PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of f1000medLatest ContentReportsReportsReports
 
F1000 Med Rep. 2009; 1: 10.
Published online 2009 January 21. doi:  10.3410/M1-10
PMCID: PMC2920702

Does infliximab increase complications after surgery for inflammatory bowel disease?

Abstract

Conflicting data exist regarding the association between pre-operative monoclonal anti-tumor necrosis factor-alpha antibody therapy with infliximab for Crohn disease and chronic ulcerative colitis, and the occurrence of post-operative complications. This report reviews the current literature that supports and refutes this association.

Introduction and context

Gastroenterologists and surgeons who specialize in the treatment of Crohn disease (CD) and chronic ulcerative colitis (CUC) have become increasingly aware of the implications of different forms of medical therapy on surgical outcomes. This is especially important in the era of ‘top-down’ and multi-agent therapy for inflammatory bowel disease (IBD) [1,2]. Although relatively little literature exists regarding the relationship between pre-operative corticosteroid use and post-operative complications, several authors have found that increasingly higher doses of such immunosuppressive medications may result in an increased rate of post-operative septic complications [3,4]. Similarly, there is increasing concern that combination immunomodulatory therapy with multiple agents may also be associated with an increase in post-operative infectious complications [5,6]. Given reports of the association of monoclonal anti-tumor necrosis factor-alpha (anti-TNF-α) antibody therapy with pulmonary infections, this concern has specifically been focused on infliximab (IFX), which until recently has been the only FDA-approved biologic agent for IBD [7-11].

A recent meta-analysis of the association between immunomodulatory therapy and post-operative complications after surgery for IBD, which included studies of azathioprine, cyclosporine A, and three studies of IFX, found that the available evidence did not support this association [12]. Since then, several studies have been published suggesting that IFX is indeed associated with an increased risk of post-operative complications [12]. Thus, the potential association between IFX and surgical complications is controversial; studies both support and refute this potential relationship [5,13-19]. This F1000 Medicine Report will review the major findings of these studies.

Recent advances

Crohn disease

In a study of 270 patients by Colombel et al. [14], 52 patients experienced intra-abdominal septic complications (IASCs) after bowel resection for CD. Analysis did not reveal any increased risk in the IFX-treated subgroup, the moderate-to-high-dose corticosteroid subgroup, or the immunomodulator subgroup. Likewise, a matched case-control study from Belgium of 31 CD patients also concluded that pre-operative IFX use did not result in a significantly increased rate of post-operative complications, or increased hospital length of stay, as compared to a control group of IFX-naïve patients [15]. That study did note, however, a trend towards increased early post-operative infections in the IFX group. More recently, a study of 413 IBD patients (156 with CD), of which 101 had received IFX within 12 weeks of surgery, also did not find any relationship between pre-operative IFX therapy and post-operative complications [18]. That study, similar to others, was relatively limited by the absolute number of complications.

In contrast, a more recent study from Appau et al. [17] found an association between pre-operative IFX therapy for CD and post-operative complications. They concluded that IFX therapy within 3 months of surgery was associated with an increased rate of IASCs, and of hospital re-admissions. They also found that patients who received a diverting stoma had a lower risk of IASCs, thus prompting the observation that a diverting stoma may be prudent when surgeons are faced with CD patients who have recently received IFX. In light of this study, the risks associated with stoma reversal surgery must be weighted against the potential increase in complications associated with IFX for CD.

Chronic ulcerative colitis

In a study of 151 patients with CUC, 17 (10%) of whom failed IFX therapy and went to surgery and 134 of whom were IFX-naïve, no association between IFX and complications was observed [5]. However, the authors observed that IFX patients who had concurrent cyclosporine A treatment were at increased risk for overall and infectious complications.

In a larger study by Selvasekar et al. [16] in which 47 CUC patients received pre-operative [ileal pouch-anal anastomosis (IPAA)] IFX therapy and 254 did not, those who received IFX were more likely to have anastomotic leak, and after multivariate adjustment for both disease severity and other medication use, IFX remained independently associated with an increased risk of ileal pouch-related and infectious complications [16]. Finally, a recent study of 85 patients with CUC who received IFX pre-operatively also found that patients who receive pre-operative IFX were at increased risk of post-operative septic complications as well as late complications [19]. Importantly, the authors also noted that patients who received IFX were more likely to have undergone a 3-stage IPAA, likely due to surgeon reluctance to perform an anastomosis in the setting of pre-operative IFX administration.

Common limitations

Many of these retrospective studies suffer from common limitations. First is lack of adjustment for disease severity (Table 1). Disease severity determined retrospectively is often inaccurate and surrogate covariates may be inadequate substitutions for validated methods of assessing disease activity. However, it is interesting to note that in the studies of CUC, those that adjusted for disease activity showed a relationship between IFX and complications, while the converse was true for those studies that did not. Another major limitation of several of these studies is the relatively long pre-operative IFX window, often 12 weeks or more (Table 1). Recent studies of the pharmacokinetics of IFX in IBD suggest that the elimination half-life is between 7 and 18.5 days [20,21]. By 12 weeks (84 days, or 4.5 half-lives), most IBD patients should have undetectable levels of IFX. A window of 12 weeks used by several of the studies published to date may theoretically produce negative results regarding the occurrence of post-operative outcomes if a significant proportion of patients had an interval this long between IFX administration and surgery. Ideally, the duration between last infusion and surgery should be included as a continuous variable, but outpatient infusion often makes these data unavailable retrospectively.

