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Previous studies have suggested that oxidative stress may heighten atherosclerotic burden in rheumatoid arthritis (RA), but direct evidence is lacking. OBJECTIVE: To evaluate the relationship between established plasma oxidative stress biomarkers and peripheral endothelial dysfunction (ED), a marker of early atherosclerosis, in RA. METHODS: Paroxonase-1 (PON-1), protein-SH (PSH), and malondialdehyde (MDA) were measured in 164 RA patient s and 100 age- and sex-matched healthy controls without previous cardiovascular events. Peripheral ED, evaluated by flow-mediated pulse amplitude tonometry, was defined by log-transformed reactive hyperemia index (Ln-RHI) values < 0.51. RESULTS: PON-1 activity and PSH concentrations were significantly reduced in RA patients compared to controls. In regression analysis, increased plasma MDA levels were significantly associated with reduced Ln-RHI [B coefficient (95% CI) = -0.003 (-0.005 to -0.0008), p = 0.008] and the presence of peripheral ED (OR (95% CI) = 1.75 (1.06-2.88), p = 0.028). Contrary to our expectations, increased PON-1 activity was significantly associated, albeit weakly, with the presence of ED (OR (95% CI) = 1.00 (1.00-1.01), p = 0.017). CONCLUSIONS: In this first evidence of a link between oxidative stress and markers of atherosclerosis, MDA and PON-1 showed opposite associations with peripheral vasodilatory capacity and the presence of ED in RA. Further studies are needed to determine whether this association predicts atherosclerotic events in the RA population.
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Artrite Reumatoide/sangue , Arildialquilfosfatase/sangue , Endotélio Vascular/metabolismo , Malondialdeído/sangue , Estresse Oxidativo , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/patologia , Artrite Reumatoide/fisiopatologia , Biomarcadores/sangue , Estudos Transversais , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , VasodilataçãoRESUMO
BACKGROUND: Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon. METHODS: We isolated plasmacytoid dendritic cells from healthy persons and from patients with systemic sclerosis who had distinct clinical phenotypes. We then performed proteome-wide analysis and validated these observations in five large cohorts of patients with systemic sclerosis. Next, we compared the results with those in patients with systemic lupus erythematosus, ankylosing spondylitis, and hepatic fibrosis. We correlated plasma levels of CXCL4 protein with features of systemic sclerosis and studied the direct effects of CXCL4 in vitro and in vivo. RESULTS: Proteome-wide analysis and validation showed that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in circulation and in skin. The mean (±SD) level of CXCL4 in patients with systemic sclerosis was 25,624±2652 pg per milliliter, which was significantly higher than the level in controls (92.5±77.9 pg per milliliter) and than the level in patients with systemic lupus erythematosus (1346±1011 pg per milliliter), ankylosing spondylitis (1368±1162 pg per milliliter), or liver fibrosis (1668±1263 pg per milliliter). CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro, CXCL4 down-regulated expression of transcription factor FLI1, induced markers of endothelial-cell activation, and potentiated responses of toll-like receptors. In vivo, CXCL4 induced the influx of inflammatory cells and skin transcriptome changes, as in systemic sclerosis. CONCLUSIONS: Levels of CXCL4 were elevated in patients with systemic sclerosis and correlated with the presence and progression of complications, such as lung fibrosis and pulmonary arterial hypertension. (Funded by the Dutch Arthritis Association and others.).
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Células Dendríticas/metabolismo , Fator Plaquetário 4/sangue , Escleroderma Sistêmico/sangue , Adulto , Animais , Biomarcadores/sangue , Citocinas/metabolismo , Hipertensão Pulmonar Primária Familiar , Feminino , Humanos , Hipertensão Pulmonar/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Fator Plaquetário 4/metabolismo , Proteoma , Fibrose Pulmonar/sangue , RNA Mensageiro/metabolismo , Escleroderma Sistêmico/etiologia , Pele/patologiaRESUMO
Development of personalized treatment regimens is hampered by lack of insight into how individual animal models reflect subsets of human disease, and autoimmune and inflammatory conditions have proven resistant to such efforts. Scleroderma is a lethal autoimmune disease characterized by fibrosis, with no effective therapy. Comparative gene expression profiling showed that murine sclerodermatous graft-versus-host disease (sclGVHD) approximates an inflammatory subset of scleroderma estimated at 17% to 36% of patients analyzed with diffuse, 28% with limited, and 100% with localized scleroderma. Both sclGVHD and the inflammatory subset demonstrated IL-13 cytokine pathway activation. Host dermal myeloid cells and graft T cells were identified as sources of IL-13 in the model, and genetic deficiency of either IL-13 or IL-4Rα, an IL-13 signal transducer, protected the host from disease. To identify therapeutic targets, we explored the intersection of genes coordinately up-regulated in sclGVHD, the human inflammatory subset, and IL-13-treated fibroblasts; we identified chemokine CCL2 as a potential target. Treatment with anti-CCL2 antibodies prevented sclGVHD. Last, we showed that IL-13 pathway activation in scleroderma patients correlated with clinical skin scores, a marker of disease severity. Thus, an inflammatory subset of scleroderma is driven by IL-13 and may benefit from IL-13 or CCL2 blockade. This approach serves as a model for personalized translational medicine, in which well-characterized animal models are matched to molecularly stratified patient subsets.
