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1.
Front Immunol ; 10: 2448, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31736939

RESUMO

Autoinflammatory diseases include disorders with a monogenic cause and also complex conditions associated to polygenic or multifactorial factors. An increased number of both monogenic and polygenic autoinflammatory conditions have been identified during the last years. Although skin manifestations are often predominant in monogenic autoinflammatory diseases, clinical and histopathological information regarding their dermatological involvement is still scarce. Monogenic autoinflammatory diseases with cutaneous expression can be classified based on the predominant lesion: (1) maculopapular rashes or inflammatory plaques; (2) urticarial rashes; (3) pustular, pyogenic or neutrophilic dermatosis-like rashes; (4) panniculitis or subcutaneous nodules; (5) vasculitis or vasculopathy; (6) hyperkeratotic lesions; (7) hyperpigmented lesions; (8) bullous lesions; and (9) aphthous lesions. By using this classification, this review intends to provide clinical and histopathological knowledge about cutaneous involvement in monogenic autoinflammatory diseases.

2.
Front Immunol ; 10: 2325, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681265

RESUMO

Primary immunodeficiencies (PIDs) refer to a clinically, immunologically, and genetically heterogeneous group of over 350 disorders affecting development or function of the immune system. The increasing use of next-generation sequencing (NGS) technology has greatly facilitated identification of genetic defects in PID patients in daily clinical practice. Several NGS approaches are available, from the unbiased whole exome sequencing (WES) to specific gene panels. Here, we report on a 3-year experience with clinical exome sequencing (CES) for genetic diagnosis of PIDs. We used the TruSight One sequencing panel, which includes 4,813 disease-associated genes, in 61 unrelated patients (pediatric and adults). The analysis was done in 2 steps: first, we focused on a virtual PID panel and then, we expanded the analysis to the remaining genes. A molecular diagnosis was achieved in 19 (31%) patients: 12 (20%) with mutations in genes included in the virtual PID panel and 7 (11%) with mutations in other genes. These latter cases provided interesting and somewhat unexpected findings that expand the clinical and genetic spectra of PID-related disorders, and are useful to consider in the differential diagnosis. We also discuss 5 patients (8%) with incomplete genotypes or variants of uncertain significance. Finally, we address the limitations of CES exemplified by 7 patients (11%) with negative results on CES who were later diagnosed by other approaches (more specific PID panels, WES, and comparative genomic hybridization array). In summary, the genetic diagnosis rate using CES was 31% (including a description of 12 novel mutations), which rose to 42% after including diagnoses achieved by later use of other techniques. The description of patients with mutations in genes not included in the PID classification illustrates the heterogeneity and complexity of PID-related disorders.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31033198

RESUMO

OBJECTIVE: to compare the accuracy of Birmingham Vasculitis score (BVAS) v.3, and Five Factors Score (FFS) v.1996 and v.2009, to assess survival in ANCA-associated Vasculitis (AAV). METHODS: 550 patients with AAV (41.1% GPA, 37.3% MPA, 21.6% EGPA) diagnosed between 1990-2016 were analyzed. ROC curves and multivariable Cox analysis were used to assess the relationships between the outcome and the different scores. RESULTS: Overall mortality was 33.1%. The mean BVAS at diagnosis was 17.96±7.82, and was significantly higher in non-survivors than in survivors (20.0±8.14 vs. 16.95±7.47, p<0.001). The mean 1996FFS and 2009FFS were 0.81±0.94 and 1.47±1.16, respectively, and were significantly higher in non-survivors than in survivors (1.17±1.07 vs. 0.63±0.81, p<0.001; 2.13±1.09 vs. 1.15±1.05, p<0.001). Mortality rates increased accordingly to the different 1996FFS and 2009FFS categories. In multivariate analysis BVAS, 1996FFS and 2009FFS were significantly related to death (p=0.007, p=0.020, p<0.001), but the stronger predictor was the 2009FFS (HR 2.9, 2.4-3.6). When the accuracy of BVAS, 1996FFS and 2009FFS to predict survival was compared in the global cohort, ROC analysis yielded AUC values of 0.60, 0.65 and 0.74, respectively, indicating that 2009FFS had the best performance. Similar results were obtained when comparing these scores in patients diagnosed before and after 2001, and assessing the 1-year, 5-years and long-term mortality. Correlation among BVAS and 1996FFS was modest (r=0.49, p<0.001), but higher than between BVAS and 2009FFS (r=0.28, p<0.001). CONCLUSION: BVAS and FFS are useful to predict survival in AAV, but 2009FFS has the best prognostic accuracy at any point of the disease course. SIGNIFICANCE AND INNOVATION: This is the first study comparing the BVAS, 1996FFS and 2009FFS accuracy to assess survival in patients with AAV, and the first to validate 2009FFS in these patients. This article is protected by copyright. All rights reserved.

