RESUMO
Our aim was to explore possible relationships between serum levels of biomarkers in patients with hand-arm vibration injury in relation to the severity of the vascular, i.e., Raynaud's phenomenon (RP), and neurosensory manifestations, the current exposure level, and the duration of exposure. This study was of case series design and involved 92 patients diagnosed with hand-arm vibration injury. Jonckheere's trend test was used to assess any association between serum levels of biomarkers and RP as well as neurosensory manifestations, graded by the International Consensus Criteria. Generalized linear models with adjustment for possible confounders were also used for associations between serum levels of biomarkers and; (1) severity of RP recorded as the extent of finger blanching calculated with Griffin score, (2) vibration perception thresholds, (3) magnitude of current exposure as [A(8); (m/s2)] value, and (4) the duration of exposure in years. Serum levels of thrombomodulin, von Willebrand factor, calcitonin gene related peptide (CGRP), heat shock protein 27, and caspase-3 were positively associated with severity of RP. Serum levels of CGRP were positively associated with the neurosensory component. No associations with exposure were shown for these biomarkers. For Intercellular adhesion molecule 1 and monocyte chemoattractant protein 1, no associations were found with neither severity nor exposure. Levels of serum biomarkers associated with endothelial injury or dysfunction, inflammation, vasodilation, neuroprotection, and apoptosis were positively associated with the severity of hand-arm vibration injury.
Assuntos
Biomarcadores , Síndrome da Vibração do Segmento Mão-Braço , Doença de Raynaud , Vibração , Humanos , Doença de Raynaud/sangue , Doença de Raynaud/diagnóstico , Biomarcadores/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Vibração/efeitos adversos , Adulto , Síndrome da Vibração do Segmento Mão-Braço/sangue , Síndrome da Vibração do Segmento Mão-Braço/diagnóstico , Índice de Gravidade de Doença , Fator de von Willebrand/metabolismo , Fator de von Willebrand/análise , Peptídeo Relacionado com Gene de Calcitonina/sangue , IdosoRESUMO
OBJECTIVES: To compare the microRNAs (miRNAs) contained within serum exosomes isolated from patients with Raynaud's phenomenon (RP) and negative antinuclear antibodies (ANA) to the miRNA contained in serum exosomes isolated from patients with RP and positive ANA. METHODS: Serum exosomes were isolated employing a polymer precipitation procedure. Next Generation Sequencing (NGS) was used to identify the miRNAs contained in the exosomes isolated from the two clinical cohorts and to analyse the differences in their contents. RESULTS: The NGS results identified six miRNAs that displayed significant differences in their content between serum exosomes from patients with RP with negative serum ANA compared to miRNAs contained in serum exosomes from patients with ANA-positive RP. CONCLUSIONS: A comparative analysis of miRNAs contained within serum exosomes of patients with RP and negative ANA vs. samples from patients with RP and positive ANA identified several differentially expressed miRNAs that may represent non-invasive biomarkers to assist in the identification of patients with RP at risk of evolving into systemic sclerosis.
Assuntos
Anticorpos Antinucleares , Exossomos , MicroRNAs , Doença de Raynaud , Humanos , Doença de Raynaud/sangue , Doença de Raynaud/genética , Doença de Raynaud/imunologia , Doença de Raynaud/diagnóstico , Anticorpos Antinucleares/sangue , Feminino , Exossomos/genética , Pessoa de Meia-Idade , MicroRNAs/sangue , MicroRNAs/genética , Masculino , Adulto , Biomarcadores/sangue , Sequenciamento de Nucleotídeos em Larga Escala , MicroRNA Circulante/sangue , MicroRNA Circulante/genética , Idoso , Valor Preditivo dos TestesRESUMO
Hand-arm vibration is a common occupational exposure that causes neurological impairment, myalgia, and vibration-induced Raynaud's phenomena or vibration white fingers (VWF). The pathological mechanism is largely unknown, though several mechanisms have been proposed, involving both immunological vascular damage and defective neural responses. The aim of this study was to test whether the substances interleukin-33 (IL-33), macrophage-derived chemokine (MDC), interleukin-10 (IL-10), endothelin-1 (ET-1), C-C motif chemokine ligand 20 (CCL20), calcitonin, and thromboxane (TXA2) changed before and after occupational hand-arm vibration exposure. 38 full-time shift workers exposed to hand-arm vibration were recruited. All the participants underwent medical examinations regarding symptoms of Raynaud's phenomena. In 29 of the participants, the concentration of IL-33, MDC, IL-10, ET-1, CCL20, calcitonin, and TXA2 was measured before and after a workday. There was a significant increase in ET-1 and calcitonin concentration and a decrease in the CCL20 concentration after the work shift in all participants. In the group suffering from VWF, but not in the non-VWF group, MDC was statistically significantly lower before the work shift (p = .023). The VWF group also showed a significant increase in MDC after the work shift. Exposure to occupational hand-arm vibration is associated with changes in ET-1, calcitonin, and MDC concentration in subjects suffering from vibration white fingers, suggesting a role of these biomarkers in the pathophysiology of this condition.
