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1.
J Intern Med ; 295(5): 651-667, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38462959

RESUMO

BACKGROUND: Microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) are the two major antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). OBJECTIVES: To characterize a homogenous AAV cohort and to assess the impact of clinicopathological profiles and ANCA serotypes on clinical presentation and prognosis. Clinical differences in GPA patients according to ANCA serotype and the diagnostic yield for vasculitis of biopsies in different territories were also investigated. RESULTS: This retrospective study (2000-2021) included 152 patients with AAV (77 MPA/75 GPA). MPA patients (96.1% myeloperoxidase [MPO]-ANCA and 2.6% proteinase 3 [PR3]-ANCA) presented more often with weight loss, myalgia, renal involvement, interstitial lung disease (ILD), cutaneous purpura, and peripheral nerve involvement. Patients with GPA (44% PR3-ANCA, 33.3% MPO, and 22.7% negative/atypical ANCA) presented more commonly with ear, nose, and throat and eye/orbital manifestations, more relapses, and higher survival than patients with MPA. GPA was the only independent risk factor for relapse. Poor survival predictors were older age at diagnosis and peripheral nerve involvement. ANCA serotypes differentiated clinical features in a lesser degree than clinical phenotypes. A mean of 1.5 biopsies were performed in 93.4% of patients in different territories. Overall, vasculitis was identified in 80.3% (97.3% in MPA and 61.8% in GPA) of patients. CONCLUSIONS: The identification of GPA presentations associated with MPO-ANCA and awareness of risk factors for relapse and mortality are important to guide proper therapeutic strategies in AAV patients. Biopsies of different affected territories should be pursued in difficult-to-diagnose patients based on their significant diagnostic yield.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Granulomatose com Poliangiite , Poliangiite Microscópica , Humanos , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/tratamento farmacológico , Poliangiite Microscópica/diagnóstico , Poliangiite Microscópica/complicações , Anticorpos Anticitoplasma de Neutrófilos/uso terapêutico , Estudos Retrospectivos , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Mieloblastina , Recidiva
2.
J Autoimmun ; 146: 103240, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38754238

RESUMO

BACKGROUND: Giant cell arteritis (GCA) is an immune-mediated large-vessels vasculitis with complex etiology. Although the pathogenic mechanisms remain poorly understood, a central role for CD4+ T cells has been demonstrated. In this context, understanding the transcriptome dysregulation in GCA CD4+ T cells will yield new insights into its pathogenesis. METHODS: Transcriptome analysis was conducted on CD4+ T cells from 70 patients with GCA with different disease activity and treatment status (active patients before treatment and patients in remission with and without glucocorticoid treatment), and 28 healthy controls. The study also evaluated potential impacts of DNA methylation on gene expression alterations and assessed cross-talk with CD14+ monocytes. RESULTS: This study has uncovered a substantial number of genes and pathways potentially contributing to the pathogenicity of CD4+ T cells in GCA. Specifically, CD4+ T cells from GCA patients with active disease exhibited altered expression levels of genes involved in multiple immune-related processes, including various interleukins (IL) signaling pathways. Notably, IL-2, a decisive interleukin for regulatory T cells homeostasis, was among the most significant. Additionally, impaired apoptotic pathways appear crucial in GCA development. Our findings also suggest that histone-related epigenetic pathways may be implicated in promoting an inflammatory phenotype in GCA active patients. Finally, our study observed altered signaling communication, such as the Jagged-Notch signaling, between CD4+ T cells and monocytes that could have pathogenic relevance in GCA. CONCLUSIONS: Our study suggests the participation of novel cytokines and pathways and the occurrence of a disruption of monocyte-T cell crosstalk driving GCA pathogenesis.


