Risk of Liver Fibrosis in Methotrexate-Treated Patients: A Systematic Review

Methotrexate (MTX), an antifolate agent, is recommended as the first-line disease-modifying antirheumatic drug (DMARD). In this systematic review, our goals were to assess liver fibrosis in methotrexate-treated patients, evaluate liver fibrosis in relation to treatment duration and cumulative dose, and identify differences based on the underlying disease. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to perform the systematic review. We thoroughly searched PubMed, PubMed Central (PMC), and Cochrane library databases to identify relevant articles based on predefined selection criteria. Studies were selected based on the following predefined eligibility criteria: English language, papers from the last 20 years, systematic reviews, observational studies, randomized controlled trials (RCTs), and clinical trials, which included papers on MTX playing roles in the development of liver fibrosis with the derived data transferred to a template. Following that, quality was assessed using the appropriate assessment tool for each study. The initial search yielded 512 results. Following a thorough review, 10 studies were chosen for final consideration: eight observational studies and two systematic reviews. Liver enzyme (LE) elevations during MTX therapy are a common but transient problem. Serial abnormal LE tests may be associated with liver pathology, but fibrosis development is uncommon. However, it is unclear from the literature how therapy should be adjusted in the case of elevated LE and to what extent MTX is linked to liver toxicity; definitive conclusions cannot be drawn because more research is needed.