Assuntos
Biomarcadores , Síndrome da Vibração do Segmento Mão-Braço , Exposição Ocupacional , Vibração , Humanos , Exposição Ocupacional/efeitos adversos , Biomarcadores/sangue , Masculino , Adulto , Síndrome da Vibração do Segmento Mão-Braço/sangue , Síndrome da Vibração do Segmento Mão-Braço/diagnóstico , Vibração/efeitos adversos , Pessoa de Meia-Idade , Endotelina-1/sangue , Feminino , Interleucina-33/sangue , Interleucina-10/sangue , Doença de Raynaud/sangue , Doença de Raynaud/etiologia , Tromboxano A2/sangueRESUMO
Neutrophil extracellular traps (NETs) are cell-extruded DNA strands coated with neutrophils' nuclear proteins and enzymes from cytotoxic granules, produced by NETosis, a cell death pathway. They perform an important defensive role in innate immunity, but their increased production and/or inefficient degradation expose new antigens, such as DNA or citrullinated histone peptides, triggering autoimmunity. This study aimed to access possible associations between serum NETs levels with epidemiological, clinical, and serological data from a well-characterized SLE Brazilian patients' cohort. NET levels were evaluated in one hundred seventy serum samples of patients with Systemic Lupus Erythematosus (SLE) using an Immunoassay. Univariate and multivariate binary logistic regression used clinical patients' data as independent variables. Parametric and non-parametric tests compared log10 base serum NET levels transformed between patients' groups. SLE patients were also dichotomized into "High serum NET levels" and "Low serum NET levels" groups. All analyses were performed in R language 4.1.2, and p < 0.05 were considered significant. Increased susceptibility for high serum NET levels was observed in SLE patients with Raynaud's phenomenon (OR = 2.30, 95 % CI = 1.06-5.21 and p = 0.039), independently of any other risk factor. Also, SLE patients with Raynaud's phenomenon presented higher mean NET serum levels (mean = -0.13 vs. -0.51, p = 0.01). In addition, higher mean NET serum levels were associated with glomerulonephritis (mean = -0.45 vs. -0.12, p = 0.03). Ultimately, the SLEDAI index scored higher in the high NETs serum levels group (median = 2.0 vs. 0.0, p = 6 × 10-3). The formation of NETs might be implicated in Raynaud's phenomenon, glomerulonephritis, and disease index score in SLE patients. Our results highlight the importance of serum NET levels as a possible therapeutical target to modulate the clinical course of SLE.
Assuntos
Armadilhas Extracelulares , Lúpus Eritematoso Sistêmico , Doença de Raynaud , Humanos , Armadilhas Extracelulares/metabolismo , Armadilhas Extracelulares/imunologia , Feminino , Masculino , Brasil/epidemiologia , Adulto , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/imunologia , Doença de Raynaud/etiologia , Doença de Raynaud/sangue , Doença de Raynaud/imunologia , Pessoa de Meia-Idade , Neutrófilos/imunologia , Índice de Gravidade de Doença , Glomerulonefrite/sangue , Glomerulonefrite/imunologia , Glomerulonefrite/diagnóstico , Adulto Jovem , Biomarcadores/sangueRESUMO
BACKGROUND: CXCL4, a chemokine with anti-angiogenic property, is involved in systemic sclerosis (SSc) related pulmonary arterial hypertension (PAH). OBJECTIVE: To investigated the contribution of CXCL4 to SSc development by focusing on the correlation of circulatory CXCL4 levels with their peripheral vasculopathy, and the effect of CXCL4 on endothelial cell dysfunction and the potential signaling. METHODS: We measured the plasma CXCL4 levels in 58 patients with SSc, 10 patients with the very early diagnosis of SSc (VEDOSS), and 80 healthy controls (HCs). Then, CXCL4 concentrations were correlated with clinical features, especially the peripheral vasculopathy. These observations were further validated in an additional cohort. Moreover, we studied the anti-angiogenic effects of CXCL4 and the underlying downstream signaling in human umbilical vein endothelial cells (HUVECs) in vitro. RESULTS: Circulating CXCL4 levels were 103.62 % higher in patients with SSc and 201.51 % higher in patients with VEDOSS than matched HCs, which were confirmed in two independent cohorts. CXCL4 levels were associated with digital ulcers (DU) and nailfold videocapillaroscopy (NVC) abnormalities in SSc. The proliferation, migration, and tube formation of HUVECs were inhibited by CXCL4 or SSc derived plasma, which reversed by CXCL4 neutralizing antibody, but failed by CXCR3 inhibitor. CXCL4 downregulated the transcription factor Friend leukaemia integration factor-1 (Fli-1) via c-Abl signaling. Furthermore, CXCL4 blocked the transforming growth factor (TGF) -ß or platelet-derived growth factor (PDGF) induced cell proliferation of HUVECs. CONCLUSIONS: CXCL4 may contribute to peripheral vasculopathy in SSc by downregulating Fli-1 via c-Abl signaling in endothelial cells and interfering angiogenesis.
