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Abstract Introduction The aim of this study was to assess cancer incidence in childhood-onset systemic lupus erythematosus (SLE). Methods We ascertained cancers within SLE registries at 10 pediatric centers. Subjects were linked to cancer registries for the observational interval, spanning 1974 to 2009. The ratio of observed to expected cancers represents the standardized incidence ratio (SIR) or relative cancer risk in childhood-onset SLE, versus the general population. Results There were 1020 patients aged

INTRODUCTION: The aim of this study was to assess cancer incidence in childhood-onset systemic lupus erythematosus (SLE). METHODS: We ascertained cancers within SLE registries at 10 pediatric centers. Subjects were linked to cancer registries for the observational interval, spanning 1974 to 2009. The ratio of observed to expected cancers represents the standardized incidence ratio (SIR) or relative cancer risk in childhood-onset SLE, versus the general population. RESULTS: There were 1020 patients aged

Objectives To (i) validate the JIA parent global assessment (parent global) as a health-related quality of life (HRQoL) instrument; (ii) evaluate measurement properties of accepted HRQoL measures relative to those of the parent global; and (iii) assess causal pathways determining parent global scores. Methods Data from the Research in Arthritis in Canadian Children emphasizing outcomes (ReACCh-Out) cohort were used. Measurement properties were assessed in 344 patients at enrolment and 6 months later. Causal pathways were tested by structural equation modelling to understand root causes and mediators leading to parent global scores. Results Construct validity was supported by Spearman correlations of 0.53–0.70 for the parent global with the Juvenile Arthritis Quality of Life Questionnaire, Quality of My Life health scale (HRQoML), Pediatric Quality of Life Inventory (PedsQL)-Parent, and Child Health Questionnaire (CHQ)-Physical. Exceptions were PedsQL-Child (0.44) and CHQ-Psychosocial (0.31). Correlations were lower (0.14–0.49) with disease activity measures (physician global assessment of disease activity, active joint count, ESR). Responsiveness of the parent global to improvement according to parent ratings (0.51) was acceptable and within the range (0.32–0.71) of that of other measures. Reliability estimates and measurement errors for all measures were unsatisfactory, likely due to the prolonged time between assessments. Causal pathways for the parent global matched those previously reported for HRQoML. Conclusions Our results offer support for the parent global as a valid measure of HRQoL for JIA. If confirmed, existing studies using the parent global may be re-interpreted, enhancing our knowledge of HRQoL in children with JIA. [ABSTRACT FROM AUTHOR]

Objective: The aim of the Paediatric Rheumatology International Trials Organisation (PRINTO) juvenile idiopathic arthritis (JIA) classification criteria, which is still in development, is to identify homogeneous groups of JIA patients. This study was undertaken to compare International League of Associations for Rheumatology (ILAR) JIA classification criteria and PRINTO JIA classification criteria using data from the ReACCh‐Out (Research in Arthritis in Canadian Children, Emphasizing Outcomes) cohort. Methods: We used clinicobiologic data recorded within 7 months of diagnosis to assign a diagnosis of JIA and identify subcategories of JIA among 1,228 patients according to the 2 JIA classification systems. We compared the proportions of patients classified and the alignment of classification categories with clinicobiologic subtypes and adult arthritis types. Results: The PRINTO criteria classified 244 patients (19.9%) as having early‐onset antinuclear antibody–positive JIA, 157 (12.8%) as having enthesitis/spondylitis–related JIA, 38 (3.1%) as having systemic JIA, and 10 (0.8%) as having rheumatoid factor–positive JIA. A total of 12% of patients were unclassifiable using the ILAR criteria, while 63.3% were unclassifiable using the PRINTO criteria (777 with other JIA and 2 with unclassified JIA). In sensitivity analyses, >50% of patients remained unclassifiable using the PRINTO criteria. Compared to the PRINTO criteria, ILAR JIA categories aligned better with clinicobiologic subtypes in 131 patients (χ2 = 44, P = 0.005, versus χ2 = 15, P = 0.07 for PRINTO), and ILAR categories aligned better with adult types of arthritis in 389 evaluable patients. Conclusion: Currently identified PRINTO disorders can only be used to classify a minority of JIA patients, leaving a large proportion of JIA patients with other disorders requiring further characterization. Current PRINTO JIA classification criteria do not align better with clinicobiologic subtypes or adult forms of arthritis compared with the older ILAR classification system. [ABSTRACT FROM AUTHOR]

