Is split-dose methotrexate superior to single-dose methotrexate in RA?

An Indian study compared the efficacy of weekly oral split-dose methotrexate with single-dose methotrexate in participants with rheumatoid arthritis (RA). At 24 weeks, the primary endpoint, an EULAR good response, was not significantly different. However, EULAR good response and other secondary outcomes at 16 weeks favoured oral split-dose methotrexate. No major adverse events (AEs) were detected.

The bioavailability of methotrexate above an oral dose of 15 mg is limited. A subcutaneous formula has been shown to improve efficacy, but many patients do not widely accept it, and it is unavailable in numerous countries. Split-dose oral methotrexate results in higher blood levels compared with single-dose, but its clinical efficacy is unknown. A multicentre, open-label, randomised clinical trial compared the efficacy, safety, and tolerability of once-weekly oral split-dose methotrexate with single-dose methotrexate in RA [1].

Participants were randomised 1:1 to a single dose (25 mg) or split-dose (10 mg in the morning, 15 mg in the evening of the same day) once a week for 24 weeks. Disease activity was measured by Disease Activity Score 28-joint count (DAS28) using erythrocyte sedimentation rate (ESR) at 16 and 24 weeks. At 16 weeks, either leflunomide or sulfasalazine could be added if DAS28 was ≥3.2. The primary outcome was EULAR good response at 24 weeks, while secondary outcomes were EULAR responses at 16 weeks, DAS28, ACR20, ACR50, ACR70 and Health Assessment Questionnaire (HAQ) at 16 and 24 weeks.

The study cohort consisted of 253 RA participants. The mean age was 42.2 years, and the mean disease duration was 2.1 years. Baseline DAS28 was comparable between groups. After 16 weeks, split-dose methotrexate showed better efficacy than the single-dose group, with a significantly higher EULAR good response (21.9% vs 9.6%; P=0.007), lower DAS28 (4.4 vs 5.1; P<0.001), and higher ACR20 (76.6% vs 52%; P<0.001), ACR50 (54.7% vs 35.2%; P=0.002), and ACR70 (25.8% vs 13.6%; P=0.02) responses. However, no differences in efficacy measures were observed at 24 weeks. The percentage of participants reaching the primary endpoint of EULAR good response after 24 weeks was 28.9% in the split-dose group and 22.4% in the single-dose group (P=0.236). Additionally,  after 16 weeks, fewer patients in the split-dose group (35%) needed the addition of a DMARD compared with the single-dose group (54.5%; P=0.005). The authors hypothesised that the lack of a significant difference between the groups after 24 weeks may be related to the study design, including an erroneous choice of the primary endpoint.

There were 3 major AEs in the split-dose group and 1 in the single-dose group. Any symptomatic AE was reported by 67.8% and 58.8% of participants, respectively.

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   1. Dhir V, et al. Comparison of two dosing schedules for oral methotrexate (split-dose versus single-dose) once weekly in patients with active rheumatoid arthritis: A multicenter, open label, parallel group, randomized controlled trial (SMART Study). 1583, ACR Convergence 2023, 10–15 November, San Diego, USA.

 

Medical writing support was provided by Michiel Tent.
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Posted on 1 December 20231 December 2023