Assuntos
Endotélio Vascular/patologia , Úlcera do Pé/imunologia , Fator Plaquetário 4/metabolismo , Doença de Raynaud/imunologia , Escleroderma Sistêmico/complicações , Adulto , Idoso , Estudos de Casos e Controles , Movimento Celular , Proliferação de Células , Diagnóstico Precoce , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Feminino , Úlcera do Pé/sangue , Úlcera do Pé/diagnóstico , Úlcera do Pé/patologia , Voluntários Saudáveis , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Angioscopia Microscópica , Pessoa de Meia-Idade , Fator Plaquetário 4/sangue , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteínas Proto-Oncogênicas c-abl/metabolismo , Doença de Raynaud/sangue , Doença de Raynaud/diagnóstico , Doença de Raynaud/patologia , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia , Transdução de Sinais/imunologia , Pele/irrigação sanguínea , Pele/diagnóstico por imagem , Pele/imunologia , Pele/patologia , Células THP-1 , Adulto JovemRESUMO
Raynaud phenomenon (RP) may be the first manifestation of a systemic connective tissue disease (SCTD). Early detection of dysfunction of small vessels called microangiopathy is essential for the diagnostic process. The focus of this single-center, retrospective study was to investigate the potential dependencies between microvascular image and laboratory markers measured in children with RP. The study analyzed the nail-fold video-capillaroscopy (NVC) findings and laboratory results of 81 children between the ages 6 and 17 who were referred to pediatric rheumatologist with a suspicion of SCTD. Out of 52 patients presenting with RP at the time of evaluation, abnormalities in capillary microscopic imaging were found in 34. NVC findings were then compared to levels of specific biomarkers in serum. Vitamin D3 serum levels have been significantly decreased in patients with RP (23.4 ng/mL ± 8.76 vs. 30.0 ng/mL ± 12.66, P = 0.0148). There were positive significant correlations between levels of vitamin D3 and acute-phase reactants in serum, such as C-reactive protein (P = 0.0292). Furthermore, free thyroxine levels (fT4) in patients with both RP (P = 0.0126) and micro-angiopathy (P = 0.05496) persisted in the lower range of the normal limit (< 1.0 ng/dL). Regular oral supplementation of vitamin D3 should be always considered in children with RP if deficiency is found. Additionally, low fT4 level (< 1.0 ng/dL) should be considered as an indication to perform NVC in patients suspected of SCTD even when they do not present RP.
Assuntos
Colecalciferol/deficiência , Doenças do Tecido Conjuntivo/sangue , Doença de Raynaud/sangue , Tiroxina/deficiência , Adolescente , Biomarcadores/sangue , Criança , Colecalciferol/sangue , Doenças do Tecido Conjuntivo/diagnóstico , Feminino , Humanos , Masculino , Angioscopia Microscópica , Doença de Raynaud/diagnóstico , Estudos Retrospectivos , Tiroxina/sangueRESUMO
OBJECTIVE: A key unanswered question in systemic sclerosis (SSc) is how microvascular abnormality and fibrosis inter-relate. Our aim was to use state-of-the-art non-invasive imaging methods to gain new insights into pathophysiology, comparing patients with different subtypes of SSc, including early dcSSc, not only to healthy controls but also to patients with causes of Raynaud's phenomenon not progressing to fibrosis. METHODS: Laser Doppler imaging, nailfold capillaroscopy, spectroscopy, and ultrasound measured (respectively) perfusion, microvascular structure, oxygenation/oxidative stress, and skin thickening in the hands of 265 subjects: 31 patients with primary Raynaud's phenomenon (PRP), 35 with undifferentiated connective tissue disease (UCTD), 93 with limited cutaneous SSc (lcSSc), 46 with diffuse cutaneous SSc (dcSSc, including 27 'early') and 60 healthy controls. RESULTS: Mean perfusion was reduced in SSc groups compared to controls (lcSSc 172 perfusion units [standard deviation 157], late-dcSSc 90 [145], early-dcSSc 68 [137] vs. controls 211 [146]; p = 0.0002) as was finger-oxygenation (lcSSc 12.1 [13.6] arbitrary units [AU], late-dcSSc 12.2 [8.4], early-dcSSc 11.1 [11.3] vs controls 14.9 [10.5]; p = 0.0049). Oxidative stress was increased at the hand-dorsum in SSc groups (p = 0.0007). Perfusion positively correlated with oxygenation (r = 0.23, p < 0.001), and capillary density negatively with skin thickness (r = -0.26, p < 0.001). CONCLUSION: Our findings lend support to the hypothesis that in SSc, particularly early dcSSc, (but not in PRP or UCTD), reduced perfusion (together with structural microvascular abnormality) associates with reduced oxygenation, with oxidative stress and with skin thickening/fibrosis, most likely driving a vicious cycle which ultimately results in irreversible tissue injury. Findings in skin may mirror alterations in internal organs.