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Quimiocina CCL2/genética , Doença Enxerto-Hospedeiro/genética , Interleucina-13/genética , Escleroderma Sistêmico/genética , Animais , Quimiocina CCL2/antagonistas & inibidores , Modelos Animais de Doenças , Fibroblastos/metabolismo , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Receptores de Interleucina-13/metabolismo , Receptores de Interleucina-4/metabolismo , Transdução de Sinais , Linfócitos T/metabolismo , Regulação para CimaRESUMO
OBJECTIVE: To explore the relationship between biomarkers of pulmonary arterial hypertension (PAH), interferon (IFN)-regulated gene expression, and the alternative activation pathway in systemic sclerosis (SSc). METHODS: Peripheral blood mononuclear cells (PBMCs) were purified from healthy controls, patients with idiopathic PAH, and SSc patients (classified as having diffuse cutaneous SSc, limited cutaneous SSc [lcSSc] without PAH, and lcSSc with PAH). IFN-regulated and "PAH biomarker" genes were compared after supervised hierarchical clustering. Messenger RNA levels of selected IFN-regulated genes (Siglec1 and MX1), biomarker genes (IL13RA1, CCR1, and JAK2), and the alternative activation marker gene (MRC1) were analyzed on PBMCs and on CD14- and CD14+ cell populations. Interleukin-13 (IL-13) and IL-4 concentrations were measured in plasma by immunoassay. CD14, MRC1, and IL13RA1 surface expression was analyzed by flow cytometry. RESULTS: Increased PBMC expression of both IFN-regulated and biomarker genes distinguished SSc patients from healthy controls. Expression of genes in the biomarker cluster, but not in the IFN-regulated cluster, distinguished lcSSc with PAH from lcSSc without PAH. The genes CCR1 (P<0.001) and JAK2 (P<0.001) were expressed more highly in lcSSc patients with PAH compared with controls and mainly by CD14+ cells. MRC1 expression was increased exclusively in lcSSc patients with PAH (P<0.001) and correlated strongly with pulmonary artery pressure (r=0.52, P=0.03) and higher mortality (P=0.02). MRC1 expression was higher in CD14+ cells and was greatly increased by stimulation with IL-13. IL-13 concentrations in plasma were most highly increased in lcSSc patients with PAH (P<0.001). CONCLUSION: IFN-regulated and biomarker genes represent distinct, although related, clusters in lcSSc patients with PAH. MRC1, a marker for the effect of IL-13 on alternative monocyte/macrophage activation, is associated with this severe complication and is related to mortality.
