The contribution of Asian researchers to the field of rheumatology

eVIewS 

Institute of Medical 

Science, St Marianna 

University School of 

Medicine, Kanagawa, 

2‑16‑1 Sugao, 

Miyamae‑ku, Kawasaki‑ 

shi, Kanagawa 

216‑8512, Japan 

(Y. Yamano). Institute 

of Medical Science, 

Tokyo Medical 

University, 1‑6‑1 

Shinjyuku, Shinjyuku‑ku, 

Tokyo 160‑8402, Japan 

K. Nishioka). 

Correspondence to: 

K. Nishioka 

toranomon‑nishioka@ 

cpost.plala.or.jp 

The contribution of Asian researchers 

to the field of rheumatology 

Yoshihisa Yamano and Kusuki Nishioka 

Abstract | Asia is home to more than half of the world’s population and is a region of diverse ethnicity, culture, 

microbial endemicity, and economic backgrounds. This diversity is also reflected in the heterogeneity among 

Asian patients with rheumatic diseases in terms of clinical manifestations, disease courses, treatment 

responses and outcomes, which provides opportunities for researchers to conduct some unique studies. 

Several disease entities, such as Behçet syndrome, Takayasu arteritis, Kawasaki disease, and immunological 

disorders associated with human T‑lymphotropic virus type 1 (HTLV‑1), were first observed and defined in 

Asia. In addition, the region’s researchers have been at the forefront of research in some interesting scientific 

topics, which has opened up new research avenues in rheumatology, such as the direct targeting of synovial 

cells in patients with rheumatoid arthritis via activation of the agonistic Fas pathway, establishment of the field 

of osteoimmunology, the discovery of regulatory T cells and synoviolin, and the development of tocilizumab, a 

humanized monoclonal antibody against interleukin‑6 receptor. 

Yamano, Y. & Nishioka, K. Nat. Rev. Rheumatol. 6, 106–111 (2010); doi:10.1038/nrrheum.2009.257 

Introduction 

Asia is a region of diverse ethnicities, cultures, economies, 

and microbial endemicity, providing unique opportunities 

for Asian researchers to contribute to the field of rheumatology. 

For example, the Community Oriented Program 

for the Control of Rheumatic Diseases (COPCORD), 

sponsored by the WHO and International League Against 

Rheumatism (WHO-ILAR), has generated extensive data 

on the epidemiology and charac teristics of rheumatic diseases 

in Asia. 1 These data revealed that the incidence of 

rheumatic fever has markedly increased in Central Asia 

during the past decade. 2 Several Asian countries have 

active rheumatology communities in clinical practice and 

academic and research capacities, as well as an active professional 

society, the Asia Pacific League of Associations 

for Rheumatology (APLAR). 

On the basis of the varied ethnicity and microbial 

endemicity in Asia, rheumatologists have identified novel 

disease entities endemic to the region, such as Behçet syndrome, 

3 Takayasu arteritis, Kawasaki disease, and immunological 

disorders associated with human T-lymphotropic 

virus type 1 (HTLV-1). 4–8 Research into the pathogenesis of 

these diseases has profoundly increased our understanding 

of other immune-mediated disorders. 

Progress in conventional scientific disciplines has 

opened up new research avenues in rheumatology, 

which has resulted in various advances, such as the 

establishment of the new field of osteoimmunology 9 and 

the discoveries of T-regulatory (T REG ) cells 10,11 and the 

Competing interests 

K. Nishioka declares an association with the following company: 

Argenes. See the article online for full details of the relationship. 

Y. Yamano declares no competing interests. 

E3 ubiquitin ligase synoviolin. 12 Moreover, large-scale 

genetic studies of rheumatic diseases have identified polymorphisms 

in multiple genes associated with disease susceptibility, 

including PADI4 and PTPN22. Notably, disease 

suscepti bility conferr ed by genetic factors varies between 

ethnic groups. 13 

Translation of laboratory research findings to clinical 

practice is a challenging prospect for rheumatologists. 

In this respect, Asian rheumatologists have achieved 

consider able success, exemplified by the clinical application 

of tocilizumab, a humanized monoclonal antibody 

to interleukin (IL)-6 receptor (anti-IL-6R), for the 

treatment of rheumatoid arthritis (RA), systemic juvenile 

idiopathic arthritis, Castleman disease, and Crohn 

disease. 14 Studies have also highlighted benefits achieved 

with agonistic antibodies against Fas receptor (FasR; 

also known as CD95, Apo-1 and tumor necrosis factor 

[TNF] receptor superfamily, member 6) in the treatment 

of patients with RA. This Review focuses on new disease 

entities and advances in scientific disciplines and treatments 

reported from Asia, and outlines the contributions 

of Asian researchers to the field of rheumatology. 

