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Deficiency of X-linked Inhibitor of Apoptosis Protein (XIAP) is a rare genetic condition that can present with recurrent episodes of hemophagocytic lymphohistiocytosis (HLH), though the exact mechanisms leading to this hyperinflammatory disorder are unclear. Understanding its biology is critical to developing targeted therapies for this potentially fatal disease. Here we report on a novel multi-exonic intragenic duplication leading to XIAP deficiency with recurrent HLH that demonstrated complete response to interleukin (IL)-1b blockade. We further demonstrate using both primary patient cells and genetically modified THP-1 monocyte cell lines that, contrary to what has previously been shown in mouse cells, XIAP-deficient human macrophages do not produce excess IL-1b when stimulated under standard conditions. Instead, NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated hyperproduction of IL-1b is observed only when the XIAP-deficient cells are stimulated under autophagy-promoting conditions and this correlates with defective autophagic flux as measured by decreased accumulation of the early autophagy marker LC3-II. This work therefore highlights IL-1b blockade as a therapeutic option for patients with XIAP deficiency experiencing recurrent HLH and identifies a critical role for XIAP in promoting autophagy as a means of limiting IL-1b-mediated hyperinflammation during periods of cellular stress.
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OBJECTIVES: Juvenile idiopathic arthritis (JIA) is the most common type of arthritis among children. It can cause joint pain and permanent physical damage, which affects mobility and daily activities. The EQ-5D-Y-3L self-report version has been validated in JIA, but the validity of EQ-5D-Y-5L remains unknown. We examined the psychometric properties of the EQ-5D-Y-5L parent-proxy version among children with JIA. METHODS: We used data from the Understanding Childhood Arthritis Network Canadian-Dutch collaboration study cohort, including patients with new-onset JIA, and those starting or stopping biologics. Clinical data and the parent-proxy version of the childhood health assessment questionnaire (CHAQ) and EQ-5D-Y-5L were collected. We evaluated the ceiling and floor effect; convergent and divergent validity using Spearman's rank correlation; known-group validity using one-way ANOVA (Analysis of Variance) and effect size; and informativity using Shannon's evenness index. RESULTS: 467 patient visits representing 407 patients were analyzed. The EQ-5D-Y-5L had no ceiling/floor effect. The EQ-5D-Y-5L showed good convergent (e.g., EQ-5D-Y-5L pain/discomfort dimension vs. CHAQ pain index (Spearman's r = 0.74, 95% confidence interval (C.I.): 0.69-0.79)), divergent (e.g., EQ-5D-Y-5L pain/discomfort dimension vs. CHAQ eating dimension (Spearman's r = 0.19, 95% C.I.: 0.09-0.29)) and known-group validity (e.g., mean EQ-5D-Y-5L level summary score for patients with inactive versus active disease status, 6.34 vs. 10.52 (p < 0.001, effect size = 1.20 (95% C.I.: 0.95-1.45)). Shannon's evenness index ranged from 0.52 to 0.88, suggesting most dimensions had relatively even distributions. CONCLUSIONS: In this patient sample, EQ-5D-Y-5L parent-proxy version exhibited construct validity and informativity, suggesting the EQ-5D-Y-5L can be used to measure the quality of life of children with JIA.
Juvenile idiopathic arthritis is the most common type of arthritis affecting children. It can cause pain and permanent physical damage to joints and affects mobility and daily activities. While there is no cure yet, new therapies like biologics are effective. However, biologics are expensive and can have side effects. To decide when is the best time to use these biologics, we need to understand their cost and impact on patients. EQ-5D-Y-5L is a common tool to measure how the disease affects a patient's life. It is unclear whether EQ-5D-Y-5L works well for patients with juvenile idiopathic arthritis. In this study, we compared the EQ-5D-Y-5L to another tool that measures how the illness impacts functional ability. We looked to see if the EQ-5D-Y-5L could tell the difference between children who were more or less sick. We also assessed whether the EQ-5D-Y-5L has the ability to describe patients with different severity in health status. This study indicates that the EQ-5D-Y-5L is a good tool to measure the health of patients with juvenile idiopathic arthritis. Findings from this study support the use of the EQ-5D-Y-5L among this patient population in future clinical trials and research studies.
