Elsevier

The Lancet

Volume 372, Issue 9636, 2–8 August 2008, Pages 375-382
The Lancet

Articles
Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial

https://doi.org/10.1016/S0140-6736(08)61000-4Get rights and content

Summary

Background

Remission and radiographic non-progression are goals in the treatment of early rheumatoid arthritis. The aim of the combination of methotrexate and etanercept in active early rheumatoid arthritis (COMET) trial is to compare remission and radiographic non-progression in patients treated with methotrexate monotherapy or with methotrexate plus etanercept.

Methods

542 outpatients who were methotrexate-naive and had had early moderate-to-severe rheumatoid arthritis for 3–24 months were randomly assigned to receive either methotrexate alone titrated up from 7·5 mg a week to a maximum of 20 mg a week by week 8 or methotrexate (same titration) plus etanercept 50 mg a week. Coprimary endpoints at 52 weeks were remission measured with the disease activity score in 28 joints (DAS28) and radiographic non-progression measured with modified total Sharp score. Treatment was allocated with a computerised randomisation and enrolment system, which masked both participants and carers. Analysis was done by modified intention to treat with last observation carried forward for missing data. This study is registered with ClinicalTrials.gov, number NCT00195494).

Findings

274 participants were randomly assigned to receive combined treatment and 268 methotrexate alone. 132 of 265 (50%, 95% CI 44–56%) patients who took combined treatment and were available for assessment achieved clinical remission compared with 73 of 263 (28%, 23–33%) taking methotrexate alone (effect difference 22·05%, 95%CI 13·96–30·15%, p<0·0001). 487 evaluable patients had severe disease (DAS28>5·1). 196 of 246 (80%, 75–85%) and 135 of 230 (59%, 53–65%), respectively, achieved radiographic non-progression (20·98%, 12·97–29·09%, p<0·0001). Serious adverse events were similar between groups.

Interpretation

Both clinical remission and radiographic non-progression are achievable goals in patients with early severe rheumatoid arthritis within 1 year of combined treatment with etanercept plus methotrexate.

Funding

Wyeth Research.

Introduction

Major consequences in rheumatoid arthritis are related to the disease itself and its associated comorbidities. Although outcomes have improved over the past few decades with the advent of new treatments and therapeutic approaches, patients still have substantial functional disability and loss of ability to work.1, 2 Intensive but safe treatments have the potential to improve long-term outcomes.

Remission is the best outcome for early therapy. There are several definitions of remission based on clinical criteria, but disease activity score in 28 joints (DAS28) is the most commonly used validated method for the measurement of remission,3, 4, 5 which has been recognised in the European League Against Rheumatism working group recommendations for the management of early rheumatoid arthritis as a goal of therapy.6 Remission is best achieved by reducing or eliminating inflammation, thereby stopping radiographic progression at an early stage when the disease is most destructive and before joint damage occurs.7 Thus, remission has become the aim of management of early rheumatoid arthritis, and this aim needs to be included in trial design.8

Disease-modifying antirheumatic drugs (DMARDs), alone or in combination, have been the mainstay of treatment for rheumatoid arthritis.9, 10, 11 Before the recent era of biological therapy, clinical remission was not commonly reported.12 New treatment strategies advocate the use of earlier, more intensive therapy than previously applied to prevent joint damage and functional disability.13 In this context, remission has emerged as a realistic goal, especially in patients with early rheumatoid arthritis.6, 14 Support for remission in disease activity and radiographic outcomes as a primary endpoint in clinical trials has grown as treatment options have improved and combined-treatment regimens have emerged.15, 16, 17, 18, 19, 20 Recent data indicate that conventional disease modifying antirheumatic drugs might not halt radiographic progression, even when they produce clinical remission, which could be attributed to incomplete suppression of synovitis.16, 18, 21 Combination therapy with methotrexate and an anti-tumour-necrosis-factor (TNF) agent seems to be best in this respect, nearly halting structural progression and producing clinically relevant responses.15, 22

The combination of methotrexate and etanercept in early rheumatoid arthritis (COMET) trial investigates clinical remission, radiographic non-progression, and restoration of function in a continuing 2-year study comparing the effects of combined etanercept (a fully human TNF soluble receptor) and methotrexate with those of methotrexate alone in patients with moderate-to-severe, active, early rheumatoid arthritis. The aim of this study was to investigate aggressive therapy for early disease with combined treatment as the regimen of choice to achieve clinical and radiographic treatment targets and normalisation of function. The results in this report are for the first year (period 1).

Section snippets

Patients

Participants were enrolled at 70 sites in Europe, Latin America, Asia, and Australia from October, 2004, to February, 2006. Patients were age 18 years or older with diagnosis of adult-onset rheumatoid arthritis, disease duration of at least 3 months but not more than 2 years, DAS28 of 3·2 or more, and either Westergren ESR of 28 mm/h or more or C-reactive protein of 20 mg/L or more. Patients were ineligible if they had received previous treatment with methotrexate, etanercept, or another TNF

Results

542 patients from 22 countries participated in this trial; 472 (87%) were from Europe and Australia, and the remainder were from Latin America and Asia. 528 patients (263 on methotrexate alone and 265 on combined treatment) were available for clinical efficacy analysis; all 542 were included in the safety analysis. 230 in the methotrexate group and 246 in the combined-treatment group had data that were valid for radiographic analysis. At baseline, 487 (92%) of 528 patients had DAS28 >5·1,

Discussion

Half the patients on combination therapy with etanercept and methotrexate successfully achieved clinical remission (as judged with DAS28), significantly more than those receiving conventional methotrexate monotherapy. The primary outcome had a higher threshold of clinical response than in previous large randomised, double blind, controlled clinical trials for rheumatoid arthritis.9, 11, 16, 30 Almost two-thirds of patients in the combination group achieved low disease activity (DAS28 ≤3·2),

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