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Objective: Characterization of the stages that patients with juvenile idiopathic arthritis (JIA) pass until they are diagnosed, and analysis of the different causes that lead to a delay in JIA diagnosis in Israel., Methods: This is a retrospective cohort study conducted in 8 pediatric rheumatology centers in Israel. All patients diagnosed with JIA between October 2017 and October 2019 were included in the study. Demographic, clinical, and data regarding the referring physicians were collected from hospital and community medical charts., Results: Of 207 patients included in the study, 201 cases were analyzed, 71.1% of the population were female. Patients, on average, were evaluated during the diagnostic process by 3.1 different physicians. In most cases, they initially met with a pediatrician in the community setting (61.2%), and later, most commonly referred to a rheumatologist by the community pediatrician (27.9%). The median time until diagnosis was 56.0 days (range: 1.0-2451.0 days). Patients diagnosed with polyarticular and spondyloarthritis/enthesitis-related arthritis (SpA/ERA) JIA subtypes had the longest period until diagnosis (median: 115.5 and 112.0 days, respectively). Younger age correlated with a quicker diagnosis, and females were diagnosed earlier compared to males. Fever at presentation significantly shortened the time to diagnosis ( P < 0.01), whereas involvement of the small joints/sacroiliac joints significantly lengthened the time ( P < 0.05)., Conclusion: This is the first nationwide multicenter study that analyzes obstacles in the diagnosis of JIA in Israel. Raising awareness about JIA, especially for patients with SpA/ERA, is crucial in order to avoid delays in diagnosis and treatment., (Copyright © 2023 by the Journal of Rheumatology.)

Objectives: Some adults with rheumatic and musculoskeletal diseases (RMDs) are at increased risk of COVID-19-related death. Excluding post-COVID-19 multisystem inflammatory syndrome of children, children and young people (CYP) are overall less prone to severe COVID-19 and most experience a mild or asymptomatic course. However, it is unknown if CYP with RMDs are more likely to have more severe COVID-19. This analysis aims to describe outcomes among CYP with underlying RMDs with COVID-19., Methods: Using the European Alliance of Associations for Rheumatology COVID-19 Registry, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry, and the CARRA-sponsored COVID-19 Global Paediatric Rheumatology Database, we obtained data on CYP with RMDs who reported SARS-CoV-2 infection (presumptive or confirmed). Patient characteristics and illness severity were described, and factors associated with COVID-19 hospitalisation were investigated., Results: 607 CYP with RMDs <19 years old from 25 different countries with SARS-CoV-2 infection were included, the majority with juvenile idiopathic arthritis (JIA; n=378; 62%). Forty-three (7%) patients were hospitalised; three of these patients died. Compared with JIA, diagnosis of systemic lupus erythematosus, mixed connective tissue disease, vasculitis, or other RMD (OR 4.3; 95% CI 1.7 to 11) or autoinflammatory syndrome (OR 3.0; 95% CI 1.1 to 8.6) was associated with hospitalisation, as was obesity (OR 4.0; 95% CI 1.3 to 12)., Conclusions: This is the most significant investigation to date of COVID-19 in CYP with RMDs. It is important to note that the majority of CYP were not hospitalised, although those with severe systemic RMDs and obesity were more likely to be hospitalised., Competing Interests: Competing interests: RC reports personal AstraZeneca shares, unrelated to this manuscript. IK-P reports personal fees by Novartis, SOBI, Chugai, Pfizer, AbbVie, BMS, all unrelated to this manuscript. FOR reports consulting/speaker’s fees from Abbvie, Novartis, Pfizer and Sobi, all unrelated to this manuscript. NMW reports personal consultant fees from UCB, BMS, all unrelated to this manuscript. AS reports personal fees from lectures for AbbVie, Celltrion, MSD, Janssen, Lilly, Roche, BMS, and Pfizer, all unrelated to this manuscript. EFM reports personal consultant fees from Boehringer Ingelheim Portugal, Lda, all unrelated to this manuscript. LPCDR received support for specific activities: grants from Abbvie, Novartis, Lilly Portugal, Amgen Biofarmacêutica, Grünenthal S.A., MSD, Medac, A. Menarini Portugal - Farmacêutica, S.A., Pfizer, UCB Pharma, Roche Farmacêutica Química, Lda; and non-financial support from Pfizer, and Grünenthal GmbH, all unrelated to this manuscript.PMM has received consulting/speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript, and is supported by the National Institute for Health Research (NIHR), University College London Hospitals (UCLH), Biomedical Research Centre (BRC). MN reports funding from Childhood Arthritis & Rheumatology Research Alliance, Inc (CARRA) to his informatics research and operations group at Boston Children’s Hospital in its capacity as the CARRA Data Warehouse and associated work for CARRA and the CARRA Registry and has sponsored the COVID-19 Global Pediatric Rheumatology Database study, of which he is the Principal Investigator. MN also serves as Director of Informatics for CARRA, for which he receives no direct compensation but do receive research sponsorship for CARRA-related research, development, and operations (see above). He is also a co-investigator of the CARRA Registry and site Principal Investigator at Massachusetts General Hospital. KLH reports non-personal speaker’s fees from Abbvie and grant income from BMS, UCB, and Pfizer, all unrelated to this manuscript, and is supported by the NIHR Manchester Biomedical Research Centre. All other authors report no disclosures., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The aim of this study was to determine the seasonality of month of birth (MOB) in children with juvenile idiopathic arthritis (JIA) as compared to the general population., Methods: Cosinor analysis was used to analyse MOB rhythmicity in 558 children with JIA from a simple rheumatology clinic compared with the MOB pattern of the general population in Israel (n=1.040558). Statistical differences between groups were also analysed by non-parametrical tests., Results: Patients with JIA showed different patterns from that of the general population. A rhythmic pattern of 12 months was found in the MOB patterns of JIA patients. This rhythm with a peak between November to March and a nadir in summer was a mirror image of the rhythmic pattern observed for MOB of the healthy population. Males showed a pattern with combined rhythm of 8 and 6 months with peaks in winter, while females' MOB pattern showed no rhythmicity. Testing different JIA subtypes, only the patients with the enthesitis-related arthritis (ERA) subtype showed rhythmicity in MOB. Rhythmicity patterns were different for males and females, and differed according to several disease characteristics., Conclusions: The observed pattern of MOB in JIA patients is distinctive and different from that in the healthy population supporting the hypothesis that autoimmune process may begin in utero or in the perinatal period due to seasonal environmental pathogenic agents.