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Kawasaki disease (KD) is a hyperinflammatory syndrome manifesting as an acute systemic vasculitis characterized by fever, nonsuppurative conjunctival injection, rash, oral mucositis, extremity changes, and cervical lymphadenopathy. KD predominantly affects young children and shares clinical features and immunobiology with other hyperinflammation syndromes including systemic juvenile idiopathic arthritis (sJIA) and multisystem inflammatory syndrome in children (MIS-C). Cytokine storm syndrome (CSS) is an acute complication in ~2% of KD patients; however, the incidence is likely underestimated as many clinical and laboratory features of both diseases overlap. CSS should be entertained when a child with KD is unresponsive to IVIG therapy with recalcitrant fever. Early recognition and prompt institution of immunomodulatory treatment can substantially reduce the mortality and morbidity of CSS in KD. Given the known pathogenetic role of IL-1ß in both syndromes, the early use of IL-1 blockers in refractory KD with CSS deserves consideration.
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Síndrome da Liberação de Citocina , Síndrome de Linfonodos Mucocutâneos , Síndrome de Linfonodos Mucocutâneos/complicações , Síndrome de Linfonodos Mucocutâneos/imunologia , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Humanos , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Imunoglobulinas Intravenosas/uso terapêutico , Criança , Citocinas/metabolismoRESUMO
OBJECTIVE: Von Willebrand Factor (VWF) antigen plays a role in vascular inflammation and thrombosis, both important in the pathogenesis of Antineutrophil Cytoplasmic Antibody-associated vasculitis (AAV). Previous work found that VWF correlates with disease activity in childhood-onset primary CNS vasculitis. We sought to determine the relationship between VWF and disease activity over time in children with AAV. METHODS: AAV patients with more than one VWF level measured were included in this retrospective stuy, and the relationship between active vasculitis, VWF and other disease measures were analyzed. Generalized estimating equations (GEE) analysis was used to account for repeated VWF measurements within a patient. Repeated measures correlation was used to determine associations of paired laboratory observations. Diagnostic performance was evaluated using receiver operating curve (ROC) analysis. RESULTS: 732 total VWF measurements were collected in 33 AAV patients. VWF antigen levels were higher during active disease (median = 2.03 IU/ml, IQR = [1.35, 2.55]) compared with inactive disease (median = 1.18 IU/ml, IQR = [0.94, 1.53). VWF antigen was the only variable that was significantly associated with active disease (OR 3.01, p< 0.001, 95CI [2.3, 3.93]). The effect of VWF did not show a substantial difference between the disease subtypes. There was a moderate positive correlation between VWF antigen and disease activity, with an acceptable sensitivity and specificity rates. CONCLUSION: Increased VWF antigen levels correlate with active vasculitis in this paediatric-onset AAV cohort and may be used as an additional biomarker in childhood AAV.
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OBJECTIVE: To investigate medication prescription patterns among children with JIA, including duration, sequence and reasons for medication discontinuation. METHODS: This study is a single-centre, retrospective analysis of prospective data from the electronic medical records of JIA patients receiving systemic therapy aged 0-18 years between 1 April 2011 and 31 March 2019. Patient characteristics (age, gender, JIA subtype) and medication prescriptions were extracted and analysed using descriptive statistics, Sankey diagrams and Kaplan-Meier survival methods. RESULTS: Over a median of 4.2 years follow-up, the 20 different medicines analysed were prescribed as monotherapy (n = 15) or combination therapy (n = 48 unique combinations) among 236 patients. In non-systemic JIA, synthetic DMARDs were prescribed to almost all patients (99.5%), and always included MTX. In contrast, 43.9% of non-systemic JIA patients received a biologic DMARD (mostly adalimumab or etanercept), ranging from 30.9% for oligoarticular persistent ANA-positive JIA, to 90.9% for polyarticular RF-positive JIA. Among systemic JIA, 91.7% received a biologic DMARD (always including anakinra). When analysing medication prescriptions according to their class, 32.6% involved combination therapy. In 56.8% of patients, subsequent treatment lines were initiated after unsuccessful first-line treatment, resulting in 68 unique sequences. Remission was the most common reason for DMARD discontinuation (44.7%), followed by adverse events (28.9%) and ineffectiveness (22.1%). CONCLUSION: This paper reveals the complexity of pharmacological treatment in JIA, as indicated by: the variety of mono- and combination therapies prescribed, substantial variation in medication prescriptions between subtypes, most patients receiving two or more treatment lines, and the large number of unique treatment sequences.
