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Pathology and Pharmacology, Division of Clinical Pharmacology, Department of Medicine, New York University School of Medicine, New York, New York
Abstract
Abstract I. The Use of Methotrexate in the Therapy of Rheumatoid Arthritis A. Pharmacology of Low-Dose Methotrexate B. Efficacy of Methotrexate in the Therapy of Rheumatoid Arthritis C. Concomitant Use of Methotrexate with Other Anti-Inflammatory Drugs D. Use of Folic Acid to Prevent Methotrexate-Induced Toxicity II. Mechanism of Action of Methotrexate As an Anti-Inflammatory Agent A. Folate Antagonism B. Inhibition of Spermine and Spermidine Production C. Methotrexate Alters Cellular Redox State D. Methotrexate Increases Extracellular Adenosine Concentrations III. Pharmacogenetics of Methotrexate in the Treatment of Rheumatoid Arthritis A. Genetic Factors Predicting Increased Risk of Drug Toxicity B. Genetic Factors Predicting Increased Drug Efficacy
Methotrexate administered weekly in low doses is a mainstay in the therapy of rheumatoid arthritis. Although originally developed as a folate antagonist for the treatment of cancer, its mechanism of action in the therapy of rheumatoid arthritis remains less clear. Several mechanisms have been proposed including inhibition of T cell proliferation via its effects on purine and pyrimidine metabolism, inhibition of transmethylation reactions required for the prevention of T cell cytotoxicity, interference with glutathione metabolism leading to alterations in recruitment of monocytes and other cells to the inflamed joint, and promotion of the release of the endogenous anti-inflammatory mediator adenosine. These mechanisms of action and the role of methotrexate in the suppression of rheumatoid arthritis are reviewed.
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