Autoantibodies Against Proteins Previously Associated With Autoimmunity in Adult and Pediatric Patients With COVID-19 and Children With MIS-C.

The antibody profile against autoantigens previously associated with autoimmune diseases and other human proteins in patients with COVID-19 or multisystem inflammatory syndrome in children (MIS-C) remains poorly defined. Here we show that 30% of adults with COVID-19 had autoantibodies against the lung antigen KCNRG, and 34% had antibodies to the SLE-associated Smith-D3 protein. Children with COVID-19 rarely had autoantibodies; one of 59 children had GAD65 autoantibodies associated with acute onset of insulin-dependent diabetes. While autoantibodies associated with SLE/Sjögren's syndrome (Ro52, Ro60, and La) and/or autoimmune gastritis (gastric ATPase) were detected in 74% (40/54) of MIS-C patients, further analysis of these patients and of children with Kawasaki disease (KD), showed that the administration of intravenous immunoglobulin (IVIG) was largely responsible for detection of these autoantibodies in both groups of patients. Monitoring in vivo decay of the autoantibodies in MIS-C children showed that the IVIG-derived Ro52, Ro60, and La autoantibodies declined to undetectable levels by 45-60 days, but gastric ATPase autoantibodies declined more slowly requiring >100 days until undetectable. Further testing of IgG and/or IgA antibodies against a subset of potential targets identified by published autoantigen array studies of MIS-C failed to detect autoantibodies against most (16/18) of these proteins in patients with MIS-C who had not received IVIG. However, Troponin C2 and KLHL12 autoantibodies were detected in 2 of 20 and 1 of 20 patients with MIS-C, respectively. Overall, these results suggest that IVIG therapy may be a confounding factor in autoantibody measurements in MIS-C and that antibodies against antigens associated with autoimmune diseases or other human proteins are uncommon in MIS-C.

Wide variation in glucocorticoid dosing in paediatric ANCA-associated vasculitis with renal disease: a paediatric vasculitis initiative study.

OBJECTIVES: High-dose glucocorticoids for remission-induction of ANCA-associated vasculitis are recommended and commonly used in adults, but recent studies suggest lower glucocorticoid doses can reduce toxicity without reducing efficacy. No paediatric-specific data exists to inform optimal glucocorticoid dosing in paediatric ANCA-associated vasculitis (pAAV). Our objectives were to describe glucocorticoid use in pAAV-related renal disease, and to explore associations between glucocorticoid dose, baseline patient characteristics and 12-month outcomes. METHODS: Youth <18 years with pAAV, biopsy-confirmed pauci-immune glomerulonephritis and 12-month follow-up data were included from an international paediatric vasculitis registry. Presenting features and 12-month outcomes (eGFR, glucocorticoid-related adverse effects), were compared between patients receiving no, low-moderate (≤90mg/kg) and high (>90mg/kg) cumulative intravenous methylprednisolone (IVMP), and low (<0.5mg/kg/day prednisone equivalent), moderate (0.5-1.5mg/kg/day) and high (>1.5mg/kg/day) starting doses of oral glucocorticoids. RESULTS: Among 131 patients (101 granulomatosis with polyangiitis, 30 microscopic polyangiitis), 27 (21%) received no IVMP, 64 (49%) low-moderate and 29 (22%) high-dose IVMP, while 9 (7%) received low, 75 (57%) moderate and 47 (36%) high initial doses of oral glucocorticoids. Renal failure at diagnosis (p=0.022) and plasmapheresis use (p=0.0001) were associated with high-dose IVMP. Rates of glucocorticoid-related adverse effects ranged from 15-31% across dose levels, and glucocorticoid dosing did not associate with 12-month outcomes. CONCLUSIONS: Glucocorticoid dosing for pAAV-related renal disease was highly variable, and rates of adverse effects were high across all dosing groups. A significant proportion of patients received oral glucocorticoid or IVMP doses that were discordant with current adult guidelines. Higher glucocorticoid doses did not associate with improved outcomes.

Profiling Behavioral and Psychological Symptoms in Children Undergoing Treatment for Spondyloarthritis and Polyarthritis.

