PERSPECTIVES SCIENCE & SOCIETY
A new look at rheumatology in China —opportunities and challenges Zhan-guo Li Abstract | In the past two decades, Chinese rheumatology has developed rapidly in terms of both clinical practice and basic research. Many rheumatology departments and divisions have been established, creating positions for more residents to join rheumatology practices. Numerous studies of rheumatic diseases have been published in recent years by Chinese rheumatologists and immunologists, supported by government funding that has dramatically increased over the past few years. These studies are focused mainly on epidemiology, mechanisms, early diagnosis and interventions of rheumatic diseases. Increasing numbers of national and international scientific activities in China, including research collaborations, education programmes and conferences have greatly helped the development of rheumatology. In this APLAR series article, the major, high-impact studies and latest developments in Chinese rheumatology are reviewed. Li, Z.-g. Nat. Rev. Rheumatol. advance online publication 20 January 2015; doi:10.1038/nrrheum.2014.218
Introduction
The field of rheumatology research in China covers almost all rheumatic diseases, and includes epidemiology, complications, early diagnosis and treatment strategies, as well as basic research in genetics, mechanisms and novel therapeutics. In this article, I focus only on the major findings in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), Sjögren syndrome, Behçet disease, dermatomyositis and polymyositis.
Research on rheumatic diseases Rheumatoid arthritis A large-scale survey of residents estimated that the prevalence of RA (age-adjusted) in China is 0.28%.1 In another study, the rate of remission in patients with RA was 8.6% according to 28‑joint disease activity score (DAS28) criteria.2 These data indicate that more than 4 million patients with RA live in China and that, when combined with insufficient public awareness of the disease and a low rate of remission, RA creates a huge social and economic burden on this country. Classification criteria for early RA, with 84.4% sensitivity and 87.4% specificity, have Competing interests The author declares no competing interests.
now been published.3 These criteria were created for patients with a disease duration of ≤1 year, and are more feasible in clinical practice than previously proposed criteria. In the past few years, the Chinese Rheumatology Association (CRA) also published management guidelines for 23 rheumatic diseases to direct rheumatology practice in China. In terms of treatment, the strategy and available medications in China are almost the same as in developed countries. All biologic and some biosimilar agents are available nationwide, and 10.1% of patients with RA in China are treated with these drugs; however, leflunomide (62.4%) is more commonly used than methotrexate (54.9%). In the past 10 years, a variety of RA‑ related issues have been addressed and clarified in China, including epidemiology, disability, comorbidities and the financial cost of the disease. Great progress has been made in these areas by rheumatologists and immunologists in China (Figure 1). In terms of basic research, a number of projects have been carried out to understand the mechanisms of RA pathogenesis and the number of Chinese publications in this field has steadily increased over the years. Twelve novel RA genetic risk loci have been identified in Chinese cohorts of
NATURE REVIEWS | RHEUMATOLOGY
patients with RA,4–7 and novel inflammatory pathways, diagnostic imaging studies and proteomic analyses have been published.8–10 One early study showed that TREG‑cell function in RA was impaired by TNFi n du c e d f or k h e a d b ox prot e i n P 3 (FOXP3) dephosphorylation by increasing protein phosphatase 1 expression by TREG cells derived from patients with RA.11 A study from my group in collaboration with D. Yu from Monash University in Melbourne, Australia, showed that inducible follicular helper T cell precursors are detectable in patients with active RA, and that various parameters of these cells correlate with severity of RA and SLE. 12 In another study, my group showed that IL‑17-producing TREG cells with plasticity of inflammatory features were detected in the peripheral blood of patients with RA; these cells are a novel T‑cell subset that is induced by TNF, IL‑6 and IL‑23.13 The function of leptin in enhancing type 17 T helper (TH17) cell responses and exacerbating joint inflammation was also discovered by researchers in China.14 Jiao et al.15 showed that Notch signalling might play a role in autoimmune arthritis through type 1 T helper (TH1) and TH17 responses. In another study, hypoxia and hypoxiainducible factor 1α (HIF‑1α) were identified as critical for synovitis and the development