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1.
Pediatr Rheumatol Online J ; 17(1): 31, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31242923

RESUMO

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) refers to a complex group of systemic vasculitides that are characterized by primary small-to-medium sized blood vessel inflammation with the presence of autoantibodies known as ANCA. AAV diseases include Granulomatosis with Polyangiitis (GPA), Eosinophilic Granulomatosis with Polyangiitis (EGPA), and Microscopic Polyangiitis (MPA). AAVs are challenging conditions associated with high cumulative disease and treatment related morbidity and mortality. Given its rarity and the resulting paucity of pediatric-specific clinical trial evidence, pediatric rheumatologists have had to often extrapolate from adult literature for management and therapeutic decisions. The aim of this review is to provide a comprehensive overview of the important findings and overall conclusions of critical landmark clinical trials in the induction and maintenance treatments in adult AAV for the pediatric rheumatologist. This review also highlights the outcomes of recent pediatric AAV observational studies and discusses the future research priorities in pediatric AAV management.

2.
Pediatr Rheumatol Online J ; 17(1): 20, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060557

RESUMO

BACKGROUND: This study aims to describe current practice in identifying and measuring health care resource use and unit costs in economic evaluations or costing studies of juvenile idiopathic arthritis (JIA). METHODS: A scoping review was conducted (in July 2018) in PubMed and Embase to identify economic evaluations, costing studies, or resource utilization studies focusing on patients with JIA. Only English language peer-reviewed articles reporting primary research were included. Data from all included full-text articles were extracted and analysed to identify the reported health care resource use items. In addition, the data sources used to obtain these resource use and unit costs were identified for all included articles. RESULTS: Of 1176 unique citations identified by the search, 20 full-text articles were included. These involved 4 full economic evaluations, 5 cost-outcome descriptions, 8 cost descriptions, and 3 articles reporting only resource use. The most commonly reported health care resource use items involved medication (80%), outpatient and inpatient hospital visits (80%), laboratory tests (70%), medical professional visits (70%) and other medical visits (65%). Productivity losses of caregivers were much more often incorporated than (future) productivity losses of patients (i.e. 55% vs. 15%). Family borne costs were not commonly captured (ranging from 15% for school costs to 50% for transportation costs). Resource use was mostly obtained from family self-reported questionnaires. Estimates of unit costs were mostly based on reimbursement claims, administrative data, or literature. CONCLUSIONS: Despite some consistency in commonly included health care resource use items, variability remains in including productivity losses, missed school days and family borne costs. As these items likely substantially influence the full cost impact of JIA, the heterogeneity found between the items reported in the included studies limits the comparability of the results. Therefore, standardization of resource use items and unit costs to be collected is required. This standardization will provide guidance to future research and thereby improve the quality and comparability of economic evaluations or costing studies in JIA and potentially other childhood diseases. This would allow better understanding of the burden of JIA, and to estimate how it varies across health care systems.

4.
Arthritis Rheumatol ; 2019 Apr 22.
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.

5.
Front Immunol ; 10: 185, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30949161

RESUMO

The human Fc-gamma receptors (FcγRs) link adaptive and innate immunity by binding immunoglobulin G (IgG). All human low-affinity FcγRs are encoded by the FCGR2/3 locus containing functional single nucleotide polymorphisms (SNPs) and gene copy number variants. This locus is notoriously difficult to genotype and high-throughput methods commonly used focus on only a few SNPs. We performed multiplex ligation-dependent probe amplification for all relevant genetic variations at the FCGR2/3 locus in >4,000 individuals to define linkage disequilibrium (LD) and allele frequencies in different populations. Strong LD and extensive ethnic variation in allele frequencies was found across the locus. LD was strongest for the FCGR2C-ORF haplotype (rs759550223+rs76277413), which leads to expression of FcγRIIc. In Europeans, the FCGR2C-ORF haplotype showed strong LD with, among others, rs201218628 (FCGR2A-Q27W, r 2 = 0.63). LD between these two variants was weaker (r 2 = 0.17) in Africans, whereas the FCGR2C-ORF haplotype was nearly absent in Asians (minor allele frequency <0.005%). The FCGR2C-ORF haplotype and rs1801274 (FCGR2A-H131R) were in weak LD (r 2 = 0.08) in Europeans. We evaluated the importance of ethnic variation and LD in Kawasaki Disease (KD), an acute vasculitis in children with increased incidence in Asians. An association of rs1801274 with KD was previously shown in ethnically diverse genome-wide association studies. Now, we show in 1,028 European KD patients that the FCGR2C-ORF haplotype, although nearly absent in Asians, was more strongly associated with susceptibility to KD than rs1801274 in Europeans. Our data illustrate the importance of interpreting findings of association studies concerning the FCGR2/3 locus with knowledge of LD and ethnic variation.

