The contribution of Asian researchers to the field of rheumatology

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Increased bone resorption Osteoclasts Bone Cytokine production e.g. IL-6, IL-17 T REG Proinammatory cytokines T cell Treatments developed in Asia humanized monoclonal antibody to il‑6 receptor The development of anticytokine therapies has led to a paradigm shift in the therapeutic strategies for rheumatic diseases. However, many of these therapies are inadequate, as they sometimes induce adverse effects and do not always elicit a clinically meaningful response. The anti-IL-6R tocilizumab was engineered by grafting the complementarity determining regions from the mouse antibody to human IL-6R to the human IgG1 framework to minimize potential immunogenic responses in human patients. 46 This agent has proven to be effective in several immunological disorders, including RA, systemic juvenile idiopathic arthritis, adult-onset Still disease, Castleman disease, and Crohn disease. 15 IL-6 is a pleiotropic cytokine that is overexpressed in the synovial tissue and present at high levels in the serum and synovial fluid of patients with RA. It increases the function of neutrophils, T cells, B cells, monocytes, and osteoclasts, all of which are overactivated in RA, and is also the major inducer of the hepatic acutephase response. IL-6 exerts its effects by binding to its receptor, IL-6R, which is expressed as a cell surface receptor and in a circulating soluble form. Tocilizumab is capable of binding both forms of IL-6R. Tocilizumab has already been licensed in Japan for the treatment of RA and Castleman disease. Results of large studies of tocilizumab therapy, including two international phase III clinical trials, have shown that the drug improved signs and symptoms in patients with active RA when used alone 47 or in combination with methotrexate 48 or DMARDs. 49 Furthermore, tocilizumab is an effective Activation Activation Synovial broblast Cytokine production e.g. IL-1, TNF B cell Macrophage Proliferation Proliferation alternative for patients who fail to respond to anti-TNF therapy. 50 This drug is not yet available for the treatment of RA in the uSA, but was approved by the European Medicines Agency (EMEA) in January 2009. Agonistic antibody to Fasr Apoptosis is essential for normal development and homeostasis maintenance in multicellular organisms. 51 Several stimuli, such as ligation of FasR, TNF receptors and other death receptors by their respective ligands or agonistic antibodies, have been reported to induce apoptosis in various mammalian cell systems. 52,53 FasR is a cell surface death receptor that transduces apoptotic signals in cells when activated by binding with Fas ligand (FasL; also known as CD178 and TNF superfamily, member 6) or agonistic monoclonal antibody to FasR. 52,53 RA is a chronic inflammatory disease associated with persistent synovial inflammation, proliferation of synovial fibroblasts, macrophages and lymphocytes, and destruction of the adjacent bone and cartilage (Figure 1). The mechanisms underlying the chronicity of RA inflammation remain elusive; however, increased proliferation or insufficient apoptosis, or both, might contribute to the increased numbers of synovial fibroblasts and chronic inflammatory cells present in RA-affected joints. Researchers have, therefore, examined RA-affected synovial tissue to characterize the process of apop tosis in this setting. 