Randomized controlled trial comparing 2 different starting doses of methotrexate in rheumatoid arthritis.Clin Ther 2014; 36(7):1005-15CT
Methotrexate (MTX) remains the gold standard disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA). Few studies have compared different starting doses of MTX in RA. We hypothesized that starting with a higher MTX dose may be more effective but associated with more adverse effects. We compared a starting dose of 7.5 versus 15 mg per week of MTX followed by similar fast escalation.
This was an open-label (blinded assessor), parallel-group, randomized controlled trial that included RA patients aged 18 to 65 years, not on MTX, and having active disease (Disease Activity Score for 28 joints using 3 variables [DAS28(3)] ≥5.1). Patients were randomized to receive MTX at a starting dose of 7.5 mg (group 1) or 15 mg (group 2) per week. The dose of MTX was escalated by 2.5 mg every 2 weeks to a maximum of 25 mg. Patients were seen every 4 weeks, and dose escalation was continued if DAS28(3) was >2.6 and there were no laboratory abnormalities (transaminitis [>2 × upper limit of normal] or cytopenia). The primary endpoint was change in disease activity at 12 weeks (assessed by using the DAS28). Secondary endpoints were patient withdrawals and episodes ofcytopenia or transaminitis. Adverse effects were ascertained by using a questionnaire. Both intention-to-treat and per-protocol analyses were performed.
We enrolled 100 patients (female:male ratio, 78:22) with a mean (SD) age of 43.6 (10.8) years and a disease duration of 4.7 (4.8) years. At baseline, patients had a mean DAS28(3) of 6.2 (0.7) and a Health Assessment Questionnaire score of 1.3 (0.6). Group 1 (7.5 mg) and group 2 (15 mg) included 47 and 53 patients, respectively, with no significant differences in baseline characteristics. At 12 weeks, the mean dose of MTX reached was 17.3 (4.6) mg in group 1 and 23.6 (3.0) mg in group 2 (P < 0.001). The 2 groups had a similar number of patient withdrawals. The mean change in DAS28(3) at 12 weeks in group 1 (-0.47 [0.86]) and group 2 (-0.55 [0.79]) was not significantly different (P = 0.60). The change in the Health Assessment Questionnaire score was also similar in the groups. The frequency of episodes of transaminitis (6 and 7; P = 0.8) and cytopenia (1 and 2; P = 0.9) did not differ significantly between groups 1 and 2, respectively. Results remained the same according to the per-protocol analysis. Among adverse effects, nausea was more common in group 2 compared with group 1 (relative risk, 1.6 [95% CI, 1.1-2.2]).
There were no significant differences in efficacy between the 2 starting doses of MTX. The fast escalation of dose in both groups may have blunted any advantage of starting at a higher dose. Nausea occurred more commonly in patients started on 15 mg of MTX. We suggest longer trials to confirm our findings. ClinicalTrials.gov identifier: NCT01404429.