Pro: Perioperative anti-TNF Biologics are safe and do not increase complications associated with surgery. Miguel Regueiro, M.D. Professor of Medicine Associate Chief for Education Clinical Head and Co-Director, IBD Center University of Pittsburgh School of Medicine

% 20% 30% 40% 50% 60% 70% 80% 90% 100% Probability of receiving biologics at 5 years Probability of receiving immunosuppressants at 5 years Rate of surgery at 5 years Disease duration before introduction of biologics (yr) ? 0 10% 20% 30% 40% 50% 60% 70% Population-based studies (within 5 yr) Randomised controlled trials (at 1 yr) Referral centre trials (within 5 yr) Before the era of biologics In the era of biologics Bouguen G, Peyrin-Biroulet L. Gut 2011 Surgery for adult Crohn’s disease: what is the actual risk ?

Peyrin-Biroulet L et al. Gut 2011 Probability of using IMM before 1 st abd surgery (n=296)

Peyrin-Biroulet L et al. Gut 2011 Probability of receiving at least 1 antiTNF before 1 st surgery (296)

This means that most IBD patients undergoing surgery are taking an IMM and/or antiTNF -If it’s an emergent surgery, we don’t have much choice on altering pre-op meds. -Should the type of operation be altered? -If the surgery is elective: -Should we alter pre-op meds? Is starting an antiTNF in the postop setting safe?

Dr Remzi will argue that peri- operative antiTNF is unsafe As you may know, there’s a bit of a rivalry between Pittsburgh and Cleveland

Pittsburgh vs Cleveland

Despite the intercity rivalry, I have the utmost respect for Dr Remzi and the Cleveland Clinic In reality, our hospitals and cities are quite similar

UPMC and Pittsburgh on a typical summer morning

Cleveland Clinic on that same, bright summer morning

A Tale of Two Cities – a surgeon’s perspective on postop outcome 27 yo CD from Youngstown OH sees Dr Regueiro in Pittsburgh on AZA/ADA Develops SBO while in Cleveland and requires emergent surgery w Dr Remzi Scenario 1: dc’d 4 days later, “great!” – Dr Remzi – “I am a brilliant surgeon!!” Scenario 2: POD 2 develops an anast leak – Dr Remzi – “it’s all because of those poisons Dr Regueiro was giving you!”

Peri-operative complications in IBD – independent of meds Wound sepsis wound infection wound dehiscence Intraabdominal infections anastomotic leak intrabdominal abscess enterocutaneous fistula Extraabdominal infections sepsis pneumonia bacteremia urosepsis other infections CD recurrence Small bowel obstruction GI bleeding Thromboembolism Septic complicationsNon-septic Colombel JF et al. Am J Gastroenterol 2004

Three Scenarios to Consider PRE-operative antiTNF for CROHN’S disease and POST-op complications PRE-operative antiTNF for ULCERATIVE COLITIS disease and POST-op complications POST-operative antiTNF for CROHN’S disease and POST-op complications

PRE-operative antiTNF for CROHN’S disease and POST-op complications What are the data?

9 Crohn’s ds Postop References Tay et al. Surgery 2003 Marchal et al. Aliment Pharmacol Ther 2004 Colombel et al. Am J Gastroenterol 2004 Appau et al. J Gastrointest Surg 2008 Indar et al. World J Surg 2009 Canedo et al. Colorectal Dis 2011 Nasir et al. J Gastrointest Surg 2012 Kasparek et al. Inflamm Bowel Dis 2012 Kopylov et al. Inflamm Bowel Dis 2012

Tay – Multivariate analysis suggests improved perioperative outcome in CD pts receiving IMMs before resection Overall, 11% Postop complications (5.6% on IMM, 25% not on IMM)

Marchal – The risk of postop complications associated with IFX for CD: a controlled cohort study 12.5% IFX vs 7.7% control: Early complication Major complications Early (within 10 days) 5 (12.5%) IFX3 (7.7%) No IFXN.S. Catheter sepsis: 2 Anastomotic leak: 2 N.S. Anaemia + tr ansfusion: 1 Faecal peritonitis: 1 N.S Wound infection: 1 Candida sepsis: 1 N.S Wound failure: 1 Anaemia + transfusion: 1 N.S

Colombel – Early postop complications are not increased in CD treated preop with IFX or IMM Overall, 23 % postoperative complications NN (%)OR (95% CI) No steroids19342 (22)1.0 (ref) Hi steroids4313 (30)1.6 (0.7–3.3) No IMM16537 (22)1.0 (ref) Any IMM10526 (25)1.1 (0.6–2.0) No IFX21851 (23)1.0 (ref) Any IFX5212 (23)1.0 (0.5–2.0)

Indar – Effect of periop IMM/TNF on early outcome in CD pts Overall, 33% postoperative complications DrugNo. of patients No. of complications None4311 Corticosteroids214 IMMs156 Anti-TNFα antibodies 21

