Triple Therapy as Good as Biologics for Rheumatoid Arthritis

Alice Goodman

June 17, 2013

MADRID, Spain — A triple regimen of older drugs is as effective as biologics for patients with active rheumatoid arthritis (RA) who fail to respond to methotrexate, according to the results of a large clinical trial.

The triple therapy of sulfasalazine, hydroxychloroquine, and methotrexate is notably cheaper. It is $10,200 less per patient-year than the combination of the biologic etanercept (Enbrel, Immunex) and methotrexate.

"The 2 strategies resulted in comparable benefits in disease measures, function, and radiographic progression," reported lead investigator James O'Dell, MD, here at the European League Against Rheumatism Congress 2013.

"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 clinical outcomes," said Dr. O'Dell, who is from the University of Nebraska Medical Center in Omaha.

The results were published online June 13 in the New England Journal of Medicine to coincide with their presentation.

The investigator-initiated multinational double-blind noninferiority 48-week trial randomized 353 patients with active RA despite methotrexate therapy to the triple regimen or etanercept plus methotrexate. At 24 weeks, patients with an inadequate response were switched to the other therapy.

At baseline, both groups had comparable characteristics. Mean age was 57 years, 54% were males, mean disease activity score in 28 joints (DAS28) was 5.8, mean disease duration was 5.2 years, and mean initial dose of methotrexate was 19.6 mg/week.

We have to consider whether these findings have arrived too late to influence modern practice.

Over the first 24 weeks of the trial, both groups had comparable and significant improvement from baseline (< .001) on the DAS28.

Former nonresponders — the 27% of patients in each group who switched therapy at 24 weeks because of inadequate response — achieved similar and significant improvement on the DAS28 at 48 weeks (< .0001).

At 48 weeks, the reduction in DAS28 was virtually the same with the triple therapy and etanercept plus methotrexate (2.1 vs 2.3).

That response was maintained at 48 weeks in the 73% of patients in each group who responded at week 24. Radiographic progression was not significantly different between the triple therapy and etanercept plus methotrexate (0.54 vs 0.29).

Patient-reported outcomes, including function, pain, and quality of life, were also comparable, as were major adverse events.

When asked by Medscape Medical News to comment on this trial, Philip Mease, MD, from the Swedish Medical Center in Seattle, said the clinical outcomes were close for both groups, but noted that the devil is in the details.

"Looking at radiographic progression in more detail, the TNF inhibitor beat out triple therapy at 24 weeks," he said, pointing to the mean change for triple therapy and etanercept plus methotrexate (0.19 vs 0.3). However, "the 2 regimens looked more similar at week 48," he added.

"It is easy to give RA patients a TNF inhibitor, he explained. "At 12 weeks, you see striking changes. You don't see that with triple therapy."

"I applaud the effort by O'Dell and coauthors to be cost-conscious and safety-conscious," he said. "At the end of the day, patients will vote with their feet."

In an accompanying editorial, Joan Bathon, MD, and Donald McMahon, MS, from Columbia University in New York City, write that "we have to consider whether these findings have arrived too late to influence modern practice, in which arguably a TNF inhibitor is the preferred next step when methotrexate alone is inadequate."

Whether third-party payers who require the failure of methotrexate monotherapy before they will cover expensive biologic therapy will change their policy to require failure of the cheaper nonbiologic combination is an interesting question, they note.

"The development of more affordable biosimilar agents may change the treatment choices yet again, potentially rendering the studies with nonbiologic agents irrelevant. 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 the study by O'Dell et al."

Dr. O'Dell, Dr. Bathon, and Mr. McMahon have disclosed no relevant financial relationships. Dr. Mease reports receiving funding from AbbVie, Amgen, Biogen Idec, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, and UCB.

European League Against Rheumatism (EULAR) Congress 2013: Abstract THU0224. Presented June 13, 2013.


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