Definition and Validation of the American College of Rheumatology 2021 Juvenile Arthritis Disease Activity Score Cutoffs for Disease Activity States in Juvenile Idiopathic Arthritis.

OBJECTIVE: To develop and validate new Juvenile Arthritis Disease Activity Score 10 (JADAS10) and clinical JADAS10 (cJADAS10) cutoffs to separate the states of inactive disease (ID), minimal disease activity (MiDA), moderate disease activity (MoDA), and high disease activity (HDA) in children with oligoarthritis and with rheumatoid factor-negative polyarthritis, based on subjective disease assessment by the treating pediatric rheumatologist. METHODS: The cutoffs definition cohort was composed of 1,936 patients included in the multinational Epidemiology, Treatment and Outcome of Childhood Arthritis (EPOCA) study. Using the subjective physician rating as an external criterion, 4 methods were applied to identify the cutoffs: mapping, Youden index, 90% specificity, and maximum agreement. The validation cohort included 4,014 EPOCA patients, patients from 2 randomized trials, and 88 patients from the PharmaChild registry. Cutoff validation was conducted by assessing discriminative and predictive ability. RESULTS: The JADAS10 cutoffs were 1.4, 4, and 13, respectively, for oligoarthritis and 2.7, 6, and 17, respectively, for polyarthritis. The cJADAS10 cutoffs were 1.1, 4, and 12, respectively, for oligoarthritis and 2.5, 5, and 16, respectively, for polyarthritis. The cutoffs discriminated strongly among different levels of pain and morning stiffness, between patients who were and those who were not prescribed a new medication, and between different levels of improvement in clinical trials. Achievement of ID and MiDA according to the new JADAS cutoffs at least twice in the first year of disease predicted better outcome at 2 years. CONCLUSION: The 2021 JADAS and cJADAS cutoffs revealed good metrologic properties in both definition and validation samples, and are therefore suitable for use in clinical trials and routine practice.

Association analysis of juvenile idiopathic arthritis genetic susceptibility factors in Estonian patients.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition of childhood. Genetic association studies have revealed several JIA susceptibility loci with the strongest effect size observed in the human leukocyte antigen (HLA) region. Genome-wide association studies have augmented the number of JIA-associated loci, particularly for non-HLA genes. The aim of this study was to identify new associations at non-HLA loci predisposing to the risk of JIA development in Estonian patients. METHODS: We performed genome-wide association analyses in an entire JIA case-control sample (All-JIA) and in a case-control sample for oligoarticular JIA, the most prevalent JIA subtype. The entire cohort was genotyped using the Illumina HumanOmniExpress BeadChip arrays. After imputation, 16,583,468 variants were analyzed in 263 cases and 6956 controls. RESULTS: We demonstrated nominal evidence of association for 12 novel non-HLA loci not previously implicated in JIA predisposition. We replicated known JIA associations in CLEC16A and VCTN1 regions in the oligoarticular JIA sample. The strongest associations in the All-JIA analysis were identified at PRKG1 (P = 2,54 × 10-6), LTBP1 (P = 9,45 × 10-6), and ELMO1 (P = 1,05 × 10-5). In the oligoarticular JIA analysis, the strongest associations were identified at NFIA (P = 5,05 × 10-6), LTBP1 (P = 9,95 × 10-6), MX1 (P = 1,65 × 10-5), and CD200R1 (P = 2,59 × 10-5). CONCLUSION: This study increases the number of known JIA risk loci and provides additional evidence for the existence of overlapping genetic risk loci between JIA and other autoimmune diseases, particularly rheumatoid arthritis. The reported loci are involved in molecular pathways of immunological relevance and likely represent genomic regions that confer susceptibility to JIA in Estonian patients. Key Points • Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease with heterogeneous presentation and genetic predisposition. • Present genome-wide association study for Estonian JIA patients is first of its kind in Northern and Northeastern Europe. • The results of the present study increase the knowledge about JIA risk loci replicating some previously described associations, so adding weight to their relevance and describing novel loci. • The study provides additional evidence for the existence of overlapping genetic risk loci between JIA and other autoimmune diseases, particularly rheumatoid arthritis.

The Estonian version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient-reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Estonian language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability, and construct validity (convergent and discriminant validity). A total of 110 JIA patients (71.8% oligoarticular, 18.2% RF-negative polyarthritis, 10% other categories) and 98 healthy children were enrolled in one paediatric rheumatology centre. Notably, none of the enrolled JIA patients is affected with systemic JIA. The JAMAR components discriminated healthy subjects from JIA patients, except for the Paediatric Rheumatology Quality of Life (HRQoL) Psychosocial Health (PsH) subscales and for the satisfaction with current health status. All JAMAR components revealed good psychometric performances. In conclusion, the Estonian version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.

Low Serum IGF-1 in Boys with Recent Onset of Juvenile Idiopathic Arthritis.

