Effect of folic or folinic acid supplementation on methotrexate-associated safety and efficacy in inflammatory disease: a systematic review

Br J Dermatol. 2009 Mar;160(3):622-8. doi: 10.1111/j.1365-2133.2008.08876.x. Epub 2008 Oct 20.


Background: Methotrexate is a folic acid antagonist widely used for the treatment of inflammatory disorders for more than 50 years. Methotrexate is a standard systemic therapy for severe psoriasis and rheumatoid arthritis. Folic acid supplementation has been advocated to limit the toxicity of methotrexate on blood cells, gastrointestinal tract and liver. However, there is still controversy regarding the usefulness of folic acid supplementation.

Objectives: We sought to assess the evidence for the efficacy of folic acid supplementation in patients treated with methotrexate for inflammatory diseases. We also investigated whether folic acid supplementation may decrease the efficacy of methotrexate.

Methods: Cochrane and MEDLINE databases were systematically searched. Randomized controlled trials in patients treated with methotrexate for rheumatoid arthritis or psoriasis with or without arthritis were included. Study selection, assessment of methodological quality, data extraction and analysis were carried out by two independent researchers. We selected double-blind randomized placebo-controlled trials. Analysis was performed for each subgroup of side-effects: gastrointestinal, mucocutaneous, haematological and hepatic.

Results: Six randomized controlled trials met the inclusion criteria, with a total sample of 648 patients. There were 257 patients in the placebo group, 198 patients treated with folic acid, and 193 patients treated with folinic acid. The statistical analysis showed a significant reduction of 35.8% of hepatic side-effects induced by methotrexate for patients with supplementation with folic or folinic acid (95% confidence interval -0.467 to -0.248). There was no statistical difference for mucocutaneous and gastrointestinal side-effects although there was a trend in favour of supplementation. The effect of supplementation on haematological side-effects could not be assessed accurately due to a low incidence of these events in the population studied. We were unable to analyse the effect of supplementation on the effectiveness of methotrexate, as markers of activity used in each study were not comparable.

Conclusions: Supplementation with folic acid is an effective measure to reduce hepatic adverse effects associated with methotrexate treatment. There is no difference between folinic acid and folic acid, but the lower cost of the latter promotes its use.

Publication types

  • Review
  • Systematic Review

MeSH terms

  • Arthritis, Rheumatoid / drug therapy
  • Chemical and Drug Induced Liver Injury
  • Drug Eruptions / etiology
  • Drug Eruptions / prevention & control
  • Folic Acid / therapeutic use*
  • Gastrointestinal Diseases / chemically induced
  • Gastrointestinal Diseases / prevention & control
  • Hematologic Diseases / chemically induced
  • Hematologic Diseases / prevention & control
  • Humans
  • Immunosuppressive Agents / adverse effects*
  • Immunosuppressive Agents / therapeutic use
  • Leucovorin / therapeutic use*
  • Liver Diseases / prevention & control
  • Methotrexate / adverse effects*
  • Methotrexate / therapeutic use
  • Psoriasis / drug therapy
  • Randomized Controlled Trials as Topic


  • Immunosuppressive Agents
  • Folic Acid
  • Leucovorin
  • Methotrexate