DMARD triple therapy noninferior to, but less costly than, TNF inhibitor

In rheumatoid arthritis patients in whom first-line methotrexate therapy has failed, triple therapy with disease-modifying antirheumatic drugs (DMARDs) was noninferior to the tumor necrosis factor (TNF) inhibitor etanercept plus methotrexate, a study found.

The study was a 48-week, double-blind, noninferiority trial at 16 Veterans Affairs hospitals, 12 Rheumatoid Arthritis Investigational Network sites, and 8 Canadian medical centers from July 2007 through December 2010. Researchers randomly assigned 353 participants to the triple DMARD regimen of methotrexate, sulfasalazine and hydroxychloroquine or to therapy with etanercept plus methotrexate.

Participants who were assigned to the triple-therapy group received sulfasalazine at a dose of 1 g daily for the first 6 weeks, with the dose increased thereafter to 2 g daily, and also received hydroxychloroquine at a dose of 400 mg daily and an injection of a placebo for etanercept weekly. Participants who were assigned to the etanercept–methotrexate group received a 50-mg injection of etanercept weekly and a placebo of sulfasalazine and hydroxychloroquine tablets daily.

The primary outcome was improvement in the Disease Activity Score for 28-joint counts (DAS28, with scores ranging from 2 to 10 and higher scores indicating more disease activity) at week 48. If the score on the DAS28 improved by 1.2 or more by 24 weeks, the initial therapy continued. If the score on the DAS28 improved by less than 1.2, the patient was switched to the alternative regimen.

Results were published June 11 by the New England Journal of Medicine.

Both groups had significant improvement during the first 24 weeks (P=0.001 for the comparison with baseline). Twenty-seven percent of participants in each group switched treatment at 24 weeks. Participants who switched therapies then improved (P<0.001), and the response after switching did not differ significantly between the two groups (P=0.08). The change in the DAS28 score between baseline and 48 weeks was similar in the two groups (−2.1 with triple therapy and −2.3 with etanercept and methotrexate, P=0.26).

The researchers concluded triple therapy was noninferior to etanercept and methotrexate, since the upper limit of the confidence interval for the difference in change in DAS28 was below the margin for noninferiority (P=0.002). There were no significant differences in secondary outcomes, including radiographic progression, pain, and health-related quality of life, or in major adverse events.

The researchers wrote, “Our findings suggest that a strategy of first administering triple therapy, with a switch to etanercept–methotrexate in patients who do not have an adequate response to triple therapy, will allow a substantial percentage of patients to be treated in a more cost-effective way without adversely affecting the clinical outcomes.”

An editorial noted that in current practice, the default for patients with failure of methotrexate alone is a TNF inhibitor. Insurers might pressure physicians to switch to DMARDs due to their lower cost, or the development of new drugs may again change the playing field. “We hope that with the ever-increasing number of effective treatments for rheumatoid arthritis, future recommendations for treatment will be guided by additional comparative-effectiveness studies such as [this study],” the editorial stated.