Assuntos
Linfócitos T CD4-Positivos , Perfilação da Expressão Gênica , Arterite de Células Gigantes , Monócitos , Transdução de Sinais , Transcriptoma , Humanos , Arterite de Células Gigantes/imunologia , Arterite de Células Gigantes/genética , Monócitos/imunologia , Monócitos/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Feminino , Masculino , Idoso , Metilação de DNA , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Epigênese Genética , Comunicação Celular/imunologia , Regulação da Expressão Gênica
3.
Int J Mol Sci ; 25(14)2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-39062798

RESUMO

Fibrosing interstitial lung diseases (ILDs) are characterized by the gradual and irreversible accumulation of scar tissue in the lung parenchyma. The role of the immune response in the pathogenesis of pulmonary fibrosis remains unclear. In recent years, substantial advancements have been made in our comprehension of the pathobiology driving fibrosing ILDs, particularly concerning various age-related cellular disturbances and immune mechanisms believed to contribute to an inadequate response to stress and increased susceptibility to lung fibrosis. Emerging studies emphasize cellular senescence as a key mechanism implicated in the pathobiology of age-related diseases, including pulmonary fibrosis. Cellular senescence, marked by antagonistic pleiotropy, and the complex interplay with immunity, are pivotal in comprehending many aspects of lung fibrosis. Here, we review progress in novel concepts in cellular senescence, its association with the dysregulation of the immune response, and the evidence underlining its detrimental role in fibrosing ILDs.


Assuntos
Senescência Celular , Doenças Pulmonares Intersticiais , Fibrose Pulmonar , Humanos , Senescência Celular/imunologia , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/patologia , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , Animais , Pulmão/imunologia , Pulmão/patologia , Imunidade
4.
Rheumatology (Oxford) ; 62(SI): SI82-SI90, 2023 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-35713496

RESUMO

OBJECTIVE: The objective of this study was to analyse the clinico-serological and histological phenotypes of patients with SSc with associated myopathy. METHODS: From November 2002 to September 2020, 52 patients with SSc underwent a muscle biopsy for suspected myopathy. We established two subgroups according to the histological findings based on the presence of isolated fibrosis or fibrosis together with significant inflammation. These patterns were designated as fibrosing and inflammatory, respectively. Clinical data, antibody profile, electrophysiologic studies, muscle biopsy findings and data regarding treatment, mortality and survival were compared between the two groups. RESULTS: Fourteen biopsies had a fibrosing pattern, whereas 26 showed an inflammatory pattern that could be classified (according to the predominant pattern) into DM (n = 7), necrotizing myopathy (n = 4) and non-specific myositis (n = 15). Additionally, 12 muscle biopsies were reported as neurogenic atrophy (n = 2), or normal muscle or minimal changes (n = 10). Compared with the inflammatory group, SSc patients with the fibrosing pattern presented a higher prevalence of ischaemic heart disease (38.5% vs 3.8%, P = 0.011), conduction abnormalities or arrhythmias (61.5% vs 26.9%, P = 0.036), anti-topo I antibodies (42.9% vs 11.5%, P = 0.044), greater median ESR (53.5 mm/h vs 32.5 mm/h, P = 0.013), with poor response to treatment and a higher mortality (42.9% vs 3.8%, P = 0.004) and lower cumulative survival (P = 0.035). CONCLUSIONS: Patients with SSc-associated myopathy require a comprehensive approach that encompasses clinical, serological and histopathological aspects, given their outcome predictive capacity. At least two different phenotypes can be drawn, considering clinico-pathological features. Significant differences are delineated between both a fibrotic and an inflammatory phenotype.


Assuntos
Doenças Musculares , Escleroderma Sistêmico , Humanos , Doenças Musculares/complicações , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/patologia , Fibrose , Biópsia , Fenótipo
5.
Ann Rheum Dis ; 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35705375

