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 Ed and Joey Story Chair Digestive Disease Institute Cleveland Clinic Cleveland, OH Cleveland, OH

Disclosure None

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

Immunosuppressives Malnutrition/overall health Patient perceptions of surgery Surgical Plan

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

Anastomotic leaks! Wound complications!!

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

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

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

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

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

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

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.

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

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

Infliximab and Surgical Outcome in Crohn’s Disease Results Results nM:FMean Age IFX6029: / CC329151: / HC6936: /- 12.5

Infliximab and Surgical Outcome in Crohn’s Disease

Variable Odds Ratio (95% CI) CC Infliximab 2.00 (0.96 – 4.18) Immunomo 0.53 ( ) Steroids 1.59 ( ) Stoma 0.49 ( ) Multivariable logistic regression Model-Factors Associated with any post-operative complications Adjusted for Age, Sex, Comorbidity, and behavior of disease

Variable Odds Ratio (95% CI) CC Infliximab 2.30 (0.99 – 5.36) Immunomo ( ) Steroids 1.74 ( ) Stoma 0.28 ( ) Multivariable logistic regression Model-Factors associated with post-operative INFECTIOUS Complications. Multivariable logistic regression Model-Factors associated with post-operative INFECTIOUS Complications. Adjusted for Age, Sex, Comorbidity, and behavior of disease

Multivariable logistic regression Model-Factors Associated with 30-day Sepsis. Variable Odds Ratio (95% CI) CC Infliximab 2.62 (1.12 – 6.13) Immunomod (0.66 – 2.98) Steroids 1.10 (0.50 – 2) Stoma 0.28 ( ) Adjusted for Age, Sex, Comorbidity, and behavior of disease

Multivariable logistic regression Model-Factors Associated with 30-day Abscess. Variable Odds Ratio (95% CI) CC Infliximab 5.78 ( ) Immunomod ( ) Steroids 2.94 ( ) Stoma 0.16 ( ) Adjusted for Age, Sex, Comorbidity, and behavior of disease

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.

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

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

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

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

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

Results Over 3000 patients underwent IPAA since 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

Results Early post-operative complications, univariate analysis Infliximab (n=46) Non- infliximab (n=46) p-value Sepsis Leak 10 (22%) 8 (17.4%) 1 (2.2%) 1* (2.2%) Post-op hemorrhage 3 (6.5%)1 (2.2%)0.62 Thrombotic event 4 (8.7%)1 (2.2%)0.36 Ileus2 (4.3%)3 (6.5%)1 Overall16 (35%)7 (15%)0.022 * Sub-clinical leak not associated with pelvic sepsis

Results Late post-operative complications, univariate analysis Infliximab (n=46) Non- infliximab (n=46) p-value Pouchitis18 (39%)7 (15%)0.012 Stricture5 (11%)9 (20%)0.25 SBO3 (6.5%)6 (13%)0.49 Overall24 (52%)17(37%)0.14

Results Early post-op complications, multivariate analysis Infliximab (n=46) Non- infliximab (n=46) p-value Sepsis Leak 10 (22%) 8 (17.4%) 1 (2.2%) 1* (2.2%) Post-op hemorrhage 3 (6.5%)1 (2.2%)0.21 Thrombotic event 4 (8.7%)1 (2.2%)0.07 Ileus2 (4.3%)3 (6.5%)0.58 Overall16 (35%)7 (15%)0.022 * Sub-clinical leak not associated with pelvic sepsis

Results Late post-operative complications, multivariate analysis Infliximab (n=46) Non- infliximab (n=46) p-value Pouchitis18 (39%)7 (15%)0.011 Stricture5 (11%)9 (20%)0.3 SBO3 (6.5%)6 (13%)0.44 Overall24 (52%)17 (37%)0.08

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)

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

Author (year of ublication) Ref. Study period Study design Diagnosi s Biologics (cut-off value) Impact on initial surgery Patient Number (user/non- user) End pointRisk factor Selvasekar ( 2007) RCUCIFX (None)TPC/IPAA301 (47/254) 30-day complication Yes Schluender (2007) RCUCIFX (None)TPC/IPAA151(17/134) 30-day complication No Mor (2008) RCMUC/ICIFX (None)TPC/IPAA92 (46/46) 30-day complication Yes Ferrante (2009) RCUC/ICIFX (< 12 weeks)TPC/IPAA144 (22/119) 30-day complication No Coquet-Reinier (2010) RCMUCIFX (None) Laparoscopic TPC/IPAA 26 (13/13) 30-day complication No Gainsbury (2011) RCUCIFX (< 12 weeks)TPC/IPAA81(29/52) 30-day complication No Bregnbak (2012) RCUCIFX (< 12 weeks)Colectomy71 (20/51) 30-day complication No Nørgård (2012) RCUCIFX (< 12 weeks)Colectomy 1200 (199/1027) 30- and 60- day complication No Eshuis (2012) RCUCIFX (None)TPC/IPAA72 (38/34) 30-day complication Yes * Present study RCUC/IC IFX (<12 weeks); adalimumab or certolizumab pegol (<4 weeks) STC/EI or TPC/IPAA 588 (167/421) Long-term f/u, pouch function, QOL Yes *

Time after surgery (month) No pelvic sepsis (---- biologics) No pelvic sepsis ( no-biologics) Patient free of pelvic sepsis (%) Kaplan-Meier Estimate of Pelvic Sepsis-free Survival Kaplan-Meier Estimate of Pelvic Sepsis-free Survival Gu et al unpublished data 2012

Early active disease Remission Complications ? Surgery Maintenance

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

Early active disease Remission Complications High risk profile Early surgery

Early active disease Remission Complications Low risk profile Aggressive medical therapy

Genetic Biomarker Study Patients with index ileocolic resection for terminal ileal Crohn’s disease Whole human genome array Endoscopic and clinical recurrence as endpoints Goal: define “genetic fingerprint” to predict disease behavior

Index ileocolic resection Low-risk High-risk infliximab 5-ASA6-MPFlagyl

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

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

Impact of Surgery on Quality of Life Cleveland 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

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

Conclusions Medical therapy appears to have major impact on surgery for IBD in era of biologics

Conclusions Accurate predictors of disease behavior needed to guide therapy Psychological aspects of surgery need to be studied