Association with HLA-DRß1 position 37 distinguishes juvenile dermatomyositis from adult-onset myositis.

Juvenile dermatomyositis (JDM) is a rare, severe autoimmune disease and the most common idiopathic inflammatory myopathy of children. JDM and adult-onset dermatomyositis (DM) have similar clinical, biological and serological features, although these features differ in prevalence between childhood-onset and adult-onset disease, suggesting that age of disease onset may influence pathogenesis. Therefore, a JDM-focused genetic analysis was performed using the largest collection of JDM samples to date. Caucasian JDM samples (n = 952) obtained via international collaboration were genotyped using the Illumina HumanCoreExome chip. Additional non-assayed human leukocyte antigen (HLA) loci and genome-wide single-nucleotide polymorphisms (SNPs) were imputed. HLA-DRB1*03:01 was confirmed as the classical HLA allele most strongly associated with JDM [odds ratio (OR) 1.66; 95% confidence interval (CI) 1.46, 1.89; P = 1.4 × 10-14], with an independent association at HLA-C*02:02 (OR = 1.74; 95% CI 1.42, 2.13, P = 7.13 × 10-8). Analyses of amino acid positions within HLA-DRB1 indicated that the strongest association was at position 37 (omnibus P = 3.3 × 10-19), with suggestive evidence this association was independent of position 74 (omnibus P = 5.1 × 10-5), the position most strongly associated with adult-onset DM. Conditional analyses also suggested that the association at position 37 of HLA-DRB1 was independent of some alleles of the Caucasian HLA 8.1 ancestral haplotype (AH8.1) such as HLA-DQB1*02:01 (OR = 1.62; 95% CI 1.36, 1.93; P = 8.70 × 10-8), but not HLA-DRB1*03:01 (OR = 1.49; 95% CR 1.24, 1.80; P = 2.24 × 10-5). No associations outside the HLA region were identified. Our findings confirm previous associations with AH8.1 and HLA-DRB1*03:01, HLA-C*02:02 and identify a novel association with amino acid position 37 within HLA-DRB1, which may distinguish JDM from adult DM.

A protocol for scoping reviews on the role of whole-body and dedicated body-part magnetic resonance imaging for assessment of adult and juvenile idiopathic inflammatory myopathies.

Currently, standardized magnetic resonance imaging (MRI) scoring systems and protocols for assessment of idiopathic inflammatory myopathies (IIMs) in children and adults are lacking. Therefore, we will perform a scoping review of the literature to collate and evaluate the existing semi-quantitative and quantitative MRI scoring systems and protocols for the assessment and monitoring of skeletal muscle involvement in patients with IIMs. The aim is to compile evidence-based information that will facilitate the future development of a universal standardized MRI scoring system for both research and clinical applications in IIM. A systematic search of electronic databases (PubMed, EMBASE, and Cochrane) will be undertaken to identify relevant articles published between January 2000 and October 2023. Data will be synthesized narratively. This scoping review seeks to comprehensively summarize and evaluate the evidence on the scanning protocols and scoring systems used in the assessment of diagnosis, disease activity, and damage using skeletal muscle MRI in IIMs. The results will allow the development of consensus recommendations for clinical practice and enable the standardization of research methods for the MRI assessment of skeletal muscle changes in patients with IIMs.

Adipose tissue distribution is associated with cardio-metabolic alterations in adult patients with juvenile-onset dermatomyositis.

OBJECTIVES: Primary aims were to compare adipose tissue distribution in adult patients with juvenile-onset DM (JDM), with matched controls. Secondary aims were to explore how adipose tissue distribution is associated with cardio-metabolic status (cardiac dysfunction and metabolic syndrome) in patients. METHODS: Thirty-nine JDM patients (all aged ≥18 y, mean age 31.7 y and 51% female) were examined mean 22.7 y (s.d. 8.9 y) after disease onset and compared with 39 age/sex-matched controls. In patients, disease activity and lipodystrophy were assessed by validated tools and use of prednisolone noted. In all participants, dual-energy X-ray absorptiometry (DXA) and echocardiography were used to measure visceral adipose tissue (VAT)(g) and cardiac function, respectively. Risk factors for metabolic syndrome were measured and associations with adipose tissue distribution explored. For primary and secondary aims, respectively, P-values ≤0.05 and ≤0.01 were considered significant. RESULTS: Patients exhibited a 2.4-fold increase in VAT, and reduced HDL-cholesterol values compared with controls (P-values ≤ 0.05). Metabolic syndrome was found in 25.7% of the patients and none of the controls. Cardiac dysfunction (systolic and/or diastolic) was found in 23.7% of patients and 8.1% of controls (P = 0.07). In patients, VAT levels were correlated with age, disease duration and occurrence of metabolic syndrome and cardiac dysfunction. Occurrence of lipodystrophy (P = 0.02) and male sex (P = 0.04) tended to be independently associated with cardiac dysfunction. CONCLUSION: Adults with JDM showed more central adiposity and cardio-metabolic alterations than controls. Further, VAT was found increased with disease duration, which was associated with development of cardio-metabolic syndrome.

