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Maintenance of low disease activity is essential to prevent progression of joint damage in patients with active rheumatoid arthritis (RA); however, some individuals fail to respond to standard treatment with methotrexate.To determine the efficacy of conventional DMARD therapies in patients with early RA who do not respond to methotrexate monotherapy.This study was a post-hoc analysis of patients with recent-onset RA who formed two subgroups within the multicenter, randomized, controlled BeSt (Behandelstrategieën voor Reumatoide Artritis) trial. Patients' disease activity score (DAS; European League Against Rheumatism criteria) was assessed every 3 months for the 2-year study period. Patients were classified as treatment 'successes' if they achieved a DAS ≤2.4 and continued on that therapy during the remainder of the 2-year follow-up, or as 'failures' if they did not achieve a DAS ≤2.4. All patients began on mono-therapy with methotrexate 7.5 mg/week, which was increased to 15 mg/week after 4 weeks. At 3 months, methotrexate dose was increased to 25 mg/week in patients with a DAS >2.4. Patients who continued to have a DAS >2.4, or experienced adverse events, proceeded to the next treatment step with sequential DMARD monotherapy (group 1) or DMARD combination therapy (group 2).Sequential monotherapy, with a 1 month overlap period when treatments were switched, involved sulfasalazine 2,000-3,000 mg/day, then leflunomide 20 mg/day and finally methotrexate 25 mg/week plus 3-10 mg/kg/8 weeks infliximab; combination therapy comprised methotrexate 25 mg/week plus sulfasalazine 2,000-3,000 mg/day, then the addition of hydroxychloroquine 400 mg/day and prednisone 7.5 mg/day, and an eventual switch to methotrexate 25 mg/week and 3-10 mg/kg/8 weeks infliximab.The main outcome measure of treatment success or failure was DAS, assessed every 3 months. Radiography of hands and feet was assessed at baseline and after 2 years.A total of 244 patients were included in this analysis (126 in group 1 and 118 in group 2), of whom 107 (44%) were methotrexate successes after 6 months of therapy and 79 (32%) remained methotrexate successes at 2 years. Hand and foot radiographs from 213 patients showed that methotrexate successes had significantly less joint damage than did methotrexate failures (P = 0.007). During follow-up, 69 methotrexate failures proceeded to sulfasalazine monotherapy (group 1) and 69 added sulfasalazine to methotrexate (group 2); 15 (22%) patients in each group were treatment successes. Ninety-eight patients were sulfasalazine failures and progressed to the next therapy; a significantly greater proportion of these patients achieved treatment success with methotrexate, sulfasalazine and hydroxychloroquine than with leflunomide monotherapy (16 [36%] versus 7 [13%]; P = 0.028). Methotrexate and infliximab therapy was initiated in 48 patients (38 from group 1 and 10 from group 2) who were failures on ≥3 DMARDs, 34 (71%) of whom achieved treatment success.Patients with early RA who do not respond to methotrexate do not benefit from further treatment with conventional DMARDs and should be switched to a tumor necrosis factor blocker.