ArticlesMaintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial
Introduction
In individuals with rheumatoid arthritis, high disease activity is associated with joint destruction and functional disability.1, 2, 3, 4 The ultimate goals of treatment of rheumatoid arthritis are to slow or stop joint damage and maximally reduce disability, by attaining long-term clinical remission or at least low disease activity.5 Whether these goals are achieved in patients with moderate disease activity—a large proportion of the overall population of individuals with rheumatoid arthritis6, 7—has not yet been well studied. Importantly, patients with moderate disease activity are still prone to substantial progression of joint damage and therefore have serious disability.4, 8
Although biologics such as inhibitors of tumour necrosis factor have been essential for increasing the likelihood of disease remission and low disease activity, these treatments are expensive compared with traditional disease-modifying antirheumatic drugs. Accordingly, use of biologics is restricted in some countries to patients with high disease activity despite receiving traditional disease-modifying antirheumatic drugs.9 Because personalised medicine is a focus in research and practice,10 dose adjustments once a treatment target has been sustained are highly important. Although some observational data for withdrawal of biologics in early rheumatoid arthritis have been reported,11, 12, 13 no controlled trial has yet assessed withdrawal or dose reduction. Therefore, investigation of the best possible use of biologic agents is of interest, including potential dosing alternatives and so-called induction, maintenance, and withdrawal treatment strategies. The aim of PRESERVE was to assess whether the response to treatment with conventional doses of the biologic etanercept and background methotrexate in adults with moderately active rheumatoid arthritis despite methotrexate treatment would be sustained when doses of etanercept were reduced or withdrawn.
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Study design and participants
In this randomised controlled trial, patients with rheumatoid arthritis aged between 18 and 70 years with moderate disease activity at screening (4–42 days before baseline) and baseline (week 0) visits were enrolled at 80 centres in Europe, Latin America, Asia, and Australia between March 6, 2008, and Sept 9, 2009. Moderate disease activity was defined as a disease activity score in 28 joints (DAS28; on the basis of erythrocyte sedimentation rate) of more than 3·2 and 5·1 or less. Participants
Results
Figure 1 shows the trial profile. In the open-label period, all patients achieved at least 80% compliance with injection and oral treatment. In the double-blind period, 199 (98·5%) of 202 patients given 50 mg etanercept, 199 (98·5%) of 202 given 25 mg etanercept, and 199 (99·5%) of 200 given placebo achieved 80% compliance. The proportion of patients who were eligible to continue to the double-blind period (604 [72%] of 834) was higher than had been predicted; therefore, the sample size for the
Discussion
This trial has shown that withdrawal of etanercept in patients with rheumatoid arthritis who have achieved sustained low disease activity causes disease activity to increase again. More than half of patients who stopped taking etanercept lost low disease activity compared with fewer than one in five in the groups who continued taking the drug. The combination of etanercept and methotrexate led to more favourable secondary outcomes at all timepoints in the double-blind period than did
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