Monoclonal anti-tumor necrosis factor (TNF) antibodies have been employed in the treatment of Crohn's disease (CD), ulcerative colitis (UC), and other inflammatory disorders for over a decade. Infliximab (IFX) therapy has proven to be effective in induction and maintenance of remission in CD patients.1 However, this medication has also been associated with diverse adverse effects such as an increased risk of infections, infusion reactions, and a possible increased incidence of lymphoma.2
Up to two-thirds of all CD patients are expected to require surgery at least once during the course of their disease,3, 4, 6 and ≈40% will undergo two or more surgical interventions. Surgery is an effective method for induction of remission and for treatment of CD complications. However, surgical procedures may be associated with considerable morbidity in CD patients, with a reported complication rate of up to 22%.7–10 Nonetheless, the data concerning the influence of IFX on surgical risk in patients with inflammatory bowel disease (IBD) are equivocal. For patients with UC, a meta-analysis by Yang et al11 pointed to an increased risk of short-term postoperative complications in patients who received preoperative IFX. Although several studies pertaining to complications of preoperative IFX therapy in CD patients have been published, the impact of anti-TNF therapy on the rate of postoperative complications in CD patients remains unclear.
The aim of our study was to evaluate the impact of preoperative use of anti-TNF antibodies on the rate of postoperative complications in patients with CD by conducting a systematic review and meta-analysis of the existing literature.
- Top of page
- MATERIALS AND METHODS
- APPENDIX: NOS: CODING MANUAL FOR COHORT STUDIES
- Supporting Information
Anti-TNF medications are among the most valuable tools in the therapeutic arsenal in IBD. However, the use of these medications may be associated with significant adverse effects, including an increased incidence of infections. As the majority of patients with CD will undergo at least one operation during their lifetimes,1, 2, 4 this anti-TNF-related susceptibility to infection may raise concerns pertaining to perioperative management. A potential influence of TNF inhibitors on wound healing is another matter of concern for these patients. However, most of the data pertaining to this issue include in vitro and animal studies, with equivocal results regarding collagen synthesis, wound healing, and anastomotic strength.25–28
Despite a continuing debate on this subject, no prospective study analyzing the risk for postoperative complications in CD patients treated with TNF inhibitors has been published so far. Several observational studies pertaining to CD, UC, and rheumatoid arthritis (RA) patients have been published. Comparing these studies, however, poses a significant challenge due to small cohort sizes and multiple important confounders.
Studies assessing surgical risks in RA patients treated with TNF inhibitors were mostly small and retrospective.29–34 No statistically significant increase in surgical complications was noted in any but one retrospective study,32 which suggested an increased risk of surgical site infections and deep venous thrombosis. Importantly, rheumatological data reported so far included mixed cohorts of patients treated with IFX, adalimumab, and Etanercept, the latter frequently employed in RA but ineffective in IBD.
A meta-analysis focusing on a similar issue in patients with UC11 summarized the surgical outcomes of IFX-treated patients with UC from five observational studies.35–39 Perioperative treatment with IFX was associated with increased risk of total short-term complications (OR 1.80, 95% CI 1.12–2.87). A trend for increased risk of postoperative infectious complications was also demonstrated (OR 2.23, 95% CI, 0.63–7.95).
However, no such meta-analysis has been hitherto published on TNF inhibitors treatment in CD patients undergoing surgery. Our meta-analysis addressed the risk of postoperative complications following abdominal surgery in CD patients who received perioperative IFX. We found a small but statistically significant increased risk of infectious complications (OR 1.50, 95% CI 1.08–2.08) and a nonsignificant trend toward increased rate of noninfectious (OR 2.00, 95% CI 0.89–4.46) and overall complications (OR 1.72, 95% CI, 0.93–3.19). Interestingly, a subanalysis of the infectious complications showed them to be unrelated to local infectious complications such as anastomotic leak or intraabdominal abscess. These findings imply an increased rate of remote or systemic infections such as respiratory, urinary infections, and sepsis, which are in line with the systemic immune suppression conferred by anti-TNFs.
