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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.

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 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.

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.

Background Juvenile idiopathic arthritis (JIA) is a serious and potentially debilitating pediatric illness. Improved disease self-management may help to improve health outcomes. Objective This study aimed to evaluate the effectiveness of the Teens Taking Charge Web-based self-management intervention in reducing symptoms and improving health-related quality of life (HRQL) in adolescents with JIA compared with a Web-based education control condition. Methods Adolescents with JIA aged 12 to 18 years were recruited from 11 Canadian pediatric rheumatology centers. Caregivers were invited to participate along with their child. In addition to standard medical care, participants were randomized to receive either (1) the Teens Taking Charge self-management intervention or (2) a Web-based education control condition for a period of 12 weeks. Adolescents in the intervention group completed website modules addressing cognitive behavioral coping skills, stress management, and other self-management topics, while also receiving monthly telephone calls from a trained health coach. Adolescents in the education control group were instructed to view a series of preselected public JIA educational websites and received monthly calls from a coach who asked about their own best efforts at managing JIA. Caregivers in the intervention group completed website modules related to promoting independence and disease self-management in their child. Caregivers in the education control group were instructed to view a series of preselected public JIA educational websites. Outcome assessment occurred at baseline, 12 weeks (posttreatment), and at 6 and 12 months postrandomization. The primary outcomes were pain intensity, pain interference, and HRQL. Secondary outcomes were emotional symptoms, adherence, coping, knowledge, and self-efficacy. Results In total, 333 adolescents and 306 caregivers were enrolled. Significant overall reductions in pain intensity (P=.02) and pain interference (P=.007) were observed for intervention group participants compared with those in the education control group, after adjusting for baseline levels. There was a significant overall improvement in HRQL related to problems with pain (P=.02) and problems with daily activities (P=.01). There was also a significant difference in the intervention group over time (P=.008) for HRQL related to treatment problems, with the intervention group participants demonstrating improved HRQL by 12 months compared with education control group participants. Both groups showed nonsignificant improvements compared with baseline in other primary outcomes. There were no significant differences between the groups in any secondary outcomes or caregiver-reported outcomes. Conclusions The results of this randomized trial suggest that the Teens Taking Charge Web-based intervention is effective at reducing both pain intensity and pain interference, as well as improving HRQL in adolescents with JIA, compared with education control. These effects are sustained for up to 12 months following program completion. The Teens Taking Charge program is now publicly available at no cost. Trial Registration ClinicalTrials.gov NCT01572896; https://clinicaltrials.gov/ct2/show/NCT01572896

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.

IKBKB immune deficiency is a rare but life-threatening primary immunodeficiency disorder, involving activation defects in adaptive and innate immunity. We present sixteen cases of a homozygous IKBKB mutation (c.1292dupG) in infants characterized by early-onset bacterial, viral, fungal and Mycobacterial infections. In most cases, T- and B-cells were quantitatively normal, but phenotypically naive, with severe hypogammaglobulinemia. T-cell receptor excision circles were normal, meaning newborn screening by TREC analysis would miss IKBKB cases. Although IKBKB immune deficiency does not meet traditional laboratory based definitions for SCID, this combined immune deficiency appears to be at least as profound. Urgent HSCT, performed in eight patients, remains the only known curative therapy, although only three patients are survivors. Ongoing infections after transplant remain a concern, and may be due to combinations of poor social determinants of health, secondary graft failure, and failure of HSCT to replace non-hematopoietic cells important in immune function and dependent upon IKK/NF-κB pathways.

BACKGROUND Juvenile idiopathic arthritis (JIA) is a serious and potentially debilitating pediatric illness. Improved disease self-management may help to improve health outcomes. OBJECTIVE This study aimed to evaluate the effectiveness of the Teens Taking Charge Web-based self-management intervention in reducing symptoms and improving health-related quality of life (HRQL) in adolescents with JIA compared with a Web-based education control condition. METHODS Adolescents with JIA aged 12 to 18 years were recruited from 11 Canadian pediatric rheumatology centers. Caregivers were invited to participate along with their child. In addition to standard medical care, participants were randomized to receive either (1) the Teens Taking Charge self-management intervention or (2) a Web-based education control condition for a period of 12 weeks. Adolescents in the intervention group completed website modules addressing cognitive behavioral coping skills, stress management, and other self-management topics, while also receiving monthly telephone calls from a trained health coach. Adolescents in the education control group were instructed to view a series of preselected public JIA educational websites and received monthly calls from a coach who asked about their own best efforts at managing JIA. Caregivers in the intervention group completed website modules related to promoting independence and disease self-management in their child. Caregivers in the education control group were instructed to view a series of preselected public JIA educational websites. Outcome assessment occurred at baseline, 12 weeks (posttreatment), and at 6 and 12 months postrandomization. The primary outcomes were pain intensity, pain interference, and HRQL. Secondary outcomes were emotional symptoms, adherence, coping, knowledge, and self-efficacy. RESULTS In total, 333 adolescents and 306 caregivers were enrolled. Significant overall reductions in pain intensity (P=.02) and pain interference (P=.007) were observed for intervention group participants compared with those in the education control group, after adjusting for baseline levels. There was a significant overall improvement in HRQL related to problems with pain (P=.02) and problems with daily activities (P=.01). There was also a significant difference in the intervention group over time (P=.008) for HRQL related to treatment problems, with the intervention group participants demonstrating improved HRQL by 12 months compared with education control group participants. Both groups showed nonsignificant improvements compared with baseline in other primary outcomes. There were no significant differences between the groups in any secondary outcomes or caregiver-reported outcomes. CONCLUSIONS The results of this randomized trial suggest that the Teens Taking Charge Web-based intervention is effective at reducing both pain intensity and pain interference, as well as improving HRQL in adolescents with JIA, compared with education control. These effects are sustained for up to 12 months following program completion. The Teens Taking Charge program is now publicly available at no cost. CLINICALTRIAL ClinicalTrials.gov NCT01572896; https://clinicaltrials.gov/ct2/show/NCT01572896

Gene set analysis is a well-established approach for analyzing high-throughput gene expression data. The choice of gene set database used for gene set analysis may affect the outcome of the analysis. Therefore, understanding characteristics of these databases is vital to the success of gene set analysis. Due to the sheer size of the gene set databases, a comprehensive qualitative evaluation of them is impractical. In this paper, we quantitatively study several well-established gene set databases. We propose and use a quantitative measure for assessing the similarity between gene set databases. Also, we introduce presence score, for quantifying the degree to which a given gene is represented in a database, and permeability score, for quantifying the degree to which genes in a given list co-occur in the gene sets of a database. A maximum achievable coverage score is defined based on the permeability score. Using the maximum achievable coverage score, we propose a methodology to statistically determine whether a phenotype of interest is well-represented in a given database. To study the effect of the choice of gene set database on the result of gene set analysis and show the utility of the maximum achievable coverage score, we conduct an experiment using two widely used gene set analysis methods and three expression datasets. The results suggest that the choice of gene set database might profoundly affect the outcome of the analysis. Also, our findings show that the permeability score and maximum achievable coverage can be used to guide the selection of an appropriate gene set database for a given study.

