Screening for comorbid autoimmune disease should be considered in children with ANA positive juvenile idiopathic arthritis – results from the south-Swedish juvenile idiopathic arthritis cohort

Screening for comorbid autoimmune disease should be considered in children with ANA positive juvenile idiopathic arthritis – results from the south-Swedish juvenile idiopathic arthritis cohort | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Screening for comorbid autoimmune disease should be considered in children with ANA positive juvenile idiopathic arthritis – results from the south-Swedish juvenile idiopathic arthritis cohort Alma Dahlberg, Helena Tydén, Anna Saxne Jöud, Fredrik Kahn, Elisabet Berthold This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4448474/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Oct, 2024 Read the published version in Pediatric Rheumatology → Version 1 posted 5 You are reading this latest preprint version Abstract Background There is no consensus or clinical guidelines for screening routines of autoimmune disease in individuals with juvenile idiopathic arthritis (JIA), since results are conflicting whether the risk for such conditions is increased or not among individuals with JIA. The aim of this study was to investigate if the frequency of comorbid autoimmune conditions is increased after JIA diagnosis in a validated population-based JIA cohort in southern Sweden. Methods Autoimmune comorbidities were evaluated in a pre-existing population-based JIA cohort of 302 participants, constituting of individuals diagnosed with a validated JIA diagnosis 2000–2010 in southern Sweden. The comorbidities were determined through analysis of diagnosis codes registered after the JIA diagnosis and until 2019. With the use of a reference population of 1510 age- and sex matched individuals, hazard ratios (HR) were calculated with Cox proportional models. Results During the study period, 7.7% of the JIA cohort received an autoimmune diagnosis after their JIA diagnosis. Individuals with JIA had an increased risk of autoimmune diseases in general (HR 2.01, 95% CI 1.16–3.51), as well as separately for coeliac disease (HR 3.98, 95% CI 1.44–11.01) compared to the reference population. Antinuclear antibody (ANA) positivity as well as treatment with disease-modifying anti-rheumatic drugs (DMARD) was associated with a significantly increased risk of comorbid autoimmune disease in the JIA cohort, with HR 5.11 (95% CI 1.54–16.96) for ANA positive individuals and HR 7.23 (95% CI 1.65–31.70) for those with DMARD treatment. Conclusions Individuals with JIA have a significantly increased risk of being diagnosed with an autoimmune condition after receiving their JIA diagnosis compared to matched references. ANA positivity and DMARD treatment is associated with a further increased risk. Our results emphasize awareness in physicians of additional autoimmune disorders in individuals with JIA and advocate serological screening of autoimmune conditions during follow-up. Juvenile arthritis Juvenile idiopathic arthritis JIA Comorbidity Outcome Autoimmunity Hypothyroidism Coeliac disease Diabetes Mellitus Type 1. Figures Figure 1 Figure 2 Figure 3 Background Juvenile idiopathic arthritis (JIA) serves as an umbrella term for seven heterogenous arthritis subcategories, defined by joint inflammation with duration for at least six weeks, onset before the 16th birthday and unknown aetiology ( 1 , 2 ). The JIA subcategories are categorized by the number of inflamed joints, presence of extraarticular organ involvement, and serological features. The disease can hence present in various ways but share the feature of arthritis, possibly causing pain and mobility limitations leading to short- and long-term consequences. The present definition and classification criteria were proposed by the International League of Associations for Rheumatology (ILAR) and have been the international diagnostic standard since 2001 ( 2 ). Due to heterogenous presentation in the same JIA subgroup, and since the current JIA criteria separate children from their adult counterparts by its specific paediatric arthritis definition, new subgroups have been proposed. A unique childhood specific subgroup without a clear adult equivalent is suggested, defined by presence of antinuclear antibodies (ANA) in early onset arthritis (diagnosis before the age of six), independent of the number of affected joints ( 3 , 4 ). JIA is the most common paediatric rheumatic disease with a reported incidence rate estimated to 12.8/100 000 children/year in southern Sweden ( 5 ). Both genetic and environmental factors are believed to be involved in the pathogenesis ( 1 ). Current treatment guidelines include non-steroid anti-inflammatory drugs, intra-articular corticosteroid injections and disease-modifying anti-rheumatic drugs (DMARD) ( 1 ). Biological DMARDs (bDMARD) have been available as treatment for JIA in Sweden since 1999. JIA is a chronic disease with long-term follow-up data showing approximately 40% of the individuals having active disease or inactive disease on medication after 18 and 30 years respectively ( 6 , 7 ). Thus, despite the biological era, a considerable number of individuals with JIA still have active disease persisting into adulthood. It is poorly established what impact JIA have on adult life in terms of risk of comorbidities due to autoimmunity, persistent inflammation, and/or immunomodulatory treatment. Autoimmune disorders are more common conditions in Northern Europe as compared to other countries ( 8 – 10 ). The estimated European prevalence of hypothyroidism in the adult population is 3–5% ( 10 ) and the Swedish prevalence of coeliac disease is approximately 2% in children ( 9 ). Since genetic factors contribute to the development of autoimmune disease, autoimmune conditions tend to co-occur. Due to differences in study design and number of study participants, previous results on autoimmune comorbidity in JIA are conflicting and screening for autoimmune conditions in JIA is not uniformly recommended ( 11 – 14 ). However, some studies implicate an elevated risk of comorbid autoimmune diseases in JIA ( 15 – 17 ). Reports from Finland suggest a 5-fold increased risk of type 1 diabetes mellitus, coeliac disease, and hypothyroidism in children with JIA compared to the general population ( 17 ), in contrast to Swedish results showing prevalence of coeliac disease among children with JIA similar to that in the general population, thus not recommending screening for coeliac disease in Swedish individuals with JIA ( 11 ). However, screening for disease specific autoantibodies could detect organ-specific autoimmunity before the development of clinical autoimmune disease, potentially preventing morbidity and irreversible tissue damage. A recent multicentre registry study proposed the benefit of yearly serological screening for autoimmune thyroid disease in female ANA positive individuals with JIA and family history of autoimmune thyroid disease ( 18 ). Therefore, before establishing uniform clinical guidelines regarding screening for autoimmune comorbidities in JIA with potential benefits of early diagnostic detection of a comorbid condition, more research is still needed. The overall purpose of this study was to investigate whether persons with JIA have an increased risk of being diagnosed with a comorbid autoimmune condition after their JIA diagnosis in a validated population-based JIA cohort in southern Sweden, compared to a reference population matched for age, sex and residential region. The study further aimed to explore if the factors; sex, immunological data, and DMARD treatment, could be used as predictors of comorbid autoimmune diagnosis. Methods Study area For the study of autoimmune comorbidities in JIA we used a pre-existing south-Swedish JIA cohort with individuals collected in Skåne, the southernmost region of Sweden ( 5 , 19 ). In 2019, Skåne was the third largest region by population in Sweden with 1 377 827 inhabitants, constituting 13.3% of the Swedish population. Children aged 0–15 years accounted for 19.4% of the population ( 20 ). The study area has one university hospital, nine other hospital-associated paediatric outpatient facilities, and six private paediatric outpatient facilities. The healthcare in Sweden is tax-funded, and the paediatric care is subsidized for all children. Additionally, children undergo regular controls both at child healthcare and in school. These factors, combined with mandatory diagnosis registration, diminishes the risk of missing to include persons in a population-based cohort, since symptoms suspicious of JIA rarely are neglected or missed at primary healthcare facilities. Study population For this study, 302 individuals with a validated JIA diagnosis with date of diagnosis between 1 January 2000 and 31 December 2010 were included from the previously published south-Swedish JIA cohort. The south-Swedish JIA cohort is a population-based cohort and consists of retrospectively collected JIA cases validated through medical record review (process described in detail in previous publications) ( 5 , 19 ). Information about immunological data and annually prescribed pharmacological treatment was collected during the case collection process. Methotrexate, chloroquine phosphate, sulfasalazine, azathioprine, gold, mycophenolate, cyclosporine, penicillamine and chlorambucil was registered as conventional synthetic DMARDs (csDMARD), while tumor necrosis factor inhibitors, anakinra, tocilizumab and ustekinumab was registered as bDMARD. Data source We acquired registered diagnoses for autoimmune conditions between 1 January 1998 and 31 December 2019 from the regional administrative healthcare register, Skåne Healthcare Register (SHR). SHR includes information from healthcare visits in primary care, as well as from in- and outpatient hospital care visits in the region. The register was established in 1998 and contains diagnosis codes from public healthcare visits according to “International Statistical Classification of Diseases and Related Health Problems, tenth revision” (ICD-10). Due to reimbursement purposes, diagnosis code registration is mandatory in Skåne. Thus, SHR contains close to 100% assigned diagnosis codes per each healthcare visit from 1998 for inpatient care, and since 2004 also for outpatient care ( 21 ). The acquired diagnosis codes analysed