6.
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.

7.
Arthritis Rheumatol ; 71(5): 836-838, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30592381
8.
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 (ReACCh-Out) inception cohort were used to estimate the annual incidence of new-onset uveitis following JIA diagnosis and 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, 1183 patients enrolled within 6 months of JIA diagnosis met inclusion criteria, median age (IQR) at diagnosis of 9.0 (3.8-12.9) years, median follow-up of 35.2 (22.7-48.3) months. Of these, 87 patients developed uveitis after enrollment. The incidence of new-onset uveitis was 2.8% per year (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 5th year although confidence intervals overlapped. Uveitis was associated with young age (< 7 years) at JIA diagnosis (HR=8.29, p<0.001), positive ANA (HR=3.20, p<0.001), oligoarthritis (HR=2.45, p=0.002), polyarthritis RF-negative (HR=1.65, p=0.002), 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 placed on young age (< 7 years) at JIA diagnosis and a positive ANA. This article is protected by copyright. All rights reserved.

9.
J Clin Rheumatol ; 2018 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-29782425

RESUMO

BACKGROUND/OBJECTIVE: Takayasu arteritis (TA) is characterized by extensive aortic, large and midsize arterial wall inflammation. The aim of this study was to assess the morphological and elastic properties of the aorta and large arteries and the impact on left ventricular (LV) mechanics in children with TA. METHODS: Seven pediatric TA patients (6 female patients, 13.8 ± 3.2 years) were assessed with magnetic resonance imaging, vascular ultrasound, applanation tonometry, and echocardiography from February 2015 until July 2017 and compared with 7 age- and sex-matched controls. Takayasu arteritis disease activity was assessed clinically by the Pediatric Vasculitis Activity Score (PVAS). RESULTS: Pediatric TA patients showed increased carotid-to-radial artery pulse wave velocity (8.1 ± 1.8 vs. 6.4 ± 0.6 m/s, P = 0.03) and increased carotid-to-femoral artery pulse wave velocity (8.3 ± 1.9 vs. 5.1 ± 0.8 m/s, P < 0.01) when compared with controls. Patients demonstrated increased LV mass index (74.3 ± 18.8 vs. 56.3 ± 10.9 g/m, P = 0.04), altered myocardial deformation with increased basal rotation (-9.8 ± 4.5 vs. -4.0 ± 2.0 degrees, P = 0.01) and torsion (19.9 ± 8.1 vs. 9.1 ± 3.1 degrees, P = 0.01), and impaired LV diastolic function with decreased mitral valve E/A ratio (1.45 ± 0.17 vs. 2.40 ± 0.84, P = 0.01), increased mitral valve E/E' ratio (6.8 ± 1.4 vs. 4.9 ± 0.7, P < 0.01), and increased pulmonary vein A-wave velocity (26.7 ± 5.7 vs. 16.8 ± 3.3 cm/s, P = 0.03). Carotid-to-radial artery pulse wave velocity was associated with systolic (R = 0.94, P < 0.01), diastolic (R = 0.85, P = 0.02), and mean blood pressure (R = 0.91, P < 0.01), as well as disease activity by PVAS (R = 0.75, P = 0.05). The PVAS was associated with carotid-to-radial artery pulse wave velocity (R = 0.75, P = 0.05), as well as systolic (R = 0.84, P = 0.02), diastolic (R = 0.82, P = 0.03), and mean blood pressure (R = 0.84, P = 0.02). CONCLUSIONS: Increased arterial stiffness is present in pediatric TA patients and associated with increased blood pressure and TA disease activity. Pediatric TA patients demonstrate altered LV mechanics, LV hypertrophy, and impaired diastolic function.

