CHU de Bicêtre, Service de Gastroentérologie, APHP-Université Paris Sud, Le Kremlin Bicêtre, France; CHU de Besançon, Hôpital Jean Minjoz, Service de Gastroentérologie, Besançon, France.
Helmsley Inflammatory Bowel Disease Center, Icahn Medical School of Medicine at Mount Sinai, New York, New York.
Gastroenterology. 2016 Feb;150(2):380-8.e4. doi: 10.1053/j.gastro.2015.10.050. Epub 2015 Nov 26.
BACKGROUND & AIMS: Parenteral methotrexate is an effective treatment for patients with Crohn's disease, but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC.
We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/wk) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe from 2007 through 2013. Patients were given prednisone (10 to 40 mg/d) when the study began and were randomly assigned to groups (1:1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary end point was steroid-free remission (defined as a Mayo score ≤2 with no item >1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore ≤2 with no item >1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24.
Steroid-free remission at week 16 was achieved by 19 of 60 patients given methotrexate (31.7%) and 10 of 51 patients given placebo (19.6%)--a difference of 12.1% (95% confidence interval [CI]: -4.0% to 28.1%; P = .15). The proportion of patients in steroid-free clinical remission at week 16 was 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI: 1.1% to 35.2%; P = .04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group--a difference of 9.5% (95% CI: -7.5% to 26.5%; P = .28). No differences were observed in other secondary end points. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7%; P = .03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9%; P = .006).
In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC. ClinicalTrials.gov ID NCT00498589.
肠外甲氨蝶呤是治疗克罗恩病患者的有效方法，但在溃疡性结肠炎（UC）患者中尚未得到充分评估。我们进行了一项随机对照试验，以确定其在类固醇依赖性 UC 患者中的安全性和疗效。
我们在 2007 年至 2013 年间在欧洲的 26 个医学中心进行了一项双盲、安慰剂对照试验，评估了肠外甲氨蝶呤（25mg/周）在 111 例类固醇依赖性 UC 患者中的疗效。研究开始时，患者给予泼尼松龙（10-40mg/d），并随机分为两组（1:1），分别给予安慰剂或甲氨蝶呤（肌内或皮下，每周 25mg）24 周。主要终点是在第 16 周达到无类固醇缓解（定义为 Mayo 评分≤2，无任何项目>1，且完全停用类固醇）。次要终点包括第 16 周和/或第 24 周时无类固醇的临床缓解（定义为 Mayo 临床评分≤2，无任何项目>1）和内镜下无类固醇愈合，第 24 周时无类固醇缓解，第 16 周和第 24 周时均缓解。
在第 16 周，60 例接受甲氨蝶呤治疗的患者中有 19 例（31.7%）和 51 例接受安慰剂治疗的患者中有 10 例（19.6%）达到无类固醇缓解，差异为 12.1%（95%可信区间[CI]：-4.0%至 28.1%；P=.15）。第 16 周时无类固醇临床缓解的患者比例在甲氨蝶呤组为 41.7%，安慰剂组为 23.5%，差异为 18.1%（95%CI：1.1%至 35.2%；P=.04）。第 16 周时无类固醇内镜愈合的患者比例在甲氨蝶呤组为 35%，安慰剂组为 25.5%，差异为 9.5%（95%CI：-7.5%至 26.5%；P=.28）。其他次要终点未见差异。因不良事件（主要是 UC 引起的）而退出研究的安慰剂组患者（47.1%）多于接受甲氨蝶呤治疗的患者（26.7%；P=.03）。甲氨蝶呤组恶心和呕吐的患者比例（21.7%）高于安慰剂组（3.9%；P=.006）。
在一项随机对照试验中，肠外甲氨蝶呤在诱导 UC 患者无类固醇缓解方面并不优于安慰剂。然而，甲氨蝶呤在无类固醇的情况下诱导了临床缓解，在更大比例的患者中实现了这一目标，从而减少了因活动性 UC 而退出治疗的患者数量。临床试验.gov 注册号 NCT00498589。
