Assessing the Impact of Metabolic Syndrome on Liver Outcomes in Methotrexate Users: A Retrospective Cohort Study

<b>Background/Objectives</b>: Methotrexate (MTX) is associated with hepatotoxicity, but distinguishing MTX-induced liver injury from hepatic dysfunction due to metabolic syndrome (MetS) is challenging. This study investigates the incidence of hepatic outcomes in long-term MTX users with and without MetS and metabolic dysfunction-associated steatotic liver disease (MASLD) using real-world data. <b>Methods</b>: This cohort study used the TriNetX research network to identify U.S. adults (≥18 years) on MTX, excluding those with pre-existing liver injury. Patients were grouped by MetS status (MTX-MetS vs. controls) and further sub-stratified based on MASLD status. Propensity score matching (1:1) was adjusted for demographics, comorbidities, and treatment. The primary outcomes included hepatic-enzyme elevations, hyperbilirubinemia, prolonged INR, and clinically significant drug-induced liver injury (DILI) at 3-, 5-, and 10-year follow-up. <b>Results</b>: Among 324,219 MTX users, 59,733 MTX-MetS patients were propensity matched with 59,733 controls. MTX-MetS patients demonstrated increased 10-year odds of hepatic-enzyme elevations (aOR = 1.41; 95%CI: 1.38-1.46), hyperbilirubinemia (aOR = 1.40; 95%CI: 1.32-1.49), prolonged INR (aOR = 1.58; 95%CI: 1.49-1.67), clinically significant DILI (aOR = 1.49; 95%CI: 1.41-1.57), and liver cirrhosis (aOR = 1.48; 95%CI: 1.35-1.63) compared to the controls. Patients with and without MASLD showed similar hepatic-enzyme, bilirubin, and INR elevations, with higher odds of DILI with MASLD (aOR = 1.56; 95%CI: 1.28-1.89). <b>Conclusions</b>: This study highlights the increased liver injury risk in MTX users with MetS and MASLD. Further studies are needed to distinguish the effects of MTX and metabolic dysfunction on liver outcomes.