Publications by authors named "Alan M Rosenberg"

55 Publications

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

J Rheumatol 2020 Oct 15. Epub 2020 Oct 15.

The BBOP Study was supported by The Canadian Institutes of Health Research (FRN #82517); The Arthritis Society (Canada), Canadian Arthritis Network (SRI-IJD-01); University of Saskatchewan; The Clinical Research Centre of the Centre Hospitalier Universitaire de Sherbrooke; University of British Columbia; McGill University; Memorial University; Manitoba Institute of Child Health; Children's Health Research Trust Fund; Jim Pattison Children's Hospital Foundation of Saskatchewan; The Pediatric Rheumatic Disease Research and Innovation Laboratory, University of Saskatchewan; The Haslam Research Fund, University of Saskatchewan; and The Kleiman Fund, University of Saskatchewan. E. Rezaei, MD, PhD, A.M. Rosenberg, MD, Departments of Pediatrics, University of Saskatchewan, Saskatoon, Saskatchewan; M.M. Newkirk, PhD, Department of Medicine, McGill University Health Center, Montreal, Quebec; Z. Li, MSc, RC-CHUM, University of Montreal, Montreal, Quebec; J.R. Gordon, PhD, Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan; K.G. Oen, MD, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba; S.M. Benseler, MD, PhD, Department of Pediatrics, Alberta Children's Hospital, University of Calgary, Calgary, Alberta; G. Boire, MD, Département de Médecine, Université de Sherbrooke, Sherbrooke, Quebec; D.A. Cabral, MD, K. Houghton, MD, K.A. Morishita, MD, R.E. Petty, MD, PhD, L.B. Tucker, MD, S.E. Turvey, MD, Department of Pediatrics, British Columbia Children's Hospital, Vancouver, British Columbia; S. Campillo, MD, G. Chédeville, MD, R. Scuccimarri, MD, Department of Pediatrics, McGill University Health Center, Montreal, Quebec; A.L. Chetaille, MD, Département de Médecine le Centre Hospitalier Universitaire de Quebec, Quebec City, Quebec; P. Dancey, MD, Department of Pediatrics, Janeway Children's Health and Rehabilitation Centre, St. John's, Newfoundland; C. Duffy, MD, R. Jurencak, MD, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario; K. Watanabe Duffy, MD, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario; A.M. Huber, MD, B. Lang, MD, S.E. Ramsey, MD, E. Stringer, MD, Department of Pediatrics, IWK Health Centre and Dalhousie University, Halifax, Nova Scotia; J. Roth, MD, Department of Pediatrics, Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario; R. Schneider, MD, L. Spiegel, MD, S.M. Tse, MD, R.S. Yeung, MD, PhD, Department of Paediatrics, University of Toronto and the Hospital for Sick Children, Toronto, Ontario, Canada. The authors declare no conflict of interest. Address correspondence to Dr. A.M. Rosenberg, Department of Pediatrics, Royal University Hospital, 103 Hospital Drive, Saskatoon, SK S7N 0W8, Canada. Email: Accepted for publication October 2, 2020.

Objective: This study aimed to expand knowledge about soluble low-density lipoprotein receptor-related protein 1 (sLRP1) in juvenile idiopathic arthritis ( JIA) by determining associations of sLRP1 levels in nonsystemic JIA patients with clinical and inflammatory biomarker indicators of disease activity.

Methods: Plasma sLRP1 and 44 inflammation-related biomarkers were measured at enrollment and 6 months later in a cohort of 96 newly diagnosed Canadian patients with nonsystemic JIA. Relationships between sLRP1 levels and indicators of disease activity and biomarker levels were analyzed at both visits.

