Elsevier

The Lancet

Volume 363, Issue 9410, 28 February 2004, Pages 675-681
The Lancet

Articles
Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial

https://doi.org/10.1016/S0140-6736(04)15640-7Get rights and content

Summary

Background

Etanercept and methotrexate are effective in the treatment of rheumatoid arthritis but no data exist on concurrent initiation or use of the combination compared with either drug alone. We aimed to assess combination treatment with etanercept and methotrexate versus the monotherapies in patients with rheumatoid arthritis.

Methods

In a double-blind, randomised, clinical efficacy, safety, and radiographic study, 686 patients with active rheumatoid arthritis were randomly allocated to treatment with etanercept 25 mg (subcutaneously twice a week), oral methotrexate (up to 20 mg every week), or the combination. Clinical response was assessed by criteria of the American College of Rheumatology (ACR). The primary efficacy endpoint was the numeric index of the ACR response (ACR-N) area under the curve (AUC) over the first 24 weeks. The primary radiographic endpoint was change from baseline to week 52 in total joint damage and was assessed with the modified Sharp score. Analysis was by intention to treat.

Findings

Four patients did not receive any drug; thus 682 were studied. ACR-N AUC at 24 weeks was greater for the combination group compared with etanercept alone and methotrexate alone (18·3%-years [95% CI 17·1–19·6] vs 14·7%-years [13·5–16·0], p<0·0001, and 12·2%-years [11·0–13·4], p<0·0001; respectively). The mean difference in ACR-N AUC between combination and methotrexate alone was 6·1 (95% CI 4·5–7·8, p<0·0001) and between etanercept and methotrexate was 2·5 (0·8–4·2, p=0·0034). The combination was more efficacious than methotrexate or etanercept alone in retardation of joint damage (mean total Sharp score –0·54 [95% CI –1·00 to –0·07] vs 2·80 [1·08 to 4·51], p<0·0001, and 0·52 [–0·10 to 1·15], p=0·0006; respectively). The mean difference in total Sharp score between combination and methotrexate alone was –3·34 (95% CI –4·86 to –1·81, p<0·0001) and between etanercept and methotrexate was –2·27 (–3·81 to –0·74, p=0·0469). The number of patients reporting infections or adverse events was similar in all groups.

Interpretation

The combination of etanercept and metho-trexate was significantly better in reduction of disease activity, improvement of functional disability, and retardation of radiographic progression compared with methotrexate or etanercept alone. These findings bring us closer to achievement of remission and repair of structural damage in rheumatoid arthritis.

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.

Section snippets

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

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