Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 52
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Artigo em Inglês | MEDLINE | ID: mdl-31919503

RESUMO

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.

2.
J Bioinform Comput Biol ; 17(5): 1940010, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31856670

RESUMO

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.

3.
Clin Immunol ; 211: 108298, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31706029
4.
Artigo em Inglês | MEDLINE | ID: mdl-31074591

RESUMO

OBJECTIVE: Under-valuing the effectiveness of conventional treatments may lead to overtreatment with biologic medications in children with juvenile idiopathic arthritis (JIA). We used data from a nation-wide inception cohort and strict methods to control bias to estimate the real-world effectiveness of simple JIA treatment strategies recommended in current guidelines. METHODS: Children with JIA recruited at 16 Canadian centers in 2005-2010 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 acceptable for children with polyarticular course. Success rates were calculated for treatments tried ≥25 times and logistic regression identified features associated with success. RESULTS: 4,429 treatment episodes were observed in 1352 children. NSAID monotherapy was tried 697 times, mostly as initial treatment when <5 joints were involved, with 54.4% success (CI: 50.3-58.6). NSAID plus joint injections had 64.7% success (CI: 59.8-69.7). Adding methotrexate to NSAID and/or joint injections, tried 566 times, had 60.5% success (CI: 55.7-65.3). In adjusted analyses, each additional active joint reduced chances of success for NSAID (OR=0.90, CI: 0.85-0.94) and for methotrexate combinations (OR=0.96, CI: 0.94-0.99). Each additional year after disease onset reduced chances of success with methotrexate combinations (OR=0.83, CI: 0.72-0.95). CONCLUSION: These real-world effectiveness estimates show conventional non-biologic treatment strategies recommended in current guidelines are effective in achieving treatment targets in many children with JIA. This article is protected by copyright. All rights reserved.

5.
Arthritis Rheumatol ; 71(10): 1747-1755, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31008556

RESUMO

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.

6.
Artigo em Inglês | MEDLINE | ID: mdl-30740939

RESUMO

OBJECTIVE: To estimate the impact of enthesitis on patient-reported outcomes (PROs) in children with juvenile idiopathic arthritis (JIA), irrespective of JIA category. METHODS: Children in the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) cohort were studied. Entheseal tenderness by physician examination in 33 defined locations, Juvenile Arthritis Quality of life Questionnaire (JAQQ), Quality of My Life questionnaire (QoML), Childhood Health Assessment Questionnaire (CHAQ), and a pain visual analogue scale (VAS) were completed at enrolment, 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 ANCOVA. RESULTS: Among 1371 patients followed a median of 35.3 months (IQR 22.1, 49.2), 214 (16%) had enthesitis, of whom 137 (64%) were classified as having enthesitis-related arthritis (ERA). After adjusting for JIA category and covariates, children with enthesitis reported higher JAQQ (mean raw score 2.71 vs 2.16; adjusted difference 0.41 points; 0.22, 0.59), higher CHAQ (0.47 vs 0.31; 0.14 points; 0.07, 0.22), higher pain (3.01 vs 1.68; 0.94 points; 0.64, 1.25) and lower QoML (7.02 vs 8.23; -0.80 points; -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 PROs than those without enthesitis. Thus, enthesitis should be assessed in all children with JIA. This article is protected by copyright. All rights reserved.

7.
PLoS Med ; 16(2): e1002750, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30807586

RESUMO

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.


Assuntos
Artrite Juvenil/diagnóstico , Artrite Juvenil/epidemiologia , Progressão da Doença , Articulações/patologia , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Valor Preditivo dos Testes , Estudos Prospectivos
8.
J Rheumatol ; 46(6): 628-635, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30647178

RESUMO

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 a priori 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.

9.
Arthritis Care Res (Hoboken) ; 71(11): 1436-1443, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30320957

RESUMO

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.

10.
Clin Immunol ; 205: 138-147, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30391351

RESUMO

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.

11.
Pediatr Rheumatol Online J ; 16(1): 34, 2018 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-29769136

RESUMO

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.


Assuntos
Artrite Juvenil/sangue , Deficiência de Vitamina D/complicações , Vitamina D/análogos & derivados , Adolescente , Artrite Juvenil/complicações , Criança , Pré-Escolar , Suplementos Nutricionais , Humanos , Lactente , Vitamina D/sangue , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina D/epidemiologia
12.
Arthritis Rheumatol ; 70(8): 1319-1330, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29609200

RESUMO

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.


