Prevention of Postoperative Crohn’s disease Miguel Regueiro, M.D. Professor of Medicine Associate Chief for Education Clinical Head and Co-Director, IBD Center University of Pittsburgh School of Medicine

50-65% of CD pts still go to surgery despite earlier and more IMM/antiTNF usage IN 2014: CD treatment relies on initiation of med rx in response to ds – in many, the tissue damage may be irreversible…therefore…

Surgery is still required in IBD …and should not be considered a failure…..it is how we medically prevent/manage postop CD that is the trick.

The Natural Course of postop CD Recurrence is clinically silent initially Histologic Endoscopic Radiologic Clinical Surgical 30% 3 yr 60% 5 yr Within 1 week 70-90% by 1 yr Tissue damage 50% by 5 yrs Surgery [1] D’Haens G, Geboes K, Peeters M, et al. Gastroenterology 1998;114:262-267. [2] Olaison G, S medh K, Sjodahl R. Gut 1992;33:331-335. [3] Rutgeerts P, Geboes K, Vantrappen G, et al Gastroenterology 1990;99:956-983. [4] Sachar DB. Med Clin North Am 1990;74:183-188.

Endoscopic Recurrence Endoscopic Remission i0: no lesions i1: < 5 aphthous lesions i2: > 5 aphthous lesions with normal intervening mucosa i3: diffuse aphthous ileitis with diffusely inflamed mucosa i4: diffuse inflammation with large ulcers, nodules, and/or narrowing Endoscopic Recurrence Rutgeerts P, Geboes K, Vantrappen G, et al Gastroenterology 1990;99:956-983.

>70% of Pts Have i2,3,4 Recurrence 1 Year after Surgery – Rutgeerts et al Gastro 1990 i0 and i1 remission -low likelihood of progression i4 i,3 i2,i3,i4 recurrence Likely progression to another surgery

More Questions than Answers Algorithm for post-op CD management More Questions than Answers ??? 5-ASA? Antibiotics? Steroids? 6MP/AZA? What about anti-TNFs/Biologics? How should we follow these patients? When to Colonosocope? Are there predictors of disease recurrence?

Medications for Preventing Postoperative Crohn’s Disease

Summary of Postop RCTs 5ASA, Nitroimidazoles, AZA/6MP Postop Prevention RCTs Clinical Recurrence Endoscopic recurrence Placebo 25% – 77% 53% - 79% 5 ASA 24% - 58% 63% - 66% Budesonide 19% - 32% 52% - 57% Nitroimidazole 7% - 8% 52% - 54% AZA/6MP 34% – 50% 42 – 44% Regueiro M. Inflammatory Bowel Diseases. 2009

Out of these options…the best seems to be….

Metronidazole 250mg TID x 3 m then AZA 2.5mg/kg p=0.05 D’Haens G, Norman M, Van Assche G, et al. Gastroenterology 2007;132:289

Limitation of the studies: the best we can expect are endoscopic recurrence rates of ~45% This means that despite postop meds, nearly half of CD pts will have also have a clinical recurrence and require future surgery

What about Postop antiTNF? Recently: A lot of discussion and focus on postop antiTNFs – is it worth the hype?

Pittsburgh Likes Hype

RCT: Infliximab Prevents Crohn’s Disease Recurrence after Ileal Resection Regueiro M, Schraut W, Baidoo L, Kip KE, Sepulveda AR, Pesci M, Harrison J, Plevy SE. Gastroenterology 2009;136:441-50.

Randomized, two-armed, double-blind, placebo-controlled trial Sample size power calculation Assuming 80.0% recurrence in placebo group, 20.7% recurrence in infliximab group 24 total pts needed (2-sided type I error rate of 0.05) 24 patients randomly assigned to infliximab 5mg/kg or placebo within 4 weeks of surgery (0,2,6, and every 8 weeks for one year)

Infliximab vs placebo p=0.0006 1/11 11/13 Endoscopic Recurrence defined as endoscopic scores of i2, i3, or i4.

