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BackgroundMethodsResultsConclusion\nKEY POINTSUveitis is an inflammatory ocular disease secondary to disruption of the retinal pigmented epithelium (RPE) and blood retinal barrier (BRB). Known clinical factors do not accurately predict uveitis risk in Juvenile Idiopathic Arthritis (JIA). Tear fluid is easily obtained for biomarker study. We aim to identify tear-based markers associated with the presence of uveitis in children with JIA.In a cross-sectional comparative cohort study, tears were collected by Schirmer strips from children with oligoarticular JIA-associated uveitis (JIA-U) and JIA without uveitis (JIA-no-U). A tandem isotope tagging (iTRAQ and TMT) strategy was used for relative quantitation via nanoLC-MS/MS to quantify proteins in the affected eye. Log transformed relative protein abundance of protein levels was compared between groups using Wilcoxon exact test. We explored the influence of arthritis activity and topical corticosteroids (CS) use on protein levels. STRING analysis was performed.Tear samples of 14 JIA-U and 14 JIA-no-U patients were analyzed. Thirteen proteins were differentially expressed between both groups. Stratified analysis based on arthritis activity (inactive arthritis) and topical CS (off CS) showed that alpha-2-macroglobulin (p = 0.012), apolipoprotein A1 (p = 0.036), S100A9 (p = 0.05), haptoglobin (p = 0.066), and transthyretin (p = 0.066) consistently differentiated between both groups. On STRING analysis, these proteins were associated with the RPE, BRB, and inflammation.Importantly, we identified proteins involved in the RPE, BRB, and immune response that were differentially abundant in the tears of children with JIA-U compared to JIA-no-U, regardless of arthritis activity or topical CS. Candidate tear-based biomarkers may represent a non-invasive means to detect uveitis.Question: Is it possible to identify tear-based biomarkers able to identify patients with uveitis in children with Juvenile Idiopathic Arthritis (JIA)?Findings: We identified proteins involved in the immune response and in the retinal barrier that were differentially abundant in the tears of children with JIA-Uveitis compared to JIA-no-Uveitis.Meaning: Tears may be a suitable sample to identify children with JIA with and without uveitis in a non-invasive and objective way. [ABSTRACT FROM AUTHOR]

Multi-system inflammatory syndrome in children (MIS-C) is a severe post-acute sequela of SARS-CoV-2 infection in children, and there is a critical need to unfold its highly heterogeneous disease patterns. Our objective was to characterize the illness spectrum of MIS-C for improved recognition and management. We conducted a retrospective cohort study using data from March 1, 2020–September 30, 2022, in 8 pediatric medical centers from PEDSnet. We included 1139 children hospitalized with MIS-C and used their demographics, symptoms, conditions, laboratory values, and medications for analyses. We applied heterogeneity-adaptive latent class analyses and identified three latent classes. We further characterized the sociodemographic and clinical characteristics of the latent classes and evaluated their temporal patterns. Class 1 (47.9%) represented children with the most severe presentation, with more admission to the ICU, higher inflammatory markers, hypotension/shock/dehydration, cardiac involvement, acute kidney injury and respiratory involvement. Class 2 (23.3%) represented a moderate presentation, with 4–6 organ systems involved, and some overlapping features with acute COVID-19. Class 3 (28.8%) represented a mild presentation. Our results indicated that MIS-C has a spectrum of clinical severity ranging from mild to severe and the proportion of severe or critical MIS-C decreased over time. [ABSTRACT FROM AUTHOR]