In recent years, it has become increasingly clear that the term Juvenile Idiopathic Arthritis (JIA) comprises not one disease but several. Moreover, recent studies strongly suggest that some of these clinico-pathophysiologic entities appear to cross current diagnostic categories. The ultimate goal of the JIA classification is to facilitate development of better, more specific therapy for different forms of disease though improved understanding of pathophysiology. The past two decades have witnessed significant advances in treatment and improved outcomes for many children with chronic arthritis. However, understanding of the basic biologic processes underlying these diseases remains far from complete. As a result, even the best biologic agents of today represent "halfway technologies". Because they do not treat fundamental biologic processes, they are inherently expensive, need to be given for a long time in order to ameliorate the adverse effects of chronic inflammation, and do not cure the disease. Pediatric rheumatology is now entering an era in which diagnostic categories may need to change to keep up with discovery. A more precise, biologically based classification is likely to contribute to development of more specific and improved treatments for the various forms of childhood arthritis. In this review, we discuss how genetic, gene expression, and immunologic findings have begun to influence how these diseases are understood and classified., (Copyright © 2014. Published by Elsevier Ltd.)

Pentraxin 3 (PTX3) is an acute phase protein produced in different body tissues. The aims of this study were to characterize PTX3 secretion in synovial fluid (SF) of juvenile idiopathic arthritis (JIA) patients and to analyze the correlation of PTX3 levels in SF with clinical characteristics and the course of the disease. SF-PTX3 levels were measured in a cohort of 75 consecutive JIA patients followed in a single center. Patients' clinical characteristics, disease course, and therapies were analyzed for their correlation with SF-PTX3 levels. A synovial cell line was used to study the kinetics of PTX3 secretion by synoviocytes. SF-PTX3 levels varied over a wide range. Elevated SF-PTX3 levels were detected in patients who subsequently required treatment with disease-modifying antirheumatic drugs during the follow-up period. SF-PTX3 levels were found to be inversely correlated with the length of time from onset of joint swelling. No correlation was found between synovial and serum PTX3 or C-reactive protein (CRP). Following in vitro stimulation of synovial cell line with TNFa or IL1, the secretion of PTX3 increases transiently in the first 48-72 h. A similar increase was obtained in patients' synovial fluids but not with IL6. Higher SF-PTX3 levels were found when tested closer to arthritis exacerbation and 48-72 h after in vitro stimulation of cells from a synovial cell line, implying that PTX3 plays a role in early stages of inflammation. Higher SF-PTX3 levels were associated with several clinical features reflecting disease severity and prognostic data. Measuring SF-PTX3 levels may help in providing a more focused and patient-adjusted treatment.