Results: At enrollment, sLRP1 levels correlated negatively with age and active joint counts. Children showed significantly higher levels of sLRP1 than adolescents (mean ranks: 55.4 and 41.9, respectively; = 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; = 0.006). At enrollment, considering the entire cohort, sLRP1 correlated negatively with the number of active joints (r = -0.235, = 0.017). In the entire cohort, sLRP1 levels at enrollment and 6 months later correlated with 13 and 6 pro- and antiinflammatory biomarkers, respectively. In JIA categories, sLRP1 correlations with inflammatory markers were significant in rheumatoid factor-negative polyarticular JIA, oligoarticular JIA, enthesitis-related arthritis, and psoriatic arthritis at enrollment. Higher sLRP1 levels at enrollment increased the likelihood of absence of active joints 6 months later.

Conclusion: Plasma sLRP1 levels correlate with clinical and biomarker indicators of short-term improvement in JIA disease activity, supporting sLRP1 as an upstream biomarker of potential utility for assessing JIA disease activity and outcome prediction.
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http://dx.doi.org/10.3899/jrheum.200391DOI Listing
October 2020

Teens Taking Charge: A Randomized Controlled Trial of a Web-Based Self-Management Program With Telephone Support for Adolescents With Juvenile Idiopathic Arthritis.

J Med Internet Res 2020 07 29;22(7):e16234. Epub 2020 Jul 29.

Institute for Clinical Evaluative Sciences, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.2196/16234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424488PMC
July 2020

Associations of clinical and inflammatory biomarker clusters with juvenile idiopathic arthritis categories.

Rheumatology (Oxford) 2020 05;59(5):1066-1075

Department of Pediatrics, University of Saskatchewan, Saskatoon, Canada.

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.
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http://dx.doi.org/10.1093/rheumatology/kez382DOI Listing
May 2020

Clinical and associated inflammatory biomarker features predictive of short-term outcomes in non-systemic juvenile idiopathic arthritis.

Rheumatology (Oxford) 2020 09;59(9):2402-2411

Department of PediatricsUniversity of Saskatchewan, Saskatoon, SK, Canada.

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.
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http://dx.doi.org/10.1093/rheumatology/kez615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449798PMC
September 2020

Measuring consistency among gene set analysis methods: A systematic study.

J Bioinform Comput Biol 2019 10;17(5):1940010

Department of Computer Science, University of Saskatchewan, 110 Science Place, Saskatoon SK S7N 5C9, Canada.

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.
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http://dx.doi.org/10.1142/S0219720019400109DOI Listing
October 2019

Do we need a new classification of juvenile idiopathic arthritis?

Authors:
Alan M Rosenberg

Clin Immunol 2020 02 6;211:108298. Epub 2019 Nov 6.

Department of Pediatrics, Division of Rheumatology, University of Saskatchewan, 103 Hospital Drive, Saskatoon, Saskatchewan S7N 0W8, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.clim.2019.108298DOI Listing
February 2020

Real-World Effectiveness of Common Treatment Strategies for Juvenile Idiopathic Arthritis: Results From a Canadian Cohort.

Arthritis Care Res (Hoboken) 2020 07 5;72(7):897-906. Epub 2020 Jun 5.

British Columbia Children's Hospital and University of British Columbia, Vancouver, British Columbia, Canada.

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.
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http://dx.doi.org/10.1002/acr.23922DOI Listing
July 2020

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

Arthritis Rheumatol 2019 10 26;71(10):1747-1755. Epub 2019 Aug 26.

University of British Columbia and BC Children's Hospital, Vancouver, British Columbia, Canada.

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.
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http://dx.doi.org/10.1002/art.40913DOI Listing
October 2019

Patterns of joint involvement in juvenile idiopathic arthritis and prediction of disease course: A prospective study with multilayer non-negative matrix factorization.

PLoS Med 2019 02 26;16(2):e1002750. Epub 2019 Feb 26.

Division of Rheumatology, Department of Paediatrics, The Hospital for Sick Children (SickKids), Toronto, Ontario, Canada.

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 (<60%; 157). Localized patients more often maintained their baseline patterns (P < 0.05 for five groups by permutation test) than nonlocalized patients (P < 0.05 for three groups by permutation test) over a five-year follow-up period. 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.
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http://dx.doi.org/10.1371/journal.pmed.1002750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390994PMC
February 2019

Worse Quality of Life, Function, and Pain in Children With Enthesitis, Irrespective of Their Juvenile Arthritis Category.

