RA Treatment Strategies
Abstract 1308: A Randomised Controlled Trial of Step Up Therapy Versus Triple Therapy In Early Active Rheumatoid Arthritis - The TEAR Study
Early, aggressive treatment of RA with combinations of DMARDs with the aim for tight control of disease activity has been shown to be more effective at achieving and maintaining disease remission, delaying radiographic progression, and delaying work disability. For example, in the BeSt study (link to EULAR 2004 OP0001), the early non-biologic DMARD combination regimen using the COBRA combination (methotrexate, sulfasalazine, and rapidly-tapered high-dose prednisolone) was superior to sequential monotherapy and step-up combination therapy. However, many practitioners prefer “triple therapy” (methotrexate, sulfasalazine, and hydroxychloroquine) to the COBRA regimen. Here, Irvine et al compare initial triple therapy vs “step-up” therapy in patients with early RA.
Methods: DMARD naïve (except hydroxychloroquine) RA patients with disease duration of less than 5 years and a DAS28 > 5.1 were randomized to receive initial triple therapy (starting doses: methotrexate 7.5 mg/wk, sulfasalazine 1000 mg/day, and hydroxychloroquine 200 mg/day) vs. step-up therapy with sulfasalazine monotherapy 40 mg/kg for three months followed by methotrexate (maximum 25mg/wk) and then hydroxychloroquine (maximum 400 mg/day). In both groups, treatment was escalated if DAS28 of 3.2 or better was not achieved. In both groups, any joint amenable to injection was injected with corticosteroid at each visit. Subjects in both groups were evaluated on a monthly basis with assessments by a blinded joint assessor every three months. Clinical and radiographic outcomes were assessed at 12 months.
Results: 96 subjects were randomized. Subjects were predominantly female (78%) with a mean age of 55 years. Rheumatoid factor was present in 70% of subjects. The mean duration of disease from the onset of symptoms was 11 months. Disease activity was high with a mean DAS28 at entry of 6.8. Subject characteristics were balanced between the two groups with the exception of CRP (58 mm/hr vs. 38 mm/hr in the step-up vs. triple therapy groups, respectively).
At the end of the 12 months, only 1 subject in the step-up group had “stepped-up” to triple therapy. The remainder of subjects in this group were able to achieve the pre-defined clinical outcomes using sulfasalazine monotherapy or combination therapy with methotrexate and sulfasalazine.
At 12 months, DAS28 score had improved by an average of 4.0 ± 1.8 units in the step-up group compared to 3.3 ± 1.6 in the initial triple therapy group, a difference that was not statistically significant. Similar substantial improvements were observed for other measures (HAQ, EULAR response criteria, and ACR response criteria); however, no statistically significant differences were observed between the two treatment groups.
Conclusions: There is no benefit to initial triple therapy over step-up therapy starting with sulfasalazine when an intensive “tight control” strategy is used in RA patients with early disease.
Editorial Comment: These results are somewhat at odds with the findings of previous similar trials (Fin-RACo and BeSt), in which initial combination regimens (including triple therapy in Fin-RACo) were superior to step-up monotherapy regimens. The reason behind the discrepancy may be that in the present trial the initial sulfasalazine monotherapy dosing (40 mg/day) is very aggressive compared to the much less aggressive starting doses for the triple therapy regimen (half-dose or less for each of the components). Even with rapid dose escalation, considering the time delay in efficacy of the component drugs, it is likely that the full 12 months was required for the agents in the triple therapy group to reach reasonable efficacy at their effective doses. Regardless, the clinical potency of very aggressively dosed sulfasalazine is highlighted. Longer term follow-up and radiographic outcomes await future disclosure.
It should be noted that another trial with the acronym TEAR is currently underway in the U.S. This study, entitled “Treatment of Early Aggressive RA”, is a larger, multicenter trial very akin to the BeSt trial in design, with the exceptions that triple therapy is used instead of the COBRA combination, etanercept is used instead of infliximab, and a step-up to etanercept arm is included to compare to an initial methotrexate + etanercept combination arm. Results of this trial will likely be forthcoming in the next few years and will be very instructive in informing the propriety of triple therapy against biologic DMARD containing regimens in early RA.
