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Background The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans (CTPs) to compare treatment initiation strategies for systemic juvenile idiopathic arthritis (sJIA). First-line options for sJIA treatment (FROST) was a prospective observational study to assess CTP outcomes using the CARRA Registry. Methods Patients with new-onset sJIA were enrolled if they received initial treatment according to the biologic CTPs (IL-1 or IL-6 inhibitor) or non-biologic CTPs (glucocorticoid (GC) monotherapy or methotrexate). CTPs could be used with or without systemic GC. Primary outcome was achievement of clinical inactive disease (CID) at 9 months without current use of GC. Due to the small numbers of patients in the non-biologic CTPs, no statistical comparisons were made between the CTPs. Results Seventy-three patients were enrolled: 63 (86%) in the biologic CTPs and 10 (14%) in the non-biologic CTPs. CTP choice appeared to be strongly influenced by physician preference. During the first month of follow-up, oral GC use was observed in 54% of biologic CTP patients and 90% of non-biologic CTPs patients. Five (50%) non-biologic CTP patients subsequently received biologics within 4 months of follow-up. Overall, 30/53 (57%) of patients achieved CID at 9 months without current GC use. Conclusion Nearly all patients received treatment with biologics during the study period, and 46% of biologic CTP patients did not receive oral GC within the first month of treatment. The majority of patients had favorable short-term clinical outcomes. Increased use of biologics and decreased use of GC may lead to improved outcomes in sJIA.

Background Biologic disease-modifying antirheumatic drugs (bDMARDs) have changed the treatment of juvenile idiopathic arthritis (JIA) patients notably, as bDMARDs enable substantially more patients to achieve remission. When sustained remission is achieved, tapering or even discontinuation of the bDMARD is advocated, to reduce side effects and costs. However, when and how to discontinue bDMARD therapy and what happens afterwards, is less known. Objectives With this scoping review we aim to collect available data in current literature on relapse rate, time to relapse (TTR) and possible flare associated variables (such as time spent in remission and method of discontinuation) after discontinuing bDMARDs in non-systemic JIA patients. Methods We performed a literature search until July 2022 using the Pubmed database. All original studies reporting on bDMARD discontinuation in non-systemic JIA patients were eligible. Data on patient- and study characteristics, the applied discontinuation strategy, relapse rates and time to relapse were extracted in a standardized template. Results Of the 680 records screened, 28 articles were included in this review with 456 non-systemic JIA patients who tapered and/or stopped bDMARD therapy. Relapse rate after discontinuation of bDMARDs, either abruptly or following tapering, were 40–48%, 36.8–45.0% and 60–78% at 6, 8 and 12 months respectively. Total relapse rate ranged from 26.3% to 100%, with mean time to relapse (TTR) of 2 to 8.4 months, median TTR 3 to 10 months. All studies stated a good response after restart of therapy after flare. JIA subtype, type of bDMARD, concomitant methotrexate use, treatment duration, tapering method, age, sex, and time in remission could not conclusively be related to relapse rate or TTR. However, some studies reported a positive correlation between flare and antinuclear antibodies positivity, younger age at disease onset, male sex, disease duration and delayed remission, which were not confirmed in other studies. Conclusion Flares seem to be common after bDMARD discontinuation, but little is known about which factors influence these flares in JIA patients. Follow up after discontinuation with careful registration of patient variables, information about tapering methods and flare rates are required to better guide tapering and/or stopping of bDMARDs in JIA patients in the future.

ObjectiveThis study investigates the relationship of child, caregiver, and caring context measurements with the care-related quality of life (CRQoL) and health-related quality of life (HRQoL) of caregivers of children with juvenile idiopathic arthritis (JIA).MethodsWe performed a cross-sectional analysis of baseline data on caregivers of children with JIA from Canada and the Netherlands collected for the “Canada-Netherlands Personalized Medicine Network in Childhood Arthritis and Rheumatic Diseases” study from June 2019 to September 2021. We used the CRQoL questionnaire (CarerQoL), adult EQ-5D-5L, and proxy-reported Youth 5-Level version of EuroQoL (EQ-5D-5L-Y) to assess caregiver CRQoL, caregiver HRQoL, and child HRQoL, respectively. We used a multivariate analysis to assess the relationship between both caregiver CRQoL and HRQoL and patient, caregiver, and caring context measurements.ResultsA total of 250 caregivers were included in this study. Most of the caregivers were from the Netherlands (n = 178, 71%) and 77% were females (n = 193). The mean CarerQoL scores was 82.7 (standard deviation (SD) 11.4) and the mean EQ-5D-5L utility score was 0.87 (SD 0.16). Child HRQoL and employment had a positive relationship with both caregiver CarerQoL and EQ-5D-5L utility scores (p p ConclusionOur findings indicated that to understand the impact of JIA on families, we need to consider socio-economic factors, such as employment and support to carry caregiving tasks, in addition to child HRQoL.

Background There is growing concern about the long-term cardiovascular health of patients with juvenile idiopathic arthritis (JIA). In this study we assessed the association between JIA polygenic risk and cardiovascular phenotypes (cardiovascular risk factors, early atherosclerosis/arteriosclerosis markers, and cardiac structure and function measures) early in life. Methods JIA polygenic risk scores (PRSs) were constructed for 2,815 participants from the Avon Longitudinal Study of Parents and Children, using the single nucleotide polymorphism (SNP) weights from the most recent JIA genome wide association study. The association between JIA PRSs and cardiovascular phenotypes at age 24 years was assessed using linear and logistic regression. For outcomes with strong evidence of association, further analysis was undertaken to examine how early in life (from age seven onwards) these associations manifest. Results The JIA PRS was associated with diastolic blood pressure (β 0.062, 95% CI 0.026 to 0.099, P = 0.001), insulin (β 0.050, 95% CI 0.011 to 0.090, P = 0.013), insulin resistance index (HOMA2_IR, β 0.054, 95% CI 0.014 to 0.095, P = 0.009), log hsCRP (β 0.053, 95% CI 0.011 to 0.095, P = 0.014), waist circumference (β 0.041, 95% CI 0.007 to 0.075, P = 0.017), fat mass index (β 0.049, 95% CI 0.016 to 0.083, P = 0.004) and body mass index (β 0.046, 95% CI 0.011 to 0.081, P = 0.010). For anthropometric measures and diastolic blood pressure, there was suggestive evidence of association with JIA PRS from age seven years. The findings were consistent across multiple sensitivity analyses. Conclusions Genetic liability to JIA is associated with multiple cardiovascular risk factors, supporting the hypothesis of increased cardiovascular risk in JIA. Our findings suggest that cardiovascular risk is a core feature of JIA, rather than secondary to the disease activity/treatment, and that cardiovascular risk counselling should form part of patient care.

Background Transcriptome profiling of blood cells is an efficient tool to study the gene expression signatures of rheumatic diseases. This study aims to improve the early diagnosis of pediatric rheumatic diseases by investigating patients' blood gene expression and applying machine learning on the transcriptome data to develop predictive models. Methods RNA sequencing was performed on whole blood collected from children with rheumatic diseases. Random Forest classification models were developed based on the transcriptome data of 48 rheumatic patients, 46 children with viral infection, and 35 controls to classify different disease groups. The performance of these classifiers was evaluated by leave-one-out cross-validation. Analyses of differentially expressed genes (DEG), gene ontology (GO), and interferon-stimulated gene (ISG) score were also conducted. Results Our first classifier could differentiate pediatric rheumatic patients from controls and infection cases with high area-under-the-curve (AUC) values (AUC = 0.8 +/- 0.1 and 0.7 +/- 0.1, respectively). Three other classifiers could distinguish chronic recurrent multifocal osteomyelitis (CRMO), juvenile idiopathic arthritis (JIA), and interferonopathies (IFN) from control and infection cases with AUC >= 0.8. DEG and GO analyses reveal that the pathophysiology of CRMO, IFN, and JIA involves innate immune responses including myeloid leukocyte and granulocyte activation, neutrophil activation and degranulation. IFN is specifically mediated by antibacterial and antifungal defense responses, CRMO by cellular response to cytokine, and JIA by cellular response to chemical stimulus. IFN patients particularly had the highest mean ISG score among all disease groups. Conclusion Our data show that blood transcriptomics combined with machine learning is a promising diagnostic tool for pediatric rheumatic diseases and may assist physicians in making data-driven and patient-specific decisions in clinical practice. We received fnancial support from the Research Foundation Flanders (1861219N to BO), Al Thrasher Early Career Grant, academic investigatorinitiated grants from AbbVie and charity support from “Cycling for the smile of a child”. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. We appreciate the participation of all patients and their families in this study. We are grateful to all unmentioned clinicians, nurses, and lab colleagues. We thank Yanick Crow for helping us with certain analyses and Yves Vandeputte who organised the charity support from “Cycling for the smile of a child”.