of RA.16 In addition, the role of B cells in RA has drawn the attention of groups in China who then discovered that IL‑10-producing regulatory B cells, so called B10 cells, have a novel role in the inhibition of arthritis progression by suppressing the generation of TH17 cells.17 Furthermore, a study of CD147 suggested that this molecule can induce angiogenesis through a vascular endothelial growth factor and HIF‑1α-mediated pathway in RA, causing persistence of synovitis.18 Taken together, these findings from research groups in China have contributed a great deal to the current understanding of molecular immune mechanisms in patients with RA (Figure 2). Several Chinese groups have also investigated novel therapeutic methods and strat egies in RA. Non-antigenic altered peptides, a tylophorine analogue (NK‑007), iguratimod and T‑cell vaccination were found to be potentially important in the treatment ADVANCE ONLINE PUBLICATION | 1
© 2015 Macmillan Publishers Limited. All rights reserved
PERSPECTIVES
Anti-P68 antibody Citrulllinated type II collagen Anti-PAD antibody HPV E47 MCV in early RA Fibrinogen Early RA criteria
Precursor TFH cell IL-17-producing TREG cells FOXP3 MiR155a HIF-1α
HLA-DRB1*0409 LCE3C_LCE3B DCIR CDKSRAP2 CCR6
Immunology
Genetics
Mechanism
Diagnosis
of allogeneic bone-marrow mesenchymal stem cell transplantation (MSCT) have generated evidence that this therapy is effective and safe for the treatment of SLE as well as for other rheumatic diseases, including vasculitis and s ystemic sclerosis.32–34
Altered peptides NK-007 T-cell vaccination Tylophorine Iguratimod Type II collagen
Treatment
In China Use of biologic agents 10.1% Remission 8.6% Cost US$1,520/py Use of DMARDs 44% Disability 50.3% Prevalence 0.28%
Figure 1 | The tree of RA research. The main areas of RA research in China over the past few years, including treatment, diagnosis, immunological mechanisms and genetics the disease, Nature Reviews of | Rheumatology are shown here as the main branches of a tree. The principle findings, as listed, have resulted in publications in peer-reviewed globally recognized journals in this field. Percentages on the trunk of the tree are representative of the total population of China. Abbreviations: FOXP3, forkhead box protein P3; HIF‑1α, hypoxia-induced factor 1α; HPV E47, human papillomavirus E47; MCV, mutated citrullinated vimentin; MiR155a, microRNA-155a; PAD, peptidyl-arginine deiminase; RA, rheumatoid arthritis; TFH cell, follicular helper T cell; TREG cell, regulatory T cell.
of RA.19–22 A randomized controlled trial indicated that therapy with methotrexate plus the traditional Chinese medicine Tripterygium wilfordii Hook F is better than methotrexate monotherapy in controlling disease activity in patients with active RA.23
Systemic lupus erythematosus An epidemiological study supported by a National Key grant from my group investigated the prevalence of eight rheumatic diseases in a suburb of Beijing. 1 In this study, the age-adjusted prevalence of SLE was 0.03%, lower than a report of 0.07% from an earlier study.24 Another study in which I was involved, indicated that the 1‑year, 3‑year and 5‑year survival rates of Chinese patients with SLE were 96%, 94% and 91%, respectively.25 A decade ago, in a
long-term follow-up study, Chen et al.26 calculated that 5‑year, 10‑year and 15‑year survival rates for SLE were 86%, 76% and 68%, respectively. These data suggest that SLE is one of the major life-threatening rheumatic diseases in China. Interestingly, a series of surveys has shown that patients with SLE in China27–29 have different clinical characteristics than patients of other ethnicity. In a genome-wide association study (GWAS), nine susceptibility loci were associated with SLE, indicating genetic heterogeneity in the Chinese population. 30 Zhu et al.31 suggested that IL‑17 contributes to SLE pathogenesis by suppressing the expression of microRNA‑23b and by promoting proi nflammatory cytokine expression, suggesting that microRNA‑23b might be a therapeutic target for SLE. Notably, studies
2 | ADVANCE ONLINE PUBLICATION
Ankylosing spondylitis Study of AS in China has become more active in the past few years. Data from an early study suggested that thalidomide might be an effective treatment.35 A GWAS of a large cohort of patients in southern China was used to identify two novel susceptibility loci that might be associated with bone formation and cartilage development,36 and an international study, including data from a large cohort of Chinese patients, identified 13 new risk loci and 12 additional AS-associated haplotypes at 11 other loci.37 These are the latest genetic studies to show that different susceptibility genes have a role in this disease. Sjögren syndrome Sjögren syndrome is one of the most common rheumatic diseases, with a prevalence of 