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Juvenile Systemic Connective Tissue Diseases (JSCTD) are a heterogeneous group of chronic autoimmune diseases, associated with dyslipidemia and increased cardiovascular risk are related. Studies from the last 10 years, from 2013 to 2022, on lipid profiles in JSCTD were collected. Different studies on lipid profiles in children affected by JSCTD were selected, because the aim is to analyze the cardiovascular risk and the possibility of atherosclerosis in these patients in whom, sometimes, corticosteroid therapies and immunosuppressants increase the state of dyslipidemia. Several studies have shown that autoimmune diseases with an inflammatory substrate also share abnormalities in lipid profile and increased cardiovascular risk. Specifically, associations have been found between Juvenile Systemic Connective Tissue Diseases and elevated triglycerides, TC-C (Total Cholesterol), LDL-C (Low-Density Lipoprotein), low HDL-C (High-Density Lipoprotein), and increased risk of developing diseases such as myocardial infarction, peripheral vascular disease, pulmonary and arterial hypertension, and atrial fibrillation. Supplementation with alpha-linolenic acid (ALA) on the other hand has also been analyzed with positive results in reducing inflammatory parameters, such as IL-6 (Interleukin-6), CRP (C-reactive protein), and fasting glucose, in subjects with dyslipidemia. These observations suggest that supplementation with ALA, an omega-3 precursor, may positively modulate both the inflammatory status and dyslipidemic conditions in patients with autoimmune disorders. [ABSTRACT FROM AUTHOR]

Juvenile systemic lupus erythematosus (jSLE) is a complex inflammatory autoimmune disorder. In the last decades, genetic factors and activation pathways have been increasingly studied to understand their potential pathogenetic role better. Genetic and transcriptional abnormalities directly involved in the type I interferon (IFN) signaling cascade have been identified through family-based and genome-wide association studies. IFNs trigger signaling pathways that initiate gene transcription of IFN-stimulated genes through the activation of JAK1, TYK2, STAT1, and STAT2. Thus, the use of therapies that target the IFN pathway would represent a formidable advance in SLE. It is well known that JAK inhibitors have real potential for the treatment of rheumatic diseases, but their efficacy in the treatment of SLE remains to be elucidated. We report the case of a 13-year-old girl affected by jSLE, carrying a novel heterozygous missense variant on Three prime Repair EXonuclease 1 (TREX1), successfully treated with baricitinib on top of mofetil mycophenolate. The TREX1 gene plays an important role in DNA damage repair, and its mutations have been associated with an overproduction of type 1 interferon. This report underlines the role of translational research in identifying potential pathogenetic pathways in rare diseases to optimize treatment. [ABSTRACT FROM AUTHOR]

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition in childhood. The disease etiology remains largely unknown; however, a key role in JIA pathogenesis is surely mediated by T cells. T‐lymphocytes activity is controlled via signals, known as immune checkpoints. Delivering an inhibitory signal or blocking a stimulatory signal to achieve immune suppression is critical in autoimmune diseases. However, the role of immune checkpoints in chronic inflammation and autoimmunity must still be deciphered. In this study, we investigated at the single‐cell level the feature of T cells in JIA chronic inflammation, both at the transcriptome level via single‐cell RNA sequencing and at the protein level by flow cytometry. We found that despite the heterogeneity in the composition of synovial CD4+ and CD8+ T cells, those characterized by PD‐1 expression were clonally expanded tissue‐resident memory (Trm)‐like cells and displayed the highest proinflammatory capacity, suggesting their active contribution in sustaining chronic inflammation in situ. Our data support the concept that novel therapeutic strategies targeting PD‐1 may be effective in the treatment of JIA. With this approach, it may become possible to target overactive T cells regardless of their cytokine production profile. [ABSTRACT FROM AUTHOR]

