Learning Objectives 1. To learn about the relevance of epidemiology in pediatric rheumatology (PR) 2. To understand the challenges that are encountered when analysing epidemiologic studies in JIA 3. To appreciate that there are racial differences in the prevalence of JIA 4. To study the epidemiology of other PR diseases Introduction Epidemiology is the study of the distribution and determinants of health-related conditions or events in defined populations. Knowledge of the epidemiology of a particular medical condition may lead to better understanding of the extent of the condition, possible aetiological factors, possible therapies, the course and outcome of the illness, definition and characterisation of subgroups of disease and associated demographic, genetic and racial data of the condition. In addition, knowing epidemiology allows health resources planning. In pediatric rheumatology, it can be difficult to define epidemiology accurately with most conditions being relatively rare and often poorly diagnosed. To perform quality epidemiology studies, one must have standardised case definition, case ascertainment and a definable population at risk. Changing statistics in epidemiology over decades is more likely to be due to these factors rather than to real changes in the distribution of pediatric rheumatological diseases. With time, knowledge and better diagnostic tools, the picture becomes clearer; however, the epidemiology of pediatric rheumatology remains in its infancy. Juvenile Idiopathic Arthritis Juvenile idiopathic arthritis (JIA) is the most common of the pediatric rheumatological conditions, and its epidemiology has been best studied. In 1995, the International League of Associations for Rheumatology (ILAR) classification (first version) [ 1] was published defining seven separate conditions aimed at being homogenous, clearly defined and appropriate for research purposes as first priority whilst also being useful for clinicians. The third version was published in 2004 [ 2]. This has made epidemiological studies of childhood arthritis somewhat more comparable. However, many variables remain, and it can be seen that the results of even recent epidemiological studies remain widely divergent for reasons considered below (Table 5.1). Table 5.1 Epidemiological studies of juvenile arthritis from 1992 [ 3– 27] Publication year Reference Authors District Case ascertainment JIA etc. Max (years) Prev. cases Prev per 100,000 Prev 95 % C.I. A.I.* per 100,000 1992 [ 3] Andersson Gare and Fasth Southwest Sweden Hospital and specialist attendance JCA 15 334 86.3 77–96 10.9 1993 [ 4] Mielants et al. Belgium Ccl* exam in schools JCA 18 5 167 54–381 1995 [ 5] Oen et al. Manitoba Hospital attendance JRA 15 5.34 1995 [ 6] Arguedas et al. Costa Rica Referral from physicians JCA 15 5.4 1996 [ 7] Malleson et al. Canada Attendance at 13 centres JRA 16 2.39 1996 [ 8] Symmons et al. United Kingdom Attendance at 2 centres JCA 15 10 1996 [ 9] Peterson et al. Rochester, Minnesota Hospital records JCA 15 65 1980: (i) 94.3 1990: (ii) 86.1 (i) 41–148 (ii) 37–135 1960–69:15 1970–79:14.1 1980–93:7.8 1996 [ 10] Kaipiainen-Seppanen and Savolainen Finland Sickness insurance records JRA 15 0.14 1996 [ 11] Manners and Diepeveen Australia Community JCA 12 9 401 184–753 10.6 (separate study) 1997 [ 12] Fujikawa and Okuni Japan Quest* to hospitals JRA 15 0.83 1998 [ 13] Ozen et al. Turkey Exam in homes JCA 15 30 64 43–91 1998 [ 14] Moe and Rygg Norway Disease registry JCA 15 71 148.1 115–187 22.6 1998 [ 15] Kiessling et al. Germany Hospital records JCA 15 50.2 mean 9 y 200 166–247 03.5 1998 [ 16] Arguedas et al. Costa Rica From physicians JCA 15 122 34.9 28.9–41.6 6.8 2004 [ 17] Huang et al. Taiwan Case data JCA 15 3.8 3.3–4.3 2006 [ 18] Hanova et al. Czech Republic From registers JIA 15 43 140 117–280 2–65 13 2006 [ 19] Danner et al. France Physicians JIA 15 67 19.8 19.3–20.3 3.2 (1.62–5.8) 2007 [ 20] Kurahara et al. Hawaii (i) urban (ii) rural From physicians JRA 15 38.3 63.2 2007 [ 21] Martinez-Minguel et al. Spain Chart review JIA 15 51.4 40.6–68.5 2010 [ 22] Solau-Gervais et al. France Survey of doctors JIA 15 48 15.7 11.6–20.8 2010 [ 23] Modesto et al. Spain Trained doctors JIA 15 432 39.7 36.1–43.7 6.9 (5.8–8.1) 2012 [ 24] Azam et al. Bangladesh In homes JIA 15 10 60.5 2013 [ 25] Harrold et al. California Insurance JIA 15 44.7 39.1–50.2 11.9 2014 [ 26] Abujam et al. India In schools JIA 