Triple therapy in early active rheumatoid arthritis: a randomized, single-blind, controlled trial comparing stepwise incremental and combination treatment regimens. Objective: Early studies of tightly controlled rheumatoid arthritis have shown that intensive stepwise escalation with a palliative anti-rheumatic drug (DMARD) is superior to conventional regimens as a treatment option in the management of early rheumatoid arthritis (RA) for persistent disease activity. We undertook this study to test the hypothesis that early triple therapy has better efficacy than stepwise incremental therapy in a severe disease treatment dosing regimen. Methods: Ninety-six patients with early RA (mean duration of disease 11.5 months) were randomized to step-up therapy (3 months of monotherapy with salazosulfapyridine [SSZ] followed by methotrexate [MTX]. When MTX reaches maximum tolerated dose, add hydroxychloroquine [HCQ].) Or triple therapy (SSZ/MTX/HCQ). All patients were evaluated monthly for 12 months. If patients had a disease activity score (DAS28) greater than or equal to 3.2 in 28 joints, the DMARD dose was increased according to the experimental design protocol and tretinoin was injected into the swollen joint (maximum dose of 80 mg per month). Assessments were performed every 3 months by a metrologist who was unaware of the treatment allocation. The primary outcome metric was the determination of the mean reduction in DAS28 at month 12. Results: Both groups demonstrated substantial improvement in disease activity and functional outcomes. At month 12, the mean DAS28 reduction scores were -4.0 (stepwise incremental treatment group) and -3.3 (combination treatment group), respectively (P=0.163). percentage of patients with DAS28 remission (45% and 33% in the stepwise incremental treatment and combination treatment groups, respectively), good DAS28 response (60% and 41%, respectively), or meeting the American College of Rheumatology No significant differences were found in the percentages of patients who met the criteria for a good response of 20% (ACR20) (77% and 76%, respectively), ACR50 (60% and 51%, respectively), or ACR70 (30% and 20%, respectively). Radiographic (imaging) progression was similar between the two groups. CONCLUSIONS: This study confirms that the use of conventional DMARDs as part of an intensive disease treatment regimen can be very effective in controlling disease activity. In this condition, stepwise incremental therapy and triple therapy are at least as effective.