Distinct clinical profiles of methotrexate intolerance and hepatotoxicity in psoriatic arthritis

Introduction: Methotrexate (MTX) is the most widely used conventional DMARD for psoriatic arthritis (PsA), but intolerance and hepatotoxicity often limit its long-term use. This study aimed to describe the prevalence and clinical correlates of MTX intolerance and hepatotoxicity in PsA patients. Methods: We conducted a retrospective study on adults with PsA who were exposed to MTX. Demographic, clinical, and treatment data were retrieved from electronic medical records. Intolerance was defined as discontinuation or dose reduction due to adverse effects, while hepatotoxicity was defined as discontinuation or dose reduction due to persistent liver enzyme elevation (≥2 times the upper limit of normal). Independent associations were explored using multivariable logistic regression. Results: Among the 341 patients included, MTX intolerance occurred in 26.7% and hepatotoxicity in 10.3%. Bivariate analysis showed that intolerance was associated with female sex, shorter psoriasis–arthritis delay, enthesitis, higher use of csDMARDs and ts/bDMARDs, and lower persistence of TNF and IL-17 inhibitors. No independent predictors of intolerance were identified. Hepatotoxicity was linked to male sex, dactylitis, hypertension, hyperuricemia, and treatment-refractory PsA. In multivariable analysis, hepatotoxicity was independently associated with arterial hypertension (OR 4.40; p 0.007) and treatment-refractory PsA (OR 6.23; p 0.016), and inversely associated with intolerance (OR 0.09; p 0.023). Conclusion: MTX intolerance and hepatotoxicity in PsA were associated with distinct clinical patterns: intolerance predominates in women and is associated with frequent therapeutic modifications, whereas hepatotoxicity is more common in men with metabolic comorbidities and treatment-refractory disease. Recognizing these patterns may help optimize MTX safety, guide therapeutic decisions, and enhance treatment persistence.