10.
Transfusion ; 58(8): 2027-2035, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29744883

RESUMO

BACKGROUND: Monocyte monolayer assay (MMA) is a compatibility testing method for evaluating the clinical significance of red blood cell (RBC) alloantibodies. Time-consuming monocyte isolation procedures and requirement for fresh monocytes have limited application of the MMA. The aim of this study was to develop and assess the utility and efficacy of cryopreserved buffy coat (BC)-derived monocytes for MMA application. STUDY DESIGN AND METHODS: Peripheral blood mononuclear cells (PBMNCs) were isolated from BC or peripheral blood (PB) and pooled and BC PBMNCs were cryopreserved. Monocytes from pooled PBMNCs were incubated with anti-D-sensitized, anti-Scianna2 (Sc2)-sensitized, anti-AnWj-sensitized, or anti-Jra -sensitized RBCs or lipopolysaccharide (LPS). MMA phagocytic index (PI) and membrane integrity were determined microscopically, and cytokine release was measured by Luminex technology. RESULTS: PBMNC isolation rates from fresh BC and PB were not comparable (67.4 ± 6.3 and 75.8 ± 7.7% respectively, p = 0.024). There was no significant difference in PBMNC membrane integrity (fresh PB, 100%; fresh BC, 100%; cryopreserved BC, 95.2 ± 1.2%), postwash recovery (fresh PB, 85.9 ± 3.1; fresh BC, 86.9 ± 6.7; cryopreserved BC, 84.8 ± 5.1), or monocyte PI (fresh PB, 82 ± 10; fresh BC, 77 ± 11; cryopreserved BC = 80 ± 6). Monocytes from pooled cryopreserved BC PBMNCs reacted with RBCs sensitized with anti-D and RBC alloantibodies, including anti-Sc2, anti-Jra , and anti-AnWj. CONCLUSIONS: Monocytes from pooled cryopreserved BC PBMNCs can be used reliably to evaluate phagocytic responses of sensitized RBCs and to assess clinical significance of RBC alloantibodies.

11.
Arthritis Rheumatol ; 70(8): 1319-1330, 2018 Aug.
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.

12.
Pediatr Rheumatol Online J ; 16(1): 17, 2018 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-29540190

RESUMO

BACKGROUND: Anti-TNF (Tumor necrosis factor) therapy is effective in treating pediatric patients with refractory rheumatic disease. There is however a concern that anti-TNF usage may increase the risk of malignancy. Reports on specific types of malignancy in this patient population have been emerging over the past decade, but there is a need for additional malignancy reports, as these events are rare. Therefore, a retrospective chart review was performed on the biologic database of pediatric rheumatology patients at The Hospital for Sick Children (SickKids) from 1997 to 2013 for neoplasms, patient demographic information and rheumatologic treatment course. FINDINGS: 6/357 (1.68%) rheumatology patients treated with anti-TNF therapy between 1997 and 2013 developed neoplasms. One patient had two malignancies. One patient had a benign neoplasm. Cases were exposed to etanercept, infliximab or both. Neoplasms developed late after anti-TNF exposure (median 5.0 years) and infliximab treatment was associated with a shorter time to malignancy. The neoplasms identified were as follows: 2 renal clear cell carcinoma, 1 pilomatricoma, 1 nasopharyngeal carcinoma, 1 Ewing's sarcoma, 1 hepatic T-cell lymphoma, 1 lymphoproliferative disease. CONCLUSIONS: The malignancy rate at our centre is low, however more than half of the neoplasms identified were rare and unusual in the pediatric population. The 5-year malignancy-free probability for patients with juvenile idiopathic arthritis (JIA) treated with biologic therapy was 97% from our database. Long-term screening for rare neoplasms is important as part of the safety monitoring for any pediatric rheumatology patient receiving anti-TNF therapy.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antirreumáticos/efeitos adversos , Neoplasias/induzido quimicamente , Doenças Reumáticas/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adolescente , Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Feminino , Humanos , Masculino , Neoplasias/epidemiologia , Sistema de Registros , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
13.
Arthritis Rheumatol ; 70(6): 957-962, 2018 Jun.
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.

