How does methotrexate work?

Biochem Soc Trans. 2020 Apr 29;48(2):559-567. doi: 10.1042/BST20190803.

Abstract

Developed over 70 years ago as an anti-folate chemotherapy agent, methotrexate (MTX) is a WHO 'essential medicine' that is now widely employed as a first-line treatment in auto-immune, inflammatory diseases such as rheumatoid arthritis (RA), psoriasis and Crone's disease. When used for these diseases patients typically take a once weekly low-dose of MTX - a therapy which provides effective inflammatory control to tens of millions of people worldwide. While undoubtedly effective, our understanding of the anti-inflammatory mechanism-of-action of low-dose MTX is incomplete. In particular, the long-held dogma that this disease-modifying anti-rheumatic drug (DMARD) acts via the folate pathway does not appear to hold up to scrutiny. Recently, MTX has been identified as an inhibitor of JAK/STAT pathway activity, a suggestion supported by many independent threads of evidence. Intriguingly, the JAK/STAT pathway is central to both the inflammatory and immune systems and is a pathway already targeted by other RA treatments. We suggest that the DMARD activity of MTX is likely to be largely mediated by its inhibition of JAK/STAT pathway signalling while many of its side effects are likely associated with the folate pathway. This insight into the mechanism-of-action of MTX opens the possibility for repurposing this low cost, safe and effective drug for the treatment of other JAK/STAT pathway-associated diseases.

Keywords: drug effects; pharmacology; repurposing.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antirheumatic Agents / therapeutic use*
  • Arthritis, Rheumatoid / drug therapy
  • Autoimmune Diseases / drug therapy*
  • Cell Line
  • Crohn Disease / drug therapy
  • Folic Acid / metabolism
  • Humans
  • Inflammation / drug therapy*
  • Janus Kinases / metabolism
  • MAP Kinase Signaling System
  • Methotrexate / pharmacology*
  • Psoriasis / drug therapy
  • STAT Transcription Factors / metabolism
  • Signal Transduction

Substances

  • Antirheumatic Agents
  • STAT Transcription Factors
  • Folic Acid
  • Janus Kinases
  • Methotrexate