Prevalent diseases in Asia 

Behçet syndrome 

In 1937, Hulusi Behçet first described patients with 

symp toms of oral aphtae, genital ulcers, and uveitis. 15 

Sub sequently, the syndrome was also shown to include 

articular, gastrointestinal, central nervous system, and 

peripheral vascular manifestations. The regions with 

the highest incidence of Behçet syndrome are the Mediterranean 

basin, Middle East, and Far East. The reasons for 

this peculiar geographic distribution of Behçet syndrome 

106 | FEBRUARY 2010 | volUmE 6 www.nature.com/nrrheum 

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Macmillan Publishers Limited. All rights reserved

emain unknown. The putative etiological agents associated 

with Behçet syndrome may have spread along the 

ancient Silk Routes, which extend from Eastern Europe 

to Japan. 16 The geographical distribution of several predisposing 

genetic factors, such as the HLA‑B*51 allele, 16 

might also be associated with this regional variation 

in incidence. The pathogenesis of this syndrome also 

remains unclear, and several studies have focused on a 

potential infectious etiology. The acne lesions associated 

with Behçet syndrome are frequently colonized by 

Staphylococcus aureus, and to a lesser extent by Prevotella 

spp., 17 suggesting that at least some patients with this syndrome 

develop a reactive inflammatory response to infective 

agents. Thus, the characteristics of Behçet syndrome 

are different from the classic features of autoimmune 

disease, and there is an ongoing debate about whether 

Behçet syndrome belongs to a newly designated group of 

autoinflammatory diseases. 18 

Takayasu arteritis 

Takayasu arteritis, first described in 1908 by Mikoto 

Takayasu, is an idiopathic chronic inflammatory disease 

that results in granulomatous panarteritis involving the 

large vessels, such as the aorta and its major branches. 

This disease has a worldwide distribution, with a high 

prevalence in people of Latin American and Asian ancestry. 

19 The annual incidence of Takayasu arteritis in Japan 

is estimated to be 150 new cases per million people, 20 compared 

with 1–3 new cases per million people in the uSA 

and Europe. 21 Several reports indicate an increased frequency 

of the antigens HLA-Bw52 and HLA-B39.2 among 

patients in Japan, suggesting an immunogenetic association. 

22 Although the pathogenesis of Takayasu arteritis 

remains unclear, evidence strongly indicates the involvement 

of T cells. Interestingly, immuno histopathologic 

examination has shown that the cells infiltrating aortic 

tissue mainly consist of cytotoxic lymphocytes, particularly 

γδ T lymphocytes, 23 which might cause vascular 

injury by releasing large amounts of cytolytic compounds, 

such as perforin. 

Kawasaki disease 

Kawasaki disease, initially described by Tomisaku 

Kawasaki in 1967, is one of the most common forms of 

childhood vasculitides that predominantly affects the 

medium and small arteries. The incidence of Kawasaki 

disease is highest in children residing in East Asia 

(annual incidence 140 per 100,000 in Japan, 69 per 

100,000 in Taiwan, and 51 per 100,000 in Beijing) 24 and 

those of Asian ancestry residing in other parts of the 

world. In the uSA, the annual incidence of Kawasaki 

disease was highest among Asians and Pacific Islanders 

(33 per 100,000), and lowest among white people (9 per 

100,000). 25 Thus, genetic susceptibility factors seem to 

contribute to the pathogenesis of this disorder. Although 

the precise cause of Kawasaki disease remains elusive, 

evidence suggests an infectious etiology. For example, 

incidence varies seasonally, with increases seen during 

the winter month of January and summer months of June 

and July, 26 outbreaks have been linked to clusters of cases 

Key points 

■ Varied ethnicity, microbial endemicity and heterogeneity among Asian 

patients in presentation and outcomes provide opportunities for some 

unique studies 

reviews 

■ Several diseases, such as Behçet syndrome, Takayasu arteritis, Kawasaki 

disease, and immunological disorders associated with human T‑lymphotropic 

virus type 1 were first defined in Asia 

■ Asian research has been at the forefront of several avenues in rheumatology, 

such as establishment of the field of osteoimmunology, and the discoveries 

of regulatory T cells and synoviolin 

■ Asian scientists have achieved considerable success in the translation 

of laboratory findings to clinical practice, exemplified by the therapeutic 

application of tocilizumab and agonistic antibodies to Fasr 

occurring in association with heavy rainfall, and the clinical 

features of Kawasaki disease are similar to those of 

other infectious diseases, such as adenovirus infection 

and scarlet fever. However, no single infectious agent has 

yet been identified. 