This is only one small study, we need more data…. #24 The Pittsburgh Postop Bus

antiTNF Control PO- Endo Recur 0% 100% (5ASA) 9% 85% (PBO) 21% Sorrentino1 (MTX/IFX v 5ASA 2yr) 0% 100% (5ASA) Regueiro2 (IFX vs PBO RCT 1 yr) 9% 85% (PBO) Yoshida3 (IFX vs PBO Open 1 yr) 21% 81% (5ASA) Armuzzi8 (IFX vs AZA Open 1 yr) 40% (AZA) Fernandez-Blanco 4 (ADA) 10% N/A Papamichael5 (ADA 6m) Savarino6 (ADA 3yr) Aguas7 (ADA 1 yr) De Cruz9 (ADA vs AZA 6mos) 6% 38% (AZA) Savarino10 (ADA vs AZA vs 5ASA 2 yrs) 65% (AZA), 83%(5ASA)

Anti-TNF Postop References Sorrentino et al. Arch Intern Med 2007 Regueiro et al. Gastroenterol 2009 Yoshida et al. Inflamm Bowel Ds 2011 Fernandez-Blanco et al. Gastroenterol 2010A Papamichael et al. JCrohnsColitis 2012 Savarino et al. Europ Journal Gastro Hep 2012 Aguas et al. World J Gastro 2012 Armuzzi et al. JCrohnsColitis 2013 DeCruz et al. Gastro 2012A Savarino et al. Am Journal Gastro 2014

Antitumor necrosis factor [alpha] is more effective than conventional medical therapy for the prevention of postoperative recurrence of Crohn's disease: a meta-analysis. Nguyen, Douglas; Solaimani, Pejman; Nguyen, Emily; Jamal, Mohammad; Bechtold, Matthew European Journal of Gastroenterology & Hepatology. 26(10):1152-1159, October 2014.

Clinical Remission 1 yr postop

Endoscopic Remission 1 yr postop

Histologic Remission 1 yr postop

Comparison of the effectiveness of infliximab and adalimumab in preventing postop recurrence in patients with Crohn’s disease (Tursi A et al. Tech Coloproctol 2014)

What about long-term postoperative Crohn’s ds? Most studies stop at one year

Infliximab Maintenance Prevents Endoscopic and Surgical Crohn’s Disease Recurrence: Long-term Outcomes from the Randomized Controlled Postoperative Prevention Study Regueiro M, Kip K, Baidoo L, Swoger J, Schraut W. Clinical Gastroenterology and Hepatology 2014

Long-term outcomes in patients assigned to placebo or infliximab after surgery 1 year End RCT IFX Status > 5 years After Surgery Time 0 Surgery IFX (11) PBO (13) Figure 1

Long-term outcomes in patients assigned to placebo or infliximab after surgery 1 year End RCT IFX Status > 5 years After Surgery Time 0 No Recurrence* No Surgery Cont. IFX (3) Recurrence (1) Remission (10) Surgery IFX (11) Recurrence (8) Surgery (5) Stop IFX (8) PBO (13) *1 IFX patient i3 at 1 year after surgery, remained i3 through 6 years +All 5 patients had been i3 or i4 and all progressed to surgery ^This pt had been i1 at end of RCT but progressed to i4 and another surgery Figure 1

Long-term outcomes in patients assigned to placebo or infliximab after surgery 1 year End RCT IFX Status > 5 years After Surgery Time 0 Surgery IFX (11) Recurrence (5)+ Surgery (5) Start IFX (12) Recurrence(11) Remission (2) PBO (13) No IFX (1) Recurrence and Surgery^ *1 IFX patient i3 at 1 year after surgery, remained i3 through 6 years +All 5 patients had been i3 or i4 and all progressed to surgery ^This pt had been i1 at end of RCT but progressed to i4 and another surgery Figure 1

How should we manage a Crohn’s ds pt who recently had surgery? Take into account risk factors for postop recurrence

Active cigarette smoking Relative Risk Factors Early age of surgery (<30) Short time to first surgery Ileocolonic disease Active cigarette smoking Progressed to surgery despite immunomodulators Penetrating (fistulizing) disease History of prior resection

My Approach – Almost All of my patients start a med after surgery …but NOT necessarily an antiTNF - take into account Risk Factors for Recurrence

Risk of Post-Op Recurrence Low Moderate High No Meds 6MP or AZA ± metronidazole Anti-TNF Colonoscopy 6-12 months post-op Colonoscopy 6-12 months post-op No Recurrence Recurrence No Recurrence Recurrence Colonoscopy every 1-3 yrs Immunomodulator or anti-TNF Colonoscopy every 1-3 yrs  anti-TNF or Δ biologics Penetrating disease, > 2 surgeries <10yrs CD, long stricture or inflammatory CD Long-standing CD, 1st surgery, short stricture

Coming Next Year The PREVENT Study

Thank you!