RESUMO

OBJECTIVES: Giant cell arteritis (GCA) is a complex systemic vasculitis mediated by the interplay between both genetic and epigenetic factors. Monocytes are crucial players of the inflammation occurring in GCA. Therefore, characterisation of the monocyte methylome and transcriptome in GCA would be helpful to better understand disease pathogenesis. METHODS: We performed an integrated epigenome-and transcriptome-wide association study in CD14+ monocytes from 82 patients with GCA, cross-sectionally classified into three different clinical statuses (active, in remission with or without glucocorticoid (GC) treatment), and 31 healthy controls. RESULTS: We identified a global methylation and gene expression dysregulation in GCA monocytes. Specifically, monocytes from active patients showed a more proinflammatory phenotype compared with healthy controls and patients in remission. In addition to inflammatory pathways known to be involved in active GCA, such as response to IL-6 and IL-1, we identified response to IL-11 as a new pathway potentially implicated in GCA. Furthermore, monocytes from patients in remission with treatment showed downregulation of genes involved in inflammatory processes as well as overexpression of GC receptor-target genes. Finally, we identified changes in DNA methylation correlating with alterations in expression levels of genes with a potential role in GCA pathogenesis, such as ITGA7 and CD63, as well as genes mediating the molecular response to GC, including FKBP5, ETS2, ZBTB16 and ADAMTS2. CONCLUSION: Our results revealed profound alterations in the methylation and transcriptomic profiles of monocytes from GCA patients, uncovering novel genes and pathways involved in GCA pathogenesis and in the molecular response to GC treatment.

6.
J Antimicrob Chemother ; 76(12): 3296-3302, 2021 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-34473275

RESUMO

BACKGROUND: The use of remdesivir has demonstrated a significant reduction in the time to recovery in patients with COVID-19. However, the impact on mortality is still controversial. Therefore, it is necessary to evaluate whether there is a specific subgroup of patients in whom an active antiviral therapy also reduces the mortality. METHODS: Patients admitted for >48 h in our hospital for a SARS-CoV-2 confirmed or suspected infection from February 2020 to February 2021 were retrospectively analysed. The primary outcome of the study was mortality at 30 days. Univariate and multivariate analyses were performed to identify predictors of mortality. RESULTS: In total, 2607 patients (438 receiving remdesivir and 2169 not) were included with a median (IQR) age of 65 (54-77) years and 58% were male. Four hundred and seventy-six were admitted to the ICU (18.3%) and 264 required invasive mechanical ventilation (10.1%). The global 30 day mortality rate was 10.7%. Pre-admission symptom duration of 4-6 days and ≤3 days was associated with a 1.5- and 2.5-fold increase in the mortality rate, respectively, in comparison with >6 days and treatment with remdesivir was independently associated with a lower mortality rate (OR = 0.382, 95% CI = 0.218-0.671). The analysis showed that the major difference was among patients with shorter pre-admission symptom duration (<6 days). CONCLUSIONS: Patients with ≤3 days and 4-6 days from symptom onset to admission are associated with a 2.5- and 1.5-fold higher risk of death, respectively. Remdesivir was associated with 62% reduced odds of death versus standard-of-care and its survival benefit increased with shorter duration of symptoms.


Assuntos
Tratamento Farmacológico da COVID-19 , Monofosfato de Adenosina/análogos & derivados , Idoso , Alanina/análogos & derivados , Antivirais/uso terapêutico , Humanos , Masculino , Respiração Artificial , Estudos Retrospectivos , SARS-CoV-2
7.
J Autoimmun ; 117: 102580, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33338707