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Antirreumáticos , Artrite Juvenil , Produtos Biológicos , Criança , Humanos , Artrite Juvenil/tratamento farmacológico , Estudos Retrospectivos , Estudos Prospectivos , Países Baixos , Antirreumáticos/uso terapêutico , Produtos Biológicos/uso terapêutico , Análise de Dados , Resultado do TratamentoRESUMO
OBJECTIVE: To quantify differences in hospital-associated costs, and accompanying travel costs and productivity losses, before and after withdrawing TNFi in JIA patients. METHODS: Retrospective analysis of prospectively collected data from electronic medical records of paediatric JIA patients treated with TNFi, which were either immediately discontinued, spaced (increased treatment interval) or tapered (reduced subsequent doses). Costs of hospital-associated resource use (consultations, medication, radiology procedures, laboratory testing, procedures under general anaesthesia, hospitalisation) and associated travel costs and productivity losses were quantified during clinically inactive disease until TNFi withdrawal (pre-withdrawal period) and compared with costs during the first and second year after withdrawal initiation (first and second year post-withdrawal). RESULTS: Fifty-six patients were included of whom 26 immediately discontinued TNFi, 30 spaced and zero tapered. Mean annual costs were 9,165/patient on active treatment (pre-withdrawal) and decreased significantly to 5,063/patient (-44.8%) and 6,569/patient (-28.3%) in the first and second year post-withdrawal, respectively (p< 0.05). Of these total annual costs, travel costs plus productivity losses were 834/patient, 1,180/patient, and 1,320/patient, in the three periods respectively. Medication comprised 80.7%, 61.5% and 72.4% of total annual costs in the pre-withdrawal, first, and second year post-withdrawal period, respectively. CONCLUSION: In the first two years after initiating withdrawal, the total annual costs are decreased compared with the pre-withdrawal period. However, cost reductions were lower in the second year compared with the first year post-withdrawal, primarily due to restarting or intensifying biologics. To support biologic withdraw decisions, future research should assess the full long-term societal cost impacts, and include all biologics.
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BACKGROUND: Paediatric inflammatory multisystem syndrome (PIMS) is a rare condition temporally associated with SARS-CoV-2 infection. Using national surveillance data, we compare presenting features and outcomes among children hospitalized with PIMS by SARS-CoV-2 linkage, and identify risk factors for intensive care (ICU). METHODS: Cases were reported to the Canadian Paediatric Surveillance Program by a network of >2800 pediatricians between March 2020 and May 2021. Patients with positive versus negative SARS-CoV-2 linkages were compared, with positive linkage defined as any positive molecular or serologic test or close contact with confirmed COVID-19. ICU risk factors were identified with multivariable modified Poisson regression. RESULTS: We identified 406 children hospitalized with PIMS, including 49.8% with positive SARS-CoV-2 linkages, 26.1% with negative linkages, and 24.1% with unknown linkages. The median age was 5.4 years (IQR 2.5-9.8), 60% were male, and 83% had no comorbidities. Compared to cases with negative linkages, children with positive linkages experienced more cardiac involvement (58.8% vs. 37.4%; p < 0.001), gastrointestinal symptoms (88.6% vs. 63.2%; p < 0.001), and shock (60.9% vs. 16.0%; p < 0.001). Children aged ≥6 years and those with positive linkages were more likely to require ICU. CONCLUSIONS: Although rare, 30% of PIMS hospitalizations required ICU or respiratory/hemodynamic support, particularly those with positive SARS-CoV-2 linkages. IMPACT: We describe 406 children hospitalized with paediatric inflammatory multisystem syndrome (PIMS) using nationwide surveillance data, the largest study of PIMS in Canada to date. Our surveillance case definition of PIMS did not require a history of SARS-CoV-2 exposure, and we therefore describe associations of SARS-CoV-2 linkages on clinical features and outcomes of children with PIMS. Children with positive SARS-CoV-2 linkages were older, had more gastrointestinal and cardiac involvement, and hyperinflammatory laboratory picture. Although PIMS is rare, one-third required admission to intensive care, with the greatest risk amongst those aged ≥6 years and those with a SARS-CoV-2 linkage.