in this study were: hypothyroidism (E03), thyrotoxicosis (E05.0), autoimmune thyroiditis (E06.3), coeliac disease (K90.0), type 1 diabetes mellitus (E10), vitiligo (L80), and alopecia areata (L63). To minimize the risk of including persons with an incorrectly registered autoimmune diagnosis, a person was considered to have a verified autoimmune disease if they were diagnosed with any of the above-mentioned conditions at one inpatient healthcare visit or had at least two registered diagnosis codes at two separate outpatient healthcare visits (primary and specialized outpatient care) with a physician. Statistical Analyses For the JIA cohort, a reference population with five individuals without JIA, matched for year of birth, sex, residential region, and for having at least one healthcare visit during the study period, has been established and used in previous studies ( 19 ). These references are used as comparators in the present study. Demographics of the study population is presented with descriptive statistics. Conditional Cox proportional hazard regression models are used for calculation of hazard ratios (HR) with 95% confidence interval (CI) for all the autoimmune diseases, and for coeliac disease and hypothyroidism separately. These conditions were chosen for separate analysis since they are easily screened for with blood samples. Date of JIA diagnosis was used as inclusion variable. JIA cases as well as references were followed until migration, death, diagnosis with an autoimmune disease, or end of study period 31 December 2019, whichever occurred first. Individuals with date of comorbid autoimmune disease before JIA diagnosis or within 90 days from JIA diagnosis were excluded, as were individuals lost to follow-up within the same period. Also, we chose not to include the years 1998–1999 in the statical analyses to secure exclusion of prevalent comorbid autoimmune cases prior to 1998. We believe that the majority of the Swedish patients with autoimmune diseases have regular check-ups with at least two years interval. In total, 14 individuals with JIA received an autoimmune diagnosis before or within 90 days from their JIA diagnosis, and 15 JIA cases were lost to follow-up before their JIA diagnosis. Among the reference population, 219 persons were excluded due to following causes; exclusion of their corresponding individual with JIA (n = 145), autoimmune diagnosis prior to study inclusion (n = 26), migration from the study area prior to study inclusion (n = 44), death prior to study inclusion (n = 2), and no available lost to follow-up date (n = 2). Correspondingly, 273 individuals with JIA and 1291 persons of the reference population were included in the conditional Cox proportional hazard regression analyses. Of the individuals with JIA, 208 were compared to five references, 56 to four references, and nine to three references. Statistical calculations were made using readxl, dplyr, lubridate, survival, survminer in R 3.6.2 software (R Foundation for Statistical Computing; https://www.r-project.org/ ), and Statistical Package for the Social Sciences (SPSS), version 27 (IBM Corp., Armonk, N.Y.). The study was conducted in accordance with the Declaration of Helsinki and approved by the Regional Ethical Board for southern Sweden (2011/379, 2013/192 and 2015/62) and the National Ethical Review Agency (2020–02935). Results Demographic information Among the 302 persons diagnosed with JIA between 2000–2010, persistent oligoarthritis was the most common subgroup (36.8%), followed by undifferentiated arthritis (14.6%) and rheumatoid factor (RF) negative polyarthritis (12.6%) (Table 1 ). Approximately half the cohort was ANA positive, and 29.6% was categorized into the proposed JIA subgroup of early onset arthritis with ANA positivity. Two thirds of the cohort were female and the median age at diagnosis was 9.4 years. In the JIA cohort, 58.9% had ever been treated with a DMARD, 58.6% with csDMARD (of which methotrexate had been prescribed to 93.2%), and 22.5% with bDMARD. Table 1 Demographic information Characteristics JIA cohort (n = 302) References (n = 1510) Female, n (%) 204 (67.5%) 1020 (67.5%) Age at JIA diagnosis or cohort entry in years, median (IQR) 9.4 (3.5–13.1) 9.4 (3.5–13.1) ANA positive, n (%) 150 (50.8%) n = 295 NA ANA positive early onset, n (%) 88 (29.6%) n = 297 NA ILAR category, n (%) Systemic arthritis 11 (3.6%) NA Oligoarthritis 145 (48.0%) NA Polyarthritis, RF- 38 (12.6%) NA Polyarthritis, RF+ 17 (5.6%) NA Psoriatic arthritis 23 (7.6%) NA Enthesitis-related arthritis 24 (7.9%) NA Undifferentiated arthritis 44 (14.6%) NA DMARD history, n (%) Any DMARD 178 (58.9%) NA csDMARD 177 (58.6%) NA bDMARD 68 (22.5%) NA Clinical and serological characteristics of the included 302 individuals with juvenile idiopathic arthritis (JIA) and 1510 references from the south-Swedish JIA cohort, diagnosed 2000–2010. Abbreviations: ANA: antinuclear antibodies, DMARD: disease-modifying antirheumatic drug, bDMARD: biological DMARD, csDMARD: conventional synthetic DMARD, ILAR: International League of Associations for Rheumatology, IQR: Interquartile range Autoimmune diagnosis was more common in the JIA group During the study period excluding the wash-out period (- 2 years - + 90 days after JIA diagnosis), 21 (7.7%) individuals with JIA were diagnosed with at least one of the autoimmune conditions; hypothyroidism, thyrotoxicosis, autoimmune thyroiditis, coeliac disease, type 1 diabetes mellitus, vitiligo, or alopecia areata after their JIA diagnosis. During the same period 43 (3.3%) of the reference population was diagnosed with an autoimmune diagnosis. Hypothyroidism was the most common autoimmune condition in both the JIA cohort (3.3%) and reference population (1.5%). Coeliac disease was the second most common comorbidity in the JIA cohort (2.6%), while coeliac disease (0.7%) and type 1 diabetes mellitus (0.7%) were equally the second most common among the references. Only one individual with JIA was diagnosed with thyrotoxicosis or vitiligo respectively, while none was diagnosed with autoimmune thyroiditis or alopecia areata during the follow-up period. In the JIA cohort, two (0.7%) individuals were diagnosed with more than one autoimmune condition during the study period, and five (0.4%) individuals in the reference population. A table with the number of individual autoimmune diagnoses is enclosed as Additional file 1 (see Additional file 1). Antinuclear antibodies were present in 15 (71.4%) of the individuals with autoimmune comorbidity in the JIA group, where ANA was detected after the autoimmune diagnosis in three cases. The number of ANA positive individuals in the reference population is unknown due to lack of information about their medical history. Individuals with JIA have increased risk of being diagnosed with autoimmune disease Hazard ratio for autoimmune disease in general was 2.01 (95% CI 1.16–3.51) (Figure 1) for the total cohort compared to the reference population. HR for autoimmune diseases was 1.98 (95% CI 1.08–3.62) for females and 2.24 (95% CI 0.56–8.99) for males. In the ANA positive JIA cases HR was 3.23 (95% CI 1.63–6.39). Similarly, in the group with ANA positive, early onset (£ 6 years) arthritis HR was significant (HR 2.78, 95% CI 1.09–7.07). In individuals with JIA and DMARD treatment HR was 3.44 (95% CI 1.79–6.60). ANA positivity and DMARD treatment was associated with further increased risk for autoimmune comorbidity in the JIA group To further explore predictors of comorbid autoimmune diagnosis in JIA, analyses of disease characteristics were repeated within the JIA cohort (Figure 2). ANA positivity and DMARD treatment significantly increased the risk of comorbid autoimmune conditions, HR 5.11 (95% CI 1.54–16.96) in the ANA positive subgroup and 7.23 (95% CI 1.65–31.70) in the group ever treated with DMARD. Age at JIA diagnosis and sex did not affect the risk of autoimmune comorbidity in the JIA group. The risk of being diagnosed with coeliac disease, but not hypothyroidism, was increased in JIA Since hypothyroidism and coeliac disease are conditions that can be asymptomatic and still be detected by blood sample screening, these conditions were chosen for separate analysis. Comparisons were made for the entire JIA cohort, and if possible, regarding population size, for sex, ANA positivity, and DMARD treatment. Hazard ratio for coeliac disease was 3.98 (95% CI 1.44–11.01) in the total JIA cohort, with further increase in the ANA positive subgroup (HR 5.49, 95% CI 1.47–20.55) as well as the subgroup ever treated with DMARD (HR 6.24, 95% CI 1.98–19.73) (Figure 3). There was no statistically significant HR in the analyses of hypothyroidism, neither in the total JIA cohort compared to the reference population, nor in subgroup analysis within the JIA cohort. Discussion In this study we showed that individuals with JIA diagnosed in the biological era in the population-based south-Swedish JIA cohort have an increased risk of being diagnosed with a comorbid autoimmune condition compared to age- and sex-matched references from the general population. ANA positive disease and DMARD treatment were associated with a further increased risk. Our results suggest a need of laboratory screening for autoimmune conditions, particularly coeliac disease, and urges physicians to investigate symptoms indicative of comorbid autoimmune disease in individuals with JIA. Individuals with manifest JIA were diagnosed with coeliac disease more than twice as often as the age- and sex-matched reference population. The presence of coeliac disease in our cohort is in line with previously published Swedish point prevalence in JIA of 2.8% by Öman, et al. In their study, they screened JIA patients with autoantibodies against tissue transglutaminase and confirmed the diagnosis with small intestine biopsies. Two out of six cases had asymptomatic coeliac disease. Their finding of 2.8% did not support screening with antibodies against tissue transglutaminase in individuals with JIA, since their point prevalence was close to the described prevalence in the general population. The authors did however not compare the results to an age- and sex-matched reference population, which might had changed their conclusion (11). The frequency of 2.6% in our study is lower than reported numbers from Italy (14, 16), although the risk of coeliac disease was increased among JIA cases