Background: Interleukin-1 is pivotal in the pathogenesis of systemic juvenile idiopathic arthritis (JIA). We assessed the efficacy and safety of canakinumab, a selective, fully human, anti-interleukin-1β monoclonal antibody, in two trials., Methods: In trial 1, we randomly assigned patients, 2 to 19 years of age, with systemic JIA and active systemic features (fever; ≥2 active joints; C-reactive protein, >30 mg per liter; and glucocorticoid dose, ≤1.0 mg per kilogram of body weight per day), in a double-blind fashion, to a single subcutaneous dose of canakinumab (4 mg per kilogram) or placebo. The primary outcome, termed adapted JIA ACR 30 response, was defined as improvement of 30% or more in at least three of the six core criteria for JIA, worsening of more than 30% in no more than one of the criteria, and resolution of fever. In trial 2, after 32 weeks of open-label treatment with canakinumab, patients who had a response and underwent glucocorticoid tapering were randomly assigned to continued treatment with canakinumab or to placebo. The primary outcome was time to flare of systemic JIA., Results: At day 15 in trial 1, more patients in the canakinumab group had an adapted JIA ACR 30 response (36 of 43 [84%], vs. 4 of 41 [10%] in the placebo group; P<0.001). In trial 2, among the 100 patients (of 177 in the open-label phase) who underwent randomization in the withdrawal phase, the risk of flare was lower among patients who continued to receive canakinumab than among those who were switched to placebo (74% of patients in the canakinumab group had no flare, vs. 25% in the placebo group, according to Kaplan-Meier estimates; hazard ratio, 0.36; P=0.003). The average glucocorticoid dose was reduced from 0.34 to 0.05 mg per kilogram per day, and glucocorticoids were discontinued in 42 of 128 patients (33%). The macrophage activation syndrome occurred in 7 patients; infections were more frequent with canakinumab than with placebo., Conclusions: These two phase 3 studies show the efficacy of canakinumab in systemic JIA with active systemic features. (Funded by Novartis Pharma; ClinicalTrials.gov numbers, NCT00889863 and NCT00886769.).

The pathogenesis of juvenile idiopathic arthritis (JIA) is thought to involve multiple components of the cellular immune system, including subsets of γδ T cells. In this study, we conducted experiments to define the functional roles of one of the major synovial fluid (SF) T cell subsets, Vγ9(+)Vδ2(+) (Vγ9(+)) T cells, in JIA. We found that as opposed to CD4(+) T cells, equally high percentages (∼35%) of Vγ9(+) T cells in SF and peripheral blood (PB) produced TNF-α and IFN-γ. Furthermore, stimulation with isopentenyl pyrophosphate (IPP), a metabolite in the mevalonate pathway, which is a specific potent Ag for Vγ9Jγ1.2(+) T cells, similarly amplified cytokine secretion by SF and PB Vγ9(+) T cells. Significantly, the SF subset expressed higher levels of CD69 in situ, suggesting their recent activation. Furthermore, 24-h coculturing with SF-derived fibroblasts enhanced CD69 on the SF > PB Vγ9(+) T cells, a phenomenon strongly augmented by zoledronate, a farnesyl pyrophosphate synthase inhibitor that increases endogenous intracellular IPP. Importantly, although Vγ9(+) T cell proliferation in response to IPP was significantly lower in SF than PBMC cultures, it could be enhanced by depleting SF CD4(+)CD25(+)FOXP3(+) cells (regulatory T cells). Furthermore, coculture with the Vγ9(+) T cells in medium containing zoledronate or IPP strongly increased SF-derived fibroblasts' apoptosis. The findings that IPP-responsive proinflammatory synovial Vγ9(+) T cells for which proliferation is partly controlled by regulatory T cells can recognize and become activated by SF fibroblasts and then induce their apoptosis suggest their crucial role in the pathogenesis and control of synovial inflammation.

Introduction: Juvenile idiopathic arthritis (JIA) is an autoimmune disease where T cells are key players. It can be classified into two main clinical diseases: polyarticular and pauciarticular, based on the number of joints involved. Oligoarthritis, which is considered a pauciarticular subtype since it involves up to four joints upon presentation, is further divided into persistent or extended forms based on disease progression., Methodology/principal Findings: Here we assessed the T-cell compartment in synovial fluid obtained from 33 JIA patients with active disease and correlated the analyzed parameters with the patients' clinical characteristics. The T-cell compartment was determined by the representation of T-cell receptor (TCR) repertoires and the amount of TCR excision circles (TRECs)., Results: Patients with polyarticular disease have more a clonal pattern of their TCR repertoire. These findings were consistent in all tested TCR-Vγ consensus primers. Similarly, patients with polyarticular disease had lower TREC levels than patients with pauciarticular disease. A predictive value of TRECs may be suggested, as lower TREC levels were observed in patients in whom disease modifying anti rheumatic drugs were initiated subsequently during the follow-up., Conclusion: In pediatric JIA patients, we showed an alteration in the T cells from synovial fluid, which correlated with disease phenotype, assumedly secondary to enhanced proliferation, clonal TCR restriction, and reduced T-cell production, possibly reflecting a different disease or a different course of disease progression.