0.77% in China.38 In the past few years, novel autoantibodies, including antibodies specific for α‑fodrin or the type 3 muscarinic acetylcholine receptor, have been used for the diagnosis of Sjögren syndrome.39,40 These autoantibodies are now routinely used for diagnosis in a number of hospitals in China. Data from a GWAS of a large cohort of Chinese patients suggests that the gene encoding general transcription factor II‑I, GTF2I on chromosome 7q11.23, is a primary Sjögren syndrome susceptibility locus.41 Other rheumatic diseases For many years, Chinese rheumatologists have also contributed to the knowledge of other rheumatic diseases. Some of the major findings in this country include an epidemiological study that calculated the prevalence of soft-tissue rheumatic diseases to be 2.0–5.3% in China, 42 and an epigenetic study identifying that demethylation of CD40L regulates its overexpression by CD4+ T cells from female patients with systemic sclerosis, a possible explanation for female susceptibility to this disease.43 Furthermore, several research groups in our country have been working on polymyositis and dermatomyositis. One of these groups showed that allogeneic MSCT is effective and safe for patients with drug-resistant polymyositis or dermatomyositis.44 Results www.nature.com/nrrheum
© 2015 Macmillan Publishers Limited. All rights reserved
PERSPECTIVES indicate that a TNF-like weak inducer of apoptosis (TWEAK)–fibroblast growth factor (FGF)-inducible 14 axis is involved in the pathogenesis of these diseases, and that it might be a new drug target.45 In a therapeutic study of clinically amyopathic dermatomyositis, basiliximab (an anti-CD25 antibody) treatment improved the survival rate of patients with rapidly progressive interstitial pneumonia.46 GWAS, of a large cohort from Chongqing, was used to identify a new susceptibility locus, in STAT4, for Behçet disease in Han Chinese people.47 A study from the same group indicated that a high copy number of complement component C4A confers risk for Behçet disease by modulating the expression of C4A and increasing IL‑6 production.48
Naive CD4+ T cell
FOXP3
REFS 11
RORγt
TREG
REFS 14,15
IL-12 IFN-γ REF. 15
T-bet TH1
TH17
GATA3
REF. 12
BCL6 TH2
TFH
IL-21 IL-4 IL-17A IL-17F IL-21
IL-17A
IL-6 IL-21
IL-4
IL-6 IL-1 IL-23
Development in rheumatology
There is no doubt that rheumatology in China is flourishing due to the efforts of thousands of rheumatologists all over the country. An early survey in 2008 calculated there were 2,612 rheumatologists in China; however, this number increased up to 4,500 in 2012.49 Most of the rheumatologists are aged
A new look at rheumatology in China —opportunities and challenges Zhan-guo Li Abstract | In the past two decades, Chinese rheumatology has developed rapidly in terms of both clinical practice and basic research. Many rheumatology departments and divisions have been established, creating positions for more residents to join rheumatology practices. Numerous studies of rheumatic diseases have been published in recent years by Chinese rheumatologists and immunologists, supported by government funding that has dramatically increased over the past few years. These studies are focused mainly on epidemiology, mechanisms, early diagnosis and interventions of rheumatic diseases. Increasing numbers of national and international scientific activities in China, including research collaborations, education programmes and conferences have greatly helped the development of rheumatology. In this APLAR series article, the major, high-impact studies and latest developments in Chinese rheumatology are reviewed. Li, Z.-g. Nat. Rev. Rheumatol. advance online publication 20 January 2015; doi:10.1038/nrrheum.2014.218
Introduction
The field of rheumatology research in China covers almost all rheumatic diseases, and includes epidemiology, complications, early diagnosis and treatment strategies, as well as basic research in genetics, mechanisms and novel therapeutics. In this article, I focus only on the major findings in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), Sjögren syndrome, Behçet disease, dermatomyositis and polymyositis.
Research on rheumatic diseases Rheumatoid arthritis A large-scale survey of residents estimated that the prevalence of RA (age-adjusted) in China is 0.28%.1 In another study, the rate of remission in patients with RA was 8.6% according to 28‑joint disease activity score (DAS28) criteria.2 These data indicate that more than 4 million patients with RA live in China and that, when combined with insufficient public awareness of the disease and a low rate of remission, RA creates a huge social and economic burden on this country. Classification criteria for early RA, with 84.4% sensitivity and 87.4% specificity, have Competing interests The author declares no competing interests.