Objective Structural equation modelling was applied to data from the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) cohort to help elucidate causal pathways to decreased health-related quality of life (HRQoL) in children with JIA. Methods Based on published literature and clinical plausibility, a priori models were constructed with explicit root causes (disease activity, treatment intensity) and mediators (pain, disease symptoms, functional impairments) leading to HRQoL [measured by the Quality of my Life (QoML) scale and the Juvenile Arthritis Quality of Life Questionnaire (JAQQ)] at five disease stages: (i) diagnosis, (ii) 3–9 months after diagnosis, (iii) flare, (iv) remission on medications, (v) remission off medications. Following structural equation modelling, a posteriori models were selected based on data fit and clinical plausibility. Results We included 561, 887, 137, 186 and 182 patients at each stage, respectively. In a posteriori models for active disease stages, paths from disease activity led through pain, functional impairments, and disease symptoms, directly or through restrictions in participation, to decreased QoML scores. Treatment intensity had detrimental effects through psychosocial domains; while treatment side effects had a lesser role. Pathways were similar for QoML and JAQQ, but JAQQ models provided greater specificity. Models for remission stages were not supported by the data. Conclusion Our findings support disease activity and treatment intensity as being root causes of decreased HRQoL in children with JIA, with pain, functional impairments, and participation restrictions being mediators for disease activity; they support psychosocial effects and side effects as being mediators for treatment intensity. [ABSTRACT FROM AUTHOR]

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 <5 joints were involved, with a 54.4% success rate (95% confidence interval [95% CI] 50.3-58.6). NSAIDs plus joint injections had a 64.7% success rate (95% CI 59.8-69.7). Adding methotrexate to NSAIDs and/or joint injections (attempted 566 times) had a 60.5% success rate (95% CI 55.7-65.3). In adjusted analyses, each additional active joint reduced chances of success for treatment with NSAIDs (odds ratio [OR] 0.90 [95% CI 0.85-0.94]) and for methotrexate combinations (OR 0.96 [95% CI 0.94-0.99]). Each additional year after disease onset reduced chances of success for treatment with methotrexate combinations (OR 0.83 [95% CI 0.72-0.95]).Conclusion: These real-world effectiveness estimates show that conventional nonbiologic treatment strategies that are recommended in current guidelines are effective in achieving treatment targets in many children with JIA. [ABSTRACT FROM AUTHOR]