compared to age- and sex-matched non-JIA controls from the general population (16). The prevalence of 0.7% coeliac disease in the reference population was lower than expected, likely due to our exclusion of individuals with the studied autoimmune conditions prior to inclusion. However, the same exclusion criteria were applied to the individuals with JIA and the somewhat low prevalence among the references emphasize that they should not be considered as general population. Undiagnosed coeliac disease might lead to severe adverse effects such as malnutrition and poor growth. The result from our study shows increased risk of coeliac disease after JIA diagnosis and indicates that screening routines for coeliac disease should be considered in the clinic. Hypothyroidism was diagnosed in 3.3% of the individuals in our JIA cohort, which was not significantly more often compared to the reference population. The presence of hypothyroidism in our study was lower than in a previously published Italian study (10.1%) (14), but higher than numbers reported from Finland (0.7%) (17). Our restriction to only include autoimmune conditions diagnosed post JIA diagnosis, contrary to the Italian study (14), may have contributed to the non-significant difference between JIA cases and the references. More importantly, in the Italian study the patients were actively screened for autoimmune comorbidity with blood test, thereby possibly diagnosing also subclinical, asymptomatic patients. Hypothyroidism is also more common in the adult than paediatric population and since our cohort is diagnosed 2000–2010, only a minor portion of the individuals were in their 30’ies at the end of the study period. A longer follow-up period can potentially increase the difference. Our finding of increased risk of autoimmune disease in ANA positive individuals with JIA compared to ANA negative is supported by other studies showing increased presence of ANA in autoimmune thyroid disease (22, 23). The mechanism behind the occurrence of ANA is not known, and ANA can be considered a general marker of autoimmune processes since many autoimmune diseases share common genes and pathophysiological processes. The increased risk in the ANA positive group might also reflect the paediatric distinction of this JIA subgroup compared to the other JIA subgroups with adult counterparts. This hypothesis is supported by the significantly increased risk of autoimmune comorbidities in the subgroup with ANA positive disease with early onset in our study. Interestingly, our study further emphasises a specifically increased risk of coeliac disease in individuals with ANA positive disease. To our knowledge, the association with ANA to the risk of comorbid coeliac disease in other autoimmune diseases has been analysed in two previous studies, indicating no increased risk of coeliac disease in ANA positive JIA (24) or ANA positive autoimmune thyroid disease (22). Our finding of increased risk for autoimmune conditions in the group treated with DMARD was interesting. This might reflect the group in the JIA cohort with more severe disease, hence more inflammation possibly also affecting other organs, but can also reflect treatment side effects or certain genetic risk factors. We lack information of the time relation between start of DMARD treatment and diagnosis of autoimmune comorbidity, as well as objective markers of inflammation such as active joint count, and the results must therefore be interpreted with great caution. Our study has some limitations. Diagnosis codes for comorbid autoimmune conditions were collected from the regional healthcare register SHR with data from 1998. The SHR did not have full regional coverage of diagnosis codes registered in outpatient care, especially in primary care, until 2004 (21). However, we believe the number of missed autoimmune cases to be few, since paediatric autoimmune conditions are primarily diagnosed in specialized healthcare facilities in Sweden. However, the lack of full coverage may have contributed to underestimation as well as overestimation of comorbid autoimmune diagnosis in JIA, depending on whether the missing diagnosis code was registered prior to or after JIA diagnosis. Another limitation is that the autoimmune diagnoses were not confirmed by a review of the medical records or with data on prescribed insulin, levothyroxine, or gluten free nutriments. Unfortunately, this was not possible for our study. To reduce the risk of overestimation as bias, we required that an individual had a registered autoimmune diagnosis at two separate outpatient visits or at one inpatient healthcare visit. The choice of two registered codes in outpatient care has previously been investigated by a medical record review with high validation of correct diagnostics for autoimmune diseases (25). An alternative explanation for the higher presence of autoimmune disease in our JIA cohort compared to references is that individuals in the JIA cohort have regular healthcare visits, increasing the risk of further diagnostics. To reduce this risk, autoimmune comorbidities registered within 90 days after JIA diagnosis were excluded due to the chance of finding such conditions during arthritis diagnostics. Moreover, the references were also selected on having at least one healthcare visit during follow-up, hence not excluding individuals with other autoimmune (not included in our statistical analyses) or inflammatory conditions, where comorbidities might be detected during laboratory diagnostic at disease onset. Further, a larger cohort would have enabled additional subgroup analysis, possibly identifying other predisposing factors for autoimmune comorbidities in JIA than ANA positive disease and DMARD treatment. There are also strengths to this study. We have a well-defined study population with validated cases of JIA, including all disease severities from mild to erosive and disabling, and all states of disease activity. The cases chosen for this study have all been diagnosed in the biologic era, making the results applicable to individuals with JIA diagnosed today. Finally, our study provides longitudinal results on cumulative incidence of autoimmune comorbidities with an exceptional follow-up up to 20 years after JIA diagnosis. Conclusions Individuals with JIA have a significantly increased risk of acquiring a second autoimmune diagnosis, especially coeliac disease, after their initial JIA diagnosis. Presence of ANA and treatment with DMARD are predictors of autoimmune comorbidity. Our results emphasize awareness in physicians of additional autoimmune disorders in individuals with JIA and advocate serological screening of autoimmune conditions during follow-up. How often and when to start this screening needs to be further evaluated. Abbreviations ANA: Antinuclear antibodies CI: Confidence interval DMARD: Disease-modifying antirheumatic drug bDMARD: Biological disease-modifying antirheumatic drug csDMARD: Conventional synthetic disease-modifying antirheumatic drug HR: Hazard ratio ICD: International Statistical Classification of Diseases and Related Health Problems ILAR: International League of Associations for Rheumatology IQR: Interquartile range JIA: Juvenile idiopathic arthritis SHR: Skåne Healthcare Register Declarations Ethics approval and consent to participate The study was approved by the Regional Ethical Review Board for southern Sweden (2011/379, 2013/192 and 2015/62) and the National Ethical Review Agency (2020–02935). Consent for publication Not applicable. Availability of data and materials The datasets generated and analysed during this current study are not publicly available as they contain information that could compromise research participant privacy. The data are available and anonymized from the corresponding author (AD) on reasonable request and appropriate permission from regulatory authorities. Competing interests The authors declare that they have no competing interest. Funding Open access funding provided by Lund university. This study was supported by grants from Thelma Zoega’s foundation (to AD), Greta and Johan Kock’s foundation (EB), The Samaritan foundation (EB), and by governmental funding of clinical research within the NHS (national health service) (EB). The funders had no role in the concept, design, or interpretation of data. Author’s contributions AD acquired, analysed, and interpreted the data and wrote the manuscript. HT assisted in the analysis and interpretation of data. ASJ collected the data from Skåne healthcare register. FK analysed and interpreted data. EB conceptualized the study, interpreted data and wrote the manuscript together with AD. All authors have reviewed and revised the manuscript. 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The risk of depression and anxiety is not increased in individuals with juvenile idiopathic arthritis – results from the south-Swedish juvenile idiopathic arthritis cohort. 2022. Population by region, marital status, age and sex. Year 1968-2022. Statistics Sweden. Available from: https://www.statistikdatabasen.scb.se/pxweb/en/ssd/START__BE__BE0101__BE0101A/BefolkningNy/. Accessed 25 Dec 2023. Löfvendahl S, Schelin MEC, Jöud A. The value of the Skåne Health-care Register: Prospectively collected individual-level data for population-based studies. Scand J Public Health. 