Improving Outcomes of Pediatric Lupus Care Delivery With Provider Goal-Setting Activities and Multidisciplinary Care Models.

OBJECTIVE: The present study was undertaken to evaluate high-quality care delivery in the context of provider goal-setting activities and a multidisciplinary care model using an electronic health record (EHR)-enabled pediatric lupus registry. We then determined associations between care quality and prednisone use among youth with systemic lupus erythematosus (SLE). METHODS: We implemented standardized EHR documentation tools to autopopulate a SLE registry. We compared pediatric Lupus Care Index (pLCI) performance (range 0.0-1.0; 1.0 representing perfect metric adherence) and timely follow-up 1) before versus during provider goal-setting activities and population management, and 2) in a multidisciplinary lupus nephritis versus rheumatology clinic. We estimated associations between pLCI and subsequent prednisone use adjusted for time, current medication, disease activity, clinical features, and social determinants of health. RESULTS: We analyzed 830 visits by 110 patients (median 7 visits per patient [interquartile range 4-10]) over 3.5 years. The provider-directed activity was associated with improved pLCI performance (adjusted ß 0.05 [95% confidence interval (95% CI) 0.01, 0.09]; mean 0.74 versus 0.69). Patients with nephritis in multidisciplinary clinic had higher pLCI scores (adjusted ß 0.06 [95% CI 0.02, 0.10]) and likelihood of timely follow-up than those in rheumatology (adjusted relative risk [RR] 1.27 [95% CI 1.02, 1.57]). A pLCI score of ≥0.50 was associated with 0.72-fold lower adjusted risk of subsequent prednisone use (95% CI 0.53, 0.93). Minoritized race, public insurance, and living in areas with greater social vulnerability were not associated with reduced care quality or follow-up, but public insurance was associated with higher risk of prednisone use. CONCLUSION: Greater attention to quality metrics is associated with better outcomes in childhood SLE. Multidisciplinary care models with population management may additionally facilitate equitable care delivery.

Temporal Relationship Between Juvenile Idiopathic Arthritis Disease Activity and Uveitis Disease Activity.

OBJECTIVE: To determine whether there is a temporal association between arthritis and uveitis activity among children with juvenile idiopathic arthritis-associated uveitis (JIA-U). METHODS: Uveitis and arthritis data from patients with JIA-U age ≤21 years were collected from July 2013 to December 2019 at a tertiary care center. Arthritis activity was assessed at each rheumatology visit, and the primary outcome was the presence of active uveitis at ophthalmologic examination within 45 days of the rheumatology visit. Repeated-measures logistic regression was used to evaluate the temporal association between any uveitis activity within 45 days of arthritis activity. Models were adjusted for demographic-, disease-, and treatment-related factors. RESULTS: A total of 98 patients were included: 81 (83%) female, 67 (69%) antinuclear antibody positive, 59 (60%) oligoarticular, and 13 (13%) enthesitis-related arthritis (ERA) subtypes. There were 1,229 rheumatology visits, with a median of 13 visits per patient (interquartile range 7-18). Concordance between arthritis and uveitis activity was observed 73% of the time (694 of 947). There was an independent temporal association between uveitis and arthritis activity (odds ratio 2.47 [95% confidence interval 1.72-3.54]; P < 0.01), adjusted for demographic and disease characteristics. Use of combination biologic and nonbiologic disease-modifying antirheumatic drugs, female sex, HLA-B27 positivity, and ERA and polyarticular (rheumatoid factor negative) subtypes were associated with decreased odds of active uveitis at any time point. CONCLUSION: In patients with JIA-U, there is a significant temporal association between arthritis and uveitis disease activity. These novel results suggest that an arthritis flare should prompt an expedited referral to the ophthalmologist.

Distinct immune trajectories in patients with chromosome 22q11.2 deletion syndrome and immune-mediated diseases.

BACKGROUND: Identification of biomarkers associated with immune-mediated diseases in 22q11.2 deletion syndrome is an evolving field. OBJECTIVES: We sought to use a carefully phenotyped cohort to study immune parameters associated with autoimmunity and atopy in 22q11.2 deletion syndrome to define biomarkers associated with immune-mediated disease in this syndrome. METHODS: Chart review validated autoimmune disease and atopic condition diagnoses. Laboratory data were extracted for each subcohort and plotted according to age. A random-effects model was used to define statistical significance. RESULTS: CD19, CD4, and CD4/45RA lymphocyte populations were not different from the general cohort for patients with atopic conditions. CD4/45RA T cells were significantly lower in the subjects with immune thrombocytopenia compared with the general cohort, and CD4 T-cell counts were lower in patients with autoimmune thyroid disease. CONCLUSIONS: The mechanisms of autoimmunity in cytopenias may be distinct from those of solid-organ autoimmunity in 22q11.2 deletion syndrome. This study identifies potential biomarkers for risk stratification among commonly obtained laboratory studies.

Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations.

Most children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have mild or minimal disease, with a small proportion developing severe disease or multisystem inflammatory syndrome in children (MIS-C). Complement-mediated thrombotic microangiopathy (TMA) has been associated with SARS-CoV-2 infection in adults but has not been studied in the pediatric population. We hypothesized that complement activation plays an important role in SARS-CoV-2 infection in children and sought to understand if TMA was present in these patients. We enrolled 50 hospitalized pediatric patients with acute SARS-CoV-2 infection (n = 21, minimal coronavirus disease 2019 [COVID-19]; n = 11, severe COVID-19) or MIS-C (n = 18). As a biomarker of complement activation and TMA, soluble C5b9 (sC5b9, normal 247 ng/mL) was measured in plasma, and elevations were found in patients with minimal disease (median, 392 ng/mL; interquartile range [IQR], 244-622 ng/mL), severe disease (median, 646 ng/mL; IQR, 203-728 ng/mL), and MIS-C (median, 630 ng/mL; IQR, 359-932 ng/mL) compared with 26 healthy control subjects (median, 57 ng/mL; IQR, 9-163 ng/mL; P < .001). Higher sC5b9 levels were associated with higher serum creatinine (P = .01) but not age. Of the 19 patients for whom complete clinical criteria were available, 17 (89%) met criteria for TMA. A high proportion of tested children with SARS-CoV-2 infection had evidence of complement activation and met clinical and diagnostic criteria for TMA. Future studies are needed to determine if hospitalized children with SARS-CoV-2 should be screened for TMA, if TMA-directed management is helpful, and if there are any short- or long-term clinical consequences of complement activation and endothelial damage in children with COVID-19 or MIS-C.

Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2.

BACKGROUNDInitial reports from the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic described children as being less susceptible to coronavirus disease 2019 (COVID-19) than adults. Subsequently, a severe and novel pediatric disorder termed multisystem inflammatory syndrome in children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide insight into pathophysiology.METHODSWe prospectively enrolled hospitalized patients with evidence of SARS-CoV-2 infection and classified them as having MIS-C or COVID-19. Patients with COVID-19 were classified as having either minimal or severe disease. Cytokine profiles, viral cycle thresholds (Cts), blood smears, and soluble C5b-9 values were analyzed with clinical data.RESULTSTwenty patients were enrolled (9 severe COVID-19, 5 minimal COVID-19, and 6 MIS-C). Five cytokines (IFN-γ, IL-10, IL-6, IL-8, and TNF-α) contributed to the analysis. TNF-α and IL-10 discriminated between patients with MIS-C and severe COVID-19. The presence of burr cells on blood smears, as well as Cts, differentiated between patients with severe COVID-19 and those with MIS-C.CONCLUSIONPediatric patients with SARS-CoV-2 are at risk for critical illness with severe COVID-19 and MIS-C. Cytokine profiling and examination of peripheral blood smears may distinguish between patients with MIS-C and those with severe COVID-19.FUNDINGFinancial support for this project was provided by CHOP Frontiers Program Immune Dysregulation Team; National Institute of Allergy and Infectious Diseases; National Cancer Institute; the Leukemia and Lymphoma Society; Cookies for Kids Cancer; Alex's Lemonade Stand Foundation for Childhood Cancer; Children's Oncology Group; Stand UP 2 Cancer; Team Connor; the Kate Amato Foundations; Burroughs Wellcome Fund CAMS; the Clinical Immunology Society; the American Academy of Allergy, Asthma, and Immunology; and the Institute for Translational Medicine and Therapeutics.

Vitamin C deficiency mimicking inflammatory bone disease of the hand.

BACKGROUND: Severe vitamin C deficiency, or scurvy, encompasses a syndrome of multisystem abnormalities due to defective collagen synthesis and antioxidative functions. Among the more common presentations is a combination of oral or subcutaneous hemorrhage with lower extremity pain, the latter often exhibiting inflammatory bone changes on magnetic resonance imaging (MRI). CASE PRESENTATION: A 12-year-old male with anorexia nervosa presented with asymmetric painful swelling of multiple fingers of both hands. Imaging demonstrated soft tissue and bone marrow edema of several phalanges, without arthritis, concerning for an inflammatory process. Extensive imaging and laboratory evaluations were largely unrevealing, with the exception of a severely low vitamin C level and a moderately low vitamin D level. A diagnosis of scurvy was made and supplementation was initiated. Within 3 weeks of treatment, serum levels of both vitamins normalized and the digital abnormalities resolved on physical exam. CONCLUSIONS: This represents the first description of scurvy manifesting with bone and soft tissue changes limited to the hands. There must be a high index of suspicion for scurvy in children with restricted dietary intake or malabsorption who have bone pain, irrespective of location of the lesions.

