Methotrexate Alone OK in Early Arthritis
Published: Mar 13, 2014
By Nancy Walsh, Staff Writer, MedPage Today
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Monotherapy with methotrexate was as effective as methotrexate plus etanercept (Enbrel) in patients with early inflammatory arthritis, although the combination resulted in faster response, U.K. researchers reported.
After 1 year of treatment, 32.5% of patients receiving methotrexate plus etanercept had no tender or swollen joints, as did 28.1% of those given methotrexate alone (OR 1.32, 95% CI 0.56-3.09, P=0.522), according to Paul Emery, MD, of the University of Leeds in England, and colleagues.
But by the second week of treatment, after just one dose of etanercept, 38.5% of patients in the combination group versus 9.2% of those in the monotherapy group were in remission, having disease activity scores in 28 joints (DAS28) below 2.6 (adjusted OR 8.87, 95% CI 2.53-31.17, P=0.001), the researchers reported online in Annals of the Rheumatic Diseases.
Previous studies have demonstrated that among patients diagnosed with rheumatoid arthritis, prompt combination therapy with a conventional disease-modifying anti-rheumatic drug (DMARD) plus a tumor necrosis factor inhibitor successfully induced remission, which has become widely accepted as the goal of treatment since the biologic era began.
However, it's not yet been determined if combination therapy is needed for the attainment of remission even earlier in inflammatory, undifferentiated arthritis.
Accordingly, Emery and colleagues enrolled 110 patients who had been diagnosed with inflammatory arthritis for less than 3 months and were positive for rheumatoid factor, anti-citrullinated protein antibodies, or the genetic shared epitope -- all of which predict disease progression.
Participants were randomized to receive methotrexate plus either 50 mg of subcutaneous etanercept once weekly or placebo for a year. The etanercept could be stopped once patients hadn't had any tender or swollen joints for at least 26 weeks.
The methotrexate was given on a treat-to-target basis, beginning at a dosage of 10 mg per week and increased by 5 mg monthly up to 20 mg per week or 25 mg if tender or swollen joints persisted.
If patients were in remission for 3 months after stopping etanercept, the methotrexate also could be weaned.
At 1 year, 68.8% of patients in the combination group were in remission with DAS28 scores below 2.6, as were 62.5% of those in the placebo group, for an adjusted odds ratio of 1.32 (95% CI 0.58-3.04, P=0.508).
A more stringent definition of remission proposed by the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) in 2011 -- incorporating swollen and tender joints, C-reactive protein levels, and patient global assessment -- was achieved by 26.7% of patients in the combination group and 22.5% of those given methotrexate alone.
At week 78, when etanercept had been stopped for 26 weeks or more, 20.9% of the group that had been receiving the combination were still in ACR/EULAR remission, as were 20.5% of those who had received only methotrexate (OR 1.04, 95% CI 0.37-2.89, P=0.947).
The proportion of patients whose function on the Health Assessment Questionnaire (HAQ) had improved by a minimum clinically important difference of at least 0.22 units by 1 year was 59.5% in the combination group and 58.3% in the placebo group, for an adjusted odds ratio of 1.08 (95% CI 0.47-2.49, P=0.854).
Similarly, the proportions having normal function, as shown by a HAQ score below 0.5, were 51.5% and 44.5% in the combination and placebo groups, respectively, with an adjusted odds ratio of 1.37 (95% CI 0.58-3.26, P=0.474).
There also were no differences during follow-up between the groups on imaging studies, including radiographs and ultrasound.
The overall incidence of adverse events was similar in the two groups, although the etanercept-plus-methotrexate patients experienced more serious events (16.4 versus 3.7 per 100 patient-years). Only two of the serious adverse events were considered "possibly related" to treatment, however. There also were two severe pulmonary infections in the combination group.
In discussing their findings, Emery and colleagues noted that the number of patients receiving etanercept who had no swollen or tender joints after 1 year was only half what they had expected -- 30% instead of 60%.
"This primary endpoint was chosen as it was thought that complete normalization could be achieved in this early population. It is likely that [no tender or swollen joints] was too strict a target and that the achievement of no swollen joints alone may have been a more realistic outcome," they wrote.
They also pointed out that cost-effectiveness needs to be considered in the management of individuals with early arthritis.
"Ideally, determining which patients would benefit significantly and in the longer term with initial intensive induction therapy with a biological DMARD with the possibility of biologic or even drug-free remission would be of importance," they observed.
A limitation of the study was that it didn't consider other therapeutic options, such as a combination of conventional DMARDs and steroids.
The study was funded by Pfizer.
The authors disclosed relevant relationships with various companies including Pfizer, BMC, Centocor, UCB, Roche, AbbVie, Amgen, and Schering-Plough.
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Primary source: Annals of the Rheumatic Diseases
Source reference: Nam J, et al "A randomized controlled trial of etanercept and methotrexate to induce remission in early inflammatory arthritis: the EMPIRE trial" Ann Rheum Dis 2014; DOI: 10.1136/annrheumdis-2013-204882.