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1 To help protect your privacy, PowerPoint prevented this external picture from being automatically downloaded. To download and display this picture, click Options in the Message Bar, and then click Enable external content. Extra-Algorithmic i Treatment of IBD William J. Tremaine, M.D. Mayo Clinic Rochester, MN

2 Active Disease Now What? Treatment A Remission Treatment B Active Disease Active Disease Treatment C

3 SONIC: Comparison of IFX, IFX+Azathioprine, and Azathioprine for Crohn s Disease Multi-national Crohn s moderate to severely active 508 pt on steroids Randomized: d AZA 2.5 mg/d IFX 5 mg/kg infusions AZA + INF 10 * ^ ^ P< * P<0.009 AZA IFX 0 Remission at 26 wk AZA+IFX Sandborn WJ. Amer J Gastro (S1):S436 Abstract

4 Active Disease Up to 45% Therapeutic failure Now What? Treatment A Remission Treatment B Active Disease Active Disease Treatment C

5 Extra-Algorithmic Treatment Rationale Evidence-based data is incomplete Current evidence-based therapies are suboptimal Observational data has value

6 Caveat "Let every eye negotiate for itself and trust no agent Much Ado About Nothing (II, I, )

7 Extra-Algorithmic Therapies Examples Mesalamine for Crohn s colitis Dosing Down with Azathioprine / Mercaptopurine Methotrexate t t for U.C. Tacrolimus suppositories Oral tacrolimus for IBD

8 Sulfasalazine for Crohn s Induction of Remission 70 Patien nts (%) Sulfasalazine 1 g/15 kg Placebo 43% vs 30% P = Weeks After Randomization National Cooperative Crohn s Disease Study Summers et al. Gastroenterology 1979;77:

9 Sulfasalazine for Crohn s Induction of Remission Patien nts (%) 70 #Pt Pts Sulfasalazine l > 60 Placebo Colitis p = Ileocolitis p = Ileitis p = % vs 30% P = Weeks After Randomization National Cooperative Crohn s Disease Study Summers et al. Gastroenterology 1979;77:

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11 Oral Mesalamine for Induction of Remission in Crohn s Disease Overall CDAI reduction 63 points Dose = 4 g/d P = 0.04 #Pts Study Study Study Hanauer SB Clinical Gastro & Hep (5):

12 Oral Mesalamine for Induction of Remission in Crohn s Disease Overall CDAI reduction 63 points Dose = 4 g/d P = 0.04 Crohn s colitis #Pts Study 1 28/155 Study 2 39/150 Study 3 88/310 Hanauer SB Clinical Gastro & Hep (5):

13 Crohn s Disease: 5-ASA Australian Gastroenterologists 285 Gastroenterologists Questionnaire 42% response 5-ASA alone 70% 5-ASA combo 90% Rare Infrequent Occasional Often % who use 5-ASA Gearry RB. Inflamm Bowel Dis 2007; 13:

14 The Study That Needs to Be Done A Multi-Center, Multi-National, Randomized Placebo-Controlled Trial of Mesalamine for Mildly to Moderately Active Crohn s Disease Limited to the Colon

15 Extra-Algorithmic Therapies Examples Mesalamine for Crohn s colitis Dosing Down with Azathioprine / Mercaptopurine Methotrexate t t for U.C. Tacrolimus suppositories Oral tacrolimus for IBD

16 Leukopenia Mercaptopurine / Azathioprine Doses: MP mg/kg AZA mg/kg TPMT: Okay if Wild type or Heterozygote Myelotoxicity with purine analogues: Cumulative risk 7% Yearly risk 3% Cumulative incidence myelotoxicity + infection 6.5% Myelotoxicity + death 0.06% Gisbert JP, et al. Am J Gastro. 2008;

17 52 y/o with UC Pancolitis. i TPMT 15.8 (normal ) 1) Iron, Vitamin B12, Folate normal. Year Weight MP Dose WBC/ Neut MCV kg 75 mg 5.5 / kg 75 mg 2.9 / kg 50 mg 3.5 / kg 50-25mg QOD kg 50 x 5 days 25 x 2 days 5.5 / /

18 Myelotoxicity MP/ AZA: Recommendations Mild leukopenia: observe with frequent monitoring Reduce the dose if persistent Mild neutropenia: x % dose reduction Severe neutropenia: < 1.0 x 10 9 Stop treatment Okay to Dose Low Gisbert JP, et al. Am J Gastro. 2008;

19 Extra-Algorithmic Therapies Examples Mesalamine for Crohn s colitis Dosing Down with Azathioprine / Mercaptopurine Methotrexate t t for U.C. Tacrolimus suppositories Oral tacrolimus for IBD

20 Methotrexate for UC Cochrane Review Only 1 trial met inclusion criteria 30 pt MTX 12.5 mg p.o. vs. placebo for 9 months Cochrane Conclusions Under-powered Dose may have been too low Chande N, et al.. Cochrane Database Syst Rev. 2007:4