Cardiac dysfunction in mixed connective tissue disease: a nationwide observational study.

We aimed to identify cardiac function in patients with established mixed connective tissue disease (MCTD). This was a cross-sectional case-control study of well-characterised MCTD patients who had previously been included in a nationwide cohort. Assessments comprised protocol transthoracic echocardiography, electrocardiogram and blood samples. In patients only, we evaluated the findings of high-resolution pulmonary computed tomography and disease activity. We assessed 77 MCTD patients (mean age 50.5 ± 12.3 years) with a mean disease duration of 16.4 years, and 59 age- and sex-matched healthy controls (49.9 ± 11.7 years). By echocardiography, measures of left ventricular function, i.e. fractional shortening (38.1 ± 6.4% vs. 42.3 ± 6.6%, p < 0.001), mitral annulus plane systolic excursion (MAPSE) (13.7 ± 2.1 mm vs. 15.3 ± 2.3 mm, p < 0.001) and early diastolic velocity of the mitral annulus (e') (0.09 ± 0.02 m/s vs. 0.11 ± 0.03 m/s, p = 0.002) were subclinical and lower in patients than controls. Right ventricular dysfunction was found in patients assessed by tricuspid annular plane systolic excursion (TAPSE) (22.7 ± 4.0 mm vs. 25.5 ± 4.0 mm, p < 0.001). While cardiac dysfunction was not associated with pulmonary disease, e' and TAPSE were found to correlate with disease activity at baseline. In this cohort of MCTD patients, echocardiographic examinations demonstrated a higher frequency of cardiac dysfunction than in matched controls. Cardiac dysfunction was associated with disease activity at baseline, but was independent of cardiovascular risk factors and pulmonary disease. Our study indicates that cardiac dysfunction is part of the multi-organ affliction seen in MCTD.

Body composition in long-standing juvenile dermatomyositis: associations with disease activity, muscle strength and cardiometabolic measures.

OBJECTIVE: To compare body composition parameters in patients with long-standing JDM and controls and to explore associations between body composition and disease activity/inflammation, muscle strength, health-related quality of life (HRQoL) and cardiometabolic measures. METHODS: We included 59 patients (median disease duration 16.7 y; median age 21.5 y) and 59 age- and sex-matched controls in a cross-sectional study. Active and inactive disease were defined by the PRINTO criteria. Body composition was assessed by total body DXA, inflammation by high-sensitivity CRP (hs-CRP) and cytokines, muscle strength by the eight-muscle manual muscle test, HRQoL by the 36-item Short Form Health Survey physical component score and cardiometabolic function by echocardiography (systolic and diastolic function) and serum lipids. RESULTS: DXA analyses revealed lower appendicular lean mass index (ALMI; reflecting limb skeletal muscle mass), higher body fat percentage (BF%) and a higher android fat:gynoid fat (A:G) ratio (reflecting central fat distribution) in patients than controls, despite similar BMI. Patients with active disease had lower ALMI and higher BF% than those with inactive disease; lower ALMI and higher BF% were associated with inflammation (elevated monocyte attractant protein-1 and hs-CRP). Lower ALMI was associated with reduced muscle strength, while higher BF% was associated with impaired HRQoL. Central fat distribution (higher A:G ratio) was associated with impaired cardiac function and unfavourable serum lipids. CONCLUSION: Despite normal BMI, patients with JDM, especially those with active disease, had unfavourable body composition, which was associated with impaired HRQoL, muscle strength and cardiometabolic function. The association between central fat distribution and cardiometabolic alterations is a novel finding in JDM.

Associations between cardiac and pulmonary involvement in patients with juvenile dermatomyositis-a cross-sectional study.

