Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm, low dose methotrexate therapy for rheumatoid arthritis: implications for cardiovascular disease prevention

J Rheumatol. 1998 Mar;25(3):441-6.


Objective: To determine the effect of longterm methotrexate (MTX) therapy and folic acid supplementation on folate nutriture and homocysteine levels in patients with rheumatoid arthritis.

Methods: A double blind, placebo controlled trial lasting one year was conducted at one academic medical center. A total of 79 patients taking low dose MTX were followed up to one year. The patients were randomized to receive placebo or 5 or 27.5 mg folic acid supplementation per week.

Results: Plasma and erythrocyte folate levels and plasma homocysteine levels were determined. The folate nutriture of patients taking low dose MTX declined without folic acid supplementation. Plasma homocysteine levels increased significantly over a one year period in the placebo group. Low folate nutriture and hyperhomocysteinemia occurred with greater frequency in the placebo group than in the folic acid supplemented groups.

Conclusion: For longterm, low dose MTX therapy, there are now at least 3 reasons to consider supplementation with folic acid (a low cost prescription): (1) to prevent MTX toxicity, (2) to prevent or treat folate deficiency, and (3) to prevent hyperhomocysteinemia, considered by many investigators to be a risk factor for cardiovascular disease.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / metabolism
  • Cardiovascular Diseases / prevention & control
  • Dietary Supplements*
  • Double-Blind Method
  • Female
  • Folic Acid / administration & dosage
  • Folic Acid / blood
  • Folic Acid / pharmacology*
  • Folic Acid Antagonists / therapeutic use*
  • Folic Acid Deficiency / prevention & control*
  • Homocysteine / blood*
  • Humans
  • Male
  • Methotrexate / therapeutic use*
  • Middle Aged


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