Several genetic polymorphisms have been linked to 

Kawasaki disease. Notably, a 2008 study by Onouchi 

et al. 27 reported an association between a singlenucleotide 

polymorphism in ITPKC and an increased 

risk of Kawasaki disease in children. 27 ITPKC acts as a 

negative regulator of T-cell activation, and may contribute 

to immune hyper-reactivity in this disease. This finding 

provides new insights into the mechanisms of immune 

activation in Kawasaki disease, and emphasizes the role 

of activated T cells in its pathogenesis. 

hTlv‑1‑associated immunological disorders 

HTLV-1 is a retrovirus associated with chronic, persistent 

infection of human T cells. This virus is endemic in southern 

Japan, the Caribbean, and parts of South America, 

Africa, the Middle East and Melanesia. 28 Studies conducted 

in these areas have demonstrated that HTLV-1 

infection is associated with several human diseases, 

including adult T-cell leukemia, an aggressive mature 

T-cell malignancy. 29 HTLV-1 is also associated with nonneoplastic 

immunological disorders charac terized by 

multiorgan lymphocytic infiltrates, such as myelopathy/ 

tropical spastic paraparesis, 4 HTLV-1-associated arthropathy 

(HAAP), 5 uveitis, 6 bronchoalveolitis, 7 Sjögren 

syndrome, and polymyositis. 8 Some patients present 

with multiple HTLV-1-associated immuno logical disorders. 

A progressive course and persistent inflammation 

affecting various organs are frequently seen in patients 

with idiopathic autoimmune disorders. These HTLV-1associated 

multiorgan immunological disorders are, 

therefore, extremely important models for understanding 

the pathogenic mechanisms of other organ-specific 

immune disorders. 30,31 

HAAP is characterized by chronic inflammatory 

and proliferative synovitis with lymphoid follicles and 

pannus formation in the affected joints. Although the predominant 

viral reservoirs in peripheral blood of HTLV-1infected 

individuals are CD4 + CD25 + T cells, HTLV-1 has 

been reported to infect in vitro and in vivo a number 

of cell types, including synovial cells. In synoviocytes, 

NATuRE REVIEWS | rheumATologY VOLuME 6 | FEBRuARY 2010 | 107 

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eviews 

HTLV-1 Tax, a transactivator protein, has been demonstrated 

to upregulate the expression of proinflammatory 

cytokines and several oncogenes, such as FOS, JUN and 

MYC, which might contribute to synovial proliferation. 32 

Furthermore, HTLV-1 Tax transgenic mice develop an 

inflammatory arthropathy resembling human RA. 33 These 

findings suggest that HTLV‑1 tax is one of the exogenous 

retrovirus genes responsible for the synovial hyperplasia 

associated with immune dysregulation in HAAP. 

Notable advances in rheumatology 

osteoimmunology 

Research indicating that the immune and skeletal systems 

interact and share a number of regulatory molecules, 

including cytokines, receptors, signaling molecules and 

transcription factors, has led to the establishment of a 

new field: osteoimmunology. 34 Although the inter action 

between skeletal and immune systems occurs both in 

health and disease, the effects of disruption to this interaction 

are exemplified in RA. Bone destruction in RA 

is caused by increased osteoclastic activity. The osteoclasts 

are derived from the myeloid cells of the immune 

system, 35 and proinflammatory cytokines, such as TNF, 

seem to be crucial for the change in the activity levels 

of both bone cell types. TNF increases the osteoblastic 

expression of receptor activator or nuclear factor κB 

ligand (RANKL; also known as TNF ligand super family, 

member 11), 36 which in turn increases the local differentiation 

of bone-resorbing osteoclasts. RANKL is expressed 

both by bone-forming osteoblasts and activated T cells, 

indicating that osteoclastic bone resorption is influenced 

by the immune system. 37 Moreover, Takayanagi et al. 38 

discovered a crucial counter-regulatory mechanism, by 

which activated T cells can inhibit the RANKL-induced 

maturation and activation of osteoclasts. Together these 

findings indicate the crucial role of skeletal cells in both 

the hematopoietic and immune systems. 

Osteoimmunology encompasses the analysis of 

develop mental, homeostatic and pathologic consequences 

of the interactions between the immune and 

skeletal systems. understanding these complex interactions 

should provide new insights into the functional 

regulation of both systems, and also uncover new targets 

for therapeutic intervention. 

