Anti-LAMP-2 Antibody Seropositivity in Children with Primary Systemic Vasculitis Affecting Medium- and Large-Sized Vessels.

Chronic primary systemic vasculitis (PSV) comprises a group of heterogeneous diseases that are broadly classified by affected blood vessel size, clinical traits and the presence (or absence) of anti-neutrophil cytoplasmic antibodies (ANCA) against proteinase 3 (PR3) and myeloperoxidase (MPO). In small vessel vasculitis (SVV), ANCA are not present in all patients, and they are rarely detected in patients with vasculitis involving medium (MVV) and large (LVV) blood vessels. Some studies have demonstrated that lysosome-associated membrane protein-2 (LAMP-2/CD107b) is a target of ANCA in SVV, but its presence and prognostic value in childhood MVV and LVV is not known. This study utilized retrospective sera and clinical data obtained from 90 children and adolescents with chronic PSV affecting small (SVV, n = 53), medium (MVV, n = 16), and large (LVV, n = 21) blood vessels. LAMP-2-ANCA were measured in time-of-diagnosis sera using a custom electrochemiluminescence assay. The threshold for seropositivity was established in a comparator cohort of patients with systemic autoinflammatory disease. The proportion of LAMP-2-ANCA-seropositive individuals and sera concentrations of LAMP-2-ANCA were assessed for associations with overall and organ-specific disease activity at diagnosis and one-year follow up. This study demonstrated a greater time-of-diagnosis prevalence and sera concentration of LAMP-2-ANCA in MVV (52.9% seropositive) and LVV (76.2%) compared to SVV (45.3%). Further, LAMP-2-ANCA-seropositive individuals had significantly lower overall, but not organ-specific, disease activity at diagnosis. This did not, however, result in a greater reduction in disease activity or the likelihood of achieving inactive disease one-year after diagnosis. The results of this study demonstrate particularly high prevalence and concentration of LAMP-2-ANCA in chronic PSV that affects large blood vessels and is seronegative for traditional ANCA. Our findings invite reconsideration of roles for autoantigens other than MPO and PR3 in pediatric vasculitis, particularly in medium- and large-sized blood vessels.

A decade of progress in juvenile idiopathic athritis treatments and outcomes in Canada: results from ReACCh-Out and the CAPRI registry.

OBJECTIVE: To assess changes in juvenile idiopathic arthritis (JIA) treatments and outcomes in Canada, comparing a 2005-2010 and a 2017-2021 inception cohorts. METHODS: Patients enrolled within three months of diagnosis in the Research in Arthritis in Canadian Children Emphasizing Outcomes (ReACCh-Out) and the Canadian Alliance of Pediatric Rheumatology Investigators Registry (CAPRI) cohorts were included. Cumulative incidences of drug starts and outcome attainment within 70 weeks of diagnosis were compared with Kaplan Meier survival analysis and multivariable Cox regression. RESULTS: The 2005-2010 and 2017-2021 cohorts included 1128 and 721 patients, respectively. JIA category distribution and baseline clinical juvenile idiopathic arthritis disease activity (cJADAS10) scores at enrolment were comparable. By 70 weeks, 6% of patients (95% CI 5, 7) in the 2005-2010 and 26% (23, 30) in the 2017-2021 cohort had started a biologic DMARD (bDMARD), and 43% (40, 47) and 60% (56, 64) had started a conventional DMARD (cDMARD), respectively. Outcome attainment was 64% (61, 67) and 83% (80, 86) for Inactive disease (Wallace criteria), 69% (66, 72) and 84% (81, 87) for minimally active disease (cJADAS10 criteria), 57% (54, 61) and 63% (59, 68) for pain control (<1/10), and 52% (47, 56) and 54% (48, 60) for a good health-related quality of life. CONCLUSION: Although baseline disease characteristics were comparable in the 2005-2010 and 2017-2021 cohorts, cDMARD and bDMARD use increased with a concurrent increase in minimally active and inactive disease. Improvements in parent and patient reported outcomes were smaller than improvements in disease activity.

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.

Impact of the COVID-19 pandemic on juvenile idiopathic arthritis presentation and research recruitment: results from the CAPRI registry.