15 1 48 10–280 2014 [ 27] Thierry et al. Europe Lit review JIA 15 59.17 70.2 (62.9–78.1) 8.2 (7.5–9.0) C.I. confidence interval, A.I. annual incidence, Cl. Exam clinical examination, Quest questionnaire, Prev prevalence Dilemmas with Epidemiological Studies of JIA The many remaining problems in the study of epidemiology of JIA can be considered in four separate categories: Diagnostic Difficulties with JIA (a) ILAR was first published in 1995 on a proposed system of classification and nomenclature of juvenile arthritis for all nations [ 1]. Prior to this there had been little uniformity with several different systems of classification and naming in use. The third and final revision (to date) of the ILAR classification was published in 2004 [ 2] and provided international standardisation for classification and the new name “juvenile idiopathic arthritis” (JIA) which replaced “juvenile rheumatoid arthritis” (JRA) and “juvenile chronic arthritis” (JCA). JIA described seven homogenous mutually exclusive subgroups and one category (“undefined” or “other arthritis”) for conditions that did not fit precisely into only one single category. This classification system has made epidemiological studies more standardised, but many problems remain. Meantime, it is becoming apparent that with better understanding of the various subgroups of JIA, a new classification system may be due, particularly in relation to systemic arthritis (see below). A classification system should be viewed as a living organism, ready to change as the sub-speciality grows and matures, and knowledge of the area becomes more precise. (b) The diagnosis of JIA remains a clinical one. There are no tests available to confirm or exclude the diagnosis. Hence, an experienced clinician is required to make a diagnosis by defining swollen, tender or joints with limited range of movements. For the inexperienced it is sometimes difficult to do this. For the experienced clinician as well, it can pose a challenge. It is known that many children with JIA remain undiagnosed for long stretches of time, partly because joint pain itself seems to be less in children, and swelling may not be noticed by a parent [ 28]. This impacts on case ascertainment in epidemiological studies and largely explains the wide variance between true community-based studies and case-based studies, further discussed below. It is mainly for this reason that case-based epidemiology studies will always show lower prevalence than studies based on the clinical examination of a cohort of children presumed to be healthy. Children with the milder forms of JIA such as persistent oligoarthritis are the most likely to remain undiagnosed [ 11, 29]. (c) Since JIA is a diagnosis of exclusion, one first needs to know what to exclude. The differential diagnosis may be wide. Septic arthritis is a condition that requires prompt treatment. It can sometimes resemble JIA (oligoarthritis form) at presentation, but there are disastrous consequences if the diagnosis is missed. However, it is not uncommon for an unsuspecting orthopaedic surgeon to needlessly open a swollen joint due to JIA, thinking it to be septic. Many a child with JIA bears the scars of having had a joint opened for no good purpose. It is preferable just the same, to overdiagnose septic arthritis initially than to under-diagnose it, as untreated septic arthritis is quickly destructive. (d) Since there is a requirement for the presence of joint inflammation for 6 weeks for a diagnosis of JIA, this can delay a diagnosis until time has run its course. The most common cause of a swollen joint in a child is a viral illness. A viral swollen joint does not generally last for 6 weeks, and more commonly it has abated in less than 2 weeks. (e) It is now apparent that one subgroup of JIA, systemic arthritis, is fundamentally different to all other subgroups. It does not comfortably sit in the category of “autoimmune disease” implying adaptive immune system pathology [ 30]. Instead it has features of increased activity of the innate immune system and increased secretion of certain cytokines, interleukin-1 (IL-1) and interleukin-6 (IL-6). Its behaviour is similar to that of a polygenic auto-inflammatory disease [ 30]. This reminds us that classification systems should be constantly renewed as we understand more about a condition. Differences in Case Ascertainment for JIA (a) Commonly, case-based studies are