SAN ANTONIO, Texas – An emerging body of clinical evidence supports the concept that treating rheumatoid arthritis (RA) early with a combination of an antitumor necrosis factor-α (TNF-α) agent and methotrexate brings symptom relief and reduces structural damage to bones, according to a series of late breaking reports released at the 2004 annual meeting of the American College of Rheumatology.
Data from the phase III PREMIER study demonstrated that the combination of adalimumab plus methotrexate proved superior to either drug alone by several measures of disease progression for methotrexate-naïve patients with recent-onset RA (diagnosed within the previous 3 years), reported Arthur Kavanaugh, MD, Professor of Medicine and Director of the Center for Innovative Therapy in the Division of Rheumatology, Allergy, and Immunology at the University of California, San Diego, California.
The study found that 62% of patients achieved an ACR50 on the combination of the drugs after 52 weeks, compared with 42% taking adalimumab alone, and 46% on methotrexate monotherapy (P <0.001).1
The adalimumab plus methotrexate combination showed efficacy within 2 weeks, and had a sustained effect throughout the 2-year study: 59% of patients with an ACR50, compared with 37% on adalimumab and 43% on methotrexate alone (P <0.001).
"PREMIER is the first trial of a TNF antagonist to successfully achieve an ACR50 primary endpoint," Dr. Kavanaugh and colleagues reported in their poster presentation Tuesday.
After two years, nearly half of the early RA patients receiving the combination first-line therapy achieved clinical remission (as defined by a disease activity score 28<2.6) compared to only 25 percent of patients receiving methotrexate or adalimumab alone.
Dr. Kavanaugh also noted that combination therapy inhibited radiographic progression significantly greater than either monotherapy. The change in the total Sharp score for the combination was 1.9 after two years, compared with 5.5 for adalimumab and 10.4 for methotrexate when those drugs were used alone.
Those findings virtually mirrored those of a Dutch study investigating the efficacy of etanercept in combination with methotrexate or either drug alone for RA.
The TEMPO study showed that in the methotrexate, etanercept, and combination group, 60.2%, 68%, and 78.4% of patients, respectively, did not exhibit radiographic progression (total Sharp score <0.5).2
"At year 2, the combination of etanercept and methotrexate compared with monotherapies was superior in halting radiographic progression, reducing disease activity, improving functional disability and inducing remission," said Désirée van der Heijde, MD, Professor of Rheumatology at University Hospital Maastricht, Maastricht, the Netherlands. "With the combination we were actually able to see improvement rather that detriment," said Dr. van der Heijde, adding that the study will continue for a third year.
In a third study, another group of researchers in the Netherlands considered four different strategies in treating patients with early RA, comparing initial monotherapy with combination treatments. Yvonne Goekoop-Ruiterman, MD, a Post-Doctoral Fellow at Leiden University Medical Center, Leiden, the Netherlands, said that despite similar outcomes at the end of 2 years, patients who started with combination therapies had less structural damage than those who began on monotherapies.
"Patients initially treated with a combination including either prednisone or infliximab showed more rapid improvement, less radiological progression and needed fewer treatment adjustments than patients treated with sequential monotherapy or step-up combination therapy," Dr. Goekoop-Ruiterman said at her poster presentation.
Hayes Wilson, MD, Medical Advisor to the Atlanta-based Arthritis Foundation, said the trial results "fit into what we know about combination therapy. There is an additional benefit to early combination treatment that can be seen structurally."
References:
- Breedveld FC, Kavanaugh AF, Cohen SB, et al. Early treatment of rheumatoid arthritis (RA) with adalimumab (HUMIRA®) plus methotrexate vs. adalimumab alone or methotrexate alone: the PREMIER study. Presented at: Annual Meeting of the American College of Rheumatology; October 20, 2004; San Antonio, Texas. Abstract L5 .
- Klareskog L, van der Heijde D, de Jager JP, et al, for the TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) study investigators. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet. 2004;363:675-681.
- Goekoop-Ruiterman YPM, De Vries-Bouwstra JK, Van Zeben D, et al. Treatment strategies in early rheumatoid arthritis: Clinical and Radiological Outcomes after 2 year follow-up of the BeSt study. Presented at: Annual Meeting of the American College of Rheumatology; October 20, 2004; San Antonio, Texas. Abstract L4 .