Abstract
Purpose
The impact of infliximab (IFX) on postoperative complications in surgical patients with Crohn’s disease (CD) and ulcerative colitis (UC) is unclear. We examined a large patient cohort to clarify whether a relationship exists between IFX and postoperative complications.
Methods
A total of 413 consecutive patients—188 (45.5%) with suspected CD, 156 (37.8%) with UC, and 69 (16.7%) with indeterminate colitis—underwent abdominal surgery at the Massachusetts General Hospital between January 1993 and June 2007. One hundred one (24.5%) had received preoperative IFX ≤ 12 weeks before surgery. These patients were compared to those who did not receive IFX with respect to demographics, comorbidities, presence of preoperative infections, steroid use, and nutritional status. We then compared the cumulative rate of complications for each group, which included deaths, anastomotic leak, infection, thrombotic complications, prolonged ileus/small bowel obstruction, cardiac, and hepatorenal complications. Potential risk factors for infectious complications including preexisting infection, pathological diagnosis, and steroid or IFX exposure were further evaluated using logistic regression analysis.
Results
Patients were similar with respect to gender (IFX = 40.6% men vs. non-IFX = 51.9%, p = 0.06), age (36.1 years vs.37.8, p = 0.43), Charlson Comorbidity Index (5.3 vs. 5.7, p = 0.25), concomitant steroids (75.3% vs. 76.9%, p = 0.79), preoperative albumin level (3.3 vs. 3.2, p = 0.36), and rate of emergent surgery (3.0% vs. 3.5%, p = 1.00). IFX patients had higher rates of CD (56.4% vs. 41.9%, p = 0.02), concomitant azathioprine/6-mercaptopurine use (34.6% vs. 16.6%, p < 0.0001), and lower rates of intra-abdominal abscess (3.9% vs. 11%, p < 0.05). After surgery, the two groups had similar rates of death (2% vs. 0.3% p = 0.09), anastomotic leak (3.0% vs. 2.9%, p = 0.97), cumulative infections (5.97% vs. 10.1%, p = 1), thrombotic complications (3.6% vs. 3.0%, p = 0.06), prolonged ileus/small bowel obstructions (3.9 vs. 2.8, p = 0.59), cardiac complications (1% vs. 0.6%, p = 0.42), and hepatic or renal complications (1.0 vs. 0.6% p = 0.72). A logistic regression model was then created to assess the impact of IFX, as well as other potential risk factors, on the rates of cumulative postoperative infections. We found that steroids (odds ratio [OR] = 1.2, p = 0.74), IFX (OR 2.5, p = 0.14), preoperative diagnosis of CD (OR = 0.7, p = 0.63) or UC (OR = 0.6, p = 0.48), and preoperative infection (OR = 1.2, p = 0.76) did not affect rates of clinically important postoperative infections.
Conclusions
Preoperative IFX was not associated with an increased rate of cumulative postoperative complications.
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Discussion
Andreas M. Kaiser, M.D. (Los Angeles, CA): Dr. Kunitake, thank you very much for your excellent presentation and certainly for the privilege to be the first to offer my comments.
The question that you raise in your paper is definitely a very important one, as surgeons are increasingly confronted with patients who are in need of surgery but are being treated with biological immunosuppressants. Your data – at first - seem to be reassuring. However, in light of the other studies that are out there (including e.g. the one following with the next presentation) that have suggested an increased risk with infliximab, one should remain very cautious and be careful with the interpretation. Most notably, it is crucial to look for causes of the observed variance. Even if the difference in your study was not statistically significant, the infliximab showed an odds ratio of 2.5 for infectious complications, which seems relevant given that there were more abscesses in the non-infliximab group to begin with. The other point is that the cohort size, even though it is very large compared to other studies, may still be too small and too little powered to detect such a significant difference between the different groups.
Another point that you should consider is that infliximab - depending on the circumstances - may be one of the confounding factors itself: e.g., there may on one hand be situations where the infliximab increases the risk if you compare it to a normal immune system. On the other hand, there may be different circumstances where the infliximab improves the overall morbidity or complication rate if a very bad disease is ameliorated prior to surgery and a sick patient is turned into a much better patient.
