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1.
Arthritis Rheumatol ; 2021 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-33455083

RESUMO

OBJECTIVE: To identify the genetic variants that affect gene expression (expression quantitative trait loci, eQTLs) in systemic sclerosis (SSc) to investigate their role in the pathogenesis of the disease. METHODS: We performed an eQTL analysis using whole blood sequencing data of 333 SSc patients and 524 controls and integrated them with SSc GWAS data. We integrated our findings from modelling of expression, differential expression analysis and transcription factor binding site (TFBS) enrichment with key clinical features of SSc. RESULTS: We detected 49,123 validated cis-eQTLs from 4,539 SSc associated SNPs (pGWAS <10-5 ) and 565 of 1.436 genes with an SSc eQTL within 1 Mb distance to the gene. We developed a strategy to prioritize disease-associated genes based on their expression variance explained by SSc eQTLs (r2 >0.05). As a result, 233 candidates were identified, 134 (58%) of them associated with hallmarks of SSc and 105 (45%) of them differentially expressed in blood cells, skin, or lung tissue of SSc patients. TFBS analysis revealed enriched motifs of 24 TFs (5%) among SSc eQTLs, five of which were found to be differentially regulated in blood cells (ELF1 and MGA), skin (KLF4 and ID4), and lungs (TBX4) of SSc patients. Ten candidate genes (4%) can be targeted by approved medications for immune-mediated diseases, of which only two have been tested in clinical trials in patients with SSc. CONCLUSION: The data of the present study provides a new layer of the molecular complexity of SSc, contributing to a better understanding of the pathogenesis of the disease.

2.
Nat Rev Rheumatol ; 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33408338

RESUMO

During the COVID-19 pandemic, the need to provide high-level care for a large number of patients with COVID-19 has affected resourcing for, and limited the routine care of, all other conditions. The impact of this health emergency is particularly relevant in the rare connective tissue diseases (rCTDs) communities, as discussed in this Perspective article by the multi-stakeholder European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ERN ReCONNET). The clinical, organizational and health economic challenges faced by health-care providers, institutions, patients and their families during the SARS-CoV-2 outbreak have demonstrated the importance of ensuring continuity of care in the management of rCTDs, including adequate diagnostics and monitoring protocols, and highlighted the need for a structured emergency strategy. The vulnerability of patients with rCTDs needs to be taken into account when planning future health policies, in preparation for not only the post-COVID era, but also any possible new health emergencies.

3.
Int J Mol Sci ; 21(24)2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333969

RESUMO

Angiopoietin-2 (Ang-2), a ligand of the tyrosine kinase receptor Tie2, is essential for vascular development and blood vessel stability and is also involved in monocyte activation. Here, we examined the role of Ang-2 on monocyte activation in patients with systemic sclerosis (SSc). Ang-2 levels were measured in serum and skin of healthy controls (HCs) and SSc patients by ELISA and array profiling, respectively. mRNA expression of ANG2 was analyzed in monocytes, dermal fibroblasts, and human pulmonary arterial endothelial cells (HPAECs) by quantitative PCR. Monocytes were stimulated with Ang-2, or with serum from SSc patients in the presence of a Tie2 inhibitor or an anti-Ang2 neutralizing antibody. Interleukin (IL)-6 and IL-8 production was analyzed by ELISA. Ang-2 levels were elevated in the serum and skin of SSc patients compared to HCs. Importantly, serum Ang-2 levels correlated with clinical disease parameters, such as skin involvement. Lipopolysaccharide (LPS) LPS, R848, and interferon alpha2a (IFN-α) stimulation up-regulated the mRNA expression of ANG2 in monocytes, dermal fibroblasts, and HPAECs. Finally, Ang-2 induced the production of IL-6 and IL-8 in monocytes of SSc patients, while the inhibition of Tie2 or the neutralization of Ang-2 reduced the production of both cytokines in HC monocytes stimulated with the serum of SSc patients. Therefore, Ang-2 induces inflammatory activation of SSc monocytes and neutralization of Ang-2 might be a promising therapeutic target in the treatment of SSc.

