SMART study - Single vs. Split Dose Methotrexate in RA Save

Split dose weekly, oral methotrexate (MTX) was shown to be superior to single dose MTX in treating active rheumatoid arthritis (RA) patients.

This open-label (blinded assessor) randomized controlled trial was conducted across six university hospitals in India and enrolled patients with seropositive RA with active RA (TJC28 ≥ 4; SJC28 ≥ 2). Patients were treated with either split-dose (15 mg morning, 10 mg evening) or single-dose (25 mg) once weekly oral methotrexate for 24 weeks (the primary endpoint). But at 16 weeks, if patients did not achieved a DAS28 < 3.2, a second DMARD could be added (leflunomide, sulfasalazine). Primary outcome was a EULAR good response at 24 weeks and 16 weeks respectively. 

A total of 253 patients [83% female, mean age 42.2 years, mean disease duration 2.1 yrs] were enrolled  While there was no significiant difference between groups (split vs single dose) at 16 weeks (+ 6.5%, p = 0.263), there was a significant benefit for split dose MTX at at 16 weeks (before the addition of a 2nd DMARD in nonresponders)(+ 12.3%, 95% CI 3.5 to 21.3%, p = 0.008).  Moreover, split-dose patients had less need for a second DMARD at 16 weeks (p = 0.003). Numerically higher transaminitis and intolerance occurred with split-dose MTX.

Split-dose oral MTX should be preferred, especially in those RA patients receiving 15 mg or more per week.  Split-dose MTX delivers more bioavailable MTX. Hence, it is not surprising those patients may experience more intolerance and transaminitis.