OBJECTIVE: The COVID-19 pandemic has disrupted healthcare delivery and clinical research worldwide, with data from areas most affected demonstrating an impact on rheumatology care. This study aimed to characterize the impact of the pandemic on the initial presentation of JIA and JIA-related research in Canada. METHODS: Data collected from the Canadian Alliance of Pediatric Rheumatology Investigators JIA Registry from the year pre-pandemic (11 March 2019 to 10 March 2020) was compared with data collected during the first year of the pandemic (11 March 2020 to 10 March 2021). Outcomes included time from symptom onset to first assessment, disease severity at presentation and registry recruitment. Proportions and medians were used to describe categorical and continuous variables, respectively. RESULTS: The median time from symptom onset to first assessment was 138 (IQR 64-365) days pre-pandemic vs 146 (IQR 83-359) days during the pandemic. The JIA category frequencies remained overall stable (44% oligoarticular JIA pre-pandemic, 46.8% pandemic), except for systemic JIA (12 cases pre-pandemic, 1 pandemic). Clinical features, disease activity (cJADAS10), disability (CHAQ) and quality of life (JAQQ) scores were similar between the two cohorts. Pre-pandemic, 225 patients were enrolled, compared with 111 in the pandemic year, with the greatest decrease from March to June 2020. CONCLUSIONS: We did not observe the anticipated delay in time to presentation or increased severity at presentation, suggesting that, within Canada, care adapted well to provide support to new patient consults without negative impacts. The COVID-19 pandemic was associated with an initial 50% decrease in registry enrolment but has since improved.

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.

Children with systemic autoinflammatory diseases have multiple, mixed ethnicities that reflect regional ethnic diversity.

OBJECTIVES: To evaluate the ethnic diversity of children with a systemic autoinflammatory disease (SAID) in a multi-ethnic Canadian province. METHODS: Self-reported ethnicity of 149 children and adolescents with a SAID in British Columbia, Canada, was analysed for ethnic representation among individual patients, across the cohort, within particular SAIDs, and compared to provincial census data on ethnic diversity. RESULTS: Half of reported cases had a diagnosis of either PFAPA (23.5%) or an unclassifiable autoinflammatory syndrome (31.5%), with a monogenic SAID diagnosed in only 12.8% of cases. The majority of participants (73.1%) were mixed ethnicity with European and Asian heritage reported most frequently (57.0% and 23.0% of all responses, respectively). Ethnic diversity reflected regional diversity except for West Asian, Arabic, Jewish, and Eastern European heritage, which were over-represented in SAID patients, and Chinese descent, which was under-represented in our cohort compared to the general population of British Columbia. CONCLUSIONS: Results from this study show extensive multi-ethnic diversity in individual patients and across the various SAIDs inclusive of monogenic SAIDs that are frequently associated with particular ethnicities. Although not disproportionately represented, this is the first report of systemic autoinflammatory disease in Canadian children of Indigenous heritage.

Different Disease Endotypes in Phenotypically Similar Vasculitides Affecting Small-to-Medium Sized Blood Vessels.

Objectives: Chronic primary vasculitis describes a group of complex and rare diseases that are characterized by blood vessel inflammation. Classification of vasculitis subtypes is based predominantly on the size of the involved vessels and clinical phenotype. There is a recognized need to improve classification, especially for small-to-medium sized vessel vasculitides, that, ideally, is based on the underlying biology with a view to informing treatment. Methods: We performed RNA-Seq on blood samples from children (n = 41) and from adults (n = 11) with small-to-medium sized vessel vasculitis, and used unsupervised hierarchical clustering of gene expression patterns in combination with clinical metadata to define disease subtypes. Results: Differential gene expression at the time of diagnosis separated patients into two primary endotypes that differed in the expression of ~3,800 genes in children, and ~1,600 genes in adults. These endotypes were also present during disease flares, and both adult and pediatric endotypes could be discriminated based on the expression of just 20 differentially expressed genes. Endotypes were associated with distinct biological processes, namely neutrophil degranulation and T cell receptor signaling. Conclusions: Phenotypically similar subsets of small-to-medium sized vessel vasculitis may have different mechanistic drivers involving innate vs. adaptive immune processes. Discovery of these differentiating immune features provides a mechanistic-based alternative for subclassification of vasculitis.

Soluble Low-density Lipoprotein Receptor-related Protein 1 in Juvenile Idiopathic Arthritis.