4.
Ann Rheum Dis ; 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004331

RESUMO

OBJECTIVES: Genomic Risk Scores (GRS) successfully demonstrated the ability of genetics to identify those individuals at high risk for complex traits including immune-mediated inflammatory diseases (IMIDs). We aimed to test the performance of GRS in the prediction of risk for systemic sclerosis (SSc) for the first time. METHODS: Allelic effects were obtained from the largest SSc Genome-Wide Association Study (GWAS) to date (9 095 SSc and 17 584 healthy controls with European ancestry). The best-fitting GRS was identified under the additive model in an independent cohort that comprised 400 patients with SSc and 571 controls. Additionally, GRS for clinical subtypes (limited cutaneous SSc and diffuse cutaneous SSc) and serological subtypes (anti-topoisomerase positive (ATA+) and anti-centromere positive (ACA+)) were generated. We combined the estimated GRS with demographic and immunological parameters in a multivariate generalised linear model. RESULTS: The best-fitting SSc GRS included 33 single nucleotide polymorphisms (SNPs) and discriminated between patients with SSc and controls (area under the receiver operating characteristic (ROC) curve (AUC)=0.673). Moreover, the GRS differentiated between SSc and other IMIDs, such as rheumatoid arthritis and Sjögren's syndrome. Finally, the combination of GRS with age and immune cell counts significantly increased the performance of the model (AUC=0.787). While the SSc GRS was not able to discriminate between ATA+ and ACA+ patients (AUC<0.5), the serological subtype GRS, which was based on the allelic effects observed for the comparison between ACA+ and ATA+ patients, reached an AUC=0.693. CONCLUSIONS: GRS was successfully implemented in SSc. The model discriminated between patients with SSc and controls or other IMIDs, confirming the potential of GRS to support early and differential diagnosis for SSc.

5.
Semin Arthritis Rheum ; 50(5): 1150-1157, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32927376

RESUMO

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic disease characterised by autoimmunity and increased susceptibility to infections. COVID-19 is a systemic viral disease currently spreading as a pandemic. Little is known about the impact of COVID-19 in patients with SLE. OBJECTIVE: to acquire information on the impact of COVID-19 in SLE. METHODS: A 26-item anonymous questionnaire investigating demographics, SLE clinical features, COVID-19 diagnoses and changes in treatments and daily habits was administered to patients with SLE from three referral centres through www.surveymonkey.com over 10 days. Data from the survey were compared to those from published estimates about the general population. RESULTS: Four-hundred-seventeen patients responded to the survey. More than 60% of subjects complained of symptoms that are also associated to COVID-19. Fourteen COVID-19 diagnoses (five confirmed by polymerase chain reaction) were reported, in contrast to a 0.73% prevalence of confirmed cases in Lombardy. One hospitalisation was reported. Fever, anosmia, dry cough, a self-reported history of neuropsychiatric SLE and a recent contact with confirmed COVID-19 cases were more strongly associated with COVID-19, as were symptoms and lower compliance to behavioural preventive measures in patients' contacts. No protective effect was seen in subjects on hydroxychloroquine. CONCLUSION: COVID-19 morbidity might only moderately be increased in most patients with SLE, although limited information can be inferred on more severe cases. Hydroxychloroquine apparently seems not to confer protection to infection per se, although other beneficial roles cannot be excluded. Containment policies and behavioural preventive measures could have a major role in limiting the impact of COVID-19 in patients with SLE.


