Split vs single-dose oral methotrexate in rheumatoid arthritis: a randomized controlled trial (SMART study).

Objective: Pharmacokinetic evidence suggests split dose of oral methotrexate increases bioavailability, but unproven to improve efficacy. Thus, we planned to compare clinical response of split vs single-dose oral methotrexate in rheumatoid arthritis (RA).

Methods: This pragmatic, open-label (blinded assessor) randomized controlled trial was conducted across six university hospitals in India and enrolled patients with seropositive RA with active disease (TJC₂₈ ≥ 4 and SJC₂₈ ≥ 2). They were randomized 1:1 to split-dose (15 mg morning, 10 mg evening) or single-dose (25 mg) once weekly oral methotrexate for 16 weeks, after which a second DMARD could be added. Primary outcome and key secondary outcomes were EULAR good response at 24 weeks and 16 weeks respectively. Analysis was by intention-to-treat with non-response imputation. Clinical Trials Registry-India CTRI/2021/02/031361.

Results: Two hundred fifty-three patients [83% female, mean age 42.2 years, mean disease duration 2.1 yrs] were randomized to receive either split-dose (n = 128) or single-dose (n = 125) methotrexate. Primary outcome, good response at 24 weeks, was not significantly higher with split-dose methotrexate (+ 6.5%, 95% CI - 4.2 to 17.2%, p = 0.263). However, key secondary outcome, good response at 16 weeks, was significantly higher with split-dose methotrexate (+ 12.3%, 95% CI 3.5 to 21.3%, p = 0.008). Also, less patients in split-dose group required addition of second DMARD at 16 weeks (- 19.5%, p = 0.003). Numerically higher transaminitis and intolerance occurred with split-dose MTX.

Conclusion: Although the primary outcome was not met, we found faster response and better efficacy at 16 weeks with split-dose oral MTX, and reduced need for a second DMARD. Key Points • This was the first RCT to compare split-dose (same-day, morning, evening) to single-dose oral methotrexate (MTX) and included 253 patients of RA. • Primary outcome was not met, i.e., split-dose MTX was not superior in terms of EULAR good response at 24 weeks. • However, key secondary outcome was met, i.e., split-dose MTX met led to significantly higher EULAR good response at 16 weeks; also it reduced need for addition of a second DMARD. • Split-dose MTX was associated with higher adverse effects (numerically) in terms of both intolerance and transaminitis.