14.
PLoS One ; 13(2): e0191087, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29415012

RESUMO

BACKGROUND: The pathogenesis of Kawasaki disease (KD) is commonly ascribed to an exaggerated immunologic response to an unidentified environmental or infectious trigger in susceptible children. A comprehensive framework linking epidemiological data and global distribution of KD has not yet been proposed. METHODS AND FINDINGS: Patients with KD (n = 81) were enrolled within 6 weeks of diagnosis along with control subjects (n = 87). All completed an extensive epidemiological questionnaire. Geographic localization software characterized the subjects' neighborhood. KD incidence was compared to atmospheric biological particles counts and winds patterns. These data were used to create a comprehensive risk framework for KD, which we tested against published data on the global distribution. Compared to controls, patients with KD were more likely to be of Asian ancestry and were more likely to live in an environment with low exposure to environmental allergens. Higher atmospheric counts of biological particles other than fungus/spores were associated with a temporal reduction in incidence of KD. Finally, westerly winds were associated with increased fungal particles in the atmosphere and increased incidence of KD over the Greater Toronto Area. Our proposed framework was able to explain approximately 80% of the variation in the global distribution of KD. The main limitations of the study are that the majority of data used in this study are limited to the Canadian context and our proposed disease framework is theoretical and circumstantial rather than the result of a single simulation. CONCLUSIONS: Our proposed etiologic framework incorporates the 1) proportion of population that are genetically susceptible; 2) modulation of risk, determined by habitual exposure to environmental allergens, seasonal variations of atmospheric biological particles and contact with infectious diseases; and 3) exposure to the putative trigger. Future modelling of individual risk and global distribution will be strengthened by taking into consideration all of these non-traditional elements.


Assuntos
Saúde Ambiental , Saúde Global , Síndrome de Linfonodos Mucocutâneos/epidemiologia , Adolescente , Alérgenos , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Anamnese , Síndrome de Linfonodos Mucocutâneos/genética , Síndrome de Linfonodos Mucocutâneos/fisiopatologia , Estações do Ano , Vento
15.
J Liposome Res ; 28(3): 173-181, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28276279

RESUMO

Our in vivo studies on a rat model established safety of transfusing liposome-treated red blood cells (RBCs) but identified the potential for immune modulation as related to transfusion efficacy of liposome-treated RBCs. The aim of this study was at assessing the impact of liposome-induced membrane changes on the immune profile of liposome-treated RBCs by (a) evaluating their interaction with endothelial cells and monocytes; and (b) the resulting immune response derived from this interaction, in the form of cytokine release, adhesion molecules expression and phagocytosis. Unilamellar liposomes were synthesized to contain unsaturated phospholipids (1,2-dioleoyl-sn-glycero-3-phosphocholine [DOPC]:CHOL, 7:3 mol%). The human RBCs immune profile was assessed by incubating control and DOPC-treated RBCs with human umbilical vein endothelial cells (HUVECs) and monocytes. Cytokine release measured by Luminex technology, vascular cell adhesion molecule (VCAM)-1 and E-selectin on HUVECs measured by flow cytometry, and the erythrophagocytic activity of monocytes by monocyte monolayer assay (MMA) were determined. Fibroblast growth factor [FGF]-2 was the only cytokine released by HUVECs that remained increased after incubation with DOPC-treated RBCs compared to control throughout storage. The expression of both VCAM-1 (15.3 ± 5.6% versus 6.3 ± 0.9%, p = 0.008) and E-selectin (18.0 ± 6.3% versus 6.6 ± 0.7%, p = 0.004) by HUVECs were significantly increased after incubation with DOPC-treated RBCs at day 2 of storage. The MMA resulted in phagocytic indexes of zero for both control and DOPC-treated RBCs at day 2 and 42 of storage. The liposome treatment did not result in significant changes to the immune profile of stored DOPC-treated RBCs. These findings combined with previous in vivo results, make liposome treatment a potential candidate for application in RBC preservation and open the possibility for clinical use with other cell types.

16.
Arthritis Care Res (Hoboken) ; 70(1): 134-144, 2018 Jan.
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.

17.
Arthritis Res Ther ; 19(1): 255, 2017 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-29166923

RESUMO

BACKGROUND: Takayasu arteritis (TAK) is a large vessel vasculitis that rarely affects children. Data on childhood TAK are scarce. The aim of this study was to analyze the presenting features, course and outcome of children with TAK, compare efficacy of treatment regimens and identify high-risk factors for adverse outcome. METHODS: A single-center cohort study of consecutive children fulfilling the EULAR/PRINTO/PReS criteria for childhood TAK between 1986 and 2015 was performed. Clinical phenotypes, laboratory markers, imaging features, disease course and treatment were documented. Disease activity was assessed using the Pediatric Vasculitis Disease Activity Score at each visit. OUTCOME: disease flare defined as new symptoms and/or increased inflammatory markers necessitating therapy escalation and/or new angiographic lesions, or death. ANALYSIS: logistic regression tested relevant variables for flare. Kaplan-Meier analyses compared treatment regimens. RESULTS: Twenty-seven children were included; 74% were female, median age at diagnosis was 12.4 years. Twenty-two (81%) children presented with active disease at diagnosis. Treatment regimens included corticosteroids alone (15%), corticosteroids plus methotrexate (37%), cyclophosphamide (19%), or a biologic agent (11%). Adverse outcomes were documented in 14/27 (52%) children: two (7%) died within 6 months of diagnosis, and 13 (48%) experienced disease flares. The 2-year flare-free survival was 80% with biologic treatments compared to 43% in non-biologic therapies (p = 0.03); at last follow-up, biologic therapies resulted in significantly higher rates of inactive disease (p = 0.02). No additional outcome predictor was identified. CONCLUSIONS: Childhood TAK carries a high disease burden; half of the children experienced flares and 7% died. Biologic therapies were associated with better control of disease activity.


