Feza H. Remzi FACS, FASCRS, FTTS ( Hon ) Chairman Department of Colorectal Surgery

1. Perioperative anti-TNF biologics are not safe because they increase complications associated with surgery Feza H. Remzi FACS, FASCRS, FTTS ( Hon ) Chairman Department of Colorectal Surgery Professor of Surgery Ed and Joey Story Chair Digestive Disease Institute Cleveland Clinic Cleveland, OH

2. Disclosure • None

3. Crohn’s Disease Operative Incidence Jejunoileitis 50% at 5 years; 70% at 10 years Ileocolitis 75% at 5 years; 90% at 10 years Colitis 50% at 5 years; 70% at 10 years

4. Immunosuppressives Malnutrition/overall health Patient perceptions of surgery Surgical Plan

5. prednisone induce remission… rescue them from surgery 6-MP CsA infliximab

6. Anastomotic leaks! Wound complications!!

10. Infliximab and Surgical Outcome in Crohn’s Disease • Is Infliximab use associated with a higher Risk of postoperative complications? • Earlier studies were good but not without some limitations Colombel et al. Am J Gastroenterol. Marchal et al Alimentary Pharmacology & Therapeutics

11. Infliximab and Surgical Outcome in Crohn’s Disease Colombel et al. IFX No IFX N 52 218 No difference in complications Small sample size Heterogenous study sample Limited stratification for risk factors Marchal et al IFX No IFX N 39 40 No difference in complications Small sample size Heterogenous study sample Limited stratification for risk factors

12. Malnutrition/Overall Health • More difficult to quantify and examine • Related to • length and severity of illness • delayed referral for surgery • Hypoalbuminemia (<2.0 mg/dL) • Relative contraindication to IPAA, strictureplasty, ileocolic anastomosis

13. Emergent/Urgent Surgery • Fistulas • Abscesses • Bleeding • Acute obstruction Increased post-operative complications in these situations

14. Use of Infliximab within Three Months Of Ileocolonic Resection Is Associated With Adverse Postoperative Outcomes In Crohn's Patients Appau et al, Journal of Gastrointestinal surgery 2008 The Digestive Disease Institute Cleveland Clinic Foundation. Cleveland, Ohio

15. Infliximab and Surgical Outcome in Crohn’s Disease • Limit to Ileocolic resection • Limit to IFX use within 3 months before surgery • Increase sample size

16. Methods • Retrospective Cohort Study with both historical and contemporary controls • Include: -only patients having ileocolic resection at Cleveland Clinic. -first surgery for Crohn’s disease. • Exclude: -Infliximab used postoperatively. • - Infliximab used more than 3 months preoperatively.

17. Infliximab and Surgical Outcome in Crohn’s Disease Study design • IFX group: IFX within 3 months Ileocolic Res (1998 to 2007) • Contemporary Controls: No IFX Ileocolic Res (CC = 1998 to 2007) • Historical control: Ileocolic resection before IFX came to (HC = 1991 to 1997) market

18. Infliximab and Surgical Outcome in Crohn’s Disease End Points • Any 30-day post operative complication: • Abscess • Sepsis • Anastomotic Leak • 30-day readmission rate

19. Infliximab and Surgical Outcome in Crohn’s Disease Results n M:F Mean Age IFX 60 29:31 35.8 +/- 11.9 CC 329 151:178 36.8 +/- 14.4 HC 69 36:33 38.0 +/- 12.5

20. Infliximab and Surgical Outcome in Crohn’s Disease

21. Multivariable logistic regression Model-Factors Associated with any post-operative complications Adjusted for Age, Sex, Comorbidity, and behavior of disease

22. Multivariable logistic regression Model-Factors Associated with 30-day Sepsis. Adjusted for Age, Sex, Comorbidity, and behavior of disease

23. Multivariable logistic regression Model-Factors Associated with 30-day Abscess. Adjusted for Age, Sex, Comorbidity, and behavior of disease

24. Conclusion • Use of IFX three months before ileocolonic resection in CD patients appears to be associated with increased risk of post operative complications (especially: -Sepsis,abscess, and readmission rate) • However, the presence of stoma above anastomosis seems to decrease these risks.

25. Infliximab in Ulcerative Colitis Is Associated with an Increased Risk of Post-operative Complications after Restorative Proctocolectomy Mor et al Disease Colon rectum 2008

26. Introduction 2-stage procedure • Total proctocolectomy and fashioning of ileal pouch with covering ileostomy • Ileostomy closure 3-stage procedure • Sub-total colectomy • Completion proctectomy and pouch with ileostomy • Ileostomy closure

27. Aims • Assess rate of post-operative complications in infliximab-treated UC patients undergoing RP • To investigate whether there has been an increase in the requirement for subtotal colectomy and three-stage procedure

28. Methods • Case-matched comparison of post-op complications Jan 2000 – Dec 2006 • Patients identified from Ileal Pouch Registry • 2 stage patients only • Patients with pre-op diagnosis of Crohn’s Disease excluded

29. Methods • Percentage of patients requiring initial colectomy (3 stage procedure) in those treated with infliximab compared with those not treated with infliximab • Results adjusted for extent and severity of colitis, steroid dose & use of other immunomodulator

30. Results • Over 3000 patients underwent IPAA since 1983 • 523 RP performed for UC • 85 patients treated with infliximab • 46 2-stage • 39 3 stage • Infliximab administered within a median of 16 weeks preoperatively • Median of 3.2 infusions • Six patients suffered side effects attributable to infliximab • One patient developed lymphoma in the pouch

31. Results Early post-op complications, multivariate analysis * Sub-clinical leak not associated with pelvic sepsis

32. Results Late post-operative complications, multivariate analysis

33. RESULTS • 3-stage RP performed in 46% (39/85) patients who received infliximab compared with 28% (122/438) who did not • Odds ratio 2.07 (95% CI 1.18, 3.63)

34. Conclusion • Infliximab use in UC Seems to increase the risk of early and late post-operative complications Greater need for unplanned 3-stage RP • Risks of both infliximab and surgery should be presented to patients failing conventional medical therapy

36. Kaplan-Meier Estimate of Pelvic Sepsis-free Survival Patient free of pelvic sepsis (%) Time after surgery (month) 0 3 6 9 12 No pelvic sepsis (---- biologics) 25 19 18 17 17 No pelvic sepsis ( no-biologics) 156 142 137 135 131 Gu et al unpublished data 2012

37. Complications Surgery Early active disease ? Remission Maintenance

38. Referring to the Surgeon Patient health time = A good time to operate = A bad time to operate

39. Complications Early surgery Early active disease High risk Low risk Medical treatment Remission

40. Patient Perceptions • Most frustrating aspect for the surgeon • Unique to patients with IBD

42. Impact of Surgery on Quality of LifeCleveland Clinic Data Ulcerative Colitis • Functional results and QOL rated as good to excellent in 93% of patients • Only 18% with less than full daytime continence • Sexual dysfunction in 3% Crohn’s Disease • QOL improves over baseline by 30 days post-op

43. Solutions • Early discussion of surgical options and outcomes with patient by both gastroenterologist and surgeon • Clearly defining the goals of continued medical therapy • Clearly defined criteria for referral to surgery • Better understanding of contributing factors