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William Tremaine, MD

Con: Asymptomatic U lcerative Colitis Patients on an Immunomodulator with Persistent M oderate M ucosal Inflammation Should Not Add A Biologic or Switch to a Biologic . William Tremaine, MD. Disclosure.

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William Tremaine, MD

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  1. Con: Asymptomatic Ulcerative Colitis Patients on an Immunomodulatorwith Persistent Moderate Mucosal Inflammation Should Not Add A Biologic or Switch to a Biologic William Tremaine, MD

  2. Disclosure • Companies have licensed the Mayo Score for UC and I have received $12,000 personal compensation from Mayo Clinic’s royalty sharing policy.

  3. Regarding Disclosures: Editorial Comments Dollar amounts matter

  4. Case History • 32 year-old • UC for 16 years • Steroid responsive • Maintenance • mesalamine 1.2g/d • mercaptopurine 1.5 mg/kg • Asymptomatic • Surveillance colonoscopy • Moderate activity • Some normal areas

  5. Case Continued • Colon biopsies • Patchy minimally active chronic colitis, some areas of inactive colitis, some normal biopsies. No dysplasia • CrP = 9.0 normal < 8.0

  6. Case: Management Options • Status quo • Check 6-TGN, 6 MMP levels • Adjust 6-mercaptopurine dose • Add an anti-TNFα

  7. Case: Management Options • Status quo • Check 6-TGN, 6 MMP levels • Adjust 6-mercaptopurine dose • Add an anti-TNFα

  8. Alternative Title: Mucosal Healing May be Like a Fedora

  9. Mucosal Healing May be Like a Fedora

  10. Don’t Make Clinical Decisions Based on Mucosal Healing Because: • The definition of mucosal healing is fuzzy • Treatment based on mucosal healing can be unnecessary and harmful • In the long run, mucosal healing isn’t worth much • Histologic remission is what’s important • Ultimately, population-based studies not treatment trials will prove what is important

  11. What is Mucosal Healing in UC? • Mayo UC Score of 0 or 1

  12. Mayo Score: Ulcerative Colitis Stool Frequency 0-3 Rectal Bleeding 0-3 Endoscopy 0-3 Physician’s Global Assessment 0-3 Schroeder KW Tremaine WJ NEJM1987

  13. Mayo Score: Endoscopy Score • Normal mucosa 0 • Mild erythema, mild friability 1 • Marked erythema, friability erosions 2 • Spontaneous bleedings, ulcers 3 Schroeder KW Tremaine WJ NEJM1987

  14. Mayo Score: Dec 2, 2013

  15. Don’t Make Clinical Decisions Based on Mucosal Healing Because: • The definition of mucosal healing is fuzzy • Treatment based on mucosal healing can be unnecessary and harmful • In the long run, mucosal healing isn’t worth much • Histologic remission is what’s important • Ultimately, population-based studies not treatment trials will prove what is important

  16. A Mayo Score of 1 is not as good as a Mayo Score of 0

  17. Fuzzy Math 0

  18. Mucosal Healing with Infliximab (IFX): Long-term outcome in UC % Symptomatic Remission • ACT-1 & ACT-2 • 484 IFX • 244 Placebo • Mayo score: 0,1,2,3 • 8 wk • Conclusion: Mucosal healing at 8wk correlates with improved clinical outcome P< 0.0001 Mayo Score Colombel JF Gastroenterology 2011;141:1194-1201

  19. Don’t Make Clinical Decisions Based on Mucosal Healing Because: • The definition of mucosal healing is fuzzy • Treatment based on mucosal healing can be unnecessary and harmful • In the long run, mucosal healing isn’t worth much • Histologic remission is what’s important • Ultimately, population-based studies not treatment trials will prove what is important

  20. Overtreatment Based on Mucosal Healing: Number Needed to Harm • 2 Multicenter German studies • Mesalazinevs Placebo for UC • 1027 patients • Remission • Symptomatic • Endoscopic • Histologic • Post hoc analysis Wolff S et al. Inflam Bowel Dis 2013;19:2611-15

  21. Overtreatment Based on Mucosal Healing: Number Needed to Harm • Endoscopic mucosal disease activity • False positive 13.7% • NNH = 1 / 0.137 = 7.3 • For asymptomatic UC patients without mucosal healing, additional treatment isn’t needed in about one out of 7 patients. Wolff S et al. Inflam Bowel Dis 2013;19:2611-15