Introduction: New early low-invasive biomarkers are demanded for the management of Oligoarticular Juvenile Idiopathic Arthritis (OJIA), the most common chronic pediatric rheumatic disease in Western countries and a leading cause of disability. A deeper understanding of the molecular basis of OJIA pathophysiology is essential for identifying new biomarkers for earlier disease diagnosis and patient stratification and to guide targeted therapeutic intervention. Proteomic profiling of extracellular vesicles (EVs) released in biological fluids has recently emerged as a minimally invasive approach to elucidate adult arthritis pathogenic mechanisms and identify new biomarkers. However, EV-prot expression and potential as biomarkers in OJIA have not been explored. This study represents the first detailed longitudinal characterization of the EV-proteome in OJIA patients. Methods: Fourty-five OJIA patients were recruited at disease onset and followed up for 24 months, and protein expression profiling was carried out by liquid chromatography-tandem mass spectrometry in EVs isolated from plasma (PL) and synovial fluid (SF) samples. Results: We first compared the EV-proteome of SF vs paired PL and identified a panel of EV-prots whose expression was significantly deregulated in SF. Interaction network and GO enrichment analyses performed on deregulated EV-prots through STRING database and ShinyGO webserver revealed enrichment in processes related to cartilage/bone metabolism and inflammation, suggesting their role in OJIA pathogenesis and potential value as early molecular indicators of OJIA development. Comparative analysis of the EV-proteome in PL and SF from OJIA patients vs PL from age/gendermatched control children was then carried out. We detected altered expression of a panel of EV-prots able to differentiate new-onset OJIA patients from control children, potentially representing a disease-associated signature measurable at both the systemic and local levels with diagnostic potential. Deregulated EV-prots were significantly associated with biological processes related to innate immunity, antigen processing and presentation, and cytoskeleton organization. Finally, we ran WGCNA on the SF- and PLderived EV-prot datasets and identified a few EV-prot modules associated with different clinical parameters stratifying OJIA patients in distinct subgroups. Discussion: These data provide novel mechanistic insights into OJIA pathophysiology and an important contribution in the search of new candidate molecular biomarkers for the disease. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to investigate the effectiveness of corticosteroid therapy for children suffering from Sydenham chorea (SC). Methods: The design of the study was observational, retrospective and conducted at the single center of the Rheumatology Unit of Policlinic Hospital of Milan, Italy, from May 1995 to May 2022. All data about the patients were collected from medical records. Results: From a total of 59 patients enrolled in the study (44 females and 15 males; median age 9.3 years, range 7.4–10.6 years), 49 were eligible for primary outcome analysis (10 patients were excluded due to incomplete data). Overall, 75% of patients received steroid therapy, while the remaining cases were treated with symptomatic drugs, including neuroleptics and antiseizure drugs. We found that the duration of chorea was significantly shorter in patients treated with corticosteroids in comparison to those receiving symptomatic treatment (median time: 31 vs. 41 days, p = 0.023). Additionally, patients with arthritis at the onset of the disease had a longer duration of chorea than those without arthritis (median time 90.5 vs. 39 days, p = 0.02). We also found that chorea recurred in 12% of the patients and seemed to be linked to a younger age at onset (p = 0.01). Conclusions: The study suggests that corticosteroid therapy can lead to a faster resolution of SC when compared to neuroleptics and antiseizure drugs treatment. [ABSTRACT FROM AUTHOR]

An association between infectious diseases and macrophage activation syndrome (MAS) has been reported, yet the exact role of infection in MAS development is still unclear. Here, a retrospective analysis of the clinical records of patients with rheumatic diseases complicated with MAS who were treated in a pediatric tertiary care center between 2011 and 2020 was performed. Any infection documented within the 30 days preceding the onset of MAS was reported. Out of 125 children in follow-up for systemic rheumatic diseases, 12 developed MAS, with a total of 14 episodes. One patient experienced three episodes of MAS. Clinical and/or laboratory evidence of infection preceded the onset of MAS in 12 events. Clinical features, therapeutic strategies, and patient outcomes were described. The aim of this study was to evaluate the possible role of infection as a relevant trigger for MAS development in children with rheumatic conditions. The pathogenetic pathways involved in the cross-talk between uncontrolled inflammatory activity and the immune response to infection deserve further investigation. [ABSTRACT FROM AUTHOR]

Objective The objective of this study was to use real-world data to evaluate the effectiveness and safety of canakinumab in Italian patients with systemic JIA (sJIA). Methods A retrospective multicentre study of children with sJIA was performed. Clinical features, laboratory parameters and adverse events were collected at baseline, and 6 and 12 months after starting canakinumab. The primary outcome measure of effectiveness was clinically inactive disease (CID) off glucocorticoids (GCs) treatment at 6 months. Results A total of 80 children from 15 Italian centres were analysed. Of the 12 patients who started canakinumab in CID while receiving anakinra, all maintained CID. Of the 68 with active disease at baseline, 57.4% achieved CID off GCs at 6 months and 63.8% at 12 months. In univariate analysis, the variables significantly related to non-response were number of active joints (NAJs) ≥5, history of macrophage activation syndrome (MAS) and disease duration. Multivariate analysis confirmed the association between non-response and NAJs ≥5 [odds ratio (OR) 6.37 (95% CI: 1.69, 24.02), P = 0.006] and between non-response and history of MAS [OR 3.53 (95% CI: 1.06, 11.70), P = 0.039]. No serious adverse events were recorded in this series. There were two cases of MAS during canakinumab, leading to a rate of 2.9 episodes per 100 patient years. Conclusion We have confirmed, using real-world data, the efficacy of canakinumab in sJIA in a multicentric cohort. History of MAS and higher NAJ were associated with lower probability of achieving CID. [ABSTRACT FROM AUTHOR]