This study aimed at exploring the association between detectable cardiac and pulmonary involvement in long-term juvenile dermatomyositis (JDM) and to assess if patients with cardiac and pulmonary involvement differ with regard to clinical characteristics. 57 JDM patients were examined mean 17.3 (10.5) years after disease onset; this included clinical examination, myositis specific/associated autoantibodies (immunoblot), echocardiography, pulmonary function tests and high-resolution computed tomography. Cardiac involvement was defined as diastolic and/or systolic left ventricular dysfunction and pulmonary involvement as low diffusing capacity for carbon monoxide, low total lung capacity and/or high-resolution computed tomography abnormalities. Patients were stratified into the following four groups: (i) no organ involvement, (ii) pulmonary only, (iii) cardiac only, and (iv) co-existing pulmonary and cardiac involvement. Mean age was 25.7 (12.4) years and 37% were males. One patient had coronary artery disease, seven had a history of pericarditis, seven had hypertension and three had known interstitial lung disease prior to follow-up. There was no association between cardiac (10/57;18%) and pulmonary (41/57;72%) involvement (p = 0.83). After stratifying by organ involvement, 21% of patients had no organ involvement; 61% had pulmonary involvement only; 7% had cardiac involvement only and 11% had co-existing pulmonary or cardiac involvement. Patients with co-existing pulmonary or cardiac involvement had higher disease burden than the remaining patients. Patients with either cardiac or pulmonary involvement only, differed in clinical and autoantibody characteristics. We found no increased risk of developing concomitant cardiac/pulmonary involvement in JDM. Our results shed light upon possible different underlying mechanisms behind pulmonary and cardiac involvement in JDM.

Novel associations between cytokines and pulmonary involvement in juvenile dermatomyositis - a cross-sectional study of long-term disease.

OBJECTIVES: To examine associations between cytokines and pulmonary involvement in patients with medium- to long-term JDM. METHODS: In a cross-sectional study, 58 patients examined median (range) 16.8 (6.6-27.0) years after symptom onset were stratified in inactive (JDM-inactive) and active (JDM-active) disease (updated PRINTO criteria); 56 age/sex matched controls were included. Twenty-nine cytokines (in serum) were analysed (Luminex technology/ELISA). Pulmonary function test included forced vital capacity, total lung capacity (TLC) and diffusing capacity for carbon monoxide reported as % of predicted and low forced vital capacity/TLC/diffusing capacity for carbon monoxide. In patients, the presence of clinical pulmonary damage was assessed and high resolution computed tomography scans were scored for interstitial lung disease, chest wall calcinosis and airways disease. RESULTS: Median age of patients was 21 (7-55) years, 59% were female and 36% inactive. In JDM-active and all patients, higher MCP-1, IP-10 and eotaxin correlated with high-resolution computed tomography findings (rs 0.34-0.61; P < 0.05). MCP-1 and eotaxin correlated with pulmonary damage in JDM-active and all patients (rs 0.41-0.49; P < 0.01). Higher TGF-ß1 and PDGF (growth factors) were associated with lower lung volumes (forced vital capacity/TLC measures) in all patients; PDGF in JDM-active and TGF-ß1 in JDM-inactive patients. IP-10 correlated with TLC% in JDM-active patients. No associations between cytokines and pulmonary function test were found in controls. CONCLUSIONS: In JDM, we found a novel association (not previously described in myositis) between eotaxin and pulmonary involvement; we have previously shown an association between eotaxin and cardiac dysfunction. The associations between IP-10/growth factors/MCP-1 and pulmonary involvement are novel in JDM and were mostly seen in JDM-active patients.

Cardiovascular rEmodelling in living kidNey donorS with reduced glomerular filtration rate: rationale and design of the CENS study.