Objective: To assess linear growth in patients with persistent oligoarticular juvenile idiopathic arthritis (JIA) treated by intra-articular corticosteroid injections (IACSI)., Study Design: Data were obtained from a retrospective review of the charts of 95 patients with persistent oligoarticular JIA (69 females). The mean age at first visit was 4.9 ± 3.4 years, with follow-up of 6 ± 3.7 years. The height SDS for chronologic age (z-score) was correlated with the clinical course of the disease and compared among patients treated by IACSI alone (group I) or by a combination of disease-modifying antirheumatic drugs (DMARDs) (group II)., Results: Growth retardation was found in 35.8% of patients (Δ z-score <-0.3), including 11.6% with severe growth retardation (Δ z-score <-1.0). Growth retardation was found in a smaller proportion of patients in group I (any growth retardation, 30.6%; severe growth retardation, 6.5%) than in patients in group II (any growth retardation, 44.4%; severe growth retardation, 21.2%; P < .05). Elevated erythrocyte sedimentation rate values (≥ 40 mm/1sth) indicated a significantly higher risk for growth retardation. All other clinical variables had no association with growth retardation., Conclusion: A significant proportion of patients with persistent oligoarticular JIA have growth retardation and a minority have severe growth retardation. Only elevated erythrocyte sedimentation rate values were proven to be a good predictor of risk for growth retardation., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Objective: To analyze γδT cell subsets in peripheral blood (PB) and synovial fluid (SF) of patients with juvenile idiopathic arthritis (JIA), and to correlate γδT cell subsets with clinical characteristics., Methods: γδT cell subsets as percentages of CD3+ T cells in samples of PB (n = 25) and SF (n = 93) were analyzed by flow cytometry in 93 JIA patients. The percentage of Vγ9+ γδT cells after 10 days of in vitro expansion with either interleukin 2 (IL-2) or isopentenyl pyrophosphate (IPP) plus IL-2 was determined., Results: Both Vδ1+ and Vγ9+ γδT cell subsets were detected in SF of all patients, but only the percentage of Vδ1+ cells was higher in SF compared to PB (p < 0.01). The distribution of γδT cell subsets was similar in different JIA subgroups, whereas antinuclear antibody (ANA)-positive patients had a higher percentage of SF Vδ1+ T cells than ANA-negative patients (p < 0.01). The percentage of SF Vδ1+ T cells was inversely associated with age at onset, recurrence of synovitis, and erythrocyte sedimentation rate; and that of SF Vγ9+ T cells was inversely correlated with age at onset and was higher in patients who recovered from disease (n = 15). IPP-induced expansion of SF Vγ9+ T cells correlated with disease remission, whereas the expansion of SF Vγ9+ T cells in media with IL-2 alone was significantly greater in patients with uveitis., Conclusion: The percentage of Vδ1+ and Vγ9+ γδT cells among the SF T cells and their ability to respond to IPP or IL-2 correlated with specific outcomes of JIA, suggesting their role in the immunopathogenesis of this disease.

Juvenile idiopathic arthritis (JIA), the most common chronic rheumatic disease of childhood, is a clinically heterogeneous group of disorders characterized by chronic inflammatory arthritis. JIA is considered to be an autoimmune disease, which is a result of immune reaction caused or triggered by environmental factors such as infectious agents in a genetically susceptible host. The prevalence of JIA subtypes and different disease manifestations varies geographically. Various infectious agents have been suggested to be a trigger of JIA development. Numerous other factors, such as stressful life events and psychosociologic milieu, meteorological influence and maternal smoking, are suspected to be contributors of multicausal JIA pathogenesis. JIA is probably a basket of diseases rather than a single pathophysiological entity. Being a childhood autoimmune disease it could be viewed as an evolutional process or defect in the maturation of the immune system. Along the lines of the hygiene theory, multiple environment factors could interfere with the appearance and course of JIA, and no single causative factor could be been proven so far. Although many new data on the importance of the environment in JIA etiopathogenesis have appeared, the causal-result association between environmental factors and JIA remains complex and further studies are needed., (2009 Elsevier B.V. All rights reserved.)