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

ABSTRACT Vertebral fractures are an important yet underrecognized manifestation of osteoporosis in children with chronic, glucocorticoid-treated illnesses. Our goal was to determine the incidence and clinical predictors of vertebral fractures in the 3 years following glucocorticoid initiation among pediatric patients with rheumatic disorders. Incident vertebral fractures were evaluated according to the Genant semiquantitative method on lateral radiographs at baseline and then annually in the 3 years following glucocorticoid initiation. Extended Cox models were used to assess the association between vertebral fractures and clinical risk predictors. A total of 134 children with rheumatic disorders were enrolled in the study (mean ± standard deviation (SD) age 9.9 ± 4.4 years; 65% girls). The unadjusted vertebral fracture incidence rate was 4.4 per 100 person-years, with a 3-year incidence proportion of 12.4%. The highest annual incidence occurred in the first year (6.0%; 95% confidence interval (CI) 2.9% to 11.7%). Almost one-half of the patients with fractures were asymptomatic. Every 0.5 mg/kg increase in average daily glucocorticoid (prednisone equivalents) dose was associated with a twofold increased fracture risk (hazard ratio (HR) 2.0; 95% CI 1.1 to 3.5). Other predictors of increased vertebral fracture risk included: (1) increases in disease severity scores between baseline and 12 months; (2) increases in body mass index Z-scores in the first 6 months of each 12-month period preceding the annual fracture assessment; and (3) decreases in lumbar spine bone mineral density Z-scores in the first 6 months of glucocorticoid therapy. As such, we observed that a clinically significant number of children with rheumatic disorders developed incident vertebral fractures in the 3 years following glucocorticoid initiation. Almost one-half of the children were asymptomatic and thereby would have been undiagnosed in the absence of radiographic monitoring. In addition, discrete clinical predictors of incident vertebral fractures were evident early in the course of glucocorticoid therapy. © 2015 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Objective To determine the frequency of incident vertebral fractures (IVF) 12 months after glucocorticoid (GC) initiation in children with rheumatic diseases and to identify children at higher risk. Methods Children with rheumatic diseases initiating GC were enrolled in a prospective observational study. Annual spine radiographs were evaluated using the Genant semiquantitative method. Spine areal bone mineral density (aBMD) was measured every 6 months. Clinical features, including cumulative GC dose, back pain, disease and physical activity, calcium and vitamin D intake, and spine aBMD Z scores, were analyzed for association with IVF. Results Seven (6%) of 118 children (95% confidence interval 2.9-11.7%) had IVF. Their diagnoses were: juvenile dermatomyositis (n = 2), systemic lupus erythematosus (n = 3), systemic vasculitis (n = 1), and mixed connective tissue disease (n = 1). One child was omitted from the analyses after 4 months because of osteoporosis treatment for symptomatic IVF. Children with IVF received on average 50% more GC than those without ( P = 0.030), had a greater increase in body mass index (BMI) at 6 months ( P = 0.010), and had greater decrements in spine aBMD Z scores in the first 6 months ( P = 0.048). Four (67%) of 6 children with IVF and data to 12 months had spine aBMD Z scores less than −2.0 at 12 months compared to 16% of children without IVF ( P = 0.011). Conclusion The incidence of VF 12 months following GC initiation was 6%; most children were asymptomatic. Children with IVF received more GC, had greater increases in BMI, and had greater declines in spine aBMD Z scores in the first 6 months. [ABSTRACT FROM AUTHOR]

Background/Purpose: Previous studies of uveitis in Juvenile Idiopathic Arthritis (JIA) patients have reported prevalence and not incidence. The ReACCh Out cohort, a large inception cohort of newly diagnosed JIA patients provided the opportunity to prospectively ascertain the true incidence of new onset uveitis. The objectives of this study were to determine the overall incidence rate and its trajectory over time. Methods: ReACCh Out recruited newly diagnosed JIA patients between January 2005 and December 2010, from 16 Canadian centres across the country. Prospective data was collected every 6 months for the first 2 years, then yearly. Data was collected on numerous clinical and laboratory measures including the diagnosis of uveitis and its complications, determined by an ophthalmologist. A Poisson model was used to estimate the overall incidence rate. A Kaplan-Meier plot was used to evaluate the time from diagnosis of JIA to the time of diagnosis of new onset uveitis. Results: 1104 patients with newly diagnosed (≤6 months) JIA with ≥1 follow-up visit were reviewed. Patients were predominantly female (63%), age at diagnosis was 9.3 (3.9, 13.0) years. Time from diagnosis to enrollment was 0.3 (0, 1.6) months. Follow-up to last visit or study end was 34.2 (21.5, 48) months. 23 patients whose uveitis status was not available, were excluded. 77 patients with new onset uveitis were identified during the study period. The overall incidence rate of new cases of uveitis following the diagnosis of JIA was 2.9% per year (95% confidence interval 2.3-3.6). Following the trajectory of new cases of uveitis over time, the incidence of new cases showed a slow decline over time (Figure ). Importantly, new cases of uveitis occurred as far out from diagnosis as the end of the study period. Kaplan-Meier plots were also used to evaluate age at diagnosis of new onset uveitis and gender. Results support previously identified risk factors for uveitis including younger age (<5 years) and female gender. The frequency of uveitis occurred in the JIA patients in the following distribution according to subtype: oligoarthritis (43, 56%), polyarthritis RF negative (18, 23%), polyarthritis RF positive (1, 1%), psoriatic (4, 5%), ERA (1, 1%), systemic (1, 1%) and undifferentiated (9, 12%). [ABSTRACT FROM AUTHOR]