2020;48(1):56-63. Segni M, Pucarelli I, Truglia S, Turriziani I, Serafinelli C, Conti F. High prevalence of antinuclear antibodies in children with thyroid autoimmunity. J Immunol Res. 2014;2014:150239. Torok KS, Arkachaisri T. Autoimmune thyroiditis in antinuclear antibody positive children without rheumatologic disease. Pediatr Rheumatol Online J. 2010;8:15. Naddei R, Di Gennaro S, Guarino A, Troncone R, Alessio M, Discepolo V. In a large Juvenile Idiopathic Arthritis (JIA) cohort, concomitant celiac disease is associated with family history of autoimmunity and a more severe JIA course: a retrospective study. Pediatr Rheumatol Online J. 2022;20(1):31. Löfvendahl S, Theander E, Svensson Å, Carlsson KS, Englund M, Petersson IF. Validity of diagnostic codes and prevalence of physician-diagnosed psoriasis and psoriatic arthritis in southern Sweden--a population-based register study. PLoS One. 2014;9(5):e98024. Supplementary Files Additionalfile1Dahlberg.docx Additional files: Additional file 1: File format: .docx. Title of data: “Additional file 1. The occurrence of autoimmune conditions.” Description of data: A table of the individual autoimmune conditions after juvenile idiopathic arthritis (JIA) diagnosis in the JIA cohort and age- and sex matched references. Cite Share Download PDF Status: Published Journal Publication published 19 Oct, 2024 Read the published version in Pediatric Rheumatology → Version 1 posted Editorial decision: Major revision 30 Jun, 2024 Reviewers agreed at journal 09 Jun, 2024 Reviewers invited by journal 22 May, 2024 Editor assigned by journal 22 May, 2024 First submitted to journal 20 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4448474","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":305513345,"identity":"13323939-b637-4a03-b304-e3f5af82539c","order_by":0,"name":"Alma Dahlberg","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABA0lEQVRIiWNgGAWjYDACdhDBxpDAJwFiVADxAeYG/FqYoVrYwFrOgLQwkqKFsY0ILfzN3IkfGMrs8tikm499/DpvmxzfAcY2CYY/Nji1SBzm3SzBcC65mE3mWPJs2W23jSVBWhjb0nBbc5h3A1ABc2KbRI4xs+S224kbwFoaDuPUIQ+05QdjWz1QS/5nZsk5t+s3QBz2H6cWg8O824C2HAbZwsz4seF2ggFYC9sBnFoMgVosEs4dT2yTOWbMzHDstuHMw4zNFoltyTi1yB3v3XzjQ1l1Yr9082PGHzW35fmONx+88eGPHW7vg0AClGbmAZNIIgQB4w9iVY6CUTAKRsGIAgBoXFWtoM1frAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0009-0006-6224-6585","institution":"Lund University Faculty of Medicine: Lunds universitet Medicinska fakulteten","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Alma","middleName":"","lastName":"Dahlberg","suffix":""},{"id":305513346,"identity":"225b1468-415b-421c-95a0-da608272ab9e","order_by":1,"name":"Helena Tydén","email":"","orcid":"","institution":"Lund University Faculty of Medicine: Lunds universitet Medicinska fakulteten","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Helena","middleName":"","lastName":"Tydén","suffix":""},{"id":305513347,"identity":"ad288e0f-0631-4675-a9a8-d37c3cf0df79","order_by":2,"name":"Anna Saxne Jöud","email":"","orcid":"","institution":"Lund University Faculty of Medicine: Lunds universitet Medicinska fakulteten","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Anna","middleName":"Saxne","lastName":"Jöud","suffix":""},{"id":305513348,"identity":"e342d1b8-ca7a-4192-895c-292c0c023e55","order_by":3,"name":"Fredrik Kahn","email":"","orcid":"","institution":"Lund University Faculty of Medicine: Lunds universitet Medicinska fakulteten","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Fredrik","middleName":"","lastName":"Kahn","suffix":""},{"id":305513349,"identity":"1e093322-575a-4504-91c4-ea1fa5242757","order_by":4,"name":"Elisabet Berthold","email":"","orcid":"","institution":"Lund University Faculty of Medicine: Lunds universitet Medicinska fakulteten","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Elisabet","middleName":"","lastName":"Berthold","suffix":""}],"badges":[],"createdAt":"2024-05-20 10:29:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4448474/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4448474/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12969-024-01030-x","type":"published","date":"2024-10-19T15:57:12+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":57949491,"identity":"c78026e1-8f5b-4539-b96e-9eba5ea70bbf","added_by":"auto","created_at":"2024-06-07 20:44:27","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":36757,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHazard ratios for comorbid autoimmune diseases in juvenile idiopathic arthritis (JIA) compared to references.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConditional Cox proportional hazard regression models were used for the calculation of hazard ratios (HR) with 95% confidence interval (CI) for the autoimmune diseases: hypothyroidism, thyrotoxicosis, autoimmune thyroiditis, coeliac disease, type 1 diabetes mellitus, vitiligo, or alopecia areata. In all analyses, the individuals in the JIA cohort were compared to age- and sex matched references without JIA. Subgroup analyses were conducted based on sex, antinuclear antibodies (ANA) status, ANA positive disease with onset before the age of six, and treatment with any disease-modifying antirheumatic drug (DMARD). The bars illustrate the 95% CIs with markers for HR. Number of individuals with comorbid autoimmune disease in the different analyses were in the JIA cohort; 18 in the total cohort, 15 in the female subgroup, 3 in the male subgroup, 14 in the ANA positive subgroup, 4 in the ANA negative subgroup, 7 in subgroup of the ANA positive disease with onset before the age of six, and 16 in the subgroup treated with any DMARD. Corresponding numbers were in the reference population; 42 in the total cohort, 36 in the female subgroup, 6 in the male subgroup, 20 in the reference subgroup to ANA positive disease, 22 in the reference subgroup to ANA negative disease, 12 in the reference subgroup to ANA positive disease with onset before the age of six, and 22 in the reference subgroup to treatment with any DMARD. Significant differences were found in the total JIA cohort, and in the subcategories of females, presence of ANA, ANA positive disease with onset before the age of six, and in the subgroup with DMARD treatment.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4448474/v1/5dfda688ff7eeb82e7adc2d2.png"},{"id":57949493,"identity":"b5bb4746-47a0-47ed-b61e-cc56d74e749a","added_by":"auto","created_at":"2024-06-07 20:44:27","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":37476,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHazard ratios for comorbid autoimmune disease in juvenile idiopathic arthritis (JIA) depending on disease characteristics.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConditional Cox proportional hazard regression models with hazard ratios (HR) and 95% confidence interval (CI) for the autoimmune conditions: hypothyroidism, thyrotoxicosis, autoimmune thyroiditis, coeliac disease, type 1 diabetes mellitus, vitiligo, or alopecia areata, stratified on the basic disease characteristics; age at JIA diagnosis, male sex, antinuclear antibodies (ANA) positivity, and treatment with disease-modifying antirheumatic drug (DMARD). The bars illustrate the 95% CIs with markers for HR. Number of individuals with comorbid autoimmune disease in the different analyses were in the JIA cohort; 18 in the total cohort, 3 in the male subgroup, 14 in the ANA positive subgroup, and 16 in the subgroup treated with any DMARD. In the JIA cohort, DMARD treatment and ANA positivity was associated with a significantly increased risk of a comorbid autoimmune disease, respectively.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4448474/v1/29a6ade3cd7db9ea3886d48d.png"},{"id":57949700,"identity":"59a6cd6c-f4d1-44ac-8249-17b2b5656b88","added_by":"auto","created_at":"2024-06-07 20:52:27","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":93290,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHazard ratios for comorbid coeliac disease in juvenile idiopathic arthritis (JIA) compared to references.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConditional Cox proportional hazard regression models were used for the calculation of hazard ratios (HR) with 95% confidence interval (CI) for coeliac disease. In all analyses, the individuals in the JIA cohort were compared to age- and sex matched references without JIA. Subgroup analyses were conducted based on sex, antinuclear antibodies (ANA) status, ANA positive disease with onset before the age of six, and treatment with any disease-modifying antirheumatic drug (DMARD). The bars illustrate the 95% CIs with markers for HR. Number of individuals with comorbid coeliac disease in the different analyses were in the JIA cohort; 7 in the total cohort, 6 in the female subgroup, 1 in the male subgroup, 5 in the ANA positive subgroup, 2 in the ANA negative subgroup, 3 in the subgroup of ANA positive disease with onset before the age of six, and 7 in the subgroup treated with any DMARD. Corresponding numbers were in the reference population; 9 in the total cohort, 7 in the female subgroup, 2 in the male subgroup, 4 in the reference subgroup to ANA positive disease, 5 in the reference subgroup to ANA negative disease, 4 in the reference subgroup to ANA positive disease with onset before the age of six, and 6 in the reference subgroup to treatment with any DMARD. Significant differences were found in the total JIA population, and in the subcategories of females, presence of ANA, and in the subgroup with DMARD treatment.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4448474/v1/944108c1c25270ca4d0e4bf1.png"},{"id":67148914,"identity":"8fb1df17-dca9-42bf-8812-06b9f583de5f","added_by":"auto","created_at":"2024-10-21 16:09:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":705425,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4448474/v1/2ea3c4df-eb14-4e93-8c57-8c9682769ccf.pdf"},{"id":57949490,"identity":"1c7ff4a4-ec5e-4cf3-9d0b-5a70bd9f558c","added_by":"auto","created_at":"2024-06-07 20:44:27","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":15540,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdditional files:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdditional file 1: File format: .docx. Title of data: “Additional file 1. The occurrence of autoimmune conditions.” Description of data: A table of the individual autoimmune conditions after juvenile idiopathic arthritis (JIA) diagnosis in the JIA cohort and age- and sex matched references.