RESUMO

BACKGROUND AND AIM: There is increasing interest regarding SARS-CoV-2 infection in patients with autoimmune and immune-mediated inflammatory diseases (AI/IMID) with some discrepancies in different cohorts about their risk and outcomes. The aim was to describe a multidisciplinary cohort of patients with AI/IMID and symptomatic SARS-CoV-2 infection in a single tertiary center and analyze sociodemographic, clinical, and therapeutic factors associated with poor outcomes. METHODS: A retrospective observational study was conducted from the 1st of March until May 29th, 2020 in a University tertiary hospital in Barcelona, Spain. Patients with an underlying AI/IMID and symptomatic SARS-CoV-2 infection were identified in our local SARS-CoV-2 infection database. Controls (2:1) were selected from the same database and matched by age and gender. The primary outcome was severe SARS-CoV-2 infection, which was a composite endpoint including admission to the intensive care unit (ICU), need for mechanical ventilation (MV), and/or death. Several covariates including age, sex, and comorbidities among others were combined into a multivariate model having severe SARS-CoV-2 as the dependent variable. Also, a sensitivity analysis was performed evaluating AID and IMID separately. RESULTS: The prevalence of symptomatic SARS-CoV-2 infection in a cohort of AI/IMID patients was 1.3%. Eighty-five patients with AI/IMID and symptomatic SARS-CoV-2 were identified, requiring hospitalization in 58 (68%) cases. A total of 175 patients admitted for SARS-CoV-2 (58 with AI/IMID and 117 matched-controls) were analyzed. In logistic regression analysis, a significant inverse association between AI/IMID group and severe SARS-CoV-2 (OR 0.28; 95% CI 0.12-0.61; p = 0.001), need of MV (OR 0.20; IC 95% 0.05-0.71; p = 0.014), and ICU admission (OR 0.25; IC 95% 0.10-0.62; p = 0.003) was found. CONCLUSIONS: Patients with AI/IMID who require admission for SARS-CoV-2 infection have a lower risk of developing severe disease, including the need to stay in the ICU and MV.


Assuntos
Doenças Autoimunes/epidemiologia , COVID-19/epidemiologia , Sistema de Registros , SARS-CoV-2/fisiologia , Idoso , Doenças Autoimunes/mortalidade , COVID-19/mortalidade , Estudos de Coortes , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Comunicação Interdisciplinar , Masculino , Pessoa de Meia-Idade , Prevalência , Respiração Artificial/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Espanha/epidemiologia , Análise de Sobrevida , Resultado do Tratamento
8.
Rheumatology (Oxford) ; 59(7): 1574-1580, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31628810

RESUMO

OBJECTIVE: To analyse the clinical utility of trabecular bone score (TBS) evaluation for fracture risk assessment in glucocorticoid (GC)-treated patients compared with BMD assessment. METHODS: One hundred and twenty-seven patients on GC treatment were included [mean age 62 (18) years, 63% women] in this cross-sectional study. The medical history, anthropometric data, lumbar and femoral BMD (DXA) [considering osteoporosis (OP): T-score ⩽-2.5], TBS (considering degraded microarchitecture: <1.230) and dorsolumbar X-ray [to assess vertebral fractures (VF)] were evaluated. BMD and TBS sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were evaluated to determine the diagnostic accuracy of the two methods. RESULTS: All patients were receiving GC treatment for autoimmune diseases during 47.7 (68.9) months at a mean daily dose of 14.5 mg; 17% had VF, 28% any type of fragility fracture (VF + non-VF), 29% OP and 52% degraded microarchitecture. Degraded microarchitecture was significantly more frequent than densitometric OP in patients with VF (76% vs 38%) and with any fragility fracture (69% vs 36%). For VF, TBS and BMD sensitivity, specificity, PPV, and NPV were 0.76, 0.53, 0.25 and 0.92, and 0.38, 0.72, 0.22 and 0.85, respectively. Specificity increased to 0.89 for VF and 0.9 for any fragility fracture on combining BMD+TBS. TBS had better ability than BMD to discriminate between patients with fracture, especially VF (area under the curve = 0.73). CONCLUSION: TBS seems to have greater discriminative power than BMD for fracture risk assessment in GC-treated patients, confirming the utility of this method as a complementary tool in the diagnosis of GC-induced OP.


