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The microscopic transciliary SupraOrbital keyhole (mtSO) approach has been used for a wide variety of anterior and middle fossa pathologies, including aneurysms, meningiomas, craniopharyngiomas, and other skull-base tumors. Several clinical series have proven its efficacy and safety, but detailed anatomical demarcations of the anterior and middle cranial base exposure are lacking. Our aim was to define the surgical limitations of the mtSO approach to the ipsilateral and contralateral anterior and middle skull base.Five cadaveric specimens (10 sides) were studied with image guidance to illustrate the limits of the surgical exposure. In addition, 30 dry skulls were used to measure the working distances between the craniotomy and key bony landmarks of the mtSO approach.Surgical exposure at the anterior skull base covered the area between the medial half of the contra- and the medial two-thirds of the ipsilateral sphenoid wing including both optic nerves and interoptic space. The anterior limit at the midline was the sphenoethmoidal suture. Ipsilateral anterior clinoidectomy permitted exposure of the superior orbital fissure, which defined the anteromedial limit at the middle fossa, whereas the anterolateral limit was defined by the ophthalmic branch of the trigeminal nerve. Moreover, the posteromedial and posterolateral limits were the posterior clinoid process and the petrous ridge, respectively.Our findings define the surgical limitations of the mtSO approach for the treatment of anterior and middle cranial base pathologies. These limits can be reliably identified on imaging studies allowing assessment of exposure to guide preoperative case selection.

ObjectiveIn 2020, the Canadian Vasculitis Research Network (CanVasc) published their updated recommendations for the management of ANCA-associated vasculitides (AAV). The current addendum provides further recommendations regarding the use of avacopan in AAV based on a review of newly available evidence.MethodsAn updated systematic literature review on avacopan (formerly, CCX168) using Medline, Embase, and the Cochrane Library was performed for publications up to September 2022. New recommendations were developed and categorized according to the EULAR grading levels, as done for previous CanVasc recommendations. A modified Delphi procedure and videoconferences were used to reach ≥80% consensus on the inclusion, wording and grading of each recommendation.ResultsThree new recommendations were developed. They focus on avacopan therapy indication and duration, as well as timely glucocorticoid tapering.ConclusionThese 2022 addended recommendations provide rheumatologists, nephrologists and other specialists caring for patients with AAV with guidance for the use of avacopan, based on current evidence and consensus from Canadian experts.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare, life-threatening inflammation of blood vessels that can affect both adults and children. Compared to adult-onset disease, AAV is especially rare in children with an annual prevalence of 0.5-6.4 cases per million children. The etiology of AAV remains largely unknown and both environmental and genetic factors are likely involved. Genetic susceptibility factors recently identified in adult patients, including HLA-DP and HLA-DQ, are explored in pediatric patients.We performed a genome-wide association study of pediatric AAV in patients of European ancestry (n = 63 AAV cases, n = 315 population matched controls).We identified a significant genetic association with the HLA-DPB1*04:01 allele (p = 1.5e-08, OR = 3.5), with a stronger association seen in PR3-ANCA+ children than MPO-ANCA+. The HLA-DPB1*04:01 allele was the most highly associated (though not significant) HLA allele in a follow-up adult AAV cohort (p = 2.6e-04, OR = 0.4). TCR and IFN signalling pathways were also found to be enriched in the pediatric AAV cohort.Similar to previous findings in adult AAV, we found that the HLA-DPB1 locus is associated with pediatric AAV. Despite the difference in the age of onset, these findings suggest that childhood- and adult-onset vasculitis share a common genetic predisposition. The identification of genetic variants contributing to AAV is an important step to improved classification tools and treatment strategies.

A number of studies have demonstrated that patients with autoimmune disease have lower levels of vitamin D prompting speculation that vitamin D might suppress inflammation and immune responses in children with juvenile idiopathic arthritis (JIA). The objective of this study was to compare vitamin D levels in children with JIA at disease onset with healthy children. We hypothesized that children and adolescents with JIA have lower vitamin D levels than healthy children and adolescents. Data from a Canadian cohort of children with new-onset JIA (n= 164, data collection 2007-2012) were compared to Canadian Health Measures Survey (CHMS) data (n=4027, data collection 2007-2011). We compared 25-hydroxy vitamin D (25(OH)D) concentrations with measures of inflammation, vitamin D supplement use, milk intake, and season of birth. Mean 25(OH)D level was significantly higher in patients with JIA (79 ± 3.1 nmol/L) than in healthy controls (68 ± 1.8 nmol/L P.05). Patients with JIA more often used vitamin D containing supplements (50% vs. 7%; P.05). The prevalence of 25(OH)D deficiency (30 nmol/L) was 6% for both groups. Children with JIA with 25(OH)D deficiency or insufficiency (50 nmol/L) had higher C-reactive protein levels. Children with JIA were more often born in the fall and winter compared to healthy children. In contrast to earlier studies, we found vitamin D levels in Canadian children with JIA were higher compared to healthy children and associated with more frequent use of vitamin D supplements. Among children with JIA, low vitamin D levels were associated with indicators of greater inflammation.