Canedo – Surgical resection in CD: is IMM associated with higher postop infxn rates? n(%)IFX (n = 65)ND (n = 75) P value by complication Wound infection9 (13.8)8 (10.7)P2 = 0.39 Pulmonary infection 1 (1.5)0P1 = 0.14 Abscesses2 (3.0)2 (2.6)P1 = 0.34 Anastomotic leakage 2 (5.7)1 (2.43)P1 = 0.39 Reoperations2 (3.0)2 (2.6)P1 = 0.2 No infection49 (75.4)62 (82.7)P2 = 0.15

Nasir – Periop antiTNF does not increase the early postop complications in CD Overall, 29% postoperative complications Abscess/anastomotic leak N (%)OR (95% CI)ORP value No anti-TNF2515 (1.99)1.0 (ref) Anti-TNF1194 (3.36)1.7 (0.5–6.5)0.43

Kasparek – IFX does not affect postop complication rates in CD Overall, 59% postoperative complications Major complications IFX 16 in 13 patients No IFX 15 in 12 patients p1.0 Anastomotic leak2 (4%)6 (13%)0.27 Intraabdominal abscess 3 (6%)5 (10%)0.71 Patients requiring reoperation 11 (23%)10 (21%)1.0 Postoperative hospital stay (d) 13 [5–41]12 [5–54]0.64

Appau – Use of IFX within 3 mos of IC resection IS associated with postop AEs..Dr Remzi is co-author...hmmmm…… Overall, 72% postop complications Complication Non IFX group (1998–2007) n = 329 (%) IFX group n = 60 (%) Odd’s ratio (95%CI) p-Value Readmission rate (1.15, Sepsis (1.12, 4.82)0.024 Intrabdominal abscess (0.92, 6.79)0.10 Anastomotic leak Reoperation (0.95,8.81)0.06

Kopylov – AntiTNF and Postop complications in CD: Systematic Review and Meta-analysis - OR 1.7 (CI, ) postop complications - Number Needed to Harm = 20

ORs Overall Complications

ORs Infectious Complications

First Author Type of surgeryN Postoperative complications Increased postop complications Tay Segmental resection with primary anastomosis or strictureplasty % No Marchal Intestinal resection (symptomatic stenosis or refractory fistulas and/or abscesses, or intractable disease) 79 24% No Colombel Abdominal surgery % No Appau ileocolonic resection % Yes Indar Intestinal surgey (Ileocecal resection and small intestine resection++) % No Nasir surgery which included a suture or staple line % No Canedo Abdominal surgery 225 ND No Kasparek Abdominal surgery 96 59% No Kopylov et al. IBD 2012 Risk of postop complications in CD – only one “Yes”

PRE-operative antiTNF for ULCERATIVE COLITIS disease and POST-op complications What’s the data?

UC Postop References Selvasekar et al J Am Coll Surg 2007 Schluender et al Dis Colon Rectum 2007 Mor et al Dis Colon Rectum 2008 Ferrante et al Inflamm Bowel Dis 2009 Norgard et Aliment Pharmacol Ther 2012 Yang et al Aliment Pharmacol Ther 2010 UC and CD Studies combined: Kunitake et al J Gastrointest Surg 2008 Waterman et al Gut 2012

Selvasekar – Effect of IFX on short-term complications in pts undergoins operation for chronic UC – 62% complicaiton with IFX

Mor – IFX in UC is associated with an increased risk of postop complications after restorative proctocolectomy OR early complication IFX 3.54 (P = 0.004; 95% CI ). OR sepsis IFX 13.8 (P = 0.011; 95% CI, ) OR late complication IFX 2.19 times (P = 0.08; 95% CI, )

Schluender – Does IFX influence surgical morbidity of IPAA in UC pts? 28% overall complication rate 37% IFX v 27% no IFX (p>.05, NS) 5 pts rx’d with Cyclosporine + IFX –80% complication rate

Norgard – Pre-op use of antiTNF and the risk of postop complications in pts with UC – a nationwide cohort study 1226 UC pts – 199 IFX Most underwent ileostomy (not IPAA) OR reoperation 1.07 (95% CI: ) OR anastomosis leakage 0.52 (95% CI: ) respectively

Ferrante – Corticosteroids but not IFX increase short-term postop infectious complications in pts with UC

Yang – Meta-analysis: pre-op IFX + short-term postop complications UC pts 1.short term infxn (NO) 2. short term non infxn (NO) 3. short term overall (YES)

Periop antiTNF UC studies AuthorType of Surgery NPostoperative Complications Increased Postop Complications SelvasekarIPAA IFX 62%Yes SchluenderIPAA IFX 28% 37%IFX v 27% No MorIPAA IFX OR IFX 3.5 total OR IFX 13.8 infxn Yes FerranteIPAA IFX 22% overall Steroids/1 step J No NorgardMost Ileostmy IFX OR IFX 0.5No YangMost IPAA 5 studiesOR IFX 1.8Yes

