1. Asymptomatic UC patients on an immunomodulator with persistent moderate mucosal inflammation should either add a biologic or switch to a biologic William J. Sandborn, MD Professor & Chief, Division of Gastroenterology Professor & Chief, Division of Gastroenterology Director, UCSD IBD Center Director, UCSD IBD Center

2. Arguments for treating to target in ulcerative colitis It is feasibleIt is feasible It is associated with a reduced rate of colectomy and an increased rate of steroid-free remissionIt is associated with a reduced rate of colectomy and an increased rate of steroid-free remission It is associated with a reduced rate of colorectal dysplasia and cancerIt is associated with a reduced rate of colorectal dysplasia and cancer It is logical and obviously the right thing to doIt is logical and obviously the right thing to do

3. It is feasible: Treating to target in ulcerative colitis

4. Treat-to-Target Algorithm Bouguen G, Levesque BG, Sandborn WJ. Clin Gastroenterol Hepatol. 2014 (In Press) ) CRP, C-reactive protein.

5. Study population STUDY POPULATION UCSD IBD Center Only one endoscopy At least 2 consecutive assessments No inflammation at baselineI NFLAMMATION AT BASELINE No endoscopy 144 patients 31 patients 53 patients 60 patients 15 patients 45 patients Bougen G, Levesque B, Sandborn W. Inflam Bowel Dis 2014 (In Press)

6. Endoscopic procedures 159 endoscopic procedures159 endoscopic procedures 92 colonoscopy 67 flexible sigmoidoscopy 60 patients had at least 2 consecutive endoscopic procedures60 patients had at least 2 consecutive endoscopic procedures 26 patients (43%): 3 consecutive procedures26 patients (43%): 3 consecutive procedures 8 patients (13%): 4 consecutive procedures8 patients (13%): 4 consecutive procedures 2 patients (3%): 5 consecutive procedures2 patients (3%): 5 consecutive procedures median follow-up of 76 weeks (IQR75 54-92) Endoscopy 1 Endoscopy 2 Endoscopy 3 Endoscopy 4 Median time 19 weeks Median time 19 weeks Median time 20 weeks Median time 20 weeks Median time 17 weeks Median time 17 weeks Bougen G, Levesque B, Sandborn W. Inflam Bowel Dis 2014 (In Press)

7. Adjustment in medical therapy and surgery Overall cohort :Overall cohort : 5-ASA introduction: 2 events 5-ASA increase dose: 6 events Oral steroids introduction: 11 events Anti-TNF Introduction: 20 events Anti-TNF Optimization/switch: 11 events Immunosuppression introduction: 18 patients Surgery: 7 patientsSurgery: 7 patients MEDIAN FOLLOW-UP = 76 weeks (IQR75 44-79) MEDIAN TIME BETWEEN PROCEDURE = 25 weeks (16-42) Bougen G, Levesque B, Sandborn W. Inflam Bowel Dis 2014 (In Press)

8. Cumulative probability of reaching mucosal healing and histologic healing Bougen G, Levesque B, Sandborn W. Inflam Bowel Dis 2014 (In Press)

9. Reaching mucosal healing according to medical management during follow up multivariate analysis: adjustments in medical therapy Bougen G, Levesque B, Sandborn W. Inflam Bowel Dis 2014 (In Press)

10. It is associated with a reduced rate of colectomy and an increased rate of steroid-free remission

11. Mucosal Healing after treatment as predictor of subsequent disease course in ulcerative colitis Frøslie KF, et al. Gastroenterology. 2007;133:412-422. Pts with MH at 1 year Pts without MH at 1 year p=0.02

12. Mucosal Healing and Time to Colectomy in Infliximab- treated Patients: Endoscopy Subscore 1 = MILD2 = MODERATE3 = SEVERE0 = NORMAL Colombel JF, Sandborn WJ, et al. Gastroenterology 2011;141:1194-1201.

13. Association Between Week 8 Mayo Endoscopy Sub- score and and Corticosteroid-Free Symptomatic Remission at Week 30 During Anti-TNF Antibody Therapy Week 8 Mayo endoscopy sub-score Corticosteroid-free symptomatic remission, % P value 046< 0.001 134 211 36.5 Colombel JF, Sandborn WJ. Gastroenterology 2011

14. It is associated with a reduced rate of colorectal dysplasia and cancer

15. Rutter et al Gastroenterology 2004;126:451 OR=5.13 OR=2.54 P=0.001 P<0.001 Colonoscopy inflammation score Histological inflammation score 0 2 4 6 8 10 12 Odds ratio for colorectal cancer (95% CI) OR for each 1 point increase in inflammatory score Predicting cancer risk in UC Disease extent PSC Disease duration Family history of CRC Disease extent PSC Disease duration Family history of CRC

16. It is logical and obviously the right thing to do

17. Parachute use to prevent death and major trauma related to gravitational challenge: a systematic review of randomized controlled trials Objectives: To determine whether parachutes are effective in preventing major trauma related to gravitational challenge Design: Systematic review of randomized controlled trials Data sources: Medline, Web of Science, Embase, and the Cochrane Library databases; appropriate internet sites and citation lists Study selection: Studies showing the effects of using a parachute during free fall Main outcome measure: Death or major trauma, defined as an injury severity score > 15 Gordon CS. BMJ 2003

18. Parachute use to prevent death and major trauma related to gravitational challenge: a systematic review of randomized controlled trials Results: We were unable to identify any randomized controlled trials of parachute intervention Conclusions: As with many interventions intended to prevent ill health, the effectiveness of parachutes has not been subjected to rigorous evaluation by using randomized controlled trials. Advocates of evidence based medicine have criticized the adoption of interventions evaluated by using only observational data. We think that everyone might benefit if the most radical protagonists of evidence based medicine organized and participated in a double blind, randomized, placebo controlled, crossover trial of the parachute Gordon CS. BMJ 2003

19. It is logical and obviously the right thing to do You don’t need a randomized controlled trial to determine that using a parachute is the right thing to doYou don’t need a randomized controlled trial to determine that using a parachute is the right thing to do Do you need a randomized controlled trial to determine that healing the colon is the right thing to do?Do you need a randomized controlled trial to determine that healing the colon is the right thing to do?

20. Treating to Mucosal Healing in Ulcerative Colitis It is feasibleIt is feasible It is associated with a reduced rate of colectomy and an increased rate of steroid- free remissionIt is associated with a reduced rate of colectomy and an increased rate of steroid- free remission It is associated with a reduced rate of colorectal dysplasia and cancerIt is associated with a reduced rate of colorectal dysplasia and cancer It is logical and obviously the right thing to doIt is logical and obviously the right thing to do