Assuntos
Densidade Óssea , Osso Esponjoso/diagnóstico por imagem , Fêmur/diagnóstico por imagem , Glucocorticoides/efeitos adversos , Vértebras Lombares/diagnóstico por imagem , Osteoporose/diagnóstico por imagem , Fraturas por Osteoporose/epidemiologia , Fraturas da Coluna Vertebral/epidemiologia , Absorciometria de Fóton , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/induzido quimicamente , Osteoporose/complicações , Fraturas por Osteoporose/diagnóstico por imagem , Fraturas por Osteoporose/etiologia , Medição de Risco , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/etiologia
10.
Age Ageing ; 49(1): 146-148, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31697357

RESUMO

New onset of granulomatosis with polyangiitis (GPA) occurring in patients previously diagnosed with rheumatoid arthritis (RA) is very uncommon. In older individuals, this condition is associated with high mortality, especially in those with renal involvement. We describe the first case of GPA in a patient older than 65 years diagnosed with RA without exposure to biologic disease-modifying anti-rheumatic drugs, presenting with pulmonary nodules due to a limited form of anti-neutrophil cytoplasmic antibody-negative GPA.


Assuntos
Artrite Reumatoide/complicações , Granulomatose com Poliangiite/etiologia , Idoso de 80 Anos ou mais , Granulomatose com Poliangiite/patologia , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Tomografia por Emissão de Pósitrons
11.
Skeletal Radiol ; 48(5): 653-676, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30377729

RESUMO

Magnetic resonance imaging (MRI) is considered the most sensitive and specific imaging technique for the detection of muscle diseases related to myopathies. Since 2008, the use of whole-body MRI (WBMRI) to evaluate myopathies has improved due to technical advances such as rolling table platform and parallel imaging, which enable rapid assessment of the entire musculoskeletal system with high-quality images. WBMRI protocols should include T1-weighted and short-tau inversion recovery (STIR), which provide the basic pulse sequences for studying myopathies, in order to detect fatty infiltration/muscle atrophy and muscle edema, respectively. High signal intensity in T1-weighted images shows chronic disease with fatty infiltration, whereas high signal intensity in STIR indicates an acute stage with muscle edema. Additional sequences such as diffusion-weighted imaging (DWI) can be readily incorporated into routine WBMRI study protocols. Contrast-enhanced sequences have not been done. This article reviews WBMRI as an imaging method to evaluate different myopathies (idiopathic inflammatory, dystrophic, non-dystrophic, metabolic, and channelopathies). WBMRI provides a comprehensive estimate of the total burden with a single study, seeking specific distribution patterns, including clinically silent involvement of muscle areas. Furthermore, WBMRI may help to select the "target muscle area" for biopsy during patient follow-up. It may be also be used to detect related and non-related pathological conditions, such as tumors.


Assuntos
Imageamento por Ressonância Magnética , Doenças Musculares/diagnóstico por imagem , Imagem Corporal Total , Adulto , Humanos , Doenças Musculares/patologia
12.
Am J Hum Genet ; 96(4): 565-80, 2015 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-25817017

RESUMO

We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10(-40), OR = 1.73). A multivariate model including class II amino acids of HLA-DRß1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1(∗)04. An omnibus test on polymorphic amino acid positions highlighted DRß1 13 (p = 4.08 × 10(-43)) and HLA-DQα1 47 (p = 4.02 × 10(-46)), 56, and 76 (both p = 1.84 × 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10 × 10(-5), OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function.


Assuntos
Genes MHC da Classe II/genética , Arterite de Células Gigantes/genética , Herança Multifatorial/genética , Estudos de Coortes , Estudos de Associação Genética , Genótipo , Humanos , Análise Multivariada , Razão de Chances , População Branca/genética
13.
Skin Pharmacol Physiol ; 31(4): 184-187, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29649806

RESUMO

BACKGROUND: Chronic spontaneous urticaria (CSU) is a frequent mast cell-driven disease that affects approximately 0.5-1% of the population. Antihistamines are currently the drugs of choice in patients with CSU. Omalizumab has been shown to be very effective in CSU and has been recently approved as second-line therapy. However, although its introduction has markedly improved the therapeutic possibilities for CSU, there is still a hard core of patients who do not respond and require effective treatment. METHODS: We report the case of a patient who achieved an 8-month remission of refractory CSU following the use of rituximab, and perform a review of the literature regarding the use of rituximab in CSU. RESULTS: There was a remarkable improvement in her CSU after the administration of rituximab maintained over time. CONCLUSION: Rituximab is a chimeric murine/human monoclonal antibody directed against CD20, which depletes memory B-lymphocytes that are necessary for autoantibody production. The abrogation of the autoantibody production is the proposed mechanism by which it may alleviate the symptoms of CSU.