Discovery of T‑regulatory cells 

The precise mechanisms underlying the induction of 

uncontrolled immune reactions and the induction of the 

accelerated immune responses in rheumatic disorders are 

not fully understood. In the mid-1990s, Sakaguchi et al. 10 

reported the concept of T-cell-mediated suppression by 

showing that a minor population of CD4 + T cells, which 

coexpress the IL-2 receptor α-chain (CD25), is crucial for 

the control of autoreactive T cells in vivo. This discovery 

of a new CD4 + CD25 + T-cell subset, termed T REG cells, 

has provided new opportunities and generated increased 

interest in elucidating these mechanisms. 10,11 In healthy 

individuals, in vitro studies have shown that T REG cells suppress 

the proliferation of and production of cytokines by 

pathogenic T cells. 11 

Although T REG cells are phenotypically similar to 

activated T cells, they can be identified by the intracellular 

expression of the transcriptional regulator forkhead 

box P3 (FOXP3). 39 This protein is critical for the 

develop ment and function of T REG cells in both mice and 

humans. Substantial reductions in FOXP3 expression 

and/or T REG cell function have been observed in several 

human autoimmune diseases, 12 suggesting that altered 

FOXP3 expression and/or T REG function precipitates the 

loss of immunologic tolerance. A 2009 study by Miyara 

et al. 40 demonstrated that human FOXP3 + CD4 + T cells 

were composed of three phenotypically and functionally 

distinct subpopulations: CD45RA + FOXP3 low resting 

T REG cells; CD45RA – FOXP3 high activated T REG cells; and 

cytokine-secreting CD45RA – FOXP3 low T cells. The 

former two subtypes are suppressive and the latter 

is non-suppressive. Interestingly, the number of FOXP3 low 

non-suppressive memory T cells was increased in 

patients with active systemic lupus erythematosus 40 and 

in those with HTLV-1-associated neuroimmunological 

disorders. 41 Further investigations of the mechanism of 

action of T REG cells in autoimmune diseases will help 

identify new molecular pathways, which may in turn 

provide insight into understanding basic pathogenic 

mechanisms of immunological disorders. 

Discovery of synoviolin 

The pathologic features of RA include chronic, systemic 

inflammation of joints, which is associated with increased 

proliferation of synovial cells (Figure 1). Studies in Japan 

focusing on synovial cells led to the discovery of a novel 

molecule that is overexpressed in these cells: synoviolin. 

Amano et al. 42 used immunoscreening to identify the role 

of synoviolin in the process of endoplasmic-reticulumassociated 

degradation (ERAD)—an ATP-dependent 

ubiquitin–proteasome degradation process that eliminates 

defective proteins. The endoplasmic reticulum 

(ER) has an important role in protein folding. When the 

level of unfolded proteins in the ER exceeds its folding 

capacity, the burden on the ER is reduced by ERAD. 43 

A mouse study showed that approximately 30% of 

mice overexpressing synoviolin developed spontaneous 

arthropathy as a result of reduced apoptosis of synoviocytes. 

Conversely, synoviolin-heterozygous (Syvn1 +/– ) 

mice showed resistance to collagen-induced arthritis 

owing to and increase in apoptosis of synovial cells. 

Analysis of protein expression in cells from synoviolin 

knockout mice (Syvn1 –/– ) revealed that synoviolin targets 

the tumor suppressor p53 for ubiquitination. 44 Thus, 

synovi olin is thought to function as an antiapoptotic 

factor through sequestration of tumor suppressor p53, 

highlighting its important role in rheumatoid synovial 

cell hyperplasia. 

A 2006 study suggested that elevated levels of synovio lin 

in peripheral blood were associated with a lack of response 

to infliximab treatment, 45 indicating the possible use of 

synoviolin as a predictive marker for response to anti-TNF 

therapy in patients with RA. Collectively, these findings 

indicate the importance of the ubiquitin– proteasome 

degrada tion process in the pathogenesis of RA. 


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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 


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 

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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. 

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Presented at the ACr/ArHP Scientific Meeting, 

Philadelphia, PA (18 October 2009). 

Acknowledgments 

This work was partially supported by a Grant‑in‑Aid for 

Scientific research from the Japan Society for the 

Promotion of Science, The Ministry of education, 

Culture, Sports, Science and Technology, Japanese 

Ministry of Health, Labor, and welfare, National 

Institute of Biomedical Innovation, Uehara Memorial 

Foundation, Nagao Takeshi Nanbyo Foundation, 

Kanagawa Nanbyo Foundation, Mishima Kaiun 

Memorial Foundation, Takeda Science Foundation, 

and ITSUU Laboratory research Foundation. 


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