Background Treatments for juvenile idiopathic arthritis (JIA) are changing rapidly. Healthcare providers and families require up-to-date knowledge of current treatment practices and expected outcomes to inform their decisions. Objectives To assess changes in treatment practices and outcomes for children in a new Canadian inception cohort diagnosed with JIA in 2017-2018, compared to children in the Research in Arthritis in Canadian Children emphasizing Outcomes cohort (ReACCh-Out) diagnosed in 2005-2010 1. Methods A new investigator-driven Canadian Alliance of Pediatric Rheumatology Investigators (CAPRI) JIA Registry was started in February 2017 to prospectively collect information on children enrolled within 3 months of JIA diagnosis. Information about disease activity, treatments, outcomes and adverse events is collected at all clinic visits. Registry data were extracted in October 2018 and clinical characteristics at presentation, use of anti-rheumatic medications, attainment of inactive disease, cJADAS10 scores and adverse events were described. Selected findings were compared to those observed in the ReACCh-Out cohort. The proportion of patients (cumulative incidence) receiving various treatments and their outcomes were estimated with Kaplan Meier survival methods. Results A total of 166 patients enrolled a median of 6 weeks after diagnosis at 10 centres were included. Median age at diagnosis was 9 years (IQR 3, 13), 61% were female and 51% had oligoarthritis. At enrolment, subjects had a median of 2 active joints (IQR 1, 3), a Physician Global Assessment of 3 (1.5, 4) and a Parent Global Assessment of 1 (0, 3). The median cJADAS10 score was 6.5 (4, 10). Table 1 compares baseline characteristics and the cumulative incidence of medication use and inactive disease at one year after diagnosis with those observed in the ReACCh-Out cohort, diagnosed on average 10 years earlier. Figure 1 shows the Kaplan Meier curves for attainment of inactive disease. Conclusion In Canada, treatments for newly diagnosed patients with JIA have intensified in the last 10 years, and 35% will now start their first biologic within 1 year of diagnosis. Short-term outcomes have improved, 81% of current patients now attaining inactive disease within one year of diagnosis. Funding: The Arthritis Society, Canada. References [1] Guzman J, Oen K, Tucker LB, et al. The outcomes of juvenile idiopathic arthritis in children managed with contemporary treatments: results from the ReACCh-Out cohort. Ann Rheum Dis.2015;74:1854-60 Acknowledgement Funding: The Arthritis Society, Canada. Disclosure of Interests Jaime Guzman: None declared, Michelle Batthish Speakers bureau: Novartis, Abbvie, Roberta Berard: None declared, Roxana Bolaria: None declared, David Cabral: None declared, Gaelle Chedeville: None declared, Ciaran Duffy: None declared, Kerstin Gerhold: None declared, Tommy Gerschman: None declared, Adam Huber: None declared, Jean-Philippe Proulx-Gauthier: None declared, Alan Rosenberg: None declared, Dax Rumsey: None declared, Heinrike Schmeling Grant/research support from: F. Hoffmann-La Roche Ltd, Natalie Shiff: None declared, Gordon Soon: None declared, Lori Tucker: None declared

Background Joint inflammation is the common feature underlying juvenile idiopathic arthritis (JIA). Clinicians recognize patterns of joint involvement currently not part of the International League of Associations for Rheumatology (ILAR) classification. Using unsupervised machine learning, we sought to uncover data-driven joint patterns that predict clinical phenotype and disease trajectories. Methods and findings We analyzed prospectively collected clinical data, including joint involvement using a standard 71-joint homunculus, for 640 discovery patients with newly diagnosed JIA enrolled in a Canada-wide study who were followed serially for five years, treatment-naïve except for nonsteroidal anti-inflammatory drugs (NSAIDs) and diagnosed within one year of symptom onset. Twenty-one patients had systemic arthritis, 300 oligoarthritis, 125 rheumatoid factor (RF)-negative polyarthritis, 16 RF-positive polyarthritis, 37 psoriatic arthritis, 78 enthesitis-related arthritis (ERA), and 63 undifferentiated arthritis. At diagnosis, we observed global hierarchical groups of co-involved joints. To characterize these patterns, we developed sparse multilayer non-negative matrix factorization (NMF). Model selection by internal bi-cross-validation identified seven joint patterns at presentation, to which all 640 discovery patients were assigned: pelvic girdle (57 patients), fingers (25), wrists (114), toes (48), ankles (106), knees (283), and indistinct (7). Patterns were distinct from clinical subtypes (P < 0.001 by χ2 test) and reproducible through external data set validation on a 119-patient, prospectively collected independent validation cohort (reconstruction accuracy Q2 = 0.55 for patterns; 0.35 for groups). Some patients matched multiple patterns. To determine whether their disease outcomes differed, we further subdivided the 640 discovery patients into three subgroups by degree of localization—the percentage of their active joints aligning with their assigned pattern: localized (≥90%; 359 patients), partially localized (60%–90%; 124), or extended (, Using unsupervised machine learning, Rae Yeung and colleagues uncover data-driven joint patterns that predict clinical phenotype and disease trajectories in JIA., Author summary Why was this study done? Juvenile idiopathic arthritis (JIA) is a heterogeneous childhood disease for which joint inflammation is the common denominator. The current classification system, the International League of Associations for Rheumatology (ILAR) subtypes, categorize patients according to the number of active joints (four or fewer versus five or more affected joints in the first six months of disease) with little evidence to support this cut-off. Grouping frequently co-involved joints into joint patterns may help to better classify patients and predict disease course. What did the researchers do and find? We analyzed baseline joint involvement data from 640 treatment-naïve patients from 16 Canadian centers participating in the Research in Arthritis in Canadian Children, Emphasizing Outcomes (ReACCh-Out) study between 2005 and 2010. We identified seven joint patterns that grouped frequently co-involved joints using multilayer non-negative matrix factorization (NMF), an unsupervised pattern recognition technique. We named these patterns as follows: pelvic girdle, fingers, wrists, toes, knees, ankles, and indistinct. These seven patterns described more homogenous groupings of joints than the ILAR subtypes and further stratified them. Throughout disease course, we found that patients with joint involvements largely overlapping their baseline patterns, i.e., those having localized involvement, continued to have the same active joints, whereas patients with nonlocalized involvement did not. Patients with localized joint involvement reached zero joint involvement faster than those with nonlocalized involvement. What do these findings mean? Patterns of joint involvement represent prognostic features that should be incorporated into a comprehensive JIA disease classification. Patients with nonlocalized joint involvement are at high risk of poor outcome. Grouping patients by joint pattern and degree of localization may help clinicians tailor treatments based on predicted disease trajectories.