Assuntos
Fatores Imunológicos/uso terapêutico , Rituximab/uso terapêutico , Urticária/tratamento farmacológico , Adulto , Autoanticorpos/imunologia , Doença Crônica , Feminino , Humanos , Fatores Imunológicos/farmacologia , Rituximab/farmacologia , Resultado do Tratamento , Urticária/imunologia
14.
Ann Rheum Dis ; 76(9): 1624-1634, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28606962

RESUMO

BACKGROUND: Giant-cell arteritis (GCA) is an inflammatory disease of large/medium-sized arteries, frequently involving the temporal arteries (TA). Inflammation-induced vascular remodelling leads to vaso-occlusive events. Circulating endothelin-1 (ET-1) is increased in patients with GCA with ischaemic complications suggesting a role for ET-1 in vascular occlusion beyond its vasoactive function. OBJECTIVE: To investigate whether ET-1 induces a migratory myofibroblastic phenotype in human TA-derived vascular smooth muscle cells (VSMC) leading to intimal hyperplasia and vascular occlusion in GCA. METHODS AND RESULTS: Immunofluorescence/confocal microscopy showed increased ET-1 expression in GCA lesions compared with control arteries. In inflamed arteries, ET-1 was predominantly expressed by infiltrating mononuclear cells whereas ET receptors, particularly ET-1 receptor B (ETBR), were expressed by both mononuclear cells and VSMC. ET-1 increased TA-derived VSMC migration in vitro and α-smooth muscle actin (αSMA) expression and migration from the media to the intima in cultured TA explants. ET-1 promoted VSMC motility by increasing activation of focal adhesion kinase (FAK), a crucial molecule in the turnover of focal adhesions during cell migration. FAK activation resulted in Y397 autophosphorylation creating binding sites for Src kinases and the p85 subunit of PI3kinases which, upon ET-1 exposure, colocalised with FAK at the focal adhesions of migrating VSMC. Accordingly, FAK or PI3K inhibition abrogated ET-1-induced migration in vitro. Consistently, ET-1 receptor A and ETBR antagonists reduced αSMA expression and delayed VSMC outgrowth from cultured GCA-involved artery explants. CONCLUSIONS: ET-1 is upregulated in GCA lesions and, by promoting VSMC migration towards the intimal layer, may contribute to intimal hyperplasia and vascular occlusion in GCA.


Assuntos
Movimento Celular/genética , Endotelina-1/genética , Arterite de Células Gigantes/genética , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Remodelação Vascular/genética , Actinas/efeitos dos fármacos , Actinas/genética , Actinas/metabolismo , Idoso , Western Blotting , Estudos de Casos e Controles , Movimento Celular/efeitos dos fármacos , Antagonistas dos Receptores de Endotelina/farmacologia , Endotelina-1/metabolismo , Endotelina-1/farmacologia , Feminino , Imunofluorescência , Quinase 1 de Adesão Focal/antagonistas & inibidores , Quinase 1 de Adesão Focal/metabolismo , Arterite de Células Gigantes/metabolismo , Arterite de Células Gigantes/patologia , Humanos , Hiperplasia , Técnicas In Vitro , Leucócitos Mononucleares , Masculino , Microscopia Confocal , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação , Receptor de Endotelina A/efeitos dos fármacos , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Túnica Íntima/patologia , Remodelação Vascular/efeitos dos fármacos , Quinases da Família src/metabolismo
15.
Clin Exp Rheumatol ; 35 Suppl 103(1): 185-188, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27974095

RESUMO

Human immunodeficiency virus (HIV)-associated vasculitis is a rare secondary systemic vasculitis involving small and medium arteries. We report a 42-year-old man with uncontrolled HIV infection presenting with long-lasting abdominal pain. An abdominal CT angiography revealed multiple microaneurysms and stenoses in intrarenal arteries, with involvement of mesenteric and hepatic arteries. HIV-associated vasculitis was diagnosed and glucocorticoids and raltegravir-based antiretroviral therapy were administered with good initial clinical and virological response. Several episodes of acute intestinal ischaemia were later developed requiring bowel resections of which histological examination showed vascular occlusive fibrotic changes without active vasculitic lesions. Vasculitis persisted in remission and intrarenal microaneurysms disappeared.


