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

BackgroundThe risk of significant liver fibrosis from prolonged methotrexate (MTX) exposure has been estimated in around 5% of patients, which has led to intensive monitoring strategies. However, the evidence is derived from retrospective studies that underreported risk factors of liver disease. We evaluated the risk of long-term MTX therapy on liver fibrosis in a longitudinal cohort study using two non-invasive markers.MethodBetween 2014-2021, adult patients diagnosed with Rheumatoid Arthritis (RA) or psoriasis for ≥2 years were recruited prospectively from six UK sites. MTX group included patients who received MTX for ≥6 months, whereas unexposed group included those who never received MTX. All patients underwent full liver profiling, enhanced liver fibrosis (ELF) markers, and transient elastography (TE).Results999 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 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 OR = 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 (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 fibrosisConclusionThe risk of liver fibrosis attributed to MTX itself might have been previously overestimated; there is a need to consider modifying current MTX therapy monitoring guidelines.