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COVID-19 , SARS-CoV-2 , Humanos , Masculino , Criança , Pré-Escolar , Feminino , COVID-19/epidemiologia , COVID-19/terapia , Canadá/epidemiologia , Síndrome de Resposta Inflamatória Sistêmica/diagnóstico , Síndrome de Resposta Inflamatória Sistêmica/epidemiologiaRESUMO
OBJECTIVES: Transitioning from paediatric to adult care can be challenging. Whereas transition models of care have been shared in some rheumatological conditions, reported experience in vasculitis is lacking. METHODS: Retrospective chart review of adolescents aged 16-18 years assessed at the vasculitis transition clinic by paediatric and adult rheumatologists, and then scheduled for follow-up at the Adult Vasculitis Clinic (Toronto, Canada) from January 2013 until May 2020. RESULTS: Twenty-eight patients were seen at the transition clinic and included. Mean age at transition was 17 years and 11 (± SD 2) months, with a mean follow up from diagnosis of 32 (± 24) months. Most patients had ANCA-associated vasculitis (N=19, 39%), followed by Takayasu's arteritis (N=4, 14%); all but one were in remission at the time of transition. Twenty-six (93%) patients showed up for their first booked adult visit (two did not, were called and rebooked), after a mean of 4 (± 2) months after transition clinic. Subsequently, two patients missed 1 appointment, and three missed ≥ 2 appointments; only one (4%) stopped coming, while in remission for >2 years post-transition. Five (18%) patients were identified to have medication non-adherence after transition. With a mean follow up post-transition of 32 (± 25) months, 7 (25%) patients had minor and five (18%) had major relapses, at a mean of 17 (± 9) and 25 (± 15) months post-transition, respectively (compared to 12 (43%) and 9 (32%) prior to transition). At their last visit, all were in remission, 18 (64%) off glucocorticoids, and damage had remained stable. CONCLUSIONS: This model of care of vasculitis transition clinic resulted in favourable outcomes, as reflected by continuity of follow-up, and no increased risk of relapse.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Arterite de Takayasu , Transição para Assistência do Adulto , Adolescente , Adulto , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Criança , Humanos , Recidiva , Estudos Retrospectivos , Arterite de Takayasu/tratamento farmacológicoRESUMO
OBJECTIVES: High-dose glucocorticoids for remission-induction of ANCA-associated vasculitis are recommended and commonly used in adults, but recent studies suggest lower glucocorticoid doses can reduce toxicity without reducing efficacy. No paediatric-specific data exists to inform optimal glucocorticoid dosing in paediatric ANCA-associated vasculitis (pAAV). Our objectives were to describe glucocorticoid use in pAAV-related renal disease, and to explore associations between glucocorticoid dose, baseline patient characteristics and 12-month outcomes. METHODS: Youth <18 years with pAAV, biopsy-confirmed pauci-immune glomerulonephritis and 12-month follow-up data were included from an international paediatric vasculitis registry. Presenting features and 12-month outcomes (eGFR, glucocorticoid-related adverse effects), were compared between patients receiving no, low-moderate (≤90mg/kg) and high (>90mg/kg) cumulative intravenous methylprednisolone (IVMP), and low (<0.5mg/kg/day prednisone equivalent), moderate (0.5-1.5mg/kg/day) and high (>1.5mg/kg/day) starting doses of oral glucocorticoids. RESULTS: Among 131 patients (101 granulomatosis with polyangiitis, 30 microscopic polyangiitis), 27 (21%) received no IVMP, 64 (49%) low-moderate and 29 (22%) high-dose IVMP, while 9 (7%) received low, 75 (57%) moderate and 47 (36%) high initial doses of oral glucocorticoids. Renal failure at diagnosis (p=0.022) and plasmapheresis use (p=0.0001) were associated with high-dose IVMP. Rates of glucocorticoid-related adverse effects ranged from 15-31% across dose levels, and glucocorticoid dosing did not associate with 12-month outcomes. CONCLUSIONS: Glucocorticoid dosing for pAAV-related renal disease was highly variable, and rates of adverse effects were high across all dosing groups. A significant proportion of patients received oral glucocorticoid or IVMP doses that were discordant with current adult guidelines. Higher glucocorticoid doses did not associate with improved outcomes.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Poliangiite Microscópica , Adolescente , Adulto , Anticorpos Anticitoplasma de Neutrófilos , Criança , Feminino , Glucocorticoides/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Masculino , Indução de Remissão , Rituximab/uso terapêuticoRESUMO
