Split-Dose Methotrexate Shows Early Advantage in Rheumatoid Arthritis Control: Indian SMART Trial
India: An Indian multicentre randomized controlled trial (SMART study) has provided new evidence on dosing strategies of oral methotrexate (MTX) in rheumatoid arthritis (RA).
The findings, published in Clinical Rheumatology by Dr. Chandra Bhushan Prasad and colleagues from the Division of Clinical Immunology and Rheumatology, PGIMER, Chandigarh, highlight that splitting the weekly methotrexate dose into morning and evening administrations may help achieve quicker disease control compared to the traditional single-dose regimen.
Methotrexate is widely regarded as the cornerstone drug in RA management, but debate continues on the optimal dosing schedule. Pharmacokinetic data have suggested that splitting the dose could improve bioavailability, yet clinical evidence on efficacy and safety has been limited until now.
The SMART trial, conducted across six leading university hospitals in India, enrolled 253 patients with active seropositive RA. The study population, predominantly female (83%), had a mean age of 42 years and an average disease duration of just over two years. Participants were randomly assigned to receive either a split-dose MTX regimen (15 mg in the morning and 10 mg in the evening) or a single weekly 25 mg oral dose for 16 weeks.
The primary endpoint was the proportion of patients achieving a “good” response by the European Alliance of Associations for Rheumatology (EULAR) criteria at 24 weeks. Secondary endpoints included response at 16 weeks and the need for additional disease-modifying antirheumatic drugs (DMARDs).
The key findings of the study were as follows:
- At 24 weeks, there was no significant difference between the two dosing strategies, with the split-dose group showing only a modest, non-significant 6.5% higher rate of good response compared to the single-dose group.
- At 16 weeks, patients on the split-dose regimen achieved a significantly higher EULAR good response (+12.3%).
- Fewer patients in the split-dose group required the addition of a second DMARD at 16 weeks (−19.5%).
- Both dosing regimens were generally well tolerated.
- The split-dose regimen showed slightly higher rates of transaminitis and drug intolerance, though these differences were not statistically significant.
The authors concluded that while the split-dose strategy did not outperform the single-dose regimen at 24 weeks, it offered earlier benefits in disease control and reduced the immediate need for treatment escalation. They noted that this pragmatic trial—the first to directly compare the two dosing schedules in RA—adds valuable insight for clinicians tailoring methotrexate therapy.
"The study reinforces methotrexate’s central role in RA treatment while suggesting that a split-dose regimen could be particularly beneficial for patients requiring faster control of disease activity, albeit with careful monitoring for side effects," the authors wrote.
Reference:
Prasad, C.B., Dhir, V., Gupta, R. et al. Split vs single-dose oral methotrexate in rheumatoid arthritis: a randomized controlled trial (SMART study). Clin Rheumatol (2025). https://doi.org/10.1007/s10067-025-07646-y
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