Robert P. Sundel

BACKGROUND. Macrophage activation syndrome (MAS) is a life-threatening complication of Still’s disease (SD) characterized by overt immune cell activation and cytokine storm. We aimed to further understand the immunologic landscape of SD and MAS. METHOD. We profiled PBMCs from people in a healthy control group and patients with SD with or without MAS using bulk RNA-Seq and single-cell RNA-Seq (scRNA-Seq). We validated and expanded the findings by mass cytometry, flow cytometry, and in vitro studies. RESULTS. Bulk RNA-Seq of PBMCs from patients with SD-associated MAS revealed strong expression of genes associated with type I interferon (IFN-I) signaling and cell proliferation, in addition to the expected IFN-γ signal, compared with people in the healthy control group and patients with SD without MAS. scRNA-Seq analysis of more than 65,000 total PBMCs confirmed IFN-I and IFN-γ signatures and localized the cell proliferation signature to cycling CD38⁺HLA-DR⁺ cells within CD4⁺ T cell, CD8⁺ T cell, and NK cell populations. CD38⁺HLA-DR⁺ lymphocytes exhibited prominent IFN-γ production, glycolysis, and mTOR signaling. Cell-cell interaction modeling suggested a network linking CD38⁺HLA-DR⁺ lymphocytes with monocytes through IFN-γ signaling. Notably, the expansion of CD38⁺HLA-DR⁺ lymphocytes in MAS was greater than in other systemic inflammatory conditions in children. In vitro stimulation of PBMCs demonstrated that IFN-I and IL-15 — both elevated in MAS patients — synergistically augmented the generation of CD38⁺HLA-DR⁺ lymphocytes, while Janus kinase inhibition mitigated this response. CONCLUSION. MAS associated with SD is characterized by overproduction of IFN-I, which may act in synergy with IL-15 to generate CD38⁺HLA-DR⁺ cycling lymphocytes that produce IFN-γ.

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 γδ 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.

Background: Juvenile Localized Scleroderma (jLS) is a rare pediatric inflammatory disease of skin and underlying tissues that may cause significant functional impairment and disfigurement. Management approaches vary and an optimum treatment regimen is lacking. In 2012, a group of jLS researchers of Childhood Arthritis and Rheumatology Research Alliance (CARRA) proposed consensus treatment plans (CTPs), aimed to streamline the approach to care for jLS patients. Objectives: This study aimed to evaluate a large jLS patient cohort seen over a 21-year period in a single tertiary care pediatric hospital in the USA, in order to examine treatments utilized and determine parameters for systemic therapy initiation. Methods: This retrospective cohort study included jLS patients with disease onset in childhood (≤18-years of age) who were seen in rheumatology, dermatology, or combined rheumatology-dermatology clinics from 1999-2020, with ≤ 3 years of follow-up. Data on demographics, disease characteristics, therapies prescribed, and treatment trends were analyzed. Results: Of the 270 jLS patients identified, 101 fulfilled the inclusion criteria. The primary reason for exclusion was Conclusion: This jLS cohort is one of the largest reported from a single center and reflects an increase in the use of systemic therapy since publication of CARRA CTPs in 2012. Further studies on long-term treatment outcomes and therapeutic approaches utilized when first-line treatment failures occur are warranted. References: [1]Li SC, Torok KS, Pope E, et al. Development of consensus treatment plans for juvenile localized scleroderma: a roadmap toward comparative effectiveness studies in juvenile localized scleroderma. Arthritis Care Res (Hoboken). 2012;64(8):1175-1185. Disclosure of Interests: Bugra Egeli: None declared, Johnathan Dallas: None declared, Edwin Anderson: None declared, Michelle Min: None declared, Daniel Mazori: None declared, Stephen Gellis: None declared, Mary Beth Son: None declared, Robert Sundel: None declared, Ruth Vleugels: None declared, Fatma Dedeoglu Consultant of: Novartis

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.

Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) were historically thought to be distinct entities, often managed in isolation. In fact, these conditions are closely related. A collaborative approach, which incorporates expertise from subspecialties that previously treated HLH/MAS independently, is needed. We leveraged quality improvement (QI) techniques in the form of an Evidence-Based Guideline (EBG) to build consensus across disciplines on the diagnosis and treatment of HLH/MAS. A multidisciplinary work group was convened that met monthly to develop the HLH/MAS EBG. Literature review and expert opinion were used to develop a management strategy for HLH/MAS. The EBG was implemented, and quality metrics were selected to monitor outcomes. An HLH/MAS clinical team was formed with representatives from subspecialties involved in the care of patients with HLH/MAS. Broad entry criteria for the HLH/MAS EBG were established and included fever and ferritin ≥500 ng/mL. The rheumatology team was identified as the “gate-keeper,” charged with overseeing the diagnostic evaluation recommended in the EBG. First-line medications were recommended based on the acuity of illness and risk of concurrent infection. Quality metrics to be tracked prospectively based on time to initiation of treatment and clinical response were selected. HLH/MAS are increasingly considered to be a spectrum of related conditions, and joint management across subspecialties could improve patient outcomes. Our experience in creating a multidisciplinary approach to HLH/MAS management can serve as a model for care at other institutions.

