The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis

Arthritis Rheum. 1990 Jan;33(1):9-18. doi: 10.1002/art.1780330102.


Thirty-two patients with rheumatoid arthritis completed a 24-week, placebo-controlled, double-blind trial of folic acid (FA) supplementation during low-dose methotrexate (MTX) therapy. Administration of the daily FA supplement significantly lowered toxicity scores without affecting efficacy, as measured by joint counts, joint indices, and patient and physician evaluation of disease activity. Fifteen patients experienced some sort of toxicity; 67% were in the placebo group, and 33% were in the FA supplement group. Four patients in the placebo group had toxicity levels serious enough to require discontinuation of the MTX, while no patients in the FA supplement group discontinued MTX because of toxicity. Low-normal initial plasma and red blood cell folate levels were predictive of future toxicity with MTX therapy. We conclude that a daily supplement of 1 mg of FA during low-dose MTX therapy (median dose 7.5 mg/week [16.4 mumoles]) is usefull in lessening toxicity without altering efficacy during the first 6 months of treatment.

Publication types

  • Clinical Trial
  • Controlled Clinical Trial
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / physiopathology
  • Clinical Trials as Topic
  • Double-Blind Method
  • Drug Administration Schedule
  • Folic Acid / therapeutic use*
  • Humans
  • Methotrexate / administration & dosage
  • Methotrexate / therapeutic use
  • Methotrexate / toxicity*
  • Patient Dropouts


  • Folic Acid
  • Methotrexate