Assuntos
Fluxometria por Laser-Doppler , Angioscopia Microscópica , Microvasos/diagnóstico por imagem , Doença de Raynaud/diagnóstico por imagem , Esclerodermia Difusa/diagnóstico por imagem , Esclerodermia Limitada/diagnóstico por imagem , Pele/irrigação sanguínea , Ultrassonografia , Adulto , Velocidade do Fluxo Sanguíneo , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Masculino , Microcirculação , Microvasos/fisiopatologia , Pessoa de Meia-Idade , Estresse Oxidativo , Oxigênio/sangue , Valor Preditivo dos Testes , Doença de Raynaud/sangue , Doença de Raynaud/patologia , Doença de Raynaud/fisiopatologia , Fluxo Sanguíneo Regional , Esclerodermia Difusa/sangue , Esclerodermia Difusa/patologia , Esclerodermia Difusa/fisiopatologia , Esclerodermia Limitada/sangue , Esclerodermia Limitada/patologia , Esclerodermia Limitada/fisiopatologia , Pele/metabolismo , Pele/patologia , Análise EspectralRESUMO
The earliest clinical manifestation of SSc is usually Raynaud's phenomenon, a small-arteries vasospasm driven by vascular tone dysregulation and microcirculatory abnormalities, resulting in digital ulcers (DU) in up to 50% of patients. Many cytokines as well as growth factors have been shown to play a role in promoting vascular smooth muscle cell proliferation and fibroblast activation, leading to ischemic damage as well as skin fibrosis. We aim to investigate a possible difference in venous and arterial blood levels of many cytokines (Th1- and Th17-related), GM-CSF, and endothelin-1 (ET1) in patients with and without DU. In the same patients, the correlations between capillary damage, evaluated by nailfold videocapillaroscopy (NVC), extension of skin fibrosis, calculated by modified Rodnan skin score (mRSS), and cytokines, ET-1, and GM-CSF levels were also measured. Patients with DU showed venous levels of IL-1ß (p=0.024), IL-6 (p=0.012), IL-22(p=0.006), and TGF-ß (p=0.046) significantly higher compared to arterial levels and arterial levels of GM-CSF and TNF-alpha significantly higher compared to venous levels (p < 0.001). NVC abnormalities were correlated with arterial TNFa and venous IL22, IL23, and IL17 levels and negatively correlated with venous ET-1 levels, whereas mRSS showed a negative correlation with IL-21(ρ = -0.427, p=0.050). The increased Th17-cytokine levels in venous compared to arterial blood of patients with DU suggest local cytokine production on ulcer site. The higher TNFa and GM-CSF levels in arterial blood of DU patients support the attempt to mitigate the hypoxic damage, and the correlation between Th17-cytokines, mRSS, NVC, and ET1 agrees with the potent profibrotic stimulus at the onset of the disease, which decreases as the SSc progresses.
Assuntos
Artérias/metabolismo , Citocinas/sangue , Doença de Raynaud/sangue , Úlcera Cutânea/sangue , Células Th1/metabolismo , Células Th17/metabolismo , Veias/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Capilares/metabolismo , Citocinas/metabolismo , Endotelina-1/metabolismo , Feminino , Fibrose/metabolismo , Humanos , Masculino , Microcirculação/fisiologia , Angioscopia Microscópica/métodos , Pessoa de Meia-Idade , Doença de Raynaud/metabolismo , Pele/metabolismo , Úlcera Cutânea/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Raynaud's phenomenon (RP) is often the first sign of systemic sclerosis (SSc). Molecular mechanisms involved are incompletely understood, but reactive oxygen, nitrogen, and sulfur species are thought to play an important role in the pathogenesis of SSc. Free thiol groups play a protective role against oxidative stress and may represent an attractive therapeutic target. We aimed to investigate the effects of hypothermia-induced vasoconstriction on the responsiveness of redox-related markers. Thirty participants (n = 10/group [SSc, primary Raynaud's phenomenon (PRP), healthy controls (HC)]) were included in this study. Fingertip photoelectric plethysmography was performed during a standardized cooling and recovery experiment. Venous blood was collected at four predetermined time points. Free thiols, NO-derived species (nitros(yl)ated species, nitrite, nitrate), sulfate and endothelin-1 were measured. Lower baseline concentrations of free thiols were observed in PRP and SSc patients (HC: 5.87 [5.41-5.99] µmol/g; PRP: 5.17 [4.74-5.61]; SSc 5.28 [4.75-5.80], P = 0.04). Redox-related markers remained unchanged during cooling. However, an unexpected increase in systemic free thiol concentrations was observed in all groups during the recovery phase. The response of this marker differed between groups, with a higher increase found in SSc patients (HC Δ = 1.30 [1.48-1.17]; PRP Δ = 1.04 [1.06-1.03]; SSc Δ = 1.72 [1.13-1.49], P = 0.04). NO-derived species, sulfate and endothelin-1 levels remained unchanged throughout the recovery phase. This exploratory study sheds light on the rapid responsiveness of systemic free thiol concentrations following reperfusion, which may reflect overall redox balance. The robust response to reperfusion in SSc patients suggests that reductive systems involved in this response are functionally intact in these patients.