Study Design Technical Report Objective Cerebrospinal fluid (CSF) leak secondary to anterior osteophytes at the cervico-thoracic junction is a rare cause of intracranial hypotension. In this article we describe a technique for anterior repair of spontaneous ventral cerebrospinal fluid leaks in the upper thoracic spine. Methods In this technical report and operative video, we describe a 23-year-old male who presented with positional headaches and bilateral subdural hematoma. Dynamic CT myelography demonstrated a high flow ventral cerebrospinal fluid leak associated with a ventral osteophyte at the level of the T1-T2 disc space. Targeted blood patch provided only temporary improvement in symptoms. An anterior approach was chosen to remove the offending spur and micro-surgically repair the dural defect. Results The patient had complete resolution of his preoperative symptoms after primary repair. Conclusions In select cases, an anterior approach to the upper thoracic spine is effective to repair Type 1 cerebrospinal fluid leaks.

ObjectiveIn 2015, the Canadian Vasculitis Research Network (CanVasc) created recommendations for the management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) in Canada. The current update aims to revise existing recommendations and create additional recommendations, as needed, based on a review of new available evidence.MethodsA needs assessment survey of CanVasc members informed questions for an updated systematic literature review (publications spanning May 2014 to September 2019) using Medline, Embase, and Cochrane. New and revised recommendations were developed and categorized according to the level of evidence and strength of each recommendation. The CanVasc working group used a 2-step modified Delphi procedure to reach > 80% consensus on the inclusion, wording, and grading of each new and revised recommendation.ResultsEleven new and 16 revised recommendations were created and 12 original (2015) recommendations were retained. New and revised recommendations are discussed in detail within this document. Five original recommendations were removed, of which 4 were incorporated into the explanatory text. The supplementary material for practical use was revised to reflect the updated recommendations.ConclusionThe 2020 updated recommendations provide rheumatologists, nephrologists, and other specialists caring for patients with AAV in Canada with new management guidance, based on current evidence and consensus from Canadian experts.

OBJECTIVE Undervaluing the effectiveness of conventional treatments may lead to overtreatment with biologic medications in children with juvenile idiopathic arthritis (JIA). Using data from a nationwide inception cohort and strict methods to control bias, the aim of our study was to estimate the real-world effectiveness of simple JIA treatment strategies recommended in current guidelines. METHODS Children with JIA who were recruited at 16 Canadian centers from 2005 to 2010 were followed for up to 5 years. For each child, all observed treatment changes over time were assessed by independent physicians using prospectively collected data and published response criteria. Success was defined as attainment of inactive disease or maintenance of this state when stepping down treatment; minimally active disease was deemed acceptable for children with polyarticular JIA. Success rates were calculated for treatments tried ≥25 times, and logistic regression analysis identified features associated with success. RESULTS A total of 4,429 treatment episodes were observed in 1,352 children. Nonsteroidal antiinflammatory drug (NSAID) monotherapy was attempted 697 times, mostly as initial treatment when

Objective To assess long-term outcomes of children with JIA diagnosed in the biologic era. Methods Chart review of patients prospectively enrolled in the Research in Arthritis in Canadian Children Emphasizing Outcomes inception cohort at two Canadian centres. Inactive disease and remission were defined according to Wallace criteria. Results We included 247 of 254 (97%) eligible patients diagnosed 2005–10. At the last follow-up visit at a median age of 16.9 years, 47% were in remission off medications, 25% in remission on medications and 27% had active disease; 51% were on at least one anti-rheumatic medication (22% on biologics). Patients with systemic JIA had the highest frequency of remission off medications (70%) and patients with RF-positive polyarthritis had the lowest (18%) (P Conclusion Relative to historical cohorts, this study suggests a reduction in JIA permanent damage, a more favourable prognosis for systemic JIA and a lower progression to oligoarthritis extended category. However, in an era of biologic therapy, one in four patients with JIA still enter adulthood with active disease and one in two still on treatment.