Objective: To compare the frequency of joint and tendon disease on ultrasound (US) and clinical examination, and to investigate agreement between US and clinical evaluation in ankles with clinically active juvenile idiopathic arthritis (JIA).Methods: US and clinical evaluation were performed independently in the joint and tendon compartments of 105 ankles. Gray-scale (GS) US and power Doppler (PD) US joint abnormalities were scored on a 4-point semiquantitative scale. A joint with a GS score ≥2 and/or a PD score ≥1 was defined as active on US. Agreement was tested using kappa statistics.Results: A total of 163 joints in 89 ankles had active synovitis on US. The tibiotalar (TT) joint was the most commonly affected joint on US and on clinical evaluation. The intertarsal (IT) joint and the subtalar (ST) joint were the second in frequency on US and on clinical evaluation, respectively. Tenosynovitis was found more commonly on US than on clinical evaluation (70.5% and 32.4%, respectively), and was more frequent in the medial and lateral than in the anterior tendon compartment. Isolated tenosynovitis was detected on US in 12 of 105 ankles. Agreement between US and clinical evaluation for detection of active synovitis and tenosynovitis was less than acceptable (κ <0.4). No correlation was found between any feature of active disease recorded on clinical evaluation (joint swelling, tenderness/pain on motion, and restricted motion) and active synovitis on US in the TT joint, ST joint, and IT joint.Conclusion: Coupling clinical evaluation with US aids in correctly localizing pathology. US training of practitioners is recommended to manage ankle disease in JIA. [ABSTRACT FROM AUTHOR]

Abstract The epidemiology of juvenile idiopathic arthritis (JIA) is variable worldwide. In particular, a wide disparity exists in the prevalence of the diverse disease subtypes across different geographic areas. The therapeutic approach to JIA is not standardized and no established and widely accepted guidelines are available. In the past decade, there have been important progresses in the management of the disease, but the availability of the novel and costly biologic medications is not uniform throughout the world. This issue may have significant impact on disease prognosis, with children living in poorer countries being at greater risk of accumulating disease- and treatment-related damage than children followed in Western pediatric rheumatology centers. The multinational study of the EPidemiology, treatment and Outcome of Childhood Arthritis (EPOCA study) is aimed to obtain information on the frequency of JIA subtypes in different geographic areas, the therapeutic approaches adopted by pediatric rheumatologists practicing in diverse countries or continents, and the disease and health status of children with JIA currently followed worldwide. Parent- and child-reported outcomes are meant to be recorded through the administration of a new multidimensional questionnaire, the Juvenile Arthritis Multidimensional Assessment Report (JAMAR). The first step of the study is based on the translation and cross-cultural adaptation of the questionnaire in the national language of each participating country. Each center is, then, asked to enroll a sample of consecutive JIA patients, who should undergo a retrospective assessment and a cross-sectional evaluation, including completion of the JAMAR, a standardized joint examination, and the assessment of articular and extra-articular damage. At the end of May 2012, 124 centers in 55 countries have agreed to participate in the study. The JAMAR has been or is currently being translated in 38 national languages. The target patient sample is more than 10,000 JIA children worldwide.

Objective To build a prediction model for uveitis in children with JIA for use in current clinical practice. Methods Data from the international observational Pharmachild registry were used. Adjusted risk factors as well as predictors for JIA-associated uveitis (JIA-U) were determined using multivariable logistic regression models. The prediction model was selected based on the Akaike information criterion. Bootstrap resampling was used to adjust the final prediction model for optimism. Results JIA-U occurred in 1102 of 5529 JIA patients (19.9%). The majority of patients that developed JIA-U were female (74.1%), ANA positive (66.0%) and had oligoarthritis (59.9%). JIA-U was rarely seen in patients with systemic arthritis (0.5%) and RF positive polyarthritis (0.2%). Independent risk factors for JIA-U were ANA positivity [odds ratio (OR): 1.88 (95% CI: 1.54, 2.30)] and HLA-B27 positivity [OR: 1.48 (95% CI: 1.12, 1.95)] while older age at JIA onset was an independent protective factor [OR: 0.84 (9%% CI: 0.81, 0.87)]. On multivariable analysis, the combination of age at JIA onset [OR: 0.84 (95% CI: 0.82, 0.86)], JIA category and ANA positivity [OR: 2.02 (95% CI: 1.73, 2.36)] had the highest discriminative power among the prediction models considered (optimism-adjusted area under the receiver operating characteristic curve = 0.75). Conclusion We developed an easy to read model for individual patients with JIA to inform patients/parents on the probability of developing uveitis. [ABSTRACT FROM AUTHOR]

