Identification of eight novel proteasome variants in five unrelated cases of proteasome-associated autoinflammatory syndromes (PRAAS).

Mutations in genes coding for proteasome subunits and/or proteasome assembly helpers typically cause recurring autoinflammation referred to as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE) or proteasome-associated autoinflammatory syndrome (PRAAS). Patients with CANDLE/PRAAS present with mostly chronically elevated type I interferon scores that emerge as a consequence of increased proteotoxic stress by mechanisms that are not fully understood. Here, we report on five unrelated patients with CANDLE/PRAAS carrying novel inherited proteasome missense and/or nonsense variants. Four patients were compound heterozygous for novel pathogenic variants in the known CANDLE/PRAAS associated genes, PSMB8 and PSMB10, whereas one patient showed additive loss-of-function mutations in PSMB8. Variants in two previously not associated proteasome genes, PSMA5 and PSMC5, were found in a patient who also carried the PSMB8 founder mutation, p.T75M. All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes. Our observations expand the spectrum of PRAAS-associated genetic variants and improve a molecular diagnosis and genetic counseling of patients with sterile autoinflammation.

Lupus Nephritis, Autoantibody Production and Kidney Outcomes in Males with Childhood-Onset Systemic Lupus Erythematosus.

Childhood-onset systemic lupus erythematosus (cSLE) only represents 20% of all SLE patients, and males with SLE only represent 10%. To study this rare SLE subset, males diagnosed with cSLE over a 30-year period were identified. Organ involvement, autoantibody production, hypocomplementemia, and kidney biopsy findings were compared to cSLE females. Outcomes were assessed using SLE Disease Activity Index scores, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, and Childhood Arthritis and Rheumatology Research Alliance definitions for nephritis responsiveness. Of 95 males and 545 females with cSLE, 62% and 57% developed nephritis, respectively. Median age of cSLE onset was 14 years in both genders. Among males, 80% of non-Hispanic whites, 64% of blacks, 59% of Hispanics, and 50% of Asians developed nephritis. The prevalence of pure and mixed class V membranous nephritis was 33%. Median follow-up was 3.2 years (range 0.1-18). Complete kidney responses were seen in 70% after a median 24 months; however, relapse rates were 46%. Kidney disease flares were 56% nephritic and 44% proteinuric. Males and females with cSLE present with comparable rates and nephritis class. While overall and kidney response rates are favorable, kidney disease relapses are common among males.

Utility of the 2018 revised ISN/RPS thresholds for glomerular crescents in childhood-onset lupus nephritis: a Pediatric Nephrology Research Consortium study.

BACKGROUND: The revised 2018 ISN/RPS Classification System for lupus nephritis (LN) includes calculations for both activity index (A.I.) and chronicity index (C.I.). Unchanged were the thresholds of < 25%, 25-50%, and > 50% crescents to distinguish between mild, moderate, and severe activity/chronicity. We aimed to evaluate these thresholds for percent crescents in childhood-onset LN. METHODS: Eighty-six subjects < 21 years of age were enrolled from the Pediatric Glomerulonephritis with Crescents Registry, a retrospective multi-center cohort sponsored by the Pediatric Nephrology Research Consortium. Thresholds of 10%, 25%, and 50% for both cellular/fibrocellular and fibrous crescents were interrogated for primary outcomes of kidney failure, eGFR, and eGFR slope. RESULTS: Median age at time of initial biopsy was 14 years (range 1-21). Median follow-up time was 3 years (range 1-11). Cumulative incidence of kidney failure was 6% at 1 year and 10% at latest follow-up. Median eGFR slope was - 18 mL/1.73 m2/min (IQR - 51 to + 8) at 1 year and - 3 mL/min/1.73 m2/year (IQR - 19 to + 6) at latest follow-up. We found no difference in kidney failure at the proposed < 25% and 25-50% cellular crescents thresholds, and thus added a new provisional threshold of 10% that better predicted outcomes in children. Moreover, use of 10% and 25% thresholds for fibrous crescents showed a fourfold and sevenfold increase in risk of kidney failure. CONCLUSIONS: In children with crescentic LN, use of 10% and 25% thresholds for cellular crescents better reflects disease activity, while these thresholds for fibrous crescents better discriminates kidney disease outcomes. A higher resolution version of the Graphical abstract is available as Supplementary information.

From Telemedicine to the ICU-Fever and Rash in a 9-Year-Old Girl.