ObjectivesTo investigate the ability of high-sensitivity C-reactive protein (hsCRP) and S100A12 to serve as predictive biomarkers of successful drug withdrawal in children with clinical remission of juvenile idiopathic arthritis (JIA).MethodsThis multicentre trial (PREVENT-JIA) enrolled 119 patients with JIA in clinical remission, and 100 patients reached the intervention phase in which the decision whether to continue or stop treatment was based on S100A12 and hsCRP levels. Patients were monitored for 12 months after stopping medication for flares of disease. Results were compared with withdrawal of therapy without biomarker-based stratification in patients from the German Biologika in der Kinderrheumatologie (BiKeR) pharmacovigilance registry.ResultsIn the PREVENT-JIA group, 49 patients had a flare, and 45% of patients stopping medication showed flares within the following 12 months. All patients (n=8) continuing therapy due to permanently elevated S100A12/hsCRP at more than one visit flared during the observation phase. In the BiKeR control group, the total flare rate was 62%, with 60% flaring after stopping medication. The primary outcome, time from therapy withdrawal to first flare (cumulative flare rate after therapy withdrawal), showed a significant difference in favour of the PREVENT-JIA group (p=0.046; HR 0.62, 95% CI 0.38 to 0.99). As additional finding, patients in the PREVENT-JIA trial stopped therapy significantly earlier.ConclusionBiomarker-guided strategies of therapy withdrawal are feasible in clinical practice. This study demonstrates that using predictive markers of subclinical inflammation is a promising tool in the decision-making process of therapy withdrawal, which translates into direct benefit for patients.Trial registration numberISRCTN69963079.

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 (

Objective To identify discrete clusters comprising clinical features and inflammatory biomarkers in children with JIA and to determine cluster alignment with JIA categories. Methods A Canadian prospective inception cohort comprising 150 children with JIA was evaluated at baseline (visit 1) and after six months (visit 2). Data included clinical manifestations and inflammation-related biomarkers. Probabilistic principal component analysis identified sets of composite variables, or principal components, from 191 original variables. To discern new clinical-biomarker clusters (clusters), Gaussian mixture models were fit to the data. Newly-defined clusters and JIA categories were compared. Agreement between the two was assessed using Kruskal–Wallis analyses and contingency plots. Results Three principal components recovered 35% (three clusters) and 40% (five clusters) of the variance in patient profiles in visits 1 and 2, respectively. None of the clusters aligned precisely with any of the seven JIA categories but rather spanned multiple categories. Results demonstrated that the newly defined clinical-biomarker lustres are more homogeneous than JIA categories. Conclusion Applying unsupervised data mining to clinical and inflammatory biomarker data discerns discrete clusters that intersect multiple JIA categories. Results suggest that certain groups of patients within different JIA categories are more aligned pathobiologically than their separate clinical categorizations suggest. Applying data mining analyses to complex datasets can generate insights into JIA pathogenesis and could contribute to biologically based refinements in JIA classification.

Fabrication of microsystems is traditionally achieved with photolithography. However, this fabrication technique can be expensive and non-ideal for integration with microfluidic systems. As such, graphene fabrication is explored as an alternative. This graphene fabrication can be achieved with graphite oxide undergoing optical exposure, using optical disc drives, to impose specified patterns and convert to graphene. This work characterises such a graphene fabrication, and provides fabrication, electrical, microfluidic, and scanning electron microscopy (SEM) characterisations. In the fabrication characterisation, a comparison is performed between traditional photolithography fabrication and the new graphene fabrication. (Graphene fabrication details are also provided.) Here, the minimum achievable feature size is identified and graphene fabrication is found to compare favourably with traditional photolithography fabrication. In the electrical characterisation, the resistivity of graphene is measured as a function of fabrication dose in the optical disc drive and saturation effects are noted. In the microfluidic characterisation, the wetting properties of graphene are shown through an investigation of the contact angle of a microdroplet positioned on a surface that is treated with varying fabrication dose. In the SEM characterisation, the observed effects in the previous characterisations are attributed to chemical or physical effects through measurement of SEM energy dispersive X-ray spectra and SEM images, respectively. Overall, graphene fabrication is revealed to be a viable option for development of microsystems and microfluidics.

