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      Interleukin-6 inhibitors in the treatment of rheumatoid arthritis

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          Abstract

          Recent developments in understanding the immunopathogenesis of rheumatoid arthritis (RA), combined with progress in biopharmaceutical development, have facilitated the introduction of novel immune modulating therapies for this progressive debilitating disorder. Efficacy achieved with certain agents, particularly the TNF inhibitors, has spurred the development of additional biologic agents targeting other components of the dysregulated immune response relevant to the etiology and sustenance of immune driven systemic inflammation characteristic of RA. Among these other potential targets is IL-6, a cytokine with effects on numerous cell types, including those involved in the pathogenesis of RA. Based on its activities, IL-6 appeared to be a viable target for autoimmune disease. Inhibitors of IL-6 were successful in animal models of autoimmune disease paving the way for subsequent studies in humans. The greatest experience to date has been with tocilizumab, a humanized monoclonal antibody specific for the IL-6 receptor (IL-6R). Beginning with open label studies, and progressing through larger and more rigorous controlled trials, tocilizumab has been shown to have significant Efficacy in patients with RA. Additional studies analyzing its effects in varied populations of RA patients, as well as greater detail concerning its longer-term tolerability and safety, will help define the ultimate role of tocilizumab and other future inhibitors of IL-6 activity as potential therapies for RA.

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          Most cited references 28

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

          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. 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. 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. Tocilizumab could be an effective therapeutic approach in patients with moderate to severe active rheumatoid arthritis. F Hoffmann-La Roche, Chugai Pharmaceutical.
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            IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin.

            Hypoferremia is a common response to systemic infections or generalized inflammatory disorders. In mouse models, the development of hypoferremia during inflammation requires hepcidin, an iron regulatory peptide hormone produced in the liver, but the inflammatory signals that regulate hepcidin are largely unknown. Our studies in human liver cell cultures, mice, and human volunteers indicate that IL-6 is the necessary and sufficient cytokine for the induction of hepcidin during inflammation and that the IL-6-hepcidin axis is responsible for the hypoferremia of inflammation.
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              Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab.

              To evaluate the ability of tocilizumab (a humanised anti-IL-6 receptor antibody) monotherapy to inhibit progression of structural joint damage in patients with RA. In a multi-centre, x ray reader-blinded, randomised, controlled trial, 306 patients with active RA of <5 years' duration were allocated to receive either tocilizumab monotherapy at 8 mg/kg intravenously every 4 weeks or conventional disease-modifying antirheumatic drugs (DMARDs) for 52 weeks. Radiographs of hands and forefeet were scored by the van der Heijde modified Sharp method. Patients had a mean disease duration of 2.3 years and a disease activity score in 28 joints of 6.5 at baseline. Mean total modified Sharp score (TSS) was 29.4, which was very high despite the relatively short disease duration. At week 52, the tocilizumab group showed statistically significantly less radiographic change in TSS (mean 2.3; 95% CI 1.5 to 3.2) than the DMARD group (mean 6.1; 95% CI 4.2 to 8.0; p<0.01). Tocilizumab monotherapy also improved signs and symptoms. The overall incidences of AEs were 89% and 82% (serious AEs: 18% and 13%; serious infections: 7.6% and 4.1%) in the tocilizumab and DMARD groups, respectively. Tocilizumab monotherapy was generally well tolerated and provided radiographic benefit in patients with RA.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                August 2008
                August 2008
                : 4
                : 4
                : 767-775
                Affiliations
                Division of Rheumatology, Allergy, Immunology, The University of California, San Diego, CA, USA
                Author notes
                Correspondence: Arthur Kavanaugh, Center for Innovative Therapy, UCSD, Division of Rheumatology, Allergy and Immunology, 9500 Gilman Drive, Mail Code 0943, La Jolla, CA 92093-0943, USA, Tel +1 858 657 7044, Fax +1 858 657 7045), Email akavanaugh@ 123456ucsd.edu
                Article
                tcrm-4-767
                2621374
                19209259
                © 2008 Dove Medical Press Limited. All rights reserved
                Categories
                Review

                Medicine

                il-6, rheumatoid arthritis, tocilizumab, biologic agents

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