Assuntos
Aneurisma/etiologia , Infecções por HIV/complicações , Artéria Hepática , Artérias Mesentéricas , Isquemia Mesentérica/etiologia , Oclusão Vascular Mesentérica/etiologia , Artéria Renal , Vasculite Sistêmica/etiologia , Dor Abdominal/etiologia , Adulto , Aneurisma/diagnóstico por imagem , Aneurisma/imunologia , Aneurisma/terapia , Biópsia , Angiografia por Tomografia Computadorizada , Glucocorticoides/uso terapêutico , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Inibidores de Integrase de HIV/uso terapêutico , Artéria Hepática/diagnóstico por imagem , Humanos , Hospedeiro Imunocomprometido , Masculino , Artérias Mesentéricas/diagnóstico por imagem , Isquemia Mesentérica/diagnóstico por imagem , Isquemia Mesentérica/imunologia , Isquemia Mesentérica/terapia , Oclusão Vascular Mesentérica/diagnóstico por imagem , Oclusão Vascular Mesentérica/imunologia , Oclusão Vascular Mesentérica/terapia , Raltegravir Potássico/uso terapêutico , Indução de Remissão , Artéria Renal/diagnóstico por imagem , Vasculite Sistêmica/diagnóstico por imagem , Vasculite Sistêmica/imunologia , Vasculite Sistêmica/terapia , Fatores de Tempo , Resultado do Tratamento
16.
Ann Rheum Dis ; 75(6): 1177-86, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26698852

RESUMO

BACKGROUND: Interferon γ (IFNγ) is considered a seminal cytokine in the pathogenesis of giant cell arteritis (GCA), but its functional role has not been investigated. We explored changes in infiltrating cells and biomarkers elicited by blocking IFNγ with a neutralising monoclonal antibody, A6, in temporal arteries from patients with GCA. METHODS: Temporal arteries from 34 patients with GCA (positive histology) and 21 controls were cultured on 3D matrix (Matrigel) and exposed to A6 or recombinant IFNγ. Changes in gene/protein expression were measured by qRT-PCR/western blot or immunoassay. Changes in infiltrating cells were assessed by immunohistochemistry/immunofluorescence. Chemotaxis/adhesion assays were performed with temporal artery-derived vascular smooth muscle cells (VSMCs) and peripheral blood mononuclear cells (PBMCs). RESULTS: Blocking endogenous IFNγ with A6 abrogated STAT-1 phosphorylation in cultured GCA arteries. Furthermore, selective reduction in CXCL9, CXCL10 and CXCL11 chemokine expression was observed along with reduction in infiltrating CD68 macrophages. Adding IFNγ elicited consistent opposite effects. IFNγ induced CXCL9, CXCL10, CXCL11, CCL2 and intracellular adhesion molecule-1 expression by cultured VSMC, resulting in increased PBMC chemotaxis/adhesion. Spontaneous expression of chemokines was higher in VSMC isolated from GCA-involved arteries than in those obtained from controls. Incubation of IFNγ-treated control arteries with PBMC resulted in adhesion/infiltration by CD68 macrophages, which did not occur in untreated arteries. CONCLUSIONS: Our ex vivo system suggests that IFNγ may play an important role in the recruitment of macrophages in GCA by inducing production of specific chemokines and adhesion molecules. Vascular wall components (ie, VSMC) are mediators of these functions and may facilitate progression of inflammatory infiltrates through the vessel wall.


