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Busting the myth of methotrexate chronic hepatotoxicity

Nature Reviews Rheumatology volume 19, pages 96–110 (2023)Cite this article

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Abstract

Methotrexate is a key component of the treatment of inflammatory rheumatic diseases and the mainstay of therapy in rheumatoid arthritis. Hepatotoxicity has long been a concern for prescribers envisaging long-term treatment with methotrexate for their patients. However, the putative liver toxicity of methotrexate should be evaluated in the context of advances in our knowledge of the pathogenesis and natural history of liver disease, especially non-alcoholic fatty liver disease (NAFLD). Notably, patients with NAFLD are at increased risk for methotrexate hepatotoxicity, and methotrexate can worsen the course of NAFLD. Understanding the mechanisms of acute hepatotoxicity can facilitate the interpretation of elevated concentrations of liver enzymes in this context. Liver fibrosis and the mechanisms of fibrogenesis also need to be considered in relation to chronic exposure to methotrexate. A number of non-invasive tests for liver fibrosis are available for use in patients with rheumatic disease, in addition to liver biopsy, which can be appropriate for particular individuals. On the basis of the available evidence, practical suggestions for pretreatment screening and long-term monitoring of methotrexate therapy can be made for patients who have (or are at risk for) chronic liver disease.

Key points

  • Methotrexate is a key component in the treatment of inflammatory rheumatic diseases and the mainstay of therapy in rheumatoid arthritis.

  • In light of current evidence, it seems unlikely that methotrexate alone is capable of inducing chronic liver disease; the risk of methotrexate-induced liver injury is primarily acute in nature.

  • The cumulative dose of methotrexate has no predictive value for the occurrence of fibrosis.

  • In non-alcoholic fatty liver disease, several pathophysiological arguments suggest (in the absence of proof from clinical trials) that long-term methotrexate therapy worsens liver damage and the progression of liver disease.

  • Pretreatment screening is advisable to check for the possible presence of liver disease in patients being considered for methotrexate treatment.

  • Monthly monitoring is advocated at the beginning of methotrexate treatment, followed by 3-monthly monitoring comprising complete blood counts, liver function tests and calculation of the Fib-4 fibrosis score.

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Fig. 1: Mechanisms of methotrexate-induced acute hepatotoxicity and hypothetical methotrexate-induced fibrogenesis.
Fig. 2: Possible mechanisms involved in the worsening of NAFLD secondary to chronic methotrexate administration.
Fig. 3: Suggested protocol for liver risk assessment and monitoring in relation to methotrexate treatment.

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Acknowledgements

The authors thank F. Ecarnot (EA3920, University of Franche-Comté and University Hospital Besançon, France) for editorial assistance.

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Authors and Affiliations

  1. Department of Hepatology, CHRU de Besançon, Besançon, France

    Vincent Di Martino, Delphine Weil Verhoeven & Thierry Thévenot

  2. EA 4266 EPILAB, UFR Santé, University of Franche-Comté, Besançon, France

    Vincent Di Martino, Delphine Weil Verhoeven, Thierry Thévenot & Daniel Wendling

  3. INSERM UMR RIGHT 1098, Besançon, France

    Vincent Di Martino, Delphine Weil Verhoeven, François Aubin & Thierry Thévenot

  4. Department of Rheumatology, CHRU de Besançon, Besançon, France

    Frank Verhoeven & Daniel Wendling

  5. EA 4267 PEPITE, UFR Santé, University of Franche-Comté, Besançon, France

    Frank Verhoeven & Lucine Vuitton

  6. Department of Dermatology, CHRU de Besançon, Besançon, France

    François Aubin

  7. Department of Rheumatology, AP-HP Hôpital Cochin, Paris, France

    Jérome Avouac

  8. Cochin Institute, INSERM U1016 UMR 8104, Paris, France

    Jérome Avouac

  9. Department of Gastroenterology, CHRU de Besançon, Besançon, France

    Lucine Vuitton

  10. Department of Rheumatology, DMU Locomotion, AP-HP Nord & Inserm UMR 1132, Bioscar (Centre Viggo Petersen), Hôpital Lariboisière, Paris, France

    Frédéric Lioté

  11. Université de Paris, UFR de Médecine, Paris, France

    Frédéric Lioté

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Contributions

V.D.M., D.W.-V., F.V., F.A., J.A. and T.T. researched data for the article. V.D.M., D.W.-V., F.V., J.A., T.T. and D.W. wrote the article. All authors contributed substantially to the discussion of content and to the review/editing of the manuscript before submission.

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Nature Reviews Rheumatology thanks Devaraj Ezhilarasan, Shunsuke Mori and the other, anonymous, reviewer for their contribution to the peer review of this work.

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Di Martino, V., Verhoeven, D.W., Verhoeven, F. et al. Busting the myth of methotrexate chronic hepatotoxicity. Nat Rev Rheumatol 19, 96–110 (2023). https://doi.org/10.1038/s41584-022-00883-4

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