Background Antibiotics are commonly prescribed for children with acute respiratory infections (ARIs). This study describes the distribution of ARI diagnoses and specifically quantifies antibiotic dispensing for bronchitis and upper respiratory infection (URI) by treatment setting and specialty. Methods This retrospective, observational cross-sectional study used data from the HealthCore Integrated Research Environment containing claims from 14 commercial health plans for 2012 to 2014. Children (2-17 years) with first-episode ARI were identified by diagnosis of acute otitis media (AOM), sinusitis, pharyngitis, bronchitis or URI with no competing infections or chronic illnesses. Treatment setting was where diagnoses were made: primary care offices, urgent care centers (UCC), retail health clinics (RHCs) or emergency departments. Primary outcome measure was antibiotic prescription fills from pharmacies within 2 days of start of ARI episode. Results For URI, the highest proportions in antibiotic dispensing were ordered by office-based or UCC family physicians (28% and 30%, respectively) and office-based or UCC nurse practitioners/physician assistants (30% and 29%, respectively). Across all settings and specialties, there was high proportion of antibiotic dispensing for bronchitis (75%). Overall, 48% of 544,531 children diagnosed with ARI filled antibiotics. Nurse practitioners/physician assistants in RHC made the most diagnoses of AOM (24%) and streptococcal pharyngitis (22%). Conclusions Outreach efforts to decrease antibiotic dispensing for URI can be focused on office-based and UCC family physicians and nurse practitioners/physician assistants. All specialties need widespread interventions to reduce antibiotic dispensing for bronchitis. RHC nurse practitioners/physician assistants can be targeted to reduce high proportion of AOM and streptococcal pharyngitis diagnoses.

Objective.To determine cancer incidence in a large pediatric-onset systemic lupus erythematosus (SLE) population.Methods.Data were examined from 12 pediatric SLE registries in North America. Patients were linked to their regional cancer registries to detect cancers observed after cohort entry, defined as date first seen in the clinic. The expected number of malignancies was obtained by multiplying the person-years in the cohort (defined from cohort entry to end of followup) by the geographically matched age-, sex-, and calendar year–specific cancer rates. The standardized incidence ratio (SIR; ratio of cancers observed to expected) was generated, with 95% CI.Results.A total of 1168 patients were identified from the registries. The mean age at cohort entry was 13 years (SD 3.3), and 83.7% of the subjects were female. The mean duration of followup was 7.6 years, resulting in a total observation period of 8839 years spanning the calendar period 1974–2009. During followup, fourteen invasive cancers occurred (1.6 cancers per 1000 person-yrs, SIR 4.13, 95% CI 2.26–6.93). Three of these were hematologic (all lymphomas), resulting in an SIR for hematologic cancers of 4.68 (95% CI 0.96–13.67). SIR were increased for both male and female patients, and across age groups.Conclusion.Although cancer remains a relatively rare outcome in pediatric-onset SLE, our data do suggest an increase in cancer for patients followed an average of 7.6 years. About one-fifth of the cancers were hematologic. Longer followup, and study of drug effects and disease activity, is warranted.

OBJECTIVE: To determine whether systemic juvenile idiopathic arthritis (JIA) susceptibility loci that were identified by candidate gene studies demonstrate association with systemic JIA in the largest study population assembled to date. METHODS: Single-nucleotide polymorphisms (SNPs) from 11 previously reported systemic JIA risk loci were examined for association in 9 populations, including 770 patients with systemic JIA and 6,947 controls. The effect of systemic JIA-associated SNPs on gene expression was evaluated in silico in paired whole genome and RNA sequencing data from the lymphoblastoid cell lines (LCLs) of 373 European subjects from the 1000 Genomes Project. Responses of systemic JIA-associated SNPs to anakinra treatment were evaluated in 38 US patients for whom treatment response data were available. RESULTS: We found no association between the previously reported 26 SNPs and systemic JIA. Expanded analysis of the regions containing the 26 SNPs revealed only 1 significant association: the promoter region of IL1RN (P < 1 × 10(-4) ). Systemic JIA-associated SNPs correlated with IL1RN expression in LCLs, with an inverse correlation between systemic JIA risk and IL1RN expression. The presence of homozygous IL1RN high expression alleles correlated strongly with a lack of response to anakinra therapy (odds ratio 28.7 [95% confidence interval 3.2-255.8]). CONCLUSION: In our study, IL1RN was the only candidate locus associated with systemic JIA. The implicated SNPs are among the strongest known determinants of IL1RN and interleukin-1 receptor antagonist levels, linking low expression with increased systemic JIA risk. Homozygous high expression alleles predicted nonresponsiveness to anakinra therapy, making them ideal candidate biomarkers to guide systemic JIA treatment. This study is an important first step toward the personalized treatment of systemic JIA.

Purpose Universal and timely access to pediatric critical care and specialized transportation is a substantial challenge, particularly in rural and remote areas. This study evaluates the utilization of the FDA-approved RP7i remote presence device (InTouch Technology Inc.) to assess, manage, and triage pediatric patients in determining need for inter-facility transportation. The primary objective of this study is to compare the number of transports that occur in the cases (with RP7i) …

Objective Childhood arthritis encompasses a heterogeneous family of diseases. Significant variation in clinical presentation remains despite consensus-driven diagnostic classifications. Developments in data analysis provide powerful tools for interrogating large heterogeneous data sets. We report a novel approach to integrating biologic and clinical data toward a new classification for childhood arthritis, using computational biology for data-driven pattern recognition. Methods Probabilistic principal components analysis was used to transform a large set of data into 4 interpretable indicators or composite variables on which patients were grouped by cluster analysis. Sensitivity analysis was conducted to determine key variables in determining indicators and cluster assignment. Results were validated against an independent validation cohort. Results Meaningful biologic and clinical characteristics, including levels of proinflammatory cytokines and measures of disease activity, defined axes/indicators that identified homogeneous patient subgroups by cluster analysis. The new patient classifications resolved major differences between patient subpopulations better than International League of Associations for Rheumatology subtypes. Fourteen variables were identified by sensitivity analysis to crucially determine indicators and clusters. This new schema was conserved in an independent validation cohort. Conclusion Data-driven unsupervised machine learning is a powerful approach for interrogating clinical and biologic data toward disease classification, providing insight into the biology underlying clinical heterogeneity in childhood arthritis. Our analytical framework enabled the recovery of unique patterns from small cohorts and addresses a major challenge, patient numbers, in studying rare diseases.

