Methotrexate Is Not Superior to Placebo for Inducing Steroid-Free Remission, but Induces Steroid-Free Clinical Remission in a Larger Proportion of Patients With Ulcerative Colitis

Gastroenterology. 2016 Feb;150(2):380-8.e4. doi: 10.1053/j.gastro.2015.10.050. Epub 2015 Nov 26.

Abstract

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.

Methods: 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.

Results: 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).

Conclusions: 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.

Keywords: Clinical Trial; Drug; IBD; Methotrexate.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Hormones / adverse effects
  • Adrenal Cortex Hormones / therapeutic use*
  • Adult
  • Anti-Inflammatory Agents / administration & dosage
  • Anti-Inflammatory Agents / adverse effects
  • Anti-Inflammatory Agents / therapeutic use*
  • Colitis, Ulcerative / diagnosis
  • Colitis, Ulcerative / drug therapy*
  • Colon / drug effects*
  • Colon / pathology
  • Double-Blind Method
  • Drug Therapy, Combination
  • Europe
  • Female
  • Gastrointestinal Agents / administration & dosage
  • Gastrointestinal Agents / adverse effects
  • Gastrointestinal Agents / therapeutic use*
  • Humans
  • Injections, Intramuscular
  • Injections, Subcutaneous
  • Male
  • Methotrexate / administration & dosage
  • Methotrexate / adverse effects
  • Methotrexate / therapeutic use*
  • Middle Aged
  • Remission Induction
  • Time Factors
  • Treatment Outcome
  • Wound Healing / drug effects

Substances

  • Adrenal Cortex Hormones
  • Anti-Inflammatory Agents
  • Gastrointestinal Agents
  • Methotrexate

Associated data

  • ClinicalTrials.gov/NCT00498589