21 Evidence-Based Efficacy in IBD Crohn s Disease Ulcerative Colitis Corticosteroids + + Azathioprine / 6 MP + + Infliximab ASA + Methotrexate + Antibiotics

22 Methotrexate for UC Retrospective, Australia 23 UC pt AZA failure 91% Infliximab failure 22% mg S.Q weekly 1-37 mo. Median 15 mo. Remission 48% Response 13% Adverse Effects 6/23 Leukopenia 2 Abnormal LFT 2 Diarrhea 1 Dyspnea 1 Nathan D, et al. Journ of Gastro and Hep :954-58

23 67 y/o with UC Pancolitis, 2 years Mesalamine: inadequate response Mercaptopurine: fever, nausea Comorbidities: CHF, eject fx 44% Asymptomatic on: Parkinson s Depression Prednisone 30mg/day, Balsalazide 6.75 g/d

24 67 y/o with UC (cont) Declined colectomy RX: Methotrexate 25 mg S.Q. weekly Folic Acid 1 mg orally daily Prednisone tapered and discontinued over 6 months Balsalazide stopped after 2 years Lab monitoring each 2 months Rare symptoms

25 Extra-Algorithmic Therapies Examples Mesalamine for Crohn s colitis Dosing Down with Azathioprine / Mercaptopurine Methotrexate t t for U.C. Tacrolimus suppositories Oral tacrolimus for IBD

26 Refractory Distal UC 50 y/o man. Distal UC for 25 yrs. Symptoms: Fecal urgency 2-5 loose stools daily Blood and mucus per rectum Co-morbidity Osteoporosis Lumbar T score 2.4 Femur T score 2.3

27 Refractory Distal UC Current Meds for IBD Mercaptopurine Balsalazide Mesalamine Suppositories Previous Med Infliximab 5mg/ kg. 4 doses, no improvement

28 Refractory Distal UC Colonoscopy: Active colitis from the splenic flexure, distally. Normal proximal colon and TI. Biopsies: Normal proximal colon. Mildly active colitis Labs: Hb 13.9 MCV 103 WBC 5.3

29 Refractory Distal UC Tacrolimus suppositories 1 mg H.S. Trough level=16 (therapeutic 5-20) Reduced to 1mg QOD Trough level = 4 One year follow-up Occasional urgency Stools 0-3/day Tacrolimus trough level= 2.4 ng/ml

30 Tacrolimus Suppositories 7 pt with refractory proctitis Suppositories 1 mg BID or Q.D x 28d 5 responded Trough levels < 1.5 mcg/l 2 hr and 6 hr peak levels < 4.3 mcg/l Van Bodegraven, et al. Gastroenterology (4);Supplemt 2: A-588

31 Extra-Algorithmic Therapies Examples Mesalamine for Crohn s colitis Dosing Down with Azathioprine / Mercaptopurine Methotrexate t t for U.C. Tacrolimus suppositories Oral tacrolimus for IBD

32 Oral Tacrolimus for IBD Retrospective, NWestern N Western 35 UC, 15 CD, refractory 0.1 mg/kg BID UC: Remission 3/32 Response 22/32 Colectomy 12/32 Crohn s Remission 1/15 Response 8/15 Failure 6/16 Adverse Effects 32/32 Low magnesium 28 Headache 4 Tremor 4 Arthralgia 3 Nausea 2 Insomnia 2 Leukoencephalopathy (reversible) 1 Benson A, et al. Inflamm Bowel Dis : 7-12

33 Oral Tacrolimus for IBD Retrospective, St Mark s 6 UC, 12 CD, 1 pouchitis 0.05 mg/kg BID 4 weeks Response UC 4/6 CD 10/12 Pouchitis 1/1 Adverse Effects 5/19 Tremor 3 Arthralgia 1 Malaise 1 Insomnia 1 Arthralgia 1 Ng S.W. et al. Inflamm Bowel Dis ;2:

34 60 pt Tacrolimus for UC Moderate to severe UC Steroid refractory Two wk, double-blind blind placebo controlled Hi trough tacrolimus ( ng/ml) Lo trough tacrolimus (5-10 mg/ml) Placebo Open label 10 wk extension Ogata H. Gut. 2006; 55:

35 Tacrolimus for UC Response at 2 wk HT LT Placebo # of participants Complete response Partial response p vs placebo 13 < =.067 No response p vs placebo Ogata H. Gut. 2006; 55:

36 Tacrolimus for UC Open Label HT wk 10 Former HT Former LT Former Placebo # of participants Complete Partial response No response Ogata H. Gut. 2006; 55:

37 Tacrolimus: Summary Tacrolimus suppositories Local action, often sub-therapeutic blood levels Oral A non-biologic option for extensive disease Caveat: few EBMs Evidence Based Medicine studies Expectations ti of Becoming a Marketing success

38 Extra-Algorithmic Therapies Rational Inadequately tested Expectations of safety Pragmatic Optimistic