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

## TL;DR

This study finds that methotrexate users with metabolic syndrome and MASLD have higher risks of liver injury over time.

## Contribution

The study uses real-world data to show increased liver injury risks in methotrexate users with metabolic syndrome and MASLD.

## Key findings

- MTX users with metabolic syndrome had higher odds of hepatic enzyme elevations and liver cirrhosis over 10 years.
- Patients with MASLD had higher odds of clinically significant drug-induced liver injury compared to those without MASLD.
- Propensity score matching confirmed increased liver injury risks in MTX users with metabolic syndrome.

## Abstract

Background/Objectives: 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. Methods: 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. Results: 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). Conclusions: 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.