Background Documentation of critical data elements is a focus of the Pediatric Rheumatology Care and Outcomes Improvement Network to aid in clinical care and research for patients with juvenile idiopathic arthritis. We aimed to increase data capture for critical data elements and hypothesized that quality improvement methodology would improve data capture. We also hypothesized that data capture for all critical data elements would be lower for virtual visits compared to in-person visits. Methods All visits for patients with JIA between 9/14/2020 and 12/31/2021 at the University of Minnesota were included. We assessed completeness of critical data element capture. Sixteen interventions with providers were conducted, including email reminders, individual discussions, group meetings, and feedback reports. We used statistical process control charts to evaluate change over time. Results Baseline included 355 patient-visits: 221 (62%) in-person and 134 (38%) virtual with critical data elements entry ranging between 50 and 60%. Post-intervention included 1,596 patient-visits: 1,350 (85%) in-person and 246 (15%) virtual, with critical data elements entry reaching 91%. All providers improved data entry during this study. In-person visits had significantly higher data capture rates than virtual visits for all 4 critical data elements. Conclusion We achieved our aim to increase critical data element documentation by focusing on provider buy-in, frequent reminders, and individualized feedback. We also found that collection of critical data elements occurred significantly less often with virtual visits than with in-person visits. Now that we improved capture of critical data elements, we can shift the focus to efforts aimed at improving outcomes for patients with juvenile arthritis.

Background Kinesiophobia may hinder physical performance measures and functional quality of life in children with juvenile idiopathic arthritis (JIA). This study aims to quantify differences in physical function in patients with JIA compared to healthy controls, and determine the effects of kinesiophobia on physical function and physical activity. Methods This was a comparative study of participants with JIA and healthy controls (JIA n = 26, control n = 17). All children with JIA had lower extremity joint involvement. Performance-based measures included gait speed, chair and stair navigation performance. Self-reported measures included Patient Reported Outcome Measurement Information System (PROMIS®) Physical Function Mobility, and Pain Interference and the Pediatric Functional Activity Brief Scale (Pedi-FABS). The Tampa Scale of Kinesiophobia (TSK-11) assessed patient fear of movement due to pain. Linear regression models were used to determine the contribution of TSK-11 scores on performance test and Pedi-FABS scores. Results Gait speeds were 11–15% slower, chair rise repetitions were 28% fewer, and stair ascent and descent times were 26–31% slower in JIA than controls (p p = .003). TSK-11 scores were higher in JIA than controls (p p Conclusions Children with JIA experience difficulty with tasks related to body transfers. Kinesiophobia is a significant contributor to the functional task performance and may impact clinical outcomes.

Objectives Unlike in adult rheumatology, for most forms of juvenile idiopathic arthritis (JIA) no reliable biomarkers currently exist to assess joint and disease activity. However, electrophoresis is frequently found changed in active juvenile arthritis. The objective of this study was to evaluate the α2-fraction of serum electrophoresis and its main components as biomarkers for JIA, categories extended/persistent oligoarthritis and seronegative polyarthritis, in comparison with the conventionally used erythrocyte sedimentation rate and C-reactive protein. Methods Serum samples and clinical data from 181 patients with JIA were collected. Serum electrophoresis and α2-fraction and its components were determined using standard methods. Relationship between calculated α2-fraction of serum electrophoresis (CA2F) and its components, acute-phase parameters and cJADAS27 was assessed using Pearson’s correlation coefficient and linear regression modelling, adjusting for confounding effects. Results were confirmed in a second cohort with 223 serum samples from 37 patients, using a mixed model to account for repeated measures. Results Compared to ESR and CRP, CA2F showed higher correlation to cJADAS27, in particular for persistent oligoarthritis. Of the three components of the α2-fraction, haptoglobin showed the highest correlation to cJADAS27. Regression analysis demonstrated higher ability to predict cJADAS27 for CA2F, and especially for haptoglobin as a component thereof, than for CRP and ESR. Conclusion Compared to conventional methods, α2-fraction of serum electrophoresis and specifically, haptoglobin show higher correlations with disease activity in common subtypes of JIA, representing excellent candidates as biomarkers for disease activity. Further studies are necessary to determine diagnostic value and correlations in other subtypes.

Background Systemic juvenile idiopathic arthritis (SJIA) is a chronic systemic inflammatory disease in children. Overproduction of inflammatory cytokines in SJIA resembles that in adult onset Still disease. Chronic inflammation causes insulin resistance and consequently leading to abnormal glucose metabolism. Adults with rheumatoid arthritis (RA) have increased risks of abnormal glucose metabolism and diabetes. To date, glucose metabolism in patients with SJIA has not been elucidated. Methods Patients with SJIA aged 4–25 years were recruited. All patients underwent an oral glucose tolerance test (OGTT). Indices of insulin sensitivity [homeostasis model assessment for insulin resistance (HOMA-IR) and whole-body insulin sensitivity index (WBISI)] and β-cell function [insulinogenic index (IGI) and disposition index (DI)] were calculated. Obese children with normoglycemia who underwent the OGTT were served as a control group. Results A total of 39 patients with SJIA, aged 4–25 years, median (IQR) BMI SDS was 0.1 (-0.5 to 1.7). Patients were divided into 2 groups, overweight/obese (OW/OB) (n = 11) and lean (n = 28). Only one obese patient had prediabetes and none had diabetes. In comparison with sex- and age-matched OW/OB controls (n = 33), OW/OB patients with SJIA had higher insulin resistance [median (IQR) HOMA-IR: 2.6 (2.1–3.3) vs 1.5 (0.8–2.0), p = 0.001], lower insulin sensitivity [median (IQR) WBISI: 3.7 (2.7–5.9) vs 5.4 (4.5–8.7), p = 0.024], and higher insulin secretion [median (IQR) IGI: 2.5 (2.0–3.5) vs 1.0 (0.8–1.9), p = 0.001]. In lean patients with SJIA, insulin sensitivity indices seemed to be comparable with those of lean controls. Conclusions Overweight/obese children with SJIA seemed to have increased insulin resistance and thus may have an increased risk for developing diabetes.

Background To report baseline characteristics, patient reported outcomes and treatment of children with Juvenile Dermatomyositis (JDM) in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. Methods Children newly diagnosed with JDM were enrolled in the CARRA Registry from 41 pediatric rheumatology centers. Baseline patient demographics, disease characteristics, assessments, patient reported outcome and treatments were recorded. Results In the first year, 119 JDM participants were enrolled. Most were female (63.4%), and white (72.3%) with a median diagnosis age 8.0 years (IQR 4.0–11.5), and median age of disease onset 7.0 years (IQR 3.5–7.5). They had characteristic rashes (92.4%), elevated muscle enzymes (83.2%), physician global score 4.0 (IQR 2.5–5.0) and manual muscle testing score 63.5 (IQR 51.0–75.0). Calcinosis (3.4%) and interstitial lung disease ( Childhood Health Assessment Questionnaire (CHAQ) results showed mild-moderate disability (median 0.750, IQR 0.030–1.875), as did patient/parent global assessments of disease activity (median 3, patient IQR: 1.75–5.25; parent IQR: 1–7). Patient Reported Outcomes Measurement Information System (PROMIS®) Pediatric Global Health 7 scores, Pain Interference, Physical Function scores for Mobility, and Upper Extremity Function were commonly worse than 95% of the general pediatric population. Conclusions In its inaugural year, 119 JDM patients were successfully enrolled in participapte in the New CARRA Registy. This registry will provide the necessary foundation to advance clinical research to improve outcomes using traditional measures and patient reported outcomes. With the CARRA biorepository, this infrastructure will enable future translational research. Together, these efforts may aid in future clinical trials, including comparative effectiveness trials.

Background Juvenile idiopathic arthritis is characterised by recurring episodes of acute inflammation, with joint swelling in one or more joints, often accompanied by pain. These episodes can now be controlled better than in the past because of a new category of medications. However, despite more stable disease activity, pain may continue to cause problems in the children with juvenile idiopathic arthritis and can reduce their performance of routine physical activities and participation in social or school activities. Aim To evaluate the prevalence of pain, pain intensity, pain behaviour, and pain interference in Icelandic children with juvenile idiopathic arthritis compared with healthy peers. Methods A cross-sectional, case-control study including 8-18 years old children; 28 with juvenile idiopathic arthritis and 36 in a control group. The children answered questions on pain experienced during the last 7 days, painful areas of the body and pain frequency. They completed short form versions of the Patient-Reported Outcome Measurement Information System (PROMIS) questionnaires on pain intensity, pain behaviour, and pain interference. Results Significantly more children with juvenile idiopathic arthritis had pain compared with the control group (p = 0.02). Children with JIA also had a greater number of painful body areas (p = 0.03), more pain intensity (p = 0.009), and showed more pain behaviour (p = 0.006), and pain interference (p = 0.002). Children with juvenile idiopathic arthritis who had pain, experienced more pain interference (p = 0.023) than their peers who had pain. However, the groups did not differ in terms of pain intensity (p = 0.102) and pain behaviour (p = 0.058). Conclusion The research results indicate that pain experience was different between children with juvenile idiopathic arthritis and the control group. The results suggest that further research of the role of pain management on functional outcomes in children with juvenile idiopathic arthritis is needed.