Purpose: Until recently, it has been believed that donating a kidney not represents any risk for development of cardiovascular disease. However, a recent Norwegian epidemiological study suggests that kidney donors have an increased long-term risk of cardiovascular mortality. The pathophysiological mechanisms linking reduced kidney function to cardiovascular disease are not known. Living kidney donors are screened for cardiovascular morbidity before unilateral nephrectomy, and are left with mildly reduced glomerular filtration rate (GFR) after donation. Therefore, they represent an unique model for investigating the pathogenesis linking reduced GFR to cardiovascular disease and cardiovascular remodelling. We present the study design of Cardiovascular rEmodelling in living kidNey donorS with reduced glomerular filtration rate (CENS), which is an investigator-initiated prospective observational study on living kidney donors. The hypothesis is that living kidney donors develop cardiovascular remodelling due to a reduction of GFR.Materials and methods: 60 living kidney donors and 60 age and sex matched healthy controls will be recruited. The controls will be evaluated to fulfil the Norwegian transplantation protocol for living kidney donors. Investigations will be performed at baseline and after 1, 3, 6 and 10 years in both groups. The investigations include cardiac magnetic resonance imaging, echocardiography, bone density scan, flow mediated dilatation, laser Doppler flowmetry, nailfold capillaroscopy, office blood pressure, 24-h ambulatory blood pressure, heart rate variability and investigation of microbiota and biomarkers for inflammation, cardiovascular risk and the calcium-phosphate metabolism.Conclusions: The present study seeks to provide new insight in the pathophysiological mechanisms linking reduced kidney function to cardiovascular disease. In addition, we aim to enlighten predictors of adverse cardiovascular outcome in living kidney donors. The study is registered at Clinical-Trials.gov (identifier: NCT03729557).

Cardiorespiratory fitness in long-term juvenile dermatomyositis: a controlled, cross-sectional study of active/inactive disease.

OBJECTIVES: To compare cardiorespiratory fitness (CRF) expressed as maximal oxygen uptake (VO2max) between patients with long-term JDM and controls and between patients with active and inactive disease, as well as to explore exercise limiting factors and associations between CRF and disease variables. METHODS: JDM patients (n = 45) and age- and gender-matched controls (n = 45) performed a cardiopulmonary exercise test (CPET) on a treadmill until exhaustion. Physical activity was measured by accelerometers. Disease activity, damage and muscle strength/function were assessed by validated tools. Clinically inactive disease was defined according to PRINTO criteria. RESULTS: The mean disease duration was 20.8 (s.d. 11.9) years and 29/45 (64%) patients had inactive disease. A low VO2max was found in 27% of patients vs 4% of controls (P = 0.006). The mean VO2max and maximal ventilation (VEmax) were lower in patients with active and inactive disease compared with controls. Patients with active disease also had lower maximal voluntary ventilation (MVV) compared with controls and lower VEmax and MVV compared with those with inactive disease. Patients with inactive disease had lower physical activity levels compared with controls. VO2max correlated negatively with disease damage in patients with inactive disease and positively with muscle strength/function in patients with active disease. CONCLUSION: CRF was lower in JDM patients, both with active and inactive disease, compared with controls after a mean 20 years disease duration. Cardiopulmonary exercise test results suggested different limiting factors contributing to the reduced CRF according to disease activity, including deconditioning in inactive disease and reduced ventilatory capacity in active disease. Further research is needed to verify this.

2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups.

OBJECTIVE: To develop and validate new classification criteria for adult and juvenile idiopathic inflammatory myopathies (IIM) and their major subgroups. METHODS: Candidate variables were assembled from published criteria and expert opinion using consensus methodology. Data were collected from 47 rheumatology, dermatology, neurology and paediatric clinics worldwide. Several statistical methods were used to derive the classification criteria. RESULTS: Based on data from 976 IIM patients (74% adults; 26% children) and 624 non-IIM patients with mimicking conditions (82% adults; 18% children), new criteria were derived. Each item is assigned a weighted score. The total score corresponds to a probability of having IIM. Subclassification is performed using a classification tree. A probability cut-off of 55%, corresponding to a score of 5.5 (6.7 with muscle biopsy) 'probable IIM', had best sensitivity/specificity (87%/82% without biopsies, 93%/88% with biopsies) and is recommended as a minimum to classify a patient as having IIM. A probability of ≥90%, corresponding to a score of ≥7.5 (≥8.7 with muscle biopsy), corresponds to 'definite IIM'. A probability of <50%, corresponding to a score of <5.3 (<6.5 with muscle biopsy), rules out IIM, leaving a probability of ≥50 to <55% as 'possible IIM'. CONCLUSIONS: The European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for IIM have been endorsed by international rheumatology, dermatology, neurology and paediatric groups. They employ easily accessible and operationally defined elements, and have been partially validated. They allow classification of 'definite', 'probable' and 'possible' IIM, in addition to the major subgroups of IIM, including juvenile IIM. They generally perform better than existing criteria.