Arthritis Care Res (Hoboken) 2020 03;72(3):441-446

University of Alberta, Edmonton, Alberta, Canada.

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.
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http://dx.doi.org/10.1002/acr.23844DOI Listing
March 2020

Predicting Which Children with Juvenile Idiopathic Arthritis Will Not Attain Early Remission with Conventional Treatment: Results from the ReACCh-Out Cohort.

J Rheumatol 2019 06 15;46(6):628-635. Epub 2019 Jan 15.

From the British Columbia Children's Hospital and the University of British Columbia, Vancouver; Simon Fraser University, Burnaby, British Columbia; London Health Sciences Centre and Western University, London; Children's Hospital of Eastern Ontario and University of Ottawa, Ottawa, Ontario; IWK Health Centre and Dalhousie University, Halifax, Nova Scotia; Winnipeg Children's Hospital and University of Manitoba, Winnipeg, Manitoba; Hospital for Sick Children and University of Toronto, Toronto, Ontario; McGill University Health Centre and McGill University, Montreal, Quebec; Janeway Children's Health and Rehabilitation Centre and Memorial University, Saint John's, Newfoundland and Labrador; Royal University Hospital and University of Saskatchewan, Saskatoon, Saskatchewan; Centre Hospitalier Universitaire Sainte-Justine and Université de Montréal, Montreal; Centre Hospitalier Universitaire de Sherbrooke and Université de Sherbrooke, Sherbrooke, Quebec; Alberta Children's Hospital and University of Calgary, Alberta, Canada; Shands Children's Hospital and University of Florida, Gainesville, Florida, USA.

Objective: To estimate the probability of early remission with conventional treatment for each child with juvenile idiopathic arthritis (JIA). Children with a low chance of remission may be candidates for initial treatment with biologics or triple disease-modifying antirheumatic drugs (DMARD).

Methods: We used data from 1074 subjects in the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) cohort. The predicted outcome was clinically inactive disease for ≥ 6 months starting within 1 year of JIA diagnosis in patients who did not receive early biologic agents or triple DMARD. Models were developed in 200 random splits of 75% of the cohort and tested on the remaining 25% of subjects, calculating expected and observed frequencies of remission and c-index values.

Results: Our best Cox logistic model combining 18 clinical variables a median of 2 days after diagnosis had a c-index of 0.69 (95% CI 0.67-0.71), better than using JIA category alone (0.59, 95% CI 0.56-0.63). Children in the lowest probability decile had a 20% chance of remission and 21% attained remission; children in the highest decile had a 69% chance of remission and 73% attained remission. Compared to 5% of subjects identified by JIA category alone, the model identified 14% of subjects as low chance of remission (probability < 0.25), of whom 77% failed to attain remission.

Conclusion: Although the model did not meet our performance threshold (c-index > 0.70), it identified 3 times more subjects with low chance of remission than did JIA category alone, and it may serve as a benchmark for assessing value added by future laboratory/imaging biomarkers.
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http://dx.doi.org/10.3899/jrheum.180456DOI Listing
June 2019

Clinical presentation, immunologic features, and hematopoietic stem cell transplant outcomes for IKBKB immune deficiency.

Clin Immunol 2019 08 31;205:138-147. Epub 2018 Oct 31.

Manitoba Blood and Marrow Transplant Program, CancerCare Manitoba, Division of Pediatric Hematology-Oncology-BMT, University of Manitoba, Winnipeg, Manitoba, Canada.

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 naïve, 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.
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http://dx.doi.org/10.1016/j.clim.2018.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106064PMC
August 2019

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

Arthritis Care Res (Hoboken) 2019 11;71(11):1436-1443

Children's Hospital of Eastern Ontario and University of Ottawa, Ottawa, Ontario, Canada.

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.
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http://dx.doi.org/10.1002/acr.23783DOI Listing
November 2019

Vitamin D and juvenile idiopathic arthritis.

Pediatr Rheumatol Online J 2018 May 16;16(1):34. Epub 2018 May 16.

