ArticlesTherapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial
Introduction
Rheumatoid arthritis affects almost 1% of the population1 and is associated with rapid functional loss2, 3 and reduced life expectancy.4 Guidelines5, 6 delineate goals for treatment, including preservation of function, prevention or control of joint damage, and remission of disease activity.
Tumour necrosis factor (TNF) is a key cytokine in the pathogenesis of rheumatoid arthritis.7, 8, 9 Successful treatment of clinical signs and symptoms and radiographic progression has been reported for three TNF-blocking drugs, two monoclonal antibodies10, 11 and a recombinant TNF receptor.12, 13, 14
Etanercept is a human, soluble, dimeric, TNF type II receptor linked to an IgG1-Fc moiety that binds to and inactivates TNF.15 Etanercept administered to patients with early rheumatoid arthritis more rapidly reduced disease activity and slowed joint destruction compared with methotrexate.12 In patients with active rheumatoid arthritis despite treatment with methotrexate, addition of etanercept to methotrexate was superior to methotrexate alone in reduction of disease activity.14
Although TNF-blocking drugs have been studied in patients with rheumatoid arthritis treated with metho-trexate,10, 11, 14 none of these studies included the three arms necessary to fully evaluate the clinical and radiographic efficacy of the combination of TNF-blockade and metho-trexate compared with the two monotherapies. Our aim was to compare safety and efficacy of the combination of etanercept and methotrexate with the monotherapies in patients with rheumatoid arthritis who had failed previous disease-modifying antirheumatic drug treatment other than methotrexate; we report 52-week results.
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Patients
Between October, 2000, and July, 2001, we screened individuals for inclusion in TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes). Eligible patients were those aged 18 years or older with disease duration of 6 months to 20 years who had active, adult-onset rheumatoid arthritis (American College of Rheumatology [ACR] functional class I–III), defined as ten or more swollen and 12 or more painful joints and at least one of the following: erythrocyte sedimentation rate
Results
686 patients were randomly assigned; four did not receive any drug, 228 received methotrexate (33%), 223 etanercept (33%), and 231 the combination (34%; figure 1). Demographics or baseline disease characteristics including previous methotrexate use did not differ between the treatment groups (table 1).
522 patients completed the first year of the study. Adverse events were the most common reason for discontinuation (24 combination, 32 methotrexate, and 25 etanercept). Fewer patients withdrew for
Discussion
We have shown that combination treatment was more efficacious than methotrexate or etanercept alone for control of rheumatoid arthritis disease activity. Additionally, just over a third of patients treated with the combination achieved remission at 52 weeks compared with an eighth of those given methotrexate and about a sixth of those given etanercept. These observations were lent support by changes in health-assessment questionnaire scores. The combination was also more efficient than
References (31)
- et al.
Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis
Lancet
(1989) - et al.
Effects of hydroxychloroquine and sulphasalazine on progression of joint damage in rheumatoid arthritis
Lancet
(1989) - et al.
Epidemiology of the rheumatic diseases
(1993) - et al.
Long-term course and outcome of functional capacity in rheumatoid arthritis: the effect of disease activity and radiologic damage over time
Arthritis Rheum
(1999) - et al.
Functional impairment and disability in early rheumatoid arthritis: development over 5 years
J Rheumatol
(1995) - et al.
Premature mortality in patients with rheumatoid arthritis: evolving concepts
Arthritis Rheum
(2001) - et al.
Updated consensus statement on biological agents for the treatment of rheumatoid arthritis and other rheumatic diseases (May 2002)
Ann Rheum Dis
(2002) American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update
Arthritis Rheum
(2002)- et al.
Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis
Arthritis Rheum
(1995) - et al.
Cytokine pathways and joint inflammation in rheumatoid arthritis
N Engl J Med
(2001)
Infliximab and methotrexate in the treatment of rheumatoid arthritis
N Engl J Med
Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial
Arthritis Rheum
A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis
N Engl J Med
Etanercept therapy in rheumatoid arthritis:a randomized, controlled trial
Ann Intern Med
A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate
N Engl J Med
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TEMPO study investigators listed at end of report