Evidence that the strategy is more important than the agent to treat rheumatoid arthritis. Data from clinical trials of combinations of non-biologic DMARDs, with protocol-driven intensification of therapy for tight control or treat-to-target.

Eight major "strategy trials" in rheumatoid arthritis (RA) are reviewed, with protocol-driven escalation of combinations of methotrexate and other small molecule non-biological disease modifying antirheumatic drugs (DMARDs). All documented the value of intensive treatment adjusted according to quantitative data, generally a disease activity score (DAS) or its 28 joint count version (DAS28). Three of the 8 trials, TICORA, Dutch DAS-driven care, and CAMERA, may be termed "pure strategy trials," to com- pare a protocol-driven "intensive" strategy to usual care. Five other trials, BeSt, CIMESTRA, TICORA 2, Step-down versus step-up, and TEAR, may be termed "hybrid trials," in which an initial parallel design was supplemented with incremental protocol-driven intensification of treatment. A strategy of aiming for low disease activity or remission appears more important than the specific agent used. In group data, the proportion of good responses seen in these trials with combinations of non-biologic, small molecule DMARDs are comparable to data from clinical trials of biological agents although responses appear more rapid with biological agents, and certain individual patients may require a biologic agent for adequate control. These trials also illustrate the value of a quantitative index, monitored frequently for rational intensification of therapy. The data make a compelling case for both routine monitoring with a quantitative index and consideration of routine adjustment of therapy at each visit. Combinations of methotrexate with other non-biologic DMARDs and glucocorticoids, toward a target of low disease activity or remission, may improve outcomes for patients with RA at levels similar to biologic agents in many patients.