy and biopsies consistent with moderately active extensive ulcerative colitis Past medical history Hip osteoarthritis, s/p hip replacement Pneumonia 3 months prior Admitted to ICU, intubated Quit smoking at that time Current meds: none other than occasional naproxen

25. Case: 67 year old gentleman with UC First treatment options in new diagnosis of moderately active UC? Does “top down” apply to UC also? Initiated on prednisone 40mg daily + 4.8 grams of 5- ASA, Rowasa nightly Unable to taper down below 20mg Now what?  Uceris  Anti-TNF  Immunomodulator  Vedolizumab  Some combination of above  Surgery

26. Case: 67 year old gentleman with UC Initiated on infliximab monotherapy (with prednisone 40mg daily) Start to taper prednisone Week 14 infliximab concentration = 11, negative antibody But unable to taper below prednisone 20mg Repeat colonoscopy with moderately active extensive colitis (no significant change) Now what?  Increase infliximab dose  Add immunomodulator  Change to vedolizumab  Start smoking  Surgery

27. Cigarette Smoking in UC: Immunology Immunologic mechanisms for the protective effect of cigarette smoking in UC remain unclear Immunologic and clinical studies in IBD have focused on nicotine Therapeutic trial experience in UC with nicotine gum, transdermal nicotine, enemas has been inconclusive Otterbein L et al, Nat Med 2000;6:422-8 One component of cigarette smoke, carbon monoxide (CO), possesses potent anti-inflammatory effects in numerous models of acute inflammation

28. ALERT: “BAD AIR”

29. CO as a Therapeutic?

30. Other delivery vehicles? Iskander H, et al. IBD LIVE case series. Inflamm Bowel Dis 2014. Lee, S, et al. E-cigarettes as salvage therapy for medically refractory ulcerative colitis. Presented at Advances in IBD, 2013.

31. Case: 67 year old gentleman with UC Started to smoke ½ pack per day Within 2 weeks started to taper prednisone OFF ALL prednisone 4 weeks later Continues infliximab 5mg/kg every 8 weeks Follow-up colonoscopy with near complete mucosal healing!!!!

32. Case: 41 year old woman with Crohn’s disease (2 scenarios) Diagnosed with ileal and perianal Crohn’s disease At diagnosis started on 6MP + Infliximab + Cipro Elevated LFTs – shunting with 6MP (despite heterozygous TPMT – with half dosing!) Infliximab monotherapy – did GREAT Complete mucosal healing No further perianal lesions Asymptomatic

33. 41 year old woman with Crohn’s disease (2 scenarios) One year later – performed therapeutic drug monitoring Prometheus ANSER assay Infliximab trough concentration = 0 Antibody level = 24 Options?  Ignore  Repeat the test with a different assay  Increase infliximab dose  Add back an immunomodulator  Switch to another anti-TNF  Switch class of biologic

34. BRIDGe “anti-TNF optimizer” RAND appropriateness panel Evaluated two aspects of therapeutic drug monitoring 1.When to test? 2.What to do with the results When to test? At end of induction, primary non- response Secondary non-response During maintenance, responding Restarting after drug holiday Melmed GY, et al. Presented at ACG and UEGW 2014

35. BRIDGe “anti-TNF optimizer” www.BRIDGeIBD.com

36. BRIDGe “anti-TNF optimizer” www.BRIDGeIBD.com

37. BRIDGe “anti-TNF optimizer” www.BRIDGeIBD.com

38. BRIDGe “anti-TNF optimizer” www.BRIDGeIBD.com

39. BRIDGe “anti-TNF optimizer” www.BRIDGeIBD.com

40. 41 year old woman with Crohn’s disease (scenario #2) Recurrent perianal disease, mild-moderate ileal recurrence One year later – performed therapeutic drug monitoring ANSER assay Infliximab trough concentration = 2 Antibody level = 4 Options?  Ignore  Repeat the test with a different assay  Increase infliximab dose  Add back an immunomodulator  Switch to another anti-TNF  Switch class of biologic

41. BRIDGe “anti-TNF optimizer” www.BRIDGeIBD.com

42. BRIDGe “anti-TNF optimizer” www.BRIDGeIBD.com

43. BRIDGe “anti-TNF optimizer” www.BRIDGeIBD.com

44. BRIDGe “anti-TNF optimizer” www.BRIDGeIBD.com

45. BRIDGe “anti-TNF optimizer” www.BRIDGeIBD.com

46. Can you make antibodies go away? Ben-Horin S, et al. Clin Gastroenterol Hepatol. 2013; 11:444-447. IFX levels closed squares ATI open squares