Background/Purpose: Although children with JIA have lower fitness levels than healthy peers, little is known about their level of habitual physical activity. The LEAP study is a prospective longitudinal multicentre study of children and teens with JIA, aimed at describing the trajectory of physical activity (PA) in JIA, and its relationship to disease factors, inflammation, quality of life, bone health and muscle function. We report PA levels of children with JIA in early and late disease at study entry. Methods: We enrolled patients with JIA (aged 8-16 y) at 12 pediatric rheumatology centres in Canada as either an inception cohort (early disease; within 6 mos of diagnosis) or an established disease cohort (late disease; > 2yr after diagnosis). We assessed PA with a validated Physical Activity Questionnaire for children (PAQ-C, age 8-13 y) or teens (PAQ-A, age 14-16 y). This 7-day recall self-report tool has scores from 0 (no PA)- 5(high PA). Participants record weekly PA across a wide range of activities and sports. Patients completed a pain scale (VAS 0-100), the Childhood Health Assessment Questionnaire (CHAQ), and Juvenile Arthritis Quality of life Questionnaire (JAQQ). Examining physicians recorded physician global assessment of disease activity (PGA;VAS 0-100) and active joint count. We used univariate and multivariate regression (controlled for gender) to examine relationships between disease and patient factors and PAQ score at study entry. We used PAQ standard population normative values to compare to subjects (female 2.69, SD 0.62; male 3.0 SD 0.72). Results: We included the first 189 patients enrolled (126 F, 63 M, med age 13 y) from March 2012-November 2013. The early cohort included 81 patients (enrolled median 2.4 mo after diagnosis) and the late cohort included 108 patients (enrolled median 4.8 yr after diagnosis). Active arthritis was found in 88 patients, with a mean of 5.5 active joints (range 1-56). PGA was a mean of 13.45 (range 0-74). Overall mean PAQ score for the JIA patients was 2.55 (SD 0.73, range 1-4). Table describes PAQ scores by sex, disease cohort, and presence of active arthritis. When controlled for sex, PAQ scores were significantly different between new onset and late disease, and between patients with active arthritis compared with no active arthritis. Univariate analyses revealed that higher PAQ score were associated with lower pain (p = 0.02), lower CHAQ score (p < 0.0001), higher JAQQ score (p = 0.0001), lower active joints (p = 0.002) and low PGA (p = 0.003). Multivariate analysis confirmed these associations, with R2 = 0.25, p = 0.000 (girls), R2 = 0.17, p = 0.01 (boys). [ABSTRACT FROM AUTHOR]

Background/Purpose: According to the ILAR criteria, undifferentiated juvenile idiopathic arthritis (U-JIA) includes children who fail to meet criteria for 1 of the other 6 categories or who meet criteria in more than 1 category. Classification requires category-specific application of 5 exclusion criteria: 1. Psoriasis in the patient or a 1st degree relative; 2. Arthritis beginning after the 6th birthday in an HLA-B27 + male; 3. HLAB27 associated disease in a 1st degree relative; 4. Rheumatoid factor positivity (RF+) on 2 occasions; and 5. The presence of systemic JIA (SoJIA). A pilot single-centre study (n=21) revealed that psoriasis in a 1st degree relative was the most common reason for classifying patients as U-JIA; disregarding this criterion would allow re-classification of most U-JIA patients and had no impact on the classification of JPsA patients (Chan et al., 2011). We aimed to determine the most frequent reasons for classifying children as U-JIA from a large multicenter prospective cohort of children with JIA (n=1104). Methods: Two investigators reviewed data on patients diagnosed with UJIA extracted from the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) database. They identified by consensus the reasons for classifying patients as U-JIA and the JIA category they would fall in if the following two changes were made: disregarding psoriasis in a 1st degree relative, considering patients as RF negative when only a single positive RF test was recorded. Results: 84 patients (51 female), were classified as U-JIA for the reasons shown in the . [ABSTRACT FROM AUTHOR]

