ArticlesEffect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial
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
References (41)
- et al.
New therapies for treatment of rheumatoid arthritis
Lancet
(2007) - et al.
Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group
Lancet
(1999) - et al.
Effects of repeated infliximab therapy on serum lipid profile in patients with refractory rheumatoid arthritis
Clin Chim Acta
(2006) - et al.
Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study
Lancet
(2002) - et al.
Heart failure in rheumatoid arthritis: rates, predictors, and the effect of anti-tumor necrosis factor therapy
Am J Med
(2004) Evolving concepts of rheumatoid arthritis
Nature
(2003)- et al.
The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial
Arthritis Rheum
(2006) - et al.
A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: radiologic progression and correlation of Genant and Larsen scores
Arthritis Rheum
(2000) - et al.
Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial
Ann Intern Med
(2006) - et al.
Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group
N Engl J Med
(2000)
Early rheumatoid arthritis: time to aim for remission?
Ann Rheum Dis
Assessing remission in clinical practice
Rheumatology (Oxford)
Quantitative analysis of cytokine gene expression in rheumatoid arthritis
J Immunol
Cytokine production by synovial T cells in rheumatoid arthritis
Rheumatology (Oxford)
The paradigm of IL-6: from basic science to medicine
Arthritis Res
Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score
Arthritis Res Ther
Interrelationship of outcome measures and process variables in early rheumatoid arthritis. A comparison of radiologic damage, physical disability, joint counts, and acute phase reactants
J Rheumatol
Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial
Arthritis Rheum
Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate
Arthritis Rheum
The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis
Arthritis Rheum
Cited by (1238)
A review of hyaluronic acid-based therapeutics for the treatment and management of arthritis
2024, International Journal of Biological MacromoleculesClotting of the Extracorporeal Circuit in Hemodialysis: Beyond Contact-Activated Coagulation
2024, Seminars in NephrologyTocilizumab for antibody-mediated rejection treatment in lung transplantation
2023, Journal of Heart and Lung TransplantationLeveraging decagonal in-silico strategies for uncovering IL-6 inhibitors with precision
2023, Computers in Biology and Medicine
- ‡
Listed at end of paper