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)
Authors: Varun Dhir et al.
Methotrexate (MTX) has limited bioavailability above an oral dose of 15 mg and not infrequently the tolerance of higher doses of MTX is problematic. This randomized open-label (but blinded assessor) RCT compared the efficacy, safety and tolerability of oral split-dose to single-dose MTX once a week in RA. 253 patients were randomized 1:1 to either a single dose (25 mg) or split-dose (10 mg morning, 15 mg evening, same day) once weekly MTX for 24 weeks. After 16 weeks of MTX monotherapy, DAS28 was significantly lower in split-dose (4.4) than single-dose (5.1, p< 0.001) group, which was maintained at week 24 (4.1 versus 4.5, p=0.03). The response rates (EULAR good response, ACR20, ACR50 and ACR70) were also higher in split MTX versus single-dose MTX group. Overall, the authors do not describe significant difference in tolerance between groups, but slightly more transaminitis was recorded in the split-dose group and more leucopenia in the single-dose group.
This pragmatic trial challenges the dogma of once weekly MTX. The authors demonstrate convincingly that oral split-dose MTX (MTX 10 mg in the morning and 15 mg in the evening, on a single day/week) resulted in higher efficacy and reduced the need for additional DMARDs. The results of this Indian trial could certainly be applied to Swiss patients, in particular when higher doses of MTX are required and when the patient is co-operative and compliant.