54 Apoptotic cells are rarely observed in RA-affected tissues in vivo, but in vitro studies have shown that synoviocytes, synovial T cells and macro phages express high levels of FasR and/or FasL, and are highly susceptible to Fas-induced apoptosis. This discrepancy NATuRE REVIEWS | rheumATologY VOLuME 6 | FEBRuARY 2010 | 109 FasR Fas-mediated apoptosis Anti-Fas antibody Figure 1 | A schematic representation of the pathogenesis of rheumatoid arthritis. T and B cells are attracted to synovial tissue, where they undergo activation and proliferation. These cells secrete proinflammatory cytokines, including IL‑6 and IL‑17, which activate synovial cells, such as fibroblasts and macrophages, and cause further migration of T and B cells to the joint. The activated macrophages secrete cytokines, such as TNF and IL‑1, which contribute to cartilage and bone destruction induced by osteoclasts. The proliferated synovial fibroblasts, macrophages and lymphocytes are resistant to apoptosis, but sensitive to Fas‑mediated cell death. Intra‑articular injection of agonistic anti‑Fasr antibodies might, therefore, reduce synovial hyperproliferation in rA‑affected joints. Abbreviations: IL, interleukin; TNF, tumor necrosis factor. © 20 10 Macmillan Publishers Limited. All rights reserved reviews
eviews 1. Zeng, Q. Y. et al. rheumatic diseases in China. Arthritis Res. Ther. 10, r17 (2008). 2. Omurzakova, N. A. et al. High incidence of rheumatic fever and rheumatic heart disease in the republics of Central Asia. Int. J. Rheumatic Dis. 12, 79–83 (2009). 3. Yazici, H., Fresko, I. & Yurdakul, S. Behcet’s syndrome: disease manifestations, management, and advances in treatment. Nat. Clin. Pract. Rheumatol. 3, 148–155 (2007). 4. Osame, M. et al. HTLV‑I associated myelopathy, a new clinical entity. Lancet 1, 1031–1032 (1986). 5. Nishioka, K. et al. Chronic inflammatory arthropathy associated with HTLV‑I. Lancet 1, 441 (1989). 6. Mochizuki, M. et al. Uveitis associated with human T‑cell lymphotropic virus type I. Am. J. Ophthalmol. 114, 123–129 (1992). 7. Maruyama, I., Mori, S., Kawabata, M. & Osame, M. Bronchopneumonopathy in HTLV‑1 associated myelopathy (HAM) and non‑HAM HTLV‑1 carriers [Japanese]. Nihon Kyobu Shikkan Gakkai Zasshi 30, 775–779 (1992). 8. Nakagawa, M. et al. HTLV‑I‑associated myelopathy: analysis of 213 patients based on clinical features and laboratory findings. J. Neurovirol. 1, 50–61 (1995). 9. Takayanagi, H. Osteoimmunology: shared mechanisms and crosstalk between the immune between the in vivo and in vitro results can be attributed to the presence of multiple antiapoptotic processes and/or phenomena in the rheumatoid syno vium. For instance, invading T cells have been found to possess defective FasL expression, which possibly accounts for the ineffec tive clearance of FasR-expressing cells. 55 In addition, cytokines derived from synoviocytes and stromal cells, including TNF and IL-1, protect synovi ocytes involved in RA from Fas-induced apoptosis. 56 These factors might account for the capability of T cells involved in RA to escape apoptosis via close interactions with synoviocytes. 57 Moreover, synovial macrophages and fibroblasts in RA-affected joints upregulate endo genous inhibitors of the Fas pathway, including c-FLIP. 58 Thus, multiple pathways—both intracellular and extracellular—impair Fas-induced apoptosis in RA-affected joints. The above observations strongly suggest that modulation of the Fas pathway in vivo could be a useful therapeutic strategy. More-direct evidence for the involvement of the Fas pathway in arthritis was obtained in mouse studies— many of which were conducted in Japan—in which the agonistic apoptosis-inducing antibodies to FasR were shown to be efficacious in treating arthritis. 59 Similar findings have also been confirmed in humanized experimental models. 60 Thus, current evidence suggests that activation of the agonistic Fas pathway can be considered as a potentially useful treatment strategy for the treatment of RA and other inflammatory arthritides. Indeed, clinical trials of antibody to FasR, administered via intra-articular injection, in patients with RA are currently underway. Preliminary results of a Belgian phase I clinical trial indicate that this therapy is safe and effective, even at very low antibody concentrations. 