Dr. Louthrenoo has received consultant fees, speaking fees, and/or investigator fees (less than $10,000 each) from Roche, Merck Sharp and Dohme, American Taiwan Biopharm, Actelion, Pfizer, and TRB Chemedica.
Systemic lupus erythematosus (SLE), a chronic multisystem autoimmune disease with a wide spectrum of manifestations, shows considerable variation across the globe, although there is little evidence to indicate its relative prevalence in Asia. This review describes its prevalence, severity, and outcome across countries in the Asia-Pacific region.
We conducted a systematic literature search using 3 groups of terms (SLE, epidemiology, and Asia-Pacific countries) of EMBase and PubMed databases and non–English language resources, including Chinese Wanfang, Korean KMbase, Korean College of Rheumatology, Japana Centra Revuo Medicina, Taiwan National Digital Library of Theses and Dissertations, and Taiwanese, Thai, and Vietnamese journals.
The review showed considerable variation in SLE burden and survival rates across Asia-Pacific countries. Overall crude incidence rates (per 100,000 per year) ranged from 0.9–3.1, while crude prevalence rates ranged from 4.3–45.3 (per 100,000). Higher rates of renal involvement, one of the main systems involved at death, were observed for Asians (21–65% at diagnosis and 40–82% over time) than for whites. While infections and active SLE were leading causes of death, a substantial proportion (6–40%) of deaths was due to cardiovascular involvement. The correlation between the Human Development Index and 5-year survival was 0.83.
This review highlights the need to closely monitor Asian SLE patients in Asian countries for renal and cardiovascular involvement, especially those who may not receive proper treatment and are therefore at greater risk of severe disease. We hope this will encourage further research specific to this region and lead to improved clinical management.
Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease with a wide spectrum of manifestations ranging from minor cutaneous involvement to severe major organ damage. While the prevalence, severity, and outcome of the disease show considerable variation across the globe, there is little evidence to indicate its relative prevalence in Asia (1, 2). However, clinical manifestations of the disease as observed in one study were of greater severity in Asia, with greater renal involvement in particular (3). Probability of long-term survival appears to be generally lower in Asia compared to America and Europe (4–6).
Differences in the causes of mortality have also been reported among SLE patients in different geographic regions. A bimodal distribution of the cause of death has been reported in the US, Denmark, and other European countries (7, 8), i.e., mortality late in the course of SLE is more often due to cardiovascular disease, and mortality early in the course of SLE is more frequently due to active disease or infection. In Asia, infections and active SLE remain the major causes of death both early and late in the course of the disease (9–11). However, the typical cohort followup periods in Asia may be too short to draw conclusions on the latter.
The epidemiology of SLE has been described worldwide, and there is a suggestion that differences between Asia and the other parts of the world exist, with Asia generally showing a poorer prognosis. However, a comprehensive review of the available SLE epidemiologic data in the Asia-Pacific region has not been performed thus far. This review intends to provide a better understanding of the patient population in that region and encourage more efficient clinical management for this population. The objectives of this review article are the following: 1) to provide an overview of SLE prevalence and incidence, as well as the clinical manifestations, long-term outcome, and causes of mortality among adult SLE patients in the Asia-Pacific region and 2) to describe any difference in the disease epidemiology across the countries in the region.
Significance & Innovations
This is the first review article that summarizes published data from English and non–English language resources on systemic lupus erythematosus (SLE) prevalence and incidence as well as the clinical manifestations, long-term outcome, and causes of mortality among adult SLE patients in the Asia-Pacific region.
Higher rates of renal involvement were observed for Asians (21–65% at diagnosis and 40–82% over time) than for whites, making it one of the main organs involved at death. While infections and active SLE were the leading causes of death, a substantial proportion (6–40%) of deaths was due to cardiovascular involvement.
Using the Human Development Index (HDI) as a proxy for standards of health care and the medical system, we found a strong correlation (0.83, P < 0.0005) between the HDI and the 5-year survival rates of SLE patients.
