Epidemiology and risk of juvenile idiopathic arthritis among children with allergic diseases: a nationwide population-based study

Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease in childhood that can lead to long-term morbidities such as uveitis, osteoporosis, depression, poor pain control, and even severe disability due to joint damage [1, 2]. JIA comprises a heterogeneous group of diseases, with chronic arthritis as a common feature [3, 4]. Although the etiology and pathogenesis of JIA are not fully understood, individual gene susceptibility and various environmental triggers (e.g. trauma, bacterial or viral infection, and hormone levels) may lead to an immune imbalance that subsequently results in articular and systemic manifestations [4, 5].

The autoimmune and inflammatory features of JIA appear complex. Children with JIA were found increased levels of activated CD4+ T-cells both in circulation and in the synovium [6–10]. In In oligo/polyarticular JIA, the activation of auto-reactive T-cells including Th1 and Th17 cells induced IFN-γ and IL-17 production, respectively, leading to the production of proinflammatory cytokines, chemokines and mediators such as IL-1, IL-6 and TNF-α [7–9]. On the other hand, the immunosuppressive function of regulatory T-cells (Tregs) with decreased anti-inflammatory cytokine IL-10 results in a loss of immune tolerance. Imbalance between auto-reactive Th1/Th17 and Tregs leads to the failure of T-cell tolerance to self-antigens, which contributes to synovial inflammation and subsequent joint damage [8–10].

Despite advances in the pathophysiology of JIA, the clear understanding of the initiating and perpetuating factors of JIA remains limited. Recent studies have revealed that the incidences of allergic and autoimmune diseases have been increasing in parallel, making them a serious health-care burden [11–13]. Interest in a complexity link between allergic and autoimmune diseases is increasing [13], as both involve chronic inflammatory processes with complex etiologies, influenced by some common genetic determinants or environmental factors. In contrast to Th2-mediated allergic diseases, JIA is a Th1-driven chronic inflammatory disease. However, human epidemiological studies evaluating the temporal interaction between Th1-mediated JIA and Th2-mediated allergic diseases are sparse. In addition, the epidemiological data of JIA in Asian countries are limited.

The Taiwan National Health Insurance Research database (NHIRD) provides unrestricted and universal access to health-care facilities for Taiwan’s population. In the present study, we used this claims dataset to investigate the incidence and clinical presentations of JIA, and define the influence of allergic diseases on the development of JIA so that we could provide better insights into the common immunological aberrancies of these conditions. We hypothesized that children with atopy have increased subsequent risk of JIA.

Although the exact etiology of autoimmune diseases such as JIA remains unknown, it is believed to develop when a combination of genetic susceptibility and environmental encounters leads to the breakdown of tolerance [16–18]. Although methods for identifying JIA-susceptibility genes have advanced [19], only few studies have reported on the identification of environmental factors that trigger immunological aberrancies of JIA. Most of these studies described the associations between early-life infections, maternal smoking, and JIA [18–22]. Recently, three studies showed conflicting results on the association between atopic disorders and rheumatoid arthritis [23–26]. However, no reports have described the influence of childhood-onset allergic diseases on the risk of developing JIA. To the best of our knowledge, this is the first report on the increased risk of JIA in children with allergic diseases. The risk increased further with the accumulation of evidence on concurrent allergic diseases and the clinical burden of allergic diseases. Although our results only showed that children with allergic conjunctivitis, allergic rhinitis, or asthma were at significantly increased risk of developing JIA, the patients with other allergic disorders revealed increased frequency of JIA.