Similar to other meta-analyses in this field,6–7 the present meta-analysis has several limitations stemming from the retrospective design of the included studies and resulting primarily from different inclusion criteria and nonuniform definitions of the complications. Thus, six out of eight analyzed studies included patients who received IFX only before surgery, whereas two studies also included patients who received IFX up to 30 days after the procedure. Our analysis was underpowered to discern an influence of the timing of the last preoperative IFX effusion on the rate of complications. However, a sustained effect of IFX beyond 12 weeks is unlikely due to its pharmacokinetic characteristics.24 Heterogeneity in timing of the assessment of complications is yet another limitations, since the surgical complications were assessed at 4 weeks postoperatively in six studies, and at 10 days or 90 days in one study,15 and at an average of 12 days postoperatively in another study.21
Importantly, the definitions of infectious and noninfectious complications vary substantially between different studies. In our meta-analysis, we addressed all anastomotic leaks and wound failures as infectious complications, even if they were not classified as such by the primary authors. It is clear that discrepancies in the classification of the complications may have had an influence on the statistical analysis.
The type and technique of the surgical procedures are other important factors that could influence outcome. Interestingly, the only study that has demonstrated a significant increase in adverse outcomes11 included exclusively patients who underwent ileocolonic resection without a history of previous abdominal operations. All other studies included patients undergoing a variety of abdominal surgical procedures, with ileocecal resections comprising only 31% of the included surgical procedures.
An important limitation in our meta-analysis is the concomitant use of nonanti-TNF immunomodulators. Patients treated with IFX were more likely to be treated with immunomodulators (OR 2.00, 95% CI 0.95–4.2), but less likely to receive corticosteroids (OR 0.68, 95% CI 0.50–0.93). Corticosteroid treatment has been consistently reported to be associated with increased risk of surgical complications, while no such association has been reported for 6-mercaptopurine and azathioprine.40–42 In addition, our analysis is restricted by the fact that only one study included patients who were treated with adalimumab and certolizumab in addition to patients treated with IFX. To the best of our knowledge, there are no other published studies that have analyzed the effect of adalimumab and certolizumab on perioperative complications. Finally, CD patients frequently have additional risk factors for adverse surgical outcomes such as malnutrition, anemia, fistulae, past surgeries, and urgent indications for surgery. It is not unreasonable to assume that patients treated with anti-TNFs had more severe disease. However, it was impossible to stratify the meta-analysis results for these important confounders due to insufficient data.
Despite the aforementioned limitations, this is the first meta-analysis to summarize the impact of preoperative anti-TNF therapy on postoperative complications in CD. To date, this topic has been addressed only by retrospective studies and in most of them only a nonsignificant trend for an association could be demonstrated. However, pooling the data from these studies enabled us to reach meaningful conclusions on this important and common therapeutic dilemma. In addition, this is the first study to point out an increased susceptibility of IFX-treated CD patients to systemic (nonlocal) infectious complication. This association has not been previously reported.
This meta-analysis points out that surgery in patients treated with TNF inhibitors may be associated with an increased risk of complications, mostly attributed to nonanastomotic postoperative infectious complications. When the clinical condition of the patient allows, we suggest scheduling elective abdominal surgical interventions in CD patients as far from anti-TNF therapy as possible. The optimal interval from the last dose of anti-TNF antibody to a planned surgery remains to be defined and the potential adverse influence of treatment withdrawal should also be taken into consideration. When emergent surgery is required in a patient treated with anti-TNFs, a higher risk of complications should be expected, and prompt preventive measures should be considered. Currently, a case-by-case approach to this therapeutic dilemma should be recommended. Undoubtedly, there is a need for large randomized controlled trials stratified for patient-related, disease-related, and surgery-related confounders in order to define the best management approach for these patients.