\u003c/p\u003e","description":"","filename":"Additionalfile1Dahlberg.docx","url":"https://assets-eu.researchsquare.com/files/rs-4448474/v1/e6abf6d023ed69657b36d92d.docx"}],"financialInterests":"","formattedTitle":"Screening for comorbid autoimmune disease should be considered in children with ANA positive juvenile idiopathic arthritis – results from the south-Swedish juvenile idiopathic arthritis cohort","fulltext":[{"header":"Background","content":"\u003cp\u003eJuvenile idiopathic arthritis (JIA) serves as an umbrella term for seven heterogenous arthritis subcategories, defined by joint inflammation with duration for at least six weeks, onset before the 16th birthday and unknown aetiology (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The JIA subcategories are categorized by the number of inflamed joints, presence of extraarticular organ involvement, and serological features. The disease can hence present in various ways but share the feature of arthritis, possibly causing pain and mobility limitations leading to short- and long-term consequences. The present definition and classification criteria were proposed by the International League of Associations for Rheumatology (ILAR) and have been the international diagnostic standard since 2001 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Due to heterogenous presentation in the same JIA subgroup, and since the current JIA criteria separate children from their adult counterparts by its specific paediatric arthritis definition, new subgroups have been proposed. A unique childhood specific subgroup without a clear adult equivalent is suggested, defined by presence of antinuclear antibodies (ANA) in early onset arthritis (diagnosis before the age of six), independent of the number of affected joints (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eJIA is the most common paediatric rheumatic disease with a reported incidence rate estimated to 12.8/100 000 children/year in southern Sweden (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Both genetic and environmental factors are believed to be involved in the pathogenesis (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Current treatment guidelines include non-steroid anti-inflammatory drugs, intra-articular corticosteroid injections and disease-modifying anti-rheumatic drugs (DMARD) (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Biological DMARDs (bDMARD) have been available as treatment for JIA in Sweden since 1999. JIA is a chronic disease with long-term follow-up data showing approximately 40% of the individuals having active disease or inactive disease on medication after 18 and 30 years respectively (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Thus, despite the biological era, a considerable number of individuals with JIA still have active disease persisting into adulthood. It is poorly established what impact JIA have on adult life in terms of risk of comorbidities due to autoimmunity, persistent inflammation, and/or immunomodulatory treatment.\u003c/p\u003e \u003cp\u003eAutoimmune disorders are more common conditions in Northern Europe as compared to other countries (\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). The estimated European prevalence of hypothyroidism in the adult population is 3\u0026ndash;5% (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) and the Swedish prevalence of coeliac disease is approximately 2% in children (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Since genetic factors contribute to the development of autoimmune disease, autoimmune conditions tend to co-occur. Due to differences in study design and number of study participants, previous results on autoimmune comorbidity in JIA are conflicting and screening for autoimmune conditions in JIA is not uniformly recommended (\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). However, some studies implicate an elevated risk of comorbid autoimmune diseases in JIA (\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Reports from Finland suggest a 5-fold increased risk of type 1 diabetes mellitus, coeliac disease, and hypothyroidism in children with JIA compared to the general population (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e), in contrast to Swedish results showing prevalence of coeliac disease among children with JIA similar to that in the general population, thus not recommending screening for coeliac disease in Swedish individuals with JIA (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). However, screening for disease specific autoantibodies could detect organ-specific autoimmunity before the development of clinical autoimmune disease, potentially preventing morbidity and irreversible tissue damage. A recent multicentre registry study proposed the benefit of yearly serological screening for autoimmune thyroid disease in female ANA positive individuals with JIA and family history of autoimmune thyroid disease (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Therefore, before establishing uniform clinical guidelines regarding screening for autoimmune comorbidities in JIA with potential benefits of early diagnostic detection of a comorbid condition, more research is still needed.\u003c/p\u003e \u003cp\u003eThe overall purpose of this study was to investigate whether persons with JIA have an increased risk of being diagnosed with a comorbid autoimmune condition after their JIA diagnosis in a validated population-based JIA cohort in southern Sweden, compared to a reference population matched for age, sex and residential region. The study further aimed to explore if the factors; sex, immunological data, and DMARD treatment, could be used as predictors of comorbid autoimmune diagnosis.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy area\u003c/h2\u003e \u003cp\u003eFor the study of autoimmune comorbidities in JIA we used a pre-existing south-Swedish JIA cohort with individuals collected in Sk\u0026aring;ne, the southernmost region of Sweden (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). In 2019, Sk\u0026aring;ne was the third largest region by population in Sweden with 1 377 827 inhabitants, constituting 13.3% of the Swedish population. Children aged 0\u0026ndash;15 years accounted for 19.4% of the population (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). The study area has one university hospital, nine other hospital-associated paediatric outpatient facilities, and six private paediatric outpatient facilities. The healthcare in Sweden is tax-funded, and the paediatric care is subsidized for all children. Additionally, children undergo regular controls both at child healthcare and in school. These factors, combined with mandatory diagnosis registration, diminishes the risk of missing to include persons in a population-based cohort, since symptoms suspicious of JIA rarely are neglected or missed at primary healthcare facilities.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eFor this study, 302 individuals with a validated JIA diagnosis with date of diagnosis between 1 January 2000 and 31 December 2010 were included from the previously published south-Swedish JIA cohort. The south-Swedish JIA cohort is a population-based cohort and consists of retrospectively collected JIA cases validated through medical record review (process described in detail in previous publications) (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Information about immunological data and annually prescribed pharmacological treatment was collected during the case collection process. Methotrexate, chloroquine phosphate, sulfasalazine, azathioprine, gold, mycophenolate, cyclosporine, penicillamine and chlorambucil was registered as conventional synthetic DMARDs (csDMARD), while tumor necrosis factor inhibitors, anakinra, tocilizumab and ustekinumab was registered as bDMARD.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData source\u003c/h2\u003e \u003cp\u003eWe acquired registered diagnoses for autoimmune conditions between 1 January 1998 and 31 December 2019 from the regional administrative healthcare register, Sk\u0026aring;ne Healthcare Register (SHR). SHR includes information from healthcare visits in primary care, as well as from in- and outpatient hospital care visits in the region. The register was established in 1998 and contains diagnosis codes from public healthcare visits according to \u0026ldquo;International Statistical Classification of Diseases and Related Health Problems, tenth revision\u0026rdquo; (ICD-10). Due to reimbursement purposes, diagnosis code registration is mandatory in Sk\u0026aring;ne. Thus, SHR contains close to 100% assigned diagnosis codes per each healthcare visit from 1998 for inpatient care, and since 2004 also for outpatient care (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe acquired diagnosis codes analysed in this study were: hypothyroidism (E03), thyrotoxicosis (E05.0), autoimmune thyroiditis (E06.3), coeliac disease (K90.0), type 1 diabetes mellitus (E10), vitiligo (L80), and alopecia areata (L63). To minimize the risk of including persons with an incorrectly registered autoimmune diagnosis, a person was considered to have a verified autoimmune disease if they were diagnosed with any of the above-mentioned conditions at one inpatient healthcare visit or had at least two registered diagnosis codes at two separate outpatient healthcare visits (primary and specialized outpatient care) with a physician.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analyses\u003c/h2\u003e \u003cp\u003eFor the JIA cohort, a reference population with five individuals without JIA, matched for year of birth, sex, residential region, and for having at least one healthcare visit during the study period, has been established and used in previous studies (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). These references are used as comparators in the present study.\u003c/p\u003e \u003cp\u003eDemographics of the study population is presented with descriptive statistics. Conditional Cox proportional hazard regression models are used for calculation of hazard ratios (HR) with 95% confidence interval (CI) for all the autoimmune diseases, and for coeliac disease and hypothyroidism separately. These conditions were chosen for separate analysis since they are easily screened for with blood samples. Date of JIA diagnosis was used as inclusion variable. JIA cases as well as references were followed until migration, death, diagnosis with an autoimmune disease, or end of study period 31 December 2019, whichever occurred first. Individuals with date of comorbid autoimmune disease before JIA diagnosis or within 90 days from JIA diagnosis were excluded, as were individuals lost to follow-up within the same period. Also, we chose not to include the years 1998\u0026ndash;1999 in the statical analyses to secure exclusion of prevalent comorbid autoimmune cases prior to 1998. We believe that the majority of the Swedish patients with autoimmune diseases have regular check-ups with at least two years interval. In total, 14 individuals with JIA received an autoimmune diagnosis before or within 90 days from their JIA diagnosis, and 15 JIA cases were lost to follow-up before their JIA diagnosis. Among the reference population, 219 persons were excluded due to following causes; exclusion of their corresponding individual with JIA (n\u0026thinsp;=\u0026thinsp;145), autoimmune diagnosis prior to study inclusion (n\u0026thinsp;=\u0026thinsp;26), migration from the study area prior to study inclusion (n\u0026thinsp;=\u0026thinsp;44), death prior to study inclusion (n\u0026thinsp;=\u0026thinsp;2), and no available lost to follow-up date (n\u0026thinsp;=\u0026thinsp;2). Correspondingly, 273 individuals with JIA and 1291 persons of the reference population were included in the conditional Cox proportional hazard regression analyses. Of the individuals with JIA, 208 were compared to five references, 56 to four references, and nine to three references.