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Interferons/imunologia , Ativação de Macrófagos/imunologia , Escleroderma Sistêmico/imunologia , Adulto , Idoso , Hipertensão Pulmonar Primária Familiar , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/imunologia , Regulação da Expressão Gênica , Humanos , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/imunologia , Hipertensão Pulmonar/mortalidade , Interleucina-13/sangue , Subunidade alfa1 de Receptor de Interleucina-13/genética , Subunidade alfa1 de Receptor de Interleucina-13/imunologia , Interleucina-4/sangue , Janus Quinase 2/genética , Janus Quinase 2/imunologia , Receptores de Lipopolissacarídeos/imunologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Pessoa de Meia-Idade , Proteínas de Resistência a Myxovirus , Receptores CCR1/genética , Receptores CCR1/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Escleroderma Sistêmico/complicações , Lectina 1 Semelhante a Ig de Ligação ao Ácido SiálicoRESUMO
OBJECTIVE: To evaluate the levels of periostin in patients with systemic sclerosis (SSc) and their association with features of systemic sclerosis. METHODS: The levels of periostin were assessed in the serum of 106 SSc patients and 22 healthy controls and by immunofluorescence staining in cardiac tissue from 4 SSc patients and 4 controls. Serum periostin was measured via enzyme-linked immunosorbent assay. The results were analyzed using Mann-Whitney test or Kruskal-Wallis test followed by Dunn's multiple comparisons tests and Spearman's test for correlations. Cardiac tissue from SSc patients and controls was stained for periostin and co-stained for periostin and collagen type I using immunofluorescence. RESULTS: Periostin levels were higher in patients with SSc compared to controls and directly correlated to modified Rodnan skin score and echocardiography parameters of left ventricular measurements. Immunofluorescence staining in SSc cardiac tissue showed patchy periostin expression in all SSc patients, but not in controls. Furthermore, there was extensive periostin expression even in areas without collagen deposition, while all established fibrotic areas showed colocalization of collagen and periostin. There was no association between periostin levels and interstitial lung disease, pulmonary hypertension or other vascular complications. CONCLUSION: Periostin is elevated in SSc cardiac tissue in vivo and circulating levels of periostin are increased in SSc, correlating with the extent of disease duration, degree of skin fibrosis, and left ventricular structural assessments. Periostin may be a potential biomarker that can provide further pathogenic insight into cardiac fibrosis in SSc.
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Esclerodermia Localizada , Escleroderma Sistêmico , Humanos , Escleroderma Sistêmico/patologia , Esclerodermia Localizada/patologia , Fibrose , Pele/patologia , BiomarcadoresRESUMO
BACKGROUND: In patients with systemic sclerosis (SSc), the relationship between innate immune activation, represented by increased expression of interferon (IFN)-regulated genes, and vascular injury/activation, manifest by increased endothelin-1 (ET-1), endothelin converting enzyme-1 (ECE1) and intercellular adhesion molecule-1, is uncertain. OBJECTIVE: To investigate the potential roles of innate immune ligands in both these pathogenic pathways. METHODS: The effect of known Toll-like receptor (TLR) ligands was tested in vitro on dermal microvascular and pulmonary arterial endothelial cells, and on dermal fibroblasts cultured from healthy controls and patients with SSc. To test the effect of double-stranded RNA (dsRNA) on vascular activation/injury in vivo, polyinosinic/polycytidylic acid (poly(I:C)) was administered continuously over 7 days by subcutaneous osmotic pump. RESULTS: dsRNA/poly(I:C), but not other TLR ligands, highly stimulated ET-1 protein and mRNA (EDN1), as well as intercellular adhesion molecule-1 (ICAM-1) and IFN-regulated MX2, by endothelial cells and dermal fibroblasts. Poly(I:C) induced EDN1, ECE1, and ICAM-1 mRNA expression in poly(I:C) treated skin. Poly(I:C)-induced EDN1, ECE1 and MX2 was not blocked in mice with the type I IFN receptor deleted. However, poly(I:C)-induced EDN1 and ECE1, but not poly(I:C)-induced ICAM-1 expression was blocked in mice with the TLR3 signalling protein TRIF/TICAM-1 deleted. CONCLUSION: Together these data show that the dsRNA can regulate genes associated with vascular activation, as seen in SSc, that type I IFNs do not mediate these effects, and that EDN1 and ECE1 but not ICAM-1 activation is mediated by TLR3.