So I have a couple of questions that you may not yet have looked at but that you may want to look at in the future. First, did you look at the different subtypes of operations and try to find out whether there is a difference whether you did an ileoanal or whether you did a stricturoplasty? Second, did you look at the different diseases as such? And third, did you consider looking at the interval when the infliximab was actually delivered? You chose a cut-off time point of 12 weeks, but it may be that if you chose it closer to the infliximab administration between, let’s say, zero to six weeks as compared to six to 12 weeks that there might have been a difference.
Thank you very much again and congratulations to your excellent work.
Hiroko Kunitake, M.D. (Boston, MA): These are excellent questions. Certainly I think your first point is a very valid one, which is that we have to look at this data with caution. Our study, although it is the largest study thus far, only has 101 patients in the infliximab group, and we calculated that we need at least 250 in the infliximab group in order to power our study well. So certainly this is preliminary data, but we are glad to present our results.
Now to your questions: You asked if we had looked at the influence of infliximab on the choice of operations performed. We have begun to look at this and hope to soon be able to answer this question.
Regarding the effect of infliximab on patients with Crohn’s compared to those with ulcerative colitis. Certainly in the literature thus far, most studies look separately at Crohn’s patients and ulcerative colitis patients, and we initially did that as well. However, we found that there was no statistically significant difference in the rate of infection for each of these groups, and therefore in order to improve our numbers, we combined the two groups together, and we felt confident in doing that.
Finally, your question about the interval between infliximab treatment and surgery. I agree, many of these papers use two months or three months as a cutoff, but in fact when you look at their patient population, many of their patients were treated outside of that three-month period. For our study, we tried to include all patients with infliximab exposure within three months of surgery, because it is generally felt that infliximab is cleared in two months. So we included patients that were treated with infliximab within three months and we found results, which, quite frankly, we were a little bit surprised at. We were expecting to see a higher rate of infection with infliximab, but we did not.
Yoram Bouhnik, M.D. (Clichy, France): Thank you for this great presentation. Your data are very interesting. I would like to know if in infliximab-treated patients, some of them were treated not instead of surgery but as an “adjuvant therapy” before surgery, for example, to decrease the length of an ileal resection or to decrease the risk of temporary stoma, and if it was the case, if you have some results in this specific subgroup.
Dr. Kunitake: Thank you for your question. I hope I understand correctly that you are questioning whether or not infliximab is used as an alternative to surgery or not. On Monday we heard Dr. Bruce Sands and Dr. Richard Hodin speaking about the approach used at our institution which is that infliximab is used only when all other medical therapies have failed. Although many patients would prefer to postpone surgery as much as possible, there is very close collaboration between our gastroenterologists and surgeons and certainly when it is felt that the patient requires surgery, this is pursued.
Rosamaria Bozzi, M.D. (Naples, Italy): I wish to ask you in the patients that receive infliximab, what is the dose? They give infusions at zero to six weeks and then maintenance at eight weeks, and how many patients did make the maintenance of eight weeks? In Italy we give infliximab regularly, but when we have sub-obstructive symptoms or like sub-obstructive symptoms, we go directly to surgery, and we don’t see other characteristic postoperative complications after the infliximab infusion. We prefer to perform surgery in patients with Crohn’s or UC in high grade.
Dr. Kunitake: Thank you for your question. Our infliximab dosing is usually 5 mg/kg every eight weeks. There are some occasions where it has actually been increased to 10 mg/kg in a few patients to see if their response is better.
As far as the use of infliximab, I think what you are suggesting is that once they get to the point where there is definite stricture, infliximab should not be used because it will not be effective. I would like to say again that there is very close collaboration between gastroenterology and surgery at our institution such that if it is felt that these strictures are not resolvable with further medical management, our patients are taken to surgery.
Dr. Sands has received research grants and honoraria for lecturing and consulting from Centocor.
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Kunitake, H., Hodin, R., Shellito, P.C. et al. 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 12, 1730–1737 (2008). https://doi.org/10.1007/s11605-008-0630-8
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DOI: https://doi.org/10.1007/s11605-008-0630-8