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Gene expression-based signatures help identify pathways relevant to diseases and treatments, but are challenging to construct when there is a diversity of disease mechanisms and treatments in patients with complex diseases. To overcome this challenge, we present a new application of an in silico gene expression deconvolution method, ISOpure-S1, and apply it to identify a common gene expression signature corresponding to response to treatment in 33 juvenile idiopathic arthritis (JIA) patients. Using pre- and post-treatment gene expression profiles only, we found a gene expression signature that significantly correlated with a reduction in the number of joints with active arthritis, a measure of clinical outcome (Spearman rho = 0.44, p = 0.040, Bonferroni correction). This signature may be associated with a decrease in T-cells, monocytes, neutrophils and platelets. The products of most differentially expressed genes include known biomarkers for JIA such as major histocompatibility complexes and interleukins, as well as novel biomarkers including α-defensins. This method is readily applicable to expression datasets of other complex diseases to uncover shared mechanistic patterns in heterogeneous samples.

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

BackgroundJuvenile idiopathic arthritis (JIA) is a serious and potentially debilitating pediatric illness. Improved disease self-management may help to improve health outcomes. ObjectiveThis 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. MethodsAdolescents 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. ResultsIn 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. ConclusionsThe 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 RegistrationClinicalTrials.gov NCT01572896; https://clinicaltrials.gov/ct2/show/NCT01572896

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 X.sup.2 test) and reproducible through external data set validation on a 119-patient, prospectively collected independent validation cohort (reconstruction accuracy Q.sup.2 = 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 ([greater than or equal to]90%; 359 patients), partially localized (60%-90%; 124), or extended ( We modelled time to zero joints in the discovery cohort using a multivariate Cox proportional hazards model considering joint pattern, degree of localization, and ILAR subtype. Despite receiving more intense treatment, 50% of nonlocalized patients had zero joints at one year compared to six months for localized patients. Overall, localized patients required less time to reach zero joints (partial: P = 0.0018 versus localized by log-rank test; extended: P = 0.0057). Potential limitations include the requirement for patients to be treatment naïve (except NSAIDs), which may skew the patient cohorts towards milder disease, and the validation cohort size precluded multivariate analyses of disease trajectories. Conclusions Multilayer NMF identified patterns of joint involvement that predicted disease trajectory in children with arthritis. Our hierarchical unsupervised approach identified a new clinical feature, degree of localization, which predicted outcomes in both cohorts. Detailed assessment of every joint is already part of every musculoskeletal exam for children with arthritis. Our study supports both the continued collection of detailed joint involvement and the inclusion of patterns and degrees of localization to stratify patients and inform treatment decisions. This will advance pediatric rheumatology from counting joints to realizing the potential of using data available from uncovering patterns of joint involvement., Author(s): Simon W. M. Eng 1,2,3, Florence A. Aeschlimann 1, Mira van Veenendaal 1, Roberta A. Berard 4,5,6, Alan M. Rosenberg 7, Quaid Morris 3,7,8,9,10,11,*, Rae S. M. Yeung 1,2,4,*, [...]

Abstract A child with isolated Mycobacterium tuberculosis monoarthritis, with features initially suggesting oligoarthritis subtype of juvenile idiopathic arthritis, is presented. This patient illustrates the need to consider the possibility of tuberculosis as the cause of oligoarthritis in high-risk pediatric populations even in the absence of a tuberculosis contact history and without evidence of overt pulmonary disease.

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: To estimate the impact of enthesitis on patient-reported outcomes in children with juvenile idiopathic arthritis (JIA), irrespective of JIA category.Methods: Children enrolled in the Research in Arthritis in Canadian Children Emphasizing Outcomes cohort were studied. Entheseal tenderness by physician examination in 33 defined locations, Juvenile Arthritis Quality of Life Questionnaire (JAQQ), Quality of My Life (QoML) Questionnaire, Childhood Health Assessment Questionnaire (C-HAQ), and a pain visual analog scale were completed at enrollment, every 6 months for 2 years, and then yearly up to 5 years. Analyses consisted of descriptive statistics, linear mixed models for longitudinal data, and analysis of covariance.Results: Among 1,371 patients followed for a median of 35.3 months (interquartile range 22.1, 49.2), 214 (16%) had enthesitis, of whom 137 (64%) were classified as having enthesitis-related arthritis. After adjusting for JIA category and covariates, children with enthesitis reported higher JAQQ (mean raw score 2.71 versus 2.16, adjusted difference 0.41 points; 95% confidence interval [95% CI] 0.22, 0.59), higher C-HAQ (0.47 versus 0.31, adjusted difference 0.14 points; 95% CI 0.07, 0.22), higher pain (3.01 versus 1.68, adjusted difference 0.94 points; 95% CI 0.64, 1.25), and lower QoML (7.02 versus 8.23, adjusted difference -0.80 points; 95% CI -1.09, -0.51) scores than children without enthesitis. These differences persisted up to 5 years.Conclusion: Children with enthesitis, regardless of JIA category, report worse patient-reported outcomes than those without enthesitis. Thus, enthesitis should be assessed in all 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]

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

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. [ABSTRACT FROM AUTHOR]