Assuntos
Antirreumáticos/farmacologia , Artrite Juvenil/genética , Predisposição Genética para Doença/genética , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Alelos , Artrite Juvenil/tratamento farmacológico , Estudos de Casos e Controles , Criança , Feminino , Estudo de Associação Genômica Ampla , Humanos , Proteína Antagonista do Receptor de Interleucina 1/efeitos dos fármacos , Proteína Antagonista do Receptor de Interleucina 1/genética , Masculino , Razão de Chances , Variantes Farmacogenômicos/efeitos dos fármacos , Variantes Farmacogenômicos/genética , Polimorfismo de Nucleotídeo Único/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética
13.
Arthritis Rheumatol ; 70(6): 957-962, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29426059

RESUMO

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 × 10-31 ). 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.


Assuntos
Artrite Juvenil/genética , Artrite Reumatoide/genética , Autoanticorpos/genética , Perfil Genético , Fator Reumatoide/genética , Adolescente , Adulto , Artrite Juvenil/imunologia , Artrite Reumatoide/imunologia , Criança , Feminino , Genótipo , Humanos , Modelos Logísticos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Fator Reumatoide/imunologia
14.
Arthritis Care Res (Hoboken) ; 70(2): 303-308, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28426894

RESUMO

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.


Assuntos
Artralgia/fisiopatologia , Artrite Juvenil/fisiopatologia , Entesopatia/fisiopatologia , Cápsula Articular/fisiopatologia , Adolescente , Fatores Etários , Artralgia/diagnóstico , Artralgia/epidemiologia , Artrite Juvenil/diagnóstico , Artrite Juvenil/epidemiologia , Canadá/epidemiologia , Criança , Pré-Escolar , Progressão da Doença , Entesopatia/diagnóstico , Entesopatia/epidemiologia , Feminino , Humanos , Masculino , Prevalência , Fatores de Tempo
15.
Arthritis Care Res (Hoboken) ; 70(1): 134-144, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28320056

RESUMO

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.


Assuntos
Comportamento do Adolescente , Artrite Juvenil/diagnóstico , Artrite Juvenil/psicologia , Comportamento Infantil , Qualidade de Vida , Inquéritos e Questionários , Adolescente , Desenvolvimento do Adolescente , Fatores Etários , Artrite Juvenil/fisiopatologia , Artrite Juvenil/terapia , Canadá , Criança , Desenvolvimento Infantil , Pré-Escolar , Avaliação da Deficiência , Feminino , Humanos , Estudos Longitudinais , Masculino , Medição da Dor , Valor Preditivo dos Testes , Prognóstico , Fatores de Tempo
16.
J Rheumatol ; 44(10): 1484-1486, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28765255

RESUMO

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.


Assuntos
Lúpus Eritematoso Sistêmico/epidemiologia , Neoplasias/epidemiologia , Adolescente , Criança , Comorbidade , Feminino , Seguimentos , Humanos , Incidência , Masculino , Sistema de Registros , Fatores Sexuais
17.
Pediatr Rheumatol Online J ; 15(1): 68, 2017 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-28830457

RESUMO

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.


Assuntos
Artrite Juvenil/complicações , Glucocorticoides/efeitos adversos , Transtornos do Crescimento/epidemiologia , Ganho de Peso/efeitos dos fármacos , Adolescente , Antropometria , Artrite Juvenil/tratamento farmacológico , Canadá/epidemiologia , Criança , Pré-Escolar , Feminino , Seguimentos , Glucocorticoides/uso terapêutico , Transtornos do Crescimento/etiologia , Humanos , Incidência , Masculino , Prevalência , Estudos Prospectivos
18.
Ann Rheum Dis ; 76(5): 906-913, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27927641

RESUMO

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.


Assuntos
Artrite Juvenil/genética , Cromossomos Humanos Par 1/genética , Complexo Principal de Histocompatibilidade/genética , Artrite Juvenil/tratamento farmacológico , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco
19.
PLoS One ; 11(5): e0156055, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27244050

RESUMO

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.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Artrite Juvenil/genética , Perfilação da Expressão Gênica , Adolescente , Algoritmos , Biomarcadores , Plaquetas/citologia , Criança , Expressão Gênica , Humanos , Contagem de Linfócitos , Modelos Teóricos , Monócitos/citologia , Neutrófilos/citologia , Projetos Piloto , Linfócitos T/citologia , Resultado do Tratamento , alfa-Defensinas/metabolismo
20.
Ann Rheum Dis ; 75(6): 1092-8, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-25985972

RESUMO

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.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/patologia , Progressão da Doença , Anticorpos Antinucleares/sangue , Artrite Juvenil/sangue , Artrite Juvenil/tratamento farmacológico , Fatores Biológicos/uso terapêutico , Canadá , Criança , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Modelos de Riscos Proporcionais , Estudos Prospectivos , Recidiva , Fator Reumatoide/sangue , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA