Background/Purpose: Methotrexate (MTX), the anchor drug for rheumatoid arthritis (RA), has limited bioavailability above an oral dose of 15 mg. Split-dose oral MTX (morning, evening same day) has been shown to lead to higher blood levels compared to single-dose, however, its effect on clinical efficacy is unknown. Thus, we planned to compare the efficacy, safety and tolerability of oral split-dose to single-dose MTX once a week in RA.

Methods: This multicenter (six centers), open-label (assessor blinded) RCT recruited patients with Rheumatoid arthritis (2010 ACR/EULAR), 18-60 years of age, seropositive (RF or ACPA), disease duration < 5 years, not on DMARDs (except hydroxychloroquine and/or low-dose prednisolone) but with active disease (TJC28 ≥4 and SJC28 ≥2). Patients were randomized 1:1 (online generator) and allocated (concealed using SNOOSE) into either single dose (25 mg) or split-dose (10 mg morning, 15 mg evening, same day) once weekly MTX for 24 weeks. Disease activity was assessed by DAS28(ESR) at 16 and 24 weeks. At 16 weeks, either leflunomide or sulfasalazine could be added if DASS28≥3.2. (Figure 1) Primary outcome was EULAR good response at 24 weeks, and secondary outcomes were EULAR response at 16 weeks, DAS28, ACR20, 50, 70 and HAQ at 16 and 24 weeks. Safety outcomes included laboratory abnormalities. Intolerance to methotrexate was assessed using MISA score. Analysis was by intention-to-treat and missing data was accounted by last-observation-carried-forward (locf), and non-response was imputed for categorical variables. Trial registration CTRI/2021/02/03136

Results: 253 patients (females 83%), with age and disease duration (mean ± SD) of 42.2±10.4 and 2.1±1.5 years, were randomized to split-dose (n=128) and single-dose (n=125) group. Baseline DAS28 was comparable, 6.5±1.0 and 6.6±1.0 (p=0.554), but after 16 weeks of MTX monotherapy, DAS28 was significantly lower in split-dose (4.4±1.4) than single-dose (5.1±1.5, p< 0.001) group. At 16 weeks, there was significantly higher EULAR good response (difference 12.3%, CI 12.4 to 66); ACR20 (difference 24.6%, CI 13.1 to 36), ACR50 (difference 19.5%, CI 7.5 to 31.5%) and ACR70 (difference 12.2%, CI 2.5 to 28.9) in split versus single-dose group. Fewer patients in the split-dose (35%) compared to single-dose (54.5%, p=0.005) group were started on additional DMARD at 16 weeks; leflunomide was started in 34 (30%) and 54 (49%), and sulfasalazine in 6 each. At 24 weeks, there was significantly lower DAS28 in split-dose (4.1±1.5) compared to single-dose (4.5±1.5, p=0.03) group, however, no difference in other efficacy measures (Table 1). There was no difference in HAQ scores at 16 or 24 weeks. There was no major AE, but significantly higher frequency of transaminitis at 16 weeks and persistent transaminitis in split-dose group. Frequency of leucopenia was higher in single-dose group at 24 weeks (Table 2). No significant difference in symptoms of intolerance between groups. (Table 2)

Conclusion: Oral split-dose MTX given once weekly in RA patients had significantly higher efficacy and reduced the need for additional DMARDs, compared to single-dose MTX given once a week. There was no major AE, but slight increase in frequency of persistent transaminitis in split-dose group.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/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/