Low-Dose Methotrexate and Mucocutaneous Adverse Events: Results of a Systematic Literature Review and Meta-Analysis of Randomized Controlled Trials

Arthritis Care Res (Hoboken). 2020 Aug;72(8):1140-1146. doi: 10.1002/acr.23999.


Objective: Methotrexate (MTX) increases the risk of alopecia and stomatitis, but the prevalence of these adverse events among rheumatic patients taking MTX is poorly defined. We conducted a systematic literature review and meta-analysis to estimate the prevalence of alopecia and stomatitis with MTX in rheumatic diseases.

Methods: We searched PubMed, The Cochrane Library, and CINAHL databases for double-blind randomized controlled trials (RCTs) with an MTX monotherapy arm. Alopecia, stomatitis, and oral/mouth ulcers data were extracted. The quality of trials was assessed by 2 authors. We included trials published since 1990 that used at least 10 mg of MTX weekly, coadministered with folic or folinic acid. We estimated the prevalence using random-effects models because heterogeneity was anticipated. Two estimates of prevalence were included; the lower bound estimate included all trials (assuming no alopecia and stomatitis if not mentioned), and the upper bound estimate included only those that specifically described prevalence estimates of alopecia or stomatitis.

Results: Of 3,954 studies identified, 20 RCTs were included, with a total of 24 MTX monotherapy arms, of which 10 reported the prevalence of alopecia (n = 1,113), and 21 reported stomatitis or mouth/oral ulcers (n = 2,056). The prevalence of alopecia was between 1.0% and 4.9%. The prevalence of stomatitis was between 5.7% and 8.0%.

Conclusion: This meta-analysis gives more precise estimates of mucocutaneous adverse events that occur in rheumatic disease patients taking MTX. These estimates will help inform patient decision-making regarding MTX.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Systematic Review

MeSH terms

  • Adult
  • Aged
  • Alopecia / chemically induced*
  • Alopecia / epidemiology
  • Antirheumatic Agents / adverse effects*
  • Double-Blind Method
  • Female
  • Folic Acid / administration & dosage
  • Humans
  • Leucovorin / administration & dosage
  • Male
  • Methotrexate / adverse effects*
  • Middle Aged
  • Oral Ulcer / chemically induced*
  • Oral Ulcer / epidemiology
  • Prevalence
  • Randomized Controlled Trials as Topic
  • Rheumatic Diseases / drug therapy*
  • Stomatitis / chemically induced*
  • Stomatitis / epidemiology


  • Antirheumatic Agents
  • Folic Acid
  • Leucovorin
  • Methotrexate