Subcutaneous methotrexate compared with oral methotrexate in rheumatoid arthritis: a systematic review and meta-analysis.

To integrate evidence from randomized controlled trials (RCTs) comparing subcutaneous (SC) and oral methotrexate (MTX) for rheumatoid arthritis (RA) to provide optimal clinical treatment strategies. This meta-analysis conducted comprehensive search of PubMed, Web of Science, Embase and Cochrane Library, retrieving all relevant RCTs published up to June 18, 2025. Random-effects models were utilized to calculate the relative risk (RR), mean difference (MD) and their 95% confidence intervals (CIs), to evaluate efficacy and safety between subcutaneous injections and oral administration of MTX. A total of 1,034 articles were retrieved, and 9 RCTs that met the criteria were ultimately included, involving 974 RA patients in total. In the primary random-effects analyses, compared to oral MTX, subcutaneous MTX increased the ACR20 response rate (RR = 1.15; 95%CI: 1.05, 1.25), increased the ACR50 response rate (RR = 1.14; 95%CI: 1.01, 1.29), and reduced the incidence of gastrointestinal (GI)-related adverse event (AE) (RR = 0.58; 95%CI: 0.40, 0.83) and diarrhea (RR = 0.42; 95%CI: 0.21, 0.84). Fixed-effect sensitivity analyses supported the ACR20 and GI-related safety findings, but the ACR50 result was attenuated. Subcutaneous MTX did not show statistically significant differences in ACR70 response rate, DAS28-ESR score, bioavailability area under the curve, Cmax, or the incidence of other AE. Compared with oral administration, subcutaneous MTX was associated with a higher ACR20 response and lower GI-related AE and diarrhea in the primary random-effects analyses. These findings suggested that subcutaneous MTX may be an effective and generally well-tolerated option, particularly for patients with inadequate response or poor gastrointestinal tolerability to oral MTX, while evidence for ACR50, ACR70, DAS28-ESR and bioavailability remains less certain.