MATERIALS AND METHODS
In this review article, the term “Asia-Pacific” refers to the following countries with available data: China, Korea, Japan, Taiwan, Hong Kong, Vietnam, Philippines, Thailand, Malaysia, Singapore, Indonesia, Australia, and New Zealand. We searched EMBase and PubMed from January 1985 to July 2010 and the inclusion criteria were according to the following search terms: 1) systemic lupus erythematosus or lupus erythematosus or lupus or lupus nephritis or CNS lupus; 2) epidemiology or incidence or prevalence or morbidity or mortality or survival or severity or hospitalis(z)ation or flare; and 3) Asia(n) or Australia(n) or Japan(ese) or China or Chinese or Taiwan(ese) or Hong Kong or Korea(n) or Thai(land) or Philippines or Filipino(s) or Singapore(an) or Malaysia(n) or Vietnam(ese) or Indonesia(n) or New Zealand. Additionally, the search was extended to identify potential articles from the following non–English language resources: Wanfang Database (Chinese), Korean KMbase, Korean College of Rheumatology, Japana Centra Revuo Medicina (Japanese), National Digital Library of Theses and Dissertations in Taiwan, Index to Taiwan Periodical Literature System, relevant local Vietnamese journals, and the local journal of the Thai Rheumatology Association. Following the identification of articles meeting the objectives of the review, the references were hand searched for articles missed by the EMBase and PubMed searches.
Based on the title and abstract, articles that met the following criteria were excluded (Figure 1): 1) commentaries, editorials, conference abstracts, review articles, meta-analyses, or studies undertaken in countries outside those prespecified; 2) animal, autopsy, genetic, laboratory, pathology, or renal biopsy studies; 3) therapeutic intervention studies, quality of life, or disease cost studies; 4) case reports or case series; 5) selected patient groups (pregnancy, pediatric, inpatients, patients with specific comorbidity, lupus nephritis); 6) association studies (e.g., smoking and risk of SLE); and 7) studies of the validation of questionnaires. Full manuscripts of the resulting articles were retrieved and carefully reviewed for inclusion by applying the above criteria; 48 articles were excluded as a result. In addition, 1 study was excluded as it based the definition of SLE upon insurance claims codes rather than standard criteria, 7 studies were excluded as the population described was a subset of those reported in selected articles, and 7 studies where there was no relevant data to extract were also excluded.
Our literature search yielded 3,650 articles from EMBase and 2,341 articles from PubMed. After reviewing these articles and applying the above exclusion criteria, 35 articles remained that met our criteria for inclusion. In addition, 1 article from the non–English language search and 2 articles found from hand searching references from selected articles were included. Therefore, this review is based on 38 articles that fulfilled our criteria and reported data on prevalence, incidence, clinical manifestations, survival, or causes of mortality among adult SLE patients in the countries of interest. Of the 38 selected studies, 3 were conducted in China, 4 in Korea, 4 in Japan, 2 in Taiwan, 6 in Hong Kong, 1 in Vietnam, 4 in the Philippines, 2 in Thailand, 4 in Malaysia, 4 in Singapore, 3 in Australia, and 1 in New Zealand.
All selected articles included patients who fulfilled at least 4 of the American College of Rheumatology (ACR) criteria for SLE (12, 13). We extracted data on prevalence, incidence, demographic profile, clinical manifestations, laboratory features, survival, and causes of death from the selected articles where available and organized them into tables or graphs, which were sorted by countries according to their geographic location and ordered from north to south. Where data in an article included patients with childhood onset of SLE (14–16), we excluded these patients during the data extraction.
We reported incidence as the number of new cases per 100,000 of population per year and prevalence as the number of cases per 100,000. In articles where only sex-specific incidence or prevalence rates were provided, we calculated the overall rate as an average of the male and female rates. In articles where results were stratified, data on demographic profile, clinical manifestations, laboratory features, or causes of death were combined and summarized as weighted mean, median, or percentage accordingly. Data on demographic profile, clinical manifestations, or laboratory features, if available from more than 1 article for the same country, were combined and summarized accordingly.
Human Development Index (HDI) analysis.
The HDI is a composite statistic that can be used to rank countries in terms of their economic and social development; its components include national income, educational attainment, and life expectancy. Using the HDI as a proxy for standards of health care and the medical system, we calculated the correlation coefficient for the association between the HDI and 5-year survival rates of the studies identified in our systematic review. The HDI values for the calendar year corresponding to the year of survival estimates were used (http://hdr.undp.org/en/data/explorer).
Incidence and prevalence in frequency of SLE.
The incidence and prevalence of SLE are summarized in Table 1. Overall crude incidence rates (per 100,000 per year) ranged from 0.9–3.1, while crude prevalence rates ranged from 4.3–45.3 (per 100,000) in the cited Asia-Pacific countries, with a trend toward higher prevalence of SLE in Australia compared to the cited Asian countries (45.3 versus 4.3–37.7). SLE was more common in Aborigines (11 for incidence and 52.6–92.8 for prevalence) compared to whites (19.3 for prevalence) in Australia and Asians in the cited Asia-Pacific countries who were mainly of Chinese (3.1 for incidence) or Japanese (0.9–2.8 for incidence and 4.3–37.7 for prevalence) ethnicity. It also affected women much more frequently than men (1.4–5.4 versus 0.4–0.8 for incidence and 7.7–68.4 versus 0.8–7.0 for prevalence).