Assuntos
Controle de Doenças Transmissíveis/métodos , Infecções por Coronavirus , Hidroxicloroquina/uso terapêutico , Lúpus Eritematoso Sistêmico , Pandemias , Pneumonia Viral , Isolamento Social/psicologia , Avaliação de Sintomas , Adulto , Antirreumáticos/uso terapêutico , Betacoronavirus , Técnicas de Laboratório Clínico/métodos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/prevenção & controle , Feminino , Humanos , Itália/epidemiologia , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/terapia , Masculino , Pessoa de Meia-Idade , Pandemias/prevenção & controle , Cooperação do Paciente/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Pneumonia Viral/prevenção & controle , Prevalência , Pesquisa Qualitativa , Avaliação de Sintomas/métodos , Avaliação de Sintomas/estatística & dados numéricos
8.
Autoimmun Rev ; 19(8): 102583, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32553611

RESUMO

Systemic sclerosis (SSc) is a rare chronic disease of unknown etiology characterized by vascular abnormalities and fibrosis involving the skin and internal organs, especially the gastrointestinal tract, lung, heart and kidneys. Although the disease was historically stratified according to the extent of skin involvement, more recent approaches place more emphasis on patterns and extent of internal organ involvement. Despite numerous clinical trials, disease-modifying treatment options are still limited resulting in persistent poor quality of life and high mortality. This review provides an overview of autoantibodies in SSc and novel approaches to stratify the disease into clinically actionable subsets.


Assuntos
Autoanticorpos , Escleroderma Sistêmico , Autoanticorpos/sangue , Autoanticorpos/imunologia , Humanos , Qualidade de Vida , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia , Escleroderma Sistêmico/terapia
9.
Ann Rheum Dis ; 79(9): 1218-1226, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32561607

RESUMO

OBJECTIVES: The analysis of annotated transcripts from genome-wide expression studies may help to understand the pathogenesis of complex diseases, such as systemic sclerosis (SSc). We performed a whole blood (WB) transcriptome analysis on RNA collected in the context of the European PRECISESADS project, aiming at characterising the pathways that differentiate SSc from controls and that are reproducible in geographically diverse populations. METHODS: Samples from 162 patients and 252 controls were collected in RNA stabilisers. Cases and controls were divided into a discovery (n=79+163; Southern Europe) and validation cohort (n=83+89; Central-Western Europe). RNA sequencing was performed by an Illumina assay. Functional annotations of Reactome pathways were performed with the Functional Analysis of Individual Microarray Expression (FAIME) algorithm. In parallel, immunophenotyping of 28 circulating cell populations was performed. We tested the presence of differentially expressed genes/pathways and the correlation between absolute cell counts and RNA transcripts/FAIME scores in regression models. Results significant in both populations were considered as replicated. RESULTS: Overall, 15 224 genes and 1277 functional pathways were available; of these, 99 and 225 were significant in both sets. Among replicated pathways, we found a deregulation in type-I interferon, Toll-like receptor cascade, tumour suppressor p53 protein function, platelet degranulation and activation. RNA transcripts or FAIME scores were jointly correlated with cell subtypes with strong geographical differences; neutrophils were the major determinant of gene expression in SSc-WB samples. CONCLUSIONS: We discovered a set of differentially expressed genes/pathways validated in two independent sets of patients with SSc, highlighting a number of deregulated processes that have relevance for the pathogenesis of autoimmunity and SSc.


Assuntos
Autoimunidade/genética , Escleroderma Sistêmico/genética , Transdução de Sinais/genética , Transcriptoma/genética , Adulto , Idoso , Estudos de Coortes , Europa (Continente) , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Imunofenotipagem , Interferon Tipo I/sangue , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Análise de Sequência de RNA , Receptores Toll-Like/sangue
10.
Clin Exp Rheumatol ; 38 Suppl 125(3): 40-47, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32301427