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Endotelina-1/biossíntese , Fibroblastos/metabolismo , Escleroderma Sistêmico/metabolismo , Animais , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotelina-1/genética , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Proteínas de Ligação ao GTP/biossíntese , Proteínas de Ligação ao GTP/genética , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Resistência a Myxovirus , Poli I-C/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , RNA de Cadeia Dupla/genética , RNA Mensageiro/genética , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/imunologia , Pele/metabolismo , Receptor 3 Toll-Like/metabolismoRESUMO
Microvascular injury is considered an initial event in the pathogenesis of scleroderma and endothelial cells are suspected of being the target of the autoimmune process seen in the disease. EBV has long been proposed as a trigger for autoimmune diseases, including scleroderma. Nevertheless, its contribution to the pathogenic process remains poorly understood. In this study, we report that EBV lytic antigens are detected in scleroderma dermal vessels, suggesting that endothelial cells might represent a target for EBV infection in scleroderma skin. We show that EBV DNA load is remarkably increased in peripheral blood, plasma and circulating monocytes from scleroderma patients compared to healthy EBV carriers, and that monocytes represent the prominent subsets of EBV-infected cells in scleroderma. Given that monocytes have the capacity to adhere to the endothelium, we then investigated whether monocyte-associated EBV could infect primary human endothelial cells. We demonstrated that endothelial cells are infectable by EBV, using human monocytes bound to recombinant EBV as a shuttle, even though cell-free virus failed to infect them. We show that EBV induces activation of TLR9 innate immune response and markers of vascular injury in infected endothelial cells and that up-regulation is associated with the expression of EBV lytic genes in infected cells. EBV innate immune modulation suggests a novel mechanism mediating inflammation, by which EBV triggers endothelial cell and vascular injury in scleroderma. In addition, our data point to up-regulation of EBV DNA loads as potential biomarker in developing vasculopathy in scleroderma. These findings provide the framework for the development of novel therapeutic interventions to shift the scleroderma treatment paradigm towards antiviral therapies.
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Endotélio Vascular/patologia , Infecções por Vírus Epstein-Barr/complicações , Imunidade Inata , Escleroderma Sistêmico/imunologia , Pele/patologia , Adulto , Idoso , Biópsia , DNA Viral/isolamento & purificação , Células Endoteliais/imunologia , Células Endoteliais/patologia , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/virologia , Pele/irrigação sanguínea , Pele/imunologia , Receptor Toll-Like 9/metabolismo , Carga Viral , Adulto JovemRESUMO
BACKGROUND: The independent association between hepatic steatosis and rheumatoid arthritis is poorly defined. METHODS: The presence of moderate to severe steatosis was assessed, using liver ultrasonography, in 364 consecutive non-diabetic subjects (223 patients with rheumatoid arthritis and 141 age- and sex-matched healthy controls). Adjusted multiple regression analysis was performed to explore the association between rheumatoid arthritis and moderate to severe steatosis in the overall sample and identify independent risk factors in the rheumatoid arthritis subgroup. RESULTS: The prevalence of moderate to severe steatosis in the overall sample was 31.3%, with a significantly higher prevalence in patients with rheumatoid arthritis than healthy controls (38.7% versus 19.7%, p < 0.0001). After adjustment for sex, age, cholesterol, triglycerides, body mass index, waist, hypertension and smoke, rheumatoid arthritis remained significantly associated with moderate to severe steatosis [odds ratio (95% confidence interval) = 2.24 (1.31, 3.84); p = 0.003]. In the rheumatoid arthritis group, male sex, higher body mass index, higher triglycerides concentrations and higher cumulative dosage of methotrexate [odds ratio (95% confidence interval) = 1.11 (1.01, 1.23); p = 0.026] were significantly associated with moderate to severe steatosis, while systemic inflammation, disease activity, use of steroids and biologics were not. CONCLUSION: Rheumatoid arthritis is independently associated with moderate to severe steatosis, with male sex, higher body mass index and cumulative dose of methotrexate being predisposing factors. Further prospective studies are warranted to confirm our findings and to investigate the effect of steatosis on liver outcomes in the rheumatoid arthritis population.
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Viral egress and autophagy are two mechanisms that seem to be strictly connected in Herpesviruses's biology. Several data suggest that the autophagic machinery facilitates the egress of viral capsids and thus the production of new infectious particles. In the Herpesvirus family, viral nuclear egress is controlled and organized by a well conserved group of proteins named Nuclear Egress Complex (NEC). In the case of EBV, NEC is composed by BFRF1 and BFLF2 proteins, although the alterations of the nuclear host cell architecture are mainly driven by BFRF1, a multifunctional viral protein anchored to the inner nuclear membrane of the host cell. BFRF1 shares a peculiar distribution with several nuclear components and with them it strictly interacts. In this study, we investigated the possible role of BFRF1 in manipulating autophagy, pathway that possibly originates from nucleus, regulating the interplay between autophagy and viral egress.
