Oral methotrexate at doses 15-25 mg/week is non-inferior to parenteral regarding efficacy and safety in the treatment of rheumatoid arthritis: a systematic review and meta-analysis

Objective The most optimal route of methotrexate (MTX) administration for the treatment of rheumatoid arthritis (RA) has not yet been established. Our aim was to compare the efficacy, safety, and bioavailability profiles of oral MTX with parenteral MTX in adult patients with RA. Methods PubMed, Web of Science, the Cochrane Central Register of Controlled Trials, and ClinicalKey were searched for published randomized trials through December 30, 2021. Random-effects models were used to assess pooled odds ratios (ORs) and mean differences (MDs) with 95% confidence intervals (95% CIs). This review was registered in PROSPERO (number CRD42022297810). Results Of 705 identified trials, 6 met the criteria and were included in our meta-analysis (644 subjects). Compared to parenteral MTX, oral MTX yielded no significant differences in response rates of 20% (OR: 0.68; 95% CI: 0.40-1.75), 50% (OR: 0.75; 95% CI: 0.44-1.28), and 70% (OR: 0.75; 95% CI: 0.51-1.09) improvement according to American College of Rheumatology criteria (ACR20/50/70 response), and no increased relative risk of any adverse event (OR: 1.20; 95% CI: 0.49-2.93). Furthermore, parenteral MTX showed a significant advantage in the value of AUC(0-t) (MD: - 536.36; 95% CI: - 1054.22 to - 18.50), but not in C-max (MD: - 12.86; 95% CI: - 84.30 to 58.58) and T-max (MD: - 0.31; 95% CI: - 0.70 to 0.08) compared with oral MTX. Conclusion Oral MTX at doses of 15-25 mg/week in active RA is not inferior to parenteral regarding efficacy and safety. This supports the initial therapy with oral MTX.