A 9-year-old girl presented to her primary care pediatrician via telemedicine during the initial months of the coronavirus disease 2019 pandemic because of 4 days of warmth perceived by her mother, decreased energy, and a new rash on her upper extremities. After 10 additional days of documented fever >38°C, worsening fatigue, and 1 day of nausea, vomiting, and diarrhea, she was allowed to schedule an in-person visit with her pediatrician after testing negative for severe acute respiratory syndrome coronavirus 2. She appeared ill on arrival to clinic, and her pediatrician recommended evaluation in an emergency department. Her initial laboratory testing revealed nonspecific elevation in several inflammatory markers and leukopenia, and she responded well to intravenous hydration. Over the next 2 weeks, her fever persisted, constitutional symptoms worsened, and she developed progressively painful cervical lymphadenopathy and pancytopenia. She was evaluated in clinic by several specialists and eventually was urged to present to the emergency department again, at which time she was admitted to the PICU. After consulting additional specialists and waiting for laboratory results, the team reached a definitive diagnosis and initiated therapy; however, she experienced rapid clinical decline shortly thereafter. The specialists who assisted with identification of the underlying etiology of her symptoms were able to work together to manage the subsequent complications.

The Utility of Self-Determination Theory in Predicting Transition Readiness in Adolescents With Special Healthcare Needs.

PURPOSE: Adolescents and young adults with chronic health conditions must learn skills to successfully manage their health as they prepare to transition into adult-based care. Self-determination theory (SDT), an empirically based theory of human motivation, posits that competence (feeling effective), autonomy (volition to perform behaviors), and relatedness (support for autonomy from others) influence behavioral change. This study evaluates the utility of SDT constructs in predicting transition readiness among adolescents and young adults recruited into an intervention to promote successful healthcare transition. METHODS: Baseline assessments were completed by 137 patients aged 17-23 years recruited from pediatric renal, gastroenterology, or rheumatology clinical services. Surveys measured transition readiness (Transition Readiness Assessment Questionnaire) as well as SDT constructs, including competence (Patient Activation Measure); provider relatedness and parent autonomy support (Health Care Climate Questionnaire); and health care-related autonomy (Treatment Self-Regulation Questionnaire). Relationships between SDT constructs and transition readiness were evaluated using linear regression. RESULTS: Between 44 and 48 participants were recruited from each service. Bivariate correlation coefficients between transition readiness and SDT constructs were competence (r = .44), autonomous autonomy (r = .34), controlled autonomy (r = .27), provider relatedness (r = .46), and parental autonomy support (r = .35) (p < .01). Age positively correlated with transition readiness (r = .47, p < .001). After controlling for age, gender, and clinical service, competence (p < .001) and provider relatedness (p = .008) successfully predicted transition readiness (R2 = .423; F change; p < .001). CONCLUSIONS: Findings from this cross-sectional study support the utility of SDT constructs in promoting transition readiness among adolescents and young adults with chronic conditions, underscoring the importance of building competence and provider support for autonomy during this critical period.

Successful treatment of chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome with tofacitinib.

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is a rare autoinflammatory disorder. Cutaneous manifestations of CANDLE syndrome include characteristic recurring violaceous annular plaques comprised of an immature dermal mononuclear cell infiltrate. In CANDLE syndrome, deleterious genetic mutations inhibit proteasome-immunoproteasome function, resulting in cellular accumulation of ubiquitinated waste proteins that activate type I interferon signaling to drive inflammation. We describe a report of successful treatment of a 12-year-old girl with CANDLE syndrome with tofacitinib.

Pulmonary manifestations and outcomes in paediatric ANCA-associated vasculitis: a single-centre experience.

OBJECTIVES: ANCA-associated vasculitis (AAV) usually involves the renal and respiratory systems, but the paediatric literature on pulmonary manifestations and outcomes is limited. We aimed to describe pulmonary manifestations and outcomes after therapy in a cohort of paediatric AAV (pAAV) patients. METHODS: A retrospective chart review of all patients <19 years presenting to our institution with AAV between 1/2008 and 2/2018 was conducted. Patient demographics, clinical presentation, diagnostic testing, therapy and pulmonary outcomes over the first 3 years after presentation were evaluated. RESULTS: A total of 38 patients were included; all had ANCA positivity by immunofluorescence. A total of 23 had microscopic polyangiitis (MPA), 13 had granulomatosis with polyangiitis and 2 had eosinophilic granulomatosis with polyangiitis. A total of 30 (79%) had pulmonary manifestations, with cough (73%) and pulmonary haemorrhage (67%) being the most common. Abnormalities were noted in 82% of chest CT scans reviewed, with nodules and ground-glass opacities being the most common. At 6, 12 and 36 months follow-up, respectively, 61.8%, 39.4% and 29% of patients continued to show pulmonary manifestations. Five MPA patients with re-haemorrhage are described in detail. CONCLUSION: MPA was more common than granulomatosis with polyangiitis, with pulmonary involvement being common in both. MPA patients had more severe pulmonary manifestations. Chest CT revealed abnormal findings in a majority of cases. A subgroup of young MPA patients experienced repeat pulmonary haemorrhage. Treatment modality and response were comparable in different subtypes of AAV, except for this young MPA group. Additional prospective studies are needed to better understand the different phenotypes of pAAV.