OBJECTIVES: This study aimed to expand knowledge about soluble low-density lipoprotein receptor-related protein 1 (sLRP1) in juvenile idiopathic arthritis (JIA) by determining associations of sLRP1 levels in nonsystemic JIA patients with clinical and inflammatory biomarker indicators of disease activity. METHODS: Plasma sLRP1 and 44 inflammation-related biomarkers were measured at enrollment and 6 months later in a cohort of 96 newly diagnosed Canadian patients with nonsystemic JIA. Relationships between sLRP1 levels and indicators of disease activity and biomarker levels were analyzed at both visits. RESULTS: At enrollment, sLRP1 levels correlated negatively with age and active joint counts. Children showed significantly higher levels of sLRP1 than adolescents (mean ranks: 55.4 and 41.9, respectively; P = 0.02). Participants with 4 or fewer active joints, compared to those with 5 or more active joints, had significantly higher sLRP1 levels (mean ranks: 56.2 and 40.7, respectively; P = 0.006). At enrollment, considering the entire cohort, sLRP1 correlated negatively with the number of active joints (r = -0.235, P = 0.017). In the entire cohort, sLRP1 levels at enrollment and 6 months later correlated with 13 and 6 pro- and antiinflammatory biomarkers, respectively. In JIA categories, sLRP1 correlations with inflammatory markers were significant in rheumatoid factor-negative polyarticular JIA, oligoarticular JIA, enthesitis-related arthritis, and psoriatic arthritis at enrollment. Higher sLRP1 levels at enrollment increased the likelihood of absence of active joints 6 months later. CONCLUSION: Plasma sLRP1 levels correlate with clinical and biomarker indicators of short-term improvement in JIA disease activity, supporting sLRP1 as an upstream biomarker of potential utility for assessing JIA disease activity and outcome prediction.

Current Approach to the Evaluation and Management of Incomplete Kawasaki Disease in the Emergency Department.

Kawasaki disease (KD) is one of the most common vasculitides of childhood and frequently presents to the emergency department. Although the diagnosis of KD is based on clinical criteria, children who do not fulfill the criteria but have sufficient supportive features of KD are diagnosed as having incomplete KD and warrant the same course of therapy as children with classic KD. The diagnosis of incomplete KD is challenging and requires a high index of suspicion. The purpose of this article is to review presenting features of incomplete KD and the diagnostic approach and management of children in the emergency department.

Kawasaki disease recognition and treatment.

Question If a child presents to my office with several days of fever and a few features of Kawasaki disease (KD) but does not meet the diagnostic criteria, could they still have KD and is treatment needed?Answer Presentations of KD have a range of clinical signs and symptoms. With the lack of a criterion standard test, the diagnosis of KD relies on syndrome recognition and a high index of suspicion in cases where KD does not present classically. It is still possible to have KD even if not all of the criteria are met, and these children are referred to as having incomplete forms of KD. The diagnosis of incomplete KD is usually made in a child or infant who presents with a history of prolonged fever, a few clinical criteria for KD, and other supportive features such as positive laboratory or echocardiographic findings. It is important to recognize children with incomplete forms of KD to avoid poor outcomes such as coronary artery aneurysms.

Complexity in unclassified auto-inflammatory disease: a case report illustrating the potential for disease arising from the allelic burden of multiple variants.

BACKGROUND: Despite recent advances in the diagnosis and understanding of many autoinflammatory diseases, there are still a great number of patients with phenotypes that do not fit any clinically- and/or genetically-defined disorders. CASE PRESENTATION: We describe a fourteen-year-old boy who presented at two and a half years of age with recurrent febrile episodes. Over the course of the disease, the episodes increased in frequency and severity, with new signs and symptoms continuing to appear. Most importantly, these included skin changes, splenomegaly and transaminitis. Only partial control of the disease was achieved with anti-IL-1 therapy. Extensive investigation showed generalized inflammation without immune deficiency, with increased levels of serum amyloid A and several pro-inflammatory cytokines including interferon-γ, as well as an increased type I interferon score. Exome sequence analysis identified P369S and R408Q variants in the MEFV innate immunity regulator, pyrin (MEFV) gene and T260 M and T320 M variants in the NLR family pyrin domain containing 12 (NLRP12) gene. CONCLUSION: Patients with unclassified and/or unexplained autoinflammatory syndromes present diagnostic and therapeutic challenges and collectively form a substantial part of every cohort of patients with autoinflammatory diseases. Therefore, it is important to acquire their full genomic profile through whole exome and/or genome sequencing and present their cases to a broader audience, to facilitate characterization of similar patients. A critical mass of well-characterized cases will lead to improved diagnosis and informed treatment.

