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

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

Regarding Disclosures: Editorial Comments 2009 Nominee Unpaid Taxes Outcome Tim Geithner $34,000 $34,000Confirmed Tom Daschle $128,000Withdrew Dollar amounts matter

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

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

Case: Management Options 1.Status quo 2.Check 6-TGN, 6 MMP levels Adjust 6-mercaptopurine dose 3.Add an anti-TNFα

Case: Management Options 1.Status quo 2.Check 6-TGN, 6 MMP levels Adjust 6-mercaptopurine dose 3.Add an anti-TNFα

Alternative Title: Mucosal Healing May be Like a Fedora

Mucosal Healing Fedora FDA Marketers Popular withHipsters Movie Stars NoEasy to SpotYes NoReally Important No Mucosal Healing May be Like a Fedora

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

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

Mayo Score: Ulcerative Colitis Stool Frequency0-3 Rectal Bleeding0-3 Endoscopy0-3 Physician’s Global Assessment0-3 Schroeder KW Tremaine WJ NEJM 1987

Mayo Score: Endoscopy Score Normal mucosa0 Mild erythema, mild friability1 Marked erythema, friability erosions2 Spontaneous bleedings, ulcers3 Schroeder KW Tremaine WJ NEJM 1987

Mayo Score: Dec 2, 2013

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

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

Fuzzy Math 0 0

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

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

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

Overtreatment Based on Mucosal Healing: Number Needed to Harm Endoscopic mucosal disease activity False positive 13.7% NNH = 1 / = 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:

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

1 Yr Mucosal 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 % Frøslie E, et al Gastroenterology 2007; 133: P=0.02

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

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

1 Yr Mucosal Healing: 5 YR Follow-up Frøslie E, et al Gastroenterology 2007; 133: NS % IBSEN 354 pt at 5 yr

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

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

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 Hep 2013; 11:991-6

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 Wolff S et al. Inflam Bowel Dis 2013;19: % Pre-treatment:

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

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 12 months Clinical Remission % Buda A et al ScienceDirect 4 Sept 2013 Inflammatory Activity

Endoscopic mucosal healing without histologic healing may not protect from cancer

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 = Bansal R Gastroenterology 2007; 133:

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

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

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

M M M M M M M M M M M M

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

Colectomy Rates in Ulcerative Colitis Pre-Biologic EraAnti-TNFα Era Population-based CohortsClinical trials + Referral Center Studies + Population-based Cohorts 29%10-36% Filippi J et al Current Drug Targets 2011; 12:1440-7

Case: Management Options 1.Status quo 2.Add an anti-TNFα Shared Decision Making

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