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Oligoarticular juvenile idiopathic arthritis (oligo JIA) is the most common form of chronic inflammatory arthritis in children, yet the cause of this disease remains unknown. To understand immune responses in oligo JIA, we immunophenotyped synovial fluid T cells with flow cytometry, bulk RNA-Seq, single-cell RNA-Seq (scRNA-Seq), DNA methylation studies, and Treg suppression assays. In synovial fluid, CD4+, CD8+, and gamma delta T cells expressed Th1-related markers, whereas Th17 cells were not enriched. Th1 skewing was prominent in CD4+ T cells, including Tregs, and was associated with severe disease. Transcriptomic studies confirmed a Th1 signature in CD4+ T cells from synovial fluid. The regulatory gene expression signature was preserved in Tregs, even those exhibiting Th1 polarization. These Th1-like Tregs maintained Treg-specific methylation patterns and suppressive function, supporting the stability of this Treg population in the joint. Although synovial fluid CD4+ T cells displayed an overall Th1 phenotype, scRNA-Seq uncovered heterogeneous effector and regulatory subpopulations, including IFN-induced Tregs, peripheral helper T cells, and cytotoxic CD4+ T cells. In conclusion, oligo JIA is characterized by Th1 polarization that encompasses Tregs but does not compromise their regulatory identity. Targeting Th1-driven inflammation and augmenting Treg function may represent important therapeutic approaches in oligo JIA. Joint Biology Consortium [P30 AR070253]; NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) [K08 AR077037, T32 HL007633-35]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [5T32AI007512-34]; NIAMSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) [P30 AR070253, R01 AR075906, R01 AR073201, K08 AR073339]; Fundacion Bechara; Arbuckle Family Fund for Arthritis Research; Rheumatology Research Foundation; Arthritis National Research Foundation; Office of Faculty Development at Boston Children's Hospital Published version We thank the patients and volunteers for participation in this study. We thank Steve Moskowit for support in preparing the graphical abstract for this study. The graphical abstract makes use of images available at Servier Medical Art (https://smart.servier.com).AMJ was supported in part by a microgrant from the Joint Biology Consortium (P30 AR070253). KW is supported by NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) K08 AR077037. JN was funded by T32 HL007633-35. JER was supported by the NIH grant 5T32AI007512-34. PAN was funded by NIAMS awards R01 AR075906, R01 AR073201, P30 AR070253; the Fundacion Bechara; and the Arbuckle Family Fund for Arthritis Research. LAH was funded by NIAMS K08 AR073339, NIAMS P30 AR070253, an Investigator Award of the Rheumatology Research Foundation, an All Arthritis grant from the Arthritis National Research Foundation, and a Career Development Award from the Office of Faculty Development at Boston Children's Hospital.

Introduction: Pain is prevalent in juvenile idiopathic arthritis (JIA). Unknowns regarding the biological drivers of pain complicate therapeutic targeting. We employed neuroimaging to define pain-related neurobiological features altered in JIA. Methods: 16 male and female JIA patients (12.7 2.8 years of age) on active treatment were enrolled, together with age-and sex-matched controls. Patients were assessed using physical examination, clinical questionnaires, musculoskeletal MRI, and structural neuroimaging. In addition, functional magnetic resonance imaging (fMRI) data were collected during the resting-state, hand-motor task performance, and cold stimulation of the hand and knee. Results: Patients with and without pain and with and without inflammation (joint and systemic) were evaluated. Pain severity was associated with more physical stress and poorer cognitive function. Corrected for multiple comparisons, morphological analysis revealed decreased cortical thickness within the insula cortex and a negative correlation between caudate nucleus volume and pain severity. Functional neuroimaging findings suggested alteration within neurocircuitry structures regulating emotional pain processing (anterior insula) in addition to the default-mode and sensorimotor networks. Conclusions: Patients with JIA may exhibit changes in neurobiological circuits related to pain. These preliminary findings suggest mechanisms by which pain could potentially become dissociated from detectable joint pathology and persist independently of inflammation or treatment status. (c) 2021 Elsevier Inc. All rights reserved.

BACKGROUND: Pediatric SARS–CoV-2 infection can be complicated by a dangerous hyperinflammatory condition termed multisystem inflammatory syndrome in children (MIS-C). The clinical and immunologic spectrum of MIS-C and its relationship to other inflammatory conditions of childhood have not been studied in detail. METHODS: We retrospectively studied confirmed cases of MIS-C at our institution from March to June 2020. The clinical characteristics, laboratory studies, and treatment response were collected. Data were compared with historic cohorts of Kawasaki disease (KD) and macrophage activation syndrome (MAS). RESULTS: Twenty-eight patients fulfilled the case definition of MIS-C. Median age at presentation was 9 years (range: 1 month to 17 years); 50% of patients had preexisting conditions. All patients had laboratory confirmation of SARS–CoV-2 infection. Seventeen patients (61%) required intensive care, including 7 patients (25%) who required inotrope support. Seven patients (25%) met criteria for complete or incomplete KD, and coronary abnormalities were found in 6 cases. Lymphopenia, thrombocytopenia, and elevation in inflammatory markers, D-dimer, B-type natriuretic peptide, IL-6, and IL-10 levels were common but not ubiquitous. Cytopenias distinguished MIS-C from KD and the degree of hyperferritinemia and pattern of cytokine production differed between MIS-C and MAS. Immunomodulatory therapy given to patients with MIS-C included intravenous immune globulin (IVIG) (71%), corticosteroids (61%), and anakinra (18%). Clinical and laboratory improvement were observed in all cases, including 6 cases that did not require immunomodulatory therapy. No mortality was recorded in this cohort. CONCLUSION: MIS-C encompasses a broad phenotypic spectrum with clinical and laboratory features distinct from KD and MAS. FUNDING: This work was supported by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Allergy and Infectious Diseases; Rheumatology Research Foundation Investigator Awards and Medical Education Award; Boston Children’s Hospital Faculty Career Development Awards; the McCance Family Foundation; and the Samara Jan Turkel Center.

Poor outcomes in COVID-19 correlate with clinical and laboratory features of cytokine storm syndrome. Broad screening for cytokine storm and early, targeted antiinflammatory therapy may prevent immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in cytokine storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID-19.