Objective: To provide guidance on the management of Multisystem Inflammatory Syndrome in Children (MIS‐C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of SARS–CoV‐2 infection. Recommendations are also provided for children with hyperinflammation during COVID‐19, the acute, infectious phase of SARS–CoV‐2 infection. Methods: The Task Force is composed of 9 pediatric rheumatologists and 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS‐C and hyperinflammation in COVID‐19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved anonymous voting and webinar discussion. A 9‐point scale was used to determine the appropriateness of each statement (median scores of 1–3 for inappropriate, 4–6 for uncertain, and 7–9 for appropriate). Consensus was rated as low, moderate, or high based on dispersion of the votes. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, which were prespecified before voting. Results: The guidance was approved in June 2020 and updated in November 2020 and October 2021, and consists of 41 final guidance statements accompanied by flow diagrams depicting the diagnostic pathway for MIS‐C and recommendations for initial immunomodulatory treatment of MIS‐C. Conclusion: Our understanding of SARS–CoV‐2–related syndromes in the pediatric population continues to evolve. This guidance document reflects currently available evidence coupled with expert opinion, and will be revised as further evidence becomes available. [ABSTRACT FROM AUTHOR]

CD163 facilitates regulation and resolution of inflammation and removal of free hemoglobin and is highly expressed in myeloid cells from patients with inflammatory disorders, such as systemic juvenile idiopathic arthritis (SJIA) and macrophage activation syndrome (MAS). Our recent studies indicate that regulation of CD163 mRNA expression is a key functional property of polarized monocytes and macrophages and is mediated at the transcriptional and posttranscriptional level, including via microRNAs. The goal of the current study is to develop a multiparameter flow cytometry panel incorporating detection of CD163 mRNAfor polarized monocyte and macrophage populations in disorders such as SJIA and MAS. THP-1 cells and CD14+ human monocytes were stained using fluorochrome-conjugated Abs to myeloid surface markers, along with CD163 mRNA. Staining for mRNA could reliably detect CD163 expression while simultaneously detecting different macrophage populations using Abs targeting CD14, CD64, CD80, CD163, and CD209. This approach was found to be highly sensitive for increased mRNA expression when macrophages were polarized with IL-10 [M(IL-10)], with a strong signal over a broad range of IL-10 concentrations, and showed distinct kinetics of CD163 mRNA and protein induction upon IL-10 stimulation. Finally, this panel demonstrated clear changes in polarization markers in unstimulated monocytes from patients with SJIA and MAS, including upregulated CD163 mRNA and increased CD64 expression. This approach represents a robust and sensitive system for RNA flow cytometry, useful for studying CD163 expression as part of a multimarker panel for human monocytes and macrophages, with broad applicability to the pathogenesis of hyperinflammatory diseases. [ABSTRACT FROM AUTHOR]

Background: Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that can cause marked disability and diminished quality of life. Data on predictors of clinical response are insufficient to guide selection of the appropriate biologic agent for individual patients. This study aimed to investigate the propensity of S100A8/9 and S100A12 as predictive biomarkers of abatacept response in polyarticular-course juvenile idiopathic arthritis (pJIA)., Methods: Data from a phase 3 trial (NCT01844518) of subcutaneous abatacept in patients with active pJIA (n = 219) were used in this exploratory analysis. Association between biomarker levels at baseline and improvements in JIA-American College of Rheumatology (ACR) criteria responses or baseline disease activity (measured by Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein [JADAS27-CRP]) were assessed. Biomarker level changes from baseline to month 4 were assessed for disease outcome prediction up to 21 months., Results: At baseline, 158 patients had available biomarker samples. Lower baseline S100A8/9 levels (≤ 3295 ng/mL) were associated with greater odds of achieving JIA-ACR90 (odds ratio [OR]: 2.54 [95% confidence interval (CI): 1.25-5.18]), JIA-ACR100 (OR: 3.72 [95% CI: 1.48-9.37]), JIA-ACR inactive disease (ID; OR: 4.25 [95% CI: 2.03-8.92]), JADAS27-CRP ID (OR: 2.34 [95% CI: 1.02-5.39]) at month 4, and JIA-ACR ID (OR: 3.01 [95% CI: 1.57-5.78]) at month 16. Lower baseline S100A12 levels (≤ 176 ng/mL) were associated with greater odds of achieving JIA-ACR90 (OR: 2.52 [95% CI: 1.23-5.13]), JIA-ACR100 (OR: 3.68 [95% CI: 1.46-9.28]), JIA-ACR ID (OR: 3.66 [95% CI: 1.76-7.61]), JIA-ACR90 (OR: 2.03 [95% CI: 1.07-3.87]), JIA-ACR100 (OR: 2.14 [95% CI: 1.10-4.17]), and JIA-ACR ID (OR: 4.22 [95% CI: 2.15-8.29]) at month 16. From baseline to month 4, decreases in S100A8/9 and S100A12 generally exceeded 50% among JIA-ACR90/100/ID responders., Conclusion: Lower baseline levels of S100A8/9 and S100A12 proteins predicted better response to abatacept treatment than higher levels and may serve as early predictive biomarkers in pJIA. Decreases in these biomarker levels may also predict longer-term response to abatacept in pJIA., (© 2024. The Author(s).)