RESUMO

OBJECTIVES: Systemic sclerosis (SSc) is a severe multiple-organ disease characterised by unpredictable clinical course, inadequate response to treatment, and poor prognosis. National SSc registries may provide large and representative patients cohorts required for descriptive and prognostic studies. Therefore, the Italian Society for Rheumatology promoted the registry SPRING (Systemic sclerosis Progression INvestiGation). METHODS: The SPRING is a multi-centre rheumatological cohort study encompassing the wide scleroderma spectrum, namely the primary Raynaud's phenomenon (pRP), suspected secondary RP, Very Early Diagnosis of Systemic Sclerosis (VEDOSS), and definite SSc. Here we describe the demographic and clinical characteristics of a population of 2,028 Italian patients at the initial phase of enrolment, mainly focusing on the cohort of 1,538 patients with definite SSc. RESULTS: Definite SSc showed a significantly higher prevalence of digital ulcers, capillaroscopic 'late' pattern, oesophageal and cardio-pulmonary involvement compared to VEDOSS, as expected on the basis of the followed classification criteria. The in-depth analysis of definite SSc revealed that male gender, diffuse cutaneous subset, and anti-Scl70 seropositivity were significantly associated with increased prevalence of the most harmful disease manifestations. Similarly, patients with very short RP duration (≤1 year) at SSc diagnosis showed a statistically increased prevalence of unfavourable clinico-serological features. CONCLUSIONS: Nationwide registries with suitable subsetting of patients and follow-up studies since the prodromal phase of the disease may give us valuable insights into the SSc natural history and main prognostic factors.


Assuntos
Doença de Raynaud , Escleroderma Sistêmico , Estudos de Coortes , Humanos , Itália , Masculino , Angioscopia Microscópica , Sistema de Registros
11.
J Autoimmun ; 111: 102444, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32284212

RESUMO

OBJECTIVE: To analyze how monocyte and macrophage exposure to CXCL4 induces inflammatory and fibrotic processes observed in Systemic sclerosis (SSc) patients. METHODS: In six independent experiments, monocytes of healthy controls (HC) and SSc patients were stimulated with CXCL4, TLR-ligands, IFNɑ or TGFß and the secretion of cytokines in the supernatant was assessed by multiplex immunoassays. PDGF-BB production by monocyte-derived macrophages was quantified using immunoassays. The number of monocytes and PDGF-BB in circulation was quantified in HC and SSc patients with the Sysmex XT-1800i haematology counter and immunoassays. Intracellular PDGF-BB was quantified in monocytes by Western blot. PDGF-receptor inhibition was achieved using siRNA-mediated knockdown or treatment with Crenolanib. The production of inflammatory mediators and extracellular matrix (ECM) components by dermal fibroblasts was analyzed by qPCR, ELISA and ECM deposition assays. RESULTS: SSc and HC monocytes released PDGF-BB upon stimulation with CXCL4. Conversely, TLR ligands, IFNɑ or TGFß did not induce PDGF-bb release. PDGF-BB plasma levels were significantly (P = 0.009) higher in diffuse SSc patients (n = 19), compared with HC (n = 21). In healthy dermal fibroblasts, PDGF-BB enhanced TNFɑ-induced expression of inflammatory cytokines and increased ECM production. Comparable results were observed in fibroblasts cultured in supernatant taken from macrophages stimulated with CXCL4. This effect was almost completely abrogated by inhibition of the PDGF-receptor using Crenolanib. CONCLUSION: Our findings demonstrate that CXCL4 can drive fibroblast activation indirectly via PDGF-BB production by myeloid cells. Hence, targeting PDGF-BB or CXCL4-induced PDGF-BB release could be clinically beneficial for patients with SSc.

12.
Semin Arthritis Rheum ; 50(6): 1489-1493, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32165035

RESUMO

OBJECTIVE: To analyze the safety and effectiveness of abatacept (ABA) given in routine care to patients with systemic sclerosis (SSc). METHODS: Retrospective multicenter observational study that enrolled patients with SSc treated with ABA. We collected epidemiological data and clinical outcomes. First, we analyzed the frequency of adverse effects. Secondly, we compared the evolution of different organ manifestations during ABA treatment. We collected data from 6 months before start of therapy to the last follow-up the following parameters: modified Rodnan Skin Score (mRSS), joints, lung and gastrointestinal involvement, concomitant medications, and laboratory tests. RESULTS: Data on twenty-seven patients with SSc were collected (93% females; 67% limited SSc). Rheumatoid arthritis was the most frequent concomitant autoimmune disease. ILD was present in 15 patients. Anti-Scl 70 antibodies were present in 13 patients and rheumatoid factor and ACPA antibodies were present in eight and seven patients respectively. The main indication to use abatacept was joint involvement (59%) followed by myositis (26%). A total of 16 adverse effects were reported in 28 months of abatacept treatment including five that required hospitalization. Most of them occurred in the first 3 months after starting abatacept. After 12 months, the number of tender and swollen joints decreased compared to baseline (p<0.03 and p<0.02 respectively). Moreover, a beneficial effect of abatacept on HAQ-DI at 3 and 6 months (p<0.05) and on morning stiffness at 6 and 12 months (p<0.03) was observed. We also observed a decrease in the modified Rodnan skin score (p<0.05). No changes in lung or gastrointestinal involvement were found. CONCLUSIONS: ABA demonstrated a good safety profile and seems to have some effectiveness on joint involvement and related disability in SSc patients treated in routine care.