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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Artrite Juvenil/sangue , Artrite Juvenil/fisiopatologia , Mediadores da Inflamação/sangue , Adolescente , Fatores Etários , Artrite Juvenil/epidemiologia , Biomarcadores/sangue , Canadá/epidemiologia , Criança , Análise por Conglomerados , Estudos de Coortes , Mineração de Dados , Feminino , Humanos , Incidência , Masculino , Distribuição Normal , Estudos Prospectivos , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais , SíndromeRESUMO
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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Artrite Juvenil/diagnóstico , Interleucinas/sangue , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/sangue , Índice de Gravidade de Doença , Vitamina D/sangue , Adolescente , Articulação do Tornozelo/patologia , Área Sob a Curva , Artrite Juvenil/sangue , Artrite Juvenil/patologia , Biomarcadores/sangue , Canadá , Criança , Pré-Escolar , Feminino , Humanos , Interleucina-10/sangue , Interleucina-12/sangue , Interleucina-17/sangue , Articulação do Joelho/patologia , Estudos Longitudinais , Masculino , Valor Preditivo dos Testes , Estudos Prospectivos , Articulação do Punho/patologiaRESUMO
Numerous studies point to the utility of blood cytokine measurements in the diagnosis and treatment of human disease. Advances in detection allow robust multiplex analysis. However, cytokines are present at low levels and are produced and act in complex networks which can remain active in stored blood. A major barrier to the routine use of cytokines as clinical biomarkers is sample management prior to analysis. Studies on cytokine stability under storage frequently use 'spiked' normal control plasma or serum to generate detectable levels of the cytokines of interest. These conditions may oversimplify the reality of clinically complex samples and provide limited information regarding optimal management of whole blood samples prior to plasma separation. Cytokine stability has also been addressed previously using plasma from normal individuals under different conditions of anticoagulant use, storage time and temperature of storage. No studies have as yet been undertaken to address cytokine stability in critically ill patients which may differ from normal, healthy individuals due to underlying cofounders such as inflammation. To address these issues, we subjected samples from five patients exhibiting an inflammatory disease state to three storage extremes which might be encountered in a clinical setting, prior to analysis of 40 cytokines. Blood drawn into EDTA or ACD anticoagulant was immediately separated and plasma stored at -80 °C. Matched samples were stored as follows; whole blood overnight at room temperature, or whole blood or plasma stored 10 days at 4 °C. We used equivalence testing to determine the similarity of stored cytokine values to baseline values. In ACD plasma, Eotaxin, IL-6, IL-11, IL-15, IP10, MDC, MCP-1 met equivalence to baseline in all storage conditions while for EDTA plasma stored 10 days at 4 °C EGF, FGF2, Fractalkine, G-CSF, IL-1ß, IL-5, IL-6, IL-7, IL-11, IP-10, TGFα and TNFα showed equivalence to baseline measurements. Intraclass Correlation Coefficients (ICC) were calculated and the following cytokines showed good to excellent agreement across all 4 storage conditions: Eotaxin, IL-5, IL-6, IL-11, IL-13, IP-10, MCP-1 and TNFα when collected in EDTA, and Eotaxin, IL-5, IL-6, IL-11, IL12-p40, IL-15, IP-10 and MCP-1 when collected in ACD. Five plasma cytokines were identified as being the least stable in both ACD and EDTA: IL-7, IL-9, IL12p70, RANTES, sCD40L, while IL-1ß was identified as unstable stored in ACD plasma. This study identified several clinically important cytokines that are remarkably stable in blood and plasma, and some that stored poorly. To our knowledge, this is the first cytokine storage study to use medically unwell patient samples and equivalence testing to evaluate the stability of measured cytokine values after storage.
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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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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 ProspectivosRESUMO
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.
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Aorta , Artérias , Arterite de Takayasu , Rigidez Vascular/fisiologia , Disfunção Ventricular Esquerda , Adolescente , Aorta/diagnóstico por imagem , Aorta/fisiopatologia , Artérias/diagnóstico por imagem , Artérias/fisiopatologia , Canadá , Criança , Correlação de Dados , Ecocardiografia/métodos , Técnicas de Imagem por Elasticidade/métodos , Feminino , Humanos , Masculino , Manometria/métodos , Gravidade do Paciente , Análise de Onda de Pulso/métodos , Arterite de Takayasu/diagnóstico , Arterite de Takayasu/fisiopatologia , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
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.