Epidemiological studies of JIA vary widely as regards to study methodology, classification criteria, and populations [27]. Comparison of epidemiological studies of JIA revealed that the annual incidence is 2.6 to 23 cases per 100,000 children per year and the estimated prevalence was 15.7–140 cases per 100,000 children [28–34]. The highest JIA incidence rates are found in some Scandinavian countries [30–32]. Studies from Asia revealed a low prevalence of JIA [35, 36]. The prevalence of JIA was estimated to be 3.8 cases per 100,000 children in Taiwan in 1995–1999 [35]. According to a smaller study from Japan, the annual incidence rate of JIA was estimated to be 0.83 case per 100,000 children in 1997 [36]. In this study, the mean annual incidence of JIA was 1.33 cases per 100,000 children in 2000–2008. All the JIA cases were obtained from the Registry for Catastrophic Illness Patient Database (RCIPD), a subpart of the NHIRD. In Taiwan, insured persons with major diseases can apply for a catastrophic illness certificate that grants exemption from copayment. The issuance of catastrophic illness certificates was validated by at least 2 specialists, based on careful examination of medical records, laboratory studies, and imaging studies. In Taiwan, the agreed-upon criteria for diagnosis and classification of JIA were based on the ILAR revised classification. Thus, the diagnostic accuracy for JIA should be high. However, the underestimated incidence of JIA based on data from the RCIPD should be considered because children with mild or oligoarticular disease may not apply or be qualified for a catastrophic illness certificate [37]. Although the most common subtype in Western European countries is represented by oligoarthritis, this is rare in countries such as Costa Rica, India, New Zealand, and South Africa, where polyarthritis predominates [27–30]. The present study revealed that the most common subtype of JIA in Taiwan was the polyarticular type. Previous studies from Asia showed that patients with oligoarticular JIA were older at disease onset and less likely to be female than their European counterparts, and that spondylarthropathy was more frequent in Asian patients [29]. Our study demonstrated a similar pattern that boys and children aged 6–12 years had higher prevalence rates of oligoarticular JIA.

JIA describes a clinically heterogeneous group of arthritis, which begins before 16 years of age. To date, the cause of the disease is still poorly understood but seems to be related to both genetic and environmental factors, which result in the heterogeneity of the illness. Our results support childhood-onset allergic diseases as risk factors of JIA. JIA is considered a complex genetic disease, and several genetic studies support that common aberrant immune responses may cause both JIA and allergic diseases. In Germany, Schubert et al. found an inverse association between several gene polymorphisms involved in Th1- and Th2-driven inflammatory pathways, such as IL-4, CTLA4, and TNF-α, and asthma and/or JIA [26]. In a Mexican population, Silvia et al. reported an association between the TNF alpha gene, a common factor in the pathogenesis of pediatric inflammatory and/or autoimmune diseases such as asthma, systemic lupus erythematosus, and JIA [32]. In Germany, Heinzmann et al. reported that an IL13 (Th2 cytokine) gene variant might prevent the development of JIA and make an individual susceptible to atopic diseases [33]. In addition to these genetic studies, common environmental triggers might be another explanation for the increased risk of JIA in atopic children. Kokkonen et al. found intestinal immune activation in most patients with JIA and observed similar features in children with delayed-type food hypersensitivity. This study implies that food-borne antigens might initiate pathological cascades in both disorders [34]. Recent evidence has suggested the role or dysfunction of Treg cells in the maintenance of immunological tolerance to environmental triggers and the prevention of autoimmune diseases and allergic diseases [31]. Treg cell dysfunction is undoubtedly connected to the two disorders; this supports our findings.

This study is the first to precisely analyze the future risk of JIA in children with common allergic diseases by using a large population database with minimal selection bias. However, it has some limitations. First, the diagnosis was based on the codes of the International Classification of Diseases, Ninth Revision. Hence, detailed clinical information such as anti-nuclear antibody titer, rheumatoid factor titer, IgE level, specific IgE, severity of arthritis and allergic symptoms, treatment response, susceptible genes, and environmental factors was lacking. Second, because JIA is a rare disease, the difference in related risk might be less significant or inconsistent depending on the limited sample size in the age- or sex-specific subpopulation analysis. Third, in this study, all the JIA cases were obtained from the RCIPD. Although the diagnostic accuracy for JIA should be high in the present study, the underestimated incidence of JIA from the RCIPD should be considered because children with mild or oligoarticular disease may not apply or be qualified for a catastrophic illness certificate [37]. In such cases, selection bias might exist, as the undiagnosed cases may be randomly selected as comparison controls. Fourth, not all patients with atopic disease would necessarily seek medical attention. These unrecognized and uncounted patients who were not included in the dataset will influence the results. Fifth, the subjects in this study were Chinese; thus, the study results cannot be generalized to other populations.

In conclusion, children with onset of allergic diseases were at increased risk of developing JIA, and the increased risk was associated with the cumulative effect of the clinical burden of allergic diseases. Further study to investigate the role of Th2-mediated allergic diseases that contribute to the development of Th1-mediated JIA is warranted.