S2561 Increased Incidence of Liver Injury and Cirrhosis in Patients With Metabolic Syndrome Taking Methotrexate: A Multi-Center Retrospective Study

Introduction: Metabolic syndrome (MetS) is a recognized risk factor for metabolic-associated steatohepatitis (MASH). Methotrexate (MTX), commonly used for various indications, is implicated in hepatotoxicity which is reported to closely resembles MASH on histology. This study investigates how the incidence of drug-induced liver injury (DILI) in MTX users varies by MetS status. Methods: Patients prescribed MTX from 2016 to 2024 were identified in the SSM Health system Virtual Data Warehouse. DILI, MetS and related comorbidities were identified by using International Classification of Diseases, Tenth Revision codes. After excluding patients with chronic liver disease (CLD) and prior DILI, we measured time to DILI and cirrhosis diagnosis and the association with MetS. Demographics and comorbidities were matched using proportional hazard regression with Inverse Probability of Treatment Weighting (IPTW). Incidence of DILI and cirrhosis was measured over 3- and 6-years period after MTX initiation in each patient. Results: Among 21,222 adult MTX users without prior CLD or DILI, 9.6% had MetS. Those with MetS were older (61.5 vs 55.0 years, P < .0001) and with higher prevalence of chronic cardiovascular (CVD), kidney (CKD), pulmonary and peripheral vascular (PVD) comorbidities (all P < .0001). DILI and cirrhosis incidence was higher in MTX users with MetS vs those without MetS (DILI: 1.10% vs 0.39% at 3 years, 1.93% vs 0.72% at 6 years; cirrhosis: 2.71% vs 0.91% at 3 years, 5.32% vs 1.47% at 6 years; all P < .0001). IPTW-adjusted HRs for MetS and DILI were 1.98 (1.50–2.62) and 1.90 (1.50–2.41) at 3 and 5 years; and 2.01 (1.67–2.41) and 2.35 (2.01–2.75) for cirrhosis, when compared with those without MetS. DILI was not associated with age, sex, or race, though Black race was linked to lower cirrhosis risk. Higher DILI risk was associated with greater socioeconomic deprivation and chronic pulmonary, CVD, and PVD; while these comorbidities were also associated with higher risk of cirrhosis. Conclusion: MetS was independently associated with increased risk of DILI and cirrhosis among MTX users. Although cumulative MTX exposure was not determined, these findings suggest metabolic factors may sensitize the liver to MTX-related injury. Future studies should evaluate the impact of cumulative dose of MTX and metabolic risk in prospective studies.