1. Treating the Outpatient with Severe IBD: Case Discussions William Tremaine, MD Corey A. Siegel, MD

2. Tremaine Case 1 36 year old man, college custodian Onset 6 months ago of diarrhea, some stools mixed with blood, urgency, abdominal cramps. Evaluated 5 months ago: Negative stool studies for infection Flexible sigmoidoscopy: moderately active colitis as far as examined Biopsies: Chronic colitis, no granulomas

3. Tremaine Case 1 continued Started: Prednisone 40 mg/d, tapered over 6wk Mesalamine 1.2 g BID Improved, but worsened 1 week off prednisone Restarted Prednisone, tapered over 6 wk Started Azathioprine 2.4 mg/kg/d Improved, but worsened 1 week off prednisone

4. Tremaine Case 1 continued Check stools for infection again…negative Colonoscopy with biopsies…left sided UC, biopsies showed chronic colitis, stains negative for CMV MR enterography?... not done

5. Tremaine Case 1 continued Infliximab added Continued symptoms after 4 weeks Restarted Prednisone 40 mg/day, improved

6. Tremaine Case 1 continued Stopped mesalamine Tapered and discontinued prednisone No symptoms on Azathioprine and Infliximab

7. Exacerbation of UC with Mesalamine 2 case reports Both got worse on mesalamine Both improved on prednisone One of the patients In remission off meds Flex sig showed quiet disease Challenged with two 4gm mesalamine enemas Repeat flex sig after 24 hours Marked worsening Biopsies showed eosinophils and neutrophils Sturgeon JB et al. Gastroenterology 1995; 108: 1889-93

8. Tremaine Case 2 53 year old nephrologist Ulcerative proctitis for 35 years Extends 12 cm above the dentate Intermittent symptoms Poorly controlled with: Mesalamine oral and rectal Steroids oral and rectal Azathioprine 2.5 mg/kg for 4 month trial

9. Tremaine Case 2 continued Stool studies: no infection Colonoscopy Moderate proctitis Normal above the rectum to the cecum Biopsies Chronic colitis No granulomas, inclusions, dysplasia Current Symptoms Fecal urgency, stools or mucus >10 day, including 2- 3 nocturnal stools

10. Tremaine Case 2 continued What to do? 1.Proctocolectomy with J pouch 2.Anti-TNFα therapy 3.Methotrexate 4.Tacrolimus 5.Diverting sigmoid colostomy

11. Tremaine Case 2 continued Tacrolimus suppositories 1 mg compounded in local pharmacy Tacrolimus blood level 12 hours post suppository 3.4 ng/ml Suppositories gradually decreased to once each 2-3 nights, as needed

12. Tacrolimus Suppositories for Ulcerative Proctitis Netherlands, multi-center Suppository composition Tacrolimus capsules adeps solidus Whole blood trough levels 10/12 pt (83%) improved μg/L Tacrolimus Blood level Van Dieren JM et al. Inflamm Bowel Dis 2009; 15:193-198

13. Tremaine Case 3 40 year old hair stylist Previous smoker, stopped 7 years ago Ulcerative colitis, hepatic flexure distally, for 5 years Treated with mesalamine 1.2 g BID Remission for 3 years Then recurrent symptoms Controlled with prednisone On Prednisone > 6 months in the past year Hates prednisone, feels jittery

14. Tremaine Case 3 continued Weight gain of 25 kg Increased ALT, Alkaline Phos. Ultrasound: steatosis Lost weight with dieting, liver tests normalized One year ago, left eye pain and loss of vision Diagnosis, optic neuritis, treated with i.v. steroids resolved over 14 days, no subsequent neurologic symptoms

15. Tremaine Case 3 continued Current symptoms 4-6 stools daily, some with blood, urgency Abdominal cramping pain 3-4 /10 severity Stopped mesalamine for a 5 days, worsened, restarted Declines further steroids Stools negative for infection Liver enzymes, TPMT normal Azathioprine: fever after 3 days to 102°F, resolved after 2 days off azathioprine

16. Tremaine Case 3 continued Treatment options? 1.Proctocolectomy with J pouch 2.Anti-TNFα therapy 3.6-mercaptopurine 4.Methotrexate 5.Cyclosporine A 6.Oral mesalamine plus mesalamine enemas

17. Methotrexate in UC: Veterans Study National VA database 2001-2011 91 pt with UC met criteria Methotrexate Prednisone > 15 mo follow-up Methotrexate Oral: 68 pt 14mg/wk I.M., S.Q. 23 pt25mg/wk Prednisone Initial average Dose Oral MTX group: 12 mg/d I.M., S.Q MTX group: 25 mg/d 12 Month Follow-up Khan N et al. Inflam Bowel Dis 2013; 19: 1379-83 %

18. Tremaine Case 3 continued Treated with MTX 25 mg S.Q. weekly Folic acid 2 mg p.o. daily Continued oral mesalamine 1.2 g BID Symptoms largely resolved after 2 months

19. Tremaine Case 4 34 year old attorney UC with pan-colonic involvement for 12 years Continued symptoms despite: mesalamine prednisone azathioprine, nausea Mercaptopurine Anti-TNFα biologics, 2 agents Currently: 2-3 stools a day with blood mixed Urgency, cramps

