Gastroenterology

Gastroenterology

Volume 155, Issue 4, October 2018, Pages 1098-1108.e9
Gastroenterology

Original Research
Full Report: Clinical—Alimentary Tract
Methotrexate Is Not Superior to Placebo in Maintaining Steroid-Free Response or Remission in Ulcerative Colitis

https://doi.org/10.1053/j.gastro.2018.06.046Get rights and content

Background & Aims

Parenteral methotrexate induces clinical remission but not endoscopic improvement of mucosal inflammation in patients with ulcerative colitis (UC). We performed a randomized, placebo-controlled trial to assess the efficacy of parenteral methotrexate in maintaining steroid-free response or remission in patients with UC after induction therapy with methotrexate and steroids.

Methods

We performed a 48-week trial, from February 2012 through May 2016, of 179 patients with active UC (Mayo score of 6–12 with endoscopy subscore ≥ 2) despite previous conventional or biological therapy. The study comprised a 16-week open label methotrexate induction period followed by a 32-week double-blind, placebo-controlled maintenance period. Patients were given subcutaneous methotrexate (25 mg/wk) and a 12-week steroid taper. At week 16, steroid-free responders were randomly assigned to groups that either continued methotrexate (25 mg/wk, n = 44) or were given placebo (n = 40) until week 48. We compared the efficacy of treatment by analyzing the proportion of patients who remained relapse free and were in remission at week 48 without use of steroids or other medications to control disease activity.

Results

Ninety-one patients (51%) achieved response at week 16, and 84 patients were included in the maintenance period study. During this period, 60% of patients in the placebo group (24/40) and 66% in the methotrexate group (29/44) had a relapse of UC (P = .75). At week 48, 30% of patients in the placebo group (12/40) and 27% of patients in the methotrexate group (12/44) were in steroid-free clinical remission without need for additional therapies (P = .86). No new safety signals for methotrexate were detected.

Conclusions

Parenteral methotrexate (25 mg/wk) was not superior to placebo in preventing relapses of UC in patients who achieved steroid-free response during induction therapy. ClinicalTrials.gov, Number: NCT01393405.

Section snippets

Trial Design and Oversight

The trial was conducted at 37 sites (see Supplementary Material for site list) across the United States. Patients were recruited between February 2012 and May 2016. The study was designed by investigators of the Crohn’s and Colitis Foundation’s Clinical Research Alliance, and the majority of centers were affiliated with the Clinical Research Alliance.20 The institutional review board at each participating institution approved the protocol, and all the patients provided written informed consent

Results

Between February 2012 and May 2016, 256 patients were screened at 37 sites across the United States. Of these, 77 patients were excluded, mostly because of insufficient disease activity, and 179 patients were included in the induction period (Table 1 and Supplementary Figure 1). At week 16, 91 of 179 (51%) of the patients achieved a steroid-free clinical response, and of these, 52 of 179 (29%) were in steroid-free clinical remission. Patients with previous therapeutic failure of thiopurines

Discussion

To our knowledge, MERIT-UC is the first randomized, placebo-controlled study investigating the efficacy of subcutaneously applied MTX at a dose of 25 mg/wk in patients who had previously responded to open label MTX. Despite a relatively large proportion of patients achieving steroid-free response and remission during the open label induction phase, which in its magnitude was similar to the METEOR trial, MTX was not superior to placebo in maintaining these therapeutic effects.18 The METEOR trial

Acknowledgments

Author contributions: Hans Herfarth: study concept and design; acquisition of data; analysis and interpretation of data; drafting and critical revision of the manuscript; statistical analysis. Edward L. Barnes: analysis and interpretation of data; drafting and critical revision of the manuscript; statistical analysis. John F. Valentine: acquisition of data; drafting and critical revision of the manuscript. John Hanson: acquisition of data; drafting and critical revision of the manuscript. Peter

References (40)

  • M. Lemaitre et al.

    Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease

    JAMA

    (2017)
  • J.A. Wessels et al.

    Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis

    Rheumatology (Oxford)

    (2008)
  • P.M. Brown et al.

    Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers

    Nat Rev Rheumatol

    (2016)
  • J.M. Kremer

    Still trying to understand methotrexate

    J Rheumatol

    (2014)
  • B.G. Feagan et al.

    Methotrexate for the treatment of Crohn's disease. The North American Crohn’s Study Group Investigators

    N Engl J Med

    (1995)
  • B.G. Feagan et al.

    A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. North American Crohn’s Study Group Investigators

    N Engl J Med

    (2000)
  • A.A. Alfadhli et al.

    Methotrexate for induction of remission in refractory Crohn’s disease

    Cochrane Database Syst Rev

    (2005)
  • V. Patel et al.

    Methotrexate for maintenance of remission in Crohn's disease

    Cochrane Database Syst Rev

    (2009)
  • B. Weiss et al.

    Methotrexate treatment in pediatric Crohn disease patients intolerant or resistant to purine analogues

    J Pediatr Gastroenterol Nutr

    (2009)
  • S. Uhlen et al.

