Overweight Impairs Escalating Optimal Methotrexate Dose and Effect via Liver Dysfunction in Japanese Patients With Rheumatoid Arthritis

Aim To evaluate the impact of overweight on methotrexate (MTX) efficacy and liver function in Japanese patients with rheumatoid arthritis (RA), and to explore whether liver dysfunction contributes to MTX dose limitation and treatment resistance in overweight individuals. Methods This retrospective cohort study included 71 RA patients who initiated MTX at a single center in Japan between April 2016 and December 2021. Patients were stratified by body mass index (BMI) into normal weight (< 25.0 kg/m 2 ) and overweight (≥ 25.0 kg/m 2 ) groups. Clinical data including DAS28‐CRP, liver enzyme levels, and MTX dosing were assessed at baseline and at 12, 24, and 48 weeks. The primary outcome was the change in DAS28‐CRP (ΔDAS28‐CRP) over time. Non‐parametric tests were used for comparisons. Results The overweight group showed significantly smaller ΔDAS28‐CRP at 24 and 48 weeks ( p < 0.05), suggesting a reduced clinical response to MTX, potentially related to lower MTX dose per body weight and elevated liver enzymes limiting dose escalation. While absolute MTX doses were similar, MTX dose per body weight was significantly lower in the overweight group throughout the study ( p < 0.05). MTX dose per body weight was negatively correlated with DAS28‐CRP at 48 weeks ( r = −0.285, p = 0.016). Overweight patients had higher AST, ALT, and γ‐GTP levels, and a greater prevalence of fatty liver, suggesting liver dysfunction may have limited MTX escalation. Tender joint counts and CRP levels remained elevated in the overweight group, independent of osteoarthritic changes. Conclusion Overweight was associated with reduced MTX response in Japanese RA patients, potentially due to elevated liver enzymes limiting MTX dose escalation and leading to suboptimal dosing per body weight. Weight management and lifestyle interventions may improve treatment outcomes in overweight RA patients.