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Split vs single-dose oral methotrexate in rheumatoid arthritis: a randomized controlled trial (SMART study)
Chandra Bhushan Prasad1, Varun Dhir2, Ranjan Gupta3
1Division of Clinical Immunology and Rheumatology, Department of Internal Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India.
Clinical Rheumatology
|August 29, 2025
Summary
Split-dose oral methotrexate showed faster clinical response and efficacy at 16 weeks in rheumatoid arthritis patients compared to single-dose. This regimen also reduced the need for additional disease-modifying antirheumatic drugs, despite similar overall efficacy at 24 weeks.
Area of Science:
- Rheumatology
- Clinical Pharmacology
- Pharmacoeconomics
Background:
- Pharmacokinetic data suggest split-dose oral methotrexate may enhance bioavailability.
- Clinical evidence supporting improved efficacy of split-dose methotrexate in rheumatoid arthritis (RA) is lacking.
- This study aimed to compare the clinical effectiveness of split-dose versus single-dose oral methotrexate in RA patients.
Purpose of the Study:
- To compare the clinical response of split-dose versus single-dose oral methotrexate in patients with active rheumatoid arthritis.
- To evaluate the efficacy and safety of different oral methotrexate dosing strategies.
Main Methods:
- A pragmatic, open-label, randomized controlled trial involving 253 patients with seropositive RA across six Indian university hospitals.
- Patients were randomized to receive either split-dose (15 mg morning, 10 mg evening) or single-dose (25 mg) oral methotrexate weekly for 16 weeks.
- Primary outcome was EULAR good response at 24 weeks; key secondary outcome was EULAR good response at 16 weeks. Intention-to-treat analysis was performed.
Main Results:
- No significant difference in EULAR good response at 24 weeks between split-dose and single-dose methotrexate (p=0.263).
- Significantly higher EULAR good response at 16 weeks was observed with split-dose methotrexate (p=0.008).
- Fewer patients in the split-dose group required a second DMARD at 16 weeks (p=0.003), though numerically higher transaminitis and intolerance were noted.
Conclusions:
- Split-dose oral methotrexate demonstrated faster efficacy and reduced the need for additional DMARDs at 16 weeks compared to single-dose, despite not meeting the primary outcome for 24-week response.
- The study provides evidence for improved short-term efficacy with split-dose oral methotrexate in RA.
- Higher rates of intolerance and transaminitis were numerically observed with the split-dose regimen.
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