College of Pharmacy & Nutrition and School of Public Health, University of Saskatchewan, 104 Clinic Place, Saskatoon, SK, S7N 2Z4, Canada.

Background: Vitamin D has been implicated in the pathogenesis of autoimmune diseases. While the roles of vitamin D in other autoimmune diseases have been investigated, less is known about the role of vitamin D in chronic childhood arthritis.

Main Body: This review summarizes and evaluates evidence relating to 25-hydroxyvitamin D (25(OH)D) and chronic childhood arthritis. A scoping literature review was conducted using Ovid Medline, Ovid Embase, Cumulative Index to Nursing and Allied Health Literature, Web of Science and Scopus. Further, we geo-mapped the results of the studies to identify the patterns of the association between vitamin D and chronic childhood arthritis across the globe. Of 38 studies reporting 25(OH)D concentrations in childhood chronic arthritis, 32 (84.2%) reported that a significant number of children had suboptimal (< 75 nmol/L) status.

Conclusion: The data indicate suboptimal vitamin D status in children with chronic arthritis. Further, the association between low vitamin D and increased arthritis activity follow a north-south geographical gradient.
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http://dx.doi.org/10.1186/s12969-018-0250-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5956785PMC
May 2018

IL1RN Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin-1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis.

Arthritis Rheumatol 2018 08 28;70(8):1319-1330. Epub 2018 Jun 28.

National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland.

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 ). 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.
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http://dx.doi.org/10.1002/art.40498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105455PMC
August 2018

Brief Report: The Genetic Profile of Rheumatoid Factor-Positive Polyarticular Juvenile Idiopathic Arthritis Resembles That of Adult Rheumatoid Arthritis.

Arthritis Rheumatol 2018 06 21;70(6):957-962. Epub 2018 Apr 21.

Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia.

Objective: Juvenile idiopathic arthritis (JIA) comprises 7 heterogeneous categories of chronic childhood arthritides. Approximately 5% of children with JIA have rheumatoid factor (RF)-positive arthritis, which phenotypically resembles adult rheumatoid arthritis (RA). Our objective was to compare and contrast the genetics of RF-positive polyarticular JIA with those of RA and selected other JIA categories, to more fully understand the pathophysiologic relationships of inflammatory arthropathies.

Methods: Patients with RF-positive polyarticular JIA (n = 340) and controls (n = 14,412) were genotyped using the Immunochip array. Single-nucleotide polymorphisms were tested for association using a logistic regression model adjusting for admixture proportions. We calculated weighted genetic risk scores (wGRS) of reported RA and JIA risk loci, and we compared the ability of these wGRS to predict RF-positive polyarticular JIA.

Results: As expected, the HLA region was strongly associated with RF-positive polyarticular JIA (P = 5.51 × 10 ). Nineteen of 44 RA risk loci and 6 of 27 oligoarticular/RF-negative polyarticular JIA risk loci were associated with RF-positive polyarticular JIA (P < 0.05). The RA wGRS predicted RF-positive polyarticular JIA (area under the curve [AUC] 0.71) better than did the oligoarticular/RF-negative polyarticular JIA wGRS (AUC 0.59). The genetic profile of patients with RF-positive polyarticular JIA was more similar to that of RA patients with age at onset 16-29 years than to that of RA patients with age at onset ≥70 years.

Conclusion: RF-positive polyarticular JIA is genetically more similar to adult RA than to the most common JIA categories and thus appears to be a childhood-onset presentation of autoantibody-positive RA. These findings suggest common disease mechanisms, which could lead to novel therapeutic targets and shared treatment strategies.
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http://dx.doi.org/10.1002/art.40443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984672PMC
June 2018

Growth and weight gain in children with juvenile idiopathic arthritis: results from the ReACCh-Out cohort.

Pediatr Rheumatol Online J 2017 Aug 22;15(1):68. Epub 2017 Aug 22.

From British Columbia Children's Hospital and University of British Columbia, Vancouver, Canada.

