Divide and conquer: splitting MTX doses in RA

2 minute read

The SMART Study invites us to re-evaluate our approach to MTX dosing.

In the world of rheumatoid arthritis (RA) treatment, methotrexate (MTX) stands as a cornerstone therapy, and most of us rheumatologists would think we know how to use this old drug effectively.

Yet its administration often follows a path of least resistance – a single weekly dose. The uncommon practice of split dosing is largely sidestepped due to concerns about patient confusion and dosing errors. I have used it (sparingly) in the hope it might reduce side effects such as nausea and some patients seem to find this approach useful.

The SMART Study, presented by Dr Varun Dhir at ACR Convergence 2023 (abstract 1583), delved into whether splitting the weekly MTX dose could enhance efficacy and affect tolerance. Split-dose oral MTX (morning, evening same day) has been shown to improve bioavailability compared to a single-dose.

Conducted across six centres, the study randomised 253 seropositive RA patients (83% female) with active disease. They were divided into two groups: one receiving a single 25mg weekly dose and the other taking a split dose (10mg in the morning and 15mg in the evening). Patients were followed 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.

At 16 weeks, the results pointed to a distinct advantage for the split-dose regimen.

The group demonstrated a significantly lower DAS28 score compared to the single-dose group (4.4 vs. 5.1). Furthermore, a higher proportion achieved EULAR good responses and ACR20, 50, and 70 scores. Notably, only 35% of patients in the split-dose group needed additional DMARDs, compared to 54.5% in the single-dose group. At the 24-week checkpoint, the split-dose group maintained a lower DAS28 (4.1 vs 4.5), though other efficacy measures showed no significant difference.

There were no major adverse events. There was a trend to higher incidence of persistent transaminitis in the split-dose group. No significant difference in symptoms of intolerance was found between the groups.

As rheumatologists, the SMART Study invites us to re-evaluate our approach to MTX dosing. The potential for improved patient outcomes with split dosing of a well-loved, very cheap medication is compelling.

  • 1583 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)

Dr Irwin Lim is the editor of Rheumatology Republic. He is a Sydney-based rheumatologist and director of BJC Health.

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