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.Youth18 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.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.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.

Context Osteoporotic fractures are an important cause of morbidity in children with glucocorticoid-treated rheumatic disorders. Objective This work aims to evaluate the incidence and predictors of osteoporotic fractures and potential for recovery over six years following glucocorticoid (GC) initiation in children with rheumatic disorders. Methods Children with GC-treated rheumatic disorders were evaluated through a prospective inception cohort study led by the Canadian STeroid-induced Osteoporosis in the Pediatric Population (STOPP) Consortium. Clinical outcomes included lumbar spine bone mineral density (LS BMD), vertebral fractures (VF), non-VF, and vertebral body reshaping. Results A total of 136 children with GC-treated rheumatic disorders were enrolled (mean age 9.9 years, SD 4.4). The 6-year cumulative fracture incidence was 16.3% for VF, and 10.1% for non-VF. GC exposure was highest in the first 6 months, and 24 of 38 VF (63%) occurred in the first 2 years. Following VF, 16 of 19 children (84%) had complete vertebral body reshaping. Increases in disease activity and body mass index z scores in the first year and declines in LS BMD z scores in the first 6 months predicted incident VF over the 6 years, while higher average daily GC doses predicted both incident VF and non-VF. LS BMD z scores were lowest at 6 months (mean –0.9, SD 1.2) and remained low by 6 years even when adjusted for height z scores (–0.6, SD 0.9). Conclusion VF occurred early and were more common than non-VF in children with GC-treated rheumatic disorders. Eighty-four percent of children with VF underwent complete vertebral body reshaping, whereas vertebral deformity persisted in the remainder of children. On average, LS BMD z scores remained low at 6 years, consistent with incomplete recovery.

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.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 patients18 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.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.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.

To describe the frequency and severity of parent-reported medication side effects (SEs) in children with juvenile idiopathic arthritis (JIA) relative to physician-reported actionable adverse events (AEs), and to assess their impact on health-related quality of life (HRQoL).Newly diagnosed JIA patients recruited between 2017 and 2019 to the Canadian Alliance of Pediatric Rheumatology Investigators (CAPRI) Registry were included. Parents reported presence and severity (0 = no problem, 10 = very severe) of medication SEs at every clinic visit. Physicians were asked to report any actionable AE. HRQoL was assessed using the Quality of My Life (QoML) questionnaire (0 = the worst, 10 = the best) and parent's global assessment (0 = very well, 10 = very poor). Analyses included proportion of visits with SEs or actionable AEs, cumulative incidence by Kaplan-Meier methods, and HRQoL impact measured with longitudinal mixed-effects models.SEs were reported at 371 of 884 (42%) visits (95% confidence interval [95% CI] 39, 45%) in 249 patients, with a median of 2 SEs per visit (interquartile range [IQR] 1-3), and median severity of 3 (IQR 1.5-5). Most SEs were gastrointestinal (32.5% of visits) or behavioral/psychiatric (22.4%). SE frequency was lowest with nonsteroidal antiinflammatory drugs alone (34.7%) and highest with prednisone and methotrexate combinations (66%). SE cumulative incidence was 67% (95% CI 59, 75) within 1 year of diagnosis, and 36% (95% CI 28, 44) for actionable AEs. Parent global and QoML scores were worse with SEs present; the impact persisted after adjusting for pain and number of active joints.Parents report that two-thirds of children with JIA experience SEs impacting their HRQoL within 1 year of diagnosis. SE mitigation strategies are needed in managing JIA.

Context Glucocorticoids (GCs) prescribed for chronic pediatric illnesses are associated with osteoporotic fractures. Objective This study aims to determine the efficacy and safety of intravenous (IV) zoledronic acid (ZA) compared with placebo to treat pediatric GC-induced osteoporosis (GIO). Methods Children aged 5 to 17 years with GIO were enrolled in this multinational, randomized, double-blind, placebo-controlled phase 3 trial (ClinicalTrials.gov NCT 00799266). Eligible children were randomly assigned 1:1 to 6 monthly IV ZA 0.05 mg/kg or IV placebo. The primary end point was the change in lumbar spine bone mineral density z score (LSBMDZ) from baseline to month 12. Incident fractures and safety were assessed. Results Thirty-four children were enrolled (mean age 12.6 ± 3.4 years [18 on ZA, 16 on placebo]), all with low-trauma vertebral fractures (VFs). LSBMDZ increased from −2.13 ± 0.79 to −1.49 ± 1.05 on ZA, compared with −2.38 ± 0.90 to −2.27 ± 1.03 on placebo (least squares means difference 0.41 [95% CI, 0.02-0.81; P = .04]); when corrected for height z score, the least squares means difference in LBMDZ was 0.75 [95% CI, 0.27-1.22; P = .004]. Two children on placebo had new low-trauma VF vs none on ZA. Adverse events (AEs) were reported in 15 of 18 children (83%) on ZA, and in 12 of 16 (75%) on placebo, most frequently within 10 days after the first infusion. There were no deaths or treatment discontinuations due to treatment-emergent AEs. Conclusion LSBMDZ increased significantly on ZA compared with placebo over 1 year in children with GIO. Most AEs occurred after the first infusion.

