Methotrexate in Rheumatoid Arthritis: A Pillar of Therapy in the Age of Precision Medicine

ABSTRACT

Objectives: To comprehensively understand the current research status of methotrexate (MTX), this study analyzed data on the phases of MTX-related clinical trials registered between 1990 and 2025. Methods: Sixteen clinical trial registries were searched for MTX trials in Rheumatoid Arthritis (RA) treatment registered by March 3, 2025, yielding 2,541 initial records. Inclusion criteria were clinical trials involving RA or MTX as the main intervention or control; trials not related to RA, non-clinical studies, or those with significant data omissions were excluded, resulting in 390 valid trials. Data were categorized by time, geography, and study type, and analyzed descriptively. Results: The number of MTX trials surged from one in 1990-2000 to 260 from 2011 to 2025, accounting for 66.7% of the total. Phase III trials were the most common during this period (67 trials, 25.8%), followed by Phase IV (45 trials, 17.3%) and Phase II (27 trials, 10.4%), highlighting a focus on efficacy validation. Combination therapy trials now represent 67.4% (263 trials) compared to 32.6% (127 trials) for monotherapy. In China, combination therapy trials notably increased, totaling 70 during 2011-2025. Conclusions: As the gold standard cornerstone of RA treatment, MTX remains indispensable in the era of targeted therapies owing to its multi-target immunomodulatory effects and cost-effectiveness. The predominance of combination therapy studies reflects MTX ’ s adaptability to modern multi-drug synergistic demands, emphasizing the need for optimized study designs to enhance the reliability of efficacy assessments.