now been published.3 These criteria were created for patients with a disease duration of ≤1 year, and are more feasible in clinical practice than previously proposed criteria. In the past few years, the Chinese Rheumatology Association (CRA) also published management guidelines for 23 rheumatic diseases to direct rheumatology practice in China. In terms of treatment, the strategy and available medications in China are almost the same as in developed countries. All biologic and some biosimilar agents are available nationwide, and 10.1% of patients with RA in China are treated with these drugs; however, leflunomide (62.4%) is more commonly used than methotrexate (54.9%). In the past 10 years, a variety of RA‑ related issues have been addressed and clarified in China, including epidemiology, disability, comorbidities and the financial cost of the disease. Great progress has been made in these areas by rheumatologists and immunologists in China (Figure 1). In terms of basic research, a number of projects have been carried out to understand the mechanisms of RA pathogenesis and the number of Chinese publications in this field has steadily increased over the years. Twelve novel RA genetic risk loci have been identified in Chinese cohorts of
NATURE REVIEWS | RHEUMATOLOGY
patients with RA,4–7 and novel inflammatory pathways, diagnostic imaging studies and proteomic analyses have been published.8–10 One early study showed that TREG‑cell function in RA was impaired by TNFi n du c e d f or k h e a d b ox prot e i n P 3 (FOXP3) dephosphorylation by increasing protein phosphatase 1 expression by TREG cells derived from patients with RA.11 A study from my group in collaboration with D. Yu from Monash University in Melbourne, Australia, showed that inducible follicular helper T cell precursors are detectable in patients with active RA, and that various parameters of these cells correlate with severity of RA and SLE. 12 In another study, my group showed that IL‑17-producing TREG cells with plasticity of inflammatory features were detected in the peripheral blood of patients with RA; these cells are a novel T‑cell subset that is induced by TNF, IL‑6 and IL‑23.13 The function of leptin in enhancing type 17 T helper (TH17) cell responses and exacerbating joint inflammation was also discovered by researchers in China.14 Jiao et al.15 showed that Notch signalling might play a role in autoimmune arthritis through type 1 T helper (TH1) and TH17 responses. In another study, hypoxia and hypoxiainducible factor 1α (HIF‑1α) were identified as critical for synovitis and the development of RA.16 In addition, the role of B cells in RA has drawn the attention of groups in China who then discovered that IL‑10-producing regulatory B cells, so called B10 cells, have a novel role in the inhibition of arthritis progression by suppressing the generation of TH17 cells.17 Furthermore, a study of CD147 suggested that this molecule can induce angiogenesis through a vascular endothelial growth factor and HIF‑1α-mediated pathway in RA, causing persistence of synovitis.18 Taken together, these findings from research groups in China have contributed a great deal to the current understanding of molecular immune mechanisms in patients with RA (Figure 2). Several Chinese groups have also investigated novel therapeutic methods and strat egies in RA. Non-antigenic altered peptides, a tylophorine analogue (NK‑007), iguratimod and T‑cell vaccination were found to be potentially important in the treatment ADVANCE ONLINE PUBLICATION | 1
© 2015 Macmillan Publishers Limited. All rights reserved
PERSPECTIVES
Anti-P68 antibody Citrulllinated type II collagen Anti-PAD antibody HPV E47 MCV in early RA Fibrinogen Early RA criteria
Precursor TFH cell IL-17-producing TREG cells FOXP3 MiR155a HIF-1α
HLA-DRB1*0409 LCE3C_LCE3B DCIR CDKSRAP2 CCR6
Immunology
Genetics
Mechanism
Diagnosis
of allogeneic bone-marrow mesenchymal stem cell transplantation (MSCT) have generated evidence that this therapy is effective and safe for the treatment of SLE as well as for other rheumatic diseases, including vasculitis and s ystemic sclerosis.32–34
Altered peptides NK-007 T-cell vaccination Tylophorine Iguratimod Type II collagen
Treatment
In China Use of biologic agents 10.1% Remission 8.6% Cost US$1,520/py Use of DMARDs 44% Disability 50.3% Prevalence 0.28%
Figure 1 | The tree of RA research. The main areas of RA research in China over the past few years, including treatment, diagnosis, immunological mechanisms and genetics the disease, Nature Reviews of | Rheumatology are shown here as the main branches of a tree. The principle findings, as listed, have resulted in publications in peer-reviewed globally recognized journals in this field. Percentages on the trunk of the tree are representative of the total population of China. Abbreviations: FOXP3, forkhead box protein P3; HIF‑1α, hypoxia-induced factor 1α; HPV E47, human papillomavirus E47; MCV, mutated citrullinated vimentin; MiR155a, microRNA-155a; PAD, peptidyl-arginine deiminase; RA, rheumatoid arthritis; TFH cell, follicular helper T cell; TREG cell, regulatory T cell.