Assuntos
Quimiocinas CXC/metabolismo , Arterite de Células Gigantes/imunologia , Interferon gama/antagonistas & inibidores , Macrófagos/imunologia , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Quimiocina CXCL11/genética , Quimiocina CXCL11/metabolismo , Quimiocina CXCL9/genética , Quimiocina CXCL9/metabolismo , Quimiocinas CXC/genética , Quimiotaxia/imunologia , Regulação para Baixo/imunologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interferon gama/biossíntese , Interferon gama/farmacologia , Masculino , Músculo Liso Vascular/imunologia , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Artérias Temporais/imunologia , Técnicas de Cultura de Tecidos
18.
Curr Opin Rheumatol ; 27(1): 53-62, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25405825

RESUMO

PURPOSE OF REVIEW: Imaging is becoming a relevant tool for the assessment of patients with systemic vasculitis. This review focuses on recently generated data with potential clinical impact in the diagnosis, evaluation of disease extent and management of systemic vasculitis. RECENT FINDINGS: Temporal artery examination by color duplex ultrasonography (CDUS) is a valuable approach to the diagnosis of giant-cell arteritis. Evaluation of additional arteries may increase its diagnostic performance. However, CDUS-specific findings may not be detected in arteries with early inflammation and CDUS-guidance of temporal artery biopsy does not seem to significantly increase its diagnostic yield. Large-vessel involvement detected by computed tomography angiography occurs in two out of three of patients with giant-cell arteritis at diagnosis. Furthermore, significant ascending aortic dilatation can be observed in one out of three of patients after long-term follow-up. Objective cut-offs for detecting large-vessel inflammation by positron emission tomography (PET) are trying to be established through prospective studies. PET may also contribute to the assessment of disease extent in patients with ANCA-associated vasculitis or Behçet's disease. SUMMARY: Data generated by existing and emerging imaging techniques are expected to have a major impact in the diagnosis, appraisal of disease extent, evaluation of disease activity and response to treatment in patients with systemic vasculitis.


Assuntos
Diagnóstico por Imagem/métodos , Vasculite Sistêmica/diagnóstico , Humanos , Reprodutibilidade dos Testes
20.
Rheumatol Int ; 35(5): 915-20, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25547622

RESUMO

The aim of the present study was to explore whether polymyositis may be considered as an isolated, organ-specific disease or more suitably as a secondary or associated entity. A retrospective re-evaluation of all the muscle biopsies performed at the Hospital Clínic of Barcelona showing histopathological pattern of polymyositis from January 1997 to May 2012 was carried out. The medical records of the patients with the aforementioned pathological pattern were also reviewed. From 1.290 muscle biopsies performed during the period evaluated, 36 with polymyositis pattern were identified. At the time of muscle biopsy, polymyositis pattern was secondary or associated with other disease in 26 patients and was classified as isolated in the remaining ten patients. After pathological re-evaluation and long-term clinical follow-up, only one patient remained with this diagnosis. Overall, the main final diagnosis related to the initial polymyositis pattern was inflammatory myopathy associated with connective tissue disease. Several other associated conditions were also identified. Isolated polymyositis is highly uncommon. Ruling out potential associated or confusing entities, like inclusion body myositis, overlap syndromes, infections, and cancer, is mandatory.


Assuntos
Doenças Autoimunes/complicações , Doenças do Tecido Conjuntivo/complicações , Músculo Esquelético/patologia , Neoplasias/complicações , Polimiosite/etiologia , Viroses/complicações , Adulto , Idoso , Doenças Autoimunes/diagnóstico , Estudos de Coortes , Doenças do Tecido Conjuntivo/diagnóstico , Bases de Dados Factuais , Diagnóstico Diferencial , Progressão da Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Miosite/diagnóstico , Miosite/etiologia , Miosite de Corpos de Inclusão/diagnóstico , Neoplasias/diagnóstico , Polimiosite/diagnóstico , Estudos Retrospectivos , Viroses/diagnóstico , Adulto Jovem
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