\u003c/p\u003e \u003cp\u003eStatistical calculations were made using readxl, dplyr, lubridate, survival, survminer in R 3.6.2 software (R Foundation for Statistical Computing; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.r-project.org/\u003c/span\u003e\u003cspan address=\"https://www.r-project.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), and Statistical Package for the Social Sciences (SPSS), version 27 (IBM Corp., Armonk, N.Y.).\u003c/p\u003e \u003cp\u003e The study was conducted in accordance with the Declaration of Helsinki and approved by the Regional Ethical Board for southern Sweden (2011/379, 2013/192 and 2015/62) and the National Ethical Review Agency (2020\u0026ndash;02935).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eDemographic information\u003c/h2\u003e \u003cp\u003eAmong the 302 persons diagnosed with JIA between 2000\u0026ndash;2010, persistent oligoarthritis was the most common subgroup (36.8%), followed by undifferentiated arthritis (14.6%) and rheumatoid factor (RF) negative polyarthritis (12.6%) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Approximately half the cohort was ANA positive, and 29.6% was categorized into the proposed JIA subgroup of early onset arthritis with ANA positivity. Two thirds of the cohort were female and the median age at diagnosis was 9.4 years. In the JIA cohort, 58.9% had ever been treated with a DMARD, 58.6% with csDMARD (of which methotrexate had been prescribed to 93.2%), and 22.5% with bDMARD.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic information\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eJIA cohort (n\u0026thinsp;=\u0026thinsp;302)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReferences (n\u0026thinsp;=\u0026thinsp;1510)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e204 (67.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1020 (67.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at JIA diagnosis or cohort entry in years, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.4 (3.5\u0026ndash;13.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.4 (3.5\u0026ndash;13.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eANA positive, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e150 (50.8%) \u003cem\u003en\u0026thinsp;=\u003c/em\u003e\u0026thinsp;295\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eANA positive early onset, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e88 (29.6%) \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;297\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eILAR category, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eSystemic arthritis\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (3.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eOligoarthritis\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e145 (48.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePolyarthritis, RF-\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (12.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePolyarthritis, RF+\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (5.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePsoriatic arthritis\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (7.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eEnthesitis-related arthritis\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (7.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eUndifferentiated arthritis\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44 (14.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDMARD history, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eAny DMARD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e178 (58.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ecsDMARD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e177 (58.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ebDMARD\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68 (22.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eClinical and serological characteristics of the included 302 individuals with juvenile idiopathic arthritis (JIA) and 1510 references from the south-Swedish JIA cohort, diagnosed 2000\u0026ndash;2010.\u003c/p\u003e \u003c/div\u003e\n\u003cp\u003e\u003cem\u003eAbbreviations:\u0026nbsp;\u003c/em\u003eANA: antinuclear antibodies, DMARD: disease-modifying antirheumatic drug, bDMARD: biological DMARD, csDMARD: conventional synthetic DMARD, ILAR: International League of Associations for Rheumatology, IQR: Interquartile range \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAutoimmune diagnosis was more common in the JIA group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the study period excluding the wash-out period (- 2 years - + 90 days after JIA diagnosis), 21 (7.7%) individuals with JIA were diagnosed with at least one of the autoimmune conditions; hypothyroidism, thyrotoxicosis, autoimmune thyroiditis, coeliac disease, type 1 diabetes mellitus, vitiligo, or alopecia areata after their JIA diagnosis. During the same period 43 (3.3%) of the reference population was diagnosed with an autoimmune diagnosis. Hypothyroidism was the most common autoimmune condition in both the JIA cohort (3.3%) and reference population (1.5%). Coeliac disease was the second most common comorbidity in the JIA cohort (2.6%), while coeliac disease (0.7%) and type 1 diabetes mellitus (0.7%) were equally the second most common among the references. Only one individual with JIA was diagnosed with thyrotoxicosis or vitiligo respectively, while none was diagnosed with autoimmune thyroiditis or alopecia areata during the follow-up period. In the JIA cohort, two (0.7%) individuals were diagnosed with more than one autoimmune condition during the study period, and five (0.4%) individuals in the reference population. A table with the number of individual autoimmune diagnoses is enclosed as Additional file 1 (see Additional file 1).\u003c/p\u003e\n\u003cp\u003eAntinuclear antibodies were present in 15 (71.4%) of the individuals with autoimmune comorbidity in the JIA group, where ANA was detected after the autoimmune diagnosis in three cases. The number of ANA positive individuals in the reference population is unknown due to lack of information about their medical history.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIndividuals with JIA have increased risk of being diagnosed with autoimmune disease\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHazard ratio for autoimmune disease in general was 2.01 (95% CI 1.16\u0026ndash;3.51) (Figure 1) for the total cohort compared to the reference population. HR for autoimmune diseases was 1.98 (95% CI 1.08\u0026ndash;3.62) for females and 2.24 (95% CI 0.56\u0026ndash;8.99) for males. In the ANA positive JIA cases HR was 3.23 (95% CI 1.63\u0026ndash;6.39). Similarly, in the group with ANA positive, early onset (\u0026pound;\u0026nbsp;6 years) arthritis HR was significant (HR 2.78, 95% CI 1.09\u0026ndash;7.07). In individuals with JIA and DMARD treatment HR was 3.44 (95% CI 1.79\u0026ndash;6.60).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eANA positivity and DMARD treatment was associated with further increased risk for autoimmune comorbidity in the JIA group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo further explore predictors of comorbid autoimmune diagnosis in JIA, analyses of disease characteristics were repeated within the JIA cohort (Figure 2). ANA positivity and DMARD treatment significantly increased the risk of comorbid autoimmune conditions, HR 5.11 (95% CI 1.54\u0026ndash;16.96) in the ANA positive subgroup and 7.23 (95% CI 1.65\u0026ndash;31.70) in the group ever treated with DMARD. Age at JIA diagnosis and sex did not affect the risk of autoimmune comorbidity in the JIA group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe risk of being diagnosed with coeliac disease, but not hypothyroidism, was increased in JIA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSince hypothyroidism and coeliac disease are conditions that can be asymptomatic and still be detected by blood sample screening, these conditions were chosen for separate analysis. Comparisons were made for the entire JIA cohort, and if possible, regarding population size, for sex, ANA positivity, and DMARD treatment. Hazard ratio for coeliac disease was 3.98 (95% CI 1.44\u0026ndash;11.01) in the total JIA cohort, with further increase in the ANA positive subgroup (HR 5.49, 95% CI 1.47\u0026ndash;20.55) as well as the subgroup ever treated with DMARD (HR 6.24, 95% CI 1.98\u0026ndash;19.73) (Figure 3). There was no statistically significant HR in the analyses of hypothyroidism, neither in the total JIA cohort compared to the reference population, nor in subgroup analysis within the JIA cohort.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study we showed that individuals with JIA diagnosed in the biological era in the population-based south-Swedish JIA cohort have an increased risk of being diagnosed with a comorbid autoimmune condition compared to age- and sex-matched references from the general population.\u0026nbsp;ANA positive disease and DMARD treatment were associated with a further increased risk.\u0026nbsp;Our results suggest a need of laboratory screening for autoimmune conditions, particularly coeliac disease, and urges physicians to investigate symptoms indicative of comorbid autoimmune disease in individuals with JIA.\u003c/p\u003e\n\u003cp\u003eIndividuals with manifest JIA were diagnosed with coeliac disease more than twice as often as the age- and sex-matched reference population.\u0026nbsp;The presence of coeliac disease in our cohort is in line with previously published Swedish point prevalence in JIA of 2.8% by Öman, et al.