4.
Clin Exp Rheumatol ; 2018 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-29745871

RESUMO

OBJECTIVES: To describe the characteristics of patients with Behçet's disease (BD) who presented with venous thrombosis. In addition, we identified the factors associated with this venous involvement and those related with recurrent venous thrombosis. METHODS: Up to January 2015, 544 BD patients from 20 Spanish hospitals had been included in the REGEB (REGistro de la Enfermedad de Behçet as Spanish nomenclature). We selected those patients who presented venous thrombosis. Descriptive analysis was performed and factors related with venous thrombosis were identified. RESULTS: Overall, 99 (18.2%) BD patients had vascular thrombosis, 91 (16.7%) of them (16.7%) involving venous vessels and 18 (19.7%) suffered from venous thrombotic relapse. Lower limbs were the most common location of deep venous thrombosis present in up to 60% of patients. In 12 (13.2%) patients, venous thrombosis affected two vascular territories simultaneously and in 6 (6.6%) the venous and arterial involvement coincided in time. Overall, at the diagnosis of venous thrombosis, 97.6% of patients presented concomitantly other clinical symptoms attributable to BD. In logistic regression multivariate analysis factors associated to venous thrombosis were male sex (Odds ratio [OR] 4.3, 95% confidence interval [CI] 2.5-7.7), erythema nodosum (OR 2.4, 95%CI 1.4-4.1), fever (OR 2.0, 95%CI 1.1-3.8), and central nervous system (CNS) involvement (OR 2.5, 95%CI 1.3-4.8). Considering relapses, CNS involvement was an independent risk factor according logistic regression. However, Cox multivariate analysis did not confirm this finding. CONCLUSIONS: We identified factors related with venous involvement in patients included in the REGEB cohort.

5.
J Clin Immunol ; 37(8): 781-789, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28942469

RESUMO

The complement system is an important effector arm of innate immunity and plays a crucial role in the defense against common pathogens. But effective defense and maintenance of homeostasis requires a careful balance between complement activation and regulation. Factor I (FI) is one of the most important regulators of the complement system. Complete FI deficiency is a rare autosomal recessive disorder typically resulting in severe, recurrent infection by encapsulated bacteria. In the present study, we describe two patients from unrelated families with complete FI deficiency diagnosed at very different ages: Patient 1 is a 60-year-old man who had experienced several severe infections (pneumonia, meningitis, sepsis) since childhood, one of which caused significant and permanent neurologic sequelae. In contrast, patient 2 was diagnosed at the age of 4 years after a single infectious episode (otitis media) and through detection of a flat beta2 peak on serum protein electrophoresis. This early diagnosis of FI deficiency enabled prompt implementation of a therapeutic intervention consisting of vaccination with encapsulated bacteria and prophylactic antibiotics. The two patients had novel homozygous mutations in the CFI gene (p.Gly162Asp and p.His380Arg) that disrupted protein function. Interestingly, p.His380Arg is the first mutation described affecting a residue of the highly conserved FI catalytic triad (His380, Asp429, and Ser525). This study illustrates the importance of early versus late diagnosis of FI deficiency and, in general, highlights the clinical relevance of prompt detection of complement system deficiencies.


Assuntos
Vacinas Bacterianas/imunologia , Complemento C3/deficiência , Fator I do Complemento/genética , Doenças Genéticas Inatas/diagnóstico , Infecção/diagnóstico , Meningites Bacterianas/diagnóstico , Mutação/genética , Antibioticoprofilaxia , Pré-Escolar , Complemento C3/genética , Diagnóstico Tardio , Diagnóstico Precoce , Família , Doenças Genéticas Inatas/genética , Homozigoto , Humanos , Imunidade Inata , Infecção/genética , Masculino , Meningites Bacterianas/genética , Meningites Bacterianas/prevenção & controle , Pessoa de Meia-Idade , Linhagem , Vacinação
6.
J Bone Miner Res ; 32(7): 1575-1581, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28263001

RESUMO

Gaucher disease (GD), one of the most common lysosomal disorders (a global population incidence of 1:50,000), is characterized by beta-glucocerebrosidase deficiency. Some studies have demonstrated bone infiltration in up to 80% of patients, even if asymptomatic. Bone disorder remains the main cause of morbidity in these patients, along with osteoporosis, avascular necrosis, and bone infarcts. Enzyme replacement therapy (ERT) has been shown to improve these symptoms. This cross-sectional study included patients with type 1 Gaucher disease (GD1) selected from the Catalan Study Group on GD. Clinical data were collected and a general laboratory workup was performed. Bone mineral density (BMD) was measured at the lumbar spine and hip using dual-energy X-ray absorptiometry (DXA). Patients with bone infarcts or any other focal lesion in the area of indentation visible on imaging were excluded. Bone Material Strength index (BMSi) was measured by bone impact microindentation using an Osteoprobe instrument. Analysis of covariance (ANCOVA) models were fitted to adjust for age, sex, weight, and height. Sixteen patients with GD1 and 29 age- and sex-matched controls were included. GD1 was associated with significantly lower BMSi (adjusted beta -9.30; 95% CI, -15.18 to -3.42; p = 0.004) and reduced lumbar BMD (adjusted beta -0.14; 95% CI, -0.22 to -0.06; p = 0.002) and total hip BMD (adjusted beta -0.09; 95% CI, -0.15 to -0.03; p = 0.006), compared to GD1-free controls. Chitotriosidase levels were negatively correlated with BMSi (linear R2 = 51.6%, p = 0.004). Bone tissue mechanical characteristics were deteriorated in patients with GD1. BMSi was correlated with chitotriosidase, the marker of GD activity. Bone disorder requires special consideration in this group of patients, and microindentation could be an appropriate tool for assessing and managing their bone health. © 2017 American Society for Bone and Mineral Research.