The number of trained specialists world-wide is insufficient to serve all children with pediatric rheumatologic disorders, even in the countries with robust medical resources. We evaluated the potential of diagnostic decision support software (DDSS) to alleviate this shortage by assessing the ability of such software to improve the diagnostic accuracy of non-specialists. Using vignettes of actual clinical cases, clinician testers generated a differential diagnosis before and after using diagnostic decision support software. The evaluation used the SimulConsult® DDSS tool, based on Bayesian pattern matching with temporal onset of each finding in each disease. The tool covered 5405 diseases (averaging 22 findings per disease). Rheumatology content in the database was developed using both primary references and textbooks. The frequency, timing, age of onset and age of disappearance of findings, as well as their incidence, treatability, and heritability were taken into account in order to guide diagnostic decision making. These capabilities allowed key information such as pertinent negatives and evolution over time to be used in the computations. Efficacy was measured by comparing whether the correct condition was included in the differential diagnosis generated by clinicians before using the software (“unaided”), versus after use of the DDSS (“aided”). The 26 clinicians demonstrated a significant reduction in diagnostic errors following introduction of the software, from 28% errors while unaided to 15% using decision support (p < 0.0001). Improvement was greatest for emergency medicine physicians (p = 0.013) and clinicians in practice for less than 10 years (p = 0.012). This error reduction occurred despite the fact that testers employed an “open book” approach to generate their initial lists of potential diagnoses, spending an average of 8.6 min using printed and electronic sources of medical information before using the diagnostic software. These findings suggest that decision support can reduce diagnostic errors and improve use of relevant information by generalists. Such assistance could potentially help relieve the shortage of experts in pediatric rheumatology and similarly underserved specialties by improving generalists’ ability to evaluate and diagnose patients presenting with musculoskeletal complaints. ClinicalTrials.gov ID: NCT02205086

Objective: Treg cell–mediated suppression of Teff cells is impaired in juvenile idiopathic arthritis (JIA); however, the basis for this dysfunction is incompletely understood. Animal models of autoimmunity and immunodeficiency demonstrate that a diverse Treg cell repertoire is essential to maintain Treg cell function. The present study was undertaken to investigate the Treg and Teff cell repertoires in JIA.Methods: Treg cells (CD4+CD25+CD127^low) and Teff cells (CD4+CD25−) were isolated from peripheral blood and synovial fluid obtained from JIA patients, healthy controls, and children with Lyme arthritis. Treg cell function was measured in suppressive assays. The T cell receptor β chain (TRB) was amplified by multiplex polymerase chain reaction and next‐generation sequencing was performed, with amplicons sequenced using an Illumina HiSeq platform. Data were analyzed using ImmunoSEQ, International ImMunoGeneTics system, and the Immunoglobulin Analysis Tools.Results: Compared to findings in controls, the JIA peripheral blood Treg cell repertoire was restricted, and clonotypic expansions were found in both blood and synovial fluid Treg cells. Skewed usage and pairing of TRB variable and joining genes, including overuse of gene segments that have been associated with other autoimmune conditions, was observed. JIA patients shared a substantial portion of synovial fluid Treg cell clonotypes that were private to JIA and not identified in Lyme arthritis.Conclusion: We identified restriction and clonotypic expansions in the JIA Treg cell repertoire with sharing of Treg cell clonotypes across patients. These findings suggest that abnormalities in the Treg cell repertoire, possibly engendered by shared antigenic triggers, may contribute to disease pathogenesis in JIA.

Background: Multicenter studies on idiopathic or viral pericarditis and pericardial effusion ( PPE ) have not been reported in children. Colchicine use for PPE in adults is supported. We explored epidemiology and management for inpatient hospitalizations for PPE in US children and risk factors for readmission. Methods and Results: We analyzed patients in the Pediatric Health Information System database for (1) a code for PPE ; (2) absence of codes for underlying systemic disease (eg, neoplastic, cardiac, rheumatologic, renal); (3) age ≥30 days and <21 years; and (4) discharge between January 1, 2007, and December 31, 2012, from 38 hospitals contributing complete data for each year of the study period. Among 11 364 hospitalizations with PPE codes during the study period, 543 (4.8%) met entry criteria for idiopathic or viral PPE . Significantly more boys were noted, especially among adolescents. No temporal trends were noted. Median age was 14.5 years (interquartile range 7.3 to 16.6 years); 78 patients (14.4%) underwent pericardiocentesis, 13 (2.4%) underwent pericardiotomy, and 11 (2.0%) underwent pericardiectomy; 157 (28.9%) had an intensive care unit stay, including 2.0% with tamponade. Median hospitalization was 3 days ( interquartile range 2 to 4 days). Medications used at initial admission were nonsteroidal anti‐inflammatory drugs (71.3%), corticosteroids (22.7%), aspirin (7.0%), and colchicine (3.9%). Readmissions within 1 year of initial admission occurred in 46 of 447 patients (10.3%), mostly in the first 3 months. No independent predictors of readmission were noted, but our statistical power was limited. Practice variation was noted in medical management and pericardiocentesis. Conclusions: Our report provides the first large multicenter description of idiopathic or viral PPE in children. Idiopathic or viral PPE is most common in male adolescents and is treated infrequently with colchicine.