Assuntos
Antioxidantes/metabolismo , Temperatura Baixa , Doença de Raynaud/sangue , Doença de Raynaud/fisiopatologia , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/fisiopatologia , Compostos de Sulfidrila/sangue , Vasoconstrição , Adaptação Fisiológica , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxirredução , Projetos Piloto , Doença de Raynaud/diagnóstico , Escleroderma Sistêmico/diagnóstico , Fatores de TempoRESUMO
Associations of Raynaud's phenomenon (RP) with venous thromboembolism (VTE) are unclear. We investigated the occurrence of RP together with prothrombotic state markers and fibrin clot properties in VTE patients. In this prospective cohort study we enrolled 360 patients free of known autoimmune disease. D-dimer, von Willebrand factor (vWF), plasma clot permeability (Ks), clot lysis time (CLT) along with fibrinolysis activators and inhibitors were determined at least 3 months since the VTE event. The presence/absence of RP was diagnosed at least 6 months before VTE. Primary RP occurred in 57 subjects (17%) with a 3.6-fold higher prevalence among women. Patients with RP had 11% higher fibrinogen, 16% higher vWF, 5% lower Ks, and 10% longer CLT (all p < 0.05). Females with RP (21%) had 6.6% lower Ks, 11.2% longer CLT, and 18.5% higher vWF (all p < 0.05) compared with men. CLT was predicted by PAI-1 and vWF levels. Regression analysis showed that RP was a predictor of prolonged CLT in the whole patient group (OR 3.46, 95% CI 1.92-6.24) and in women following VTE (OR 2.75, 95% CI 1.31-5.78). Primary RP patients tend to form denser plasma fibrin clots displaying impaired lysability and increased endothelial damage. RP might be a novel risk factor for VTE, especially in women.
Assuntos
Fibrinólise , Doença de Raynaud/sangue , Tromboembolia Venosa/sangue , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Estudos Transversais , Feminino , Fibrina/análise , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Masculino , Pessoa de Meia-Idade , Polônia/epidemiologia , Valor Preditivo dos Testes , Prevalência , Prognóstico , Estudos Prospectivos , Doença de Raynaud/diagnóstico , Doença de Raynaud/epidemiologia , Fatores de Risco , Fatores Sexuais , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiologia , Adulto Jovem , Fator de von Willebrand/análiseRESUMO
Secondary Raynaud's phenomenon (RP) is often the sentinel clinical finding in systemic sclerosis and may precede systemic disease by several years. Altered nitric oxide metabolism plays a critical role in both fibrosis and severe secondary RP phenotypes in these patients. Increased flux through inducible nitric oxide synthase (iNOS) drives cutaneous fibrosis. Failure of flux through endothelial nitric oxide synthase (eNOS) contributes to increased vasoconstriction and decreased vasorelaxation. The underproduction of nitric oxide by eNOS is in part due to increased levels of asymmetric dimethylarginine (ADMA), an endogenous competitive inhibitor of nitric oxide synthase. The inhibitory effects of increased ADMA levels may be counteracted increasing serum l-arginine, which is often an effective treatment strategy in these patients. As such, l-arginine-based therapies should be considered in managing secondary RP, particularly given their favourable safety and tolerability profile. While there is no established dosing regimen, studies of oral l-arginine in secondary RP suggest that divided dosing may begin at 1-2 g/day and may be titrated up to 10 g/day. Conversely, primary RP is not associated with increased ADMA production which likely accounts for the failure of l-arginine trials to show benefit in primary RP.
