Background/Purpose: Double-blind placebo controlled randomized trials have demonstrated the efficacy of 15 different therapies in RA patients with active disease despite methotrexate (MTX). No blinded trials have compared conventional combination therapy to biologicals.  Biologicals are roughly 100-fold more expensive than conventional therapy and have a different toxicity profile.  We examine the strategy of starting conventional combination therapy followed by switch to a biological only in the subset of non-responders.

Methods: This multinational double-blind non-inferiority trial randomized 353 patients with active disease despite MTX equally to treatment with triple therapy (MTX, sulfasalazine and hydroxychloroquine) or etanercept plus MTX.  Treatment continued for 48 weeks, with blinded treatment switch at 24 weeks allowed for patients in both groups if their DAS28 had failed to improve by a clinically significant amount (ΔDAS28 of <1.2). The primary end point of the trial was DAS28 improvement at week 48 based on the initial randomization group.  Radiographs were obtained at 0, 24 and 48 weeks and scored by the modified Sharp method (secondary endpoint).  Patients were enrolled from 16 VA centers, 12 other US sites and 8 sites in Canada.

Results:  Study population baseline: mean age 57 yrs., 54% males, DAS28 = 5.8, disease duration 5.2 years and mean initial MTX dose of 19.6 mg week. There was no significant difference between groups at baseline. Both groups improved significantly from 0 to 24 weeks (p=0.001). The percentage of patients who switched therapy at 24 weeks was nearly identical (27.9% for triple therapy group vs. 27.0% for etanercept group).  In those patients who switched both groups had significant improvement after the switch (p <0.0001) and the response was not different across therapies (p=0.08).  At 48 weeks Δ DAS28 was not different between the groups (-2.1 [triple] and- 2.3 [etanercept]). Importantly, in patients in both groups who did respond and continued on their original assignment (73% of the patients in both groups) the response was maintained at 48 weeks.  Radiographic progression (week 0 to week 48) was not different between the groups (+ 0.87 for triple vs. + 0.23 for etanercept, [p=0.09]).  Secondary patient-reported outcomes including HAQII and pain were also not different between groups.  Toxicities were similar across groups.

Conclusion: The strategy of conventional combination therapy before biological therapy provides benefit, both clinically and radiographically, that are similar to initial use of etanercept.  For the first time data support the premise that patients who respond poorly to MTX and a biological (etanercept) have significant improvement with conventional DMARD combinations (triple therapy) and vice versa.  At the health system level, the cost-saving potential and ultimately the cost-effectiveness of the strategy of starting with conventional DMARD combinations and then switching to biologicals in those who do not respond is enormous.

Funding Sources:  Supported by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development, the CIHR and the NIAMS by interagency agreements.  Placebo etanercept donated by Amgen.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/rheumatoid-arthritis-comparison-of-active-therapies-in-methotrexate-suboptimal-responders-validation-of-the-strategy-of-conventional-disease-modifying-anti-rheumatic-drugs-before-biologicals/