The BeSt Way to Treat Early Rheumatoid Arthritis?

Over the past few years, the outlook for patients who are newly diagnosed with rheumatoid arthritis (RA) has improved dramatically (1) because of several key advances, including early use of disease-modifying, antirheumatic drugs (DMARDs); the use of DMARDs in combination; use of biologicals, especially antitumor necrosis factor- agents; and recognition of the critical role of inflammation in the vascular complications that lead directly to death. Patients who are diagnosed with RA today are much less likely to become disabled, require joint replacement (2), or die of premature atherosclerotic disease, which is associated with RA-related systemic inflammation. Despite these advances, many questions remain about initial therapy for early RA. In this issue, Goekoop-Ruiterman and colleagues (3) shed light on 2 very important questions: Should patients with early RA receive combinations of DMARDs as initial therapy? Is it helpful for clinicians to set clear treatment goals? Many studies have shown that combination DMARD therapy is superior to monotherapy when treating groups of patients with RA (410). Conversely, trials have also shown that a substantial percentage of patients will do well on monotherapy (1, 912). Unfortunately, most important trials of the past decade are rigid, therapy A versus therapy B comparisons and do not allow clinicians to adjust therapy to meet treatment goals (415). These trials often give clear answers, but they don't mimic daily practice. Goekoop-Ruiterman and coworkers (3) present the 2-year outcomes of an important clinical trialthe BeSt study (Dutch acronym for BehandelStrategieen, treatment strategies)which examines 4 substantially different treatment approaches for early RA (16). Patients were randomly assigned to 1 of 4 initial treatments: a single DMARD (group 1); step-up to a combination of 3 DMARDs (group 2); methotrexate, sulfasalazine, and high-dose prednisone (group 3); or the combination of methotrexate plus infliximab (group 4). They used a trial design that much more closely mimics clinical practice by allowing the study clinicians the flexibility to change or escalate therapy to produce optimal results. Further, building on the TICORA (Tight Control for Rheumatoid Arthritis) trial (17), which taught us that clear therapeutic goals are important, the authors have defined an optimal result not as a percentage improvement over baseline (18) but as a change the disease activity score (DAS), a composite index that measures an absolute level of disease (19). Although these design differences are a clear step forward, they present us with challenges in interpreting the results, a problem compounded by the large number of treatment options (the BeSt trial allowed 9 DMARDs as monotherapy and a dizzying array of possible combinations). The main 2-year findings of the BeSt trial were as follows: 1) if clinicians are allowed the flexibility to change or escalate therapy, the vast majority of patients will be doing very well at 2 years regardless of which initial therapy they received; 2) most patients can achieve excellent outcomes when clinicians escalate therapy until the patient achieves a low level of disease activity (DAS <2.4); and 3) therapy should be individualized because patients with excellent responses were receiving a wide variety of DMARDs and combinations of drugs. What then are the limitations of BeSt? BeSt was an unblinded randomized trial with subjective end points (for example, disease activity). Therefore, patients and physicians knew the treatment that the patient received, which may have influenced the reports of disease status. However, unblinding was necessary to allow clinicians the flexibility to adjust therapies. A second problem is the measure of treatment success. Of importance, BeSt selected a clear, uniform disease activity threshold that would trigger a change in therapy. Unfortunately, we lack a uniform definition of success in treating RA. Unlike the internist, the cardiologist, or the endocrinologist, the rheumatologist does not have a clear measure of success, such as the blood pressure, the low-density lipoprotein in coronary disease, or the hemoglobin A1c in diabetes, when treating RA (20). Although the BeSt treatment goal of a DAS less than 2.4 is widely accepted (17, 19), patients at this threshold have low disease activity and are not in full remission (defined as a DAS <1.6). This distinction becomes a problem when the authors then report results on patients in remission when therapies were not specifically changed or escalated to achieve this goal. Third, people have criticized the BeSt trial for not changing therapies soon enough, for not using methotrexate in higher doses or parenterally, and for allowing the flexibility to change therapies. All of these criticisms have some validity, but they should not undermine confidence in the key findings. What are the take-to-the-clinic messages of this study, and how do we integrate this new information to provide optimal care for all patients with newly diagnosed RA? According to the report of the first-year results, patients receiving combination therapy (methotrexate either with sulfasalazine and prednisolone or with infliximab) had the best results in the least amount of time (16). This finding corroborates the findings of many other studies in early RA, which clearly show that when studying groups of patients, those who receive more drugs (combinations of conventional DMARDs or biologicals) do better in the short-term (410, 1315). However, the 2-year BeSt results, as reported here, underscore the need to individualize therapy. Treating physicians titrated and changed drugs in individual patients and achieved excellent control while using a large variety and combination of drugs. Overall, the key finding of the BeSt 2-year results is that if clinicians have the flexibility to change therapy and have a clear treatment goal, all patients achieve similar disease control, regardless of their originally assigned treatment. The costs of the different successful strategies that were used vary from approximately U.S. $50 to more than U.S. $1500 per month. Because the results were similar at 2 years regardless of initial therapy, some will argue for starting treatment with a single conventional DMARD with escalation to the more expensive biologics (needed in <10% of patients in group 2) only in those who continue to have high levels of disease activity. To address this critical issue, we will need to understand not only the cost of medications, but the costs related to joint damage (radiographic progression was different among the groups at least during the first year [16]), lost productivity, quality of life, and other potential consequences of delay in starting therapy with combined conventional and biological drugs. Despite tremendous advances in therapy, RA remains a cause of substantial morbidity and increased mortality. With our current knowledge and the results of the BeSt trial, how should we treat patients with newly diagnosed RA? First, with the ever-increasing complexity, expense, and toxicity of modern therapy, a rheumatologist should be actively involved in the care of all patients with RA in conjunction with the primary care physician. Second, all patients should receive a DMARD (in most cases methotrexate) as soon as possible. Finally, rheumatologists should adjust therapy in a timely fashion (increasing doses or adding other DMARDs) until patients have achieved low levels of disease activity (or are in remission). Some patients do very well on single DMARD therapy whereas others need biologicals plus multiple conventional drugs. The critical challenge for the next decade will be to find ways to differentiate these groups at disease onset. Matching treatment to the patient's clinical characteristics may save time and money and preserve quality of life.