Assuntos
Buffy Coat/citologia , Criopreservação , Monócitos/citologia , Bioensaio , Eritrócitos/imunologia , Humanos , Isoanticorpos/análise , FagocitoseAssuntos
Glioma , Proteínas Proto-Oncogênicas B-raf , Criança , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Glioma/tratamento farmacológico , Glioma/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/efeitos adversosRESUMO
Kawasaki disease (KD) is a multisystem vasculitis that predominantly targets the coronary arteries in children. Phenotypic similarities between KD and recurrent fever syndromes point to the potential role of inflammasome activation in KD. Mutations in NLRP3 are associated with recurrent fever/autoinflammatory syndromes. We show that the KD-associated genetic polymorphism in inositol-triphosphate 3-kinase C (ITPKC) (rs28493229) has important functional consequences, governing ITPKC protein levels and thereby intracellular calcium, which in turn regulates NLRP3 expression and production of IL-1ß and IL-18. Analysis of transcript abundance, protein levels, and cellular response profiles from matched, serial biospecimens from a cohort of genotyped KD subjects points to the critical role of ITPKC in mediating NLRP3 inflammasome activation. Treatment failure in those with the high-risk ITPKC genotype was associated with the highest basal and stimulated intracellular calcium levels and with increased cellular production of IL-1ß and IL-18 and higher circulating levels of both cytokines. Mechanistic studies using Itpkc-deficient mice in a disease model support the genomic, cellular, and clinical findings in affected children. Our findings provide the mechanism behind the observed efficacy of rescue therapy with IL-1 blockade in recalcitrant KD, and we identify that regulation of calcium mobilization is fundamental to the underlying immunobiology in KD.
Assuntos
Vasos Coronários/patologia , Síndrome de Linfonodos Mucocutâneos/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Animais , Pré-Escolar , Estudos de Coortes , Vasos Coronários/metabolismo , Genótipo , Humanos , Inflamassomos/metabolismo , Interleucina-18/genética , Interleucina-18/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Síndrome de Linfonodos Mucocutâneos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Polimorfismo de Nucleotídeo Único , Risco , Resultado do TratamentoRESUMO
Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 [P = 2.8 × 10(-17), odds ratio (OR) 2.6 (2.1, 3.3)], was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk [P = 1.0 × 10(-5), OR 0.7 (0.6, 0.8)]. Meta-analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB1*11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA [P = 2.7 × 10(-16), OR 2.3 (1.9, 2.8)], as was the HLA-DRB1*11-HLA-DQA1*05-HLA-DQB1*03 haplotype [6.4 × 10(-17), OR 2.3 (1.9, 2.9)]. By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA.
Assuntos
Artrite Juvenil/genética , Predisposição Genética para Doença/genética , Cadeias HLA-DRB1/genética , Antígenos de Histocompatibilidade Classe II/genética , Polimorfismo de Nucleotídeo Único , Criança , Frequência do Gene , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Metanálise como Assunto , Razão de Chances , Fatores de RiscoRESUMO
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.
Assuntos
Eritrócitos/imunologia , Lipossomos/imunologia , Colesterol/química , Citocinas/metabolismo , Selectina E/metabolismo , Membrana Eritrocítica/imunologia , Membrana Eritrocítica/metabolismo , Eritrócitos/metabolismo , Células Endoteliais da Veia Umbilical Humana/imunologia , Humanos , Lipossomos/química , Monócitos , Fagocitose , Fosfatidilcolinas/química , Fosfolipídeos/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
PURPOSE OF REVIEW: Kawasaki disease is an acute multisystem childhood vasculitis with a predilection for the coronary arteries. The role of corticosteroids and acetyl salicylic acid (ASA) in the treatment of acute Kawasaki disease are matters of ongoing debate and changing attitudes from one extreme to the other. Recent work has provided new evidence to guide our thinking about these two therapeutic agents, which will be the focus of this review. RECENT FINDINGS: Corticosteroids are effective and well tolerated in Kawasaki disease, both as initial adjunctive treatment in those at high-risk for poor outcome, and as rescue therapy after failed intravenous immunoglobulin (IVIG).Higher doses of ASA (> 30âmg/kg/day) in the acute phase of Kawasaki disease, have no clear benefit over antiplatelet doses in improving coronary outcome. SUMMARY: Corticosteroids should be used in patients at high-risk for poor coronary outcome, and in patients who fail IVIG. The absence of widely applicable and validated risk-scoring systems in Kawasaki disease outside of Japan remains a limiting factor to identify high-risk children. Current evidence does not demonstrate any advantage of high-dose over low-dose ASA in the acute phase of Kawasaki disease, in preventing coronary artery aneurysms.