Background The plasticity of T helper-17 (Th17) and regulatory T (Treg) cells may be a clue to pathogenesis of Juvenile Idiopathic Arthritis (JIA). It is still unclear, whether targeted suppression of Interleukin (IL)-17 is able to influence regulatory function of Treg to control pro-inflammatory effectors in JIA. This study aimed to assess the effect of a Th17-stimulating cytokine environment and of IL-17A-inhibition on phenotype plasticity and suppressive function of Treg derived from JIA patients. Methods Th17 and Treg characteristics of CD4+ helper T cells were investigated in blood samples of JIA patients with oligo- and polyarticular pattern and healthy controls (HC). Isolated CD4+CD25+CD127− cells defined as Treg were cultivated with Th17-inducing cytokine environment as well as with IL-17A-inhibitors and analyzed for plasticity of phenotype by flow cytometry. Furthermore, inhibitory function of Treg on autologous effectors after cultivation with these stimuli was determined by suppression assays. Results Our findings demonstrated significantly elevated proportions of Th17 and Th17-like Treg in JIA compared to HC. After incubation with Th17-inducing stimuli, increased FoxP3 expression in separated Treg in JIA and an impaired suppressive capacity in JIA and HC were found. Blockade of IL-17A resulted in adjustment of FoxP3-expression in JIA to proportions found in controls and in regular suppressive function. Conclusions Our results demonstrate an induction of FoxP3 expressing Treg by Th17-inducing cytokines with concomitant mitigated suppressive function. In contrast, specific IL-17A blockade maintains suppressive Treg function and adjusted FoxP3-expression in JIA to levels found in controls. These findings may help to provide experimental evidence for the successful clinical use of IL-17A inhibition in JIA patients.

Objective Pharmacological treatment is a cornerstone of care for children with juvenile idiopathic arthritis (JIA). The objective of this study is to evaluate prescription patterns of conventional and biologic disease modifying anti-rheumatic drugs (c-DMARDs and b-DMARDs) for patients with JIA. Methods We conducted a retrospective cohort study of children diagnosed with JIA at a rheumatology pediatric clinic. Eligibility criteria were defined as children and youth newly diagnosed with enthesis-related arthritis, polyarticular, or oligoarticular JIA between 2011 and 2019, with at least one year of observation. Data on c-DMARDs and b-DMARDs prescriptions were obtained from electronic medical charts. We used descriptive statistics, Kaplan–Meier survival methods, and Sankey diagrams to describe treatment prescription patterns. Results A total of 325 patients with JIA were included, with a median observation time of 3.7 years. The most frequently prescribed c-DMARD and b-DMARD were methotrexate and etanercept, respectively. Within the first year of rheumatology care, 62% and 21% of patients had a c-DMARD and a b-DMARD prescribed, respectively. These proportions varied greatly by JIA subtype. Among the 147 (147/325, 45%) patients that had at least one b-DMARD prescribed, 24% were prescribed a second, and 7% a third-line of b-DMARD. A total of 112 unique treatment sequences were observed, with c-DMARD monotherapy followed by the addition of either a b-DMARD (56%) or another c-DMARD (30%) being the two most prevalent patterns in this cohort. Conclusion We observed a variety of treatment trajectories, with many patients experiencing multiple treatment lines, illustrating the complexity of the overall JIA treatment path.

Background Social determinants of health (SDH) greatly influence outcomes during the first year of treatment in rheumatoid arthritis, a disease similar to polyarticular juvenile idiopathic arthritis (pJIA). We investigated the correlation of community poverty level and other SDH with the persistence of moderate to severe disease activity and functional disability over the first year of treatment in pJIA patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance Registry. Methods In this cohort study, unadjusted and adjusted generalized linear mixed effects models analyzed the effect of community poverty and other SDH on disease activity, using the clinical Juvenile Arthritis Disease Activity Score-10, and disability, using the Child Health Assessment Questionnaire, measured at baseline, 6, and 12 months. Results One thousand six hundred eighty-four patients were identified. High community poverty (≥20% living below the federal poverty level) was associated with increased odds of functional disability (OR 1.82, 95% CI 1.28-2.60) but was not statistically significant after adjustment (aOR 1.23, 95% CI 0.81-1.86) and was not associated with increased disease activity. Non-white race/ethnicity was associated with higher disease activity (aOR 2.48, 95% CI: 1.41-4.36). Lower self-reported household income was associated with higher disease activity and persistent functional disability. Public insurance (aOR 1.56, 95% CI 1.06-2.29) and low family education (aOR 1.89, 95% CI 1.14-3.12) was associated with persistent functional disability. Conclusion High community poverty level was associated with persistent functional disability in unadjusted analysis but not with persistent moderate to high disease activity. Race/ethnicity and other SDH were associated with persistent disease activity and functional disability.

Introduction Juvenile idiopathic arthritis (JIA) is a cluster of autoimmune rheumatic diseases occurring in children 16 years of age or less. While it is well-known that pain may be experienced during inflammatory and non-inflammatory states, much remains ambiguous regarding the molecular mechanisms that may drive JIA pain. Thus, in this pilot study, we explored the variability of the serum proteomes in relation to pain severity in a cohort of JIA patients. Methods Serum samples from 15 JIA patients (male and female, 12.7 ± 2.8 years of age) were assessed using liquid chromatography/mass spectrometry (LC/MS). Correlation analyses were performed to determine the relationships among protein levels and self-reported clinical pain severity. Additionally, how the expression of pain-associated proteins related to markers of inflammation (Erythrocyte Sedimentation Rate (ESR)) or morphological properties of the central nervous system (subcortical volume and cortical thickness) implicated in JIA were also evaluated. Results 306 proteins were identified in the JIA cohort of which 14 were significantly (p, In the current preliminary study, serum proteins associated with pain severity were identified in JIA patients. Pain-associated proteins had functional roles predominantly in immune or inflammatory processes. Correlations of pain-associated proteins with ESR and altered CNS morphology were also observed with ESR and altered CNS morphology were also observed. Larger-scale as well as longitudinal studies are needed to determine if evaluation of the proteome may provide a platform for identifying novel analgesic targets in JIA. Supplementary Information The online version contains supplementary material available at 10.1186/s12969-022-00662-1.

Juvenile Idiopathic Arthritis (JIA) is a group of chronic heterogenous disorders that manifests as joint inflammation in patients aged

Background During the Coronavirus disease 2019 pandemic, ambulatory pediatric rheumatology healthcare rapidly transformed to a mainly telehealth model. However, pediatric patient and caregiver satisfaction with broadly deployed telehealth programs remains largely unknown. This study aimed to evaluate patient/caregiver satisfaction with telehealth and identify the factors associated with satisfaction in a generalizable sample of pediatric rheumatology patients. Methods Patients with an initial telehealth video visit with a rheumatology provider between April and June 2020 were eligible. All patients/caregivers were sent a post-visit survey to assess a modified version of the Telehealth Usability Questionnaire (TUQ) and demographic and clinical characteristics. TUQ total and sub-scale (usefulness, ease of use, effectiveness, satisfaction) scores were calculated and classified as “positive” based on responses of “agree” or “strongly agree” on a 5-point Likert scale. Results were analyzed using standard descriptive statistics and Wilcoxon signed rank testing. The association between demographic and clinical characteristics with TUQ scores was assessed using univariate linear regression. Results 597 patients/caregivers met inclusion criteria, and the survey response rate was 42% (n = 248). Juvenile idiopathic arthritis was the most common diagnosis (33.5%). The majority of patients were diagnosed greater than 6 months previously (72.6%) and were prescribed chronic medications (59.7%). The median total TUQ score was 4 (IQR: 4–5) with positive responses in 81% of items. Of the subscales, usefulness scores were lowest (median: 4, p p Conclusions Our results suggest telehealth is a promising mode of healthcare delivery for pediatric rheumatic diseases but also identifies opportunities for improvement. Innovation and research are needed to design a telehealth system that delivers high quality and safe care that improves healthcare outcomes. Since telehealth is a rapidly emerging form of pediatric rheumatology care, improved engagement and training of patients, caregivers, and providers may help improve the patient experience in the future.

Background This study aimed to assess the baseline characteristics and clinical outcomes of coronavirus disease 2019 (COVID-19) in pediatric patients with rheumatic and musculoskeletal diseases (RMD) and identify the risk factors associated with symptomatic or severe disease defined as hospital admission, intensive care admission or death. Methods An observational longitudinal study was conducted during the first year of the SARS-CoV-2 pandemic (March 2020–March 2021). All pediatric patients attended at the rheumatology outpatient clinics of six tertiary referral hospitals in Madrid, Spain, with a diagnosis of RMD and COVID-19 were included. Main outcomes were symptomatic disease and hospital admission. The covariates were sociodemographic and clinical characteristics and treatment regimens. We ran a multivariable logistic regression model to assess associated factors for outcomes. Results The study population included 77 pediatric patients. Mean age was 11.88 (4.04) years Of these, 30 patients (38.96%) were asymptomatic, 41 (53.25%) had a mild-moderate COVID-19 and 6 patients (7.79%) required hospital admission. The median length of hospital admission was 5 (2–20) days, one patient required intensive care and there were no deaths. Previous comorbidities increased the risk for symptomatic disease and hospital admission. Compared with outpatients, the factor independently associated with hospital admission was previous use of glucocorticoids (OR 3.51; p = 0.00). No statistically significant risk factors for symptomatic COVID-19 were found in the final model. Conclusion No differences in COVID-19 outcomes according to childhood-onset rheumatic disease types were found. Results suggest that associated comorbidities and treatment with glucocorticoids increase the risk of hospital admission.