Development and Initial Validation of the Macrophage Activation Syndrome/Primary Hemophagocytic Lymphohistiocytosis Score, a Diagnostic Tool that Differentiates Primary Hemophagocytic Lymphohistiocytosis from Macrophage Activation Syndrome.

OBJECTIVE: To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic arthritis. STUDY DESIGN: The clinical, laboratory, and histopathologic features of 362 patients with MAS and 258 patients with pHLH were collected in a multinational collaborative study. Eighty percent of the population was assessed to develop the score and the remaining 20% constituted the validation sample. Variables that entered the best fitted model of logistic regression were assigned a score, based on their statistical weight. The MAS/HLH (MH) score was made up with the individual scores of selected variables. The cutoff in the MH score that discriminated pHLH from MAS best was calculated by means of receiver operating characteristic curve analysis. Score performance was examined in both developmental and validation samples. RESULTS: Six variables composed the MH score: age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. The MH score ranged from 0 to 123, and its median value was 97 (1st-3rd quartile 75-123) and 12 (1st-3rd quartile 11-34) in pHLH and MAS, respectively. The probability of a diagnosis of pHLH ranged from <1% for a score of <11 to >99% for a score of ≥123. A cutoff value of ≥60 revealed the best performance in discriminating pHLH from MAS. CONCLUSION: The MH score is a powerful tool that may aid practitioners to identify patients who are more likely to have pHLH and, thus, could be prioritized for functional and genetic testing.

In juvenile dermatomyositis, heart rate variability is reduced, and associated with both cardiac dysfunction and markers of inflammation: a cross-sectional study median 13.5 years after symptom onset.

OBJECTIVES: Low heart rate variability (HRV) is a well-established predictor of cardiac death. The aim of this study was to investigate arrhythmias and HRV in patients with JDM, and associations between HRV and inflammatory markers, echocardiographic measurements and disease parameters. METHODS: Fifty-five patients with JDM were examined 2-34 years (median 13.5 years) after disease onset, and compared with 55 age and sex matched controls. Holter ECG monitoring and echocardiography were analysed blinded to patient information. Arrhythmia and HRV (six parameters) were analysed by standard software, finally adjudicated by an experienced cardiologist. Markers of inflammation (ESR, high sensitivity (hs)CRP and cytokines) were analysed. Disease activity and organ damage were assessed by clinical examination at follow-up and retrospectively by chart review. RESULTS: In two out of six HRV parameters, JDM patients had lower values than controls. No difference in arrhythmias was found between the groups. In patients, but not in controls, there were significant negative correlations between five out of six HRV parameters, and ESR and hsCRP (Spearman correlation coefficient, -0.306 to -0.470; P, 0.023 to <0.001). Also, in patients, negative correlations were found between three out of six HRV parameters and systolic and diastolic function. Active disease and low HRV were associated. Patients with hsCRP in the highest quartile (Q4) had lower HRV in all parameters compared with those in pooled Q1-3 (P < 0.001). CONCLUSION: JDM patients had reduced HRV, which was associated with elevated inflammatory markers, active disease and reduced myocardial function. This suggests reduced vagal control of the heart; further studies are needed to determine whether this is also associated with cardiac morbidity or mortality.

In juvenile dermatomyositis, cardiac systolic dysfunction is present after long-term follow-up and is predicted by sustained early skin activity.

OBJECTIVE: To compare systolic cardiac function in patients with juvenile dermatomyositis (JDM) with matched controls and examine associations between systolic and diastolic cardiac function and disease variables. METHODS: Fifty-nine patients, examined at follow-up, median 16.8 years (2-38 years) after disease onset, were compared with 59 age-matched and sex-matched controls. Echocardiography was performed and analysed blinded to patient information. We used mitral annulus displacement to assess the relative long-axis shortening of the left ventricle (long-axis strain) and early diastolic tissue velocity (e'), as markers for systolic and diastolic function, respectively. Disease activity and organ damage were assessed at follow-up by clinical examination and retrospectively by chart review. RESULTS: Long-axis strain was reduced in patients compared with controls (16.6% (2.5) vs 17.7% (2.0), mean (SD), p=0.001), whereas no difference was seen between patients with active and inactive disease. Disease duration correlated with systolic and diastolic function (rsp=-0.50 and rsp=-0.73, both p<0.001) and so did Myositis Damage Index (MDI) 1 year (rsp=-0.36 and rsp=-0.46) and MDI at follow-up (rsp=-0.33 and rsp=-0.60), all p<0.01. High early disease activity score (DAS) in skin (DAS skin 1 year), but not in muscle, predicted systolic (standardised ß=-0.28, p=0.011, R(2)=48%) and diastolic dysfunction (ß=-0.36, p<0.001, R(2)=72%) at follow-up. CONCLUSIONS: Long-axis strain was reduced in JDM patients compared with controls, suggesting systolic dysfunction. Impaired systolic and diastolic function was predicted by DAS skin 1 year. This indicates a common pathway to two different cardiac manifestations in JDM, perhaps with similar pathogenesis as skin affection.