BackgroundAnti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small vessel vasculitis in adults and children that commonly affects the kidneys. Although the frequent antigenic, and presumed pathogenic, targets of ANCA in AAV are proteinase-3 (PR3) and myeloperoxidase (MPO), ANCA against lysosome associated membrane protein-2 (LAMP-2), a lesser known ANCA antigen that is expressed on the glomerular endothelium, are present in some adults with AAV-associated renal disease. LAMP-2-ANCA has not been assessed in children with chronic systemic vasculitis, and, if present, would be a potentially valuable biomarker given that treatment decisions for these pediatric patients at diagnosis are largely informed by kidney function.MethodsA custom ELISA, using commercially available reagents, was designed to detect autoantibodies to human LAMP-2 in serum. Sera obtained from 51 pediatric patients at the time of diagnosis of chronic primary systemic vasculitis (predominantly AAV) were screened. LAMP-2-ANCA titers were evaluated for correlation with clinical metrics of disease activity (pediatric vasculitis activity score [pVAS], C-reactive protein [CRP] concentration, and erythrocyte sedimentation rate [ESR]), MPO- and PR3-ANCA titers, and renal function (glomerular filtration rate [GFR], renal-specific pVAS, and serum creatinine concentration).ResultsLAMP-2-ANCA (>1,000 ng/ml) were detected in 35% (n = 18) of pediatric systemic vasculitis patients, of which, 10 (20% of all patients) were found to have high positive titers (>1,500 ng/ml). Undetectable or negative titres (1,500 ng/ml) of LAMP-2-ANCA. LAMP-2-ANCA titers did not correlate with measures of disease activity (pVAS, CRP, or ESR) at the time of diagnosis. In contrast, for patients with 12-month post diagnosis follow-up, a negative correlation was observed between the change in GFR (from diagnosis to 12-month follow-up) and LAMP-2-ANCA titer at diagnosis.ConclusionsModerate to high LAMP-2-ANCA titers were detected in 35% (18/51) of children with chronic systemic vasculitis affecting small-to-medium vessels. Although the highest concentrations of LAMP-2-ANCA in this population were observed in individuals positive for classic ANCA (MPO- or PR3-ANCA), similar to previous reports on adult patients, LAMP-2-ANCA titers do not correlate with classic ANCA titers or with overall disease activity at diagnosis. Renal disease is a common manifestation in systemic small-medium vessel vasculitis (both in adults and children, though more severe in children) and our preliminary data suggest LAMP-2-ANCA at diagnosis may be a risk factor for more severe renal disease.

ObjectivesThis 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.MethodsPlasma 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.ResultsAt 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.ConclusionPlasma 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.

Objective To identify early predictors of disease activity at 18 months in JIA using clinical and biomarker profiling. Methods Clinical and biomarker data were collected at JIA diagnosis in a prospective longitudinal inception cohort of 82 children with non-systemic JIA, and their ability to predict an active joint count of 0, a physician global assessment of disease activity of ≤1 cm, and inactive disease by Wallace 2004 criteria 18 months later was assessed. Correlation-based feature selection and ReliefF were used to shortlist predictors and random forest models were trained to predict outcomes. Results From the original 112 features, 13 effectively predicted 18-month outcomes. They included age, number of active/effused joints, wrist, ankle and/or knee involvement, ESR, ANA positivity and plasma levels of five inflammatory biomarkers (IL-10, IL-17, IL-12p70, soluble low-density lipoprotein receptor-related protein 1 and vitamin D), at enrolment. The clinical plus biomarker panel predicted active joint count = 0, physician global assessment ≤ 1, and inactive disease after 18 months with 0.79, 0.80 and 0.83 accuracy and 0.84, 0.83, 0.88 area under the curve, respectively. Using clinical features alone resulted in 0.75, 0.72 and 0.80 accuracy, and area under the curve values of 0.81, 0.78 and 0.83, respectively. Conclusion A panel of five plasma biomarkers combined with clinical features at the time of diagnosis more accurately predicted short-term disease activity in JIA than clinical characteristics alone. If validated in external cohorts, such a panel may guide more rationally conceived, biologically based, personalized treatment strategies in early JIA.