Secondary hemophagocytic lymphohistiocytosis (sHLH) has historically been defined as a cytokine storm syndrome (CSS) occurring in the setting of triggers leading to strong and dysregulated immunological activation, without known genetic predilection. However, recent studies have suggested that existing underlying genetic factors may synergize with particular diseases and/or environmental triggers (including infection, autoimmune/autoinflammatory disorder, certain biologic therapies, or malignant transformation), leading to sHLH. With the recent advances in genetic testing technology, more patients are examined for genetic variations in primary HLH (pHLH)-associated genes, including through whole exome and whole genome sequencing. This expanding genetic and genomic evidence has revealed HLH as a more complex phenomenon, resulting from specific immune challenges in patients with a susceptible genetic background. Rather than a simple, binary definition of pHLH and sHLH, HLH represents a spectrum of diseases, from a severe complication of common infections (EBV, influenza) to early onset familial diseases that can only be cured by transplantation., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Chronic lung disease in children with systemic juvenile idiopathic arthritis (SJIA-LD) is an emerging and potentially life-threatening disease complication. Despite recent descriptions of its clinical spectrum, preliminary immunologic characterization, and proposed hypotheses regaarding etiology, optimal approaches to diagnosis and management remain unclear. Here, we review the current clinical understanding of SJIA-LD, including the potential role of biologic therapy in disease pathogenesis, as well as the possibility of drug reactions with eosinophilia and systemic symptoms (DRESS). We discuss approaches to evaluation of children with suspected SJIA-LD, including a proposed algorithm to risk-stratify all SJIA patients for screening to detect LD early. We review potential pharmacologic and non-pharmacologic treatment approaches that have been reported for SJIA-LD or utilized in interstitial lung diseases associated with other rheumatic diseases. This includes lymphocyte-targeting therapies, JAK inhibitors, and emerging therapies against IL-18 and IFNγ. Finally, we consider urgent unmet needs in this area including in basic discovery of disease mechanisms and clinical research to improve disease detection and patient outcomes., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Macrophage activation syndrome (MAS) is a life-threatening complication of pediatric rheumatic diseases, occurring most commonly in children with systemic juvenile idiopathic arthritis (SJIA). Despite several classes of currently available treatment options for SJIA, including biologic agents targeting IL-1 or IL-6, there remain severe cases suffering from refractory disease and recurrent MAS. The phenotype of MAS is similar to hemophagocytic lymphohistiocytosis (HLH), but the underlying pathophysiology of MAS complicating SJIA or other disorders has not been fully clarified. These facts make it challenging to develop and utilize animal models to study MAS. To date, there is no "perfect" model replicating MAS, but several models do demonstrate aspects of SJIA and/or MAS. In this review, we examine the proposed animal models of SJIA and MAS, focusing on how they reflect these disorders, what we have learned from the models, and potential future research questions. As we better understand the key features of each, animal models can be powerful tools to further define the pathophysiology of SJIA and MAS, and develop new treatment targets and strategies., (© 2023. The Author(s).)

