MADRID – When rheumatoid arthritis patients fail initial treatment with methotrexate monotherapy, are they better served by a less expensive step-up treatment or the one that may better slow their radiographic progression and produce faster responses?
That seems to be the choice between step-up from methotrexate monotherapy by adding synthetic disease-modifying antirheumatic drugs (DMARDs) such as sulfasalazine and hydroxychloroquine, or by adding a tumor necrosis factor (TNF) inhibitor such as etanercept.
Mitchel L. Zoler/IMNG Medical Media
Dr. James O'Dell
The RACAT (Rheumatoid Arthritis: Comparison of Active Therapies) trial tested those two options in 353 rheumatoid arthritis (RA) patients at 36 U.S. or Canadian sites between July 2007 and December 2010. The study’s primary endpoint, improvement in average disease activity score in 28 joints (DAS28) from baseline to 48 weeks of treatment, was similar in both treatment arms, proving the noninferiority of the triple synthetic DMARD regimen against the etanercept, biological arm, Dr. James R. O’Dell reported in a poster at the annual European Congress of Rheumatology. The results also appeared online simultaneously with Dr. O’Dell’s poster presentation (N. Engl. J. Med. 2013 June 11 [doi: 10.1056/NEJMoal1303006]).
"We showed that starting first with a TNF inhibitor or first with triple therapy resulted in the same outcomes. But costs were not the same. We [successfully] treated another 30% of patients who did not need a biologic" with the synthetic triple therapy. "And in the patients where triple therapy doesn’t work, you can change them to a biologic and they have identical outcomes, clinically by DAS28 and radiographically," compared with patients who began on etanercept added to methotrexate from the start, he said. Dr. O’Dell is chief of rheumatology at the VA Medical Center in Omaha, Neb., and professor of medicine at the University of Nebraska.
"Nothing is lost for the patient; if they don’t do well on triple therapy they can switch to a biological. The data are persuasive and the economic case is easy to make. You absolutely ought to go with triple therapy," he concluded based on the study findings.
But "it is very difficult to get physicians to buy into this" strategy, he said in an interview. TNF inhibitors such as etanercept and other biological DMARDs are "seductive," Dr. O’Dell said, because they are effective, work quickly, and appear more "targeted" than synthetic DMARDs, and they are promoted by well-financed marketing campaigns.
Dr. O’Dell conceded that the study data showed a signal of more radiographic progression with triple synthetic DMARD treatment that could potentially, over time, accrue to more substantial differences. At 48 weeks after the onset of treatment, patients on triple therapy had an average 0.54-point increase (worsening) in their van der Heijde modified Sharp score, compared with an average 0.29-point rise in the patients who received etanercept, a 0.25-point average difference in favor of etanercept that did not reach statistical significance.
But this trend toward greater radiographic progression in patients on triple therapy was consistent with the statistically significant, roughly 1-point average additional increased radiographic progression with triple therapy, compared with patients on methotrexate plus etanercept, that was seen after 2 years of follow-up in the TEAR (Treatment of Early Aggressive Rheumatoid Arthritis) trial (Arthritis Rheum. 2012;64:2824-35).
The TEAR study, which enrolled patients with very early RA, included a subgroup with an inadequate response to methotrexate monotherapy, and in that subgroup, patients randomized to triple therapy and those randomized to etanercept plus methotrexate had similar clinical outcomes, consistent with the new study findings.
Dr. Daniel E. Furst
"It’s hard to say that 1 or 2 units on the Sharp score doesn’t matter much, even if you don’t see the difference for several years," commented Dr. Daniel Furst, professor of medicine and director of the Rheumatology Clinical Research Center at the University of California, Los Angeles.
"Triple therapy is effective clinically, but it doesn’t do so well for x-rays. There are relationships between a 1 or 2 Sharp score difference and long-term outcomes. Across the board with biologics, the difference is 1 or 2 Sharp units. If one’s philosophy is to hit the RA hard and stop it, then perhaps a biologic is better," Dr. Furst commented in an interview.
But another view was that triple therapy could play a useful and cost-effective role. The new findings, along with the TEAR results, make "initial treatment of early RA with triple therapy a reasonable approach," said Dr. Joel M. Kremer, a professor of medicine at Albany (N.Y.) Medical College and director of research at the Center for Rheumatology in Albany. The only clear downside is that if triple therapy doesn’t work, the patient loses time, but that’s true for every treatment option, he noted.