Table 1.
Summary of literature of the association of IFX with post-operative complications

Referral practice patterns may too account in part for the heterogenous findings of these studies, as these may differ substantially in various regions of the world, as demonstrated by at least a 10% variation in the proportion of surgical IBD patients who received IFX. Thus, as is usually true of most retrospective studies, results from a single institution may not be broadly generalizable; the institutions themselves may be considered as a potential confounding factor when comparing results of different studies to each other.

In one of the largest studies of the association of IFX and serious infections and mortality, the TREAT Registry study of 6290 patients found that after adjustment for corticosteroid use and disease severity, IFX was not independently associated with increased risk, although both corticosteroids and disease severity were associated with those adverse outcomes [22]. Although this study did not include surgical endpoints, the implications are nonetheless important, especially given the lack of large-scale surgical data.

Implications for clinical practice

Whether pre-operative IFX use is associated with post-operative complications after surgery for IBD remains controversial; current evidence favors this association after surgery for CUC but does not favor an increased risk after surgery for CD. The potentially practice-changing implications of this debate are occurring now; increasingly some surgeons are waiting until anti-TNF-α agents are washed out before operating or, if that is not possible, performing resections for CD with temporary diverting stomas or advising 3- rather than 2-staged IPAA.

Larger studies and/or formal meta-analysis of the relationship between IFX and post-operative complications after surgery for IBD are needed before definitive treatment recommendations can be made. The decision of whether or not to perform staged surgery for IBD patients on IFX needs to be made on an individual basis, based on the clinical context and other known risk factors, such as hypoalbuminemia and high-dose corticosteroid treatment.

Abbreviations

CD
Crohn disease
CUC
chronic ulcerative colitis
IASC
intra-abdominal septic complication
IBD
inflammatory bowel disease
IFX
infliximab
IPAA
ileal pouch anal anastomosis
TNF
tumor necrosis factor

Notes

The electronic version of this article is the complete one and can be found at: http://F1000.com/Reports/Medicine/content/1/10

Notes

Competing interests

The authors declare that they have no competing interests.

