Revisit methotrexate: Methotrexate mechanism of action

Abstract

Seventy years after its development, methotrexate（MTX）remains an anchor drug that plays a central role in the treatment of rheumatoid arthritis, even in the era of biologic agents and JAK inhibitors. The reason for this is that MTX has confidential effects such as suppressing disease activity, preventing joint destruction, reducing cardiovascular disorders, and improving mortality. The basic action of MTX is an antifolate action, that is, a cell proliferation inhibitory action. When MTX is attached polyglutamates in cells, it has a wide variety of other effects, including anti-inflammatory effects via adenosine, suppressive effects on the production of adhesion molecules and inflammatory cytokines, and suppressive effects on matrix metalloproteinases. MTX easily increases in blood concentration due to decreased renal function, causing bone marrow suppressive effects. There are also other side effects related to MTX, and it is desirable to know the characteristics and pleiotropic mechanism of action of MTX so that it can be used appropriately in the treatment against rheumatoid arthritis.