13.
J Nephrol ; 33(5): 1019-1025, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32002799

RESUMO

BACKGROUND: Belimumab (Benlysta) is currently approved for the treatment of active Lupus despite standard therapy. Few data are available on the efficacy of this drug in lupus nephritis (LN). METHODS: 17 LN female followed in two Nephrology Italian Unit received belimumab for a median period of 36 months (range 6-42 months). The indications were: arthralgia in 3 patients, cutaneous manifestations in 2, residual proteinuria in 8, and the need to reduce steroids for severe side effects in 4. Of interest, 1 patient started therapy during Peritoneal Dialysis and continued after kidney transplantation due to non-responsive arthralgias. RESULTS: Arthralgia and skin manifestations resolved in all patients. Proteinuria normalized in three patients and stabilized in all but one of the others. Steroids were indefinitely stopped in six patients (35%) and reduced to around 40% of the basal dosage in the other patients. During belimumab therapy, three extrarenal and one renal SLE flares were diagnosed accounting for a rate of renal flares of 0.02/patient/year. No major adverse events leading to therapy withdrawal occurred. CLINICAL CASE: Arthralgia resolved, immunological parameters improved and prednisone could be reduced within few months in the patient who started belimumab during peritoneal dialysis. After kidney transplantation belimumab was stopped but due to arthralgias unresponsive to standard immunosuppressive therapy it was restarted with success. CONCLUSIONS: Belimumab allows the achievement of complete response together with the withdrawal or the reduction of corticosteroids in almost all our patients. Of interest its satisfactory use in a patient in peritoneal dialysis and after kidney transplantation.

14.
Rheumatology (Oxford) ; 59(7): 1581-1586, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31637433

RESUMO

OBJECTIVES: The DETECT algorithm has been developed to identify SSc patients at risk for pulmonary arterial hypertension (PAH) yielding high sensitivity but low specificity, and positive predictive value. We tested whether cardiopulmonary exercise testing (CPET) could improve the performance of the DETECT screening strategy. METHODS: Consecutive SSc patients over a 30-month period were screened with the DETECT algorithm and positive subjects were referred for CPET before the execution of right-heart catheterization. The predictive performance of CPET on top of DETECT was evaluated and internally validated via bootstrap replicates. RESULTS: Out of 314 patients, 96 satisfied the DETECT application criteria and 54 were positive. PAH was ascertained in 17 (31.5%) and pre-capillary pulmonary hypertension in 23 (42.6%) patients. Within CPET variables, the slope of the minute ventilation to carbon dioxide production relationship (VE/VCO2 slope) had the best performance to predict PAH at right-heart catheterization [median (interquartile range) of specificity 0.778 (0.714-0.846), positive predictive value 0.636 (0.556-0.750)]; exploratory analysis on pre-capillary yielded a specificity of 0.714 (0.636-0.8) and positive predictive value of 0.714 (0.636-0.8). CONCLUSION: In association with the DETECT algorithm, CPET may be considered as a useful tool in the workup of SSc-related pulmonary hypertension. The sequential determination of the VE/VCO2 slope in DETECT-positive subjects may reduce the number of unnecessary invasive procedures without any loss in the capability to capture PAH. This strategy had also a remarkable performance in highlighting the presence of pre-capillary pulmonary hypertension.


