How does methotrexate work?

• Published in: Biochemical Society transactions Vol. 48; no. 2; p. 559
• Main Authors: Alqarni, Adel M, Zeidler, Martin P
• Format: Journal Article
• Language: English
• Published: England 29.04.2020
• Subjects: 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; Signal Transduction; STAT Transcription Factors - metabolism; drug effects; repurposing; pharmacology
• DOI: 10.1042/BST20190803

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.