Disease activity and prognostic factors in juvenile dermatomyositis: a long-term follow-up study applying the Paediatric Rheumatology International Trials Organization criteria for inactive disease and the myositis disease activity assessment tool.

OBJECTIVES: The aims of this study were to examine disease activity by the Paediatric Rheumatology International Trials Organization (PRINTO) criteria for inactive disease and the Myositis Disease Activity Assessment Tool (MDAAT) in JDM patients after long-term follow-up and to identify predictors of these outcomes. METHODS: A retrospective inception cohort of 59 patients diagnosed with JDM was clinically examined in a cross-sectional study a median of 16.8 years (range 2.0-38.1) after symptom onset. Patients were divided by the PRINTO criteria into clinically inactive and active disease. Disease activity was also measured by MDAAT and other validated tools. Medical records were reviewed for early disease variables and medication. RESULTS: By the PRINTO criteria, 31/59 (51%) patients were active and 29/59 (49%) were inactive. By MDAAT, 43/59 (73%) of the patients had measurable disease activity, most commonly found in the skin (59%) and skeletal (27%) systems. MDAAT showed moderate to strong correlations with other disease activity measures (rsp 0.39-0.87, P < 0.05) except for muscle enzymes. Active patients had higher disease activity than inactive patients measured by MDAAT (P < 0.001) and other disease characteristics (all P ≤ 0.002) except for patients' global assessment of disease activity. After controlling for gender and follow-up time, calcinosis during disease-course predicted high MDAAT, age<9 years at diagnosis predicted active disease and organ damage present 6-12 months post diagnosis predicted both outcomes. CONCLUSION: After 16.8 years, 51-73% of JDM patients had active disease. Disease activity by the PRINTO criteria and MDAAT were moderately to highly associated with most other disease characteristics and was predicted by early damage.

In active juvenile dermatomyositis, elevated eotaxin and MCP-1 and cholesterol levels in the upper normal range are associated with cardiac dysfunction.

OBJECTIVE: The aim of this study was to examine the influence of chemokines and lipids on cardiac function in patients with active and inactive JDM and matched controls. METHODS: Fifty-four JDM patients were clinically examined a median 16.8 years (range 2-38) after disease onset and compared with 54 sex- and age-matched controls. Inactive disease was defined by the PRINTO criteria. Serum levels of chemokines were analysed by Luminex technology. Echocardiography was performed and analysed blinded to patient information. Long-axis strain and e' were used as parameters of systolic and diastolic function, respectively. RESULTS: In patients, but not in controls, eotaxin and monocyte chemoattractant protein 1 (MCP-1) correlated with systolic (r = -0.65 and r = -0.45) and diastolic (r = -0.59 and r = -0.65) function, particularly in those with active disease (systolic function, r = -0.74 and r = -0.60; diastolic function, r = -0.69 and r = -0.80). Total cholesterol level was lower in patients than controls [mean 4.19 mmol/l (s.d. 0.82) vs 4.60 (0.87), P ≤ 0.01]. However, total cholesterol levels in the upper normal range were associated with systolic (r = -0.56, P < 0.01) and diastolic (r = -0.64, P < 0.001) dysfunction and with high eotaxin and MCP-1 (r = 0.56 and r = 0.50, P < 0.01) in patients with active disease, but not in those with inactive disease or in controls (all r < ±0.2). CONCLUSION: In the active disease state of JDM, eotaxin and MCP-1 were associated with cardiac dysfunction, possibly through sustained inflammation. In those with active disease and cholesterol levels in the upper normal range, eotaxin and MCP-1 might enhance susceptibility to cardiac dysfunction.

