Abstract: Folate, Homocysteine, and Cobalamin Status in Patients with Rheumatoid Arthritis Treated with Methotrexate, and the Effect of Low Dose Folic Acid Supplement

Folate, Homocysteine, and Cobalamin Status in Patients with Rheumatoid Arthritis Treated with Methotrexate, and the Effect of Low Dose Folic Acid Supplement

NETE HORNUNG, TORKELL ELLINGSEN, KRISTIAN STENGAARD-PEDERSEN, and JØRGEN H. POULSEN

ABSTRACT.

Objective. To investigate the effect of methotrexate (MTX) treatment of rheumatoid arthritis (RA) on folate metabolism, and to determine the effect of low dose folic acid on toxicity, efficacy, and folate status.

Methods. A 52-week prospective study of 81 patients with RA treated with MTX and self-administered low dose folic acid; 38 patients were included prior to MTX therapy, 33 patients continued established MTX therapy, and 10 patients were excluded. Drug efficacy and side effects were monitored with biochemical and clinical indicators.

Results. MTX treatment resulted in decreased concentrations of red blood cell (RBC) folate and a rise in plasma homocysteine. Intracellular concentrations of MTX were inversely correlated to RBC folate levels after treatment for a longer period (mean 41 months). Supplement with low dose folic acid prevented or diminished the influence of MTX on folate status and had a protective effect on MTX induced liver toxicity without changing the efficacy of MTX.

Conclusion. MTX interferes with folate and homocysteine metabolism, and the intracellular concentration of MTX may play a role. Our results indicate low dose folic acid supplementation has a beneficial effect on MTX toxicity. (J Rheumatol 2004;31:2374-81)

Key Indexing Terms:

RHEUMATOID ARTHRITIS
METHOTREXATE
ERYTHROCYTE
FOLIC ACID

From the Department of Clinical Biochemistry, Randers Central Hospital, Randers; and the Department of Rheumatology and Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.

Supported by Apotekerfonden, Danish Rheumatism Association, and Kathrine og Vigo Skovgaards Fond.

N. Hornung, MD, PhD, Department of Clinical Biochemistry, Randers Central Hospital; T. Ellingsen, MD, PhD; K. Stengaard-Pedersen, MD, Dr Sci, Professor, Department of Rheumatology; J.H. Poulsen, MD, Dr Sci, Department of Clinical Biochemistry, Aarhus University Hospital.

Address reprint requests to Dr. N. Hornung, Department of Clinical Biochemistry, Randers Centralhospital, Skovlyvej 1, 8900 Randers, Denmark. E-mail: neh@rc.aaa.dk

Submitted June 25, 2003; revision accepted July 12, 2004.