OBJECTIVE: Few studies examine psychopathology in different juvenile idiopathic arthritis (JIA) subtypes and disease activity states. We aimed to (1) evaluate emotional and behavioral symptoms in children with juvenile spondyloarthritis (SpA) and polyarticular arthritis (PolyA) as compared to a national normative population using the Child Behavior Checklist (CBCL), and (2) evaluate the relationship between CBCL scores and disease activity. METHODS: Patients with JIA aged 6-17 years with SpA or PolyA were recruited from our pediatric rheumatology clinic from April 2018 to April 2019 and the CBCL and clinical Juvenile Arthritis Disease Activity Score in 10 joints (cJADAS10) were completed. Primary outcome measures were CBCL total competence, internalizing, externalizing, and total problems raw scores. We compared outcomes from each group to national CBCL normative data. To investigate the relationship between CBCL scores and disease activity, we ran a generalized linear regression model for all patients with arthritis with cJADAS10 as the main predictor. RESULTS: There were 111 patients and 1753 healthy controls (HCs). Compared to HCs, patients with SpA or PolyA had worse total competence and internalizing scores. Higher cJADAS10 scores were associated with worse total competence, worse internalizing, and higher total problems scores. Most of these differences reached statistical significance (P < 0.01). Self-harm/suicidality was almost 4-fold higher in patients with PolyA than HCs (OR 3.6, 95% CI 1.3-9.6, P = 0.011). CONCLUSION: Our study shows that patients with SpA and PolyA with more active disease have worse psychological functioning in activities, school, and social arenas, and more internalized emotional disturbances, suggesting the need for regular mental health screening by rheumatologists.

Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19.

Pediatric Coronavirus Disease 2019 (pCOVID-19) is rarely severe; however, a minority of children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might develop multisystem inflammatory syndrome in children (MIS-C), with substantial morbidity. In this longitudinal multi-institutional study, we applied multi-omics (analysis of soluble biomarkers, proteomics, single-cell gene expression and immune repertoire analysis) to profile children with COVID-19 (n = 110) and MIS-C (n = 76), along with pediatric healthy controls (pHCs; n = 76). pCOVID-19 was characterized by robust type I interferon (IFN) responses, whereas prominent type II IFN-dependent and NF-κB-dependent signatures, matrisome activation and increased levels of circulating spike protein were detected in MIS-C, with no correlation with SARS-CoV-2 PCR status around the time of admission. Transient expansion of TRBV11-2 T cell clonotypes in MIS-C was associated with signatures of inflammation and T cell activation. The association of MIS-C with the combination of HLA A*02, B*35 and C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load than pCOVID-19 and pHC. These results identify distinct immunopathological signatures in pCOVID-19 and MIS-C that might help better define the pathophysiology of these disorders and guide therapy.

Determinants of Tumor Necrosis Factor Inhibitor Use in Juvenile Spondyloarthropathy and Impact on Clinical Disease Outcomess.

OBJECTIVE: The objectives of this study were to characterize the reasons for tumor necrosis factor inhibitor (TNFi) initiation in patients with juvenile spondyloarthropathy (JSpA) and identify clinical correlates and to assess the effect of TNFi therapy on JSpA disease activity. METHODS: We conducted a retrospective cohort study of 86 patients with JSpA with first-time use of a TNFi over a 7-year period at Stanford Children's Health. We assessed the physician's reason for TNFi initiation, disease activity at 6 months, and clinical disease status at 12 months following TNFi start. Changes in active joint count, enthesitis count, and pain were measured. Demographics, physician reasons for TNFi initiation, and clinical characteristics were summarized. RESULTS: The mean age at JSpA diagnosis was 12.4 years (SD 4.0 years), and the mean time from diagnosis to TNFi initiation was 1.6 years (SD 2.3 years). The most common reason for initiating a TNFi was active disease on physical examination (61%). At 6 months post TNFi initiation, patients on average had three fewer active joints and one fewer active enthesitis point. Patient-reported pain improved from moderate/severe to mild. After 12 months, 54% of patients had active disease. CONCLUSION: The physician's decision to initiate a TNFi relied mostly on physical examination findings. Despite improvement in arthritis, enthesitis, and patient-reported pain at 6 months post TNFi initiation, the majority of the patients still had active disease after 1 year of therapy.

Consensus Treatment Plans for Severe Pediatric Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: There is no standardized approach to the treatment of pediatric antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Because of the rarity of pediatric AAV, randomized trials have not been feasible. The present study of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) was undertaken to establish consensus treatment plans (CTPs) for severe pediatric AAV to enable the future study of comparative effectiveness and safety. METHODS: A workgroup of CARRA members (rheumatologists and nephrologists) formed the AAV Workgroup. This group performed a literature review on existing evidence-based treatments and guidelines for the management of AAV. They determined that the target population for CTP development was patients <18 years of age with new-onset granulomatosis with polyangiitis (GPA), microscopic polyangiitis, or renal-limited AAV (eosinophilic GPA was excluded), with presentation confined to those with severe disease (i.e., organ- or life-threatening). Face-to-face consensus conferences employed nominal group techniques to identify treatment strategies for remission induction and remission maintenance, data elements to be systematically collected, and outcomes to be measured over time. RESULTS: The pediatric AAV Workgroup developed 2 CTPs for each of the remission induction and remission maintenance of severe AAV. A glucocorticoid-weaning regimen for induction and maintenance, a core data set, and outcome measures were also defined. A random sample of CARRA membership voted acceptance of the CTPs for remission induction and remission maintenance, with a 94% (75 of 80) and 98% (78 of 80) approval rate, respectively. CONCLUSION: Consensus methodology established standardized CTPs for treating severe pediatric AAV. These CTPs were in principle accepted by CARRA-wide membership for the evaluation of pragmatic comparative effectiveness in a long-term registry.