Introduction Juvenile idiopathic arthritis (JIA) is the leading chronic rheumatic disease in childhood. To achieve adherence to therapy, in-depth understanding of disease and treatment options are important. Objective Development of specifically designed illustrations and standardised, easy-to-read texts for children and adolescents with JIA. Education materials were tested for comprehensibility and content validity. We hypothesised that children would be able to increase their knowledge about JIA after presentation of materials. Methods The illustrations were designed by a graphic artist and the informative texts consecutively transformed to easy-to-read language. The materials appear as a modular system to allow individualized information for each patient. The illustrations and texts were tested for knowledge gain and improvement of self-efficacy in children affected by JIA/ rheumatic diseases and controls. Health-related quality of life (HRQoL) was tested as an overall assessment of patients’ well-being. Results 46 controls (71% female) and 38 patients (48% female) with a median age of 11 years were tested in a standardised setting. In both groups knowledge gain was significant (controls: t (44) = 11.08, p d = 1.65; patients: t (37) = 7.48, p d = 1.21). The control group had a significantly higher enhancement of disease knowledge compared to patients’ group (p = .046) The follow-up testing was only performed in one school class (20 controls) due to Covid-19 pandemic with significant improvement compared to the pre-test results (p = .002). The enhancement of self-efficacy through the teaching session was significantly higher in the patients’ group. No impairment of HRQoL was seen. Conclusion Explaining juvenile rheumatic diseases and therapeutic strategies is an important task in paediatric rheumatology. To avoid incomprehensible explanations in medical jargon, illustrations and easy-to-read texts were developed. Standardised presentation of the newly created materials resulted in a significant improvement of disease knowledge in patients and controls in addition to an enhancement of self-efficacy in patients.

BackgroundChronic anterior uveitis is a sight-threatening complication of juvenile idiopathic arthritis (JIA) and a primary contributor to long-term morbidity in people with JIA. Levels of knowledge about uveitis among JIA patients and their parents are unknown. A survey of JIA patients and parents was conducted to assess knowledge about uveitis complications and recommended screening.MethodsA survey was developed consisting of six demographic questions, six arthritis/uveitis history questions, and nine uveitis knowledge questions. The survey was administered to JIA patients age 14 and older and parents of patients with JIA at three pediatric rheumatology practices and online through the Patients, Advocates, and Rheumatology Teams Network for Research and Service (PARTNERS) network. ANOVA, chi-square and Fisher’s exact tests were used to look for relationships between survey questions and demographic variables.ResultsThirty-three patients and 111 parents completed the survey. Overall, 17.4% reported a history of uveitis, and 89.6% had heard of uveitis. The mean composite knowledge score was 6.46 ± 2.6 out of 9. Patients and parents with a history of uveitis had higher composite knowledge scores than their counterparts without a uveitis history (p = 0.01 andp p = 0.04), the risk for uveitis when arthritis is controlled (p = 0.02), the need for ongoing eye exams when off of medications (p = 0.01), and had a higher overall score (p = 0.02) than those who were reminded at some visits or not at all.ConclusionsJIA patients and parents report variable levels of knowledge regarding uveitis complications and recommended screening. Frequent discussion between the rheumatology provider and family about uveitis screening is associated with higher uveitis knowledge. Incorporating detailed and frequent education about uveitis into rheumatology clinic appointments may improve early uveitis detection and visual outcomes.

Background This case study documents the first familial case of Blau syndrome (BS) in Palestine characterized with mutation in CARD15/NOD2. Case presentation Eighteen years old female was initially misdiagnosed with Juvenile idiopathic arthritis (JIA). The patient had been on steroids and methotrexate treatment for the last 16 years, but did not respond well to treatment. Initial examination at Saint John of Jerusalem Eye Hospital Group clinic showed bilateral intermediate uveitis with camptodactyly. The patient’s sister (aged 19 years) had bilateral intermediate uveitis and camptodactyly. Both eyes of their father had signs of old posterior uveitis. Father’s left eye showed 360 degrees posterior synechia, mature cataract with old Keratic precipitates (KPs). He also had camptodactyly. The patient was referred to pediatric rheumatologist to rule out sarcoidosis. Lung CT scan showed bronchiectasis, genetic consultation followed. Complete eye examination, full history, refraction, and Optical coherence tomography (oct) were done. Systemic and topical steroid therapy could not control the ocular inflammation. The family then was referred to a geneticist. Genetic analyses showed that the proband and all three family members had an R334q mutation in the CARD15/Nod2 gene. Conclusions BS should be considered in the differential diagnosis of childhood uveitis, especially in low and middle income countries where it is misdiagnosed in many cases, which delay appropriate diagnosis and thus control. Genetic analysis of the CARD15/Nod2 gene is helpful in the diagnosis. Steroids alone are not enough to control the disease, other immunosuppressants and biologics are needed.

Juvenile idiopathic arthritis (JIA) is the most common paediatric rheumatological disorder and is classified by subtype according to International League of Associations for Rheumatology criteria. Depending on the number of joints affected, presence of extra-articular manifestations, systemic symptoms, serology and genetic factors, JIA is divided into oligoarticular, polyarticular, systemic, psoriatic, enthesitis-related and undifferentiated arthritis. This review provides an overview of advances in understanding of JIA pathogenesis focusing on aetiology, histopathology, immunological changes associated with disease activity, and best treatment options. Greater understanding of JIA as a collective of complex inflammatory diseases is discussed within the context of therapeutic interventions, including traditional non-biologic and up-to-date biologic disease-modifying anti-rheumatic drugs. Whilst the advent of advanced therapeutics has improved clinical outcomes, a considerable number of patients remain unresponsive to treatment, emphasising the need for further understanding of disease progression and remission to support stratification of patients to treatment pathways.

Background Juvenile idiopathic arthritis (JIA), is the most common pediatric rheumatologic disorder with unknown etiology. Currently, no population-based data are available regarding the distribution of categories and frequency of uveitis in patients with JIA in Turkey. The purpose of this study was to evaluate the frequency of JIA-associated uveitis (JIAU) and distribution of JIA categories in a Turkish JIA cohort. Methods This was a retrospective study of 500 randomized patients in four pediatric rheumatology clinics in Turkey. Results Oligoarticular JIA (oJIA) was the most common JIA disease category in this study cohort (38.8%). The frequencies of the other categories were as follows: enthesitis-related arthritis (ERA), 23.2%; rheumatoid factor (RF)–negative polyarthritis, 15.6%; systemic arthritis, 12.2%; juvenile psoriatic arthritis, 5.2%; undifferentiated arthritis, 2.8%; and RF-positive polyarthritis, 2.2%. JIA-associated uveitis was observed in 6.8% of patients at a mean (Standard Deviation, SD) age of 9.1 (3.8) years over a mean JIA disease duration of 4 (1.9) years. Uveitis developed after joint disease, with a mean (SD) duration of 1.8 (1.9) years. Patients with oJIA had the highest rate of uveitis (12.9%) followed by patients with ERA (5.2%) and polyarticular RF-negative disease (3.8%). Compared with persistent oJIA, the extended oJIA category had a > 3-fold higher risk of uveitis (11.3% vs 27.7%; odds ratio, 3.38 [95% Confidence Interval, 1.09–10.4]). The most frequently administered drug after development of uveitis was tumor necrosis factor–alpha inhibitors (38.2%). Five patients (14.7%) had uveitis-related complications that required surgical intervention. Conclusions Turkish pediatric patients with JIA experience a lower frequency of oJIA and higher frequency of ERA than their white European counterparts; the occurrence of uveitis is also somewhat lower than expected. Geographic and ethnic factors may affect these differences and need further investigation.

Background We aimed to characterize etanercept (ETN) use in juvenile idiopathic arthritis (JIA) patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. Methods The CARRA Registry is a convenience cohort of patients with paediatric onset rheumatic diseases, including JIA. JIA patients treated with ETN for whom the month and year of ETN initiation were available were included. Patterns of ETN and methotrexate (MTX) use were categorized as follows: combination therapy (ETN and MTX started concurrently), step-up therapy (MTX started first and ETN added later), switchers (MTX started and then stopped when or before ETN started), MTX add-on (ETN started first and MTX added later), and ETN only (no MTX use). Data were described using parametric and non-parametric statistics as appropriate. Results Two thousand thirty-two of the five thousand six hundred forty-one patients with JIA met inclusion criteria (74% female, median age at diagnosis 6.0 years [interquartile range 2.0, 11.0]. Most patients (66.9%) were treated with a non-biologic disease modifying anti-rheumatic drug (DMARD), primarily MTX, prior to ETN. There was significant variability in patterns of MTX use prior to starting ETN. Step-up therapy was the most common approach. Only 34.0% of persistent oligoarticular JIA patients continued treatment with a non-biologic DMARD 3 months or more after ETN initiation. ETN persistence overall was 66.3, 49.4, and 37.3% at 24, 36 and 48 months respectively. ETN persistence among spondyloarthritis patients (enthesitis related arthritis and psoriatic JIA) varied by MTX initiation pattern, with higher ETN persistence rates in those who initiated combination therapy (68.9%) and switchers/ETN only (73.3%) patients compared to step-up (65.4%) and MTX add-on (51.1%) therapy. Conclusion This study characterizes contemporary patterns of ETN use in the CARRA Registry. Treatment was largely in keeping with American College of Rheumatology guidelines.

