Clinical and Radiological Efficacy of Four Different Treatment Strategies in Patients with Early Rheumatoid Arthritis: 3-Year Follow-up of the BeSt Study
Authors: van der Kooij, Goekoop-Ruiterman, de Vries-Bouwstra, Hazes, Kerstens, van Zeben, Han, Hulsmans, Breedveld, Dijkmans, Allaart
Background:
Much important information has derived from the BeSt (Dutch for Treatment Strategies) trial. Among these is the finding that early, aggressive, individualized RA therapy is associated with long-term improvement in disease activity in most patients, regardless of initial treatment chosen. However, differences in treatment strategies are apparent, with early combination therapy (with or without TNF inhibition) associated with earlier response and less radiographic progression, at least through two years of treatment. Here, van der Kooij et al present data on response, radiographic progression, and safety through the third year of the trial.
Methods:
The design of the BeSt trial is complex and has been described previously on this site (link to EULAR 2004 OP0001). From the third year onward, subjects in any treatment group receiving low dose monotherapy with any single DMARD with a DAS28 score < 1.6 (EULAR remission) for more than 6 months were tapered to no DMARDs. The last DMARD was restarted if the DAS28 score exceeded 1.6.
Results:
508 subjects remained in the trial through 3 years, representing 92% of the original cohort. Of these, baseline characterisitics were comparable. There was no difference in DAS28 or HAQ at the end of year three for any of the 4 treatment groups, with 44% of subjects (regardless of treatment allocation) attaining a DAS28 < 1.6 by the end of year 3. However, EULAR remission was achieved earlier for subjects in group 3 (initial COBRA combination) and group 4 (initial combination with methotrexate and infliximab), although most of the subjects in these two groups had transitioned to a single oral DMARD by the end of year 3. A higher percentage of subjects in group 4 (16%) had discontinued all DMARDs by the end of year 3 due to sustained low disease activity compared to subjects in groups 1 – 3 (11%, 6%, and 7%, respectively).
Despite little difference in cumulative response between the treatment groups, there were significant differences in radiographic progression. Subjects in treatment groups 3 and 4 had the lowest rates of radiographic progression (29% and 25%, respectively) compared to subjects in groups 1 (sequential monotherapy) and 2 (step-up combination therapy) (44% and 43%, respectively), p-value for trend across groups= 0.004. There was no difference in safety among the 4 treatment groups.
Conclusions:
Early, aggressive RA management with step-down based on predefined criteria is associated with low disease activity and even remission in many patients, regardless of initial treatment allocation at the end of three years. However, more aggressive initial therapy (either with a combination of oral DMARDs and prednisone or methotrexate and infliximab) was associated with earlier response and a significantly reduced rate of radiographic progression.
Editorial Comment:
This trial is one of the most important conducted in RA and has yielded many insights into RA therapy which have yet to be incorporated into general clinical practice. In particular, it raises the question of whether step-down strategies should be the norm rather than step-up strategies, which are most commonly used in the U.S. Regardless, the finding that aggressive treatment tailored to patient outcomes results in a good outcomes in most patients is encouraging. The finding that the rate of radiographic progression continued to be lowest in those treated with initial combination therapy, even after combination therapy was tapered to monotherapy (or even discontinued), is interesting. It will be crucial if this observation is sustained, suggesting convincingly that a “window of opportunity” exists in very early RA in which very aggressive therapy may be capable of blunting the long-term momentum of disease damage.