The use of anti-TNF agents has proved paramount in the remedy of Crohn’s disease, decreasing the overall need for surgery. However, despite this eminent introduction in therapy, the reality is 75% of CD will still undergo surgery as a result of refractory disease or complications. The dilemma for providers has become determining the safety of biologic therapy preceding surgery and whether biologic agents such as Infliximab should be stopped. Numerous studies have been performed to answer this question, the majority utilizing infliximab as their anti-TNF agent. All authors defined preoperative therapy as either two or three months preceding surgery, with 30-day postoperative follow-up. When evaluating Crohn’s disease, the consensus has been debated. Several studies such as those performed at Mayo Clinic, Scottsdale; Mount Sinai Medical Center; and Mayo Clinic, Rochester, concluded no significant increase in adverse effects and to not delay surgery. At the Cleveland Clinic however, authors concluded that the use of infliximab 3 months prior to ileocolonic resection with anastomosis (ICRA) resulted in higher postoperative intra-abdominal abscess, sepsis, anastomotic leaks, and readmission rates. Given this disagreement in safety of biologics prior to surgery, a meta-analysis was performed incorporating 8 studies with a total of 1641 patients, demonstrating a trend toward higher total and noninfectious complications, however only significant difference seen among postoperative infections. We would conclude that infectious complications in fact are a postoperative risk with anti-TNF therapy in Crohn’s disease and should consider delaying elective surgery. However, if perioperative anti-TNF cannot be avoided, consider a defunctionalizing proximal stoma to reduce adverse effects and to protect the anastomosis.

Chronic ulcerative colitis is an additional debilitating inflammatory bowel disease. After induction of remission, up to 50% will unfortunately experience a relapse in one year, and of this group, half will further require surgical management. Contrasting from Crohn’s disease, surgery in UC offers a chance for cure of intestinal symptoms and eradicates the risk of malignancy. Prior to surgery however, the ultimate goal is to sustain mucosal healing through medical management . The 2005 Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively) laid the foundation that has now made infliximab an effective agent in moderate-to-severe UC, with mucosal healing occurring in significantly more patients than placebo (p ≤ 0.009) [7]. Subsequently infliximab received FDA approval for the treatment of moderate-to-severe UC and endorsement by the American Gastroenterology Association as an agent to treat hospitalized patients with severe UC [4]. When disease surpasses medical salvage, restorative proctocolectomy (RP) and ileal pouch-anal anastomosis (IPAA) become the procedure of choice. Determining one-, two-, or three-stage RP is based on the severity of systemic illness and degree of inflammation. Two-stage procedure is defined as a total proctocolectomy and ileal pouch construction with covering loop ileostomy and then subsequent closure of ileostomy marking the second stage. Three-stage procedure is frequently utilized in acutely ill patients on high-dose steroids, immunomodulators, or severe colon and rectal inflammation [16]. Similar to Crohn’s disease, the question regarding safety of preoperative anti-TNF agents and risk of postoperative complications emerged after the introduction of infliximab for moderate-to-severe UC. Thus, multiple studies were designed in the attempt to answer this question.

One of the initial studies to investigate the influence of infliximab on surgical morbidity started at Cedars-Sinai Medical Center in 2007, 2 years after infliximab received FDA approval for moderate-to-severe UC [4]. Between October 2000 and October 2005, 30-day postoperative morbidity and mortality were recorded after two-stage proctocolectomy with ileal pouch-anal anastomosis (IPAA) or if necessary subtotal colectomy (STC). Complications were divided into medical and surgical, with medical complications being divided into major and minor. Major adverse effects included pneumonia, deep vein thrombosis, pancreatitis, acute renal failure, and cerebrovascular accident, whereas minor complications encompassed dehydration, superficial thrombophlebitis, pyoderma gangrenosum, and urinary retention. A preponderance of patients undergoing surgery were preoperatively diagnosed with pancolitis, and all were exposed to IV steroids. The study group is comprised of 17 patients exposed to infliximab preoperatively compared to 134 controls.

