Infliximab for Postsurgical Endoscopic Recurrence of Crohn’s Disease: No

To the Editor: We read with interest the article by Yamamoto et al on the impact of infliximab after early endoscopic postsurgical recurrence of Crohn’s disease (CD) published in the current issue of IBD. Although this study adds timely information to an exciting field, we believe that, for the time being, it should be interpreted with caution. Current knowledge on prevention of postsurgical recurrence of CD by infliximab stems from reports from our group as well as from a small randomized controlled trial (RCT) by Regueiro et al. Although these data would benefit from confirmation by a large trial, they uniformly show that therapy with this biologic—initiated immediately after surgery—prevents endoscopic and clinical recurrence of disease in the large majority of patients. By contrast, there are no published studies on the effect of intravenous infliximab therapy for early endoscopic postsurgical recurrence of CD. Recently, Biancone et al assessed the feasibility and safety of local injection of infliximab for early mucosal postoperative recurrence and concluded that the procedure is both feasible and safe, requiring a low dose. However, the histologic scores were reduced in only 4 patients, worsened in 3, and were unchanged in 1 patient. Whether these disappointing results were due to low/ unpredictable tissue levels of the drug or to its partial ineffectiveness in such a setting is unknown. The study by Yamamoto et al was conducted in 26 patients in clinical remission (defined as a Crohn’s Disease Activity Index [CDAI] score <150) after 6 months from surgery in treatment with mesalamine 3 g/day who presented endoscopic recurrence (defined as a Rutgeerts score 2) in the neoterminal ileum. Over the following 6 months, 10 patients were continuously treated with mesalamine, 8 with azathioprine (50 mg/day), and 8 with infliximab q8wk (without induction). In the latter 2 groups mesalamine was continued together with the medication under study. CDAI scores were reassessed every 2 months and endoscopy repeated after 6 months of therapy. In addition, the authors determined 3 cytokine mucosal levels (IL1b, IL-6 and TNFa) at baseline (6 months after surgery) and after 6 months of therapy. At baseline the cytokine levels were reported to be higher than in controls. The results show that after 6 months of therapy none of the patients treated with infliximab, 38% of patients treated with azathioprine, and 70% of patients treated with mesalamine had a clinical recurrence. In addition, 75% of infliximab-treated patients, 38% of azathioprine-treated patients, and none of the mesalaminetreated patients had an improvement of endoscopic inflammation. In the infliximab-treated group 38% of patients had complete mucosal healing compared to 13% in the azathioprine group and none in the mesalamine group. Finally, mucosal levels of the 3 cytokines significantly decreased after 6 months of therapy in the infliximab group, while they did not change in the azathioprine group and increased in the mesalamine group. Over and above the preliminary nature of this study, a few issues deserve comment. The choice of the authors to use clinical recurrence— defined as a CDAI score >150—at 6 months after therapy as the main outcome of the study is puzzling. The CDAI score is inaccurate, especially in the short term, as a measure of clinical remission after surgery, a context in which multiple factors may affect the patient’s well-being for several months. A higher CDAI cutoff level (i.e., 200) may or may not be more reliable. Although recurrence rates vary from study to study, overall the literature reports an 7%–25% peryear risk of symptomatic recurrence, with a 50% likelihood of recurrent symptoms by 5 years after intestinal resection (reviewed in Ref. 5). By contrast, considering a reported benefit of mesalamine over placebo of 10% (reviewed in Ref. 5), in Yamamoto et al’s study, 80% of mesalaminetreated patients had a clinical recurrence by year 1. This discrepancy may be difficult to explain even in a relatively selected population. Nevertheless, the outcome of the mesalaminetreated patients is crucial for the main conclusions of the study because the mean CDAI scores of the infliximab and azathioprine groups did not show a difference at any time. The impact of infliximab on endoscopic disease activity is, likewise, difficult to interpret since the authors judge improvement in terms of endoscopic score as well as of an unspecified ‘‘improvement in mucosal ulceration. ’’ Thus, were one to judge the results of this trial using the most objective and quantifiable parameter used by Yamamoto et al the conclusions would only be based on mucosal healing. However, mucosal healing differed by only 25% between the infliximab and azathioprine groups, a possibly significant but probably insufficient result to justify the use of biologics in this context. Given the uncertainty in the clinical and endoscopic outcomes of the study, the changes in the mucosal cytokine levels shown by the authors may bear little relevance to the issue of whether infliximab is truly effective in curing postsurgical endoscopic recurrence of CD. Indeed, although CD CopyrightVC 2009 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.20965 Published online 21 May 2009 in Wiley InterScience (www.interscience.wiley.com).