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Risk of liver fibrosis associated with long-term methotrexate therapy may be overestimated

Atallah, Edmond; Grove, Jane; Crooks, Colin; Burden-Teh, Esther; Abhishek, Abhishek; Moreea, Sulleman; Jordan, Kelsey; Ala, Aftab; Hutchinson, David; Aspinall, Richard J.; Murphy, Ruth; Aithal, Guruprasad

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Edmond Atallah

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Assistant Professor

Sulleman Moreea

Kelsey Jordan

Aftab Ala

David Hutchinson

Richard J. Aspinall

Ruth Murphy


Melanie Lingaya
Research Group

Davor Kresnik
Research Group

Bethany Robinson
Project Member


Background & Aims
The risk of significant liver fibrosis from prolonged methotrexate (MTX) exposure has been estimated at around 5%, prompting intensive monitoring strategies. However, the evidence is derived from retrospective studies that under-reported risk factors for liver disease. We evaluated the risk of long-term MTX therapy on liver fibrosis in a longitudinal cohort study using two non-invasive markers.
Between 2014-2021, adult patients diagnosed with rheumatoid arthritis (RA) or psoriasis for ≥2 years were recruited prospectively from six UK sites. The MTX group included patients who received MTX for ≥6 months, whereas the unexposed group included those who never received MTX. All patients underwent full liver profiling, with transient elastography (TE) and enhanced liver fibrosis (ELF) marker measurements.
A total of 999 patients (mean age 60.8 ± 12 years, 62.3% females) were included. Of 976 with valid TE values, 149 (15.3%) had liver stiffness ≥7.9 kPa. Of 892 with a valid ELF, 262 (29.4%) had ELF ≥9.8. Age and BMI were independently associated with elevated liver stiffness and ELF. Neither MTX cumulative dose nor duration was associated with elevated liver stiffness. Diabetes was the most significant risk factor associated with liver stiffness ≥7.9 kPa (adjusted odds ratio = 3.19; 95% CI 1.95–5.20; p <0.001). Regular use of non-steroidal anti-inflammatory drugs showed the strongest association with ELF ≥9.8 (odds ratio = 1.76; 95% CI 1.20–2.56; p = 0.003), suggesting the degree of joint inflammation in RA may confound ELF as a non-invasive marker of liver fibrosis.
The risk of liver fibrosis attributed to MTX itself might have been previously overestimated; there is a need to consider modifying current monitoring guidelines for MTX.
Impact and implications
Current guidelines recommend intensive (2-3 monthly) monitoring strategies for patients on long-term methotrexate therapy due to the potential risk of liver fibrosis. Evaluation of the association using two validated non-invasive markers of liver fibrosis, liver stiffness and enhanced liver fibrosis score, in a large cohort of patients with rheumatoid arthritis or psoriasis shows that the reported risk has previously been overestimated. The clinical focus should be to improve patients’ metabolic risk factors, diabetes and BMI, that are independently associated with liver stiffness. There is a need to consider modifying current treatment monitoring guidelines for methotrexate.

Journal Article Type Article
Acceptance Date Dec 19, 2022
Online Publication Date Jan 23, 2023
Publication Date 2023-05
Deposit Date Dec 19, 2022
Publicly Available Date Jan 24, 2024
Journal Journal of Hepatology
Print ISSN 0168-8278
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 78
Issue 5
Pages 989-997
Keywords Methotrexate; hepatotoxicity; rheumatoid arthritis; psoriasis; liver fibrosis; transient elastography; liver stiffness;Enhanced Liver Fibrosis
Public URL


Visual-abstract-JHEPAT-D-22-01456 (158 Kb)

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