Antibiotic exposure in prenatal and early life and risk of juvenile idiopathic arthritis: a nationwide register-based cohort study.

OBJECTIVES: Early antibiotic exposure influences the gut microbiota which is believed to be involved in the pathogenesis of juvenile idiopathic arthritis (JIA). We aimed to investigate the association between systemic antibiotics in prenatal and early life and risk of JIA. METHODS: We conducted a register-based cohort study including all children born in Norway from 2004 through 2012. The children were followed until 31 December 2020. Main exposures were dispensed antibiotics to the mother during pregnancy and to the child during 0-24 months of age. The outcome was defined by diagnostic codes indicating JIA. Multivariate logistic regression analyses were performed to estimate the association between antibiotic exposure and JIA. RESULTS: We included 535 294 children and their mothers in the analyses; 1011 cases were identified. We found an association between exposure to systemic antibiotics during 0-24 months and JIA (adjusted OR (aOR) 1.40, 95% CI 1.24 to 1.59), with a stronger association for >1 course (aOR 1.50, 95% CI 1.29 to 1.74) vs 1 course (aOR 1.31, 95% CI 1.13 to 1.53). Subanalyses showed significant associations in all age periods except 0-6 months, and stronger association with sulfonamides/trimethoprim and broad-spectrum antibiotics. There was no association between prenatal antibiotic exposure and JIA. CONCLUSIONS: The novel observation of no association with prenatal antibiotic exposure and JIA suggests that the association between antibiotics in early life and JIA is unlikely to be confounded by shared family factors. This may indicate that exposure to antibiotics in early life is an independent risk factor for JIA.

Adipokine profile in long-term juvenile dermatomyositis, and associations with adipose tissue distribution and cardiac function: a cross-sectional study.

OBJECTIVES: In long-term juvenile dermatomyositis (JDM), altered adipose tissue distribution and subclinical cardiac dysfunction have been described. Our aims were to compare adipokine levels in patients with JDM after long-term disease with controls, and explore associations between adipokines and (1) adipose tissue distribution and (2) cardiac function. METHODS: The study cohort included 59 patients with JDM (60% female, mean age 25.2 years, mean disease duration 16.9 years), and 59 age/sex-matched controls. Updated Pediatric Rheumatology International Trials Organization criteria for clinically inactive JDM were used to stratify patients into active (JDM-active) or inactive (JDM-inactive) disease groups. Lipodystrophy was clinically assessed in all patients. In all study participants, we measured adipose tissue distribution by dual-energy X-ray absorptiometry and cardiac function by echocardiography. Serum adipokines (adiponectin, apelin-12, lipocalin-2, leptin, visfatin and resistin) were analysed using ELISA. RESULTS: Patients with JDM had higher leptin levels compared with controls (p≤0.01). In JDM-active, apelin-12 and visfatin were higher compared with JDM-inactive (p≤0.05). In JDM-total and JDM-active, lower adiponectin correlated with lipodystrophy and total fat mass. Also, systolic dysfunction correlated with: lower adiponectin in JDM-total, JDM-inactive and JDM-active, and with lower apelin-12 in JDM-total and JDM-active and resistin in JDM-active (all p≤0.05). Lower adiponectin correlated with diastolic dysfunction in JDM-total and JDM-active. CONCLUSION: After long-term disease, leptin levels were unfavourably regulated in patients with JDM compared with controls, and apelin-12 and visfatin in JDM-active versus JDM-inactive. We found associations between adipokines and both adipose tissue distribution and cardiac systolic function in all patients with JDM, which was most prominent in patients with active disease.

Validity and Reliability of Four Parent/Patient-Reported Outcome Measures for Juvenile Idiopathic Arthritis Remote Monitoring.