  22. Don’t Make Clinical Decisions Based on Mucosal Healing Because: • The definition of mucosal healing is fuzzy • Treatment based on mucosal healing can be unnecessary and harmful • In the long run, mucosal healing isn’t worth much • Histologic remission is what’s important • Ultimately, population-based studies not treatment trials will prove what is important

  23. 1 YrMucosal Healing: 5 YR Follow-up • IBSEN • 354 UC pt • Colonoscopy • 1 yr & 5 yr after diagnosis • Results • Predictors of healing at 1 year • > 12 yr education • Extensive disease % P=0.02 Frøslie E, et al Gastroenterology 2007; 133:412-22

  24. Colectomy in UC: Reasons • Medically refractory disease • Fear of cancer • Adverse effects from medical therapy • Physician recommendation • Unable to afford medical therapy

  25. Colectomy in UC: Reasons • Medically refractory disease • Fear of cancer • Adverse effects from medical therapy • Physician recommendation • Unable to afford medications ?

  26. 1 YrMucosal Healing: 5 YR Follow-up NS NS NS % IBSEN 354 pt at 5 yr Frøslie E, et al Gastroenterology 2007; 133:412-22

  27. Don’t Make Clinical Decisions Based on Mucosal Healing Because: • The definition of mucosal healing is fuzzy • Treatment based on mucosal healing can be unnecessary and harmful • In the long run, mucosal healing isn’t worth much • Histologic remission is what’s important • Ultimately, population-based studies not treatment trials will prove what is important

  28. Histologic Remission is Better Than Endoscopic Remission • 82 adult UC pts • Endoscopy • Normal, or erythema • Acute histologic activity • Acute inflamcells • Crypt abscesses • Mucin depletion • Relapse rate at 12 mo Relapse Rate at 12 Months % P<0.005 P<0.02 P<0.02 Riley SA et al Gut 1991; 32:174-178

  29. Mayo Score vs Histology • Beth Israel, Boston • 103 pt, UC surveillance • 708 colonic segments • Mayo Score • Biopsies • Geboes Score • >3.1 Moderate inflam % Rosenberg L et al Clin Gastro Hep2013; 11:991-6

  30. Abnormal Histology is Like a Positive CrP • Mesalazine trials • 380 pt with active UC • Clinical Activity Index • Endoscopy Score • Outcome: • Higher remission rate if no histologic inflammation before treatment % Pre-treatment: Wolff S et al. Inflam Bowel Dis 2013;19:2611-15

  31. Histology is a better measure of remission than white light endoscopy But hi-tech endoscopy may be just as good as histology

  32. Laser Endomicroscopy for Prediction of Relapse in UC • Padova, Italy • 19 UC pt, 19 Controls • Remission Clinical Mayo Endos Score • I.V. Fluorescein • Confocal probe • Fluorescence • Crypt Diameter Clinical Remission Inflammatory Activity % 12 months Buda A et al ScienceDirect 4 Sept 2013

  33. Endoscopic mucosal healing without histologic healing may not protect from cancer

  34. Ulcerative Colitis: Mucosal inflammation is a risk factor for Colorectal Neoplasia • Mt Sinai, NYC • 408 pt • Endoscopic surveillance with biopsies • Histologic inflammation graded Mean Histology Inflammation Score HR=2.8 (95% CI = 1.2-6.2 Bansal R Gastroenterology 2007; 133: 1099-1105

  35. Don’t Make Clinical Decisions Based on Mucosal Healing Because: • The definition of mucosal healing is fuzzy • Treatment based on mucosal healing can be unnecessary and harmful • In the long run, mucosal healing isn’t worth much • Histologic remission is what’s important • Ultimately, population-based studies not treatment trials will prove what is important

  36. Babies Born on 3 Consecutive Nights Wednesday Thursday Friday Are these sequences equally likely?

  37. Babies Born on 3 Consecutive Nights Wednesday Thursday Friday The Law of Small Numbers Kahneman D Thinking Fast and Slow 2011: 115

  38. M M M M M M

  39. Litmus Test for a Disease Modifying Agent Does mucosal healing change the natural history of ulcerative colitis?

  40. Colectomy Rates in Ulcerative Colitis Filippi J et al Current Drug Targets 2011; 12:1440-7

  41. Case: Management Options • Status quo • Add an anti-TNFα Shared Decision Making

  42. Conclusions • Mucosal healing is an imperfect endpoint convenient for clinical trials and marketing • Histologic healing may be more important • Population-based studies, not treatment trials, will ultimately determine best management endpoints

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