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Autofagia , Herpesvirus Humano 4/fisiologia , Proteínas de Membrana/metabolismo , Proteínas Virais/metabolismo , Células HEK293 , Humanos , Lamina Tipo B/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Membrana Nuclear/metabolismo , Ligação Proteica , Liberação de Vírus , Proteínas rab de Ligação ao GTP/metabolismo , proteínas de unión al GTP Rab7RESUMO
OBJECTIVE: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is characterized by variable clinical outcomes, activation of innate immune pattern-recognition receptors (PRRs), and accumulation of α-smooth muscle actin (α-SMA)-expressing myofibroblasts. The aim of this study was to identify an association between these entities and mitochondrial DNA (mtDNA), an endogenous ligand for the intracellular DNA-sensing PRRs Toll-like receptor 9 (TLR-9) and cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING), which has yet to be determined. METHODS: Human lung fibroblasts (HLFs) from normal donors and SSc-ILD explants were treated with synthetic CpG DNA and assayed for α-SMA expression and extracellular mtDNA using quantitative polymerase chain reaction for the human MT-ATP6 gene. Plasma MT-ATP6 concentrations were evaluated in 2 independent SSc-ILD cohorts and demographically matched controls. The ability of SSc-ILD and control plasma to induce TLR-9 and cGAS/STING activation was evaluated with commercially available HEK 293 reporter cells. Plasma concentrations of type I interferons (IFNs), interleukin-6 (IL-6), and oxidized DNA were measured using electrochemiluminescence and enzyme-linked immunosorbent assay-based methods. Extracellular vesicles (EVs) precipitated from plasma were evaluated for MT-ATP6 concentrations and proteomics via liquid chromatography mass spectrometry. RESULTS: Normal HLFs and SSc-ILD fibroblasts developed increased α-SMA expression and MT-ATP6 release following CpG stimulation. Plasma mtDNA concentrations were increased in the 2 SSc-ILD cohorts, reflective of ventilatory decline, and were positively associated with both TLR-9 and cGAS/STING activation as well as type I IFN and IL-6 expression. Plasma mtDNA was not oxidized and was conveyed by EVs displaying a proteomics profile consistent with a multicellular origin. CONCLUSION: These findings demonstrate a previously unrecognized connection between EV-encapsulated mtDNA, clinical outcomes, and intracellular DNA-sensing PRR activation in SSc-ILD. Further study of these interactions could catalyze novel mechanistic and therapeutic insights into SSc-ILD and related disorders.
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DNA Mitocondrial/sangue , Doenças Pulmonares Intersticiais/sangue , Escleroderma Sistêmico/sangue , Actinas/metabolismo , Citocinas/metabolismo , Progressão da Doença , Feminino , Fibroblastos/metabolismo , Células HEK293 , Humanos , Doenças Pulmonares Intersticiais/etiologia , Masculino , Escleroderma Sistêmico/complicaçõesRESUMO
The below funding information was missing in the published article.
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The diagnosis of psoriasis, an immune-mediated disease that affects 2% of the population in Western countries, is largely based on history and clinical examination. The aim of this systematic review and meta-analysis was to investigate the associations between the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) and the presence and clinical severity of psoriasis. A systematic literature search was conducted in PubMed, Web of Science, and Scopus, from inception to January 2018. Twelve case-control studies enrolling 1067 psoriasis patients (537 males and 530 females) and 799 healthy controls (404 males and 395 females) were included in the meta-analysis. The NLR was evaluated in all the studies, while the PLR was assessed in four studies. Pooled results showed that both the NLR and the PLR values were significantly higher in patients with psoriasis (SMD = 0.69, 95% CI 0.53-1.85, p < 0.001, and SMD = 0.40, 95% CI 0.12-0.68, p = 0.006, respectively). There were no significant differences in NLR values according to the severity of disease (p = 0.52). The NLR and the PLR are significantly associated with the presence, but not with the severity, of psoriasis. Further studies are required to determine the additional utility of these haematological indexes in the diagnosis of psoriasis.
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Técnicas de Apoio para a Decisão , Psoríase/diagnóstico , Psoríase/patologia , Adulto , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Adulto JovemRESUMO
EBV (Epstein-Barr Virus) and other human DNA viruses are associated with autoimmune syndromes in epidemiologic studies. In this work, immunoglobulin G response to EBV-encoded proteins which share regions with human immune response proteins from the human host including ZEBRA (BZLF-1 encoded protein), BALF-2 recombinase expressed primarily during the viral lytic replication cycle, and EBNA-1 (Epstein-Barr Virus Nuclear Antigen) expressed during the viral latency cycle respectively were characterized using a laser-printed micro-array ( PEPperprint.com ). IgG response to conserved "A/T hooks" in EBV-encoded proteins such as EBNA-1 and the BALF-2 recombinase related to host DNA-binding proteins including RAG-1 recombinase and histones, and EBV-encoded virokines such as the IL-10 homologue BCRF-1 suggest further directions for clinical research. The author suggests that proteomic "molecular fingerprints" of the immune response to viral proteins shared with human immune response genes are potentially useful in early diagnosis and monitoring of autoantibody production and response to therapy in EBV-related autoimmune syndromes.