Background: Italy was the first Western country to be hit by the SARS-CoV-2 epidemic. There is now mounting evidence that a minority of children infected with SARS-CoV2 may experience a severe multisystem inflammatory syndrome, called Multisystem inflammatory Syndrome associated with Coronavirus Disease 2019 (MIS-C). To date no universally agreed approach is available for this disease. Main body: as Italy is now facing a second hity of COVID-19 cases, we fear a recrudescence of MIS-C cases. We have, therefore, decided to prepare a report that will help clinicians to face this novel and challenging disease. We propose a diagnostic algorithm, to help case definition and guide work-up, and a therapeutic approach. MIS-C should be promptly recognized, based on the presence of systemic inflammation and specific organ involvement. Early treatment is crucial, and it will be based on the combined use of corticosteroids, high-dose immunoglobulins and anti-cytokine treatments, depending on the severity of the disease. Ancillary treatments (such as. aspirin and thrombo-profilaxis) will be also discussed. Conclusions: we propose a document that will help physicians to diagnose and treat MIS-C patients. Given the level of evidence available and the methodology used, this document should not be interpreted as a guideline; the final decision about the optimal management should still be taken by the caring physician, on an individual basis. [ABSTRACT FROM AUTHOR]

The authors discuss the article "Validation of the Parent Global Assessment As a High-Related Quality of Life Measure in Juvenile Idiopathic Arthritis: Results from ReACCh-Out," published by K. Oen and colleagues in the issue. Topics include the parent global assessment of a child's wellbeing, controversy on the role of the PaGA as a measure of disease activity in juvenile idiopathic arthritis (JIA), and problems with the study.

Objective: To analyse, in a cohort of paediatric patients with recurrent pericarditis (RP) undergoing anti-IL-1 treatment: the agent and dosing used as first line treatment, the long-term efficacy of IL1-blockers, the percentage of patients achieving a drug-free remission, the presence of variables associated with drug-free remission.Study Design: Data were collected from patients' charts. Annualized relapse rate (ARR) was used for evaluation of treatment efficacy, bivariate logistic regression analysis for variables associated with drug-free remisison.Results: 58 patients, treated between 2008 and 2018, were included in the study (mean follow-up 2.6 years). 14/56 patients non-responsive to first line drugs were under-dosed. 57 patients were treated with anakinra: the ARR before and during daily treatment was 3.05 and 0.28, respectively (p<0.0001); an increase to 0.83 was observed after the reduction/withdrawal of treatment (p<.0001). The switch from anakinra to canakinumab (5 patients) was associated to an increase of the ARR (0.49 vs 1.46), but without statistical significance (p=0.215). At last follow-up only 9/58 patients had withdrawn all treatments. With the limits of a retrospective study and the heterogeneity between the patients enrolled in the study, a shorter duration of treatment with anakinra was the only variable associated with drug-free remission.Conclusion: This study shows that most of the pediatric patients with RP needing IL-1 blockade received an inadequate treatment with first line agents. The effectiveness of anakinra is supported by this study, but few patients achieved drug free-remission. The different rate of response to anakinra and canakinumab may suggest a possible role of IL1α in the pathogenesis of RP. [ABSTRACT FROM AUTHOR]

Objective: To develop and validate a weighted score, the ONCOREUM score, that aids physicians in differentiation of cancer with arthropathy from juvenile idiopathic arthritis (JIA).Study Design: Data were extracted from the ONCOREUM Study, a multicenter, cross-sectional investigation aimed at comparing children with cancer and arthropathy to children with JIA. Three statistical approaches were applied to develop the ONCOREUM score and assess the role of each variable in the diagnosis of cancer with arthropathy, including 2 approaches based on multivariable stepwise selection (models 1 and 2) and 1 approach on a Bayesian model averaging method (model 3). The β coefficients estimated in the models were used to assign score points. Considering that not missing a child with cancer is a mandatory clinical objective, discriminating performance was assessed by fixing sensitivity at 100%. Score performance was evaluated in both developmental and validation samples (representing 80% and 20% of the study population, respectively).Results: Patients with cancer and arthropathy (49 with solid tumors and 46 with hematologic malignancies without peripheral blasts) and 677 patients with JIA were included. The highest area under the receiver operating characteristic (ROC) curve (AUC) in the validation data set was yielded by model 1, which was selected to constitute the ONCOREUM score. The score ranged from -18 to 21.8, and the optimal cutoff obtained through ROC analysis was -6. The sensitivity, specificity, and AUC of the cutoff in the validation sample were 100%, 70%, and 0.85, respectively.Conclusions: The ONCOREUM score is a powerful and easily applicable tool that may facilitate early differentiation of malignancies with articular complaints from JIA. [ABSTRACT FROM AUTHOR]