The use of non-vitamin K oral anticoagulants (NOACs) has increased steadily following marketing approval; however, their relative safety in nonvalvular atrial fibrillation (NVAF) patients in real-world clinical practice remains unclear.To compare the risk of major bleeding during anticoagulation therapy between warfarin and NOACs.This retrospective cohort study analyzed administrative claims data on new NVAF users of warfarin, dabigatran, apixaban, or rivaroxaban in routine clinical care from November 2010 to February 2015 in a commercially insured population in the United States. The primary outcome was time to first major bleeding event requiring hospitalization. Patients were followed until discontinuation or switch of anticoagulants, health plan disenrollment, death, or end of study. All patient characteristics were balanced after propensity score inverse probability of treatment (IPT) weighting. Event rates by type of anticoagulant exposure were compared using IPT-weighted Cox proportional hazards models.The study cohort comprised 44,057 patients who used warfarin (n = 23,431), dabigatran (n = 8,539), apixaban (n = 3,689), and rivaroxaban (n = 8,398). Overall mean (SD) age was 70 (12) years, and 41% of the patients were women. A total of 2,337 major bleeding events occurred during 36,636.2 person-years of follow-up. The unadjusted rate of major bleeding with warfarin was 6.0 per 100 person-years versus 2.8 with dabigatran, 3.3 with apixban, and 5.0 with rivaroxaban. Relative to warfarin, major bleeding risk was lower with dabigatran (HR = 0.67, 95% CI = 0.60-0.76) and apixaban (HR = 0.52, 95% CI = 0.41-0.67). Compared with rivaroxaban, major bleeding risk was also lower with dabigatran (HR = 0.67, 95% CI = 0.58-0.78) and apixaban (HR = 0.52, 95% CI = 0.40-0.68). Major bleeding risk was similar for rivaroxaban and warfarin. Relative to apixaban, dabigatran was associated with a significantly higher risk of major gastrointestinal bleeding (HR = 1.43, 95% CI = 1.09-1.88).Study results were consistent with safety findings from pivotal clinical trials comparing NOACs with warfarin and added the perspective of a large real-world observational study that compared bleeding risks associated with NOACs during anticoagulation therapy. Apixaban and dabigatran were associated with lower major bleeding risk compared with warfarin or rivaroxaban; however, apixaban had a lower risk of major gastrointestinal bleeding than dabigatran. These findings can help inform the choice of an optimal agent, which must balance effectiveness and bleeding risk in complex patients.This study was funded by Anthem. Adeboyeje, Sylwestrzak, and Barron are employees of HealthCore, a wholly owned and independently operated subsidiary of Anthem. White, Rosenberg, Abarca, and Crawford are employees of Anthem. Study concept and design were primarily contributed by Adeboyeje and Sylwestrzak, along with the other authors. Adeboyeje took the lead in data collection, along with Sylwestrzak and Barron. Data interpretation was performed primarily by Rosenberg, Crawford, and Redberg, with assistance from the other authors. The manuscript was written by all the authors and revised primarily by White, Abarca, and Redberg, along with the other authors.

Background With modern treatments, the effect of juvenile idiopathic arthritis (JIA) on growth may be less than previously reported. Our objective was to describe height, weight and body mass index (BMI) development in a contemporary JIA inception cohort. Methods Canadian children newly-diagnosed with JIA 2005–2010 had weight and height measurements every 6 months for 2 years, then yearly up to 5 years. These measurements were used to calculate mean age- and sex-standardized Z-scores, and estimate prevalence and cumulative incidence of growth impairments, and the impact of disease activity and corticosteroids on growth. Results One thousand one hundred forty seven children were followed for median 35.5 months. Mean Z-scores, and the point prevalence of short stature (height 95th percentile, 15.8% to 16.4%) remained unchanged in the whole cohort. Thirty-three children (2.9%) developed new-onset short stature, while 27 (2.4%) developed tall stature (>97.5th percentile). Children with systemic arthritis (n = 77) had an estimated 3-year cumulative incidence of 9.3% (95%CI: 4.3–19.7) for new-onset short stature and 34.4% (23–49.4) for obesity. Most children (81.7%) received no systemic corticosteroids, but 1 mg/Kg/day prednisone-equivalent maintained for 6 months corresponded to a drop of 0.64 height Z-scores (0.56–0.82) and an increase of 0.74 BMI Z-scores (0.56–0.92). An increase of 1 in the 10-cm physician global assessment of disease activity maintained for 6 months corresponded to a drop of 0.01 height Z-scores (0–0.02). Conclusions Most children in this modern JIA cohort grew and gained weight as children in the general population. About 1 in 10 children who had systemic arthritis, uncontrolled disease and/or prolonged corticosteroid use, had increased risk of growth impairment. Electronic supplementary material The online version of this article (doi:10.1186/s12969-017-0196-7) contains supplementary material, which is available to authorized users.

Objective To describe the prevalence, associated characteristics, and course of enthesitis in a juvenile idiopathic arthritis (JIA) inception cohort. Methods Canadian children newly diagnosed with JIA between 2005 and 2010 were categorized using International League of Associations for Rheumatology criteria at the 6-month visit and followed in the Research in Arthritis in Canadian Children Emphasizing Outcomes (ReACCh-Out) cohort for up to 5 years. The presence of entheseal tenderness on examination at 33 sites shown on a homunculus was recorded at 0, 6, 12, 18, 24, 36, 48, and 60 months after enrollment. Enthesitis was defined as entheseal tenderness at more than 1 site or on more than 1 occasion. Analyses consisted of descriptive statistics and linear mixed models for longitudinal data. Results Of 1,406 patients, 219 (16%) had enthesitis and, of those with enthesitis, 141 (64%) were classified as having enthesitis-related arthritis (ERA). Children with enthesitis were more often older (10.7 versus 7.5 years), male (57% versus 31%), and with polyarthritis (57% versus 41%) and sacroiliac involvement (30% versus 4%). Entheseal tenderness was most frequent at the calcaneal plantar fascial insertion (39%), Achilles tendon insertion (31%), and tibial tuberosity (30%). The mean number of tender entheseal sites decreased in parallel with active joint counts. There was no difference in active joint counts over time in children with or without enthesitis (P = 0.73). Conclusion Enthesitis was observed in 16% of patients with JIA, but only two thirds were categorized as having ERA. Contrary to expectations, most children with enthesitis had polyarticular involvement. The course of enthesitis paralleled the course of active joint counts.