Assuntos
Algoritmos , Cateterismo Cardíaco , Teste de Esforço , Hipertensão Arterial Pulmonar/diagnóstico , Escleroderma Sistêmico/complicações , Idoso , Testes Respiratórios , Monóxido de Carbono , Ecocardiografia Doppler , Feminino , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Hipertensão Arterial Pulmonar/etiologia , Hipertensão Arterial Pulmonar/fisiopatologia , Capacidade de Difusão Pulmonar , Troca Gasosa Pulmonar , Testes de Função Respiratória , Sensibilidade e Especificidade
15.
J Pharm Biomed Anal ; 179: 112999, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31780281

RESUMO

Sjögren's Syndrome (SjS) is a complex autoimmune disease characterized by the affection of the exocrine glands and the involvement of multiple organs. Although a greater number of biomarker studies have been carried out in recent years, the origin and pathogenesis are not yet well known and therefore there is a need to continue studying this pathology. This work aims to find metabolic changes in biological samples (plasma and urine), which could help identify the metabolic pathways affected by the SjS pathogenesis. The samples collected from SjS patients and healthy volunteers were analyzed by a fingerprinting metabolomic approach based on HPLC-ESI-QTOF-MS methodology. After feature pre-selection by univariate statistical tests, an integrated PLS-DA model using data from urine and plasma was constructed obtaining a good classification between cases and controls (AUROC = 0.839 ±â€¯0.021). 31 and 38 metabolites in plasma and urine, respectively, showed significant differences between healthy volunteers and SjS patients and were proposed for their identification. From them, 12 plasma and 24 urinary metabolites could be annotated. In general, the main metabolic pathways altered in SjS patients were related to the metabolism of phospholipids, fatty acids, and amino acids, specially tryptophan, proline and phenylalanine.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Síndrome de Sjogren/metabolismo , Espectrometria de Massas por Ionização por Electrospray/métodos , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade
16.
Eur J Immunol ; 50(1): 119-129, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31424086

RESUMO

Systemic sclerosis (SSc), systemic lupus erythematosus (SLE) and primary Sjögrens syndrome (pSS) are clinically distinct systemic autoimmune diseases (SADs) that share molecular pathways. We quantified the frequency of circulating immune-cells in 169 patients with these SADs and 44 healty controls (HC) using mass-cytometry and assessed the diagnostic value of these results. Alterations in the frequency of immune-cell subsets were present in all SADs compared to HC. Most alterations, including a decrease of CD56hi NK-cells in SSc and IgM+ Bcells in pSS, were disease specific; only a reduced frequency of plasmacytoid dendritic cells was common between all SADs Strikingly, hierarchical clustering of SSc patients identified 4 clusters associated with different clinical phenotypes, and 9 of the 12 cell subset-alterations in SSc were also present during the preclinical-phase of the disease. Additionally, we found a strong association between the use of prednisone and alterations in B-cell subsets. Although differences in immune-cell frequencies between these SADs are apparent, the discriminative value thereof is too low for diagnostic purposes. Within each disease, mass cytometry analyses revealed distinct patterns between endophenotypes. Given the lack of tools enabling early diagnosis of SSc, our results justify further research into the value of cellular phenotyping as a diagnostic aid.


Assuntos
Citometria de Fluxo/métodos , Lúpus Eritematoso Sistêmico/imunologia , Escleroderma Sistêmico/imunologia , Síndrome de Sjogren/imunologia , Adulto , Idoso , Feminino , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Pessoa de Meia-Idade , Fenótipo , Escleroderma Sistêmico/diagnóstico , Síndrome de Sjogren/diagnóstico
17.
Nat Commun ; 10(1): 4955, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31672989

RESUMO

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.


