Elsevier

The Lancet

Volume 381, Issue 9870, 16–22 March 2013, Pages 918-929
The Lancet

Articles
Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial

https://doi.org/10.1016/S0140-6736(12)61811-XGet rights and content

Summary

Background

Clinical remission and low disease activity are essential treatment targets in patients with rheumatoid arthritis. Although moderately active rheumatoid arthritis is common, treatment effects in moderate disease have not been well studied. Additionally, optimum use of biologics needs further investigation, including the use of induction, maintenance, and withdrawal treatment strategies. The aim of the PRESERVE trial was to assess whether low disease activity would be sustained with reduced doses or withdrawal of etanercept in patients with moderately active disease.

Methods

In a randomised controlled trial, patients aged between 18 and 70 years with moderately active rheumatoid arthritis (disease activity score in 28 joints [DAS28] >3·2 and ≤5·1) despite treatment with methotrexate were enrolled at 80 centres in Europe, Latin America, Asia, and Australia between March 6, 2008, and Sept 9, 2009. To be eligible, patients had to have been receiving 15–25 mg of methotrexate every week for at least 8 weeks. In an open-label period of 36 weeks, all patients were given 50 mg etanercept plus methotrexate every week. To be eligible for a subsequent double-blind period of 52 weeks, participants had to have achieved sustained low disease activity. These patients were randomly assigned (1:1:1) by an interactive voice-response system to one of three treatment groups: 50 mg etanercept plus methotrexate, 25 mg etanercept plus methotrexate, or placebo plus methotrexate. Patients were stratified in blocks of three by DAS28 response (low disease activity or remission) at week 36. Patients, investigators, data analysts, and study staff were all masked to treatment allocation. The primary endpoint was the proportion of patients with low disease activity at week 88 in the groups given 50 mg etanercept or placebo in the double-blind period. A conditional primary endpoint was the proportion of patients receiving 25 mg etanercept who achieved low disease activity. Modified intention-to-treat populations were used for analyses. This trial is registered with ClinicalTrials.gov, number NCT00565409.

Findings

604 (72·4%) of 834 enrolled patients were eligible for the double-blind period, of whom 202 were assigned to 50 mg etanercept plus methotrexate, 202 to 25 mg etanercept plus methotrexate, and 200 to placebo plus methotrexate. At week 88, 166 (82·6%) of 201 patients who had received at least one dose of 50 mg etanercept and one or more DAS28 evaluations had low disease activity, compared with 84 (42·6%) of 197 who had received placebo (mean difference 40·8%, 95% CI 32·5–49·1%; p<0·0001). Additionally, 159 (79·1%) of 201 patients given 25 mg etanercept had low disease activity at week 88 (mean difference from placebo 35·9%, 27·0–44·8%; p<0·0001).

Interpretation

Conventional or reduced doses of etanercept with methotrexate in patients with moderately active rheumatoid arthritis more effectively maintain low disease activity than does methotrexate alone after withdrawal of etanercept.

Funding

Pfizer.

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.

Section snippets

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

References (34)

  • M Mierau et al.

    Assessing remission in clinical practice

    Rheumatology (Oxford)

    (2007)
  • D van der Heijde et al.

    Level of radiographic damage and radiographic progression are determinants of physical function: a longitudinal analysis of the TEMPO trial

    Ann Rheumatic Dis

    (2008)
  • Adalimumab, etanercept, and infliximab for the treatment of rheumatoid arthritis

  • MA Hamburg et al.

    The path to personalized medicine

    N Engl J Med

    (2010)
  • B Saleem et al.

    Patients with RA in remission on TNF blockers: when and in whom can TNF blocker therapy be stopped?

    Ann Rheum Dis

    (2010)
  • Y Tanaka et al.

    Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (remission induction by Remicade in RA) study

    Ann Rheum Dis

    (2010)
  • American College of Rheumatology Clinical Trial Priorities and Design Conference, July 22–23, 2010

    Arthritis Rheum

    (2011)
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