Objective.To examine perceived independence, overprotection, and support, and their association with the employment participation of young adults with rheumatic disease.Methods.One hundred and forty-three young adults, ages 18 to 30 years, with systemic lupus erythematosus (54.5%) and juvenile arthritis (45.5%) completed a 30-min online questionnaire of their work and education experiences. Information collected was demographic, health (e.g., pain, fatigue, disease activity), work context (e.g., career satisfaction, helpfulness of job accommodation/benefits, and workplace activity limitations), and psychosocial (e.g., independence, social support, and overprotection). Log-Poisson regression analysis examined factors associated with employment status.Results.Over half of respondents were employed (59%) and 26% were enrolled in school. Respondents reported moderate to high perceptions of independence and social support. However, 27% reported that “quite a bit” to “a great deal” of overprotection characterized their relationships with those closest to them. At the bivariate level, employed participants and those indicating greater perceived independence reported greater social support and less overprotection. Multivariable analysis revealed that being employed was associated with older age, more job accommodations/benefits perceived as being helpful, and greater perceived independence.Conclusion.This is one of the first studies examining the employment of young adults with rheumatic diseases. Findings highlight the importance of psychosocial perceptions such as independence and overprotection, in addition to support related to working. Additional research is needed to better understand the role of those close to young adults with rheumatic diseases in supporting independence and encouraging employment.

The management of atrial fibrillation (AF) involves two choices: (1) rate control versus rhythm control, and (2) anticoagulation treatment based upon risk of stroke. The objective of the study was to describe practice patterns in both of these treatment areas in patients with newly diagnosed AF among a commercially insured population.This retrospective administrative claims analysis included patients with ≥2 AF claims between 1 January 2008 and 30 September 2010. Patients with AF claims within a year prior to the index date (i.e., the first AF diagnosis date) were excluded. The primary outcome was the proportion of patients treated with rate control (i.e., beta blockers, calcium channel blockers, digoxin) versus rhythm control (i.e., electrical cardioversion, left atrial catheter ablation [LACA], and/or surgical ablation) and the use of anticoagulants stratified by risk of stroke based on CHADS2 score.Of 48,814 patients with a diagnosis of AF, 38,502 (78.9%) received treatment. Of those treated, the majority received only pharmacologic treatment (73.4%), of which beta blockers were predominantly used in the initial regimen (66.7%). Antiarrhythmic drugs were used in 23.9% of patients, but within the initial regimen in only 11.7% of patients. Direct current cardioversion occurred in 18.2% of patients, with the majority being either first-line (8.5%) or second-line (9.1%) therapy. LACA was used in only 5.2% of patients and was typically reserved for use after pharmacologic treatment or direct current cardioversion. Of 1924 patients who received LACA, 14.6% received a repeat procedure and 53.4% of the repeat procedures occurred within 6 months of the initial one. A little more than half of all patients (57.0%) received anticoagulant therapy (predominantly warfarin); of those at high risk for stroke, 63.8% with a CHADS2 score ≥2 received anticoagulants.It is a retrospective analysis using administrative claims data from a commercially insured population only. Identification of the first episode of AF may be inaccurate, and we cannot differentiate between paroxysmal and persistent AF.Debate continues regarding whether the preferred management of most patients with AF is through rate control or restoration of normal sinus rhythm. Our retrospective study found that treatments to restore normal heart rhythm, including LACA, which could be considered aggressive initial treatment, were typically reserved as second- or third-line alternatives. Initial standard of care for the majority patients was beta blockers. Though use of anticoagulation may be higher than other observational studies, opportunities exist to increase treatment in high risk patients.

Gene set analysis is a quantitative approach for generating biological insight from gene expression datasets. The abundance of gene set analysis methods speaks to their popularity, but raises the question of the extent to which results are affected by the choice of method. Our systematic analysis of 13 popular methods using 6 different datasets, from both DNA microarray and RNA-Seq origin, shows that this choice matters a great deal. We observed that the overall number of gene sets reported by each method differed by up to 2 orders of magnitude, and there was a bias toward reporting large gene sets with some methods. Furthermore, there was substantial disagreement between the 20 most statistically significant gene sets reported by the methods. This was also observed when expanding to the 100 most statistically significant reported gene sets. For different datasets of the same phenotype/condition, the top 20 and top 100 most significant results also showed little to no agreement even when using the same method. GAGE, PAGE, and ORA were the only methods able to achieve relatively high reproducibility when comparing the 20 and 100 most statistically significant gene sets. Biological validation on a juvenile idiopathic arthritis (JIA) dataset showed wide variation in terms of the relevance of the top 20 and top 100 most significant gene sets to known biology of the disease, where GAGE predicted the most relevant gene sets, followed by GSEA, ORA, and PAGE.

OBJECTIVE: Although unnecessary for children with headache and normal history, computed tomography (CT) scans are widely used. This study sought to determine current practice patterns of neuroimaging to diagnose pediatric headache in a variety of treatment settings and to identify factors associated with increased use of neuroimaging. METHODS: This retrospective claims analysis included children (aged 3–17 years) with ≥2 medical claims for headache. The primary outcome was CT scan utilization on or after first presentation with headache in a physician’s office or emergency department (ED). RESULTS: Of 15 836 patients, 26% (4034 patients; mean age: 11.8 years) had ≥1 CT scan, 74% within 1 month of index diagnosis. Patients with ED visits were 4 times more likely to undergo a CT scan versus those without ED visits (P < .001 [95% confidence interval: 3.9–4.8]). However, even outside the ED, use of CT scans remained widespread. Two-thirds of patients with CT scans had no ED use. Among patients with no ED utilization, >20% received a CT scan during the study period. Evaluation by a neurologist was strongly associated with a lower likelihood of CT scan compared with other provider specialties (odds ratio: 0.37; P < .01 [95% confidence interval: 0.30–0.46]). CONCLUSIONS: Use of CT scans to diagnose pediatric headache remains high despite existing guidelines, low diagnostic yield, and high potential risk. Implementing quality improvement initiatives to ensure that CT scans in children are performed only when truly indicated will reduce unnecessary exposure to ionizing radiation and associated cancer risks.