    Efficacy of methotrexate in pediatric Crohn’s disease: a French multicenter study

    Inflamm Bowel Dis

    (2006)
  • Cited by (70)

    • Ulcerative colitis

      2023, The Lancet
    • Targeting the endo-lysosomal autophagy pathway to treat inflammatory bowel diseases

      2022, Journal of Autoimmunity
      Citation Excerpt :

      However, IBD has multifactorial triggers, including genetic, microbial, and environmental factors, causing dysregulation of the innate and adaptive immune system in the intestine [3–6]. IBD has high recurrence, and low cure rates [7], and we currently lack effective treatment options, primarily due to either limited efficacy or unsustainable side effects [8–10]. Today, therapies are largely limited to treatment of symptoms with the aim of improving the patient's quality of life.

    • Methotrexate, the forgotten treatment for IBD

      2024, Hepato-Gastro et Oncologie Digestive
    View all citing articles on Scopus

    Conflicts of interest These authors disclose the following: Bincy Abraham has received consulting fees from AbbVie, Daiichi Sankyo, Diasoren, Janssen, Pfizer, Salix, Takeda, and UCB, and she has received research funding from AbbVie, Celgene, Genentech, Janssen, UCB. Edward Barnes has received consulting fees from Janssen and research support from TARGET PharmaSolutions. Raymond K. Cross has received consulting fees from AbbVie, Janssen, Pfizer, and Takeda. He has received research funding from AbbVie. Gerald Dryden has received consulting fees from AbbVie, Takeda, Janssen, Allergan, Gilead, Takeda, and he has received research funding from AbbVie, Takeda, Janssen, Gilead, Eli Lilly, TiGenix, MedImmune. Monika Fischer has received consulting fees from AbbVie and Finch Therapeutics. John Hanson has received consulting fees from AbbVie and Target PharmaSolutions. Hans Herfarth has received consulting fees from Merck, Pfizer, Celltrion, Lycera, Boehringer-Ingelheim, and Seres. Peter Higgins has received consulting fees from AbbVie, Allergan, Amgen, Eli Lilly, GI Health Foundation, Janssen, Lycera, PRIME Medical Education, Takeda, and UCB, and he has received research funding from AbbVie, Amgen, Arean, Ascentage, BCBS of Michigan, Buhlmann, Eli Lilly, Genentech, Janssen, Lycera, MedImmune, Nestle, Pfizer, Seres, Shire, Takeda, and UCB. Kim Isaacs received consulting fees from Allergan and Johnson & Johnson. James Lewis has received consulting fees from Merck, Pfizer, Janssen, AbbVie, Immune Pharmaceuticals, AstraZeneca, Amgen, MedImmune, Nestle Health Science, Lilly, Samsung Bioepis, Johnson & Johnson Consumer Products, Takeda, Gilead, Celgene, and Bridge Biotherapeutics; he has received research funding from Takeda, Shire, and Nestle Health Science; and he has received nongrant research support from AbbVie. Millie Long has received consulting fees from Pfizer, AbbVie, Takeda, Theravance, UCB, and Target PharmaSolutions, and she has received research funding from Takeda. Robert McCabe received consulting fees from Janssen. Mark Osterman has received consulting fees from AbbVie, Janssen, Lycera, Merck, Pfizer, Takeda, and UCB, and he has received research funding from UCB. Steven Polyak has received research funding from AbbVie, Celgene, Gilead, and Takeda. Bruce Sands has received consulting fees and research grants from AbbVie, Pfizer, Amgen, Bristol-Myers Squibb, Celgene, Janssen, and Takeda, and he has received consulting fees from Boehringer Ingelheim, Akros Pharma, Arena Pharmaceuticals, Forward Pharma, Immune Pharmaceuticals, Lilly, Synergy Pharmaceuticals, Theravance, Receptos, TiGenix, TopiVert Pharma, MedImmune, Vedanta Biosciences, Allergan, UCB Pharma, EnGene, Target PharmaSolutions, Lycera, Lyndra, Vivelix Pharmaceuticals, Oppilan Pharma, and Gilead. Sumona Saha received consulting fees from UCB. John Valentine received research funding from Pfizer, AbbVie, Celegene, Janssen, Roche/Genentech, Takada, and UCB. Emmanuelle Williams received consulting fees from AbbVie. Vijay Yajnik is currently a fulltime employee of Takeda Pharmaceuticals; at the time of the study he worked at Massachusetts General Hospital and received consulting fees from Jansen, Takeda, Pfizer, and NPS Pharmaceuticals. The remaining authors disclose no conflicts.

    Funding The study was funded by the National Institute of Diabetes and Digestive Kidney Diseases (U01DK092239). The Clinical Research Alliance is supported by the Crohn's and Colitis Foundation. The Data Management Center of the Center for Gastrointestinal Biology and Disease is supported by the Crohn’s and Colitis Foundation and the National Institutes of Health (P30 DK034987).

    View full text