20. Tremaine Case 4 continued Stool studies negative for infection Colonoscopy Biopsies: moderate activity Treatment options Proctocolectomy with J pouch Calcineurin inhibitor Methotrexate Anti-diarrheals, anti- spasmodics

21. Oral Tacrolimus Maintenance Rx for Refractory UC London, retrospective 25 pt with UC Failed steroids 23 failed thiopurines 5 failed anti TNFα Tacrolimus 0.1 mg/kg/day 12 hour dosing Trough levels 5-10ng/ml 6 Month Outcome % Landy J et al J Crohn’s & Colitis 2013; 7: e516-21

22. Tremaine Case 4 continued Treatment Tacrolimus 2 mg Q12 hours Dose adjusted upwards to trough level 8-10 ng/ml Prednisone 40 mg/day Tapered and stopped after 4 weeks Methotrexate 25 mg S.Q. weekly Folic acid 2 mg /day TMP/SMZ DS twice weekly while on prednisone Calcium, Vitamin D Tacrolimus and MTX continued for 6 mo, then Tacrolimus was stopped

23. Siegel Case 1 36 year old woman, attorney – NH public defender Diagnosed with Crohn’s disease at age 15 Colonic and perianal disease Prior use of 6MP, infliximab (secondary non-responder), adalimumab (horrible psoriasis) Colectomy with ileostomy and Hartmann’s pouch 2011 Fine OFF all meds until 2013…

24. Siegel Case 1 continued Presumed peristomal pyoderma

25. Siegel Case 1 continued Ileoscopy showed 5cm of mildly active inflammation in most distal neo-terminal ileum (active chronic non- specific enteritis), mild diversion colitis Topical tacrolimus for pyoderma, budesonide for small bowel inflammation – no improvement in skin (worse)

26. Siegel Case 1 continued TreatmentReceiving RxRx Successful% success Steroid injection4125% Topical antibiotics5120% Systemic steroids8112% Systemic antibiotics6117% Systemic cyclosporine7229% Infliximab6233% Stoma closure55100% Treatment options and rate of success Poritz LS, et al. J Am Coll Surg 2008;206:311

27. Siegel Case 1 continued No response to intralesional steroid injection, antibiotics, prednisone 40mg, oral antibiotics Sulfa allergy prevented use of dapsone Ustekinumab (anti-IL23) ? Responding very nicely after 1 st 2 doses of ustekinumab! Guenova E, et al. Arch Dermatol 2011;147:1203. Am J Gastroenterol 2012; 107:794.

28. Siegel Case 2 26 year old woman, works part-time for a coffee roaster Diagnosed with Crohn’s disease at age 15 Perianal and colonic disease, s/p subtotal colectomy with ileosigmoid anastomosis at age 19 6MP with GREAT drug levels, but… Recurrent colonic disease and NEW diffuse small bowel disease Suicidal on prednisone (police intervention!) Infusion reaction to to infliximab, short duration response to adalimumab, no response to certolizumab

29. Siegel Case 2 continued Prochymal (mesenchymal stem cell) trial – no response Natalizumab for 3 months, no benefit (and scared) Next treatment options?  Methotrexate  TPN  Antibiotics and budesonide  Another clinical trial  Off label use of something

30. Siegel Case 2 continued Start ustekinumab 90mg SQ at week 0 and 2, then every 8 weeks Email from patient - Dear Dr. Siegel, Ustekinumab is the drug for me! I am feeling great. Thank you, XXXXX Sandborn WJ, et al. N Engl J Med 2012;367:1519-28

31. Siegel Case 2 continued D i d very well for 1 year, then symptoms returned, endoscopically active disease (small bowel and colon), losing weight Next steps? After ruling out infection and immune deficiency syndrome, starting tofacitinib Oral JAK inhibitor (UC and Crohn’s) At 15mg, dose dependent increase in LDL Treating with 10mg PO bid 28.1% 33.7% 38.8% 40.8% Sandborn WJ, Ghosh S, Panes, J, et al. Gastroenterology 2011;140:S124

32. Siegel Case 3 20 year old woman, college student majoring in sociology Diagnosed at age 16 with ileal and esophageal disease Pancreatitis to 6MP, serious delayed hypersensitivity reaction to infliximab Secondary loss of response to adalimumab Certolizumab + methotrexate with good ileal response, but persistent esophageal disease

33. Siegel Case 3 continued Management of esophageal Crohn’s  PPIs  Topical agents  Systemic agents

34. Siegel Case 4 22 year old gentleman, college student 3 year history of ulcerative colitis, transverse colon to rectum Failing 5-ASAs and oral steroids Brief response with 1 st infliximab dose, but persistent symptoms

35. 20 year old male with UC: varying clearance of infliximab over the course of a flare Data courtesy of Dr. Randall Pellish, UMASS Medical Center Slide created by Kimberly Thompson, Dartmouth-Hitchcock Medical Center Dose 1 5mg/kg 9/24/12 Dose 2 5mg/kg 10/10/12 Dose 3 5mg/kg 11/12/12 Dose 4 10mg/kg 12/26/12 16+ weeks! Dose 5 5mg/kg 4/19/13 8 days after an infiximab dose, drug level = 1.8