Objective To describe variability of pain intensity experienced by youths with juvenile idiopathic arthritis (JIA) and examine factors related to within-day patterns of pain and the relationship between magnitude of pain variability and quality of life. Methods Pain intensity was self-reported on a visual analog scale (VAS; range 0–100) by 112 youths with JIA ages 8–18 years using electronic diaries 3 times per day for 7 days. Average absolute change in pain (AAC) was computed as a measure of the magnitude of pain variability for each participant. Logistic regression was used to examine the relationship between demographic and disease characteristics and the probability of having high pain variability (AAC ≥10 VAS units). Linear regression was used to examine the relationship between quality of life (assessed by the Pediatric Quality of Life Inventory) and AAC. The generalized estimating equations approach was used to examine the relationship between the time of day and pain intensity. Results The mean ± SD AAC was 15.6 ± 10.5. The majority of youths (65%) had high AAC (≥10 VAS units). Disease severity predicted high pain variability (β = 0.02, P = 0.044). Higher AAC predicted lower quality of life (adjusted R2 = 0.194, β = −0.59, P = 0.003). Within-day patterns of pain intensity varied by JIA subtype and sex. Conclusion This study characterized the pain intensity variability experienced by youths with JIA. Pain variability throughout the day was common, varied by JIA subtype and sex, and was related to quality of life. These findings have implications for future pain research, patient education, and development of clinical interventions for this population.

ObjectiveTo describe probabilities and characteristics of disease flares in children with juvenile idiopathic arthritis (JIA) and to identify clinical features associated with an increased risk of flare.MethodsWe studied children in the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) prospective inception cohort. A flare was defined as a recurrence of disease manifestations after attaining inactive disease and was called significant if it required intensification of treatment. Probability of first flare was calculated with Kaplan–Meier methods, and associated features were identified using Cox regression.Results1146 children were followed up a median of 24 months after attaining inactive disease. We observed 627 first flares (54.7% of patients) with median active joint count of 1, physician global assessment (PGA) of 12 mm and duration of 27 weeks. Within a year after attaining inactive disease, the probability of flare was 42.5% (95% CI 39% to 46%) for any flare and 26.6% (24% to 30%) for a significant flare. Within a year after stopping treatment, it was 31.7% (28% to 36%) and 25.0% (21% to 29%), respectively. A maximum PGA >30 mm, maximum active joint count >4, rheumatoid factor (RF)-positive polyarthritis, antinuclear antibodies (ANA) and receiving disease-modifying antirheumatic drugs (DMARDs) or biological agents before attaining inactive disease were associated with increased risk of flare. Systemic JIA was associated with the lowest risk of flare.ConclusionsIn this real-practice JIA cohort, flares were frequent, usually involved a few swollen joints for an average of 6 months and 60% led to treatment intensification. Children with a severe disease course had an increased risk of flare.

Background: The efficacy and safety of novel oral anticoagulants (NOACs) as alternatives to warfarin therapy in nonvalvular atrial fibrillation (NVAF) patients have been studied in randomized trials. Given the increasing use of NOACs, additional data is required to assess the relative effectiveness and safety of anticoagulation with warfarin, dabigatran, apixaban, or rivaroxaban therapy in real-world settings in the United States (U.S). Methods: A retrospective cohort study design was used to analyze data from a U.S. commercial claims database of > 38 million members. Study population included new users of warfarin, dabigatran, apixaban, or rivaroxaban aged ≥ 18 years with ≥ 2 diagnoses of NVAF from November 2010 to February 2015. The primary effectiveness outcome was a composite of thromboembolic event or stroke; the primary safety outcome was major bleeding event requiring hospitalization. Cox proportional hazards models with inverse probability of treatment weighting (IPTW) were used to compare event rates between NOAC and warfarin users, and among NOAC users. Results: In the final NVAF cohort studied, there were 23,431 warfarin, 8,539 dabigatran, 3,689 apixaban, and 8,398 rivaroxaban users. A total of 7,022 primary outcome events and 3,264 safety events were identified. Warfarin users were older than dabigatran, apixaban, or rivaroxaban users (mean: 73 vs 66 vs 69 vs 67 years). After IPTW, all treatment groups were balanced on all baseline risk factors including stroke and bleeding risk. Compared to warfarin, NOAC users had fewer thromboembolic events or strokes: dabigatran (hazard ratio HR, 0.77 [95% CI: 0.72 - 0.82]), apixaban (HR, 0.73 [CI: 0.65 - 0.82]), and rivaroxaban (HR, 0.80 [CI: 0.75 - 0.86]). Additionally, dabigatran ([HR], 0.67 [CI: 0.60 - 0.76]), and apixaban users (HR, 0.52 [CI: 0.41 - 0.67) experienced fewer major bleeding events compared to warfarin users. No significant difference was found in major bleeding risk between rivaroxaban (HR, 1.00 [CI: 0.89 - 1.12]) and warfarin users. All three NOAC groups had similar risks for thromboembolic event or stroke: dabigatran vs rivaroxaban (HR, 0.96 [CI: 0.88 - 1.05]); apixaban vs rivaroxaban (HR, 0.91 [CI: 0.80 - 1.04]); dabigatran vs apixaban (HR, 1.05 [CI: 0.93 - 1.19]). However, compared to rivaroxaban users, major bleeding risk was 33% and 48% lower in dabigatran and apixaban users respectively (HR, 0.67[CI: 0.58 - 0.78]) and HR, 0.52 [CI: 0.40 - 0.68]). Conclusions: Our results demonstrated a lower risk of a thromboembolic event or stroke among dabigatran, apixaban, or rivaroxaban users compared to warfarin users. Among NOACs, risks of a thromboembolic event or stroke were similar. Further studies are needed to clarify the finding of a higher major bleeding risk in warfarin and rivaroxaban users.

To determine if vitamin D intake is associated with acute lower respiratory infections (ALRI) in children.The vitamin D intakes of children younger than 5 years of age admitted to hospital with either bronchiolitis or pneumonia were compared to an unmatched control group of the same age without respiratory infection. Caregivers of 197 children completed a questionnaire collecting information on demographic variables, ALRI risk factors and diet. Associations of ALRI with vitamin D intake and other ALRI risk factors were determined.The mean vitamin D intake of children with ALRI was 48 IU/kg/d compared to 60 IU/kg/d in the control group. When controlling for age, ethnicity, socio-economic status, northern residence, breastfeeding, immunizations and smoking contact, children with a vitamin D intake of less than 80 IU/kg/d were greater than 4 times more likely to have ALRI compared to children with a vitamin D intake exceeding 80 IU/kg/d (OR=4.9; 95%CI: 1.5-16.4).A higher vitamin D intake than currently recommended might be needed to offer protection against diseases such as ALRI. Increased vitamin D supplementation could have important public health consequences, as bronchiolitis and pneumonia are the most common reasons for hospitalization in young children. (Full English version will be available online at www.amepc.org/tp.).