Identification of Novel Adenosine Deaminase 2 Gene Variants and Varied Clinical Phenotype in Pediatric Vasculitis.

OBJECTIVE: Individuals with deficiency of adenosine deaminase 2 (DADA2), a recently recognized autosomal recessive disease, present with various systemic vascular and inflammatory manifestations, often with young age at disease onset or with early onset of recurrent strokes. Their clinical features and histologic findings overlap with those of childhood-onset polyarteritis nodosa (PAN), a primary "idiopathic" systemic vasculitis. Despite similar clinical presentation, individuals with DADA2 may respond better to biologic therapy than to traditional immunosuppression. The aim of this study was to screen an international registry of children with systemic primary vasculitis for variants in ADA2. METHODS: The coding exons of ADA2 were sequenced in 60 children and adolescents with a diagnosis of PAN, cutaneous PAN, or unclassifiable vasculitis (UCV), any chronic vasculitis with onset at age 5 years or younger, or history of stroke. The functional consequences of the identified variants were assessed by ADA2 enzyme assay and immunoblotting. RESULTS: Nine children with DADA2 (5 with PAN, 3 with UCV, and 1 with antineutrophil cytoplasmic antibody-associated vasculitis) were identified. Among them, 1 patient had no rare variants in the coding region of ADA2 and 8 had biallelic, rare variants (minor allele frequency <0.01) with a known association with DADA2 (p.Gly47Arg and p.Gly47Ala) or a novel association (p.Arg9Trp, p.Leu351Gln, and p.Ala357Thr). The clinical phenotype varied widely. CONCLUSION: These findings support previous observations indicating that DADA2 has extensive genotypic and phenotypic variability. Thus, screening ADA2 among children with vasculitic rash, UCV, PAN, or unexplained, early-onset central nervous system disease with systemic inflammation may enable an earlier diagnosis of DADA2.

Innate Control of Tissue-Reparative Human Regulatory T Cells.

Regulatory T cell (Treg) therapy is a potential curative approach for a variety of immune-mediated conditions, including autoimmunity and transplantation, in which there is pathological tissue damage. In mice, IL-33R (ST2)-expressing Tregs mediate tissue repair by producing the growth factor amphiregulin, but whether similar tissue-reparative Tregs exist in humans remains unclear. We show that human Tregs in blood and multiple tissue types produced amphiregulin, but this was neither a unique feature of Tregs nor selectively upregulated in tissues. Human Tregs in blood, tonsil, synovial fluid, colon, and lung tissues did not express ST2, so ST2+ Tregs were engineered via lentiviral-mediated overexpression, and their therapeutic potential for cell therapy was examined. Engineered ST2+ Tregs exhibited TCR-independent, IL-33-stimulated amphiregulin expression and a heightened ability to induce M2-like macrophages. The finding that amphiregulin-producing Tregs have a noneffector phenotype and are progressively lost upon TCR-induced proliferation and differentiation suggests that the tissue repair capacity of human Tregs may be an innate function that operates independently from their classical suppressive function.

Prospective Determination of the Incidence and Risk Factors of New-Onset Uveitis in Juvenile Idiopathic Arthritis: The Research in Arthritis in Canadian Children Emphasizing Outcomes Cohort.

