Severe Features of Systemic Juvenile Idiopathic Arthritis in Patients With Congenital Heart Disease.

OBJECTIVE: To describe the clinical features of patients with congenital heart disease (CHD) who subsequently developed systemic juvenile idiopathic arthritis (sJIA). METHODS: We conducted a retrospective review of patients diagnosed with CHD and sJIA at our institution. Detailed clinical, laboratory, and radiographic data were collected from the medical record and reviewed with each patient's primary medical team. RESULTS: Five patients with sJIA and CHD were identified. Each child had a unique cardiac anatomy, but all the patients required surgical repair during the first year of life. Four children had thymectomies at the time of cardiac surgery. Classic signs of sJIA such as fever (n = 5), rash (n = 5), and arthritis (n = 4) developed after surgical intervention in all the patients. The individuals in this cohort displayed risk factors associated with severe sJIA, including disease onset before 2 years of age (n = 5), elevated interleukin 18 levels (n = 5), baseline eosinophilia prior to initiation of biologic disease-modifying antirheumatic drugs (n = 4), and positivity for HLA-DRB1*15:01 alleles (n = 4). Macrophage activation syndrome (MAS) occurred in 3 patients and sJIA-associated lung disease (sJIA-LD) was identified in 4 patients. Two children died from complications of their cardiac and/or pulmonary disease. CONCLUSION: We identified an association between CHD and severe forms of sJIA. Although these findings will need to be confirmed in larger, multicenter cohorts, the results highlight the importance of considering a diagnosis of sJIA in children with CHD and remaining vigilant for complications such as MAS and sJIA-LD.

COVID-19-Related Multi-systemic Inflammatory Syndrome in Children (MIS-C).

Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infections in children. This syndrome manifests about a month after the initial viral infection and is characterized by fever, multiorgan dysfunction, and systemic inflammation. This chapter will review the emergence, epidemiology, clinical characteristics, diagnosis, pathophysiology, immunomodulatory treatment, prognosis, outcomes, and prevention of MIS-C. While the pathophysiology of MIS-C remains to be defined, it is a post-infection, hyperinflammatory syndrome of childhood with elevated inflammatory cytokines.

Uncloaking the viral glycocalyx: How do viruses exploit glycoimmune checkpoints?

The surfaces of cells and enveloped viruses alike are coated in carbohydrates that play multifarious roles in infection and immunity. Organisms across all kingdoms of life make use of a diverse set of monosaccharide subunits, glycosidic linkages, and branching patterns to encode information within glycans. Accordingly, sugar-patterning enzymes and glycan binding proteins play integral roles in cell and organismal biology, ranging from glycoprotein quality control within the endoplasmic reticulum to lymphocyte migration, coagulation, inflammation, and tissue homeostasis. Unsurprisingly, genes involved in generating and recognizing oligosaccharide patterns are playgrounds for evolutionary conflicts that abound in cross-species interactions, exemplified by the myriad plant lectins that function as toxins. In vertebrates, glycans bearing acidic nine-carbon sugars called sialic acids are key regulators of immune responses. Various bacterial and fungal pathogens adorn their cells in sialic acids that either mimic their hosts' or are stolen from them. Yet, how viruses commandeer host sugar-patterning enzymes to thwart immune responses remains poorly studied. Here, we review examples of viruses that interact with sialic acid-binding immunoglobulin-like lectins (Siglecs), a family of immune cell receptors that regulate toll-like receptor signaling and govern glycoimmune checkpoints, while highlighting knowledge gaps that merit investigation. Efforts to illuminate how viruses leverage glycan-dependent checkpoints may translate into new clinical treatments that uncloak viral antigens and infected cell surfaces by removing or masking immunosuppressive sialoglycans, or by inhibiting viral gene products that induce their biosynthesis. Such approaches may hold the potential to unleash the immune system to clear long intractable chronic viral infections.

Real-world application of the pediatric Glucocorticoid Toxicity Index in childhood-onset lupus.

OBJECTIVES: The pediatric Glucocorticoid Toxicity Index (pGTI) is a new, pediatric-specific tool to quantify glucocorticoid (GC)-related morbidity in children. We evaluated the feasibility and construct validity of retrospective pGTI scoring in patients with pediatric-onset systemic lupus erythematosus (pSLE) and identified risk factors for cumulative toxicity. METHODS: We conducted a retrospective cohort study of patients with pSLE treated with GCs at two pediatric centers (1999-2023). GC exposure was estimated using interval-averaged oral prednisone-equivalent dose and cumulative prednisone-equivalent dose. We scored change in GC toxicity every 6 months (±2) using a modified pGTI including 7 of 10 domains. We calculated the Cumulative Worsening Score (CWS), a continuous summation of toxicity accrued. Mixed effects linear regression was used to identify factors associated with CWS. RESULTS: There were 126 patients with pSLE, including 88 with nephritis, with a median of 6 visits/patient. Nearly half (47 %) experienced toxicity in the Blood Pressure domain. Other common toxicities were mood disturbance (25 %), followed by increased body mass index (BMI), striae, and sleep disturbance (21 % each). Decreased growth velocity was observed in 18 %. There was modest correlation between cumulative GC dose and CWS (rho 0.3; p < 0.01). Greater cumulative toxicity was associated with younger age, elevated BMI, and rituximab use at the time of GC initiation, albeit indications for the latter were not captured. CONCLUSIONS: Patients with pSLE experience a high burden of GC toxicity, particularly related to blood pressure, BMI, sleep, and growth. Standardized, pediatric-specific GC toxicity assessment is feasible in real-world settings and can facilitate evaluation of strategies to reduce morbidity in children requiring chronic GC treatment.

