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Editor,—We read with interest the recent clinical @lert commentary by Rutgreerts (OpenUrlCrossRefPubMedWeb of Science) analysing the recently published study by Lochs and colleagues.1 Lochset al concluded that compared with placebo, 18 months of treatment with high dose Pentasa (mesalazine 4 g/day) made no difference to postoperative recurrence rates in patients with Crohn's disease involving the small intestine and colon or colon alone (26.3% v 25.6% for mesalazine and placebo, respectively). We feel that the study raises many new questions with regards to the role of 5-aminosalicylate (5-ASA) formulations in the prevention of postoperative Crohn's relapse. Furthermore, the study is not as negative as it first appears. Although in general terms the trial is well designed and includes a large number of patients (n=318), analysis of the results still presents a number of problems. Firstly, Lochs et al did not attempt to subgroup patients on the basis of the type of operation performed. This may be critical. It has been shown that the type of anastomosis performed at operation in Crohn's patients profoundly affects the efficacy and pharmacokinetics of 5-ASA formulations, possibly as a result of differential effects on intestinal transit time.2Secondly, for a number of reasons, including all disease sites (small and large bowel) in a single analysis may disguise subgroups of patients who benefit from treatment. In fact, the study of Lochset al provides extremely encouraging information with regard to the effects of mesalazine on postoperative recurrence in patients with disease limited to the small bowel. This subgroup of patients (37.8% of patients included, n=124) showed a significant improvement in relapse rates with mesalazine treatment (21.8% v 39.7% for placebo and mesalazine, respectively; p=0.002), a fact overshadowed in the overall analysis. This may reflect differences in disease behaviour between patients or may raise questions with regard to the appropriateness of using the same 5-ASA preparation for all disease sites.3 ,4 The extremely high dropout rate in the study of Lochsat al is also worthy of comment. A total of 131 of 318 randomised patients were protocol violators. Meta-analysis of previous randomised controlled trials concerned with 5-ASA use in the prevention of postoperative relapse report much lower dropout rates (64/304).5
We feel that the data of Lochs et al merit further trials in this area. Future trials need to focus on defined subgroups of operations and on subgroups of patients with Crohn's disease affecting different bowel sites. The use of single drug formulations appropriate to the sites affected would obviously be desirable and might permit lower doses to be used with consequent lower patient dropout rates. Such studies would be a logistic challenge requiring a multicentre design to recruit sufficient numbers of patients. However, we feel it would be a worthwhile exercise as postoperative recurrence is a devastating complication in Crohn's disease and it would be a shame to miss any relatively simple and non-toxic opportunity to avoid it.