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.
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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The authors thank F. Ecarnot (EA3920, University of Franche-Comté and University Hospital Besançon, France) for editorial assistance.
The authors declare no competing interests.
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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