Assuntos
Arginina/análogos & derivados , Arginina/uso terapêutico , Óxido Nítrico/metabolismo , Doença de Raynaud/sangue , Doença de Raynaud/tratamento farmacológico , Escleroderma Sistêmico/metabolismo , Arginina/sangue , Humanos , Óxido Nítrico Sintase Tipo III/metabolismo , Doença de Raynaud/etiologia , Escleroderma Sistêmico/complicações , VasodilataçãoAssuntos
Aminoacil-tRNA Sintetases/imunologia , Autoanticorpos/sangue , Miosite/complicações , Doença de Raynaud/imunologia , Úlcera Cutânea/imunologia , Adulto , Autoanticorpos/imunologia , Feminino , Humanos , Miosite/sangue , Miosite/imunologia , Doença de Raynaud/sangue , Doença de Raynaud/patologia , Recidiva , Pele/imunologia , Pele/patologia , Úlcera Cutânea/sangue , Úlcera Cutânea/patologiaRESUMO
INTRODUCTION: The diagnosis of interstitial lung disease (ILD) requires elimination of underlying connective tissue disease. Consequently, antinuclear antibodies (ANA) are routinely screened in patients with idiopathic interstitial pneumonia. However the clinical usefulness of this practice is not well clear. AIM: In this study, we evaluated the frequency of ANA in ILD's patients and investigated the clinical significance of the ANA's presence in these patients. METHODS: We conducted a retrospective study of hospitalized patients diagnosed ILD at pulmonary department and for which ANA was performed in the immunology laboratory of our institution. Demographic features, clinical symptoms, biological and radiologic findings and CTD-ILD diagnoses were compared between patients with positive ANA versus negative ANA. RESULTS: We enrolled 73 patients. The ANA's prevalence was 32%. There were no significant differences in demographics, pulmonary function test values and radiologic findings between patients with and without ANA. Patients with positive ANA had more cutaneous manifestations (pê0.011) and Raynaud's phenomenon (pê0.029). The diagnosis of connective tissue disease was made in 42% of patients with positive ANA versus 8% with negative ANA (pê 0.001). ANA's titer higher than 1/320 was predictive of CTD diagnosis (ORê14.4) (p<0.001). CONCLUSIONS: The research of ANA in PID's patients is an important tool of CTD diagnosis specially in those with suggestive symptoms of autoimmune disease.
Assuntos
Anticorpos Antinucleares/sangue , Doenças Autoimunes/epidemiologia , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/epidemiologia , Doenças Autoimunes/sangue , Doenças Autoimunes/complicações , Doenças Autoimunes/diagnóstico , Estudos de Casos e Controles , Doenças do Tecido Conjuntivo/sangue , Doenças do Tecido Conjuntivo/diagnóstico , Doenças do Tecido Conjuntivo/epidemiologia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Fibrose Pulmonar Idiopática/sangue , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/epidemiologia , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/terapia , Masculino , Prevalência , Prognóstico , Doença de Raynaud/sangue , Doença de Raynaud/diagnóstico , Doença de Raynaud/epidemiologia , Testes de Função Respiratória , Estudos Retrospectivos , Estudos Soroepidemiológicos , Tomografia Computadorizada por Raios XAssuntos
Antagonistas dos Receptores H2 da Histamina/efeitos adversos , Inibidores da Bomba de Prótons/efeitos adversos , Doença de Raynaud/epidemiologia , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Arginina/análogos & derivados , Arginina/sangue , Arginina/metabolismo , Refluxo Gastroesofágico/tratamento farmacológico , Humanos , Farmacovigilância , Doença de Raynaud/sangue , Doença de Raynaud/induzido quimicamenteRESUMO
CXCL13, a chemokine for B cells, follicular T cells, T helper 17 cells, and regulatory T cells, is reported to contribute to the development of systemic sclerosis (SSc), reflecting aberrant activation of immune system. To better understand the role of CXCL13 in SSc, we investigated the influence of Fli1 deficiency, a potential predisposing factor of this disease, on CXCL13 expression and assessed the clinical correlation of serum CXCL13 levels by multivariate regression analysis. Haploinsufficient loss of Fli1 remarkably induced CXCL13 expression in murine peritoneal macrophages, while gene silencing of FLI1 did not affect the expression of CXCL13 in human dermal fibroblasts and human dermal microvascular endothelial cells. Serum CXCL13 levels were elevated in SSc patients compared with healthy controls and correlated positively with skin score and negatively with pulmonary function test results. SSc patients with elevated serum CXCL13 levels had longer disease duration, diffuse cutaneous involvement, interstitial lung disease (ILD), heart involvement, pulmonary arterial hypertension, Raynaud's phenomenon, pitting scars, digital ulcers, telangiectasia, and high serum IgG levels more frequently than the other patients. In particular, serum CXCL13 levels were associated with ILD and digital ulcers by multivariate regression analysis. Taken together, these results indicate that CXCL13 expression is upregulated by Fli1 deficiency in macrophages, potentially contributing to the development of tissue fibrosis, vasculopathy and immune activation in SSc, especially ILD and digital ulcers.