BACKGROUND: Liver-derived insulin-like growth factor-1 (IGF-1) contributes bone formation. Decreased IGF-1 levels are common in juvenile idiopathic arthritis (JIA), but whether IGF-1 is related to sex and differ during the pathogenic progress of JIA is unknown. OBJECTIVE: The aim of this study was to examine IGF-1 levels in boys and girls with newly diagnosed JIA, with established JIA and in controls. METHODS: The study group included 131 patients from the Estonian population-based prevalence JIA study. Blood samples were obtained from 27 boys and 38 girls with early JIA (≤1 month from the diagnosis), 29 boys and 36 girls with established JIA (mean disease duration 18 months), and from 47 age- and sex-matched controls. RESULTS: IGF-1 levels in boys were significantly decreased in early JIA compared to male controls, while IGF-1 levels in girls were comparable between JIA and controls. In early JIA, IGF-1 levels were 12-fold lower in boys relative to girls. In controls, IGF-1 levels correlated with both age and height, while these correlations were lost in boys with early JIA. CONCLUSION: We report a sex-dependent deficiency in serum IGF-1 in boys with early JIA, which argues for sex-related differences in biological mechanisms involved in the disease pathogenesis.

High mobility group box protein 1-A prognostic marker for structural joint damage in 10-year follow-up of patients with juvenile idiopathic arthritis.

OBJECTIVE: High mobility group box protein 1 (HMGB1) is an important pro-inflammatory mediator in adult rheumatoid arthritis. The diagnostic utility of HMGB1 in Juvenile Idiopathic Arthritis (JIA) is still unclear. The aim was to examine whether serum HMGB1 levels are associated with inflammation, radiological disease progression, and long-term prognosis in JIA. METHODS: We included 131 children with JIA from a population-based prevalence study; 38 of them were prospectively followed up for 10 years. Clinical and laboratory disease characteristics at study entry and after 10 years as well as radiological progression over 10 years were recorded. HMGB1 levels were analyzed by an ELISA. RESULTS: The HMGB1 levels were similar in children with different JIA subgroups and in children with established (53%) or newly diagnosed (47%) disease. HMGB1 levels did not differ between groups at entry into the study or at 10 years, by sex, or by the presence or absence of RF or ANA antibodies. HMGB1 levels at the study entry correlated with HMGB1 levels at 10 years and with blood neutrophil count. Most importantly, children with destructive arthritis at 10 years had a tendency toward higher HMGB1 levels at study entry (median 1.2 vs 0.6ng/ml, ns) and displayed 4-fold higher circulating HMGB1 levels (median 3.4 vs 0.8ng/ml, p = 0.0014) than children without radiological destructions. CONCLUSIONS: Our results suggest that HMGB1 is a marker of inflammatory activity in children with JIA. Higher serum HMGB1 levels are related to more destructive JIA and could be used as a negative prognostic marker at the disease start. TRIAL REGISTRATION: Clinicaltrials.gov NCT01905319. Registered July 16, 2013.

Contemporary management of TMJ involvement in JIA patients and its orofacial consequences.

Juvenile idiopathic arthritis is the most common chronic rheumatic condition during childhood. Temporomandibular joint arthritis is frequently asymptomatic. When it takes place during childhood, it may affect condylar growth; therefore, these children are at risk of unfavorable long-term outcomes from the associated joint damage. The etiology is not completely understood, but it is considered as multifactorial with both genetic and environmental factors involved. The standardized examination and imaging protocols serve important purpose to diagnose temporomandibular joint (TMJ) arthritis not only to establish an early interventional strategy but also to assess craniofacial growth and the progression of signs and symptoms in those patients. Although the treatment of juvenile idiopathic arthritis (JIA) has changed dramatically over the last decades due to new therapeutic options, TMJ arthritis still can develop during the course of the disease. In clinical experience, TMJs appear to respond less well to the standard of care used to treat other joints. More individualized approach to the patient's treatment serves as the main goal of personalized medicine. It could be achieved by adopting new methods of medical imaging such as conebeam computer tomography as well as developing reliable biomarkers which may assist with predicting disease type, course, or severity and predicting response to medication. This article provides an overview of current information on orofacial complications in JIA and its management. Based on information provided in this review, more precise diagnosis, proper tools for recognizing people at risk, and more efficient treatment approaches could be implemented. This may lead to more personalized treatment management strategies of TMJ complications of JIA patients.

Increased carotid artery intima-media thickness and myeloperoxidase level in children with newly diagnosed juvenile idiopathic arthritis.

