Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review

Rheumatology (Oxford). 2004 Mar;43(3):267-71. doi: 10.1093/rheumatology/keh088. Epub 2004 Jan 6.


Objectives: The folate antagonist methotrexate (MTX) has become established as the most commonly used disease-modifying anti-rheumatic drug (DMARD) in the treatment of rheumatoid arthritis (RA) but is commonly discontinued due to adverse effects. Adverse effects are thought to be mediated via folate antagonism. In this paper we summarize the current data on the use of folates as a supplement to MTX use in RA for the prevention of adverse effects and as a potential modulator of cardiovascular risk, and propose guidelines for standard practice.

Methods: A Medline search was performed using the search terms "methotrexate", "folic acid", "folinic acid", "folate" and "homocysteine". Literature relevant to the use of folates as a supplement to MTX in the treatment of RA was reviewed and other papers referred to as references were explored.

Results: The use of supplemental folates, including folic and folinic acid, in RA patients treated with MTX has been shown to improve continuation rates by reducing the incidence of liver function test abnormalities and gastrointestinal intolerance. Folate supplements do not appear to significantly reduce the effectiveness of MTX in the treatment of RA. Furthermore, supplemental folic acid offsets the elevation in plasma homocysteine associated with the use of MTX. This may in turn reduce the risk of cardiovascular disease, which is over-represented amongst patients with RA, and for which hyperhomocysteinaemia is now recognized as an independent risk factor.

Conclusions: We propose that folic acid supplements be prescribed routinely to all patients receiving MTX for the treatment of RA. We recommend a pragmatic dosing schedule of 5 mg of oral folic acid given on the morning following the day of MTX administration.

Publication types

  • Review

MeSH terms

  • Antirheumatic Agents / adverse effects
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / drug therapy*
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • Folic Acid / administration & dosage*
  • Folic Acid Antagonists / adverse effects
  • Folic Acid Antagonists / therapeutic use*
  • Humans
  • Methotrexate / adverse effects
  • Methotrexate / therapeutic use*


  • Antirheumatic Agents
  • Folic Acid Antagonists
  • Folic Acid
  • Methotrexate