Revisiting Liver Monitoring During Methotrexate Therapy in Rheumatoid Arthritis: Implications of HBV Reactivation, MASLD, and Non-invasive Fibrosis Assessment

Abstract

Liver function monitoring remains a cornerstone of safety surveillance during methotrexate (MTX) therapy for rheumatoid arthritis (RA). Traditionally, monitoring has focused on hepatitis B virus (HBV) reactivation and chronic MTX hepatotoxicity. Because HBV persists in hepatocytes as covalently closed circular DNA (cccDNA) even after apparent clinical resolution of infection, all individuals with previous HBV exposure remain at risk of viral reactivation. Accordingly, screening for previous HBV infection before initiating MTX is essential, and regular monitoring of HBV DNA should be considered in patients with resolved or chronic HBV infection. Close collaboration with hepatology specialists is required to ensure timely initiation of nucleos(t)ide analogue therapy when indicated.

In contrast, the conventional concept of chronic MTX-induced hepatotoxicity has been increasingly challenged. Recent studies employing non-invasive fibrosis assessment tools have demonstrated little or no association between cumulative MTX dose or treatment duration and the progression of liver fibrosis. These findings suggest that severe chronic liver injury caused solely by MTX is uncommon and that the hepatotoxic potential of MTX may have been substantially overestimated.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the leading chronic liver disease worldwide and appears to be at least as prevalent among patients with RA than in the general population. Therefore, evaluation and management of MASLD should be considered as part of routine clinical care for patients with RA. Because liver fibrosis is the most important determinant of long-term hepatic outcomes, monitoring strategies should incorporate fibrosis assessment using non-invasive tools such as the fibrosis-4 (FIB-4) index and elastography-based liver stiffness measurement.