Variability in Kawasaki Disease Practice Patterns: A Survey of Hospitalists at Pediatric Hospital Medicine 2017.

OBJECTIVE: To explore practice variations in the care of patients with Kawasaki disease (KD) among pediatric hospitalist physicians (PHPs). METHODS: A 13-item questionnaire was developed by a multi-institutional group of KD experts. The survey was administered via live-audience polling by using smartphone technology during a KD plenary session at the 2017 Pediatric Hospital Medicine National Meeting, and simple descriptive statistics were calculated. RESULTS: Of the 297 session attendees, 90% responded to at least 1 survey question. Approximately three-quarters of respondents identified as PHPs practicing in the United States. The reported length of inpatient monitoring after initial intravenous immunoglobulin (IVIG) therapy demonstrated a wide time distribution (30% 24 hours, 36% 36 hours, and 31% 48 hours). Similarly, PHP identification of the treatment failure interval, indicated by recrudescent fever after IVIG, demonstrated a broad distribution (56% 24 hours, 27% 36 hours, and 16% 48 hours). Furthermore, there was variation in routine consultation with non-PHP subspecialists. In contrast, PHPs reported little variation in their choice of initial and refractory treatment of patients with KD. CONCLUSIONS: In a convenience sample at a national hospitalist meeting, there was variation in reported KD practice patterns, including observation time after initial treatment, time when the recurrence of fever after initial therapy was indicative of nonresponse to IVIG, and routine consultation of non-PHP subspecialists. These results may guide future study of KD practice patterns and inform efforts to improve evidence-based practices in the care of patients with KD.

Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome.

The proteasome processes proteins to facilitate immune recognition and host defense. When inherently defective, it can lead to aberrant immunity resulting in a dysregulated response that can cause autoimmunity and/or autoinflammation. Biallelic or digenic loss-of-function variants in some of the proteasome subunits have been described as causing a primary immunodeficiency disease that manifests as a severe dysregulatory syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). Proteasome maturation protein (POMP) is a chaperone for proteasome assembly and is critical for the incorporation of catalytic subunits into the proteasome. Here, we characterize and describe POMP-related autoinflammation and immune dysregulation disease (PRAID) discovered in two unrelated individuals with a unique constellation of early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity. We also begin to delineate a complex genetic mechanism whereby de novo heterozygous frameshift variants in the penultimate exon of POMP escape nonsense-mediated mRNA decay (NMD) and result in a truncated protein that perturbs proteasome assembly by a dominant-negative mechanism. To our knowledge, this mechanism has not been reported in any primary immunodeficiencies, autoinflammatory syndromes, or autoimmune diseases. Here, we define a unique hypo- and hyper-immune phenotype and report an immune dysregulation syndrome caused by frameshift mutations that escape NMD.

Rapid infusion of rituximab is well tolerated in children with hematologic, oncologic, and rheumatologic disorders.

Traditional administration of rituximab requires careful titration and may involve many hours to minimize the risk of reactions. The objective of this study was to evaluate the safety of rapid infusions of rituximab in a pilot group of children with hematologic, oncologic, and rheumatologic disorders, and to determine the incidence of rate-related infusion reactions. Twenty patients enrolled in the study. All patients tolerated the rapid infusion of rituximab and no patient had an infusion-related reaction. We conclude that rapid infusions of rituximab are well tolerated and safe in our pilot group of patients.

Copa Syndrome: a Novel Autosomal Dominant Immune Dysregulatory Disease.

Inherently defective immunity typically results in either ineffective host defense, immune regulation, or both. As a category of primary immunodeficiency diseases, those that impair immune regulation can lead to autoimmunity and/or autoinflammation. In this review we focus on one of the most recently discovered primary immunodeficiencies that leads to immune dysregulation: "Copa syndrome". Copa syndrome is named for the gene mutated in the disease, which encodes the alpha subunit of the coatomer complex-I that, in aggregate, is devoted to transiting molecular cargo from the Golgi complex to the endoplasmic reticulum (ER). Copa syndrome is autosomal dominant with variable expressivity and results from mutations affecting a narrow amino acid stretch in the COPA gene-encoding COPα protein. Patients with these mutations typically develop arthritis and interstitial lung disease with pulmonary hemorrhage representing a striking feature. Immunologically Copa syndrome is associated with autoantibody development, increased Th17 cells and pro-inflammatory cytokine expression including IL-1ß and IL-6. Insights have also been gained into the underlying mechanism of Copa syndrome, which include excessive ER stress owing to the impaired return of proteins from the Golgi, and presumably resulting aberrant cellular autophagy. As such it represents a novel cellular disorder of intracellular trafficking associated with a specific clinical presentation and phenotype.

