Elsevier

The Lancet

Volume 371, Issue 9617, 22–28 March 2008, Pages 987-997
The Lancet

Articles
Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial

https://doi.org/10.1016/S0140-6736(08)60453-5Get rights and content

Summary

Background

Interleukin 6 is involved in the pathogenesis of rheumatoid arthritis via its broad effects on immune and inflammatory responses. Our aim was to assess the therapeutic effects of blocking interleukin 6 by inhibition of the interleukin-6 receptor with tocilizumab in patients with rheumatoid arthritis.

Methods

In this double-blind, randomised, placebo-controlled, parallel group phase III study, 623 patients with moderate to severe active rheumatoid arthritis were randomly assigned with an interactive voice response system, stratified by site with a randomisation list provided by the study sponsor, to receive tocilizumab 8 mg/kg (n=205), tocilizumab 4 mg/kg (214), or placebo (204) intravenously every 4 weeks, with methotrexate at stable pre-study doses (10–25 mg/week). Rescue therapy with tocilizumab 8 mg/kg was offered at week 16 to patients with less than 20% improvement in both swollen and tender joint counts. The primary endpoint was the proportion of patients with 20% improvement in signs and symptoms of rheumatoid arthritis according to American College of Rheumatology criteria (ACR20 response) at week 24. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00106548.

Findings

The intention-to-treat analysis population consisted of 622 patients: one patient in the 4 mg/kg group did not receive study treatment and was thus excluded. At 24 weeks, ACR20 responses were seen in more patients receiving tocilizumab than in those receiving placebo (120 [59%] patients in the 8 mg/kg group, 102 [48%] in the 4 mg/kg group, 54 [26%] in the placebo group; odds ratio 4·0 [95% CI 2·6–6·1], p<0·0001 for 8 mg/kg vs placebo; and 2·6 [1·7–3·9], p<0·0001 for 4 mg/kg vs placebo). More people receiving tocilizumab than those receiving placebo had at least one adverse event (143 [69%] in the 8 mg/kg group; 151 [71%] in the 4 mg/kg group; 129 [63%] in the placebo group). The most common serious adverse events were serious infections or infestations, reported by six patients in the 8 mg/kg group, three in the 4 mg/kg group, and two in the placebo group.

Interpretation

Tocilizumab could be an effective therapeutic approach in patients with moderate to severe active rheumatoid arthritis.

Funding

F Hoffmann-La Roche, Chugai Pharmaceutical.

Introduction

Rheumatoid arthritis is a systemic autoimmune inflammatory disease associated with progressive joint damage, pain, fatigue, and disability. Although the exact cause of rheumatoid arthritis is still unknown, insights into its pathogenesis have confirmed the role of proinflammatory cytokines—eg, tumour necrosis factor α (TNFα), interleukin 1, and interleukin 6—in disease pathways.1, 2

Current treatments target the inflammatory system with disease modifying antirheumatic drugs (DMARDs; eg, methotrexate) or biological agents. The available biological agents inhibit the action of cytokines (eg, TNFα or interleukin 1) or limit B-cell function or T-cell costimulation, especially in combination with methotrexate.1, 3, 4, 5, 6 Despite their efficacy, none of these agents leads to response in all patients, and even among responders the improvement is often limited.1, 7, 8

Interleukin 6 is a pleiotropic cytokine that is over-expressed in synovial tissue in patients with rheumatoid arthritis, with raised concentrations in serum and synovial fluid.9, 10 Interleukin 6 affects the function of neutrophils, T cells, B cells, monocytes, and osteoclasts—cells that are highly activated in rheumatoid arthritis—and is the major inducer of the hepatic acute phase response,11 which is also a key feature of rheumatoid arthritis that is correlated with disease activity and joint destruction.12, 13 The effects of interleukin 6 are mediated by binding to the interleukin-6 receptor (CD126, IL6Rα chain), which is expressed on cell surfaces and as a circulating soluble form.

Thus, targeting interleukin 6 is an attractive therapeutic option in rheumatoid arthritis. Tocilizumab, a humanised monoclonal antibody that binds to both forms of the interleukin-6 receptor, showed clinical efficacy in a Japanese phase II study in rheumatoid arthritis.14 The results of the 16-week, phase II, double-blind, multicentre, European dose-ranging study CHARISMA15 confirmed the Japanese monotherapy data. In view of these promising early phase data, we undertook the tOcilizumab Pivotal Trial in methotrexate Inadequate respONders (OPTION) to assess the efficacy of tocilizumab in patients with active rheumatoid arthritis who were receiving background methotrexate therapy.

Section snippets

Patients

Adult patients with moderate to severe active rheumatoid arthritis (diagnosed according to American College of Rheumatology [ACR] criteria16) of more than 6 months' duration who had an inadequate response to methotrexate were recruited. Active disease was defined by a swollen joint count of 6 or more plus a tender joint count of 8 or more and C-reactive protein (CRP) over 10 mg/L or ESR of 28 mm/h or more. To be eligible, patients had to have received methotrexate for 12 weeks or longer before

Results

The trial profile is shown in figure 1. One patient in the tocilizumab 4 mg/kg group did not receive study treatment and was withdrawn; therefore, 622 patients were included in the ITT population. Baseline patient characteristics were much the same in all three groups (table 1). There were no important differences between the groups with respect to comorbidities (data not shown). Most patients had begun to take folic acid before the start of the study; only nine (4%) patients in the 4 mg/kg

Discussion

These data provide evidence that inhibition of interleukin-6-mediated proinflammatory effects significantly and rapidly improves the signs and symptoms of rheumatoid arthritis. Thus, tocilizumab could be an effective agent for the treatment of patients with moderate to severe rheumatoid arthritis.

In this study, tocilizumab produced a marked improvement from baseline in all ACR core set variables and significantly more patients on the drug achieved ACR20, ACR50, and ACR70 responses than did

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