INTRODUCTION: Juvenile idiopathic arthritis (JIA) is a frequent childhood rheumatic disease characterized by chronic inflammation. The latter has been related to impairment of arterial functional-structural properties, atherogenesis and later cardiovascular events. The objective of this study was to examine intima-media thickness (IMT) and the parameters of arterial stiffness in children with JIA at diagnosis and their correlation with JIA subtype and markers of inflammation and atherosclerosis. METHODS: Thirty-nine newly diagnosed patients with JIA (26 girls; mean age, 13.2 ± 2.6 years) and 27 healthy controls (9 girls; mean age, 13.6 ± 3.4 years) were included in the study. Twelve patients had oligoarthritis, fifteen had extended oligoarthritis and twelve had rheumatoid factor-negative polyarthritis. IMT of the common carotid artery was determined by ultrasonography, carotid-femoral pulse wave velocity (cfPWV) and augmentation index adjusted to a heart rate of 75 beats/min (AIx@75) were determined by applanation tonometry. The serum levels of atherosclerosis-related biomarkers, such as asymmetric dimethylarginine (ADMA), myeloperoxidase (MPO) and adiponectin, were measured by enzyme-linked immunosorbent assay. RESULTS: Mean IMT (0.46 ± 0.04 vs. 0.42 ± 0.04 mm; p = 0.0003) and MPO concentration (115.2 [95% confidence interval {95% CI}, 97.4-136.3] vs. 57.6 [95% CI, 47.1-70.3] ng/ml; p < 0.0001) were higher in the patients with JIA than in the control subjects. The cfPWV, AIx@75 and serum ADMA and adiponectin levels did not significantly differ between the groups and JIA subtypes. Serum adiponectin level correlated negatively with AIx@75 in patients with JIA (r = -0.38; p < 0.05). CONCLUSIONS: Patients with JIA have increased mean IMT and elevated MPO levels at early stages of the disease. AIx@75 was inversely independently associated with adiponectin level in the patients, suggesting that lower adiponectin levels might influence arterial subclinical stiffening in patients with newly diagnosed JIA.

HMGB1 levels are increased in patients with juvenile idiopathic arthritis, correlate with early onset of disease, and are independent of disease duration.

OBJECTIVE: High mobility group box chromosomal protein 1 (HMGB1) has been implicated as a mediator of inflammation in rheumatoid arthritis (RA), while its role in juvenile idiopathic arthritis (JIA) has not been described. To evaluate the role of HMGB1 in the inflammatory process in JIA and its potential as a therapeutic target, we investigated whether extracellular HMGB1 is detectable in JIA and if so, to correlate the levels with established inflammatory markers and clinical measures. METHODS: Matching samples of blood and synovial fluid (SF) were collected from 23 patients with JIA. Levels of HMGB1, soluble receptor for advanced glycation endproducts, S100A12, myeloid-related protein 8/14, and other inflammatory mediators were analyzed. RESULTS: Significantly increased HMGB1 levels were recorded in SF compared to blood samples from patients with JIA. The amount of HMGB1 was highest in patients with early disease onset irrespective of disease duration. In contrast, the proinflammatory S100 protein and interleukin 8 were highest in patients in early phases of disease. Matrix metalloproteinase-3, a marker of cartilage destruction, was higher in patients with late disease onset, indicating similarities with RA in that patient subgroup. CONCLUSION: Levels of extracellular HMGB1 are increased in the inflamed joints of patients with JIA. This warrants further studies of HMGB1 as a mediator of JIA pathogenesis as well as a biomarker for inflammatory activity and as a target for therapy. The variation in levels of HMGB1 and S100 proteins in relation to disease onset indicates a difference in inflammatory phenotype during disease progression.

EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria.

OBJECTIVES: To validate the previously proposed classification criteria for Henoch-Schönlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA). METHODS: Step 1: retrospective/prospective web-data collection for children with HSP, c-PAN, c-WG and c-TA with age at diagnosis

Inflammatory/oxidative stress during the first week after different types of cardiac surgery.

OBJECTIVES: To compare inflammatory and oxidative stress time course during the first week after different types of cardiac surgery. DESIGN: In patients undergoing coronary artery bypass grafting with cardiopulmonary bypass (CABG) or on the working heart (OPCAB) and aortic valve replacement (VALVE) blood samples for high-sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6), myeloperoxidase (MPO), asymmetric dimethylarginine (ADMA) and homocysteine (Hcy) were taken preoperatively and for six consecutive postoperative days. RESULTS: Exploitation of cardiopulmonary bypass (CABG, VALVE groups), but not OPCAB, resulted in significant rise of MPO for two postoperative days. ADMA and Hcy changed in parallel fashion, being significantly decreased in the first postoperative morning and rising to the preoperative levels thereafter. In comparison with coronary artery disease patients, VALVE group had lower preoperative levels of ADMA and different postoperative time course. Postoperative concentrations of IL-6 and hsCRP were increased significantly in all groups and remained elevated during the first postoperative week. CONCLUSIONS: Cardiac surgery results in extensive and complex inflammatory/oxidative stress response regardless of the method or type of surgical procedure used. Myeloperoxidase could be one of the parameters to evaluate the cardiopulmonary bypass-associated inflammatory and oxidative stress response.