Uma Mahadevan MD Professor of Medicine University of California, San Francisco

1. A patient with severe Crohn'sdisease, an ileal stricture and proximal dilation on CTE should have medical therapy first Uma Mahadevan MD Professor of Medicine University of California, San Francisco

2. What is your goal? • Achieve remission • Endoscopic and radiologic improvement • Symptomatic improvement • Avoid surgery • Spare small bowel

3. All patients are not the same • Patient with inflammation and stricture • Naïve to biologic therapy? • Failed prior biologic therapy? • Response to steroids? • How much small bowel is involved? • How much of it is strictured? • Prestenotic fistula

4. Do we have any data? • Does anti-TNF therapy make strictures worse? • Does anti-TNF therapy make strictures better?

5. Anti-TNF therapy does NOT cause strictures • Theoretical concern: rapid luminal healing in CD with anti-TNF increases risk of intestinal stenosis, stricture, obstruction (SSOs). • Treat Registry • SSOs occurred at a significantly higher rate in patients treated with infliximab compared with other therapy • (1.95 events/100 patient-years vs 0.99 events/100 patient-years; p < 0.001) • Using multivariable analyses, however, infliximab therapy was not associated with SSO development. • CD severity at the time of event onset (HR = 2.35, 95% CI 1.35-4.09) • CD duration (HR = 1.02, 95% CI 1.00-1.04) • Ilealdisease (HR = 1.56, 95% CI 1.04-2.36) • New corticosteroid use (HR = 2.85, 95% CI 1.23-6.57) • ACCENT 1: no increase in SSOs on IFX maintenance vs. episodic therapy, despite higher median IFX exposure • No increase in SSO development with rapid mucosal healing (healing at week 10) • IFX use NOT associated with increased SSO, but with severity, duration, ileal location and new steroids Lichtenstein Am J Gastroenterol. 2006 May;101(5):1030-8

6. Does anti-TNF therapy improve strictures?

7. 11 patients • Retrospective analysis, single center experience with infliximab in CD patients with inflammatory stenoses. • Among a total of 21 patients treated with infliximab, 11 patients had an inflammatory stenosis. • 9 responded well, became completely asymptomatic • Infliximab was tolerated well except for one patient who developed an intrabdominal abscess. Holtmann Z Gastroenterol. 2003 Jan;41(1):11-7.

8. 6 patients • Six patients with a documented and symptomatic small bowel stricture caused by CD refractory to corticosteroids and/or immunosuppressives, and not in need for immediate surgery. • Single infusion of infliximab 5 mg/kg and followed up at w1, 2, 4 and 8. • RESULTS: • Only two patients completed the 8 weeks study, with a positive response to infliximab and improvement of inflammation confirmed by the CRP and CT scan. • Two patients had to be operated early and the last two patients first did well but worsened after one month and were operated 35 and 42 days after infliximab, respectively. • No surgical complications occurred in the 4 operated patients. • In conclusion, a subset of patients with subocclusive small bowel stricturing CD may benefit from infliximab. Louis ActaGastroenterol Belg. 2007 Jan-Mar;70(1):15-9

9. 18 patients • Retrospective study of symptomatic patients treated with infliximab after conventional treatment had failed. The short-term (week 8) and long-term results were classified according to predefined criteria as complete, partial response, or failure. • RESULTS: • Before infliximab, 18 patients had complete obstruction or intermittent chronic abdominal pain. • Fourteen patients were treated by corticosteroids and 13 received immunosuppressive drugs. • At week 8, complete (10), partial response (7) and failure (1) patients • Fourteen patients continued maintenance infliximab treatment after week 8. • Follow up (median 18 months): 8 patients were on maintenance infliximab treatment; only eight were still on prednisone; there were five complete responses, 10 partial responses and three failures. Pelletier Aliment PharmacolTher. 2009 Feb 1;29(3):279-85.

10. Biologics Decrease Surgery Due to “Low-Risk” Strictures in Patients with CD • Historical cohort study of 226 patients with stricturing CD that had CTE or MRE • 49% surgery within median of 1 year SSS 0 SSS 1-5 100 Development Simplified Stricture Severity (SSS) Score 80 60 Internal Fistula Small Bowel Obstruction (SBO) Prox. Dilation ≥ 3cm Abdominal mass/abscess Mesenteric stranding Surgery-Free % 40 No Biologics No Biologics 20 Biologics Biologics p-value – 0.007 p-value – 0.3 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Biologics 39 32 30 25 17 9 6 3 60 34 28 22 14 4 2 0 No Biologics 47 34 26 22 13 9 5 2 60 36 31 23 16 9 7 2 AUC = 0.7 for predicting surgery at 1 year Biologics may reduce the risk of surgery by up to 44% in stricturing CD. HR =.44 (p=0.007) No impact of endoscopic dilation (n=50) This benefit may be more pronounced in patients with a “low-risk” (SSS=0) enterographic findings. CTE, computed tomography enterography MRE, magnetic resonance enterography Nepal S, Shen B et al. Presented at DDW; May 19, 2012. Abstract 271.

11. Individualize your approach (i.e. common sense) • Patient with inflammation and stricture • Naïve to biologic therapy * yes, consider therapy • Failed biologic therapy* Go to surgery • Response to steroids? * yes, consider therapy. Reversible component • How much small bowel is involved? How much is strictured? • Long segment of inflammation, not all stricture * yes, consider therapy • Short stricture * Go to surgery • Prestenotic fistula *? vent. Surgery likely best option

12. Conclusion A patient with severe Crohn's disease, an ileal stricture and proximal dilation on CTE should have medical therapy first • To prevent unnecessary surgery • To minimize loss of small bowel prior to surgery • Dilation in the setting of inflammation or a non-anastomotic stricture is unlikely to be durable