Split-dose methotrexate lowers need for more DMARDs vs single dose in rheumatoid arthritis
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SAN DIEGO — Split-dose methotrexate had greater efficacy and reduced the need for additional disease-modifying antirheumatic drugs at 16 weeks vs. a single dose for rheumatoid arthritis, according to data presented at ACR Convergence 2023.
“I don’t need to tell this audience the utility of methotrexate in rheumatoid arthritis,” Varun Dhir, MD, of the Postgraduate Institute of Medical Education and Research, in Chandigarh, India, told attendees. “It is the gold standard.”
However, Dhir added that there remain questions about whether patients can sustain methotrexate monotherapy without adding on other disease-modifying antirheumatic drugs or biologics.
“So, we asked the question: Can we use pharmacokinetics to improve efficacy of methotrexate?” he said.
For Dhir, the answer is “yes,” due to the established efficacy of the drug’s subcutaneous formulation. However, injections are not attractive for some patients, which raises the additional question of whether an oral split dose might be another solution to prolonged methotrexate use.
The researchers suggested that splitting the dose in morning and evening may lead to increased blood levels and, consequently, improved efficacy in patients with RA. However, little is known about the effectiveness of this approach.
To compare the efficacy, safety and tolerability of weekly, oral split-dose vs. single-dose methotrexate in patients with RA, Dhir and colleagues conducted SMART, a multicenter, open-label, parallel-group, randomized controlled trial. Participants included 253 patients aged 18 to 60 years with a RA disease duration greater than 5 years, who were not using DMARDs save for hydroxychloroquine and/or low-dose prednisolone.
Among these patients, 128 were randomly assigned the split-dose regimen, while 125 were assigned the single dose. Patients in the split-dose group received 10 mg in the morning and 15 mg in the evening. The single dose was 25 mg. The treatments were administered once weekly for a duration of 24 weeks. The cohort was 83% women, with a mean age of 42.2 years (SD, ±10.4) and a mean disease duration of 2.1 years (SD, ±1.5). The primary endpoint was EULAR good response at 24 weeks. Secondary endpoints included EULAR response at 16 weeks, as well as DAS28, ACR20, ACR50 and ACR70 response, along with HAQ and safety outcomes, at 24 weeks.
EULAR good response rates were 28.9% for the split-dose regimen and 22.4% for the single-dose regimen (P = .236), according to Dhir.
“There were higher taller peaks for the split dose group, but it was not statistically significant,” he said.
According to the researchers, the mean difference in EULAR good/moderate response was 17.4% higher in the split-dose group at 16 weeks. Also at 16 weeks, the split-dose group bested the single dose in terms of ACR20 (difference, 24.6%; 95% CI, 13.1-36), ACR50 (difference, 19.5%; 95% CI, 7.5-31.5%) and ACR70 (difference, 12.2%; 95% CI, 2.5-28.9) response.
However, results from 24 weeks did not demonstrate a persistent improvement of the split dose over the single dose in the other outcomes of interest.
“At 24 weeks, none of the differences in secondary response were statistically significant,” Dhir said.
HAQ scores also were comparable between the two groups at both 16 and 24 weeks.
No major adverse events were reported. Transaminitis and persistent transaminitis incidence were significantly greater in the split-dose group at 16 weeks, while leucopenia was more common in the single-dose group at 24 weeks. Both regimens were tolerated comparably, according to the researchers.
“The primary efficacy outcome of this study was not met,” Dhir said. “However, the secondary outcomes at 16 weeks showed that the split dose of methotrexate had better efficacy than the single dose.”
Dhir suggested that different endpoints may be considered for future research assessing this approach.
“It did seem that splitting the dose helps in many ways,” he said.
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Dhir V. Abstract 1583. Presented at: ACR Convergence 2023; Nov. 10-15, 2023; San Diego.
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