\u0026nbsp;In their study, they screened JIA patients with autoantibodies against tissue transglutaminase and confirmed the diagnosis with small intestine biopsies. Two out of six cases had asymptomatic coeliac disease. Their finding of 2.8% did not support screening with antibodies against tissue transglutaminase in individuals with JIA, since their point prevalence was close to the described prevalence in the general population. The authors did however not compare the results to an age- and sex-matched reference population, which might had changed their conclusion (11).\u0026nbsp;The frequency of 2.6% in our study is lower than reported numbers from Italy\u0026nbsp;(14, 16), although the risk of coeliac disease was increased among JIA cases compared to\u0026nbsp;age- and sex-matched non-JIA controls from the general population (16). The prevalence of 0.7% coeliac disease in the reference population was lower than expected, likely due to our exclusion of individuals with the studied autoimmune conditions prior to inclusion. However, the same exclusion criteria were applied to the individuals with JIA and the somewhat low prevalence among the references emphasize that they should not be considered as general population. Undiagnosed coeliac disease might lead to severe adverse effects such as malnutrition and poor growth. The result from our study shows increased risk of coeliac disease after JIA diagnosis and indicates that screening routines for coeliac disease should be considered in the clinic.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHypothyroidism was diagnosed in 3.3% of the individuals in our JIA cohort, which was not significantly more often compared to the reference population. The presence of hypothyroidism in our study was lower than in a previously published Italian study (10.1%) (14), but higher than numbers reported from Finland (0.7%) (17). Our restriction to only include autoimmune conditions diagnosed post JIA diagnosis, contrary to the Italian study (14), may have contributed to the non-significant difference between JIA cases and the references. More importantly, in the Italian study the patients were actively screened for autoimmune comorbidity with blood test, thereby possibly diagnosing also subclinical, asymptomatic patients. Hypothyroidism is also more common in the adult than\u0026nbsp;paediatric\u0026nbsp;population and since our cohort is diagnosed 2000–2010, only a minor portion of the individuals were in their 30’ies at the end of the study period. A longer follow-up period can potentially increase the difference.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur finding of increased risk of autoimmune disease in ANA positive individuals with JIA compared to ANA negative is supported by other studies showing increased presence of ANA in autoimmune thyroid disease (22, 23). The mechanism behind the occurrence of ANA is not known, and ANA can be considered a general marker of autoimmune processes since many autoimmune diseases share common genes and pathophysiological processes. The increased risk in the ANA positive group might also reflect the paediatric distinction of this JIA subgroup compared to the other JIA subgroups with adult counterparts. This hypothesis is supported by the significantly increased risk of autoimmune comorbidities in the subgroup with ANA positive disease with early onset in our study.\u003c/p\u003e\n\u003cp\u003eInterestingly, our study further emphasises a specifically increased risk of coeliac disease in individuals with ANA positive disease. To our knowledge, the association with ANA to the risk of comorbid coeliac disease in other autoimmune diseases has been analysed in two previous studies, indicating no increased risk of coeliac disease in ANA positive JIA (24) or ANA positive autoimmune thyroid disease (22).\u003c/p\u003e\n\u003cp\u003eOur finding of increased risk for autoimmune conditions in the group treated with DMARD was interesting. This might reflect the group in the JIA cohort with more severe disease, hence more inflammation possibly also affecting other organs, but can also reflect treatment side effects or certain genetic risk factors. We lack information of the time relation between start of DMARD treatment and diagnosis of autoimmune comorbidity, as well as objective markers of inflammation such as active joint count, and the results must therefore be interpreted with great caution.\u003c/p\u003e\n\u003cp\u003eOur study has some limitations. Diagnosis codes for comorbid autoimmune conditions were collected from the regional healthcare register SHR with data from 1998. The SHR did not have full regional coverage of diagnosis codes registered in outpatient care, especially in primary care, until 2004 (21). However, we believe the number of missed autoimmune cases to be few, since\u0026nbsp;paediatric\u0026nbsp;autoimmune conditions are primarily diagnosed in specialized healthcare facilities in Sweden. However, the lack of full coverage may have contributed to underestimation as well as overestimation of comorbid autoimmune diagnosis in JIA, depending on whether the missing diagnosis code was registered prior to or after JIA diagnosis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAnother limitation is that the autoimmune diagnoses were not confirmed by a review of the medical records or with data on prescribed insulin, levothyroxine, or gluten free nutriments. Unfortunately, this was not possible for our study. To reduce the risk of overestimation as bias, we required that an individual had a registered autoimmune diagnosis at two separate outpatient visits or at one inpatient healthcare visit. The choice of two registered codes in outpatient care has previously been investigated by a medical record review with high validation of correct diagnostics for autoimmune diseases (25).\u003c/p\u003e\n\u003cp\u003eAn alternative explanation for the higher presence of autoimmune disease in our JIA cohort compared to references is that individuals in the JIA cohort have regular healthcare visits, increasing the risk of further diagnostics. To reduce this risk, autoimmune comorbidities registered within 90 days after JIA diagnosis were excluded due to the chance of finding such conditions during arthritis diagnostics. Moreover, the references were also selected on having at least one healthcare visit during follow-up, hence not excluding individuals with other autoimmune (not included in our statistical analyses) or inflammatory conditions, where comorbidities might be detected during laboratory diagnostic at disease onset.\u003c/p\u003e\n\u003cp\u003eFurther, a larger cohort would have enabled additional subgroup analysis, possibly identifying other predisposing factors for autoimmune comorbidities in JIA than ANA positive disease and DMARD treatment.\u003c/p\u003e\n\u003cp\u003eThere are also strengths to this study. We have a well-defined study population with validated cases of JIA, including all disease severities from mild to erosive and disabling, and all states of disease activity. The cases chosen for this study have all been diagnosed in the biologic era, making the results applicable to individuals with JIA diagnosed today. Finally, our study provides longitudinal results on cumulative incidence of autoimmune comorbidities with an exceptional follow-up up to 20 years after JIA diagnosis.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIndividuals with JIA have a significantly increased risk of acquiring a second autoimmune diagnosis, especially coeliac disease, after their initial JIA diagnosis. Presence of ANA and treatment with DMARD are predictors of autoimmune comorbidity. Our results emphasize awareness in physicians of additional autoimmune disorders in individuals with JIA and advocate serological screening of autoimmune conditions during follow-up. How often and when to start this screening needs to be further evaluated.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eANA:\u0026nbsp;Antinuclear antibodies\u003c/p\u003e\n\u003cp\u003eCI:\u0026nbsp;Confidence interval\u003c/p\u003e\n\u003cp\u003eDMARD:\u0026nbsp;Disease-modifying antirheumatic drug\u003c/p\u003e\n\u003cp\u003ebDMARD:\u0026nbsp;Biological disease-modifying antirheumatic drug\u003c/p\u003e\n\u003cp\u003ecsDMARD:\u0026nbsp;Conventional synthetic disease-modifying antirheumatic drug\u003c/p\u003e\n\u003cp\u003eHR: Hazard ratio\u003c/p\u003e\n\u003cp\u003eICD:\u0026nbsp;International Statistical Classification of Diseases and Related Health Problems\u003c/p\u003e\n\u003cp\u003eILAR:\u0026nbsp;International League of Associations for Rheumatology\u003c/p\u003e\n\u003cp\u003eIQR:\u0026nbsp;Interquartile range\u003c/p\u003e\n\u003cp\u003eJIA: Juvenile idiopathic arthritis\u003c/p\u003e\n\u003cp\u003eSHR: Skåne Healthcare Register\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Regional Ethical Review Board for southern Sweden (2011/379, 2013/192 and 2015/62) and the National Ethical Review Agency (2020\u0026ndash;02935).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analysed during this current study are not publicly available as they contain information that could compromise research participant privacy. The data are available and anonymized from the corresponding author (AD) on reasonable request and appropriate permission from regulatory authorities.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOpen access funding provided by Lund university. This study was supported by grants from Thelma Zoega\u0026rsquo;s foundation (to AD), Greta and Johan Kock\u0026rsquo;s foundation (EB), The Samaritan foundation (EB), and by governmental funding of clinical research within the NHS (national health service) (EB). The funders had no role in the concept, design, or interpretation of data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAD acquired, analysed, and interpreted the data and wrote the manuscript. HT assisted in the analysis and interpretation of data. ASJ collected the data from Sk\u0026aring;ne healthcare register. FK analysed and interpreted data. EB conceptualized the study, interpreted data and wrote the manuscript together with AD. All authors have reviewed and revised the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRavelli A, Martini A. Juvenile idiopathic arthritis. Lancet. 2007;369(9563):767-78.\u003c/li\u003e\n\u003cli\u003ePetty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31(2):390-2.