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Doenças Autoimunes/diagnóstico , Doenças Autoimunes/genética , Herpesvirus Humano 4/genética , Mimetismo Molecular/genética , Animais , Formação de Anticorpos/genética , Autoanticorpos/genética , Humanos , Proteômica/métodosRESUMO
OBJECTIVES: The aim of this analysis was to provide an estimate of drug utilization indicators (persistence, switch rate and drug consumption) on biologics and the corresponding costs (drugs, admissions and specialist care) incurred by the Italian National Health Service in the management of adult patients with rheumatoid arthritis (RA). METHODS: We conducted an observational retrospective cohort analysis using the administrative databases of three local health units. We considered all patients aged ≥18 years with a diagnosis of RA and at least one biologic drug prescription between January 2010 and December 2012 (recruitment period). Persistence was defined as maintenance over the last 3 months of the follow-up period of the same biological therapy administered at the index date. A switch was defined as the presence of a biological therapy other than that administered at the index date during the last 3 months of the follow-up period. Hospital admissions (with a diagnosis of RA or other RA-related diagnoses), specialist outpatient services, instrumental diagnostics and pharmaceutical consumption were assessed. RESULTS: The drug utilization analysis took into account only biologics with at least 90 patients on treatment at baseline (adalimumab n=144, etanercept n=236 and infliximab n=94). In each year, etanercept showed better persistence with initial treatment than adalimumab or infliximab. Etanercept was characterized by the lowest number of patients increasing the initial drug consumption (2.6%) and by the highest number of patients reducing the initial drug consumption (10.5%). The mean cost of treatment for a patient persisting with the initial treatment was 12,388 (14,182 for adalimumab, 12,103 for etanercept and 11,002 for infliximab). The treatment costs for patients switching from initial treatment during the first year of follow-up were higher than for patients who did not switch (12,710 vs. 11,332). CONCLUSION: Persistence, switch rate and drug consumption seem to directly influence treatment costs. In subjects not persisting with initial treatment, other health care costs were approximately three times higher than for persistent patients. This difference could suggest a positive effect on the quality of life for persistent patients. Etanercept showed the highest persistence with treatment.
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Cartilage oligomeric matrix protein (COMP) is an extracellular glycoprotein that belongs to the thrombospondin gene family. It is found predominantly in cartilage, tendon, ligament, and bone. Mutations in the COMP gene have been linked to the development of pseudoachondroplasia and multiple epiphysial dysplasia. COMP influences the organization of collagen fibrils by interacting with collagens I, II and IX. Gene expression profiling of cultured skin fibroblasts suggested that COMP mRNA levels were elevated in scleroderma. We therefore examined COMP expression in SSc and normal skin biopsies. Immunohistochemistry confirmed that COMP protein accumulates in SSc but not normal skin, with SSc skin showing striking deposition in the papillary and deeper dermis. Significant staining was also seen in non-lesional skin from patients. Due to its involvement in the development of fibrosis, TGFbeta was examined for a possible role in regulating COMP expression. Cultured SSc fibroblasts demonstrated greater staining for COMP compared to normal controls prior to stimulation, and TGFbeta-1 induced a large increase in mRNA and protein. Murine fibroblasts engineered to overexpress human COMP demonstrated increased levels of fibronectin and collagen in the extracellular matrix. Taken together, these data demonstrate that COMP is overexpressed in SSc skin and cultured fibroblasts possibly due to autocrine TGFbeta stimulation, and COMP overexpression is sufficient to stimulate excess matrix deposition. By interactions with other matrix proteins and cells, COMP may play a role in pathogenic matrix deposition.