Harlequin ichthyosis (HI) is the most severe phenotype of autosomal recessive congenital ichthyosis. Juvenile Idiopathic Arthritis (JIA) represents a heterogenous group of disorders all sharing the clinical manifestation of chronic arthritis. Association of HI and chronic arthritis has been reported in few cases.We report the case of a child with HI who developed a severe form of chronic polyarthritis during the first years of life, treated with repeated multiple joint injections, methotrexate and etanercept with good response and without any adverse events.The reported case and the literature review highlighted the presence of a peculiar severe seronegative polyarthritis with early onset in a series of patients with HI, suggesting that polyarthritis may be a specific manifestation of HI, rather than a rare combination of two separate conditions.

Background Glucocorticoid exposure is a significant driver of morbidity in children with systemic juvenile idiopathic arthritis (sJIA). We determined the effect of early initiation of biologic therapy (IL-1 or IL-6 inhibition) on glucocorticoid exposure in hospitalized patients with new-onset sJIA. Methods We emulated a pragmatic sequence of trials (“pseudo-trials”) of biologic initiation in children (≤ 18 years) hospitalized with new-onset sJIA utilizing retrospective data from an administrative database from 52 tertiary care children’s hospitals from 2008 to 2019. Eligibility window, treatment assignment and start of follow-up between biologic and non-biologic study arms were aligned for each pseudo-trial. Patients in the source population could meet eligibility criteria at several timepoints. Mixed-effects logistic regression was used to determine the effect of biologic initiation on in-hospital glucocorticoid exposure. Results Four hundred sixty-eight children met eligibility criteria, of which 19% received biologic therapy without preceding or concomitant initiation of immunomodulatory medications. This proportion significantly increased over time during the study period (p Conclusion Biologic initiation in children hospitalized with new-onset sJIA significantly increased over time and may be associated with reduced glucocorticoid exposure. The increasing use of first-line biologic therapy may lead to clinically relevant reductions in treatment-related adverse effects of glucocorticoid-reliant therapeutic approaches.

Background Physical activity (PA) patterns in children with juvenile idiopathic arthritis (JIA) over time are not well described. The aim of this study was to describe associations of physical activity (PA) with disease activity, function, pain, and psychosocial stress in the 2 years following diagnosis in an inception cohort of children with juvenile idiopathic arthritis (JIA). Methods In 82 children with newly diagnosed JIA, PA levels, prospectively determined at enrollment, 12 and 24 months using the Physical Activity Questionnaire for Children (PAQ-C) and Adolescents (PAQ-A) raw scores, were evaluated in relation to disease activity as reflected by arthritis activity (Juvenile Arthritis Disease Activity Score (JADAS-71)), function, pain, and psychosocial stresses using a linear mixed model approach. Results in the JIA cohort were compared to normative Pediatric Bone Mineral Accrual Study data derived from healthy children using z-scores. Results At enrollment, PA z-score levels of study participants were lower than those in the normative population (median z-score − 0.356; p = 0.005). At enrollment, PA raw scores were negatively associated with the psychosocial domain of the Juvenile Arthritis Quality of Life Questionnaire (r = − 0.251; p = 0.023). There was a significant decline in PAQ-C/A raw scores from baseline (median and IQR: 2.6, 1.4–3.1) to 24 months (median and IQR: 2.1, 1.4–2.7; p = 0.003). The linear mixed-effect model showed that PAQ-C/A raw scores in children with JIA decreased as age, disease duration, and ESR increased. The PAQ-C/A raw scores of the participants was also negatively influenced by an increase in disease activity as measured by the JADAS-71 (p Conclusion Canadian children with newly diagnosed JIA have lower PA levels than healthy children. The decline in PA levels over time was associated with disease activity and higher disease-specific psychosocial stress.

Background Recognition of temporomandibular joint (TMJ) involvement in children with juvenile idiopathic arthritis (JIA) has gained increasing attention in the past decade. The clinical assessment of mandibular range of motion characteristics is part of the recommended variables to detect TMJ involvement in children with JIA. The aim of this study was to explore explanatory variables for mandibular range of motion outcomes in children with JIA, with and without clinically established TMJ involvement, and in healthy children. Methods This cross-sectional study included children with JIA and healthy children of age 6–18 years. Mandibular range of motion variables included active and passive maximum interincisal opening (AMIO and PMIO), protrusion, laterotrusion, dental midline shift in AMIO and in protrusion. Additionally, the TMJ screening protocol and palpation pain were assessed. Adjusted linear regression analyses of AMIO, PMIO, protrusion, and laterotrusion were performed to evaluate the explanatory factors. Two adjusted models were constructed: model 1 to compare children with JIA and healthy children, and model 2 to compare children with JIA with and without TMJ involvement. Results A total of 298 children with JIA and 169 healthy children were included. Length was an explanatory variable for the mandibular range of motion excursions. Each centimeter increase in length increased AMIO (0.14 mm), PMIO (0.14 mm), and protrusion (0.02 mm). Male gender increased AMIO by 1.35 mm. Having JIA negatively influenced AMIO (3.57 mm), PMIO (3.71 mm), and protrusion (1.03 mm) compared with healthy children, while the discrepancy between left and right laterotrusion raised 0.68 mm. Children with JIA and TMJ involvement had a 8.27 mm lower AMIO, 7.68 mm lower PMIO and 0.96 mm higher discrepancy in left and right laterotrusion compared to healthy children. Conclusion All mandibular range of motion items were restricted in children with JIA compared with healthy children. In children with JIA and TMJ involvement, AMIO, PMIO and the discrepancy between left and right laterotrusion were impaired more severely. The limitation in protrusion and laterotrusion was hardly clinically relevant. Overall, AMIO is the mandibular range of motion variable with the highest restriction (in millimeters) in children with JIA and clinically established TMJ involvement compared to healthy children.

Background Inadequate systemic exposure to infliximab (IFX) is associated with treatment failure. This work evaluated factors associated with reduced IFX exposure in children with autoimmune disorders requiring IFX therapy. Methods In this single-center cross-sectional prospective study IFX trough concentrations and anti-drug antibodies (ADAs) were measured in serum from children diagnosed with inflammatory bowel disease (IBD) (n = 73), juvenile idiopathic arthritis (JIA) (n = 16), or uveitis (n = 8) receiving maintenance IFX infusions at an outpatient infusion clinic in a tertiary academic pediatric hospital. IFX concentrations in combination with population pharmacokinetic modeling were used to estimate IFX clearance. Patient demographic and clinical data were collected by chart review and evaluated for their relationship with IFX clearance. Results IFX trough concentrations ranged from 0 to > 40 μg/mL and were 3-fold lower in children with IBD compared to children with JIA (p = 0.0002) or uveitis (p = 0.001). Children with IBD were found to receive lower IFX doses with longer dosing intervals, resulting in dose intensities (mg/kg/day) that were 2-fold lower compared to children with JIA (p = 0.0002) or uveitis (p = 0.02). Use of population pharmacokinetic analysis to normalize for variation in dosing practices demonstrated that increased IFX clearance was associated with ADA positivity (p = 0.004), male gender (p = 0.02), elevated erythrocyte sedimentation rate (ESR) (p = 0.02), elevated c-reactive protein (CRP) (p = 0.001), reduced serum albumin concentrations (p = 0.0005), and increased disease activity in JIA (p = 0.009) and IBD (p ≤ 0.08). No significant relationship between diagnosis and underlying differences in IFX clearance was observed. Multivariable analysis by covariate population pharmacokinetic modeling confirmed increased IFX clearance to be associated with anti-IFX antibody positivity, increased ESR, and reduced serum albumin concentrations. Conclusions Enhanced IFX clearance is associated with immunogenicity and inflammatory burden across autoimmune disorders. Higher systemic IFX exposures observed in children with rheumatologic disorders are driven primarily by provider drug dose and interval selection, rather than differences in IFX pharmacokinetics across diagnoses. Despite maintenance IFX dosing at or above the standard recommended range for IBD (i.e., 5 mg/kg every 8 weeks), the dosing intensity used in the treatment of IBD is notably lower than dosing intensities used to treat JIA and uveitis, and may place some children with IBD at risk for suboptimal maintenance IFX exposures necessary for treatment response.

