Biologics Beat Triple DMARDs Therapy on Cost, But No Winner in Debate on Efficacy, Safety in RA

During their “Great Debate” keynote session of the American College of Rheumatology (ACR) 2013 Annual Meeting in San Diego, CA, two leading rheumatologists took direct aim at each other’s significant clinical trial data to provide rationale for choosing biologics over triple therapy — or vice versa — as the treatment of choice for rheumatoid arthritis (RA).

In the corner of combined methotrexate, sulfasalazine, and hydroxychloroquine disease-modifying antirheumatic drugs (DMARDs), James R. O’Dell, MD, Chief of the Division of Rheumatology at the University of Nebraska Medical Center and former ACR President, cited five major studies in support of conventional triple treatment. But one of those studies — known as the Swefot trial — was conducted and penned by O’Dell’s debate opponent, Ronald van Vollenhoven, MD, PhD, Chief of the Unit for Clinical Therapy Research in Inflammatory Diseases at the Karolinska Institute, who used the trial’s efficacy data to argue that biologic therapy is more effective in RA than triple therapy.

According to O’Dell, van Vollenhoven’s Swefot trial — which compared methotrexate monotherapy to methotrexate with the anti-tumor necrosis factor (TNF) drug infliximab in 487 new-onset RA patients — “showed that at 6 months, there was no clinical response difference (between the treatments); there was a difference seen at 9 months, but at 2 years, that difference had been lost.” While Van Vollenhoven said it was true that there was no statistical difference in response after 2 years, he explained that “some understand that the anti-TNF lost its effect, (but) that’s not shown by the data. The reason it lost it is sample size.”

“Patients left this trial, so the difference we see with our eyes is due to chance,” van Vollenhoven emphasized. “Or, the difference is there, but we weren’t able to prove it. But what we were able to prove is there’s a radiological benefit for having anti-TNF therapy over triple therapy.”

Turning the tables, van Vollenhoven pointed out that O’Dell’s Rheumatoid Arthritis Comparison to Active Therapy (RACAT) trial — which randomized RA patients taking methotrexate to add either the anti-TNF etanercept or sulfasalazine with hydroxychloroquine to their medication regimens — “proved that anti-TNF is better than triple therapy, as he concluded, ‘Finally, our study showed clear trend favoring a more rapid response in the etanercept group.’ In fact, it showed that the change in disease activity score (DAS) was greater in the anti-TNF group, and 3 times as many etanercept patients achieved [70% improvement in RA (ACR70)] at 24 weeks compared to triple therapy.”

But O’Dell said van Vollenhoven took that interpretation of the trial results out of context and missed the point of the findings.

“RACAT was not about being better than the biologic; it was about finding which strategy of biologic or traditional therapy first was more effective,” O’Dell said. “And the conclusions were that starting DMARDs first was not inferior to starting the biologic first.”

Comparing the two treatments’ safety profiles, van Vollenhoven noted that in the RACAT trial, “there were 4 patients in the triple therapy group with a serious cardiac disorder and 3 with a serious respiratory disorder, so I’m not committed to say conventional therapy is so completely safe.”

But O’Dell pointed out that in RACAT, there was also a two-fold increase in serious infections with the biologics infliximab and adalimumab that was “never seen in the other arm of DMARDs.” Nevertheless, van Vollenhoven explained that “in the first year of biologic treatment, there’s an increase in infections, but then it goes down.”

Although van Vollenhoven conceded that biological therapies are probably overused in RA patients, he said “the reason is there’s difficulty in choosing the next-best therapy when you know what the best therapy is. Can you explain to your patient that you will try something suboptimal when there is something optimal?”

Nevertheless, there was no clear winner on drug efficacy or toxicity, although O’Dell took home the prize for cost effectiveness, as he successfully argued that “biologics work out to $887,000 for cost per quality-adjusted life-year (QALY)” and noted that results from the 2-year Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) clinical trial showed that “initial triple therapy dominated in terms of cost and was very similar to biologic therapy in terms of quality.”