Triple Therapy Outperforms Biologics in RA


Researchers are suggesting the adoption of triple therapy as a first-line treatment after RA patients fail methotrexate monotherapy.

Researchers writing in the journal Arthritis Care and Research are suggesting the adoption of triple therapy as a first-line treatment after patients have had an inadequate response to methotrexate monotherapy.

The recommendation comes as a result of a follow-up observational study of 353 patients who were randomized to receive either combination therapy with methotrexate-etanercept therapy or triple therapy with methotrexate, sulfasalazine and hydroxychloroquine in a 48-week double-blinded trial. Triple therapy was found to be non-inferior to combination therapy in both clinical and radiographic progression of disease.

The study was led by Shana Peper, M.D., of the Nebraska Medical Center in Omaha. “These results suggest biologic agents should be reserved for those patients who continue to have disease activity following an adequate trial of combination conventional DMARDs,” Dr. Peper and colleagues wrote.

The study

The study was a follow-up to the Rheumatoid Arthritis Comparison of Active Therapies (RACAT) trial, a double-blinded trial that assigned patients with active rheumatoid arthritis (RA) who were on methotrexate (mean dose of 19.6 mg per week) to receive additional treatment of sulfasalazine and hydroxychloroquine as triple therapy, or etanercept in combination with methotrexate. The primary outcome was measured at 48 weeks for DAS28. At 24 weeks, if patients from either group had an inadequate response to therapy (a DAS28 score of < 1.2), they were switched to an alternative therapy (blinded). Of the 352 patients, 289 agreed to participating a follow-up period through 72 weeks. DAS28 scores, joint assessments, erythrocyte sedimentation rate (ESR, mm/hr), and patient global health assessments (measured using a 100 mm visual analog scale) and changes in therapy were measured every 24 weeks.

Researchers found that patients were more likely to stay on triple therapy as compared to combination therapy (78% vs 63%, respectively). And, more patients changed from methotrexate-etanercept to triple therapy than from triple therapy to methotrexate-etanercept.

In terms of disease activity measures, the two treatment groups were similar so there was almost no difference in treatment outcomes. The mean DAS28 scores and other disease activity measures were close for the two groups throughout the study and follow-up period (3.8 ± 1.4 and 3.5±1.3, p = 0.052). There was a trend toward a decrease in DAS28 scores with conventional DMARDs and a very small trend toward an increase in DAS28 scores with biologic DMARDs, but neither of these were statistically significance.

“All disease activity outcomes for both groups remained stable and similar for up to 72 weeks of observational follow-up. Specifically, there was no statistically significant difference in DAS 28 scores, swollen or tender joint counts, patient global health assessments, or ESR values between Groups T and E,” researchers wrote.

The authors noted several limitations, including its approach which depended on the judgement of clinicians during the open phase.


The American College of Rheumatology 2015 rheumatoid arthritis treatment guidelines recommend that for patients with early rheumatoid arthritis who have moderate to high disease activity despite DMARD monotherapy, a TNFi or a non-TNF biologic agent should be introduced with or without methotrexate. And, for patients with established rheumatoid arthritis with moderate to high disease activity despite DMARD monotherapy, the ACR also recommends adding a TNFi or a non-TNF biologic, but they also suggest adding tofacitinib with or without methotrexate.

Approximately two-thirds of patients will require an add-on therapy in order to achieve low-disease therapy.  Three randomized clinical trials have shown that a combination of disease modifying anti-rheumatic drugs (DMARDs) and a biologic DMARD can offer a degree of improvement in disease activity when methotrexate monotherapy fails. But at this point, physicians sometimes opt to add a tumor necrosis factor inhibitor (TNFi), such as etanercept, to methotrexate despite the steep financial costs of biologics. Etanercept costs approximately $26,516 in the U.S. as compared to $641 for the triple therapy featured in this study.


Grants/major financial supporters: None relevant

Dr. Ted Mikuls has consulted for Pfizer and received research support from BMS and Astra Zeneca. Dr. James O’Dell has consulted for Medac, Antares, Lilly, Coherus and GSK.



Shana M. Peper M.D., Robert Lew PhD, Ted Mikuls M.D. , et al. "Rheumatoid Arthritis Treatment after Methotrexate: Triple Therapy is more Durable than Etanercept," Arthritis Care & Research. Accepted manuscript online: 7 APR 2017.

Jasvinder A. Singh, Kenneth G. Saag, S. Louis Bridges Jr., et al. "2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis," Arthritis Care & Research. DOI 10.1002/acr.22783. 

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