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 < 2.5th percentile, 2.5% to 3.4%) and obesity (BMI > 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.
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http://dx.doi.org/10.1186/s12969-017-0196-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567720PMC
August 2017

Malignancy in Pediatric-onset Systemic Lupus Erythematosus.

J Rheumatol 2017 Oct 1;44(10):1484-1486. Epub 2017 Aug 1.

From the Research Institute of the McGill University Health Centre, Montreal, Quebec; University of Calgary, Calgary, Alberta; The Hospital for Sick Children, Hospital for Sick Children Research Institute, University of Toronto, Toronto; Children's Hospital of Eastern Ontario, Ottawa, Ontario; University of Manitoba, Winnipeg, Manitoba; University of Saskatchewan, Saskatoon, Saskatchewan, Canada; Duke University Medical Center, Durham, North Carolina; Seattle Children's Hospital, Seattle, Washington; Columbia University Medical Center, New York, New York; Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Hackensack University Medical Center, Hackensack, New Jersey; University of Alabama at Birmingham, Birmingham, Alabama; University of Chicago; Northwestern University Feinberg School of Medicine, Chicago, Illinois; Riley Hospital for Children, Indianapolis, Indiana; University of California, San Francisco, San Francisco, California, USA.

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.
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http://dx.doi.org/10.3899/jrheum.170179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657309PMC
October 2017

Characteristics and Course of Enthesitis in a Juvenile Idiopathic Arthritis Inception Cohort.

Arthritis Care Res (Hoboken) 2018 02;70(2):303-308

University of Alberta, Edmonton, Alberta, Canada.

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.
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http://dx.doi.org/10.1002/acr.23256DOI Listing
February 2018

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

Arthritis Care Res (Hoboken) 2018 01 6;70(1):134-144. Epub 2017 Dec 6.

Children's Hospital of Eastern Ontario and University of Ottawa, Ottawa, Ontario, Canada.

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.
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http://dx.doi.org/10.1002/acr.23236DOI Listing
January 2018

Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: clinical and therapeutic implications.

Ann Rheum Dis 2017 May 7;76(5):906-913. Epub 2016 Dec 7.

Arthritis Research UK Centre for Genetics and Genomics, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, Manchester, UK.

Objectives: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of conditions unified by the presence of chronic childhood arthritis without an identifiable cause. Systemic JIA (sJIA) is a rare form of JIA characterised by systemic inflammation. sJIA is distinguished from other forms of JIA by unique clinical features and treatment responses that are similar to autoinflammatory diseases. However, approximately half of children with sJIA develop destructive, long-standing arthritis that appears similar to other forms of JIA. Using genomic approaches, we sought to gain novel insights into the pathophysiology of sJIA and its relationship with other forms of JIA.

Methods: We performed a genome-wide association study of 770 children with sJIA collected in nine countries by the International Childhood Arthritis Genetics Consortium. Single nucleotide polymorphisms were tested for association with sJIA. Weighted genetic risk scores were used to compare the genetic architecture of sJIA with other JIA subtypes.

Results: The major histocompatibility complex locus and a locus on chromosome 1 each showed association with sJIA exceeding the threshold for genome-wide significance, while 23 other novel loci were suggestive of association with sJIA. Using a combination of genetic and statistical approaches, we found no evidence of shared genetic architecture between sJIA and other common JIA subtypes.

Conclusions: The lack of shared genetic risk factors between sJIA and other JIA subtypes supports the hypothesis that sJIA is a unique disease process and argues for a different classification framework. Research to improve sJIA therapy should target its unique genetics and specific pathophysiological pathways.
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http://dx.doi.org/10.1136/annrheumdis-2016-210324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530341PMC
May 2017

Gene Expression Deconvolution for Uncovering Molecular Signatures in Response to Therapy in Juvenile Idiopathic Arthritis.

PLoS One 2016 31;11(5):e0156055. Epub 2016 May 31.

Department of Computer Science, University of Toronto, Toronto, ON, Canada.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156055PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887077PMC
July 2017

Diffraction-Enhanced Computed Tomographic Imaging of Growing Piglet Joints by Using a Synchrotron Light Source.