Background Despite the risk for poor outcomes and gaps in care in the transfer from pediatric to adult care, most pediatric rheumatology centers lack formal transition pathways. As a first step in designing a pathway, we evaluated preparation for transition in a single-center cohort of adolescents and young adults (AYA) with rheumatologic conditions using the ADolescent Assessment of Preparation for Transition (ADAPT) survey. Findings AYA most frequently endorsed receiving counseling on taking charge of their health and remembering to take medications. Less than half reported receiving specific counseling about transferring to an adult provider. AYA with lower education attainment compared with those who had attended some college or higher had lower scores in self-management (1.51 vs 2.52, p = 0.0002), prescription medication counseling (1.96 vs 2.41, p = 0.029), and transfer planning (0.27 vs 1.62, p p = 0.048). Non-white youth indicated receiving more thorough medication counseling than white youth (2.71 vs 2.07, p = 0.027). When adjusting for age, educational attainment remained an independent predictor of transfer planning (p = 0.037). AYA with longer duration of seeing their physician had higher transition preparation scores (p = 0.021). Conclusion Few AYA endorsed receiving comprehensive transition counseling, including discussion of transfer planning. Those who were younger and with lower levels of education had lower preparation scores. A long-term relationship with providers was associated with higher scores. Further research, including longitudinal assessment of transition preparation, is needed to evaluate effective processes to assist vulnerable populations.

Background Many children and young people with juvenile idiopathic arthritis (JIA) experience delay in diagnosis and access to right care. The reasons for delay are multi-factorial and influenced by patient and family, clinician and organisational factors. Our aim was to explore the experiences of care, from initial symptoms to initial referral to paediatric rheumatology. Methods We analysed one-to-one and joint qualitative interviews with families of children with JIA (n = 36) presenting to a regional paediatric rheumatology service in the UK. We interviewed 51 family members (including mothers, fathers, patients, grandmothers and an aunt) and 10 health professionals (including orthopaedic surgeons, paediatricians, paediatric immunologist, General Practitioner and nurse) and a teacher involved in the care pathway of these JIA patients. Interviews were audio-recorded and analysed according to the standard procedures of rigorous qualitative analysis - coding, constant comparison, memoing and deviant case analysis. Results The median age of the children was 6 years old (range 1–17), with a spread of JIA subtypes. The median reported time to first PRh MDT visit from symptom onset was 22 weeks (range 4-364 weeks). Three key factors emerged in the pathways to appropriate care: (i) the persistence of symptoms (e.g. ‘change’ such as limp or avoidance of previously enjoyed activities); (ii) the persistence of parents help-seeking actions (e.g. repeat visits to primary and hospital care with concern that their child is not ‘normal’; iii) the experience and skills of health professionals resulting in different trajectories (e.g. no-real-concern-at-this-point or further-investigation-is-required). JIA was more likely to be considered amongst health practitioner if they had prior experiences of a child with JIA (moreso with a ‘protracted pathway’) or exposure to paediatric rheumatology in their training. Conversely JIA was more likely to be overlooked if the child had comorbidity such as learning disability or a chronic illness. Conclusions Care pathways are often ‘turbulent’ prior to a diagnosis of JIA with physical and emotional distress for families. There is need for greater awareness about JIA amongst health care professionals and observations of change (from family and non-health care professionals such as teachers) are key to trigger referral for paediatric rheumatology opinion.

Background Pediatric patients with juvenile idiopathic arthritis (JIA) are at risk for a lower health-related quality of life compared to their healthy peers. Remote monitoring of health-related quality of life using electronic patient-reported outcomes could provide important information to treating physicians. The aim of this study was to investigate if self-assessment with the EuroQol five-dimensional ‘youth’ questionnaire with five levels (EQ-5D-Y-5 L) inside a mobile E-health application could identify JIA patients in need of possible treatment adjustments. Methods The EQ-5D-Y-5 L was completed via a mobile application (Reuma2Go) between October 2017 and January 2019. The clinical juvenile arthritis disease activity score with 71 joint count (cJADAS-71) was reported at every corresponding visit as reference for disease activity. Previously described cJADAS-71 thresholds were used to identify patients in possible need of treatment adjustments. Discriminatory power of the EQ-5D-Y-5 L was assessed by ROC-curves and diagnostic characteristics. Results Sixty-eight JIA patients completed the EQ-5D-Y-5 L questionnaire. Median cJADAS-71 indicated low disease activity overall in the studied population. ROC curves and diagnostic characteristics demonstrated that self-assessment with the EQ-5D-Y-5 L could distinguish between patients with inactive disease (or minimal disease activity) and moderate to high disease activity with good accuracy (87%), sensitivity (85%), specificity (89%) and negative predictive value (86%). Conclusions Results demonstrate that the EQ-5D-Y-5 L was able to identify JIA patients in need of possible treatment adjustments in our studied population. Remote monitoring of health-related quality of life and patient-reported outcomes via E-health applications could provide important additional information to determine the frequency of clinical visits, assess therapeutic efficacy and guide treat-to-target strategies in pediatric patients with JIA.

Juvenile Idiopathic Arthritis is one of the most prevalent chronic diseases in children, with an annual incidence of 2–20 cases per 100,000 and a prevalence of 16–150 per 100,000. It is associated with several complications that can cause short-term or long-term disability and reduce the quality of life. Among these, growth and pubertal disorders play an important role. Chronic inflammatory conditions are often associated with growth failure ranging from slight decrease in height velocity to severe forms of short stature. The prevalence of short stature in JIA varies from 10.4% in children with polyarticular disease to 41% of patients with the systemic form, while oligoarthritis is mostly associated with localized excessive bone growth of the affected limb, leading to limb dissymmetry. The pathogenesis of growth disorders is multifactorial and includes the role of chronic inflammation, long-term use of corticosteroids, undernutrition, altered body composition, delay of pubertal onset or slow pubertal progression. These factors can exert a systemic effect on the GH/IGF-1 axis and on the GnRH-gonadotropin-gonadic axis, or a local influence on the growth plate homeostasis and function. Although new therapeutic options are available to control inflammation, there are still 10–20% of patients with severe forms of the disease who show continuous growth impairment, ending in a short final stature. Moreover, delayed puberty is associated with a reduction in the peak bone mass with the possibility of concomitant or future bone fragility. Monitoring of puberty and bone health is essential for a complete health assessment of adolescents with JIA. In these patients, an assessment of the pubertal stage every 6 months from the age of 9 years is recommended. Also, linear growth should be always evaluated considering the patient’s bone age. The impact of rhGH therapy in children with JIA is still unclear, but it has been shown that if rhGH is added at high dose in a low-inflammatory condition, post steroids and on biologic therapy, it is able to favor a prepubertal growth acceleration, comparable with the catch-up growth response in GH-deficient patients. Here we provide a comprehensive review of the pathogenesis of puberty and growth disorders in children with JIA, which can help the pediatrician to properly and timely assess the presence of growth and pubertal disorders in JIA patients.

Background Children with JIA may experience difficulty with health related quality of life (HRQOL). The Patient Reported Outcomes Measurement Information System (PROMIS) a patient related outcome (PRO) measure, covers HRQOL domains that include physical function, mental health, and social interactions. During initial use, we found PROMIS identified children with symptoms of depression, sometimes before they shared those feelings with parents or members of the clinic team. We studied the use of PROMIS for this purpose, and to determine what demographic, clinical, and other characteristics might be related to higher depressive symptom scores. Methods From March 2014 – February 2017, at each visit, all JIA patients having met ILAR classification criteria seen by M.L.M. received the PROMIS Short Form 35 v.1.0, as part of routine care. T scores were calculated from raw scores for mobility, anxiety, depressive symptoms, fatigue, peer relationships, and pain interference domains. Data extracted by optical mark recognition software were merged with electronic medical record (EMR data), extracted by Extract/Transform/Load software, including joint counts, visit age, ANA, RF, and HLA-B27 status. Mixed effects models were used to identify significant associations of independent variables with depression T scores. Results Data from 148 patients were analyzed (114 females for 435 visits, 34 males for 118 visits; 13.8 ± 2.8 years): 70 persistent oligoarthritis, 9 extended oligoarthritis, 19 ERA, 21 polyarthritis (RF-), 5 polyarthritis (RF+), 11 undifferentiated arthritis, 3 psoriatic arthritis, 10 systemic arthritis). T scores showed wide ranges within individual JIA categories, with similar mean scores for all groups. Univariate linear mixed effects models showed significant relationships to depression T scores of gender and race (males and Asian patients with lower T scores, p p = 0.091, respectively), joint count (p = 0.002), pain interference score (p = 0.0004), and Patient and Physician Global Assessment (p = 0.004, p Conclusion PROMIS is useful in screening JIA patients for symptoms of depression, particularly to identify patients who might not otherwise report these symptoms. The other PROMIS domain scores are related to reporting of symptoms of depression, as is Patient and Physician Global Assessment. Future studies will use PROMIS questionnaires incorporated into the EMR, permitting data entry by tablets and an online patient portal. This will make possible comparisons of HRQOL in children with JIA to those with other chronic rheumatic and non-rheumatic diseases.