Background Human adenosine deaminase 2 (ADA2) is an extracellular enzyme that negatively regulates adenosine-mediated cell signaling by converting adenosine to inosine. Altered ADA2 enzyme activity has been associated with some viral infections and rheumatic diseases. The potential utility of ADA2 as a biomarker is, however, limited by the absence of established ranges of ADA2 concentration and enzyme activity in the healthy population. It is known that ADA2 enzyme activity is lower in adults, but when (and why) this decline happens is not known. The purpose of this study was to establish normative ranges of ADA2 enzyme activity and protein concentration in the healthy pediatric population. Methods We modified a commercially available ADA2 enzyme activity assay to enable higher throughput analysis of fresh, frozen and hemolyzed blood samples. With this assay and ADA2 protein immunoblotting, we analyzed ADA2 enzyme activity and protein concentration in blood plasma from a cohort of children and adolescents (n = 94) aged 5 months to 18 years. One-way ANOVA with subsequent Tukey multiple comparison test was used to analyze group differences. Reference intervals were generated using the central 95% of the population (2–97.5 percentiles). Results ADA2 enzyme activity was consistent in fresh, frozen, and hemolyzed sera and plasma as measured by our modified assay. Analysis of plasma samples from the healthy pediatric cohort revealed that ADA2 enzyme activity is significantly lower in older children than in younger children (p Conclusion We observed that ADA2 enzyme activity, but not ADA2 protein concentration, negatively correlates with age in a cohort of children and adolescents. Our findings stress the importance of appropriate age-matched controls for assessing ADA2 enzyme activity in the clinical setting.

O manejo da dor infantil é complexo devido as limitações de comunicação das crianças e tem seu ponto de partida em uma avaliação adequada da dor, contudo há uma gama de escalas de avaliação da dor e os profissionais em dificuldade em escolher a ferramenta adequada. Objetivo: construir e validar aplicativo de avaliação de dor em crianças a partir do estudo das escalas disponíveis. Metodologia: Trata-se de um estudo descritivo de desenvolvimento experimental. A pesquisa se desenvolveu nas seguintes etapas: desenvolvimento do aplicativo, validação por especialistas e análise de dados. Realizou-se a revisão exploratória sobre as escalas de avaliação de dor em crianças para fundamentar o aplicativo. O desenvolvimento do aplicativo foi realizado em parceria com profissional de computação a fim de fornecer uma interface amigável. A validação foi realizada por especialistas profissionais de saúde (médicos, enfermeiros e fisioterapeutas) através de um questionário pré-estabelecido contendo informações sobre a formação acadêmica e profissional dos validadores, e sobre os itens a serem validados. Resultados: Para análise de dados, utilizou-se o índice de validade de conteúdo (IVC), sendo considerado válido quando o quesito obtivesse IVC > 0.8. O aplicativo foi validado com IVC de 1.0 pelos especialistas. Conclusão: A avaliação positiva do aplicativo demonstra que é uma ferramenta válida e com boa aceitação pelos profissionais de saúde envolvidos nos cuidados da dor em crianças e que a incorporação de novas tecnologias pode otimizar e facilitar o uso de escalas na avaliação de dor em crianças.

Purpose of the Review To provide an overview of recent advances in the treatment of pediatric antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Recent Findings With advances in research, use of standardized clinical assessment tools, advent of biologic therapies, and use of patient registries, concepts relating to the optimal management of pediatric patients with chronic primary systemic vasculitis have evolved and newer treatments strategies and treatment guidelines continue to emerge. Conclusion Although most of what we have learned about pediatric AAV has come from adult data, the quality and breadth of pediatric data is accumulating because of multicenter, international collaborations. These efforts are critical given that optimal treatment strategies likely differ in the context of a developing immune system, and in a physically and emotionally developing child. Pragmatic clinical trials linked with international patient registries could help close the pediatric AAV evidence gap.