Table 1. Incidence and prevalence of SLE in the Asia-Pacific region*
The demographic profile of adult SLE patients in the Asia-Pacific region is summarized in Table 2. A preponderance of female patients was consistently observed across the cited countries, ranging from 83–97% (excluding studies that recruited only female or male patients). The mean age at SLE onset ranged from 25.7–34.5 years, with patients in Malaysia (25.7 years) and Philippines (26.7 years) demonstrating earlier onset compared to patients in the other countries. SLE duration (since diagnosis of SLE) ranged from 1.4–9.3 years, with longer disease duration observed among patients in Australia (7.6 years) and Hong Kong (9.3 years).
Table 2. Demographic profile of adult SLE patients in the Asia-Pacific region*
The main clinical manifestations and laboratory findings at diagnosis and during the course of SLE of the adult patients described in Table 2 are illustrated in Figure 2. Nonerosive arthritis, malar rash, and renal disorder were the most common clinical manifestations observed at diagnosis (ranging from 31–80%, 48–63%, and 14–65%, respectively) and over time (ranging from 48–83%, 41–84%, and 30–82%, respectively). The most frequently observed laboratory findings at diagnosis and over the course of the disease were positive antinuclear antibodies, ranging from 93–100% and 55–100%, respectively, anti-DNA ranging from 51–86% and 41–83%, respectively, and hematologic disorder ranging from 19–61% and 67–87%, respectively.
The clinical and laboratory profile appeared broadly similar across the populations in the Asia-Pacific region except for strikingly lower rates of renal involvement observed in New Zealand (14% at diagnosis) and Australia (30% over time) compared to the Asian countries (21–65% at diagnosis and 40–82% over time).
Survival and main causes of death in SLE.
Survival rates in the Asia-Pacific region are summarized in Table 3. Survival rates ranged from 93–98% at 1 year, 60–97% at 5 years, and 70–94% at 10 years (excluding survival data specified as calculated from SLE onset) across the cited countries, with a general trend of improvement in survival for more recent studies. Among the cited countries in the Asia-Pacific region, prognosis of SLE appeared to be better in China (Shanghai; 98% at 5 years), Hong Kong (97% at 5 years and 94% at 10 years), and South Korea (94% at 5 years), while the Aborigines in Australia showed poor prognosis at 5 years (60%).
Table 3. SLE survival rates in the Asia-Pacific region*
Survival rates (%)
Time zero for calculation of survival rates were not specified unless otherwise stated. SLE = systemic lupus erythematosus; NS = not specified; ND = not done.
From SLE onset.
From SLE diagnosis.
Adult onset = age 16–50 years; late onset = age >50 years.
From SLE diagnosis; exact survival rates were not indicated in the cited article. Rates were extrapolated from the survival curve shown in the article.
Indicates publication year.
From SLE diagnosis; derived from reported cumulative mortality rate.
The main causes of death in SLE in the Asia-Pacific region are summarized in Table 4. Infections (30–80%) and active SLE disease (19–95%) were the leading causes of death among the cited countries in the Asia-Pacific region, and cardiovascular (6–40%) and renal involvement (7–36%) were the main systems involved at death.
Table 4. Underlying causes of death in SLE in the Asia-Pacific region*
For the 13 studies where 5-year survival rates were available, the correlation between the HDI and 5-year survival was 0.83 (P < 0.0005). We excluded the Australian study (22) as its subjects were rural Aborigines, and we felt that the very high HDI for Australia did not represent the Aborigine population.
This is the first review article that summarizes published data from English and non–English language resources on SLE prevalence and incidence, as well as the clinical manifestations, long-term outcome, and causes of mortality among adult SLE patients in the Asia-Pacific region. It also describes differences in the disease epidemiology observed across the cited countries in that region.
We found considerable variation in SLE burden across the cited countries in the Asia-Pacific region. Most of our cited studies from Australia showed that Aborigines have higher SLE rates than local whites. While these studies concurred with an earlier review of white populations in the US, Europe, Canada, and Australia, as reported by Danchenko et al (1), our findings do not provide sufficient evidence to conclude whether SLE is more common in some countries or races in the Asia-Pacific region compared to others due to limited epidemiologic data from studies in this region. Further, it should be noted that while disease burden may be influenced by true differences across the countries or races, other differences between studies, such as year of study and whether incidence of a single year or over a period of time was reported, and methodologic issues such as study design, referral pattern, inconsistencies in definition of ACR criteria for SLE, and method of case ascertainment also contribute to variability in the reported rates.