Objective.To compare access to biologic therapies for children with juvenile idiopathic arthritis (JIA) across Canada, and to identify differences in provincial regulations and criteria for access.Methods.Between June and August 2010, we compiled the provincial guidelines for reimbursement of biologic drugs for children with JIA and conducted a multicenter Canada-wide survey of pediatric rheumatologists to determine their experience with accessing biologic therapies for their patients.Results.There were significant difficulties accessing biologic treatments other than etanercept and abatacept for children. There were large discrepancies in the access criteria and coverage of biologic agents across provinces, notably with age restrictions for younger children.Conclusion.Canadian children with JIA may not receive optimal internationally recognized “standard” care because pediatric coverage for biologic drugs through provincial formularies is limited and inconsistent across the country. There is urgent need for public policy to improve access to biologic therapies for these children to ensure optimal short-term and longterm health outcomes.

Objective.To present preliminary data on incidence of malignancy in juvenile idiopathic arthritis (JIA), compared to general population rates.Methods.We examined cancer occurrence within JIA registries at 3 Canadian pediatric rheumatology centers. The subjects in the clinic registries were linked to regional tumor registries to determine the occurrence of invasive cancers over the observation period (spanning 1974–2006). The total number of cancers expected was determined by multiplying the person-years in the cohort by age, sex, and calendar year-specific cancer rates. The standardized incidence ratio (SIR, ratio of cancers observed to expected) was generated, with 95% confidence intervals.Results.The study sample consisted of 1834 patients. The female proportion was 67.6%; average age at entry to cohort was 8.6 years (SD 5.1). The majority were Caucasian. Subjects contributed 22,341 patient-years (average 12.2, SD 7.8). Within this observation period, one invasive cancer occurred, compared to 7.9 expected (SIR 0.12, 95% CI 0.0, 0.70). This was a hematological cancer (Hodgkin’s lymphoma), representing a SIR for hematological malignancies of 0.76 (95% CI 0.02, 4.21).Conclusion.Only one invasive cancer was identified in this large sample of individuals with JIA, observed for an average of 12.2 years each. These data suggest that, at least in the initial years following diagnosis of JIA, the risk of invasive cancers overall is not markedly increased. The results do not rule out the possibility of a baseline increased risk of hematological malignancies.

Objective.To determine demographic and epidemiologic characteristics in children with unexplained joint pain.Methods.The study population included 730 children (< 18 yrs of age) referred between 1981 and 2007 to the Saskatchewan Pediatric Rheumatology Program, University of Saskatchewan, because of arthralgia. Parents and patients completed a questionnaire at the time of initial presentation, and a diagnosis of unexplained arthralgia was assigned based on clinical assessment. Serum vitamin D levels were measured in 73 patients diagnosed with arthralgia.Results.Subjects with arthralgia were more likely to report psychosocial stresses including family discord and illness in the family, and to be cared for by a single parent as a consequence of parental separation or death. Significantly more patients reported fall and winter (30%) as the season of symptom onset compared to spring or summer (20%; p = 0.01). Significantly more survey respondents in the arthralgia group reported missing school compared to the control group (62% vs 31%; p = 0.001). Referrals from northern Saskatchewan were significantly more numerous than from southern Saskatchewan (107 vs 45 per 100,000; p < 0.001). Serum vitamin D concentrations measured in a subgroup of patients (n = 73) showed that 62 (82%) were abnormally low, 42% between 50 and 75 nmol/l (insufficient), and 40% < 50 nmol/l (deficient).Conclusion.Our results suggest an association between psychosocial stress, school absenteeism, vitamin D insufficiency, and unexplained arthralgia in children.

This study compared 25-hydroxyvitamin D [25(OH)D] measurements in capillary and venous blood samples collected, respectively by fingerprick and venipuncture. Capillary blood for measuring 25(OH)D has potential advantages by reducing blood volume required (2mL versus 0.3mL for venipuncture and capillary sampling, respectively), facilitating blood collection for those populations in whom venipuncture is difficult (e.g. infants and children), improving patient convenience and reducing costs associated with phlebotomy. The results demonstrated a highly significant relationship between 25(OH)D levels in serum derived from venous and capillary blood samples (r(2)=0.901). Despite statistically higher 25(OH)D levels in fingerprick samples (108+/-9nmol/L) compared with venipuncture samples (90+/-7nmol/L), the correlation between venous and capillary samples provides support for this approach as a practical alternative to venipuncture for vitamin D determination. However, clinical application may require the incorporation of a correction factor for the assessment of insufficiency, and research studies should avoid using the two methods interchangeably. Studying vitamin D's role in health and disease requires collection techniques and measurement methods that are reliable, reproducible, easily accessible, inexpensive and minimally burdensome to the patient. The option to collect patient samples by fingerprick may facilitate the collection process.

The objective of this project was to develop and test a new technology for imaging growing joints by means of diffraction-enhanced imaging (DEI) combined with CT and using a synchrotron radiation source. DEI–CT images of an explanted 4-wk-old piglet stifle joint were acquired by using a 40-keV beam. The series of scanned slices was later ‘stitched’ together, forming a 3D dataset. High-resolution DEI-CT images demonstrated fine detail within all joint structures and tissues. Striking detail of vasculature traversing between bone and cartilage, a characteristic of growing but not mature joints, was demonstrated. This report documents for the first time that DEI combined with CT and a synchrotron radiation source can generate more detailed images of intact, growing joints than can currently available conventional imaging modalities.

Objective To examine demographic and disease-related variables that affect pain in a large cohort of patients with juvenile rheumatoid arthritis (JRA). Methods Selection criteria were an onset of JRA ≥5 years prior to study and age ≥8 years at the time of the study. Pain was measured by a self-administered 10-cm visual analog scale. Possible explanatory variables studied included age at study, sex, race, onset subtype, active disease duration, active joint count, and physician's global assessment (PGA). Results In a multiple regression model, active disease duration, PGA, and age at study were independent predictors explaining 22% of the variation in pain scores. Stratified analyses showed an effect of age in the 8–15-year group, but not in older patients. Conclusion Disease-related factors explain only a small proportion of the variation in pain scores. Age has an effect on pain scores only in younger patients. The role of other factors, including psychosocial factors, needs further study.