Gaps in Mental Health Care for Youth With Rheumatologic Conditions: A Mixed Methods Study of Perspectives From Behavioral Health Providers.

OBJECTIVE: To identify behavioral health provider perspectives on gaps in mental health care for youth with rheumatologic conditions. METHODS: Social workers (n = 34) and psychologists (n = 8) at pediatric rheumatology centers in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) completed an online survey assessing current practices and mental health care needs of youth with rheumatologic conditions. Responses were compared to a published survey of CARRA rheumatologists (n = 119). Thematic analysis of 20 semi-structured interviews with behavioral health providers was performed. RESULTS: One-third of CARRA centers (n = 100) had no affiliated social worker or psychologist. Only 1 behavioral health provider reported current universal mental health screening at their rheumatology clinic, yet routine depression screening was supported by >85% of behavioral health providers and rheumatologists. Support for anxiety screening was higher among behavioral health providers (90% versus 65%; P < 0.01). Interviews illustrated a need for interventions addressing illness-related anxiety, adjustment/coping/distress, transition, parent/caregiver mental health, and peer support. Limited resources, lack of protocols, and patient cost/time burden were the most frequent barriers to intervention. Inadequate follow-up of mental health referrals was indicated by 52% of providers. More behavioral health providers than rheumatologists favored mental health services in rheumatology settings (55% versus 19%; P < 0.01). Only 7 social workers (21%) provided counseling/therapy, and interviews indicated their perceived underutilization of these services. CONCLUSION: Behavioral health providers indicated an unmet need for mental health interventions that address illness-related issues affecting youth with rheumatologic conditions. Implementation of mental health protocols and optimizing utilization of social workers may improve mental health care for these youth.

Pediatric Integrative Medicine in Academia: Stanford Children's Experience.

Pediatric integrative medicine is an emerging field which, to date, has not been described in detail in academic medical centers in the United States. Early research of pediatric integrative medicine modalities shows promise for the treatment of common pediatric conditions such as irritable bowel syndrome, acute and chronic pain, headache, and allergy, among others. In light of the growing prevalence of pediatric illnesses and patient complexity, it is crucial to emphasize the patient's overall well-being. As academic centers around the world start to develop pediatric integrative medicine programs, the aim of this manuscript is to briefly highlight evidence of effective integrative treatments in pediatric subspecialties, to describe the establishment of our integrative medicine program, to summarize its early efforts, and to discuss potential barriers and keys to success.

Pediatric Integrative Medicine in Residency Program: Relationship between Lifestyle Behaviors and Burnout and Wellbeing Measures in First-Year Residents.

It is widely recognized that burnout is prevalent in medical culture and begins early in training. Studies show pediatricians and pediatric trainees experience burnout rates comparable to other specialties. Newly developed Accreditation Council for Graduate Medical Education (ACGME) core competencies in professionalism and personal development recognize the unacceptably high resident burnout rates and present an important opportunity for programs to improve residents experience throughout training. These competencies encourage healthy lifestyle practices and cultivation of self-awareness, self-regulation, empathy, mindfulness, and compassion—a paradigm shift from traditional medical training underpinned by a culture of unrealistic endurance and self-sacrifice. To date, few successful and sustainable programs in resident burnout prevention and wellness promotion have been described. The University of Arizona Center for Integrative Medicine Pediatric Integrative Medicine in Residency (PIMR) curriculum, developed in 2011, was designed in part to help pediatric programs meet new resident wellbeing requirements. The purpose of this paper is to detail levels of lifestyle behaviors, burnout, and wellbeing for the PIMR program’s first-year residents (N = 203), and to examine the impact of lifestyle behaviors on burnout and wellbeing. The potential of the PIMR to provide interventions addressing gaps in lifestyle behaviors with recognized association to burnout is discussed.

Pediatric Integrative Medicine.

The American Academy of Pediatrics is dedicated to optimizing the well-being of children and advancing family-centered health care. Related to this mission, the American Academy of Pediatrics recognizes the increasing use of complementary and integrative therapies for children and the subsequent need to provide reliable information and high-quality clinical resources to support pediatricians. This Clinical Report serves as an update to the original 2008 statement on complementary medicine. The range of complementary therapies is both extensive and diverse. Therefore, in-depth discussion of each therapy or product is beyond the scope of this report. Instead, our intentions are to define terms; describe epidemiology of use; outline common types of complementary therapies; review medicolegal, ethical, and research implications; review education and training for select providers of complementary therapies; provide educational resources; and suggest communication strategies for discussing complementary therapies with patients and families.