Background Intraarticular injections (IAI) were first reported in adult rheumatology in the 1950s and subsequently gained acceptance as a safe and efficacious treatment in Juvenile idiopathic arthritis (JIA). IAIs are now widely performed and recommended as the initial or only treatment of oligoarticular JIA and ancillary treatment of actively inflamed joints in other varieties of JIA. However, the performance of the procedure is currently not guided by standardized recommendations, and several practice variations are observed. Methods This worldwide survey of pediatric rheumatologists (with 48.5% response from Pediatric Rheumatology International Trials Organization [PRINTO and Pediatric Rheumatology Collaborative Study Group [PRCSG] members) captures the differences in pre-procedural, procedural and post-procedural protocols and practices observed across the globe and asks the necessity of developing consensus in this area of Pediatric Rheumatology. Results This worldwide survey of Pediatric Rheumatologists had a response rate of just under 50% and the views of about 42% who routinely performed the procedure. It captured the differences in IAI protocols and practices observed across the globe. Significant variations in practice were noted in use of Local anesthesia, choice, and dose of therapeutic agent for the intraarticular injection and use of ultrasound to guide injections. While some practice variations may be explained by institutional protocols in different parts of the world, the clinical implications of these are largely unknown and beg the need for further studies. Conclusions Given these practice variations, the authors recommend further studies to explore the cost and clinical implications and subsequently work towards developing consensus plans to ensure uniformity in this widely used procedure in Pediatric Rheumatology.

Background STING-associated vasculopathy with onset in infancy (SAVI) is a type 1 interferonopathy manifesting as a pulmonary and vascular syndrome resulting from gain-of-function mutations in TMEM173, the gene encoding STING. Familial reports in the literature are sparse. Case presentation We report a case series of SAVI in a three generation kindred, with a phenotype of interstitial lung disease (ILD) and rheumatoid factor positive polyarticular juvenile idiopathic arthritis (JIA). Current and historical medical records were reviewed for clinical and laboratory information. Whole blood from cases 1 and 2, plus stored appendicectomy tissue from case 3, underwent DNA sequencing of the TMEM173 gene. Peripheral blood RNA was obtained from cases 1 and 2 for functional assessment of the TMEM173 mutation. DNA sequencing identified the same heterozygous TMEM173 mutation (c.463G > A; p.Val155Met) in all three cases, consistent with a diagnosis of the autosomal dominant condition SAVI. Functional assessment of this mutation identified a prominent interferon signature which was confirmed on repeat testing. Conclusions SAVI presented in this family as ILD with early onset juvenile rheumatoid arthritis. This condition should be considered in all rheumatoid arthritis patients with early-onset ILD and in all JIA patients with ILD.

In 2018, an international Task Force formulated recommendations for treating Juvenile Idiopathic Arthritis (JIA) to target. The Task Force has not yet resolved three issues. The first issue is the lack of a single “best” target. The Task Force decided not to recommend the use of a specific instrument to assess inactive disease or remission. Recent studies underscore the use of a broad target definition. The second issue is the basic assumption that a treatment aggressively aimed at the target will have ‘domino effects’ on other treatment goals as well. Thus far, this assumption was not confirmed for pain, fatigue and stiffness. The third issue is shared decision-making, and the role of individual patient targets. Nowadays, patients and parents should have a more active role in choosing targets and their personal treatment goals. In our department the electronic medical records have been restructured in such a way that the patient’s personal treatment goals with a target date appears on the front page. The visualization of their specific personal goals helps us to have meaningful discussions on the individualized treatment strategy and to share decisions. In conclusion, a joint treat to target (T2T) strategy is a promising approach for JIA. The Task Force formulated valuable overarching principles and a first version of recommendations. However, implementation of T2T needs to capture more than just inactive disease. Patients and parents should have an active role in choosing personal targets as well.

Background The primary caregiver is an important person in the life of patients with JIA. Their reactions depend on social, emotional and economic factors that affect the therapeutic alliance. Some generic instruments have been used to evaluate burden, anxiety, or quality of life of caregivers. This study aims to develop a specific instrument to measure the psychosocial and economic impacts on primary caregivers of patients with JIA. Methodology This is a mixed methods research, that includes qualitative and quantitative data, and was carried out in two phases. First phase: a pragmatic qualitative study (questionnaire construction) was conducted in two parts, a non-systematic literature review followed by interviews with primary caregivers. Second phase: a cross-sectional study (questionnaire validation) to complete validation and estimate Cronbach’s alphas based on tetrachoric correlation coefficients, correlation matrix and Cohen’s kappa coefficient test. Results There were 38 articles found related to the experience of caregivers. 15 primary caregivers were interviewed (female 93%, median age 45 years). Thematic analysis identified 9 important topics from the perspective of participants (economic impact, coping, family roles, impact of diagnosis, mental health, couple/mate relationships, impact at work, religion, and knowledge of the disease). These topics were combined to create the interview questionnaire (56 items). Later, it was modified to 62 items that were divided into five dimensions: impact of the disease (psychosocial, economic, family, and relationships), knowledge of the disease, alternative medicine, future, and religion. The interview questionnaire was applied to 32 primary caregivers (female 93%, median age 37 years), results identify depression on 29 (90%), 18 (56%) feel sadness at diagnosis, 20 (63%) mentioned that JIA has influenced in their financial situation, 23 (72%) feel anxiety about the future, and 11 (37%) considered that their family relationships have changed. Statistical analysis identified inconsistencies during convergent and divergent validity of the construct. Consequently, 11 items were eliminated, 3 relocated, 6 modified, and 39 compacted obtaining the “Impact of Pediatric Rheumatic Diseases on Caregivers Multi-assessment Questionnaire” (CAREGIVERS questionnaire). This final version resulted on an eight-dimension (28 items) instrument. Conclusions The CAREGIVERS questionnaire captures perspectives of both the participants and clinicians. It will be helpful to measure the impact of the disease and thus, to improve the quality of care of children with JIA and their families.

Background This study aimed to determine the influence of tocilizumab (TCZ) in modifying the clinical and laboratory features of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (s-JIA). Furthermore, we assessed the performance of the 2016 MAS classification criteria for patients with s-JIA-associated MAS while treated with TCZ. Methods A panel of 15 pediatric rheumatologists conducted a combination of expert consensus and analysis of real patient data. Clinical and laboratory features of s-JIA-associated MAS in 12 TCZ-treated patients and 18 untreated patients were evaluated. Possible MAS was defined as having characteristic laboratory features but lack of clinical features of MAS, or atypical MAS, or early treatment that prevented full-blown MAS. Results Clinically, the TCZ-treated patients with s-JIA-associated MAS were less likely febrile and had significantly lower ferritin, triglyceride, and CRP levels than the untreated patients with s-JIA-associated MAS. Other laboratory features of MAS including lower platelet counts and lower fibrinogen were more pronounced in TCZ-treated patients. The TCZ-treated patients with s-JIA-associated MAS were less likely to be classified as MAS based on the MAS classification criteria (25% vs 83.3%, p Conclusion TCZ could modify the clinical and laboratory features of s-JIA-associated MAS. When evaluating the s-JIA patients while treated with TCZ, it is not applicable to use MAS classification criteria. Care must be taken to not underdiagnose MAS based on the MAS classification criteria.

Background The oral microbiota has been implicated in the pathogenesis of rheumatoid arthritis through activation of mucosal immunity. This study tested for associations between oral health, microbial communities and juvenile idiopathic arthritis (JIA). Methods A cross-sectional exploratory study of subjects aged 10–18 years with oligoarticular, extended oligoarticular and polyarticular JIA was conducted. Control groups included pediatric dental clinic patients and healthy volunteers. The primary aim was to test for an association between dental health indices and JIA; the secondary aim was to characterize the microbial profile of supragingival plaque using 16S rRNA gene sequencing. Results The study included 85 patients with JIA, 62 dental patients and 11 healthy child controls. JIA patients overall had significantly more gingival inflammation compared to dental patients, as evidenced by bleeding on probing of the gingiva, the most specific sign of active inflammation (p = 0.02). Overall, however, there was a trend towards better dental hygiene in the JIA patients compared to dental patients, based on indices for plaque, decay, and periodontitis. In the JIA patients, plaque microbiota analysis revealed bacteria belonging to genera Haemophilus or Kingella elevated, and Corynebacterium underrepresented. In poly JIA, bacteria belonging to the genus Porphyromonas was overrepresented and Prevotella was underrepresented. Conclusion Increased gingival inflammation in JIA was independent of general oral health, and thus cannot be attributed to poor dental hygiene secondary to disability. The variation of microbial profile in JIA patients could indicate a possible link between gingivitis and synovial inflammation.