e18290 Background: We sought to describe outcomes following granulocyte-colony stimulating factor (G-CSF) prophylaxis in patients with lung cancer receiving chemotherapy regimens with low to intermediate risk for inducing neutropenia related hospitalization. Methods: We identified 11,233 lung cancer (all histologies) patients ≥ 18 years from 14 commercial US health plans. All patients received first cycle chemotherapy during 2008–2013. 5,423 patients received one of the 3 regimens: carboplatin and paclitaxel, cisplatin and etoposide, carboplatin and etoposide. Primary prophylaxis (PP) was defined as G-CSF administration within 5 days of chemotherapy. Outcome was neutropenia, fever, or infection-related hospitalization within 21 days. Regression and number-needed-to-treat (NNT) analyses were used. Results: A total of 11,233 patients received any chemotherapy (21.2% PP), were older (median years 64 PP; 64 no PP) and had at least 1 non-cancer comorbidity (79.8% PP; 77.9% no PP). About 2,776 patients received Carbo/Paclitaxel (13.9% PP), 1,356 patients received Cisp/Etop (23% PP) and 1,291 patients received Carbo/Etop (45.8% PP) regimens. PP was associated with lower risk of neutropenia related hospitalization for any chemotherapy (4.7% PP; 7.5% no PP; odds ratio [OR] 0.61; 95% CI 0.49 – 0.74), for Cisp/Etop (5.1% PP; 8.8% no PP; OR 0.56; 95% CI 0.32 – 0.97) and Carbo/Etop (5.6% PP; 11% no PP; OR 0.48; 95% CI 0.31 – 0.73), but not Carbo/Paclitaxel (5.7% PP; 6.7% no PP; OR 0.84; 95% CI 0.53 – 1.32) regimens. Based on NNT, the total cost of PP for 36 patients with any chemotherapy regimen to avoid one hospitalization would be $128,952 (mean hospitalization cost = $11,900, Standard Deviation [SD] = $9,541). For 28 patients with Cisp/Etop, it would be $101,920 (mean hospitalization cost = $16,957, SD = $16,135). For 19 patients with Carbo/Etop, it would be $63,270 (mean hospitalization cost = $11,356, SD = $6,949). Conclusions: Primary G-CSF prophylaxis was associated with some benefit in lowering neutropenia-related hospitalization in patients with lung cancer receiving Cisp/Etop and Carbo/Etop regimens, although the cost to treat patients remains high. Future studies need to examine the value of continued G-CSF use in subsequent cycles.

Objective.To describe the trajectories of longitudinal joint disease activity in juvenile idiopathic arthritis (JIA), and to examine associations of clinical and laboratory characteristics with the identified trajectories.Methods.A retrospective cohort study at 2 Canadian centers was performed. The longitudinal trajectories of active joint counts were described in a proof-of-concept study using a latent growth curve analysis. Baseline patient characteristics were compared across trajectory groups.Results.Data were analyzed on 659 children diagnosed with JIA between March 1980 and September 2009. The median age at diagnosis was 10.0 years (interquartile range 3.7–13.4) and 61% (402/659) were female. The International League of Associations for Rheumatology (ILAR) diagnoses were as follows: oligoarthritis (36%), enthesitis-related arthritis (20%), rheumatoid factor (RF)-negative polyarthritis (13%), undifferentiated arthritis (12%), psoriatic arthritis (8%), systemic arthritis (7%), and RF-positive polyarthritis (4%). Based on the trajectories of their active joint counts, the 659 patients were each classified in 1 of 5 latent classes (which can be described as high decreasing, moderate increasing, persistent moderate, persistent low, and minimal joint activity). These latent classes were clinically and statistically distinct from the ILAR categories.Conclusion.In this proof-of-concept study, in which we used an analytic methodology in a novel way, we identified 5 clinically and statistically distinct trajectories of disease course. The subsets of patients within each class were different from those described by the ILAR classification criteria. This successful application of this method supports its use in a chronic disease with a fluctuating course such as JIA. These methods should be expanded for the purposes of predictive modeling.

This prospective study investigated associations between cord blood vitamin D, risk factors for low vitamin D, and pregnancy and neonatal outcomes. The study included 65 maternal-fetal dyads delivering between December and February in Saskatoon, Saskatchewan. Eighty-five percent of mothers reported taking daily prenatal vitamin D but 70% of their newborns had insufficient or deficient cord blood vitamin D, suggesting that usual prenatal supplementation may be inadequate to achieve sufficient cord blood vitamin D in most newborns.

Objective To describe clinical outcomes of juvenile idiopathic arthritis (JIA) in a prospective inception cohort of children managed with contemporary treatments. Methods Children newly diagnosed with JIA at 16 Canadian paediatric rheumatology centres from 2005 to 2010 were included. Kaplan–Meier survival curves for each JIA category were used to estimate probability of ever attaining an active joint count of 0, inactive disease (no active joints, no extraarticular manifestations and a physician global assessment of disease activity 12 months after discontinuing treatment) and of receiving specific treatments. Results In a cohort of 1104 children, the probabilities of attaining an active joint count of 0 exceeded 78% within 2 years in all JIA categories. The probability of attaining inactive disease exceeded 70% within 2 years in all categories, except for RF-positive polyarthritis (48%). The probability of discontinuing treatment at least once was 67% within 5 years. The probability of attaining remission within 5 years was 46–57% across JIA categories except for polyarthritis (0% RF-positive, 14% RF-negative). Initial treatment included joint injections and non-steroidal anti-inflammatory drugs for oligoarthritis, disease-modifying antirheumatic drugs (DMARDs) for polyarthritis and systemic corticosteroids for systemic JIA. Conclusions Most children with JIA managed with contemporary treatments attain inactive disease within 2 years of diagnosis and many are able to discontinue treatment. The probability of attaining remission within 5 years of diagnosis is about 50%, except for children with polyarthritis.

Arthritis is among the most common chronic diseases in both children and adults. Although intraarticular inflammation is the feature common among all patients with chronic arthritis there are, in addition to age at onset, clinical characteristics that further distinguish the disease in pediatric and adult populations. In this study, we aimed to demonstrate the utility of microCT (µCT) and ultrasonography in characterizing pathologic age-related differences in a collagen-induced arthritis (CIA) rat model. Juvenile (35 d old) and young adult (91 d old) male Wistar rats were immunized with bovine type II collagen and incomplete Freund adjuvant to induce polyarthritis. Naïve male Wistar rats served as controls. All paws were scored on a scale of 0 (normal paw) to 4 (disuse of paw). Rats were euthanized at 14 d after the onset of arthritis and the hindpaws imaged by µCT and ultrasonography. Young adult rats had more severe signs of arthritis than did their juvenile counterparts. Imaging demonstrated that young adult CIA rats exhibited more widespread and severe skeletal lesions of the phalanges, metatarsals, and tarsal bones, whereas juvenile CIA rats had more localized and less proliferative and osteolytic damage that was confined predominantly to the phalanges and metatarsals. This report demonstrates the utility of imaging modalities to compare juvenile and young adult rats with CIA and provides evidence that disease characteristics and progression differ between the 2 age groups. Our observations indicate that the CIA model could help discern age-related pathologic processes in inflammatory joint diseases.