Background
Juvenile idiopathic arthritis (JIA) is a diagnosis of exclusion that includes all forms of chronic arthritis of unknown origin with onset below the age of 16 years [
1]. It is the most common childhood rheumatic disease with an estimated global incidence of 1.6 – 23 cases per 100,000 children [
2] and often persists into adulthood [
3]. The International League of Associations for Rheumatology (ILAR) distinguishes seven JIA categories with different clinical and laboratory measures [
4], although another classification system is under development [
5].
There is some evidence that children with JIA suffer more often from autoimmune thyroid disease (AITD) than the general pediatric population [
6‐
8]. AITD comprises Hashimoto’s thyroiditis which causes hypothyroidism and Graves’ disease which causes hyperthyroidism. If undiagnosed and thus left untreated, hyper- and hypothyroidism may lead to a variety of complaints, such as constipation or diarrhea, irritability, fatigue, hair loss but ultimately also growth retardation and depression [
9].
Currently, little is known about the association between JIA and AITD and therefore there are no indications for AITD screening in this population, which is possible using standard blood tests. Previous studies reported a prevalence of (subclinical) AITD in JIA varying from 1 to 44% [
7,
8,
10‐
16]. One study of 81 JIA patients reported a significant association between a family history of thyroid disease and AITD [
17]. Nevertheless, studies that primarily focus on AITD in JIA are scarce and most include not only symptomatic but also subclinical AITD. Furthermore, no study has yet established independent predictor variables for AITD in JIA.
The purpose of this study is to determine the prevalence of symptomatic AITD in JIA and moreover to identify independent predictors for AITD using data from the international observational Pharmachild registry.
Discussion
The prevalence of AITD observed in the current study (1.1%) was lower compared to prevalence rates reported in the majority of previous studies about AITD in JIA (5.0 – 44.4%) [
7,
8,
10,
11,
14‐
17]. These studies, however, also included cases of subclinical AITD based on active screening for serum levels of thyroid hormones (T
3 and T
4), thyroid-stimulating hormone (TSH) and anti-thyroid antibodies (TgA: thyroglobulin antibodies and/or TPOA: thyroid peroxidase antibodies). Two previous studies focused on clinical AITD in JIA and found similar prevalence rates as the current study (0.8 and 1.3%) [
12,
13]. AITD has a varying prevalence in the general pediatric population (0.1 – 9.6%) according to the criteria used for diagnosis [
22‐
26]. A population-based study from Scotland focused on clinical hypothyroidism in young people aged < 22 years and found a prevalence of 0.14% [
27], which is over 4 times as low as the prevalence of clinical hypothyroidism in JIA found in the current study. In addition, several studies reported increased serum levels of anti-thyroid antibodies in children with JIA compared to healthy controls [
7,
8,
15,
17].
Our study highlighted as independent predictors of AITD in JIA a family history of AITD, female sex, a positive ANA status and older age at JIA onset. In fact, previous studies about AITD in JIA also report a female predominance in the AITD group [
7,
8,
10,
11,
17]. This can be explained by the predominance of girls in most JIA categories [
28] and autoimmunity in general [
29]. Previous studies have suggested that oligoarthritis might be associated with AITD in JIA [
7,
8,
11,
15], but with the current study we conclude that this effect is likely explained by ANA positivity and female sex, which is highly frequent in oligoarthritis [
28]. Similarly, the association between AITD and RF positivity and RF+ polyarthritis that we observed in univariable analyses is probably explained by older age and female sex [
28].
This is the first study to report an (adjusted) association between AITD and a positive ANA status in JIA, likely due to a limited sample size in previous studies. An association between thyroid disorders and ANA positivity has previously been reported in adult RA [
30] and a raised prevalence of ANA in AITD patients has also been previously reported, although the mechanism behind this phenomenon is not known [
31‐
33]. More interestingly, we found a significant association between AITD in JIA patients and a family history of AITD, as described before in another study [
17]. Previous studies on AITD patients have also reported high frequencies of familial AITD [
34‐
36] or familial autoimmune disease in general [
37]. The association between older age at JIA onset and AITD has not been previously reported. We hypothesize that this effect is caused by merely age rather than age at JIA onset, since older patients in general have an increased cumulative risk of developing any disease including AITD. In fact, it is known that the prevalence of pediatric AITD peaks during adolescence [
25,
26,
38]. Systemic arthritis was observed considerably less in AITD patients than non-AITD patients in the current study, which might be explained by the fact that this JIA category resembles more an auto-inflammatory rather than an autoimmune disease and does not predominantly affect girls [
39].
After a median observation period of 5.5 years, we observed a considerable increase in AITD prevalence for JIA patients at increased risk for developing AITD according to our analyses, providing rationale for yearly AITD screening in this high-risk group. Based on the Pharmachild data, only five ANA positive girls with a family history of AITD and an age at JIA onset of ≥12 years would have to be screened during 5.5 years to detect one case of clinical AITD. According to the coefficients in our prediction model, it is safe to conclude that a family history of AITD is the most important predictor of AITD in JIA, with an even larger OR for AITD than a 10-year increase in age at JIA onset. Hence, this would be the most important factor for clinicians to determine in JIA patients when estimating the risk of developing AITD. Screening for thyroid disease is based on abnormal levels of free thyroxine (T
4) and thyroid stimulating hormone (TSH), which are standard blood tests. AITD is diagnosed when these abnormal levels are found in the presence of anti-thyroid antibodies. Interestingly, it has previously been mentioned that female sex, older age and a family history of autoimmune should raise suspicion for anti-thyroid antibodies screening in children with positive ANA of unknown cause [
32].
This study has strengths and limitations. First of all, due to missing onset dates for AITD cases, no association between drug therapy, disease activity, disease duration, other endocrinopathies and AITD onset could be investigated. In the current study, we observed that AITD patients had more often received TNF inhibitors than non-AITD patients. However, although a decrease in thyroid dysfunction has been reported in autoimmune disease patients treated with TNF inhibitors [
40‐
42], we cannot draw conclusions from our study since it is unknown whether TNF inhibitor therapy was received before or after AITD onset. Another limitation of our study is that baseline comorbidities and subsequent adverse events in Pharmachild are gathered using spontaneous reporting (i.e. these have to be reported by treating physicians), which might have led to an underestimation of the actual AITD prevalence. Furthermore, it is possible that the median observation period of 5.5 years was too short for patients with young age at JIA onset to develop AITD. The exact NNS reported in this study might therefore be applicable for a follow-up period of ±5.5 years after onset of JIA only, but higher or lower afterwards. Also, the results of our study might not be generalizable to all JIA patients, since the Pharmachild registry has a selection bias towards JIA patients with a more severe disease course requiring DMARD treatment, Nevertheless, this is the first study to report independent predictors of AITD in JIA. Contrary to most of the few previous studies on AITD in JIA, we report only symptomatic AITD cases and have included patients from multiple centers around the world.
Given the AUC of our prediction model, there is room for improvement in identifying other relevant predictive factors for AITD in JIA. Further research should therefore focus on incorporating drug therapy and disease duration. As suggested previously [
10], the incidence of AITD increases with time from diagnosis of JIA and therefore disease duration might be a better predictor than age at JIA onset. Another relevant predictor might be iodine intake, since it is well-described that AITD is more common in iodine-replete areas around the world [
22,
26,
43,
44].
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.