Hyperferritinemia screening to aid identification and differentiation of patients with hyperinflammatory disorders.

High ferritin is an important and sensitive biomarker for hemophagocytic lymphohistiocytosis (HLH), a diverse and deadly group of cytokine storm syndromes. Early action to prevent immunopathology in HLH often includes empiric immunomodulation, which can complicate etiologic work-up and prevent collection of early/pre-treatment research samples. To address this, we instituted an alert system where serum ferritin > 1000ng/mL triggered real-time chart review, assessment of whether the value reflected "inflammatory hyperferritnemia (IHF)", and biobanking of remnant samples from consenting IHF patients. We extracted relevant clinical data; periodically measured serum total IL-18, IL-18 binding protein (IL-18BP), and CXCL9; retrospectively classified patients by etiology into infectious, rheumatic, or immune dysregulation; and subjected a subgroup of samples to a 96-analyte biomarker screen. 180 patients were identified, 30.5% of which had IHF. Maximum ferritin levels were significantly higher in patients with IHF than with either hemoglobinopathy or transplant, and highly elevated total IL-18 levels were distinctive to patients with Stills Disease and/or Macrophage Activation Syndrome (MAS). Multi-analyte analysis showed elevation in proteins associated with cytotoxic lymphocytes in all IHF samples when compared to healthy controls and depression of proteins such as ANGPT1 and VEGFR2 in samples from hyperferritinemic sepsis patients relative to non-sepsis controls. This single-center, real-time IFH screen proved feasible and efficient, validated prior observations about the specificity of IL-18, enabled early sample collection from a complex population, suggested a unique vascular biomarker signature in hyperferritinemic sepsis, and expanded our understanding of IHF heterogeneity.

Integrating circulating T follicular memory cells and autoantibody repertoires for characterization of autoimmune disorders.

Introduction: Autoimmune diseases are heterogeneous and often lack specific or sensitive diagnostic tests. Increased percentages of CD4+CXCR5+PD1+ circulating T follicular helper (cTfh) cells and skewed distributions of cTfh subtypes have been associated with autoimmunity. However, cTfh cell percentages can normalize with immunomodulatory treatment despite persistent disease activity, indicating the need for identifying additional cellular and/or serologic features correlating with autoimmunity. Methods: The cohort included 50 controls and 56 patients with autoimmune cytopenias, gastrointestinal, pulmonary, and/or neurologic autoimmune disease. Flow cytometry was used to measure CD4+CXCR5+ T cell subsets expressing the chemokine receptors CXCR3 and/or CCR6: CXCR3+CCR6- Type 1, CXCR3-CCR6- Type 2, CXCR3+CCR6+ Type 1/17, and CXCR3- CCR6+ Type 17 T cells. IgG and IgA autoantibodies were quantified using a microarray featuring 1616 full-length, conformationally intact protein antigens. The 97.5th percentile in the control cohort defined normal limits for T cell subset percentages and total number (burden) of autoantibodies. Results: This study focused on CD4+CXCR5+ T cells because CXCR5 upregulation occurs after cognate T-B cell interactions characteristic of autoimmune diseases. We refer to these cells as circulating T follicular memory (cTfm) cells to acknowledge the dynamic nature of antigen-experienced CXCR5+ T cells, which encompass progenitors of cTfh or Tfh cells as well as early effector memory T cells that have not yet lost CXCR5. Compared to controls, 57.1% of patients had increased CXCR5+CXCR3+CCR6+ cTfm1/17 and 25% had increased CXCR5+CXCR3-CCR6+ cTfm17 cell percentages. Patients had significantly more diverse IgG and IgA autoantibodies than controls and 44.6% had an increased burden of autoantibodies of either isotype. Unsupervised autoantibody clustering identified three clusters of patients with IgG autoantibody profiles distinct from those of controls, enriched for patients with active autoimmunity and monogenic diseases. An increased percentage of cTfm17 cells was most closely associated with an increased burden of high-titer IgG and IgA autoantibodies. A composite measure integrating increased cTfm1/17, cTfm17, and high-titer IgG and/or IgA autoantibodies had 91.1% sensitivity and 90.9% specificity for identifying patients with autoimmunity. Percentages of cTfm1/17 and cTfm17 percentages and numbers of high-titer autoantibodies in patients receiving immunomodulatory treatment did not differ from those in untreated patients, thus suggesting that measurements of cTfm can complement measurements of other cellular markers affected by treatment. Conclusions: This study highlights two new approaches for assessing autoimmunity: measuring CD4+CXCR5+ cTfm subsets as well as total burden of autoantibodies. Our findings suggest that these approaches are particularly relevant to patients with rare autoimmune disorders for whom target antigens and prognosis are often unknown.