Elsevier

The Lancet

Volume 383, Issue 9914, 25–31 January 2014, Pages 321-332
The Lancet

Articles
Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial

https://doi.org/10.1016/S0140-6736(13)61751-1Get rights and content

Summary

Background

Biological agents offer good control of rheumatoid arthritis, but the long-term benefits of achieving low disease activity with a biological agent plus methotrexate or methotrexate alone are unclear. The OPTIMA trial assessed different treatment adjustment strategies in patients with early rheumatoid arthritis attaining (or not) stable low disease activity with adalimumab plus methotrexate or methotrexate monotherapy.

Methods

This trial was done at 161 sites worldwide. Patients with early (<1 year duration) rheumatoid arthritis naive to methotrexate were randomly allocated (by interactive voice response system, in a 1:1 ratio, block size four) to adalimumab (40 mg every other week) plus methotrexate (initiated at 7·5 mg/week, increased by 2·5 mg every 1–2 weeks to a maximum weekly dose of 20 mg by week 8) or placebo plus methotrexate for 26 weeks (period 1). Patients in the adalimumab plus methotrexate group who completed period 1 and achieved the stable low disease activity target (28-joint disease activity score with C-reactive protein [DAS28]<3·2 at weeks 22 and 26) were randomised to adalimumab-continuation or adalimumab-withdrawal for an additional 52 weeks (period 2). Patients achieving the target with initial methotrexate continued methotrexate-monotherapy. Inadequate responders were offered adalimumab plus methotrexate. All patients and investigators were masked to treatment allocation in period 1. During period 2, treatment reallocation of patients who achieved the target was masked to patients and investigators; patients who did not achieve the target remained masked to original randomisation, but were aware of the subsequent assignment. The primary endpoint was a composite measure of DAS28 of less than 3·2 at week 78 and radiographic non-progression from baseline to week 78, compared between adalimumab-continuation and methotrexate-monotherapy. Adverse events were monitored throughout period 2. This trial is registered with ClinicalTrials.gov, number NCT00420927.

Findings

The study was done between Dec 28, 2006, and Aug 3, 2010. 1636 patients were assessed and 1032 were randomised in period 1 (515 to adalimumab plus methotrexate; 517 to placebo plus methotrexate). 466 patients in the adalimumab plus methotrexate group completed period 1; 207 achieved the stable low disease activity target, of whom 105 were rerandomised to adalimumab-continuation. 460 patients in the placebo plus methotrexate group completed period 1; 112 achieved the stable low disease activity target and continued methotrexate-monotherapy. 73 of 105 (70%) patients in the adalimumab-continuation group and 61 of 112 (54%) patients in the methotrexate-monotherapy group achieved the primary endpoint at week 78 (mean difference 15% [95% CI 2–28%], p=0·0225). Patients achieving the stable low disease activity target on adalimumab plus methotrexate who withdrew adalimumab mostly maintained their good responses. Overall, 706 of 926 patients in period 2 had an adverse event, of which 82 were deemed serious; however, distribution of adverse events did not differ between groups.

Interpretation

Treatment to a stable low disease activity target resulted in improved clinical, functional, and structural outcomes, with both adalimumab-continuation and methotrexate-monotherapy. However, a higher proportion of patients treated with initial adalimumab plus methotrexate achieved the low disease activity target compared with those initially treated with methotrexate alone. Outcomes were much the same whether adalimumab was continued or withdrawn in patients who initially responded to adalimumab plus methotrexate.

Funding

AbbVie.

Introduction

Rheumatoid arthritis is characterised by an imbalance in the activities of inflammatory cytokines, such as tumour necrosis factor and interleukin 6, within the synovial tissue of affected joints. It occurs in an estimated 0·5–1·0% of the general population, with a higher prevalence in women than in men.1 Biological disease-modifying antirheumatic drugs, such as inhibitors of tumour necrosis factor, have greatly improved the treatment of patients with rheumatoid arthritis, and methotrexate remains the traditional anchor therapy. Timely initiation of biological therapy,2, 3, 4 with rapid attainment of a clinical target (eg, remission or low disease activity),5 minimises joint damage and preserves physical function.6, 7 Nevertheless, information about the most effective use of biological agents, notably the best possible time to initiate and potential consequences of later withdrawal of these treatments, is unavailable. The European League Against Rheumatism (EULAR) recommends considering withdrawal of biological agents after attainment of a good clinical state, mainly on the basis of consensus findings.8 However, evidence from large controlled trials, in particular for patients with early disease, is scarce.8

We therefore designed the OPTIMA (Optimal Protocol for Treatment Initiation with Methotrexate and Adalimumab) trial to assess the clinical, radiographic, and functional outcomes of several therapeutic approaches in patients with early rheumatoid arthritis who had, or had not, initially achieved stable low disease activity. We tested the hypothesis that among patients who initially achieved a target of stable low disease activity, those receiving initial combination therapy with adalimumab plus methotrexate would have better clinical and radiographic outcomes than those receiving methotrexate alone. Additionally, we explored the hypothesis that therapeutic responses would be maintained after withdrawal of adalimumab in patients who initially responded to adalimumab plus methotrexate. In a post-hoc exploratory analysis, we assessed the effects of addition of adalimumab to the treatment regimens of patients who did not achieve stable low disease activity with initial placebo plus methotrexate.

Section snippets

Study design and participants

OPTIMA was a 78-week randomised, double-period, double-blind study, done at 161 sites (including academic hospitals and research centres, private practices, and rheumatology clinics) across Europe (n=71), North America (n=73), South America (n=5), Africa (n=6), Australia (n=3), and New Zealand (n=3). Eligible patients were aged 18 years or older with active rheumatoid arthritis (<1 year duration), according to 1987-revised American College of Rheumatology (ACR) classification criteria.9

Results

The study was done between Dec 28, 2006, and Aug 3, 2010. 1032 patients were enrolled, with 515 being assigned to adalimumab plus methotrexate and 517 to placebo plus methotrexate (figure 1). 466 patients in the adalimumab plus methotrexate group completed period 1, of whom 207 (44%) satisfied the stable low disease activity target; 105 were rerandomised to adalimumab-continuation and 102 to adalimumab-withdrawal. 460 participants in the placebo plus methotrexate group completed period 1, of

Discussion

Among patients who satisfied the stable low disease activity target at week 26, continued adalimumab plus methotrexate resulted in a significantly higher proportion achieving the composite endpoint of DAS28 of less than 3·2 with radiographic non-progression at week 78 compared with continued methotrexate monotherapy. Nevertheless, overall progression rates were modest and statistically much the same among responder populations. The differences between combination therapy and methotrexate

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