Importance: Minimal data are available regarding the postdischarge treatment of multisystem inflammatory syndrome in children (MIS-C)., Objectives: To evaluate clinical characteristics associated with duration of postdischarge glucocorticoid use and assess postdischarge clinical course, laboratory test result trajectories, and adverse events in a multicenter cohort with MIS-C., Design, Setting, and Participants: This retrospective cohort study included patients with MIS-C hospitalized with severe illness and followed up for 3 months in an ambulatory setting. Patients younger than 21 years who were admitted between May 15, 2020, and May 31, 2021, at 13 US hospitals were included. Inclusion criteria were inpatient treatment comprising intravenous immunoglobulin, diagnosis of cardiovascular dysfunction (vasopressor requirement or left ventricular ejection fraction ≤55%), and availability of complete outpatient data for 3 months., Exposures: Glucocorticoid treatment., Main Outcomes and Measures: Main outcomes were patient characteristics associated with postdischarge glucocorticoid treatment, laboratory test result trajectories, and adverse events. Multivariable regression was used to evaluate factors associated with postdischarge weight gain (≥2 kg in 3 months) and hyperglycemia during illness., Results: Among 186 patients, the median age was 10.4 years (IQR, 6.7-14.2 years); most were male (107 [57.5%]), Black non-Hispanic (60 [32.3%]), and Hispanic or Latino (59 [31.7%]). Most children were critically ill (intensive care unit admission, 163 [87.6%]; vasopressor receipt, 134 [72.0%]) and received inpatient glucocorticoid treatment (178 [95.7%]). Most were discharged with continued glucocorticoid treatment (173 [93.0%]); median discharge dose was 42 mg/d (IQR, 30-60 mg/d) or 1.1 mg/kg/d (IQR, 0.7-1.7 mg/kg/d). Inpatient severity of illness was not associated with duration of postdischarge glucocorticoid treatment. Outpatient treatment duration varied (median, 23 days; IQR, 15-32 days). Time to normalization of C-reactive protein and ferritin levels was similar for glucocorticoid duration of less than 3 weeks vs 3 or more weeks. Readmission occurred in 7 patients (3.8%); none was for cardiovascular dysfunction. Hyperglycemia developed in 14 patients (8.1%). Seventy-five patients (43%) gained 2 kg or more after discharge (median 4.1 kg; IQR, 3.0-6.0 kg). Inpatient high-dose intravenous and oral glucocorticoid therapy was associated with postdischarge weight gain (adjusted odds ratio, 6.91; 95% CI, 1.92-24.91)., Conclusions and Relevance: In this multicenter cohort of patients with MIS-C and cardiovascular dysfunction, postdischarge glucocorticoid treatment was often prolonged, but clinical outcomes were similar in patients prescribed shorter courses. Outpatient weight gain was common. Readmission was infrequent, with none for cardiovascular dysfunction. These findings suggest that strategies are needed to optimize postdischarge glucocorticoid courses for patients with MIS-C.

Background: Childhood obesity is an increasing public health concern, but little is known about how obesity contributes to chronic arthritis., Objective: The objective of this study was to identify and characterize children and adolescents who present with isolated arthritis of the ankle/hindfoot/midfoot complex and profound obesity., Methods: We identified all patients with juvenile idiopathic arthritis who underwent fluoroscopic-guided injections of the feet and ankles between July 2009 and June 2012. We determined their disease category as well as clinical, demographic, and serological features. We also identified patients who had body mass indices (BMIs) that were outliers., Results: Eighty-two patients received fluoroscopic-guided foot and ankle injections during the study period. Twenty-one percent of these patients were obese (BMI ≥95th percentile), and 33% were overweight or obese (BMI ≥85th percentile). We identified 5 of these patients who had isolated arthritis of the ankle/hindfoot/midfoot complex. All patients with isolated foot and ankle arthritis were significantly obese with BMI 98th to 99th percentile for age, and 3 had BMIs that were outliers from the broader population. These patients were also distinctive as being significantly older, more likely to be male, and less likely to have positive antinuclear antibody titers than other patients with ankle/hindfoot/midfoot complex arthritis. Finally, all 5 patients were negative for known laboratory markers associated with juvenile idiopathic arthritis., Conclusions: We have identified a subgroup of children with chronic inflammatory arthritis limited to their ankle/hindfoot/midfoot complex and significant obesity. This study suggests that there may be interplay between obesity, inflammation, and otherwise unexplained arthritis and highlights a previously unrecognized complication of childhood obesity.