References

1. Baert F, Caprilli R, Angelucci E. Medical therapy for Crohn's disease: top-down or step-up? Dig Dis. 2007;25:260–6. doi: 10.1159/000103897. [PubMed] [Cross Ref]
2. Velayos FS, Sandborn WJ. Positioning biologic therapy for Crohn's disease and ulcerative colitis. Curr Gastroenterol Rep. 2007;9:521–7. doi: 10.1007/s11894-007-0069-1. [PubMed] [Cross Ref]
3. Mahadevan U, Loftus EV, Jr, Tremaine WJ, Pemberton JH, Harmsen WS, Schleck CD, Zinsmeister AR, Sandborn WJ. Azathioprine or 6-mercaptopurine before colectomy for ulcerative colitis is not associated with increased postoperative complications. Inflamm Bowel Dis. 2002;8:311–6. doi: 10.1097/00054725-200209000-00001. [PubMed] [Cross Ref]
4. Lim M, Sagar P, Abdulgader A, Thekkinkattil D, Burke D. The impact of preoperative immunomodulation on pouch-related septic complications after ileal pouch-anal anastomosis. Dis Colon Rectum. 2007;50:943–51. doi: 10.1007/s10350-007-0246-1. [PubMed] [Cross Ref]
5. Schluender SJ, Ippoliti A, Dubinsky M, Vasiliauskas EA, Papadakis KA, Mei L, Targan SR, Fleshner PR. Does infliximab influence surgical morbidity of ileal pouch-anal anastomosis in patients with ulcerative colitis? Dis Colon Rectum. 2007;50:1747–53. doi: 10.1007/s10350-007-9008-3. [PubMed] [Cross Ref]
6. Zmora O, Khaikin M, Pishori T, Pikarsky A, Dinnewitzer A, Weiss EG, Nogueras JJ, Wexner SD. Should ileoanal pouch surgery be staged for patients with mucosal ulcerative colitis on immunosuppressives? Int J Colorectal Dis. 2007;22:289–92. doi: 10.1007/s00384-006-0168-8. [PubMed] [Cross Ref]
7. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, Siegel JN, Braun MM. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med. 2001;345:1098–104. doi: 10.1056/NEJMoa011110. [PubMed] [Cross Ref] F1000 Factor 6.4 Must Read
Evaluated by Stefan Kaufmann 21 Nov 2001, David Chaplin 27 Nov 2001
8. Wallis RS, Broder MS, Wong JY, Hanson ME, Beenhouwer DO. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis. 2004;38:1261–5. doi: 10.1086/383317. [PubMed] [Cross Ref]
9. Strangfeld A, Listing J. Infection and musculoskeletal conditions: Bacterial and opportunistic infections during anti-TNF therapy. Best Pract Res Clin Rheumatol. 2006;20:1181–95. doi: 10.1016/j.berh.2006.08.010. [PubMed] [Cross Ref]
10. Imaizumi K, Sugishita M, Usui M, Kawabe T, Hashimoto N, Hasegawa Y. Pulmonary infectious complications associated with anti-TNFalpha therapy (infliximab) for rheumatoid arthritis. Intern Med. 2006;45:685–8. doi: 10.2169/internalmedicine.45.1623. [PubMed] [Cross Ref]
11. Dweik M, Baethge BA, Duarte AG. Coccidioidomycosis pneumonia in a nonendemic area associated with infliximab. South Med J. 2007;100:517–8. [PubMed]
12. Subramanian V, Pollok RC, Kang JY, Kumar D. Systematic review of postoperative complications in patients with inflammatory bowel disease treated with immunomodulators. Br J Surg. 2006;93:793–9. doi: 10.1002/bjs.5375. [PubMed] [Cross Ref]
13. Tay GS, Binion DG, Eastwood D, Otterson MF. Multivariate analysis suggests improved perioperative outcome in Crohn's disease patients receiving immunomodulator therapy after segmental resection and/or strictureplasty. Surgery. 2003;134:565–72. discussion 572-3. [PubMed]
14. Colombel JF, Loftus EV, Tremaine WJ, Pemberton JH, Wolff BG, Young-Fadok T, Harmsen WS, Schleck CD, Sandborn WJ. Early postoperative complications are not increased in patients with Crohn's disease treated perioperatively with infliximab or immunosuppressive therapy. Am J Gastroenterol. 2004;99:878–83. doi: 10.1111/j.1572-0241.2004.04148.x. [PubMed] [Cross Ref]
15. Marchal L, D'Haens G, Van Assche G, Vermeire S, Noman M, Ferrante M, Hiele M, Bueno De Mesquita M, D'Hoore A, Penninckx F, Rutgeerts P. The risk of post-operative complications associated with infliximab therapy for Crohn's disease: a controlled cohort study. Aliment Pharmacol Ther. 2004;19:749–54. doi: 10.1111/j.1365-2036.2004.01904.x. [PubMed] [Cross Ref]
16. Selvasekar CR, Cima RR, Larson DW, Dozois EJ, Harrington JR, Harmsen WS, Loftus EV, Jr, Sandborn WJ, Wolff BG, Pemberton JH. Effect of infliximab on short-term complications in patients undergoing operation for chronic ulcerative colitis. J Am Coll Surg. 2007;204:956–62. doi: 10.1016/j.jamcollsurg.2006.12.044. discussion 962-3. [PubMed] [Cross Ref]
17. Appau KA, Fazio VW, Shen B, Church JM, Lashner B, Remzi F, Brzezinski A, Strong SA, Hammel J, Kiran RP. Use of infliximab within 3 months of ileocolonic resection is associated with adverse postoperative outcomes in Crohn's patients. J Gastrointest Surg. 2008;12:1738–14. doi: 10.1007/s11605-008-0646-0. [PubMed] [Cross Ref]
18. Kunitake H, Hodin R, Shellito PC, Sands BE, Korzenik J, Bordeianou L. Perioperative treatment with infliximab in patients with Crohn's disease and ulcerative colitis is not associated with an increased rate of postoperative complications. J Gastrointest Surg. 2008;12:1730–6. discussion 1736-7. [PubMed]
19. Mor IJ, Vogel JD, Moreira Ada L, Shen B, Hammel J, Remzi FH. Infliximab in ulcerative colitis is associated with an increased risk of postoperative complications after restorative proctocolectomy. Dis Colon Rectum. 2008;51:1202–7. doi: 10.1007/s10350-008-9364-7. discussion 1207-10. [PubMed] [Cross Ref]
20. Klotz U, Teml A, Schwab M. Clinical pharmacokinetics and use of infliximab. Clin Pharmacokinet. 2007;46:645–60. doi: 10.2165/00003088-200746080-00002. [PubMed] [Cross Ref]
21. Ternant D, Aubourg A, Magdelaine-Beuzelin C, Degenne D, Watier H, Picon L, Paintaud G. Infliximab pharmacokinetics in inflammatory bowel disease patients. Ther Drug Monit. 2008;30:523–9. [PubMed]
22. Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, Chen DM, Pritchard ML, Sandborn WJ. Serious infections and mortality in association with therapies for Crohn's disease: TREAT registry. Clin Gastroenterol Hepatol. 2006;4:621–30. doi: 10.1016/j.cgh.2006.03.002. [PubMed] [Cross Ref]

Articles from F1000 Medicine Reports are provided here courtesy of Faculty of 1000 Ltd