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Methotrexate in rheumatoid arthritis: an update with focus on mechanisms involved in toxicity

A E van Ede1, R F Laan, H J Blom

  • 1Department of Rheumatology, University of Nijmegen, The Netherlands.

Seminars in Arthritis and Rheumatism
|May 8, 1998
PubMed
Abstract

Insights

Low-dose methotrexate (MTX) effectively treats rheumatoid arthritis (RA) but causes side effects. Folic acid or folinic acid supplementation may reduce MTX toxicity, though more research is needed on its impact on efficacy.

Area of Science:

  • Rheumatology
  • Pharmacology
  • Immunology

Background:

  • Methotrexate (MTX) is a widely used second-line agent for rheumatoid arthritis (RA).
  • MTX efficacy is well-established, but its use is often limited by dose-dependent toxicities.
  • Understanding MTX's mechanism of action, particularly concerning toxicity, is crucial for optimizing patient treatment.

Purpose of the Study:

  • To review current knowledge on the mechanism of action of low-dose methotrexate (MTX) in rheumatoid arthritis (RA).
  • To emphasize the mechanisms underlying MTX toxicity.
  • To discuss strategies for preventing or mitigating MTX-related side effects.

Main Methods:

  • Literature review focusing on MTX treatment in RA.
  • Analysis of studies on MTX mechanisms of action related to both efficacy and toxicity.
  • Examination of strategies for MTX toxicity prevention and reduction.

Main Results:

  • Low-dose MTX demonstrates rapid and effective anti-inflammatory action in RA, potentially mediated by adenosine.
  • MTX toxicity mechanisms extend beyond folate antagonism, involving pathways like homocysteine-methionine-polyamine and purine metabolism.
  • Genetic variations, such as MTHFR C677T, may influence susceptibility to MTX side effects.
  • Concomitant folic acid or folinic acid is the most promising strategy to reduce MTX toxicity.

Conclusions:

  • MTX benefits most RA patients, but approximately 30% discontinue treatment due to side effects.
  • Folic acid or folinic acid supplementation appears to reduce MTX toxicity.
  • Further research is required to ascertain if these supplements negatively impact MTX's antirheumatic efficacy.

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