Assuntos
Quimiocina CXCL13/sangue , Doenças Pulmonares Intersticiais/sangue , Pulmão/patologia , Proteína Proto-Oncogênica c-fli-1/deficiência , Escleroderma Sistêmico/sangue , Úlcera Cutânea/sangue , Pele/patologia , Idoso , Animais , Células Cultivadas , Quimiocina CXCL13/genética , Células Endoteliais , Feminino , Fibroblastos , Fibrose , Dedos , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Inativação Gênica , Humanos , Lipopolissacarídeos/farmacologia , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/fisiopatologia , Macrófagos/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Proteína Proto-Oncogênica c-fli-1/genética , Proteína Proto-Oncogênica c-fli-1/metabolismo , RNA Mensageiro/metabolismo , Doença de Raynaud/sangue , Doença de Raynaud/etiologia , Testes de Função Respiratória , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/imunologia , Úlcera Cutânea/etiologiaRESUMO
OBJECTIVES: The imbalance between angiogenic and angiostatic factors with derangement of the microvasculature are hallmarks of systemic sclerosis (SSc). Raynaud's phenomenon in SSc probably is due to the impaired neuroendothelial control mechanisms between vasoconstriction and vasodilatation. The aim of this study is to evaluate autonomic nervous system function using heart rate variability (HRV) analysis and to correlate with vascular endothelial growth factor (VEGF). METHODS: Twenty-seven SSc patients were enrolled. HRV was measured and markers of global sympathetic and parasympathetic system, respectively standard deviation of normal-to-normal RR intervals (SDNN) and square root of the mean of the sum of the squares of differences between adjacent NN intervals (RMSSD) were evaluated. Serum VEGF levels and nailfold videocapillaroscopy (NVC) were performed. RESULTS: A linear positive correlation was observed between RMSSD and VEGF (p<0.01, r=0.55), and RMSSD and disease duration (p< 0.01, r=0.54). The RMSSD median value was significantly increased (p< 0.05) with NVC damage progression. The RMSSD median value was significantly (p<0.05) higher in SSc patients with digital ulcers (DUs) than in SSc patients without DUs [44 (39.4-60.2) vs 24.6 (23-37.1)]. CONCLUSIONS: In our study parasympathetic modulation increases in relation to VEGF. When microcirculation is modified with capillaroscopic pattern progression and DUs, autonomic system seems to stimulate vasodilatation trough parasympathetic system. We can conclude that parasympathetic activity increases with digital microvascular damage and promotes VEGF release.
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Dedos/irrigação sanguínea , Coração/inervação , Microvasos/fisiopatologia , Sistema Nervoso Parassimpático/fisiopatologia , Doença de Raynaud/etiologia , Escleroderma Sistêmico/complicações , Úlcera Cutânea/etiologia , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto , Progressão da Doença , Feminino , Frequência Cardíaca , Hemodinâmica , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Raynaud/sangue , Doença de Raynaud/diagnóstico , Doença de Raynaud/fisiopatologia , Fluxo Sanguíneo Regional , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/fisiopatologia , Úlcera Cutânea/sangue , Úlcera Cutânea/diagnóstico , Úlcera Cutânea/fisiopatologiaRESUMO
Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are two phenotypically distincts inflammatory systemic diseases. However, SLE and SSc share pathogenic features such as interferon signature, loss of tolerance against self-nuclear antigens and increased tissue damage such as fibrosis. Recently, platelets have emerged as a major actor in immunity including auto-immune diseases. Both SLE and SSc are characterized by strong platelet system activation, which is likely to be both the witness and culprit in their pathogenesis. Platelet activation pathways are multiple and sometimes redundant. They include immune complexes, Toll-like receptors activation, antiphospholipid antibodies and ischemia-reperfusion associated with Raynaud phenomenon. Once activated, platelet promote immune dysregulation by priming interferon production by immune cells, providing CD40L supporting B lymphocyte functions and providing a source of autoantigens. Platelets are actively implicated in SLE and SSc end-organ damage such as cardiovascular and renal disease and in the promotion of tissue fibrosis. Finally, after understanding the main pathogenic implications of platelet activation in both diseases, we discuss potential therapeutics targeting platelets.
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Plaquetas/fisiologia , Lúpus Eritematoso Sistêmico/etiologia , Escleroderma Sistêmico/etiologia , Anticorpos Antifosfolipídeos/sangue , Complexo Antígeno-Anticorpo/sangue , Plaquetas/imunologia , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Doença de Raynaud/sangue , Doença de Raynaud/imunologia , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/imunologiaRESUMO
Objectives Antibodies to phosphatidylserine/prothrombin complex (aPS/PT) detectable in sera of some patients with antiphospholipid syndrome (APS) have been shown to correlate with thrombosis. However, associations of aPS/PT antibodies with APS related disorders remain unclear. Aim To evaluate whether there are any associations between aPS/PT antibodies and Raynaud phenomenon, migraine and/or valvular lesions in primary thrombotic APS (PAPS). Methods We enrolled 67 consecutive patients (56 women) with thrombotic PAPS (VTE in 80.6%), aged 46.2 ± 13.5 years. The exclusion criteria were: acute coronary syndromes or stroke within preceding 6 months, cancer, severe comorbidities and pregnancy. The IgG and IgM aPS/PT antibodies were determined by ELISA with the cut-off of 30 units. We recorded Raynaud phenomenon, migraine and valvular lesions. Results Positive IgM or/and IgG aPS/PT antibodies were observed in 29 patients (43.3%), with a higher prevalence of IgM antibodies ( n = 27, 40.3%) compared with IgG isotype ( n = 12, 17.9%, p = 0.014). aPS/PT antibodies were observed most commonly in patients with triple aPL ( n = 12, 85.7%) compared with those with double ( n = 5, 35.7%) or single aPL antibodies (n = 12, 30.8%, p = 0.03), with no association with demographics, the ANA titre, the type of thrombotic events or medications. Raynaud phenomenon, migraine and valvular lesions were observed in 15% ( n = 10), 30% ( n = 20) and 18% ( n = 12) of the patients, respectively. Raynaud phenomenon and migraine, but not valvular lesions, were markedly more frequent in PAPS patients presenting with positive aPS/PT antibodies ( n = 10, 34.5% vs. n = 0, 0%; p = 0.0001). Conclusions In PAPS patients aPS/PT antibodies are related to the occurrence of both Raynaud phenomenon and migraine.