OBJECTIVE: Identification of the incidence of juvenile idiopathic arthritis (JIA)-associated uveitis and its risk factors is essential to optimize early detection. Data from the Research in Arthritis in Canadian Children Emphasizing Outcomes inception cohort were used to estimate the annual incidence of new-onset uveitis following JIA diagnosis and to identify associated risk factors. METHODS: Data were reported every 6 months for 2 years, then yearly to 5 years. Incidence was determined by Kaplan-Meier estimators with time of JIA diagnosis as the reference point. Univariate log-rank analysis identified risk factors and Cox regression determined independent predictors. RESULTS: In total, 1,183 patients who enrolled within 6 months of JIA diagnosis met inclusion criteria, median age at diagnosis of 9.0 years (interquartile range [IQR] 3.8-12.9), median follow-up of 35.2 months (IQR 22.7-48.3). Of these patients, 87 developed uveitis after enrollment. The incidence of new-onset uveitis was 2.8% per year (95% confidence interval [95% CI] 2.0-3.5) in the first 5 years. The annual incidence decreased during follow-up but remained at 2.1% (95% CI 0-4.5) in the fifth year, although confidence intervals overlapped. Uveitis was associated with young age (<7 years) at JIA diagnosis (hazard ratio [HR] 8.29, P < 0.001), positive antinuclear antibody (ANA) test (HR 3.20, P < 0.001), oligoarthritis (HR 2.45, P = 0.002), polyarthritis rheumatoid factor negative (HR 1.65, P = 0.002), and female sex (HR 1.80, P = 0.02). In multivariable analysis, only young age at JIA diagnosis and ANA positivity were independent predictors of uveitis. CONCLUSION: Vigilant uveitis screening should continue for at least 5 years after JIA diagnosis, and priority for screening should be placed on young age (<7 years) at JIA diagnosis and a positive ANA test.

Health-Related Quality of Life in an Inception Cohort of Children With Juvenile Idiopathic Arthritis: A Longitudinal Analysis.

OBJECTIVE: To describe changes in health-related quality of life (HRQoL) over time in children with juvenile idiopathic arthritis (JIA), relative to other outcomes, and to identify predictors of unfavorable HRQoL trajectories. METHODS: Children with JIA in the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) cohort were included. The Juvenile Arthritis Quality of Life Questionnaire (JAQQ, a standardized instrument), health-related Quality of My Life (HRQoML, an instrument based on personal valuations), and JIA core variables were completed serially. Analyses included median values, Kaplan-Meier survival curves, and latent trajectory analysis. RESULTS: A total of 1,249 patients enrolled at a median of 0.5 months after diagnosis were followed for a median of 34.2 months. The degree of initial HRQoL impairment and probabilities of reaching the best possible HRQoL scores varied across JIA categories (best for oligoarthritis, worst for rheumatoid factor-positive polyarthritis). Median times to attain best possible HRQoL scores (JAQQ 59.3 months, HRQoML 34.5 months), lagged behind those for disease activity, pain, and disability measures. Most patients followed trajectories with minimal or mild impairment; however, 7.6% and 13.8% of patients, respectively, followed JAQQ and HRQoML trajectories with persistent major impairment in HRQoL. JIA category, aboriginal ethnicity, and baseline disease activity measures distinguished between membership in trajectories with major and minimal impairments. CONCLUSION: Improvement in HRQoL is slower than for disease activity, pain, and disability. Improvement of a measure based on respondents' preferences (HRQoML) is more rapid than that of a standardized measure (JAQQ). Higher disease activity at diagnosis heralds an unfavorable HRQoL trajectory.

Clinical practice variation and need for pediatric-specific treatment guidelines among rheumatologists caring for children with ANCA-associated vasculitis: an international clinician survey.

BACKGROUND: Because pediatric antineutrophil cytoplasmic antibody-associated vasculitis is rare, management generally relies on adult data. We assessed treatment practices, uptake of existing clinical assessment tools, and interest in pediatric treatment protocols among rheumatologists caring for children with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). METHODS: A needs-assessment survey developed by an international working group of pediatric rheumatologists and two nephrologists was circulated internationally. Data were summarized with descriptive statistics. Pearson's chi-square tests were used in inferential univariate analyses. RESULTS: The 209 respondents from 36 countries had collectively seen ~1600 children with GPA/MPA; 144 had seen more than two in the preceding 5 years. Standardized and validated clinical assessment tools to score disease severity, activity, and damage were used by 59, 63, and 36%, respectively; barriers to use included lack of knowledge and limited perceived utility. Therapy varied significantly: use of rituximab rather than cyclophosphamide was more common among respondents from the USA (OR = 2.7 [1.3-5.5], p = 0.0190, n = 139), those with >5 years of independent practice experience (OR = 3.8 [1.3-12.5], p = 0.0279, n = 137), and those who had seen >10 children with GPA/MPA in their careers (OR = 4.39 [2.1-9.1], p = 0.0011, n = 133). Respondents who had treated >10 patients were also more likely to continue maintenance therapy for at least 24 months (OR = 3.0 [1.4-6.4], p = 0.0161, n = 127). Ninety six percent of respondents believed in a need for pediatric-specific treatment guidelines; 46% supported adaptation of adult guidelines while 69% favoured guidelines providing a limited range of treatment options to allow comparison of effectiveness through a registry. CONCLUSIONS: These data provide a rationale for developing pediatric-specific consensus treatment guidelines for GPA/MPA. While pediatric rheumatologist uptake of existing clinical tools has been limited, guideline uptake may be enhanced if outcomes of consensus-derived treatment options are evaluated within the framework of an international registry.