Assuntos
Corticosteroides/uso terapêutico , Produtos Biológicos/uso terapêutico , Ciclofosfamida/uso terapêutico , Metotrexato/uso terapêutico , Arterite de Takayasu/tratamento farmacológico , Adolescente , Antirreumáticos/uso terapêutico , Criança , Estudos de Coortes , Quimioterapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Arterite de Takayasu/patologia , Resultado do Tratamento
18.
Case Rep Nephrol Dial ; 7(2): 73-80, 2017 May-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28868297

RESUMO

Pulmonary renal syndrome refers to an association of pulmonary and glomerular disease and includes disorders, such as the ANCA-associated vasculitides, anti-glomerular basement membrane antibody disease, systemic lupus erythematosus, and IgA vasculitis (Henoch-Schönlein purpura). We present the medical history of a 26-month-old boy with an extensive purpuric rash, involving the limbs, trunk, and face, who developed clinically significant pulmonary hemorrhage and renal involvement. Rapid recognition of this rare but potentially life-threatening condition is crucial. In this report, we discuss the differential diagnosis, diagnostic studies, and treatment options to consider when facing a young child presenting with a pulmonary renal syndrome.

19.
Pediatr Nephrol ; 32(12): 2343-2350, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28766066

RESUMO

OBJECTIVES: Data on kidney transplant outcomes for pediatric patients with end-stage renal disease (ESRD) secondary to anti-neutrophil cytoplasmic antibody glomerulonephritis (ANCA GN), particularly granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), is limited. We describe our experience of kidney transplantation in pediatric ANCA GN patients. METHODS: We performed a retrospective review of patients with ANCA GN who developed ESRD and were transplanted at a single center between the years 2000 and 2014. RESULTS: Since 2000, there were seven pediatric patients with ANCA GN (four MPA) transplanted. Mean age at ANCA GN diagnosis was 11.8 ± 2.8 (range, 7.2-15.4) years. All seven were ANCA (three anti-PR3/four anti-MPO) positive. Estimated glomerular filtration rate (eGFR) at diagnosis was 11.7 ± 6.3 ml/min/1.73 m2. All received steroids and cyclophosphamide and three (23.3%) received plasma exchange. Six were dialysis dependent by 6 months post diagnosis. Time from diagnosis to transplant was 30 ± 12 (range, 17-48) months. Six of the seven received a deceased donor transplant. All patients received induction therapy and standard maintenance immunosuppression post transplant. Median duration of follow-up post transplantation was 27 months (range, 13-88 months). Median eGFR at last follow-up was 77 ml/min/1.73 m2 (range, 7.9-83.5). One patient lost her transplant to acute cellular rejection following non-adherence to immunosuppression after 21 months of stable transplant function. No patient had recurrence of vasculitis, either renal or extra-renal. CONCLUSIONS: Short-term patient and allograft survival in pediatric patients with ESRD secondary to ANCA GN seems excellent, with no recurrence of vasculitis post transplant in this small cohort.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Glomerulonefrite/terapia , Falência Renal Crônica/terapia , Transplante de Rim/métodos , Adolescente , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/mortalidade , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/terapia , Anticorpos Anticitoplasma de Neutrófilos/sangue , Criança , Feminino , Glomerulonefrite/etiologia , Glomerulonefrite/mortalidade , Humanos , Rim/fisiopatologia , Falência Renal Crônica/etiologia , Falência Renal Crônica/mortalidade , Transplante de Rim/efeitos adversos , Masculino , Estudos Retrospectivos , Resultado do Tratamento
20.
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
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