utilised in epidemiology studies of JIA, i.e. previously diagnosed cases of JIA. Where so-called “healthy” children are checked within the community for the presence of JIA, such studies can be categorised as true community-based studies (CBSs). It is known that true CBSs will include significant numbers of children who have remained undiagnosed with JIA, usually disease at the milder end of the spectrum such as persistent oligoarthritis [ 11]. It is logical to presume that true CBSs will show higher results for prevalence and incidence of JIA. True CBSs are expensive and time-consuming and rely heavily on experienced clinicians. In addition, the numbers of children needing to be examined range in the thousands, to identify relatively small numbers of cases for an uncommon disease. By their nature, such studies allow for significant chance variation, i.e. the resulting prevalence figures will have wide 95 % confidence intervals and a need for careful interpretation of the data. In true CBSs such as those of Mielants [ 4] and Manners [ 11], there is an increased number of children with the more mild forms whose condition had remained unnoticed by the family and medical authorities. In true CBSs the prevalence is usually significantly higher because of the previously undiagnosed cases. However, in the study of Aggarwal [ 26] in the Indian subcontinent, a true CBS did not show numbers of undiagnosed children with the more mild forms of JIA. This important study suggests that in India there is a scarcity of the more mild forms of JIA seen often in Caucasian population studies. This provides strong evidence that there is true genetic variation between races (see below). (b) Across epidemiology studies, there is little standardisation of whether cases are included if relapsing, in remission or continuously active. For point prevalence studies, significant data are thus not captured if juvenile arthritis at the time of the study is in remission. In theory prospective studies would be preferable so that the end result would truly reflect the situation in the base population. However, such studies are expensive and time-consuming. (c) For prevalence studies, the population base must be definable. In the modern world mobility of families adds difficulty in defining a stable population. The ideal base population would be a large and relatively isolated city where clinicians have easy access to many children. As in the study of Saurenmann et al. [ 31], the city of Toronto is one such place which would lend itself to epidemiological studies. Factors Emerging with Passage of Time Regarding JIA The following factors changing over time further complicate interpretation of results of epidemiology studies: increased living standards, increased health resources, increasing knowledge of disease and better therapeutic regimes. Racial Differences It is only in the last decade it has become quite clear that prevalence and incidence of JIA vary significantly between racial groups. In a landmark study by Abujam, Mishra and Aggarwal (2014) conducted in Lucknow, India, 2,059 children were examined within schools by a single experienced clinician using GALS (gait, arms, legs, spine) screening. If any abnormalities were identified in the clinical screening, there followed a formal rheumatological examination. The clinical examination was further supported by questionnaires answered by all participants in the study. Unlike other CBSs carried out along similar lines amongst predominantly Caucasian children, in the Indian study, cases of JIA amongst the examined students were rare. There was only one definite case found, being a child with enthesitis-related arthritis (ERA). The estimated prevalence was 48 per 100,000 (95 % CI 10–280). This is low in comparison to the study of Manners et al. where 2,241 children (85 % Caucasian) were clinically examined after questionnaires were completed, with nine cases of JIA being identified with confirmation by a visiting international pediatric rheumatologist who examined the children said to have JIA. Seven of the children in that study had not previously been diagnosed and may never have been but for the research project. The Australian study showed a prevalence of 401 per 100,000 (95 % CI 184–753). That Indian children have a lower prevalence of JIA is further supported by the study of Saurenmann 2007 who showed in a study of the multiethnic city of Toronto, Canada, that children from black, Indian or Asian subcontinents have significantly lower prevalence rates for JIA [ 31] particularly of the milder forms. A number of studies have shown that Caucasian children overall have a significantly higher prevalence of JIA. Similar studies in Sweden and Costa Rica were performed using surveys through healthcare organisations. Prevalence rates per 100,000 children were found to be 86 (95 % CI 77–96) for Sweden and 31 (95 % CI 25–37) for Cost Rica with confidence intervals failing to overlap [ 16, 32]. A study of Japanese children [ 12] with surveys to 1,290 Japanese schools showed 1,606 cases of JRA giving an annual incidence rate of 0.83 per 100,000 which is very low. In Norway, a similar study showed an annual incidence of 22.6 [ 14]. In Europe a direct standardised incidence rate was calculated to be 8.2 (95 % CI 7.5–9.0) for the year 2010 being higher than the Japanese incidence rate by a factor of 10 [ 27]. The well-demarcated racial differences in the prevalence and incidence of JIA imply a different genetic susceptibility within different races. As world populations mobilise and mix, the differences between races in incidence and prevalence for JIA are well maintained, supporting the view that the differences are true genetic differences between races and not due to differences in geography. For the Australian indigenous child, JIA is virtually never diagnosed though children of mixed racial origin very occasionally develop JIA. For these same indigenous children, there is a high incidence of systemic lupus erythematosus (SLE) and of rheumatic fever, many times that of Caucasian Australian children living in the same areas. Thus, genetics is a very powerful force in the epidemiology of JIA and other pediatric rheumatological conditions. The Need for Improvement of the Classification System for JIA As we understand JIA better, there is increasing evidence that a new classification system may be needed. The problems with the current system include the following: (i) Systemic JIA does not fit well and would be better classified as an auto-inflammatory condition [ 30]; (ii) it is considered by some that rheumatoid factor positivity, which is usually associated with positivity for anticyclic citrullinated peptide antibody, should be given hierarchal consideration, not associated with the number of joints involved [ 33, 34]; (iii) the presence of anti-nuclear antibody in association with oligoarthritis in the younger age of onset may need to be considered in a separate category [ 35]; (iv) using family history as inclusion or exclusion criteria can be difficult when family history is not known [ 36]; (v) the actual number of joints involved may be an artificial distinguishing feature between oligoarthritis and polyarthritis and in any case is often not accurately calculated [ 33]. Classification and nomenclature should always depend on known details about the condition. As more has been learned over the years since the Edmonton modification of the ILAR classification, it is logical that new modifications to the classification would be appropriate and would improve the homogeneity of subgroups. This would benefit not only research but also the clinical management of JIA. Systemic Lupus Erythematosus Research into the epidemiology of SLE, particularly the genetic epidemiology, has facilitated better understanding of the development of the condition. A neat snapshot of prevalence and incidence according to race is shown by figures from the UK published in 2006 which covers a broad variety of races and which tends to reflect the differing prevalence according to race [ 37, 38] (Table 5.2). Table 5.2 Racial groups in the UK with SLE United Kingdom: racial group Incidence per 100,000 pa Prevalence per 100,000 All races – 26.2 White 3.0 20.5 Asian 10.0 47.8 Chinese – 92.9 Afro-Caribbean 21.9 159.4 In the USA, including all races, the prevalence is quoted as 130 per 100,000 with a higher proportion of Hispanics, African Americans and Asians [ 38]. In Australia there is a similar contrasting prevalence with a prevalence of 19.3 per 100,000 in Caucasians and 63.1 per 100,000 in Australian indigenous people. In Asian countries, the reported prevalence rates range from 58.8 to 70.4 per 100,000 persons in China and Hong Kong [ 39]. In North America, the prevalence rates of SLE in black and Hispanic populations are three to four times higher than in Caucasian populations [ 40]. These differences would suggest a strong genetic component in the aetiology of SLE with clear ethnic differences reported in prevalence rates for SLE universally [ 41]. The epidemiology of SLE in the pediatric age group reflects that seen in the adult population, with approximately 20 % of disease commencing in childhood with a significantly lower representation in Caucasian children than in black, Asian and Hispanic populations. In consideration of the epidemiology of diseases, the study of genetics and epigenetics is closely allied. Genome-wide association scan (GWAS) studies can now scan hundreds of thousands of single nucleotide polymorphisms (SNPs). Using this technique, eight GWAS have been identified, four in European and four in Asian populations, from which more than 50 risk loci for SLE have been defined by meta-analysis and other strategies [ 42]. Thus, it is defined that SLE occurs in the genetically susceptible. Epigenetic modifications, which may be triggered by environmental exposures, further amplify genetic risks [ 43] and change how genes function, leading to SLE. Epidemiology of Other Pediatric Rheumatological Disorders Most conditions falling in the ambit of pediatric rheumatology, apart from JIA and SLE, are quite rare. For dermatomyositis, the incidence is reported as 3–4 per million [ 44] both in the UK and USA. The average age of onset is around 7 years with 25 % having onset before the age of 4 years and approximately 50 % with onset younger than age 6 years. In the USA, the male to female ratio has been reported as 2.5:1; in the UK it is 5:1 [ 44]. Antiphospholipid syndrome (APLS) is very rare in children. On the international register by 2007, there were 121 confirmed cases from 14 countries. Of the adults with this condition, 3 % are said to be diagnosed in childhood [ 45]. There remains lack of validated criteria for diagnosis in children [ 46]. An epidemiological survey of mixed connective tissue disorder (MCTD) in Norway showed a point prevalence of living adult MCTD patients to be 3.8 (95 % CI 3.2–4.4) per 100,000 adults. The incidence was found to be 2.1 per million per year [ 47]. It has been reported that there is pediatric onset in 23 % of all cases of MCTD seen in adults [ 48]. However, MCTD is still rare in children and has been estimated to account for only 0.6 % of patients attending a pediatric rheumatology clinic for the first time [ 49]. Of pediatric vasculitis syndromes, Henoch-Schőnlein purpura (HSP) and Kawasaki disease are the most common. Henoch-Schőnlein purpura (HSP) occurs across all ages from the age of a few months to late adulthood with more than 50 % of cases occurring in children under the age of 5 years and 75 % of cases under the age of 10 years [ 50]. The incidence is 10–20 annually per 100,000 children. A study in Manchester reported a lower incidence in black children compared with white or Asian children [ 51]. In most series there is a male predominance with a ratio of approximately 2:1 male to female. Kawasaki disease is a disease of young children with the peak incidence between 13 and 24 months, with 80 % being younger than 5 years at onset and occurring rarely before 6 months of age [ 52, 53]. The prevalence varies widely around the world in different racial groups, which would suggest a genetic predisposition. There has been significant progress in defining GWAS associations [ 54]. KD occurs in 75–125 per 100,000 Japanese children [ 55] and 9.1 per 100,000 Caucasian American children [ 56]. Other forms of vasculitis are very rare in children. Concluding Comments What is currently known about the epidemiology of pediatric rheumatology has contributed significantly to understanding of conditions, to treatment strategies and to health resource planning. There is a great deal more to be known in this area. Take-Home Messages 1. A basic understanding of the epidemiology of pediatric rheumatic diseases is very important. 2. JIA, the most common pediatric rheumatic disease, is challenging to study because it encompasses a heterogeneous population of children, changes dynamically over time, may have no pain and can be missed in case-based surveys. It is a condition with true racial differences. 3. The JIA classification system is ready for a revision 4. The other pediatric rheumatic diseases are rare and have only a few epidemiologic studies done.