Factors associated with methotrexate-related gastrointestinal intolerance and toxicity in rheumatoid arthritis and psoriatic arthritis

Background: Methotrexate (MTX) is the cornerstone therapy for rheumatoid arthritis (RA) and psoriatic arthritis (PsA), yet gastrointestinal adverse events (GIAE), including intolerance and hepatotoxicity, remain major causes of treatment modification and discontinuation. Identifying baseline predictors of these reactions is essential to optimizing treatment safety and persistence. Objectives: To identify clinical and laboratory predictors of MTX-related GIAE and to compare risk profiles between RA and PsA. Methods: Retrospective observation study including MTX-treated patients with RA or PsA. Baseline demographics, comorbidities, laboratory results, MTX characteristics, and concomitant medications were extracted from medical records. GIAE comprised either gastrointestinal (GI) intolerance or toxicity. Associations were assessed through univariate tests followed by multivariable logistic regression. Kaplan-Meier curves evaluated treatment survival according to administration route and disease type. Results: Among 369 patients (62.6% female; mean age 57.5 +/- 12.6 years), 50.9% developed GIAE. GI intolerance occurred in 127 patients, mainly presenting as nausea (68.5%). GI toxicity occurred in 75 patients, with baseline alanine transaminase (ALT) significantly higher in affected patients. Independent predictors of GIAE were diabetes mellitus (aOR 2.22), female sex (aOR 1.82) and PsA (aOR 1.67). Predictors of GI intolerance included higher baseline ALT (aOR 1.02), concomitant leflunomide (aOR 1.91), and female sex (aOR 2.08). Predictors of GI toxicity included diabetes (aOR 2.98), alcohol consumption (aOR 2.79), and baseline ALT (aOR 1.03). Survival analysis showed earlier MTX-related GIAE in patients receiving the subcutaneous formulation across diseases (p<.001). Conclusions: MTX-related GIAE are frequently and largely driven by metabolic comorbidities, lifestyle exposures, sex and baseline ALT. These routinely available parameters allow early identification of high-risk patients and may guide personalized MTX initiation and monitoring strategies.