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

• None

Disclosure

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

6-MP infliximab prednisone

induce remission… rescue them from surgery

CsA

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. Marchal et al IFX No IFX N 52 218 No difference in complications Small sample size Heterogenous study sample Limited stratification for risk factors N IFX No IFX 39 40 No difference in complications Small sample size Heterogenous study sample Limited stratification for risk

factors

Malnutrition/Overall Healt

h

•

More difficult to quantify and examine

•

Related to • length and severity of illness • delayed referral for surgery

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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 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

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Retrospective Cohort Study with both historical and contemporary controls

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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

IFX Infliximab and Surgical Outcome in Crohn’s Disease n 60 Results M:F 29:31 Mean Age 35.8 +/- 11.9

CC HC 329 69 151:178 36.8 +/- 14.4

36:33 38.0 +/- 12.5

Infliximab and Surgical Outcome in Crohn’s Disease

Multivariable logistic regression Model-Factors Associated with any post-operative complications Variable Infliximab Odds Ratio (95% CI) CC 2.00 (0.96 – 4.18) Immunomo 0.53 (0.17 - 1.62) Steroids 1.59 (0.83 - 3.04) Stoma 0.49 (0.22 - 1.09) Adjusted for Age, Sex, Comorbidity, and behavior of disease

Multivariable logistic regression Model-Factors Associated with 30-day Sepsis.

Variable Infliximab Immunomod. Steroids Stoma Odds Ratio (95% CI) CC 2.62 (1.12 – 6.13) 1.40 (0.66 – 2.98) 1.10 (0.50 – 2) 0.28 (0.09 - 0.84)

Adjusted for Age, Sex, Comorbidity, and behavior of disease

Multivariable logistic regression Model-Factors Associated with 30-day Abscess.

Variable

Infliximab Immunomod. Steroids Stoma Odds Ratio (95% CI) CC 5.78 (1.69 - 19.7) 0.41 (0.11 - 1.52) 2.94 (0.63 - 13.6) 0.16 (0.02 - 1.25) 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:

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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 1983 523 RP performed for UC

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85 patients treated with infliximab

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46 2-stage

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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-op complications, multivariate analysis Infliximab (n=46) Non infliximab (n=46) Sepsis Leak 10 (22%) 8 (17.4%) 1 (2.2%) 1* (2.2%) Post-op hemorrhage Thrombotic event Ileus 3 (6.5%) 4 (8.7%) 2 (4.3%) 1 (2.2%) 1 (2.2%) 3 (6.5%) Overall 16 (35%) 7 (15%)

* Sub-clinical leak not associated with pelvic sepsis

p-value 0.016

0.043

0.21

0.07

0.58

0.022

Results

Late post-operative complications, multivariate analysis

Infliximab (n=46) Non infliximab p-value Pouchitis 18 (39%) (n=46) 7 (15%) 0.011

Stricture SBO Overall 5 (11%) 3 (6.5%) 24 (52%) 9 (20%) 6 (13%) 17 (37%) 0.3

0.44

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 Selvasekar ( 2007) Schluender (2007) Mor (2008) Ferrante (2009)

5 6 7 8

Coquet-Reinier (2010) Gainsbury (2011) Bregnbak (2012) Nørgård (2012) Eshuis (2012)

9 10 11 12 13 2002 2005 2000 2005 2000 2006 1998 2008 1999 2008 2005 2009 2005 2010 2003 2010 2006 2009 RC RC RCM RC RCM RC RC RC RC UC UC UC/IC UC/IC UC UC UC UC UC

Biologics (cut-off value) Impact on initial surgery Patient Number (user/non user)

IFX (None) IFX (None) IFX (None) IFX (< 12 weeks) IFX (None) IFX (< 12 weeks) IFX (< 12 weeks) IFX (< 12 weeks) IFX (None) TPC/IPAA TPC/IPAA TPC/IPAA TPC/IPAA Laparoscopic TPC/IPAA TPC/IPAA Colectomy Colectomy TPC/IPAA

End point

301 (47/254) 151(17/134) 92 (46/46) 144 (22/119) 26 (13/13) 81(29/52) 71 (20/51) 1200 (199/1027) 72 (38/34) 30-day complication 30-day complication 30-day complication 30-day complication 30-day complication 30-day complication 30-day complication 30- and 60- day complication 30-day complication

Risk factor Yes No Yes No No No No No Yes * Present study 2006 2010 RC UC/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 *

Kaplan-Meier Estimate of Pelvic Sepsis-free Survival 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

Early active disease ?

Complications Surgery Remission Maintenance

Referring to the Surgeon

time = A good time to operate = A bad time to operate

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

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

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Functional results and QOL rated as good to excellent in 93% of patients

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Only 18% with less than full daytime continence

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Sexual dysfunction in 3% Crohn’s Disease

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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