Background Recent trend as well as recommendation (3e initiative) of starting with higher dose of methotrexate, i.e., 15 mg instead of conventional 7.5 mg per week in rheumatoid arthritis. However, lack of studies comparing different doses.
Objectives To compare efficacy and safety of starting methotrexate at 15 and 7.5 mg/week followed by similar escalation (2.5 mg biweekly)
Methods Open label parallel group randomized controlled trial of 12 weeks duration. Included 100 RA patients, 18 to 65 years, having active disease (DAS28-3variables≥5.1) and not on methotrexate >2 months. Could be on concomitant steroids (prednisolone=<7.5 mg/d) and other DMARDs. Patients allocated to group 1 (7.5mg) or group 2 (15 mg) by simple randomization using random number table (concealed by envelopes). Methotrexate increased biweekly by 2.5mg. Patients followed up (assessor blinded) 4 weekly for disease activity, cytopenia (platelet < 1,00,000 or WBC < 4000), transaminitis (>2ULN) and adverse symptoms. Adverse symptoms assessed using performa. Primary endpoint was change in DAS28-3v at 12 weeks. Secondary end points were (i) Patients who withdrew due to any cause (ii) Patients who withdrew due to intolerance (iii) Patients with cytopenia or transaminitis. Intention to treat analysis. Trial# NCT01404429
Results Among 100 patients, 67 were RF+, 27 had erosions, 3 on concomitant DMARDs. Group 1 (7.5mg) included 47 patients and group 2 (15mg) included 53 patients. Both these groups had similar baseline characterstics:age (44.5±10.3, 42.8±11.2 yrs), gender (F:M=36:11, 42:11), disease duration (4.8±4.8, 4.7±4.5 yrs), DAS28-3v (6.2±0.7, 6.2±0.8) and use of concomitant oral steroids (4,9, p=0.2). At 12 weeks, there were similar number of non-completers in both groups due to any reason (9, 7, p=0.4) as well as those who did not complete study due to adverse effects (2,2, p=0.9). There was no difference in DAS28-3v at 4, 8 or 12 weeks. At 12 weeks, DAS28-3v changed by -0.47±0.86 and -0.55±0.79 in group 1 and 2 (p=0.60). The change in HAQ in both groups was also similar (-0.17±0.48, -0.28±0.44, p=0.22). No difference in episodes of transaminitis (6,7, p=0.8) or cytopenias (1,2, p=0.9). More patients experienced nausea in group 2 (RR 1.6, 95%CI 1.1-2.2), but no difference in the severity of nausea. No difference in other adverse symptoms (Table)
Conclusions Starting with either 7.5 or 15 mg per week of methotrexate, when followed by similar escalation, led to similar decline in disease activity at 12 weeks. There was no difference in the episodes of cytopenias/transaminitis. Although, more patients experienced nausea in 15 mg group, this was not more severe and did not lead to higher drop outs.
Ann Rheum Dis 2009;68:1086–93.
Acknowledgements Drugs given as gift from Zydus Synovia Pharmaceuticals, India.
Disclosure of Interest None Declared