Preventing Postoperative Recurrence in Crohnʼs Disease With 6-Mercaptopurine and Azathioprine: Approaching the Cutting Edge

Postoperative Maintenance of Crohn's Disease Remission With 6-Mercaptopurine, Mesalamine, or Placebo: A 2-Year Trial. Hanauer SB, Korelitz BI, Rutgeerts P, et al. Gastroenterology. 2004;127:723-729. Hanauer SB Korelitz BI Rutgeerts P et al. Gastroenterology. 2004 127 723–729 Azathioprine and Mesalamine for Prevention of Relapse After Conservative Surgery for Crohn's Disease. Ardizzone S, Maconi G, Sampietro GM, et al. Gastroenterology. 2004;127:730-740. Ardizzone S Maconi G Sampietro GM et al. Gastroenterology. 2004 127 730–740 The natural history of Crohn's disease (CD) after bowel resection and primary intestinal anastomosis is well known. Recurrence rates vary depending on whether recurrence is defined as clinical, endoscopic, or surgical. The high rates of surgery and of subsequent postoperative recurrence in CD and the effect this has on patient quality of life underscores the importance of finding effective preventive medical therapies. In the September 2004 issue of Gastroenterology, the results of 2 large prospective studies evaluating 6-mercaptopurine (6-MP) and mesalamine (Hanauer et al) and azathioprine (AZA) and mesalamine (Ardizonne et al) in preventing postoperative recurrence after 2 years are reported. These trials differ significantly in their design and patient population and report contrasting results. Hanauer et al randomized 131 patients to receive 6-MP 50 mg/d, mesalamine 3 g/d, or placebo for 2 years after ileal and adjacent colon resection with primary ileocolic anastomosis. Patients with macroscopic involvement of the surgical margins were excluded. After 2 years, clinical relapse rates (intention-to-treat) for 6-MP, mesalamine, and placebo were 50%, 58%, and 77%, and endoscopic recurrence rates (Rutgeerts endoscopic score >1) were 43%, 63%, and 64%, respectively. 6-MP was superior to placebo at preventing postsurgical clinical relapse [hazard ratio (HR), 0.52; P = 0.045] and endoscopic recurrence (HR, 0.48; P = 0.03). Reduction of endoscopic recurrence was seen in the subgroup of patients with perforating-type disease receiving 6-MP versus placebo (P = 0.03). There was a high number of withdrawals in the study. Information on smoking was unavailable. Ardizonne et al conducted an open-label trial in which 142 patients were randomized to receive AZA 2 mg/kg/d or mesalamine 3 g/d for 2 years after conservative surgery for CD. The patient population differed significantly from the previous study with patients who had undergone minimal bowel resection and/or stricturoplasty and therefore could have residual disease. The endpoints were clinical relapse as defined by a CD activity index >200 and reoperation. Endoscopic recurrence was not considered given macroscopic lesions were already present. The rates of clinical and surgical recurrence were 17% and 6% in the AZA-treated patients and 28% and 10% in the mesalamine group. There was no significant difference between mesalamine and AZA in preventing clinical relapse in the intention-to-treat analysis [HR, 1.63; 95% confidence interval (CI), 0.79-3.35] or in preventing surgical relapse. In the subgroup of patients with previous bowel resections, mesalamine-treated patients had a significantly higher risk of clinical relapse than those who received AZA (HR, 3.16; 95% CI, 1.14-8.79). In the stepwise logistic regression, mesalamine treatment was an independent predictor of clinical relapse. There was a greater withdrawal rate caused by adverse events in patients on AZA. Smoking did not seem to influence the risk of relapse in either treatment group. Comment: To date, there has not been any accepted medical therapy that reliably prevents recurrence of CD after surgery. The 5-aminosalicylates have been evaluated the most extensively in this setting and have been shown to be of marginal or no benefit.1,2 Corticosteroids are not proven useful for postoperative prophylaxis, although budesonide was found to reduce endoscopic recurrence in patients with inflammatory but not fibrostenotic disease.3 Imidazole antibiotics may reduce severe endoscopic recurrences and delay clinical relapse.4,5 The probiotic lactobacillus GG is of no benefit in reducing endoscopic recurrence.6 The known efficacy of the purine antimetabolites 6-MP and AZA in maintaining medically induced remissions and their steroid-sparing effect in CD make these prime therapeutic candidates after surgery.7,–9 The prospective evaluation of 6-MP and AZA in this setting has long been awaited. The investigators should be commended for carrying out 2 comprehensive trials of such scope and duration. Nevertheless, certain issues arise in these studies that may impact on the reported results. In the study by Hanauer et al, the suboptimal fixed dose of 6-MP (chosen to minimize toxicity) and mesalamine, the high number of withdrawals, and the high rate of clinical relapse in the placebo arm may have affected the therapeutic benefit obtained from these agents. The finding of a greater clinical than endoscopic relapse rate was unexpected and inconsistent with the literature. This may reflect the inaccuracy of the clinical scale used (which was not validated) and may suggest symptoms were because of other causes than CD. In evaluating the more robust outcome of endoscopic recurrence, 6-MP was superior to placebo in reducing overall endoscopic lesions (Rutgeerts endoscopic score >1) arising in the neoterminal ileum. However, there was no benefit of 6-MP over placebo in avoiding moderately severe endoscopic lesions (Rutgeerts endoscopic score >2). This is the group that would be at greatest risk of symptomatic recurrence in the subsequent years.10 The study by Ardizonne et al used an open-label, unblinded study design, and all patients seemed to have been recruited from a single gastrointestinal unit. These factors in the study design may introduce bias. The AZA dose used was close to what is considered optimal, but there were more adverse events leading to study withdrawal. The more robust endpoint of endoscopic recurrence could not be assessed because of the conservative nature of the surgery, after which there was residual macroscopic disease. Nonetheless, this study offered insight on a patient population that is not traditionally evaluated in postoperative therapeutic trials but is common in clinical practice. So where do clinicians stand with the use of purine antimetabolites to prevent postoperative CD recurrence? These studies are an important first step in defining the role of 6-MP and AZA in the prevention of postsurgical relapse. Given the various issues raised and the seemingly contrasting results, these 2 trials do not provide the absolute answer. Taken together, however, there are sufficient findings in these studies that suggest 6-MP and AZA are promising preventive agents in the postsurgical setting. More definitive clinical trials, however, are required. These should evaluate homogeneous patient populations identified as being at higher risk of recurrence based on clinical (e.g., smokers, multiple previous bowel resections, and perforating-type disease) and possibly biologic and genetic markers. Higher doses of antimetabolites should be evaluated with the use of 6-MP metabolite measurements to ensure adherence and optimize drug safety and efficacy.

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