Background: Physical activity (PA) patterns in children with juvenile idiopathic arthritis (JIA) over time are not well described. The aim of this study was to describe associations of physical activity (PA) with disease activity, function, pain, and psychosocial stress in the 2 years following diagnosis in an inception cohort of children with juvenile idiopathic arthritis (JIA)., Methods: In 82 children with newly diagnosed JIA, PA levels, prospectively determined at enrollment, 12 and 24 months using the Physical Activity Questionnaire for Children (PAQ-C) and Adolescents (PAQ-A) raw scores, were evaluated in relation to disease activity as reflected by arthritis activity (Juvenile Arthritis Disease Activity Score (JADAS-71)), function, pain, and psychosocial stresses using a linear mixed model approach. Results in the JIA cohort were compared to normative Pediatric Bone Mineral Accrual Study data derived from healthy children using z-scores., Results: At enrollment, PA z-score levels of study participants were lower than those in the normative population (median z-score - 0.356; p = 0.005). At enrollment, PA raw scores were negatively associated with the psychosocial domain of the Juvenile Arthritis Quality of Life Questionnaire (r = - 0.251; p = 0.023). There was a significant decline in PAQ-C/A raw scores from baseline (median and IQR: 2.6, 1.4-3.1) to 24 months (median and IQR: 2.1, 1.4-2.7; p = 0.003). The linear mixed-effect model showed that PAQ-C/A raw scores in children with JIA decreased as age, disease duration, and ESR increased. The PAQ-C/A raw scores of the participants was also negatively influenced by an increase in disease activity as measured by the JADAS-71 (p <  0.001)., Conclusion: Canadian children with newly diagnosed JIA have lower PA levels than healthy children. The decline in PA levels over time was associated with disease activity and higher disease-specific psychosocial stress.

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., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To describe changes in health-related quality of life (HRQoL) over time in children with juvenile idiopathic arthritis (JIA), relative to other outcomes, and to identify predictors of unfavorable HRQoL trajectories., Methods: Children with JIA in the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) cohort were included. The Juvenile Arthritis Quality of Life Questionnaire (JAQQ, a standardized instrument), health-related Quality of My Life (HRQoML, an instrument based on personal valuations), and JIA core variables were completed serially. Analyses included median values, Kaplan-Meier survival curves, and latent trajectory analysis., Results: A total of 1,249 patients enrolled at a median of 0.5 months after diagnosis were followed for a median of 34.2 months. The degree of initial HRQoL impairment and probabilities of reaching the best possible HRQoL scores varied across JIA categories (best for oligoarthritis, worst for rheumatoid factor-positive polyarthritis). Median times to attain best possible HRQoL scores (JAQQ 59.3 months, HRQoML 34.5 months), lagged behind those for disease activity, pain, and disability measures. Most patients followed trajectories with minimal or mild impairment; however, 7.6% and 13.8% of patients, respectively, followed JAQQ and HRQoML trajectories with persistent major impairment in HRQoL. JIA category, aboriginal ethnicity, and baseline disease activity measures distinguished between membership in trajectories with major and minimal impairments., Conclusion: Improvement in HRQoL is slower than for disease activity, pain, and disability. Improvement of a measure based on respondents' preferences (HRQoML) is more rapid than that of a standardized measure (JAQQ). Higher disease activity at diagnosis heralds an unfavorable HRQoL trajectory., (© 2017, American College of Rheumatology.)