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Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/complicações , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Transtornos de Enxaqueca/etiologia , Fosfatidilserinas/imunologia , Protrombina/imunologia , Doença de Raynaud/etiologia , Tromboembolia Venosa/etiologia , Adulto , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/diagnóstico , Síndrome Antifosfolipídica/imunologia , Estudos Transversais , Feminino , Doenças das Valvas Cardíacas/sangue , Doenças das Valvas Cardíacas/etiologia , Doenças das Valvas Cardíacas/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/sangue , Transtornos de Enxaqueca/diagnóstico , Transtornos de Enxaqueca/imunologia , Doença de Raynaud/sangue , Doença de Raynaud/diagnóstico , Doença de Raynaud/imunologia , Fatores de Risco , Tromboembolia Venosa/sangue , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/imunologiaRESUMO
BACKGROUND: Subclinical chronic inflammation could be the driving force behind the recently revealed association between abnormal nailfold capillaries as well as autoantibodies and long-term mortality in patients with incipient Raynaud's phenomenon. Whether laboratory markers that reflect a chronic inflammatory process are directly related to mortality in Raynaud's phenomenon is not known. METHODS: In total, 2958 patients with incipient Raynaud's phenomenon without previously known connective tissue disease (CTD) were enrolled. At their initial presentation, laboratory tests for C-reactive protein (CRP), leucocytes, fibrinogen and the haemoglobin concentration were obtained. In addition, nailfold capillaries and antinuclear antibodies (ANA) were assessed. Patients' mortality was recorded through a median follow-up period of 9.3 years. RESULTS: Baseline CRP, fibrinogen and haemoglobin concentration were associated with long-term mortality in an individual analysis of patients with incipient Raynaud's phenomenon. In a multivariable model including patients' age, nailfold capillaries and ANA, a low haemoglobin concentration remained independently related to future mortality. Amongst potential predictors for mortality in patients with Raynaud's phenomenon, a low haemoglobin concentration was most strongly related to patients' mortality risk. CONCLUSION: In Raynaud's phenomenon, laboratory markers that can be attributed to a chronic inflammatory state independently yield prognostic information in addition to the presence of abnormal nailfold capillaries and ANA. Amongst all prognostic markers, the haemoglobin concentration is most strongly related to patients' mortality in Raynaud's phenomenon.
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Autoanticorpos/sangue , Proteína C-Reativa/metabolismo , Previsões , Inflamação/sangue , Doença de Raynaud/mortalidade , Adulto , Áustria/epidemiologia , Biomarcadores/sangue , Causas de Morte/tendências , Feminino , Seguimentos , Humanos , Inflamação/imunologia , Inflamação/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Doença de Raynaud/sangue , Doença de Raynaud/imunologia , Estudos Retrospectivos , Taxa de Sobrevida/tendênciasRESUMO
Raynaud's phenomenon (RP) is the earliest and most common clinical manifestation in patients with systemic sclerosis (SSc) and its related diseases containing anti-TOPO-1 and/or anti-CENP-B autoantibodies in the sera. However, the cause-effect relationship between the two autoantibodies and RP remains elucidation. Sera containing anti-CENP-B and anti-TOPO-1 autoantibodies were obtained from SSc-related diseases manifesting RP. The polyclonal auto-antibodies were purified from pooled sera by affinity chromatography. Mouse monoclonal anti-CENP-B and anti-TOPO-1 were purchased. Calf pulmonary arterial endothelial cells (CPAE) were incubated with 40% patient sera, purified polyclonal antibodies or mouse monoclonal antibodies for 1-6 days. The vascular endothelial biomarkers von Willebrand factor (vWF), thrombomodulin (CD141) and 6-keto-prostaglandin F1α (6-keto-PGF1α), cell viability marker ATP, and cell necrosis/lysis marker LDH in the culture supernatants were measured by ELISA. The cell senescence biomarker ß-galactosidase and telomere content in the cells were stained by the respective kit. The classical p53-p21 senescence pathway was detected by Western blot. We found that 40% anti-CENP-B or anti-TOPO-1-containing sera without heat-inactivation and mouse monoclonal antibodies suppressed 6-keto-PGF1α production, increased ß-galactosidase, and decreased relative telomere content. The cell senescence effects were proved not via p53-p21 pathway. The pathognomonic anti-CENP-B and anti-TOPO-1 autoantibodies in SSc-related diseases accelerate vascular endothelial cell senescence and functional impairment inducing RP. The real signaling pathway for autoantibody-induced cell senescence remains exploration.