Liver and Bile
J Hepatol. 2023;78(5):989–97
Risk of liver fibrosis associated with long-term methotrexate therapy may be overestimated
Background and 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. The authors evaluated the risk of long-term MTX therapy on liver fibrosis in a longitudinal cohort study using 2 non-invasive markers. Method: Between 2014 and 2021, adult patients diagnosed with rheumatoid arthritis (RA) or psoriasis for ≥ 2 years were recruited prospectively from 6 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.
Results: 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 body mass index 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 [OR] = 3.19; 95% confidence interval [CI]: 1.95–5.20; p < 0.001). Regular use of non-steroidal anti-inflammatory drugs showed the strongest association with ELF ≥ 9.8 (OR = 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.
Conclusion: The risk of liver fibrosis attributed to methotrexate (MTX) itself might have been previously overestimated; there is a need to consider modifying current monitoring guidelines for MTX.