Perioperative anti-TNF biologics are not safe because they increase complications

associated with surgery

Feza H. Remzi FACS, FASCRS, FTTS ( Hon ) Feza H. Remzi FACS, FASCRS, FTTS ( Hon ) Chairman Chairman

Department of Colorectal SurgeryDepartment of Colorectal SurgeryProfessor of SurgeryProfessor of Surgery

Ed and Joey Story Chair Ed and Joey Story Chair Digestive Disease InstituteDigestive Disease Institute

Cleveland ClinicCleveland Clinic Cleveland, OHCleveland, OH

Disclosure

• None

Crohn’s Disease Operative IncidenceJejunoileitis50% at 5 years; 70% at 10 yearsIleocolitis75% at 5 years; 90% at 10 yearsColitis50% at 5 years; 70% at 10 years

Immunosuppressives

Malnutrition/overall health

Patient perceptions of surgery

Surgical Plan

infliximabinfliximabCsACsA

prednisoneprednisone

6-MP6-MP

induce remission…rescue them from

surgery

Anastomotic leaks!Anastomotic leaks!Wound Wound

complications!!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 52 218No difference in complicationsSmall sample sizeHeterogenous study sampleLimited stratification for risk factors

Marchal et al IFX No IFX N 39 40 No difference in complicationsSmall sample sizeHeterogenous study sampleLimited 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

Appau et al, Journal of Gastrointestinal surgery 2008Journal 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

ResultsResultsnn M:FM:F Mean AgeMean Age

IFXIFX 6060 29:3129:31 35.8 +/- 11.935.8 +/- 11.9

CCCC 329329 151:178151:178 36.8 +/- 14.436.8 +/- 14.4

HCHC 6969 36:3336:33 38.0 +/- 12.538.0 +/- 12.5

Infliximab and Surgical Outcome in Crohn’s Disease

Variable Odds Ratio(95% CI)

CCInfliximab 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)

Multivariable logistic regression Model-Factors Associated with any post-operative complications

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

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

VariableVariableOdds RatioOdds Ratio

(95% CI)(95% CI)CCCC

InfliximabInfliximab 2.62 (1.12 – 6.13)2.62 (1.12 – 6.13)Immunomod. Immunomod. 1.40 (0.66 – 2.98)1.40 (0.66 – 2.98)Steroids Steroids 1.10 (0.50 – 2)1.10 (0.50 – 2)Stoma Stoma 0.28 (0.09 - 0.84)0.28 (0.09 - 0.84)

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

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

VariableOdds Ratio(95% CI)

CCInfliximab 5.78 (1.69 - 19.7)Immunomod. 0.41 (0.11 - 1.52)Steroids 2.94 (0.63 - 13.6)Stoma 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: -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

Introduction2-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

• 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

ResultsEarly 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%)

0.016 0.043

Post-op hemorrhage

3 (6.5%) 1 (2.2%) 0.21

Thrombotic event

4 (8.7%) 1 (2.2%) 0.07

Ileus 2 (4.3%) 3 (6.5%) 0.58Overall 16 (35%) 7 (15%) 0.022

* Sub-clinical leak not associated with pelvic sepsis* Sub-clinical leak not associated with pelvic sepsis

ResultsLate post-operative complications, multivariate analysis

Infliximab (n=46)

Non-infliximab

(n=46)p-value

Pouchitis 18 (39%) 7 (15%) 0.011

Stricture 5 (11%) 9 (20%) 0.3

SBO 3 (6.5%) 6 (13%) 0.44

Overall 24 (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 UCSeems to increase the risk of early and late post-operative complicationsGreater 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

periodStudy design

Diagnosis

Biologics (cut-off value)

Impact on initial surgery

Patient Number

(user/non-user)

End point Risk factor

Selvasekar ( 2007) 5 2002-

2005 RC UC IFX (None) TPC/IPAA 301 (47/254) 30-day complication Yes

Schluender (2007) 6 2000-

2005 RC UC IFX (None) TPC/IPAA 151(17/134) 30-day complication No

Mor (2008) 7 2000-2006 RCM UC/IC IFX (None) TPC/IPAA 92 (46/46) 30-day

complication Yes

Ferrante (2009) 8 1998-

2008 RC UC/IC IFX (< 12 weeks) TPC/IPAA 144 (22/119) 30-day complication No

Coquet-Reinier (2010) 9 1999-

2008 RCM UC IFX (None) Laparoscopic TPC/IPAA 26 (13/13) 30-day

complication No

Gainsbury (2011) 10 2005-

2009 RC UC IFX (< 12 weeks) TPC/IPAA 81(29/52) 30-day complication No

Bregnbak (2012) 11 2005-

2010 RC UC IFX (< 12 weeks) Colectomy 71 (20/51) 30-day complication No

Nørgård (2012) 12 2003-

2010 RC UC IFX (< 12 weeks) Colectomy 1200 (199/1027)

30- and 60- day complication No

Eshuis (2012) 13 2006-2009 RC UC IFX (None) TPC/IPAA 72 (38/34) 30-day

complication 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,

QOLYes *

Time after surgery (month) 0 3 6 9 12 Time after surgery (month) 0 3 6 9 12 No pelvic sepsis (---- biologics) 25 19 18 17 No pelvic sepsis (---- biologics) 25 19 18 17 17 No pelvic sepsis ( no-biologics) 156 142 137 135 17 No pelvic sepsis ( no-biologics) 156 142 137 135 131 131

Patie

nt fr

ee o

f pel

vic

seps

is

Patie

nt fr

ee o

f pel

vic

seps

is

(%)

(%)

Kaplan-Meier Estimate of Pelvic Sepsis-free SurvivalKaplan-Meier Estimate of Pelvic Sepsis-free Survival

Gu et al unpublished data 2012Gu et al unpublished data 2012

Early active Early active diseasedisease

RemissionRemission

ComplicationsComplications

??SurgerySurgery

MaintenanceMaintenance

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

Patie

nt h

ealth

Patie

nt h

ealth

timetime

Referring to the Surgeon

Early active Early active diseasedisease

RemissionRemission

ComplicationsComplicationsEarly surgeryEarly surgery

Medical Medical treatmenttreatment

High riskHigh risk

Low riskLow risk

Patient Perceptions

• Most frustrating aspect for the surgeon

• Unique to patients with IBD

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

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