Comp Med 2015 Aug;65(4):342-7

Department of Pediatrics, University of Saskatchewan, Canadian Light Source, Saskatoon, Saskatchewan, Canada.

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549680PMC
August 2015

The risk and nature of flares in juvenile idiopathic arthritis: results from the ReACCh-Out cohort.

Ann Rheum Dis 2016 06 18;75(6):1092-8. Epub 2015 May 18.

British Columbia Children's Hospital and University of British Columbia, Vancouver, British Columbia, Canada.

Objective: To 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.

Methods: We 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.

Results: 1146 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.

Conclusions: In 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.
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http://dx.doi.org/10.1136/annrheumdis-2014-207164DOI Listing
June 2016

Transitioning to employment with a rheumatic disease: the role of independence, overprotection, and social support.

J Rheumatol 2014 Dec 1;41(12):2386-94. Epub 2014 Oct 1.

From the Dalla Lana School of Public Health, University of Toronto; Arthritis Community Research and Evaluation Unit, Toronto Western Research Institute; Institute for Work and Health; Mobility Program, Clinical Research Unit, St. Michael's Hospital, Toronto, Ontario; Division of Rheumatology, Centre de recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de L'Université Laval, Quebec City, Quebec; Department of Pediatrics, University of Saskatchewan, Saskatoon, Saskatchewan; Division of Pediatric Rheumatology, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia; Division of Rheumatology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.A. Jetha, PhD; E. Badley, PhD, Dalla Lana School of Public Health, University of Toronto, and Arthritis Community Research and Evaluation Unit, Toronto Western Research Institute; M.A.M. Gignac, PhD, Dalla Lana School of Public Health, University of Toronto, and Arthritis Community Research and Evaluation Unit, Toronto Western Research Institute, and Institute for Work and Health; D. Beaton, PhD, Institute for Work and Health, and Mobility Program, Clinical Research Unit, St. Michael's Hospital; P.R. Fortin, MD, MPH, Division of Rheumatology, Centre de recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de L'Université Laval; A.M. Rosenberg, MD, Department of Pediatrics; N.J. Shiff, MD, MHSc, University of Saskatchewan; L.B. Tucker, MD, Division of Pediatric Rheumatology, BC Children's Hospital, University of British Columbia; D.P. Mosher, MD, Division of Rheumatology, Faculty of Medicine, University of Calgary.

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.
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http://dx.doi.org/10.3899/jrheum.140419DOI Listing
December 2014

Description of active joint count trajectories in juvenile idiopathic arthritis.

J Rheumatol 2014 Dec 1;41(12):2466-73. Epub 2014 Oct 1.

From Western University; Children's Hospital, London Health Sciences Centre, London; Division of Clinical Decision Making and Health Care, Toronto General Research Institute, University Health Network; Division of Rheumatology, the Hospital for Sick Children; Cell Biology Program, the Hospital for Sick Children Research Institute; Department of Pediatrics, Department of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, Department of Immunology, and the Department of Medical Science, University of Toronto; Institute for Work and Health, and Division of Rheumatology, Mount Sinai Hospital; Department of Medicine, University Health Network and Mount Sinai Hospital, Toronto, Ontario; University of Manitoba; Children's Hospital, Health Sciences Centre, Winnipeg, Manitoba; University of Saskatchewan, Saskatoon, Saskatchewan, Canada.R.A. Berard, MD, MSc, Western University, Children's Hospital, London Health Sciences Centre; G. Tomlinson, PhD, Division of Clinical Decision Making and Health Care, Toronto General Research Institute, University Health Network, and the Department of Health Policy, Management and Evaluation, and the Dalla Lana School of Public Health, University of Toronto, and the Department of Medicine, University Health Network and Mount Sinai Hospital; X. Li, MD, BSc, Division of Clinical Decision Making and Health Care, Toronto General Research Institute, University Health Network; K. Oen, MD, University of Manitoba, Children's Hospital, Health Sciences Centre; A.M. Rosenberg, MD, University of Saskatchewan; B.M. Feldman, MD, MSc, Division of Rheumatology, the Hospital for Sick Children, and the Department of Pediatrics, Department of Health Policy, Management and Evaluation, and the Dalla Lana School of Public Health, University of Toronto; R.S.M. Yeung, MD, PhD, Division of Rheumatology, the Hospital for Sick Children, and Department of Pediatrics, Department of Immunology, and Department of Medical Science, University of Toro