Results of the study revealed no statistical significance in medical (p = 0.99), surgical (p = 0.3), or overall infectious (p = 0.2) complications. The bulk underwent IPAA (112 patients, 69%) compared to STC (39 patients, 31%); however, when comparing surgical approaches, no statistical difference in medical, surgical, or infectious complications was seen. In addition, the aim of this study was to investigate the influence of infliximab with other immunosuppressive agents, such as 6-MP or cyclosporine (CsA). Whereas no significant difference in complication rates were observed in 6-MP + infliximab compared to infliximab alone, the groups receiving infliximab plus CsA demonstrated an overall 80% complication rate, specifically infectious, when compared to infliximab monotherapy. The authors concluded that preoperative infliximab use alone may not influence 30-day mortality; however, one should consider infectious complication risks when combining with CsA [4].

At the Mayo Clinic in Rochester, Minnesota, short-term (within 30 days) postoperative complications were measured between 2002 and 2005 on chronic ulcerative colitis patients exposed to infliximab preceding IPAA; the complication rates for anastomotic leak, pelvic abscess, and wound infection were determined [17]. Definition of perioperative treatment included exposure of therapy with infliximab, corticosteroids, or immunomodulators up to 6 months before surgery. Surgical inclusion was exclusive to IPAA, either two- or three-stage procedures.

A total of 301 patients was included in the study—47 of whom received infliximab. A higher percentage of the infliximab-treated arm suffered with severe colitis (p = 0.02) with the main indication for surgery being medical refractory disease. Although two- and three-stage IPAA were included in the study, majority underwent two-stage procedure with closure of the ileostomy at a mean of 3.1 months in both groups. A higher number of patients in the infliximab-treated arm were exposed to corticosteroids (89% vs. 86%, p < 0.001), on concurrent azathioprine (AZA) (91% vs. 44%, p < 0.0001), and treated with combination of high-dose corticosteroids, ASA, and AZA (70% vs. 19.3%, p < 0.001) [17].

Using univariate analysis, infliximab demonstrated an increase in pouch-specific complications (OR = 3.5, 95% CI, 1.6–7.5). However, adjusting for age, severity of colitis, and use of high-dose steroids and AZA/6-MP, there were no further increased odds of pouch-specific complications. Rates of infectious complications (including anastomotic leak, pelvic abscess, and wound infection) in the infliximab-treated arm exceeded the control arm (28% vs. 10%, OR = 3.5; 95% CI, 1.6–7.5), as well as anastomotic leaks and wound infections, without a significant difference in postoperative fistula or anastomotic stricture frequency. The study concluded that preoperative exposure to infliximab significantly increased rate of postoperative infectious complications, with nearly one in five experiencing adverse events. This becomes important since anastomotic leaks and pelvic abscesses play an important role in long-term pouch function [17, 18].

At the Cleveland Clinic, early and late postoperative complications were analyzed between January 2000 and December 2006 on chronic UC patients exposed to infliximab and matched controls undergoing two-stage restorative proctocolectomy [16]. Early complications were defined as within 30 days after ileostomy closure, whereas late complications were those that developed after 30 days of ileostomy closure (e.g., pouchitis, small bowel obstructions, and anastomotic strictures). This study differed in that timing of infliximab did not have to meet inclusion/exclusion criteria; timing ranged between 4 and 37 weeks, a median of 13.5 weeks and three infusions.

An aggregate of 85 patients received infliximab out of 523 total ileal pouches. The extent and severity of colitis, in addition to steroid exposure preceding surgery (11–20 mg) and immunomodulators, were comparable in the infliximab and non-infliximab arms. Results of the study revealed a higher prevalence of pelvic sepsis as an early complication (22% vs. 2%, p = 0.016), with parallel rates of postoperative hemorrhage, venous thrombosis, and ileus. Later complications of pouchitis were found at a higher prevalence in the infliximab exposed arm (39% vs. 15%, p = 0.037), whereas overall late morbidity, small bowel obstruction, and IPAA strictures were similar between the two groups.

Statistically adjusting for extent and severity of colitis, steroid dose, and use of immunomodulators , use of infliximab leads to greater rates of overall early complications (OR, 3.54; 95% CI 1.51–8.31), specifically rate of pelvic sepsis and pouchitis. Thus, the authors concluded that the use of infliximab therapy in moderate-to-severe UC prior to RP increased rate of early and late postoperative complications [16].