It has been reported that age at SLE onset or diagnosis is higher among white populations (38–51.7 years) compared to nonwhite populations (20–32.3 years for Asian populations and 32.2 years for Aborigines) (48). Our review showed that the mean age at SLE onset (25.7–34.5 years) or diagnosis (27–34.9 years) in the cited Asia-Pacific countries was similar to that reported in nonwhite populations. This could be attributed to the high proportion of nonwhite populations in the cited studies from Australia (28–100% Aborigines) and New Zealand (59%) (20–22, 43).
Our review showed that frequencies of renal involvement at diagnosis and over the course of SLE in the cited Asia-Pacific countries ranged from 14–65% and 30–82%, respectively, with higher rates of renal involvement observed among the cited Asian countries (21–65% at diagnosis and 40–82% over time) compared to New Zealand (14% at diagnosis) and Australia (30% over time). This concurs with reports of renal involvement being more common among Asian populations than white populations (2) and highlights the need to closely monitor the Asian populations in the Asia-Pacific region who may not be treated properly and are therefore at greater risk of severe disease. None of the selected studies specifically studied comorbidities. Therefore, available data were scarce and did not present a good picture of the comorbidities related to the disease in the Asia-Pacific region.
There was considerable variation in survival rates across the cited countries in the Asia-Pacific region. The 5-year survival rates ranged from 60% among the Aborigines in Australia to 94% in South Korea, 97% in Hong Kong, and 98% in China (Shanghai), while 10-year survival rates ranged from 70% in Malaysia to 94% in Hong Kong. Difference in survival might result from a delay in treatment and poor compliance of patients. These may vary across countries because of cultural differences, medical systems, educational background, and socioeconomic factors. Other reasons for this observation include differences in study methodology (such as those mentioned above) and other factors such as nonstandardization of “time zero” for calculation of survival rates.
Vasudevan and Krishnamurthy (49) undertook an analysis to describe the HDI against survival of SLE patients at 5 years and found a correlation of 0.56. Using the HDI as a proxy for standards of health care and the medical system, we calculated the correlation coefficient by plotting the HDI against 5-year survival rates of the studies identified in our systematic review. For the 13 studies where 5-year survival rates were available, we found a strong correlation (0.83, P < 0.0005). As countries achieve higher economic and social status, we might see improved outcome and survival in SLE patients.
We found, similar to reports on causes of death among SLE patients in Asia (50), that infections and active SLE disease remain the leading causes of death. The second peak of death due to cardiovascular disease was not observed as in the Western countries. This might be due to the short duration of followup in most cited articles. Renal involvement remains as one of the main organ systems involved at death among the SLE populations in the Asia-Pacific region. Notably, however, there appeared to be a substantial proportion of deaths due to cardiovascular involvement (6–40%) in the Asia-Pacific region. This highlights the importance of increasing the awareness of the risks of cardiovascular death for SLE patients whose susceptibility to the disease increases as they age and to implementing proactive measures to reduce the risk factors for cardiovascular disease in this population.
We recognize that regional differences in SLE epidemiology observed across the countries may be related to factors such as differences in environment, age at onset, sex, socioeconomic status, availability and accessibility to health care resources, availability of therapy, compliance to medical care, and methodologic issues across the studies. Some of these factors need to be considered when making comparisons across studies. Nonetheless, this article provides valuable information on the burden of SLE, in particular prevalence and incidence, as well as the clinical manifestations, long-term outcome, and causes of mortality among adult SLE in the Asia-Pacific region. This may encourage further research on SLE to address issues specific to this region, which may eventually lead to more efficient clinical management of this population.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Jakes had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Jakes, Bae, Louthrenoo, Mok, Navarra, Kwon.
Acquisition of data. Jakes, Bae, Louthrenoo, Mok, Navarra, Kwon.
Analysis and interpretation of data. Jakes, Bae, Louthrenoo, Mok, Kwon.
ROLE OF THE STUDY SPONSOR
GlaxoSmithKline oversaw the study design, data collection, data analysis, and writing of the manuscript, and approved the content of the submitted manuscript. Publication of this article was not contingent on the approval of GlaxoSmithKline.
Medical writing support was provided by Hui-Hwa Choo and Sen-Kwan Tay.