Background Juvenile idiopathic arthritis (JIA), the most common chronic rheumatic disease of childhood, is characterised by synovitis. Clinical assessments of synovitis are imperfect, relying on composite and indirect measures of disease activity including clinician-reported measures, patient-reported measures and blood markers. Contrast-enhanced MRI is a more sensitive synovitis assessment technique but clinical utility is currently limited by availability and inter-observer variation. Improved quantitative MRI techniques may enable future development of more stringent MRI-defined remission criteria. The objective of this study was to determine the utility and feasibility of quantitative MRI measurement of synovial volume and vascularity in JIA before and twelve weeks after intra-articular glucocorticoid injection (IAGI) of the knee and to assess the acceptability of MRI to participating families. Methods Children and young people with JIA and a new episode of knee synovitis requiring IAGI were recruited from the Great North Children’s Hospital in Newcastle upon Tyne. Quantitative contrast-enhanced MRI was performed prior to and twelve weeks after IAGI, in addition to standard clinical assessment tools, including the three-variable clinical juvenile arthritis disease activity score (cJADAS) and active joint count. Results Eleven young people (5 male, median age 13 years, range 7–16) with JIA knee flare were recruited and 10 completed follow-up assessment. Following IAGI, the median (interquartile range) cJADAS improved from 8.5 (2.7) to 1.6 (3.9), whilst the median synovial volume improved from 38.5cm3 (82.1cm3) to 0.0cm3 (0.2cm3). Six patients presented with frank synovitis outside normal limits on routine MRI reporting. A further three had baseline MRI reports within normal limits but the quantitative measurements identified measurable synovial uptake. Post-IAGI quantitative measurements highlighted significant improvements in 9 patients. Conclusions IAGI led to a marked reduction in synovial volume, with quantitative MRI identifying more patients with an improved synovial volume than routine qualitative clinical reporting. Improvements in cJADAS scores were more variable with the patient/parent global assessment component contributing most to the scores. Further work is indicated, exploring the utility of quantitative MRI in the assessment of less accessible joints and comparing the impact of different treatment modalities.

Background While pain is a common symptom in JIA patients, it remains unclear why some JIA patients develop ongoing or persistent pain. Complex clinical and social settings confound analysis of individual factors that may contribute to this pain. To address this, we first undertook a retrospective analysis of pain reports in a JIA patient cohort with the aim of identifying potential factors contributing to persistent pain. We then carried out an experimental laboratory study, using joint inflammatory pain behaviour in rodents, to validate the role of these factors in the onset of persistent pain under controlled conditions. Methods Patients: Retrospective analysis of anonymised pain visual analogue scale (VAS) scores and accompanying clinical scores from 97 JIA patients aged 13–19 (mean: 16.40 ± 1.21) collected over 50 weeks. Rats: Experimental study of pain behaviour following intra-articular microinjection of complete Freund’s adjuvant (CFA) in adolescents (n = 25) and young adults (n = 43). Some animals (n = 21) had been previously exposed to joint inflammation in infancy or adolescence. Results Patients: Cluster analysis of patient pain VAS scores revealed three trajectories over 50 weeks: consistently low pain (n = 45), variable pain (n = 30) and persistently high pain (n = 22). Number of actively inflamed joints did not differ in the three groups. High pain at a single visit correlated with greater physician global assessment of disease activity, while a high pain trajectory over 50 weeks was associated with more limited joints but fewer actively inflamed joints. Rats: Rodents administered ankle joint CFA also exhibit low, medium and high joint pain sensitivities, independent of joint inflammation. Prolonged inflammatory pain behaviour was associated with high background pain sensitivity, following joint inflammation at an earlier stage in life. Conclusions Both JIA patients and rodents differ in their individual pain sensitivity independent of the concurrent joint inflammation. Using experimental animal models allows us to isolate physiological factors underlying these differences, independently of social or clinical factors. The results suggest that a history of prior arthritic activity/joint inflammation may contribute to high pain sensitivity in adolescents with JIA. Electronic supplementary material The online version of this article (10.1186/s12969-019-0360-3) contains supplementary material, which is available to authorized users.

Background Juvenile Idiopathic Arthritis associated Uveitis (JIA-U) represents its most frequent extra-articular manifestation and the main cause of childhood uveitis in in developed countries. The broad variety of outcome measures utilized makes the comparison of the disease course, risk for complications, impairment in visual function, and responses to treatment quite difficult. Our aim was to summarize evidence regarding the current availability of outcome measures in JIA-U. Methods A systematic review between January 2000 and December 2018 was performed to identify studies investigating outcome measures used in JIA-U. Results The initial search identified 8254 articles of which 89 were potentially eligible. After the full text revision, a total of 27 studies, including 2 RCTs, were included. Among these studies 12 outcome measures for JIA-U use have been identified (grade of cells in the AC, grade of flare in the AC, VA, amblyopia, structural complications, use and sparing of oral corticosteroids and immunosuppressive drugs, surgery requirement, biomarkers, bilateral disease, JIA persistence, quality of life assessments, uveitis subtype). As regards primary outcome measures, 44% among studies included one or more variables related to disease activity (i.e. grade of flare, grade of cells); 56% included visual function performance (i.e. visual acuity); 68% (17/25) included one or more variables of disease-associated tissue damage or complications (i.e. cataract, amblyopia); 24% included disease features (i.e. bilateral disease; uveitis subtype); 44% included laboratory features (i.e. biomarkers); 8% included JIA features (i.e. persistence of disease); 12% included quality of life (i.e. EYE-Q); 44% included management (i.e. use and sparing of oral corticosteroids and other immunosuppressive drugs; surgery requirement). Conclusions Our systematic review surveys the heterogeneity around outcome measures related to JIA-U in children, even in RCTs. It does not provide the solution to overcome the heterogeneity in uveitis studies, but it does provide an estimate of the scale of the problems and provides data to inform this important debate; highlighting the requirement to obtain a new consensus regarding a common approach to identify suitable and efficient outcome measures in JIA-U.

Background Relapsing periodic arthritis is a general term used for a group of diseases with recurring and periodic nature, in which the joints are intermittently involved. The aim of this study is to evaluation of the possible relationship between MEFV gene mutations in intermittent arthritis of children which has recurring and periodic nature. Methods In this cross-sectional study we reviewed medical records of all patients with recurrent and periodic arthritis referred to pediatric rheumatology clinic from 2003 to 2019.We excluded all patients with suspicious anamnesis and/or positive history of FMF, JIA, gout, psoriasis, IBD and SLE. The peripheral blood of these patients was screened for the 12 common pathogenic MEFV gene variants (FMF Strip Assay, Vienna lab, Vienna, Austria) according to manufacturer’s instructions. Results Among 195 recorded files, 11 patients were identified with idiopathic recurrent and periodic feature. 3 patients suffering from recurrent transient synovitis hip (RSH) and 8 patients were fully compatible with the Pasero and Barbieri modified criteria of palindromic rheumatism (PR). Their mean age at diagnosis was 6.5 and 4.6 years and the average follow-up was 2.6 and 6.6 years in PR and RSH patients, respectively. The most frequently involved joints were knees and ankles in PR patients. The mean duration of attacks was 3.3 days in RSH patients and with various courses in PR. The median number of attacks was 4.75 in PR and 3 in RSH patients per year. In PR group 7 patients showed no mutations and all patients of RSH had these mutations; V726A, R761H, A744S as in heterozygote pattern. Conclusion An idiopathic relapsing periodic arthritis in children with exclusively hip involvement is a MEFV gene related arthropathy; whereas with various joint attacks it could be considered as childhood PR.

Background This study aims to describe current practice in identifying and measuring health care resource use and unit costs in economic evaluations or costing studies of juvenile idiopathic arthritis (JIA). Methods A scoping review was conducted (in July 2018) in PubMed and Embase to identify economic evaluations, costing studies, or resource utilization studies focusing on patients with JIA. Only English language peer-reviewed articles reporting primary research were included. Data from all included full-text articles were extracted and analysed to identify the reported health care resource use items. In addition, the data sources used to obtain these resource use and unit costs were identified for all included articles. Results Of 1176 unique citations identified by the search, 20 full-text articles were included. These involved 4 full economic evaluations, 5 cost-outcome descriptions, 8 cost descriptions, and 3 articles reporting only resource use. The most commonly reported health care resource use items involved medication (80%), outpatient and inpatient hospital visits (80%), laboratory tests (70%), medical professional visits (70%) and other medical visits (65%). Productivity losses of caregivers were much more often incorporated than (future) productivity losses of patients (i.e. 55% vs. 15%). Family borne costs were not commonly captured (ranging from 15% for school costs to 50% for transportation costs). Resource use was mostly obtained from family self-reported questionnaires. Estimates of unit costs were mostly based on reimbursement claims, administrative data, or literature. Conclusions Despite some consistency in commonly included health care resource use items, variability remains in including productivity losses, missed school days and family borne costs. As these items likely substantially influence the full cost impact of JIA, the heterogeneity found between the items reported in the included studies limits the comparability of the results. Therefore, standardization of resource use items and unit costs to be collected is required. This standardization will provide guidance to future research and thereby improve the quality and comparability of economic evaluations or costing studies in JIA and potentially other childhood diseases. This would allow better understanding of the burden of JIA, and to estimate how it varies across health care systems. Electronic supplementary material The online version of this article (10.1186/s12969-019-0321-x) contains supplementary material, which is available to authorized users.