title: Methotrexate in rheumatoid arthritis: an update with focus on mechanisms involved in toxicity.
abstract: OBJECTIVE
  To provide an update of the current knowledge of the mechanism of action of low-dose methotrexate (MTX) in the treatment of patients with rheumatoid arthritis (RA), with an emphasis on the mechanisms involved in toxicity. We also considered strategies currently used to prevent or decrease toxicity of MTX.
  
  
  METHODS
  We reviewed the literature dealing with the subjects of MTX treatment of RA, the mechanisms of action of low-dose MTX regarding efficacy and toxicity, and strategies used to prevent or decrease MTX toxicity.
  
  
  RESULTS
  MTX is a fast working and effective second-line antirheumatic agent (SLA). Its use is limited mainly because of side effects. The mechanisms of action regarding efficacy and toxicity are probably determined by different metabolic pathways. Recent data indicate that the antiinflammatory effect of MTX is mediated by adenosine. However, MTX side effects can only partly be explained by folate antagonism and may also depend on its action on other related metabolic pathways. The latter include the homocysteine-methionine-polyamine pathway and purine metabolism. Variants in these metabolic routes (ie, the C677T mutation in the methylene-tetrahydrofolate reductase [MTHFR] gene), may predispose to the development of side effects. Currently the most promising strategy to decrease or prevent toxicity of MTX is concomitant prescription of folic acid or folinic acid. Other strategies are currently under investigation.
  
  
  CONCLUSIONS
  MTX benefits a majority of RA patients. Approximately 30% of patients, however, abandon treatment because of drug-related side effects. Folic acid or folinic acid likely reduces MTX toxicity. More data, however, are needed to evaluate a potential detrimental effect on the antirheumatic efficacy of MTX.
authors.affiliation: Department of Rheumatology, University of Nijmegen, The Netherlands.
authors.forename: A E
authors.initials: AE
authors.lastname: van Ede
authors.forename: R F
authors.initials: RF
authors.lastname: Laan
authors.forename: H J
authors.initials: HJ
authors.lastname: Blom
authors.forename: R A
authors.initials: RA
authors.lastname: De Abreu
authors.forename: L B
authors.initials: LB
authors.lastname: van de Putte
mesh_terms: D018501:Antirheumatic Agents / Q000009:adverse effects / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism; D005492:Folic Acid / Q000378:metabolism; D005493:Folic Acid Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D008727:Methotrexate / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D018501:Antirheumatic Agents; D005493:Folic Acid Antagonists; D005492:Folic Acid; D008727:Methotrexate