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Reassessing Treatment Approaches for Asymptomatic Ulcerative Colitis with Persistent Mucosal Inflammation

This article outlines management strategies for asymptomatic ulcerative colitis (UC) patients with ongoing moderate mucosal inflammation while on immunomodulators. It emphasizes the importance of not automatically transitioning to biologic therapies based solely on the presence of mucosal inflammation. It discusses a case study involving a 32-year-old patient, treatment options, the significance of histologic remission over mucosal healing, and the implications of overtreatment based on ambiguous mucosal healing definitions.

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Reassessing Treatment Approaches for Asymptomatic Ulcerative Colitis with Persistent Mucosal Inflammation

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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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