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  • Review Article
  • Published:

Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers

Nature Reviews Rheumatology volume 12, pages 731–742 (2016)Cite this article

Subjects

Key Points

  • Methotrexate shows good efficacy in a proportion of patients: 40% of treated patients with rheumatoid arthritis achieve an ACR50 response

  • The mechanism of action of methotrexate has not fully been defined, however potentiation of adenosine signalling carries the most robust data

  • Pharmacokinetic parameters, particularly intracellular methotrexate polyglutamation, show some association with disease activity, although they cannot yet be used to predict treatment response

  • An exploration of the expression and polymorphisms of genes encoding molecules linked to proposed mechanisms of methotrexate action is underway to identify methotrexate-responsive signatures

  • At present, no robust markers or predictive models exist for methotrexate responsiveness in RA

Abstract

The treatment and outcomes of patients with rheumatoid arthritis (RA) have been transformed over the past two decades. Low disease activity and remission are now frequently achieved, and this success is largely the result of the evolution of treatment paradigms and the introduction of new therapeutic agents. Despite the rapid pace of change, the most commonly used drug in RA remains methotrexate, which is considered the anchor drug for this condition. In this Review, we describe the known pharmacokinetic properties and putative mechanisms of action of methotrexate. Consideration of the pharmacodynamic perspective could inform the development of biomarkers of responsiveness to methotrexate, enabling therapy to be targeted to specific groups of patients. Such biomarkers could revolutionize the management of RA.

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Figure 1: Pharmacodynamics of methotrexate in RA.
Figure 2: Potential mechanisms of action of low-dose methotrexate in rheumatoid arthritis.
Figure 3: Potential role of methotrexate in depletion of the nucleotide pool.
Figure 4: Proposed mechanism by which methotrexate increases adenosine signalling.
Figure 5: Role of dyhydrofolate reductase (DHFR) in the generation of methyl donors.
Figure 6: Metabolism of pterins.

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Acknowledgements

The authors' work is supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle Hospitals National Health Service (NHS) Foundation Trust and Newcastle University, UK. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

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  1. Institute of Cellular Medicine, Faculty of Medical Sciences, Framlington Place, NE2 4HH, Newcastle upon Tyne, UK

    Philip M. Brown, Arthur G. Pratt & John D. Isaacs

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P.M.B. researched the data for the article, and wrote the manuscript. All authors contributed substantially to discussions of the article content and to review or editing of the manuscript before submission.

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Brown, P., Pratt, A. & Isaacs, J. Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers. Nat Rev Rheumatol 12, 731–742 (2016). https://doi.org/10.1038/nrrheum.2016.175

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