Assuntos
Densidade Óssea , Doença de Gaucher/metabolismo , Osteoporose/metabolismo , Adulto , Idoso , Estudos Transversais , Feminino , Doença de Gaucher/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/patologia , Espanha
7.
Medicine (Baltimore) ; 96(8): e6083, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28225490

RESUMO

The aim of this study was to describe the clinical characteristics of ANCA-associated vasculitides (AAV) at presentation, in a wide cohort of Spanish patients, and to analyze the impact of the vasculitis type, ANCA specificity, prognostic factors, and treatments administered at diagnosis, in the outcome.A total of 450 patients diagnosed between January 1990 and January 2014 in 20 Hospitals from Spain were included. Altogether, 40.9% had granulomatosis with polyangiitis (GPA), 37.1% microscopic polyangiitis (MPA), and 22% eosinophilic granulomatosis with polyangiitis (EGPA). The mean age at diagnosis was 55.6 ±â€Š17.3 years, patients with MPA being significantly older (P < 0.001). Fever, arthralgia, weight loss, respiratory, and ear-nose-throat (ENT) symptoms, were the most common at disease onset. ANCAs tested positive in 86.4% of cases: 36.2% C-ANCA-PR3 and 50.2% P-ANCA-MPO. P-ANCA-MPO was significantly associated with an increased risk for renal disease (OR 2.6, P < 0.001) and alveolar hemorrhage (OR 2, P = 0.010), while C-ANCA-PR3 was significantly associated with an increased risk for ENT (OR 3.4, P < 0.001) and ocular involvement (OR 2.3, P = 0.002). All patients received corticosteroids (CS) and 74.9% cyclophosphamide (CYC). The median follow-up was 82 months (IQR 100.4). Over this period 39.9% of patients suffered bacterial infections and 14.6% opportunistic infections, both being most prevalent in patients with high-cumulated doses of CYC and CS (P < 0.001). Relapses were recorded in 36.4% of cases with a mean rate of 2.5 ±â€Š2.3, and were more frequent in patients with C-ANCA-PR3 (P = 0.012). The initial disease severity was significantly associated with mortality but not with the occurrence of relapses. One hundred twenty-nine (28.7%) patients (74 MPA, 41 GPA, 14 EGPA) died. The mean survival was 58 months (IQR 105) and was significantly lower for patients with MPA (P < 0.001). Factors independently related to death were renal involvement (P = 0.010), cardiac failure (P = 0.029) and age over 65 years old (P < 0.001) at disease onset, and bacterial infections (P < 0.001). An improved outcome with significant decrease in mortality and treatment-related morbidity was observed in patients diagnosed after 2000, and was related to the implementation of less toxic regimens adapted to the disease activity and stage, and a drastic reduction in the cumulated CYC and CS dose.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/mortalidade , Anticorpos Anticitoplasma de Neutrófilos/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/fisiopatologia , Comorbidade , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prevalência , Recidiva , Estudos Retrospectivos , Espanha/epidemiologia , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
8.
Clin Rheumatol ; 35(3): 695-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25711877

RESUMO

Microparticles (MP) are considered a key component in the haemostatic response. Beyond their in vitro procoagulant properties, a number of pieces of evidence points to procoagulant MP as efficient effectors in the haemostatic response and as pathogenic markers of thrombotic disorders and vascular damage. The aim of the present study was to analyze the procoagulant activity of MP and its correlation with clinical manifestations focusing on vascular involvement in patients with Behçet's disease (BD). We analyzed 55 BD patients in inactive phase of the disease (26 men; mean age, 35 ± 15 years) of which 19 had previously suffered from thrombosis (deep venous thrombosis in 17 and ischemic stroke in 2), and 73 healthy controls matched for age and sex. Procoagulant MP were assessed by a functional assay. BD patients showed higher procoagulant MP values than controls (22.89 ± 15.74 nM versus 14.47 ± 7.34 nM; p < 0.0001). Conversely, we did not find differences in the levels of procoagulant MP according to the gender of patients (22.22 ± 16.23 nM for men versus 21.46 ± 16.47 for women; p = 0.846) or to previous and current treatments. Moreover, the plasmatic concentration of MP does not define any clinical phenotype and it was not related to the time of evolution of the disease. Although inactive BD patients had high values of procoagulant MP, they did not differentiate between BD patients with or without thrombosis.


Assuntos
Síndrome de Behçet/patologia , Micropartículas Derivadas de Células/patologia , Trombose/patologia , Adolescente , Adulto , Idoso , Síndrome de Behçet/sangue , Biomarcadores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Trombose/sangue , Adulto Jovem
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