Assessment of traditional and non-traditional risk factors for premature atherosclerosis in children with juvenile dermatomyositis and pediatric controls.

BACKGROUND: Children with juvenile dermatomyositis (JDM), the most common inflammatory myopathy of childhood, may be at increased risk of premature atherosclerosis given a host of traditional and non-traditional risk factors. The primary aim of this study was to determine the underlying frequency of premature atherosclerosis in children with JDM compared to pediatric controls using flow-mediated dilation as a measure of endothelial function. METHODS: Children and adolescents with and without JDM were evaluated for traditional atherosclerotic risk factors and assessment of endothelial function, using Endothelial Pulse Amplitude Testing (Endo-PAT). RESULTS: In this study, 75% of pediatric controls were of Black or Hispanic descent (compared to 55% in the JDM group) and 70% were found to live in a household with a medium income less than $50,000/year (compared to 45% in the JDM group). Among traditional atherogenic risk factors, lipoprotein A appeared to be different between controls and JDM patients (66 nmol/L and 16.5 nmol/L, respectively). Using a reactive hyperemia index (RHI) < 1.67 as evidence of endothelial dysfunction, 75% of controls were defined as having endothelial dysfunction compared to 50% in JDM group. When controlled for lipoprotein A as an atherogenic confounder, JDM patients were found to have a 41% increase in RHI, thus indicating less endothelial dysfunction compared to controls. CONCLUSIONS: In this study, we have shown that atherogenic risk factors are present in the pediatric population and may be associated with endothelial dysfunction, even at very young ages. Despite increasing concerns that children with rheumatologic disorders may be at increased risk of developing premature atherosclerosis, traditional and sociodemographic features may play a greater role in the ultimate development of cardiovascular disease.

Enhancing communication and social engagement among clinicians and research teams to improve reliability of research recruitment.

The success of rare disease research relies heavily on robust partnerships with clinicians to help identify new patients and collect samples. Many studies for paediatric rheumatic diseases requiring pretreatment samples have suffered from slow enrolment rates due to the low incidence of disease and relative urgency to treat. Therefore, timely identification of all potentially eligible patients is crucial. The objective of this project was to apply quality improvement methods to increase the frequency and timeliness of identification of eligible patients with new paediatric rheumatic diagnoses to approach for research studies. A retrospective chart review was undertaken in our paediatric rheumatology clinic to measure the number of eligible patients identified for potential research recruitment between missed recruitment opportunities. Improvement methodology was used to integrate standardised communication between clinicians and the research team into clinic workflow, to leverage social feedback as positive reinforcement for good communication and to measure change in response to the interventions. The number of eligible patients identified between missed recruitment opportunities increased from every 0-1 patient to every 14 patients during the project period, corresponding to an increase in the overall identification rate from 32% to 91% of all eligible patients. Quality improvement methods can be used to successfully integrate research recruitment into routine clinical care and accelerate advances necessary to improve health outcomes.

Theaflavin-3-gallate and theaflavin-3'-gallate, polyphenols in black tea with prooxidant properties.

This study compared the in vitro responses of human gingival fibroblasts and of carcinoma cells derived from the tongue to theaflavin-3-gallate (TF-2A) and theaflavin-3'-gallate (TF-2B), polyphenols in black tea. The antiproliferative and cytotoxic effects of the theaflavin monomers were more pronounced to the carcinoma, than to the normal, cells. In phosphate buffer at pH 7.4, the theaflavins generated hydrogen peroxide and the superoxide anion, suggesting that their mode of toxicity may be due, in part, to the induction of oxidative stress. In a cell-free assay, TF-2A and TF-2B reacted directly with reduced glutathione (GSH), in a time- and concentration-dependent manner. Intracellular storages of GSH were depleted on treatment of the cells with the theaflavin monomers. Depletion of intracellular GSH was more extensive with TF-2A than with TF-2B and was more pronounced in the carcinoma, than in the normal, cells. The toxicities of the theaflavins were potentiated when the cells were cotreated with the GSH depleter, d,l-buthionine-[S,R]-sulfoximine. In the presence of catalase, pyruvate and divalent cobalt, all scavengers of reactive oxygen species, the cytotoxicities of the theaflavins were lessened. TF-2A and TF-2B induced lipid peroxidation in the carcinoma cells, whereas in the fibroblasts, peroxidation was evident upon exposure to TF-2A, but not to TF-2B. These studies demonstrated that the black tea theaflavin monomers, TF-2A and TF-2B, act as prooxidants and induce oxidative stress, with carcinoma cells more sensitive than normal fibroblasts.