The use of anakinra, an interleukin-1 receptor antagonist, in the treatment of rheumatoid arthritis
Section snippets
Efficacy of anakinra
Efficacy results from several large, controlled studies support the use of anakinra for the signs and symptoms of RA. These results are summarized separately for each study.
Safety of anakinra
Randomized, placebo-controlled studies provided data on the safety of anakinra as a monotherapy [35], [39], in combination with MTX [36], [41], and with multiple DMARDs [37], [45].
Radiographic results
Because RA frequently leads to destructive lesions of cartilage and periarticular bone and IL-1 is a known mediator of joint damage, anakinra has the potential to inhibit structural damage. The trial that investigated anakinra as a monotherapy for signs and symptoms of RA [35] also evaluated the prevention of radiographic progression [38]. Hand and wrist radiographs were obtained at baseline and 24 weeks for the placebo-treated group and three anakinra-treated groups (30 mg/kg, 75 mg/kg, and
Anakinra plus etanercept
Although IL-1 is a known mediator of RA, TNF also plays a substantial role in its pathogenesis. Several clinical trials have investigated anti-TNF therapy and found it to be clinically efficacious in the treatment of RA [51], [52], [53], [54]. Because animal models had predicted the excellent clinical responses of anti–IL-1 and anti-TNF therapy in RA, the potential of synergistic effects of combination therapy that targeted both key cytokines (IL-1 and TNF) was investigated first in a rat model
Anakinra in patients who were previously treated with tumor necrosis factor
It was postulated that patients who have RA may have disease that is mediated by IL-1 and TNF or predominantly by one or the other, although definitive evidence for this hypothesis is lacking. An indication that patients may have IL-1–mediated disease is the inadequate response to anti-TNF therapy; these patients may respond successfully to anti–IL-1 therapy. To explore this hypothesis, an ad hoc analysis of a prospective study evaluated the efficacy of anakinra in patients who were treated
Summary
Anakinra has been proven safe and effective in the treatment of RA as monotherapy and in combination with other medications. The need for daily injectable administration has limited its use, as reflected by patient preference for less frequent dosaging from postmarketing surveillance. Thus, since FDA approval, anakinra primarily has been used as a secondary line of treatment for RA, following failures of other DMARDs or anti-TNF therapy.
Preclinical models, clinical trials, and postmarketing
Acknowledgements
The author thanks Cheri Osteen, PhD for editorial assistance.
References (58)
Biologic basis for interleukin-1 in disease
Blood
(1996)- et al.
Arthritis induced by interleukin-1 is dependent on the site and frequency of intraarticular injection
Clin Immunol Immunopathol
(1990) - et al.
Interleukin 1 enhances the development of spontaneous arthritis in MRL/lpr mice
Clin Immunol Immunopathol
(1990) - et al.
Correlation of plasma interleukin 1 levels with disease activity in rheumatoid arthritis
Lancet
(1988) Uncoupling of inflammatory and destructive mechanisms in arthritis
Semin Arthritis Rheum
(2001)- et al.
Interaction of recombinant monocyte-derived interleukin 1 receptor antagonist with rheumatoid synovial cells
Cytokine
(1991) - et al.
The interleukin-1 receptor binds the human interleukin-1 alpha precursor but not the interleukin-1 beta precursor
J Biol Chem
(1987) - et al.
Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis
Lancet
(1994) - 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.
Rheumatoid arthritis, etiology, diagnosis and treatment
(2002)
Rheumatoid arthritis. Pathophysiology and implications for therapy
N Engl J Med
Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis
Arthritis Rheum
Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist
Int Rev Immunol
Anti-interleukin-1 therapy in rheumatic diseases
Curr Opin Rheumatol
Effects of murine recombinant interleukin 1 on synovial joints in mice: measurement of patellar cartilage metabolism and joint inflammation
Ann Rheum Dis
Arthritis induced by continuous infusion of hr-interleukin-1 alpha into the rabbit knee-joint
Int J Tissue React
Constitutive intra-articular expression of human IL-1 beta following gene transfer to rabbit synovium produces all major pathologies of human rheumatoid arthritis
J Immunol
In vivo administration with IL-1 accelerates the development of collagen-induced arthritis in mice
J Immunol
Interleukin-1-like activities in synovial fluids of patients with rheumatoid arthritis and traumatic synovitis
Rheumatol Int
Cytokines and the chronic inflammation of rheumatic disease. I. The presence of interleukin-1 in synovial fluids
Clin Exp Immunol
Augmented interleukin-1 production and HLA-DR expression in the synovium of rheumatoid arthritis patients. Possible involvement in joint destruction
Arthritis Rheum
Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice
J Exp Med
Direct adenovirus-mediated gene transfer of interleukin 1 and tumor necrosis factor alpha soluble receptors to rabbit knees with experimental arthritis has local and distal anti-arthritic effects
Proc Natl Acad Sci USA
IL-1 receptor antagonist protein production and gene expression in rheumatoid arthritis and osteoarthritis synovium
J Immunol
Localization of interleukin-1 alpha, type 1 interleukin-1 receptor and interleukin-1 receptor antagonist in the synovial membrane and cartilage/pannus junction in rheumatoid arthritis
Br J Rheumatol
Synovial interleukin-1 receptor antagonist and interleukin-1 balance in rheumatoid arthritis
Arthritis Rheum
Biological properties of recombinant human monocyte-derived interleukin 1 receptor antagonist
J Clin Invest
Biologic effects of an interleukin-1 receptor antagonist protein on interleukin-1-stimulated cartilage erosion and chondrocyte responsiveness
Arthritis Rheum
Natural and recombinant human IL-1 receptor antagonists block the effects of IL-1 on bone resorption and prostaglandin production
J Immunol
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