Periop antiTNF in combined UC/CD studies

Kunitake – Periop IFX in CD/UC is not assoc with postop complications

Waterman – Preop biological rx and short-term postop outcomes in IBD 195 exposed to biologics, 278 not on biologics No significant difference in most postop outcomes Operations within 14 days of antiTNF and detectable IFX levels NOT associated with increased wound infections

Waterman - results Biologics (n=195) Unexposed controls (n=278) p Value Fever28 (14)42 (15)0.81 UTI11 (6)11 (4)0.39 Pneumonia5 (3)9 (3)0.68 Wound infection 37 (19)29 (11) comboIMM Bacteremia7 (4)5 (2)0.22 Anastmotic leak 5 (3)15 (5)0.13 Reopertion8 (4)12 (4)0.91 Poor healing39 (20)35 (13) 0.03 comboIMM

UC/CD combined summary table AuthorType of Surgery NPostop ComplicationIncreased postop complications? KunitakeMixed for CD and UC 188 CD 156 UC 69 IC 101 IFX anastomotic leak (IFX 3.0% vs. no IFX 2.9%, p = 0.97), cumulative infections (IFX 5.97% vs. no IFX 10.1%, p = 1), No WatermanMixed for CD and UC 473 surgeries 195 antiTNF No

It’s difficult to assess causality of periop IBD meds and complications: too many confounders Severity of IBD Nutritional status Concomitant therapies Emergent vs Elective Surgery Different pre-operative drug window Different procedures Different expertise of surgeons

Is starting POST-op antiTNF within 1 mos of CD surgery safe? Postoperative infliximab is not associated with an increase in adverse events in Crohn's disease. Regueiro M, El-Hachem S, Kip K, et al. Dig Dis Sci Dec;56(12):

No Difference in Adverse Events between Placebo and Infliximab (started within 4 wks of surgery)

Is peri-op antiTNF Safe? Scorecard of Study Results Timing of antiTNF relative to surgery YesNo Pre-op CD 81 Pre-op UC (includes 2 CD/UC studies) 53 Post-op CD 10

What I do in practice?

My Practice – periop management MedicationEMERGENT UC – 3 step IPAA CD – Ostomy, abd sepsis ELECTIVE UC- 2-3 step CD- primary anastomosis Steroids MTX 6MP/AZA antiTNF

My Practice – periop management MedicationEMERGENT UC – 3 step IPAA CD – Ostomy, abd sepsis ELECTIVE UC- 2-3 step CD- primary anastomosis Steroids-Stress dose -Lower to pred <40mg -Taper 24 hr postop (?slow) -Stress dose -Preop < 20mg Pred -Taper 24hr postop (rapid) MTX 6MP/AZA antiTNF

My Practice – periop management MedicationEMERGENT UC – 3 step IPAA CD – Ostomy, abd sepsis ELECTIVE UC- 2-3 step CD- primary anastomosis Steroids MTX-Restart at 2wk outpt f/u-Preop no need to stop -Restart at 2wk outpt f/u -Surgeons prefer dc’d >4wks 6MP/AZA-Restart at 2wk outpt f/u-Preop no need to stop -Restart at 2wk outpt f/u -Surgeons prefer dc’d>4 wks antiTNF

My Practice – periop management MedicationEMERGENT UC – 3 step IPAA CD – Ostomy, abd sepsis ELECTIVE UC- 2-3 step CD- primary anastomosis Steroids MTX 6MP/AZA antiTNF-Preop no choice (emergent) –Restart after 2wk outpt f/u (or when previously scheduled) -Preop no need to stop -? Dose >6 wks preop (but then chance of flare if delay) -Restart >2wk postop

My Practice – periop management MedicationEMERGENT UC – 3 step IPAA CD – Ostomy, abd sepsis ELECTIVE UC- 2-3 step CD- primary anastomosis Steroids-Stress dose -Lower to pred <40mg -Taper 24 hr postop (?slow) -Stress dose -Preop < 20mg Pred -Taper 24hr postop (rapid) MTX-Restart at 2wk outpt f/u-Preop no need to stop -Restart at 2wk outpt f/u -Surgeons prefer dc’d >4wks 6MP/AZA-Restart at 2wk outpt f/u-Preop no need to stop -Restart at 2wk outpt f/u -Surgeons prefer dc’d>4 wks antiTNF-Preop no choice (emergent) –Restart after 2wk outpt f/u (or when previously scheduled) -Preop no need to stop -? Dose >6 wks preop (but then chance of flare if delay) -Restart >2wk postop

Summary Periop antiTNF CD: antiTNF is not associated with increased risk when used in the perioperative period UC: severity of ds is most associated with complications rather than antiTNF –3 step IPAA being done anyway Practically speaking: surgery should NOT be delayed because a patient is on antiTNF

With that, I give you Dr Remzi