Postoperative maintenance of Crohn’s disease remission with 6-mercaptopurine, mesalamine, or placebo: A 2-year trial

doi:10.1053/j.gastro.2004.06.002

Gastroenterology

Volume 127, Issue 3, September 2004, Pages 723-729

https://doi.org/10.1053/j.gastro.2004.06.002 Get rights and content

Background & Aims: No therapy has been shown to reliably prevent the evolution of postoperative recurrence of Crohn’s disease. The aim of the current trial was to compare 6-mercaptopurine (6-MP) and mesalamine with placebo for the prevention of clinical, endoscopic, and radiographic recurrence of Crohn’s disease after resection and ileocolic anastomosis. Methods: Five centers randomized 131 patients to receive 6-MP (50 mg), mesalamine (3 g), or placebo daily in a double-blind, double-dummy trial. Patients had clinical assessments at 7 weeks and then every 3 months; colonoscopy at 6, 12, and 24 months; and small bowel series at 12 and 24 months. End points were clinical, endoscopic, and radiographic recurrence rates at 24 months. Results: Clinical recurrence rates (intent to treat) by life-table analysis at 24 months were 50% (95% confidence interval [CI], 34%–68%), 58% (95% CI, 41%–75%), and 77% (95% CI, 61%–91%) in patients receiving 6-MP, mesalamine, and placebo, respectively. Endoscopic recurrence rates were 43% (95% CI, 28%–63%), 63% (95% CI, 47%–79%), and 64% (95% CI, 46%–81%), and radiographic recurrence rates were 33% (95% CI, 19%–54%), 46% (95% CI, 29%–66%), and 49% (95% CI, 30%–72%), respectively. 6-MP was more effective than placebo (P < 0.05) at preventing clinical and endoscopic recurrence over 2 years. Patient withdrawals resulted in 69% of the study population evaluable for the clinical recurrence end point. Conclusions: 6-MP, 50 mg daily, was more effective than placebo at preventing postoperative recurrence of Crohn’s disease and should be considered as a maintenance therapy after ileocolic resection.

Section snippets

Study Design and Procedures

The study was designed as a 5-center, double-blind, placebo-controlled trial comparing fixed dosages of mesalamine or 6-MP with placebo over a 2-year postoperative period and was conducted from 1992 to 1996. Patients undergoing a first or subsequent ileocolic resection with a primary anastomosis for disease confined to the ileum and adjacent colon were eligible for enrollment. Patients were excluded if there was evidence of gross Crohn’s disease at the operative margins or in proximal or distal

Demographics

A total of 131 patients were entered into the study from the 5 sites between 1992 and 1996. Patient demographics and baseline disease characteristics are shown in Table 3. There were no statistical differences in patient age, sex, disease duration, indications for surgical resection, or preoperative disease activity among the 3 groups. There were no dosage changes of the study drugs, although 2 patients receiving 6-MP developed leukopenia, requiring withdrawal from the study.

Clinical recurrence

Intent-to-treat

Discussion

The purpose of the current study was to assess the potential of 6-MP and mesalamine in delaying or preventing postoperative recurrence of Crohn’s disease at an ileocolic anastomosis. At the time of trial initiation, prior studies had suggested potential benefit from mesalamine for prevention of relapse in quiescent Crohn’s disease but primarily for the prevention of postoperative recurrence.¹⁸ Dosages used in these maintenance trials ranged between 1.5 and 3 g daily. However, a recently

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In the meta-analysis of IPD, 645 participants from 6 studies were included. In the total population, a superior effect was demonstrated for anti-TNF-α compared with thiopurine prophylaxis for ER (relative risk [RR], 0.52; 95% confidence interval [CI], 0.33–0.80), clinical recurrence (RR, 0.50; 95% CI, 0.26–0.96), and severe ER (RR, 0.41; 95% CI, 0.21–0.79). No differential subgroup effects were found for ER. In Poisson regression analysis, previous exposure to anti-TNF-α and penetrating disease behavior were associated with ER risk. The advantage of anti-TNF-α agents as compared with thiopurines was observed in low- and high-risk groups.
Anti-TNF-α is superior to thiopurine prophylaxis for the prevention of endoscopic and clinical postoperative CD recurrence after ileocolonic resection. The advantage of anti-TNF-α agents was confirmed in subgroup analysis and after risk stratification.
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Vitamin D deficiency is common in Crohn’s disease (CD). High-dose vitamin D had anti-inflammatory effects in preclinical studies and trials of patients with CD. We performed a randomized trial to determine whether high-dose vitamin D prevents postoperative recurrence of CD after ileocolonic resection.
Patients with CD after ileocolonic resection with ileocolonic anastomosis were assigned randomly to groups given weekly 25,000 IU oral vitamin D (n = 72) or placebo (n = 71) for 26 weeks, at 17 hospitals in The Netherlands and Belgium, from February 2014 through June 2017. Patients were assessed at baseline and at weeks 2, 6, 12, and 26 for laboratory and clinical parameters, and underwent ileocolonoscopy at 26 weeks. The primary end point was endoscopic recurrence (modified Rutgeerts score, ≥i2b, as assessed by blinded readers) at 26 weeks. Secondary end points included clinical recurrence (Crohn’s disease activity index, ≥220), quality of life (measured by the 36-Item Short Form Health Survey, Inflammatory Bowel Disease Questionnaire, and EuroQol, a 5-dimension questionnaire), and outcomes associated with the baseline serum concentration of vitamin D.
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: Supported by a research grant from the Crohn’s and Colitis Foundation of America and the David and Reva Logan GI Research Center at the University of Chicago. Study drugs and matching placebo were provided by Marion Merrill Dow (mesalamine) and Burroughs Wellcome (6-mercaptopurine).

¹: S.B.H. was a prior consultant and member of the speakers’ bureau for Marion Merrill Dow.

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Clinical-alimentary tractPostoperative maintenance of Crohn’s disease remission with 6-mercaptopurine, mesalamine, or placebo: A 2-year trial

Section snippets

Study Design and Procedures

Demographics

Clinical recurrence

Discussion

Gastroenterol Clin North Am

Gastroenterology

Baillieres Clin Gastroenterol

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Am J Gastroenterol

Gastroenterology

Gastroenterology

Gastroenterology

Reoperation and recurrence in Crohn’s colitis and ileocolitiscrude and cumulative rates

N Engl J Med

Clinical-alimentary tract
Postoperative maintenance of Crohn’s disease remission with 6-mercaptopurine, mesalamine, or placebo: A 2-year trial