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Methotrexate and its mechanisms of action in inflammatory arthritis

Nature Reviews Rheumatology volume 16, pages 145–154 (2020)Cite this article

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Abstract

Despite the introduction of numerous biologic agents for the treatment of rheumatoid arthritis (RA) and other forms of inflammatory arthritis, low-dose methotrexate therapy remains the gold standard in RA therapy. Methotrexate is generally the first-line drug for the treatment of RA, psoriatic arthritis and other forms of inflammatory arthritis, and it enhances the effect of most biologic agents in RA. Understanding the mechanism of action of methotrexate could be instructive in the appropriate use of the drug and in the design of new regimens for the treatment of RA. Although methotrexate is one of the first examples of intelligent drug design, multiple mechanisms potentially contribute to the anti-inflammatory actions of methotrexate, including the inhibition of purine and pyrimidine synthesis, transmethylation reactions, translocation of nuclear factor-κB (NF-κB) to the nucleus, signalling via the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway and nitric oxide production, as well as the promotion of adenosine release and expression of certain long non-coding RNAs.

Key points

  • Methotrexate polyglutamates inhibit aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase (ATIC), leading to intracellular accumulation of AICAR and increased adenosine release; adenosine binds to cell surface receptors and suppresses many inflammatory and immune reactions.

  • Methotrexate inhibits dihydrofolate reductase, preventing the reduction of dihydrobiopterin (BH2) to tetrahydrobiopterin (BH4), leading to nitric oxide synthase uncoupling and increased sensitivity of T cells to apoptosis, thereby diminishing immune responses.

  • Methotrexate inhibits activation of nuclear factor-κB (NF-κB) by increasing both adenosine release and activation of adenosine receptor A2a and by inhibiting the reduction of BH2 to BH4.

  • Methotrexate increases the expression of long intergenic non-coding RNA p21 (lincRNA-p21), which is a multifunction long non-coding RNA that regulates, both directly and indirectly, a variety of critical immune and inflammatory processes.

  • By modulating cell-specific signalling pathways, methotrexate inhibits important pro-inflammatory properties of major cell lineages involved in rheumatoid arthritis pathogenesis, including T cells, macrophages, endothelial cells and fibroblast-like synoviocytes.

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Fig. 1: Molecular structures of folic acid, aminopterin and methotrexate.
Fig. 2: Methotrexate regulates essential biochemical reactions.
Fig. 3: Cell-specific mechanisms of methotrexate in rheumatoid arthritis.

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Acknowledgements

The work of T.M.A. was supported by grants from the US National Institutes of Health (R21AR063846, R42AI53948, R01AI044924), the American College of Rheumatology ‘Within Our Reach’ grant programme (ACR124405), the US National Center for Advancing Translation Sciences (UL1TR000445) and the US National Science Foundation Graduate Research Fellowship Program.

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Authors and Affiliations

  1. The New York University School of Medicine, New York, NY, USA

    Bruce N. Cronstein

  2. Vanderbilt University Medical Center, Nashville, TN, USA

    Thomas M. Aune

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  1. Bruce N. Cronstein
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  2. Thomas M. Aune
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The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Bruce N. Cronstein.

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Competing interests

B.N.C. declares that he holds equity in Regenosine, a biotech start-up developing therapies for osteoarthritis, and CanFite Biopharma, that he has received grant support from AstraZeneca and Kairos Inc., and that he has a number of patents involving adenosine receptors and hepatic fibrosis, wound healing, bone regeneration and osteoarthritis. T.M.A. declares that he has no competing interests.

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Nature Reviews Rheumatology thanks W. Wei and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Long non-coding RNAs

(lncRNAs). A newly discovered class of RNAs that are defined as RNAs of more than 200 base pairs in length, are transcribed from genes but not translated into proteins due to the presence of multiple translational stop codons and, as RNAs, regulate the expression of target genes and proteins to carry out a vast array of biologic functions.

Warburg effect

A shift from oxidative phosphorylation to glycolysis during cell activation.

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Cronstein, B.N., Aune, T.M. Methotrexate and its mechanisms of action in inflammatory arthritis. Nat Rev Rheumatol 16, 145–154 (2020). https://doi.org/10.1038/s41584-020-0373-9

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