OBJECTIVE: The aim of this work was to provide evidence of validity and reliability for 4 parent/child-reported outcome measures included in the Outcome Measures in Rheumatology juvenile idiopathic arthritis core domain set: the evaluation of the child's pain and level of disease activity, the assessment of morning stiffness duration, and an active joint count for proxy/self-assessment. METHODS: Patients were included in the multinational study Epidemiology Treatment and Outcome of Childhood Arthritis. Criterion validity was assessed by examining the correlation of the 4 tested measures with physician measures and the clinical Juvenile Arthritis Disease Activity Score in 10 joints (cJADAS10) in the whole sample and after grouping patients by International League of Associations for Rheumatology (ILAR) category, geographic area, and education level. Reliability was assessed comparing 2 visits 7-14 days apart with intraclass correlation coefficients (ICCs). RESULTS: A total of 8,643 parents and 6,060 patients had all the evaluations available. Correlations of tested measures were moderate (0.4-0.7) with physician-reported measures. The level of correlation with the cJADAS10 remained stable after grouping patients by ILAR category, geographic areas, and level of education of the parent filling the questionnaire. In 442 parents and 344 children, ICCs ranged between 0.79 and 0.87 for parents and 0.81 and 0.88 for children. CONCLUSION: The 4 tested parent/child-reported outcomes showed good criterion validity and excellent reliability. These tools can be considered for remote patient assessment, when in-person evaluation might not be possible.

Anakinra in Patients With Systemic Juvenile Idiopathic Arthritis: Long-term Safety From the Pharmachild Registry.

OBJECTIVE: To evaluate the long-term safety profile of anakinra in patients with systemic juvenile idiopathic arthritis (sJIA). METHODS: Data from patients with sJIA enrolled in the Pharmachild registry (ClinicalTrials.gov: NCT03932344) prior to September 30, 2018, and treated with anakinra were analyzed. The study endpoints were the occurrence of non-serious adverse events (SAEs) of at least moderate severity and SAEs, including macrophage activation syndrome (MAS), and the duration of anakinra treatment with reasons for discontinuation. All endpoints were analyzed overall by 6-month time windows, and in different treatment sets represented by those patients treated continuously with anakinra for at least 12, 18, and 24 months (set-12, -18, and -24, respectively). RESULTS: Three hundred six patients were enrolled. Of these patients, 46%, 34%, and 28% had been treated for at least 12, 18, and 24 months, respectively. Two hundred and one AEs, mostly represented by infections, were reported for 509.3 patient-years (PY) with an overall incidence rate (IR) of 39.5 per 100 PY. Among 56 SAEs (IR 11.0/100 PY), 23.2% were infections and 19.6% MAS episodes. The IR of AEs was higher during the first 6 months of anakinra treatment, followed by decreasing IRs in the long-term treatment sets. Treatment discontinuation occurred in 76% of patients, most frequently in the first 6 months, because of inefficacy (43%), remission (31%), or AEs/intolerance (15%). No deaths or malignancies occurred during anakinra treatment. CONCLUSION: The results of the present study confirm the long-term safety profile of anakinra in patients with sJIA and demonstrate an overall decreasing incidence of AEs over time. [ClinicalTrials.gov: NCT01399281 and NCT03932344].

Cardiac dysfunction in juvenile dermatomyositis: a case-control study.

OBJECTIVE: To compare cardiac function in patients with juvenile dermatomyositis (JDM) with matched controls, and examine associations between pathological electrocardiography (ECG), echocardiographic abnormalities and disease variables in patients with JDM. METHODS: A total of 59 patients with JDM, examined a median 16.8 years (range 2-38 years) after disease onset, were compared with 59 age-matched and sex-matched controls. Echocardiography, including early diastolic transmitral flow/early diastolic tissue velocity (E/E') as a marker for diastolic dysfunction, and 12-channel ECG were performed and analysed blinded to patient information. Disease activity and damage were assessed by clinical examination at follow-up and chart review. RESULTS: E/E' was elevated (>9.5) in 13 (22%) patients versus 0 controls (p<0.001). In all, 10 patients presented with pathological ECG compared to 4 controls (p=0.054). Previous or current hypertension was found in 12 patients versus 0 controls (p<0.001). Among the patients, pathological ECG was found in 6/13 patients with versus 4/44 without elevated E/E' (p=0.002); and systolic blood pressure was correspondingly 132±24 mm Hg versus 112±18 mm Hg in the groups (p=0.012). E/E' correlated with cumulative organ damage assessed at follow-up (r(sp) 0.41, p=0.001) and disease activity at 1 year (r(sp) 0.56, p<0.001), which also predicted pathological E/E' after controlling for age and gender. During disease course, 12% of patients with JDM developed pericarditis. CONCLUSION: Only patients with JDM and no controls had subclinical left ventricular diastolic dysfunction; the patients with elevated E/E' also had high prevalence of pathological ECG and hypertension. High disease activity 1-year post diagnosis predicted high E/E' at follow-up. The findings suggest that subclinical heart disease is related to the systemic nature of JDM.