From Medscape( you have to register to read the entire article, but it is free)
Clinical trials of the 3 currently US Food and Drug Administration (FDA)-approved tumor necrosis factor (TNF) inhibitors -- etanercept, infliximab, and adalimumab -- have been conducted in patients with early RA.[1-6] In these studies, the comparator has typically been methotrexate (MTX), dosed in a regimen that years ago would have been considered quite aggressive, namely, escalation over the course of the first 2 months of therapy to a dose of 20 mg of MTX per week. In each of these trials, MTX when used in such a manner did prove to have notable efficacy.
The Etanercept in Early Rheumatoid Arthritis (ERA) trial compared etanercept at 2 different doses with MTX, all as monotherapy. Although the clinical responses to all agents were notable, patients receiving etanercept monotherapy also had a more rapid clinical response. In addition, radiographic assessments showed the superiority of TNF inhibition compared with MTX alone. The Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) trial evaluated the efficacy of infliximab at 2 different doses, given in combination with MTX vs MTX alone in MTX-naive patients with early RA. Patients treated with the combination had more rapid and greater clinical improvement and better radiographic outcomes. PREMIER evaluated the efficacy of combination therapy with adalimumab plus MTX compared with each therapy alone. In this trial, clinical responses with MTX or with the TNF inhibitor were comparable, but the greatest responses were achieved with combination therapy. With regard to joint damage, TNF inhibitor monotherapy achieved better results than MTX monotherapy, but the best radiographic results were seen with the combination. Results from all of these studies clearly showed the potential benefit of TNF inhibitors in early RA. Further, they showed the additional benefit of combination therapy with TNF inhibitors and MTX with regard to signs and symptoms of disease, improvements in functional status, and inhibition of radiographic damage.
A study that is addressing potential optimal treatment paradigms for early RA, including the role of biologic agents, is the Behandel Strategieen (BeSt) trial.[7-10] BeSt is a randomized clinical trial of 508 patients with early RA, defined as patients with less than 2 years of disease. Patients were allocated to 1 of 4 different treatment strategies: sequential monotherapy with DMARDs, beginning with escalating doses of MTX (group 1); step-up combination therapy, beginning with escalating doses of MTX and adding other DMARDs (group 2); initial combination therapy with sulfasalazine plus MTX and tapered high-dose prednisone (group 3); or initial combination therapy with MTX plus a TNF-alpha inhibitor, infliximab (group 4). Of note, therapy adjustments were mandated at each 3-monthly evaluation, on the basis of levels of disease activity calculated with the Disease Activity Score (DAS). If patients had disease activity above a predefined threshold, they were allocated to a treatment algorithm specific to their assigned groups with an increase of dose or changes in treatment. In this way, "tight control" was the goal to be achieved by frequent assessment of disease activity and changes in treatment until low disease activity was achieved. After more than 4 years of follow-up, nearly 50% of patients in each of the 4 groups of the BeSt study achieved remission according to DAS score (DAS < 1.6). Early on, patients in groups 3 and 4 appeared to respond somewhat quicker. At 2 years, patients in groups 3 and 4 had an earlier clinical response and less radiographic progression compared with patients in groups 1 and 2. Perhaps most notably, at 4 years over 10% of patients were able to withdraw all treatment, suggesting that "induction" therapy may be successful in early RA, at least for a period of time. Moreover, in group 4 over half of patients who started MTX plus a TNF inhibitor were able to successfully discontinue the TNF inhibitor while maintaining low disease activity. Regardless of the initial treatment group, a strategy of frequent evaluation of disease activity and change of therapy to achieve low disease activity -- so-called "tight control" -- resulted in a sustained clinical and functional benefit for up to 4 years.