Early Outcomes in Children With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: To characterize the early disease course in childhood-onset antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and the 12-month outcomes in children with AAV. METHODS: Eligible subjects were children entered into the Pediatric Vasculitis Initiative study who were diagnosed before their eighteenth birthday as having granulomatosis with polyangiitis (Wegener's), microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss), or ANCA-positive pauci-immune glomerulonephritis. The primary outcome measure was achievement of disease remission (Pediatric Vasculitis Activity Score [PVAS] of 0) at 12 months with a corticosteroid dosage of <0.2 mg/kg/day. Secondary outcome measures included the rates of inactive disease (PVAS of 0, with any corticosteroid dosage) and rates of improvement at postinduction (4-6 months after diagnosis) and at 12 months, presence of damage at 12 months (measured by a modified Pediatric Vasculitis Damage Index [PVDI]; score 0 = no damage, score 1 = one damage item present), and relapse rates at 12 months. RESULTS: In total, 105 children with AAV were included in the study. The median age at diagnosis was 13.8 years (interquartile range 10.9-15.8 years). Among the study cohort, 42% of patients achieved remission at 12 months, 49% had inactive disease at postinduction (4-6 months), and 61% had inactive disease at 12 months. The majority of patients improved, even if they did not achieve inactive disease. An improvement in the PVAS score of at least 50% from time of diagnosis to postinduction was seen in 92% of patients. Minor relapses occurred in 12 (24%) of 51 patients after inactive disease had been achieved postinduction. The median PVDI damage score at 12 months was 1 (range 0-6), and 63% of patients had ≥1 PVDI damage item scored as present at 12 months. CONCLUSION: This is the largest study to date to assess disease outcomes in pediatric AAV. Although the study showed that a significant proportion of patients did not achieve remission, the majority of patients responded to treatment. Unfortunately, more than one-half of this patient cohort experienced damage to various organ systems early in their disease course.

The importance of considering monogenic causes of autoimmunity: A somatic mutation in KRAS causing pediatric Rosai-Dorfman syndrome and systemic lupus erythematosus.

OBJECTIVES: Clinicians need to be aware of the growing list of defined monogenic etiologies of autoimmune diseases. This is particularly relevant when evaluating children, as these rare monogenic forms of autoimmunity tend to present very early in life. METHODS AND RESULTS: By harnessing the transformative power of next generation sequencing, we made the unifying diagnosis of RAS-associated autoimmune leukoproliferative disease (RALD), caused by the somatic gain-of-function p.G13C KRAS mutation, in a boy with the seemingly unrelated immune dysregulatory conditions of Rosai-Dorfman and systemic lupus erythematosus (SLE). CONCLUSIONS: This case expands our understanding of the clinical phenotypes associated with the extremely rare condition of RALD, and emphasizes the importance of always considering the possibility of a monogenic cause for autoimmunity, particularly when the disease manifestations begin early in life and do not follow a typical clinical course.

Comparing Presenting Clinical Features in 48 Children With Microscopic Polyangiitis to 183 Children Who Have Granulomatosis With Polyangiitis (Wegener's): An ARChiVe Cohort Study.

OBJECTIVE: To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons. RESULTS: In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n = 48) or GPA (n = 183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil. CONCLUSION: Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding.

Familial Takayasu arteritis - a pediatric case and a review of the literature.

Takayasu arteritis (TA) is a rare chronic inflammatory disease of the aorta and its major branches. It is seen predominantly in females during the second and third decades of life, although it can occur in childhood. The aetiology of TA remains unknown. To date, familial cases of TA have been considered rare; however, a review of the literature suggests that cases are accumulating. We report a case of two sisters affected by severe TA, and review other reported familial cases.