Cerebral and cerebellar volume loss in children and adolescents with systemic lupus erythematosus: a review of clinically acquired brain magnetic resonance imaging.

OBJECTIVE: Cerebral atrophy is a prominent feature in adults with systemic lupus erythematosus (SLE). We assessed cerebral and cerebellar volume loss on clinically acquired brain magnetic resonance imaging (MRI) scans of children and adolescents with SLE. METHODS: We abstracted information on disease course for patients who underwent clinical brain MRI during the period 2002-2008. We completed qualitative assessments of volume loss and measured corpus callosum thickness and ventricular enlargement for patients with lupus and controls. RESULTS: Forty-nine children underwent brain MRI during the review period due to clinical indications. The lupus cohort was predominantly female and ethnically diverse. Mean age at imaging was 15.3 +/- 2.6 years and mean disease duration was 30.6 +/- 33.3 months. Findings suggestive of cerebral and cerebellar volume loss were seen respectively in 89.8% and 91.8% of lupus patients. Cerebral volume loss was moderate or severe in 26.5% of children. Cerebellar volume loss was moderate in 20.4% of these patients. Linear measurement means reflected corpus callosum thinning and ventricular enlargement in lupus patients. Volume loss was observed in newly diagnosed patients prior to corticosteroid use. Disease duration and corticosteroid use did not predict the severity of volume loss. There were statistically significant differences in linear imaging measurements comparing lupus patients to 14 similar-age controls. CONCLUSION: Regional volume loss was observed in most adolescents with lupus undergoing clinical brain MRI scans. As in other pediatric conditions with inflammatory or vascular etiologies, these findings may be reflecting disease-associated neuronal loss and not solely the effects of corticosteroid.

MR imaging findings suggestive of posterior reversible encephalopathy syndrome in adolescents with systemic lupus erythematosus.

BACKGROUND: Endothelial damage, hypertension and cytotoxic medications may serve as risk factors for the posterior reversible encephalopathy syndrome (PRES) in systemic lupus erythematosus. There have been few case reports of these findings in pediatric lupus patients. OBJECTIVE: We describe clinical and neuroimaging findings in children and adolescents with lupus and a PRES diagnosis. MATERIALS AND METHODS: We identified all clinically acquired brain MRIs of lupus patients at a tertiary care pediatric hospital (2002-2008). We reviewed clinical features, conventional MRI and diffusion-weighted imaging (DWI) findings of patients with gray- and white-matter changes suggestive of vasogenic edema and PRES. RESULTS: Six pediatric lupus patients presenting with seizures and altered mental status had MRI findings suggestive of PRES. In five children clinical and imaging changes were seen in conjunction with hypertension and active renal disease. MRI abnormalities were diffuse and involved frontal regions in five children. DWI changes reflected increased apparent diffusivity coefficient (unrestricted diffusion in all patients). Clinical and imaging changes significantly improved with antihypertensive and fluid management. CONCLUSION: MRI changes suggestive of vasogenic edema and PRES may be seen in children with active lupus and hypertension. The differential diagnosis of seizures and altered mental status should include PRES in children, as it does in adults.

Outcomes of children with proliferative lupus nephritis: the role of protocol renal biopsy.

Outcomes in children with proliferate lupus nephritis (PLN) show 9-15% progress to end-stage renal disease (ESRD) at 5 years. Immunosuppression improves outcome, but significant side effects are possible. Clinical and laboratory analyses are poor predictors of class and progression in PLN. We describe 28 patients with systemic lupus erythematosus (SLE), between 1990 and 2005, whose initial biopsy (Bx1) showed PLN and who received nine monthly doses of intravenously administered cyclophosphamide (CYP) (500-750 mg/m(2) up to 1 g to maintain their absolute neutrophil count (ANC) > 3,000). Continued therapy with additional quarterly intravenous (i.v). administration of CYP was dictated by repeat renal biopsy (Bx2). Bx1 was done 1 +/- 1.6 years after diagnosis of SLE. Bx2 showed histological improvement by WHO classification in 20/25 children; 3/25 were unchanged, 1/25 was categorized as new class V, and 1/25 was worse. Four patients (14%) had infectious complications requiring hospitalization (one of these died). Mean follow-up (f/u) after Bx2 was 3.5 +/- 2.3 years. At last follow-up, 26 patients had normal glomerular filtration rate (GFR), with a mean of 126 +/- 42.8 ml/min per 1.73 m(2) body surface area, one non-compliant patient had ESRD, and one had chronic renal failure. At last follow-up, most patients had minimal to no proteinuria. Clinical and biopsy results greatly improved after 9 monthly intravenously administered CYP pulses in most children with class IV PLN. Those who did not improve are at risk for flares and progression of disease. The tailoring of therapies based on findings from a biopsy after induction may improve outcomes.