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Ebosin: a potential therapeutic agent for rheumatoid arthritis and autoinflammatory syndromes

Cellular & Molecular Immunology volume 15, pages 12–14 (2018)Cite this article

Rheumatoid arthritis (RA) is a chronic autoimmune disease that has a worldwide prevalence of 1%. The symptoms of RA are pain, stiffness and symmetrical synovitis of diarthrodial joints, which result in articular destruction, functional decline, and substantial comorbidity in the cardiovascular, neurologic and metabolic systems.1 In RA, fibroblast-like synoviocytes (FLS, Type B synoviocytes) and osteoclasts are the main cells that contribute to bone and cartilage degradation, respectively.2 Pro-inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and IL-6, play an essential role in the activation of FLS and the differentiation of osteoclasts, which have been implicated in the pathogenesis of RA.3 Targeting pro-inflammation cytokines and blocking their signal pathways have become an important strategy in RA treatment. The major functions of TNF-α in RA are associated with the production of pro-inflammation cytokines, inflamed synovium, chemokine amplification, Treg cells and osteoclast recruitment.4 As a TNF inhibitor, etanercept5 is a human recombinant version of the soluble p75 TNF receptor that is linked to the Fc of human immunoglobulin G subclass 1 (IgG1), and it acts as a competitive inhibitor of the binding of TNF-α to cell-surface TNF receptors and thereby inhibits TNF-α-induced pro-inflammatory activity in the joints of RA patients. It was the first biological disease-modifying antirheumatic drug (bDMARD) and the first tumor necrosis factor inhibitor to be approved for use in rheumatic diseases. In recent years, four anti-TNF therapies, infliximab, adalimumab, certolizumab and golimumab, have also been approved for the treatment of RA.6 In RA, IL-6 is responsible for the activation of immune cells, endothelial cells, synoviocytes, and osteoclasts and for the production of acute-phase proteins such as CRP. Tocilizumab, an anti-human IL-6 receptor, was approved for the treatment of RA, and it reduced disease activity and radiographic joint damage.7 IL-1 acts as a key mediator in the pathogenesis of RA, and it is expressed in abundance in the synovial membrane. An IL-1 blockade is advantageous in the context of RA. Anakinra,8 a recombinant version of the IL-1 receptor antagonist (IL-1Ra), was approved for treating refractory RA to DMARDs and for neonatal-onset multisystem inflammatory disease, which is part of the CAPS (cryopyrin-associated periodic syndromes) spectrum. Rilonacept9 is a dimeric fusion protein consisting of the extracellular domains of the IL-1 receptor and IL-1 receptor accessory protein joined at the constant region (Fc) of human IgG1. By incorporating both components of the IL-1 binding complex, rilonacept, an IL-1 inhibitor, is able to bind tightly to IL-1 with picomolar affinity. Rilonacept was approved for only the treatment of patients with rare genetic conditions called CAPS, but those with various inflammatory syndromes are also treated with rilonacept. The mAb canakinumab,10 a human monoclonal antibody that targets IL-1β, was approved for the treatment of CAPS and for the treatment of systemic-onset jejunoileal arthropathy. According to the data mentioned above, treatments for a range of the agents blocking IL-1 are derived from classic rheumatic diseases, such as RA and gout, to autoinflammatory syndromes, such as systemic jejunoileal arthropathy. Compared with the pathogenesis of autoimmune diseases, the pathogenesis of autoinflammatory syndromes does not revolve around the recognition of self-antigens by dysfunctional T lymphocytes or autoantibodies.11 Autoimmune diseases are treated with different cytokine-blocking agents, neutralizing antibodies and inhibitors of cell migration, while autoinflammatory diseases are characteristically responsive to an IL-1 blockade.

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Acknowledgements

This research was supported by grants from the Natural Science Foundation of China (No. 30530830 and No. 81302677) and grants from the National Mega-Project for Innovative Drugs (No. 2012ZX09301002-001-023-02 and No. 2014ZX09201001-004-001).

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  1. Yang Zhang and Lifei Wang: These authors contributed equally to this work.

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  1. Key Laboratory of Biotechnology of Antibiotics, Ministry of Health, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China

    Yang Zhang, Lifei Wang & Yuan Li

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Correspondence to Lifei Wang or Yuan Li.

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Zhang, Y., Wang, L. & Li, Y. Ebosin: a potential therapeutic agent for rheumatoid arthritis and autoinflammatory syndromes. Cell Mol Immunol 15, 12–14 (2018). https://doi.org/10.1038/cmi.2017.90

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