61 In Japan, a multicenter, phase I trial in more than 140 patients is in progress, with detailed results expected soon. Conclusions Some unique immunological disease entities, the study of which have influenced our understanding of the concepts involved in other rheumatic disorders, have been discovered in the Asian region. Research on the pathogenesis of these diseases has greatly increased the understanding of immune-mediated disorders. Furthermore, novel discoveries made by Asian re searchers in conventional scientific disciplines, such as the discovery of T REG cells and the antiapoptotic molecule synoviolin, and the development of the new discipline of osteoimmunology, have opened up new research avenues in rheumatology. Asian rheumatologists have also success fully applied the findings of laboratory research to clinical practice and developed new strategies, such as tocilizumab and antibodies to FasR. Clinical trials are currently underway to confirm the safety and efficacy of these therapies. Review criteria and bone systems. Nat. Rev. Immunol. 7, 292–304 (2007). 10. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self‑tolerance maintained by activated T cells expressing IL‑2 receptor alpha‑chains (CD25). Breakdown of a single mechanism of self‑tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995). 11. Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. regulatory T cells and immune tolerance. Cell 133, 775–787 (2008). 12. Yagishita, N., Yamasaki, S., Nishioka, K. & Nakajima, T. Synoviolin, protein folding and the maintenance of joint homeostasis. Nat. Clin. Pract. Rheumatol. 4, 91–97 (2008). 13. Yamada, r. & Yamamoto, K. Mechanisms of disease: genetics of rheumatoid arthritis— ethnic differences in disease‑associated genes. Nat. Clin. Pract. Rheumatol. 3, 644–650 (2007). 14. Nishimoto, N. & Kishimoto, T. Interleukin 6: from bench to bedside. Nat. Clin. Pract. Rheumatol. 2, 619–626 (2006). 15. Behçet, H. Uber rezidivierende, aphthose, dürch ein Virus verursachte Geshwure am Munde, am Auge und an den Genitalien. Dermatologische Wochenschrift 36, 1152–1157 (1937). 16. Verity, D. H., Marr, J. e., Ohno, S., wallace, G. r. & Stanford, M. r. Behçet’s disease, the Silk road Data for this review were obtained by searching the PubMed database for english and Japanese‑language papers, published from 1960 onwards, using the following search terms: “Asia”, “rheumatology”, “HTLV”, “rheumatoid arthritis”, “autoimmune disease”, “Behçet”, “Takayasu’s arteritis”, “Kawasaki disease”, “osteoimmunology”, “Treg”, “Foxp3”, “synoviolin”, “ethnic”, “IL‑6”, “Fas”, “FasL”, “apoptosis” and “cytokine”. Additional studies were identified from the abstracts of the American College of rheumatology Scientific Meetings. and HLA‑B51: historical and geographical perspectives. Tissue Antigens 54, 213–220 (1999). 17. Hatemi, G. et al. The pustular skin lesions in Behcet’s syndrome are not sterile. Ann. Rheum. Dis. 63, 1450–1452 (2004). 18. Gul, A. Behcet’s disease as an autoinflammatory disorder. Curr. Drug Targets Inflamm. Allergy 4, 81–83 (2005). 19. Numano, F. The story of Takayasu arteritis. Rheumatology (Oxford) 41, 103–106 (2002). 20. Koide, K. Takayasu arteritis in Japan. Heart Vessels Suppl. 7, 48–54 (1992). 21. Arend, w. P. et al. The American College of rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum. 33, 1129–1134 (1990). 22. Kimura, A., Kitamura, H., Date, Y. & Numano, F. Comprehensive analysis of HLA genes in Takayasu arteritis in Japan. Int. J. Cardiol. 54 (Suppl.), S61–S69 (1996). 23. Seko, Y. et al. Perforin‑secreting killer cell infiltration and expression of a 65‑kD heat‑shock protein in aortic tissue of patients with Takayasu’s arteritis. J. Clin. Invest. 93, 750–758 (1994). 24. Huang, w. C. et al. epidemiologic features of Kawasaki disease in Taiwan, 2003–2006. Pediatrics 123, e401–e405 (2009). 110 | FEBRUARY 2010 | volUmE 6 www.nature.com/nrrheum © 20 10 Macmillan Publishers Limited. All rights reserved
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