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Methotrexate—how does it really work?

Abstract

Methotrexate remains a cornerstone in the treatment of rheumatoid arthritis and other rheumatic diseases. Folate antagonism is known to contribute to the antiproliferative effects that are important in the action of methotrexate against malignant diseases, but concomitant administration of folic or folinic acid does not diminish the anti-inflammatory potential of this agent, which suggests that other mechanisms of action might be operative. Although no single mechanism is sufficient to account for all the anti-inflammatory activities of methotrexate, the release of adenosine from cells has been demonstrated both in vitro and in vivo. Methotrexate might also confer anti-inflammatory properties through the inhibition of polyamines. The biological effects on inflammation associated with adenosine release have provided insight into how methotrexate exerts its effects against inflammatory diseases and at the same time causes some of its well-known adverse effects. These activities contribute to the complex and multifaceted mechanisms that make methotrexate efficacious in the treatment of inflammatory disorders.

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Figure 1: Proposed mechanisms of the anti-inflammatory actions of methotrexate.

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Correspondence to Edwin S. L. Chan.

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Competing interests

Edwin S. L. Chan and Bruce N. Cronstein both declare that they hold patents pertinent to King Pharmaceuticals (on use of adenosine A2A receptor agonists to promote wound healing and use of A2A receptor antagonists to inhibit fibrosis; on the use of adenosine A1 receptor antagonists to treat osteoporosis and other diseases of bone; on the use of adenosine A1 and A2B receptor antagonists to treat fatty liver; and on the use of adenosine A2A receptor agonists to prevent prosthesis loosening). Bruce N. Cronstein declares that he has acted as a consultant for Cephalon, Cypress Bioscience, King Pharmaceuticals, CanFite Biopharma, Bristol-Myers Squibb, Cellzome, Takeda Pharmaceuticals, Prometheus Laboratories, Regeneron (Westat, DSMB), Sepracor, Amgen, Endocyte, Protalex, Allos, Combinatorx, Kyowa Hakka, Hoffman La Roche, Savient and Avidimer Therapeutics. Bruce N. Cronstein also declares he has stock in CanFite Biopharma, and has received grant or research support from King Pharmaceuticals, NIH and The Vilcek Foundation (of which he is a Board Member).

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Chan, E., Cronstein, B. Methotrexate—how does it really work?. Nat Rev Rheumatol 6, 175–178 (2010). https://doi.org/10.1038/nrrheum.2010.5

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