Cytopenias among patients with rheumatic diseases using methotrexate: a meta-analysis of randomized controlled clinical trials

Rheumatology (Oxford). 2020 Apr 1;59(4):709-717. doi: 10.1093/rheumatology/kez343.


Objective: To conduct a systematic literature review and meta-analysis to estimate the incidence of anaemia, leucopoenia, neutropenia and thrombocytopenia associated with MTX plus folic acid among patients with rheumatic diseases.

Methods: We searched MEDLINE, PubMed and EMBASE through August 2016 for all randomized controlled clinical trials with a MTX monotherapy arm. We excluded randomized controlled clinical trials for cancer and included only double-blind studies that reported on haematologic adverse events. Studies were excluded if patients did not receive folic acid or leucovorin supplementation. Full text articles were assessed by two independent reviewers. Incidence estimates were calculated using random-effects models.

Results: Of 1601 studies identified, 30 (1.87%) were included, representing 3858 patients; all had RA. Seventeen trials reported on anaemia (n = 2032), 17 reported on leucopoenia (n = 2220), 16 reported on neutropenia (n = 2202) and 12 reported on thrombocytopenia (n = 1507). The incidence for any anaemia was 2.55% (95% CI 0.60-5.47%), any leucopoenia 1.17% (95% CI 0.16-2.80%), any neutropenia 1.77% (95% CI 0.33-4.00%), and any thrombocytopenia 0.19% (95% CI 0.00-0.86%). Four cases of severe anaemia were reported, as defined by authors, along with three cases of severe neutropenia. No cases of severe leucopoenia, severe thrombocytopenia or pancytopenia were reported.

Conclusion: Cytopenias are an uncommon side effect of low-dose MTX with folic acid supplementation among RA patients. Further research is needed to reach a more precise estimate.

Keywords: Methotrexate; anaemia; leucopoenia; meta-analysis; neutropenia; rheumatoid arthritis; thrombocytopenia.

Publication types

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

MeSH terms

  • Anemia / chemically induced*
  • Antirheumatic Agents / adverse effects*
  • Arthritis, Rheumatoid / drug therapy*
  • Folic Acid / therapeutic use
  • Humans
  • Leucovorin / therapeutic use
  • Leukopenia / chemically induced*
  • Methotrexate / adverse effects*
  • Neutropenia / chemically induced*
  • Pancytopenia / chemically induced
  • Randomized Controlled Trials as Topic
  • Rheumatic Diseases / drug therapy
  • Severity of Illness Index
  • Thrombocytopenia / chemically induced*
  • Vitamin B Complex / therapeutic use


  • Antirheumatic Agents
  • Vitamin B Complex
  • Folic Acid
  • Leucovorin
  • Methotrexate