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Proteínas da Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Expressão Gênica , Glicoproteínas/metabolismo , Escleroderma Sistêmico/patologia , Pele/patologia , Animais , Proteína de Matriz Oligomérica de Cartilagem , Células Cultivadas , Colágeno/metabolismo , Proteínas da Matriz Extracelular/genética , Fibronectinas/metabolismo , Glicoproteínas/genética , Humanos , Proteínas Matrilinas , Camundongos , RNA Mensageiro , Pele/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
OBJECTIVES: To analyze the association of interleukin (IL-1) gene polymorphisms with susceptibility to, and severity of, rheumatoid arthritis (RA) patients, comparing them with the genotype distribution in healthy controls. Also, to assess the influence of IL1-B and IL1RN gene polymorphism on IL-1beta/IL-1Ra plasma levels and response to therapy. PATIENTS AND METHODS: We tested the allelic distribution of IL-1B (-511 and +3953) and IL-1RN (variable number of tandem repeats) gene polymorphism in 126 RA patients and 178 healthy blood donors (HBDs). The patients were categorized into two subgroups in relation to the response to methotrexate (MTX) therapy. Group A included 70 RA patients in stable partial remission after 6 months of MTX treatment (MTX-R). Group B included 56 RA patients with active disease despite MTX therapy. This group received antitumor necrosis factor (TNF) biological drugs and were defined MTX-nonresponders (MTX-NR). RESULTS: None of the two IL-1B (-511 and +3953) gene polymorphisms were significantly different in frequency between RA patients and healthy controls. We observed an increased frequency of the rare allele IL1RN*3 in RA patients with active disease, not responding to MTX therapy (MTX-NR) (4.5%) vs MTX-R (3.6%) and healthy controls (0.8%). Interestingly, RA patients whose genotypes included the IL1RN*long allele (haplotype long-C-T) showed the worse response to MTX. HBDs harboring the IL1RN*2/2 genotype showed significantly lower levels of plasma IL1-Ra, but comparable levels of IL-1beta with regard to subjects with the presence of the IL1RN* long allele. Furthermore, the presence of the TT IL-1B +3953 genotype was associated with lower plasma levels of IL1-Ra, both in HBDs and in RA patients. Carriers of the IL1RN*2 allele responded better to infliximab therapy. CONCLUSIONS: The results of this study provide evidence of an association between the IL1RN*long allele and RA, the strongest association being observed in RA patients with an aggressive disease resistant to MTX treatment.
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Artrite Reumatoide/sangue , Artrite Reumatoide/genética , Interleucina-1/genética , Metotrexato/uso terapêutico , Polimorfismo Genético/genética , Sialoglicoproteínas/genética , Adulto , Idoso , Alelos , Artrite Reumatoide/tratamento farmacológico , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-1/sangue , Masculino , Pessoa de Meia-Idade , Sialoglicoproteínas/sangueRESUMO
AIM: The aim is to evaluate prescriptive patterns of atypical antipsychotic drugs for the treatment of schizophrenia in the LHU Caserta in 2011-2013, and to indicate potentially inappropriate therapy; to plan or schedule corrective/preventive activities to support the continuous improvement of health services. METHODS: Retrospective cohort study, based on integration of health records and clinical audit. The study was performed in the following steps: data retrieval and analysis; comparison of data with international literature; editing of the Diagnostic-Therapeutic Path. The analysis was performed by using the administrative database of drug prescriptions and treatment plans in the SANIARP portal, a web platform available to specialist facilities and private and public pharmacies of LHU Caserta. The subject of our analysis was to gain information about the diagnosis and treatment of users of atypical antipsychotics in the LHU of Caserta in the years 2011-2013. RESULTS: We identified 2,768 patients with at least one prescription of atypical antipsychotics and diagnosis coded in the study period. Schizophrenia is the most frequent diagnosis (31.1%) and the most common drug in use is olanzapine (29.1%). About 70% of schizophrenics were on monotherapy with no change in drug, 23.6% were under polytherapy and 7.9% made a switch. DISCUSSION AND CONCLUSION: Our findings were a starting point for editing Diagnostic and Therapeutic Paths aimed at raising the awareness of the scientific community about the appropriateness of diagnosis and treatment in schizophrenia. Pharmacological treatment of schizophrenia should be focused on improving the overall quality of life aimed at remission and possible recovery, although difficult.