\u003c/li\u003e\n\u003cli\u003eMartini A, Ravelli A, Avcin T, Beresford MW, Burgos-Vargas R, Cuttica R, et al. Toward New Classification Criteria for Juvenile Idiopathic Arthritis: First Steps, Pediatric Rheumatology International Trials Organization International Consensus. J Rheumatol. 2019;46(2):190-7.\u003c/li\u003e\n\u003cli\u003eNigrovic PA, Colbert RA, Holers VM, Ozen S, Ruperto N, Thompson SD, et al. Biological classification of childhood arthritis: roadmap to a molecular nomenclature. Nat Rev Rheumatol. 2021;17(5):257-69.\u003c/li\u003e\n\u003cli\u003eBerthold E, M\u0026aring;nsson B, Kahn R. Outcome in juvenile idiopathic arthritis: a population-based study from Sweden. Arthritis Res Ther. 2019;21(1):218.\u003c/li\u003e\n\u003cli\u003eGlerup M, Rypdal V, Arnstad ED, Ekelund M, Peltoniemi S, Aalto K, et al. Long-Term Outcomes in Juvenile Idiopathic Arthritis: Eighteen Years of Follow-Up in the Population-Based Nordic Juvenile Idiopathic Arthritis Cohort. Arthritis Care Res (Hoboken). 2020;72(4):507-16.\u003c/li\u003e\n\u003cli\u003eSelvaag AM, Aulie HA, Lilleby V, Flat\u0026oslash; B. Disease progression into adulthood and predictors of long-term active disease in juvenile idiopathic arthritis. Ann Rheum Dis. 2016;75(1):190-5.\u003c/li\u003e\n\u003cli\u003ePatterson CC, Karuranga S, Salpea P, Saeedi P, Dahlquist G, Soltesz G, et al. Worldwide estimates of incidence, prevalence and mortality of type 1 diabetes in children and adolescents: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:107842.\u003c/li\u003e\n\u003cli\u003eSingh P, Arora A, Strand TA, Leffler DA, Catassi C, Green PH, et al. Global Prevalence of Celiac Disease: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2018;16(6):823-36.e2.\u003c/li\u003e\n\u003cli\u003eGarmendia Madariaga A, Santos Palacios S, Guill\u0026eacute;n-Grima F, Galofr\u0026eacute; JC. The incidence and prevalence of thyroid dysfunction in Europe: a meta-analysis. J Clin Endocrinol Metab. 2014;99(3):923-31.\u003c/li\u003e\n\u003cli\u003e\u0026Ouml;man A, Hansson T, Carlsson M, Berntson L. Evaluation of screening for coeliac disease in children with juvenile idiopathic arthritis. Acta Paediatr. 2019;108(4):688-93.\u003c/li\u003e\n\u003cli\u003eSchulz C, Fuehner S, Schl\u0026uuml;ter B, Fobker M, Sengler C, Klotsche J, et al. Prevalence of autoantibodies in patients with juvenile idiopathic arthritis: results from the German inception cohort ICON-JIA. Pediatr Rheumatol Online J. 2022;20(1):8.\u003c/li\u003e\n\u003cli\u003eSimon TA, Harikrishnan GP, Kawabata H, Singhal S, Brunner HI, Lovell DJ. Prevalence of co-existing autoimmune disease in juvenile idiopathic arthritis: a cross-sectional study. Pediatr Rheumatol Online J. 2020;18(1):43.\u003c/li\u003e\n\u003cli\u003eTronconi E, Miniaci A, Pession A. The autoimmune burden in juvenile idiopathic arthritis. Ital J Pediatr. 2017;43(1):56.\u003c/li\u003e\n\u003cli\u003eSchenck S, Rosenbauer J, Niewerth M, Klotsche J, Minden K, Schwarz T, et al. Comorbidity of Type 1 Diabetes Mellitus in Patients with Juvenile Idiopathic Arthritis. J Pediatr. 2018;192:196-203.\u003c/li\u003e\n\u003cli\u003eStagi S, Giani T, Simonini G, Falcini F. Thyroid function, autoimmune thyroiditis and coeliac disease in juvenile idiopathic arthritis. Rheumatology (Oxford). 2005;44(4):517-20.\u003c/li\u003e\n\u003cli\u003ePohjankoski H, Kautiainen H, Kotaniemi K, Korppi M, Savolainen A. Autoimmune diseases in children with juvenile idiopathic arthritis. Scand J Rheumatol. 2010;39(5):435-6.\u003c/li\u003e\n\u003cli\u003evan Straalen JW, Baas L, Giancane G, Grebenkina L, Brunner J, Vega-Cornejo G, et al. Juvenile idiopathic arthritis patients with positive family history of autoimmune thyroid disease might benefit from serological screening: analysis of the international Pharmachild registry. Pediatr Rheumatol Online J. 2023;21(1):19.\u003c/li\u003e\n\u003cli\u003eBerthold E, Dahlberg A, J\u0026ouml;ud A, Tyd\u0026eacute;n H, M\u0026aring;nsson B, Kahn F, et al. The risk of depression and anxiety is not increased in individuals with juvenile idiopathic arthritis \u0026ndash; results from the south-Swedish juvenile idiopathic arthritis cohort. 2022.\u003c/li\u003e\n\u003cli\u003ePopulation by region, marital status, age and sex. Year 1968-2022. Statistics Sweden. Available from: https://www.statistikdatabasen.scb.se/pxweb/en/ssd/START__BE__BE0101__BE0101A/BefolkningNy/. Accessed 25 Dec 2023. \u003c/li\u003e\n\u003cli\u003eL\u0026ouml;fvendahl S, Schelin MEC, J\u0026ouml;ud A. The value of the Sk\u0026aring;ne Health-care Register: Prospectively collected individual-level data for population-based studies. Scand J Public Health. 2020;48(1):56-63.\u003c/li\u003e\n\u003cli\u003eSegni M, Pucarelli I, Truglia S, Turriziani I, Serafinelli C, Conti F. High prevalence of antinuclear antibodies in children with thyroid autoimmunity. J Immunol Res. 2014;2014:150239.\u003c/li\u003e\n\u003cli\u003eTorok KS, Arkachaisri T. Autoimmune thyroiditis in antinuclear antibody positive children without rheumatologic disease. Pediatr Rheumatol Online J. 2010;8:15.\u003c/li\u003e\n\u003cli\u003eNaddei R, Di Gennaro S, Guarino A, Troncone R, Alessio M, Discepolo V. In a large Juvenile Idiopathic Arthritis (JIA) cohort, concomitant celiac disease is associated with family history of autoimmunity and a more severe JIA course: a retrospective study. Pediatr Rheumatol Online J. 2022;20(1):31.\u003c/li\u003e\n\u003cli\u003eL\u0026ouml;fvendahl S, Theander E, Svensson \u0026Aring;, Carlsson KS, Englund M, Petersson IF. Validity of diagnostic codes and prevalence of physician-diagnosed psoriasis and psoriatic arthritis in southern Sweden--a population-based register study. PLoS One. 2014;9(5):e98024.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-rheumatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"proj","sideBox":"Learn more about [Pediatric Rheumatology](http://ped-rheum.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/proj/default.aspx","title":"Pediatric Rheumatology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Juvenile arthritis, Juvenile idiopathic arthritis, JIA, Comorbidity, Outcome, Autoimmunity, Hypothyroidism, Coeliac disease, Diabetes Mellitus, Type 1.","lastPublishedDoi":"10.21203/rs.3.rs-4448474/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4448474/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003e There is no consensus or clinical guidelines for screening routines of autoimmune disease in individuals with juvenile idiopathic arthritis (JIA), since results are conflicting whether the risk for such conditions is increased or not among individuals with JIA. The aim of this study was to investigate if the frequency of comorbid autoimmune conditions is increased after JIA diagnosis in a validated population-based JIA cohort in southern Sweden.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eAutoimmune comorbidities were evaluated in a pre-existing population-based JIA cohort of 302 participants, constituting of individuals diagnosed with a validated JIA diagnosis 2000\u0026ndash;2010 in southern Sweden. The comorbidities were determined through analysis of diagnosis codes registered after the JIA diagnosis and until 2019. With the use of a reference population of 1510 age- and sex matched individuals, hazard ratios (HR) were calculated with Cox proportional models.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eDuring the study period, 7.7% of the JIA cohort received an autoimmune diagnosis after their JIA diagnosis. Individuals with JIA had an increased risk of autoimmune diseases in general (HR 2.01, 95% CI 1.16\u0026ndash;3.51), as well as separately for coeliac disease (HR 3.98, 95% CI 1.44\u0026ndash;11.01) compared to the reference population. Antinuclear antibody (ANA) positivity as well as treatment with disease-modifying anti-rheumatic drugs (DMARD) was associated with a significantly increased risk of comorbid autoimmune disease in the JIA cohort, with HR 5.11 (95% CI 1.54\u0026ndash;16.96) for ANA positive individuals and HR 7.23 (95% CI 1.65\u0026ndash;31.70) for those with DMARD treatment.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eIndividuals with JIA have a significantly increased risk of being diagnosed with an autoimmune condition after receiving their JIA diagnosis compared to matched references. ANA positivity and DMARD treatment is associated with a further increased risk. Our results emphasize awareness in physicians of additional autoimmune disorders in individuals with JIA and advocate serological screening of autoimmune conditions during follow-up.\u003c/p\u003e","manuscriptTitle":"Screening for comorbid autoimmune disease should be considered in children with ANA positive juvenile idiopathic arthritis – results from the south-Swedish juvenile idiopathic arthritis cohort","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-07 20:44:22","doi":"10.21203/rs.3.rs-4448474/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2024-07-01T03:48:23+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-06-09T08:59:46+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-22T13:19:38+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-22T09:34:02+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Rheumatology","date":"2024-05-20T06:28:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-rheumatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"proj","sideBox":"Learn more about [Pediatric Rheumatology](http://ped-rheum.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/proj/default.aspx","title":"Pediatric Rheumatology","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5f9d58dc-df03-420b-8ae9-e37c762cb39f","owner":[],"postedDate":"June 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-10-21T16:00:47+00:00","versionOfRecord":{"articleIdentity":"rs-4448474","link":"https://doi.org/10.1186/s12969-024-01030-x","journal":{"identity":"pediatric-rheumatology","isVorOnly":false,"title":"Pediatric Rheumatology"},"publishedOn":"2024-10-19 15:57:12","publishedOnDateReadable":"October 19th, 2024"},"versionCreatedAt":"2024-06-07 20:44:22","video":"","vorDoi":"10.1186/s12969-024-01030-x","vorDoiUrl":"https://doi.org/10.1186/s12969-024-01030-x","workflowStages":[]},"version":"v1","identity":"rs-4448474","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4448474","identity":"rs-4448474","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}