of RA.19–22 A randomized controlled trial indicated that therapy with methotrexate plus the traditional Chinese medicine Tripterygium wilfordii Hook F is better than methotrexate monotherapy in controlling disease activity in patients with active RA.23
Systemic lupus erythematosus An epidemiological study supported by a National Key grant from my group investigated the prevalence of eight rheumatic diseases in a suburb of Beijing. 1 In this study, the age-adjusted prevalence of SLE was 0.03%, lower than a report of 0.07% from an earlier study.24 Another study in which I was involved, indicated that the 1‑year, 3‑year and 5‑year survival rates of Chinese patients with SLE were 96%, 94% and 91%, respectively.25 A decade ago, in a
long-term follow-up study, Chen et al.26 calculated that 5‑year, 10‑year and 15‑year survival rates for SLE were 86%, 76% and 68%, respectively. These data suggest that SLE is one of the major life-threatening rheumatic diseases in China. Interestingly, a series of surveys has shown that patients with SLE in China27–29 have different clinical characteristics than patients of other ethnicity. In a genome-wide association study (GWAS), nine susceptibility loci were associated with SLE, indicating genetic heterogeneity in the Chinese population. 30 Zhu et al.31 suggested that IL‑17 contributes to SLE pathogenesis by suppressing the expression of microRNA‑23b and by promoting proi nflammatory cytokine expression, suggesting that microRNA‑23b might be a therapeutic target for SLE. Notably, studies
2 | ADVANCE ONLINE PUBLICATION
Ankylosing spondylitis Study of AS in China has become more active in the past few years. Data from an early study suggested that thalidomide might be an effective treatment.35 A GWAS of a large cohort of patients in southern China was used to identify two novel susceptibility loci that might be associated with bone formation and cartilage development,36 and an international study, including data from a large cohort of Chinese patients, identified 13 new risk loci and 12 additional AS-associated haplotypes at 11 other loci.37 These are the latest genetic studies to show that different susceptibility genes have a role in this disease. Sjögren syndrome Sjögren syndrome is one of the most common rheumatic diseases, with a prevalence of 0.77% in China.38 In the past few years, novel autoantibodies, including antibodies specific for α‑fodrin or the type 3 muscarinic acetylcholine receptor, have been used for the diagnosis of Sjögren syndrome.39,40 These autoantibodies are now routinely used for diagnosis in a number of hospitals in China. Data from a GWAS of a large cohort of Chinese patients suggests that the gene encoding general transcription factor II‑I, GTF2I on chromosome 7q11.23, is a primary Sjögren syndrome susceptibility locus.41 Other rheumatic diseases For many years, Chinese rheumatologists have also contributed to the knowledge of other rheumatic diseases. Some of the major findings in this country include an epidemiological study that calculated the prevalence of soft-tissue rheumatic diseases to be 2.0–5.3% in China, 42 and an epigenetic study identifying that demethylation of CD40L regulates its overexpression by CD4+ T cells from female patients with systemic sclerosis, a possible explanation for female susceptibility to this disease.43 Furthermore, several research groups in our country have been working on polymyositis and dermatomyositis. One of these groups showed that allogeneic MSCT is effective and safe for patients with drug-resistant polymyositis or dermatomyositis.44 Results www.nature.com/nrrheum
© 2015 Macmillan Publishers Limited. All rights reserved
PERSPECTIVES indicate that a TNF-like weak inducer of apoptosis (TWEAK)–fibroblast growth factor (FGF)-inducible 14 axis is involved in the pathogenesis of these diseases, and that it might be a new drug target.45 In a therapeutic study of clinically amyopathic dermatomyositis, basiliximab (an anti-CD25 antibody) treatment improved the survival rate of patients with rapidly progressive interstitial pneumonia.46 GWAS, of a large cohort from Chongqing, was used to identify a new susceptibility locus, in STAT4, for Behçet disease in Han Chinese people.47 A study from the same group indicated that a high copy number of complement component C4A confers risk for Behçet disease by modulating the expression of C4A and increasing IL‑6 production.48
Naive CD4+ T cell
FOXP3
REFS 11
RORγt
TREG
REFS 14,15
IL-12 IFN-γ REF. 15
T-bet TH1
TH17
GATA3
REF. 12
BCL6 TH2
TFH
IL-21 IL-4 IL-17A IL-17F IL-21
IL-17A
IL-6 IL-21
IL-4
IL-6 IL-1 IL-23
Development in rheumatology
There is no doubt that rheumatology in China is flourishing due to the efforts of thousands of rheumatologists all over the country. An early survey in 2008 calculated there were 2,612 rheumatologists in China; however, this number increased up to 4,500 in 2012.49 Most of the rheumatologists are aged
