Hepatotoxicity of Methotrexate in Patients with Psoriatic Arthritis: A Systematic Review of Randomized Control Trials

Abstract

Background: Methotrexate (MTX) remains widely used in the management of psoriatic arthritis (PsA), yet concerns regarding hepatotoxicity persist. Most available evidence is extrapolated from rheumatoid arthritis cohorts, with limited PsA-specific data. The extent to which MTX contributes to liver toxicity in PsA, particularly in randomized settings, remains unclear.

Objective: To systematically evaluate the hepatotoxic effects of methotrexate in adult patients with psoriatic arthritis using evidence from randomized controlled trials (RCTs).

Methods: A systematic review and meta-analysis were conducted in accordance with PRISMA 2020 guidelines (PROSPERO: CRD420261354168). Multiple databases (MEDLINE, EMBASE, CENTRAL, Web of Science, and ClinicalTrials.gov) were searched from inception to January 2026. Eligible studies included RCTs enrolling adults with PsA (CASPAR criteria) that reported liver-related outcomes with MTX exposure. Two analytical groups were defined: (1) trials in which MTX was part of the randomized intervention compared with a non-MTX comparator; and (2) trials in which MTX use was a stratification variable, enabling within-arm comparisons. The primary outcome was hepatotoxicity, defined by elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as treatment discontinuation due to liver-related adverse events. Risk ratios (RR) with 95% confidence intervals (CI) were pooled using a random-effects model. Risk of bias was assessed using the ROBUST RCT tool and Newcastle-Ottawa Scale (NOS), and certainty of evidence was evaluated using GRADE.

Results: A limited number of RCTs met inclusion criteria, reflecting the scarcity of PsA-specific hepatotoxicity data. Pooled analysis of Group 1 trials at approximately 24 weeks demonstrated a numerically higher risk of ALT elevation with MTX-containing regimens compared to active therapy alone (RR 2.22, 95% CI 0.50–9.79; I² = 38%), although this did not reach statistical significance and was characterized by wide confidence intervals. For AST elevation, no meaningful difference was observed (RR 1.14, 95% CI 0.75–1.75; I² = 0%). No cases of severe hepatotoxicity, treatment discontinuation due to liver injury, or hepatotoxicity-related mortality were reported in pooled analyses. Overall certainty of evidence was downgraded due to imprecision and limited sample size. Group 2 analyses (MTX as co-intervention) were heterogeneous and interpreted narratively. Conclusion: In RCT settings, methotrexate use in psoriatic arthritis is associated with a numerically higher but not statistically significant increase in liver enzyme elevations, without evidence of clinically significant hepatotoxicity. However, conclusions are limited by small sample sizes, heterogeneity in outcome definitions, and short follow-up durations. These findings highlight the need for larger, adequately powered studies with standardized hepatotoxicity endpoints to better define the hepatic safety profile of MTX in PsA.