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.
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http://dx.doi.org/10.3899/jrheum.130835DOI Listing
December 2014

The biologic basis of clinical heterogeneity in juvenile idiopathic arthritis.

Arthritis Rheumatol 2014 Dec;66(12):3463-75

The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada.

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.
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http://dx.doi.org/10.1002/art.38875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282094PMC
December 2014

Factors associated with cord blood vitamin D concentration in Saskatchewan newborns.

Appl Physiol Nutr Metab 2014 Oct 5;39(10):1188-91. Epub 2014 May 5.

a Department of Pediatrics, University of Saskatchewan, c/o 103 Hospital Drive, Saskatoon, SK S7N 0W8, Canada.

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.
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http://dx.doi.org/10.1139/apnm-2013-0579DOI Listing
October 2014

The outcomes of juvenile idiopathic arthritis in children managed with contemporary treatments: results from the ReACCh-Out cohort.

Ann Rheum Dis 2015 Oct 19;74(10):1854-60. Epub 2014 May 19.

Children's Hospital of Eastern Ontario and University of Ottawa, Ottawa, Canada.

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 <10 mm), disease remission (inactive disease >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.
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http://dx.doi.org/10.1136/annrheumdis-2014-205372DOI Listing
October 2015

Safety and feasibility of a home-based six week resistance training program in juvenile idiopathic arthritis.

Pediatr Rheumatol Online J 2013 Dec 20;11(1):46. Epub 2013 Dec 20.

College of Kinesiology, University of Saskatchewan, 87 Campus Drive, Saskatoon, SK, S7N 5B2 Canada.

Background: Juvenile idiopathic arthritis (JIA), among the most common chronic diseases of childhood, can be associated with attenuated physical activity levels, reduced fitness, decreased functionality and pain. This pilot study aimed to determine the safety, feasibility and effect of a six week resistance training program in children with JIA.

Methods: Youth (8-18 years) with JIA participated in a home-based resistance training program. Participants reported pain on an electronic diary once a day for one week prior to training, then once a day on non-exercise days and three times a day (before-exercise, after-exercise, and end-of-day) on exercise days for the subsequent six weeks of training. Secondary outcome measures included inflammation (assessed by ultrasound), muscle size (assessed by ultrasound), muscle strength (assessed by dynamometer) and functional ability (assessed by childhood health assessment questionnaire), measured at baseline and post-training. Participants were also instructed to wear an accelerometer one week prior to training to estimate baseline physical activity levels. Statistical analyses included safety (pain changes and any adverse events), feasibility (adherence to program and modifications made to exercises) and effect of program (differences in secondary measures pre and post training). An alpha level of p < 0.05 was accepted as significant.

Results: Seven participants completed an average of 12.7 ± 3.4 (range 8-17) exercise sessions out of a possible 18 (70.6%). No adverse events were reported and pain did not increase over the seven weeks. Secondary measures revealed a significant increase in vastus lateralis thickness from pre to post training (p < 0.05). End-of-day pain intensity was correlated to end-of-day stiffness, fatigue and mood (r = .864, r = .581, r = -.637, respectively, p < 0.001). Pain intensity was also correlated with ratings of perceived exertion of the exercise (r = 0.324, p < 0.01). Only two children met the recommended 60 minutes of moderate to vigorous physical activity per day.

Conclusions: A six week home-based resistance training program is both safe (absence of pain changes or adverse events over the six weeks) and feasible (comparable adherence rates to other exercise studies involving JIA and individually modifiable) in children with JIA.
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http://dx.doi.org/10.1186/1546-0096-11-46DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3878188PMC
December 2013