Assuntos
Antipsicóticos/uso terapêutico , Benzodiazepinas/uso terapêutico , Auditoria Clínica , Prescrições de Medicamentos/estatística & dados numéricos , Piperazinas/uso terapêutico , Qualidade de Vida , Esquizofrenia/tratamento farmacológico , Tiazóis/uso terapêutico , Aripiprazol , Dibenzocicloeptenos , Quimioterapia Combinada , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis , Humanos , Itália/epidemiologia , Masculino , Olanzapina , Palmitato de Paliperidona , Psicoterapia/métodos , Fumarato de Quetiapina , Estudos Retrospectivos , Risperidona , Esquizofrenia/diagnóstico , Esquizofrenia/epidemiologia , Esquizofrenia/reabilitação , Resultado do TratamentoRESUMO
BACKGROUND: TGF-ß has potent profibrotic activity in vitro and has long been implicated in systemic sclerosis (SSc), as expression of TGF-ß-regulated genes is increased in the skin and lungs of patients with SSc. Therefore, inhibition of TGF-ß may benefit these patients. METHODS: Patients with early, diffuse cutaneous SSc were enrolled in an open-label trial of fresolimumab, a high-affinity neutralizing antibody that targets all 3 TGF-ß isoforms. Seven patients received two 1 mg/kg doses of fresolimumab, and eight patients received one 5 mg/kg dose of fresolimumab. Serial mid-forearm skin biopsies, performed before and after treatment, were analyzed for expression of the TGF-ß-regulated biomarker genes thrombospondin-1 (THBS1) and cartilage oligomeric protein (COMP) and stained for myofibroblasts. Clinical skin disease was assessed using the modified Rodnan skin score (MRSS). RESULTS: In patient skin, THBS1 expression rapidly declined after fresolimumab treatment in both groups (P = 0.0313 at 7 weeks and P = 0.0156 at 3 weeks), and skin expression of COMP exhibited a strong downward trend in both groups. Clinical skin disease dramatically and rapidly decreased (P < 0.001 at all time points). Expression levels of other TGF-ß-regulated genes, including SERPINE1 and CTGF, declined (P = 0.049 and P = 0.012, respectively), and a 2-gene, longitudinal pharmacodynamic biomarker of SSc skin disease decreased after fresolimumab treatment (P = 0.0067). Dermal myofibroblast infiltration also declined in patient skin after fresolimumab (P < 0.05). Baseline levels of THBS1 were predictive of reduced THBS1 expression and improved MRSS after fresolimumab treatment. CONCLUSION: The rapid inhibition of TGF-ß-regulated gene expression in response to fresolimumab strongly implicates TGF-ß in the pathogenesis of fibrosis in SSc. Parallel improvement in the MRSS indicates that fresolimumab rapidly reverses markers of skin fibrosis. TRIAL REGISTRATION: Clinicaltrials.gov NCT01284322.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Escleroderma Sistêmico/terapia , Adulto , Anticorpos Monoclonais Humanizados , Proteína de Matriz Oligomérica de Cartilagem/genética , Feminino , Expressão Gênica , Marcadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Miofibroblastos/patologia , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/patologia , Trombospondina 1/genética , Fator de Crescimento Transformador beta/antagonistas & inibidores , Resultado do TratamentoRESUMO
Scleroderma (SSc) is a complex and heterogeneous connective tissue disease mainly characterized by autoimmunity, vascular damage, and fibrosis that mostly involve the skin and lungs. Epstein-Barr virus (EBV) is a lymphotropic γ-herpesvirus that has co-evolved with human species, infecting >95% of the adult population worldwide, and has been a leading candidate in triggering several autoimmune diseases. Here we show that EBV establishes infection in the majority of fibroblasts and endothelial cells in the skin of SSc patients, characterized by the expression of the EBV noncoding small RNAs (EBERs) and the increased expression of immediate-early lytic and latency mRNAs and proteins. We report that EBV is able to persistently infect human SSc fibroblasts in vitro, inducing an aberrant innate immune response in infected cells. EBV-Toll-like receptor (TLR) aberrant activation induces the expression of selected IFN-regulatory factors (IRFs), IFN-stimulated genes (ISGs), transforming growth factor-ß1 (TGFß1), and several markers of fibroblast activation, such as smooth muscle actin and Endothelin-1, and all of these genes play a key role in determining the profibrotic phenotype in SSc fibroblasts. These findings imply that EBV infection occurring in mesenchymal, endothelial, and immune cells of SSc patients may underlie the main pathological features of SSc including autoimmunity, vasculopathy, and fibrosis, and provide a unified disease mechanism represented by EBV reactivation.