Assuntos
Fibrose/genética , Escleroderma Sistêmico/genética , Doenças Vasculares/genética , Teorema de Bayes , Imunoprecipitação da Cromatina , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Conformação de Ácido Nucleico , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA
18.
Sci Rep ; 9(1): 14834, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619697

RESUMO

Fibrosis across different organs and tissues is likely to share common pathophysiological mechanisms and pathways. Recently, a polymorphism (rs12979860) near the interferon lambda gene (IFNL3) was shown to be associated with fibrosis in liver across multiple disease etiologies. We determined whether this variant is a risk factor for pulmonary fibrosis (PF) and worsening cutaneous fibrosis in systemic sclerosis (SSc). Caucasian patients with SSc (n = 733) were genotyped to test for association with the presence of PF and worsening of skin fibrosis. Serum IFN-λ3 levels from 200 SSc cases were evaluated. An association of the IFNL3 polymorphism with PF was demonstrated (OR: 1.66 (95% CI: 1.142-2.416, p = 0.008). The IFNL3 variant was not a risk factor for worsening of skin fibrosis. Functionally, IFN-λ3 serum levels were higher among subjects with PF compared to those unaffected (P < 0.0001). In conclusion, IFNL3 serum levels and the genetic variant known to be associated with liver fibrosis are similarly linked to PF, but not to worsening of skin fibrosis in SSc. These data highlight both common fibrosis pathways operating between organs, as well as differential effects within the same disease.


Assuntos
Interferons , Cirrose Hepática , Fibrose Pulmonar , Escleroderma Sistêmico , Pele/patologia , Idoso , Feminino , Predisposição Genética para Doença , Humanos , Interferons/sangue , Interferons/genética , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fibrose Pulmonar/genética , Fibrose Pulmonar/metabolismo , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/metabolismo
19.
J Clin Med ; 8(9)2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31450824

RESUMO

Dysbiosis has been described in systemic autoimmune diseases (SADs), including systemic lupus erythematosus (SLE), Sjögren's syndrome (SjS), and primary anti-phosholipid syndrome (PAPS), however the biological implications of these associations are often elusive. Stool and plasma samples from 114 subjects, including in SLE (n = 27), SjS (n = 23), PAPs (n = 11) and undifferentiated connective tissue (UCTD, n = 26) patients, and geographically-matched healthy controls (HCs, n = 27), were collected for microbiome (16s rRNA gene sequencing) and metabolome (high-performance liquid chromatography coupled to mass spectrometry) analysis to identify shared characteristics across diseases. Out of 130 identified microbial genera, a subset of 29 bacteria was able to differentiate study groups (area under receiver operating characteristics (AUROC) = 0.730 ± 0.025). A fair classification was obtained with a subset of 41 metabolic peaks out of 254 (AUROC = 0.748 ± 0.021). In both models, HCs were well separated from SADs, while UCTD largely overlapped with the other diseases. In all of the SADs pro-tolerogenic bacteria were reduced, while pathobiont genera were increased. Metabolic alterations included two clusters comprised of: (a) members of the acylcarnitine family, positively correlating with a Prevotella-enriched cluster and negatively correlating with a butyrate-producing bacteria-enriched cluster; and (b) phospholipids, negatively correlating with butyrate-producing bacteria. These findings demonstrate a strong interaction between intestinal microbiota and metabolic function in patients with SADs.

20.
Eur J Intern Med ; 66: 75-80, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31202484

RESUMO

OBJECTIVE: To compare autonomic heart rate variability (HRV) parameters at rest and during active stand in a population of SSc patients, taking into account SSc subsets age-matched to healthy control subjects. METHODS: Sixty-nine consecutive SSc patients were enrolled in study; these included 12 subjects with early SSc, 39 with limited cutaneous (lcSSc) and 18 with diffuse cutaneous SSc (dcSSc) along with 36 age- and sex-matched healthy controls (HC). ECG and respiration were recorded in supine position and in orthostatism (ORT). HRV analysis was performed on samples of 300 beats. Spectral analysis identified two oscillatory components, low frequency (LFnu, sympathetic) and high frequency (HFnu, vagal). Symbolic analysis identified three patterns, 0 V%, (sympathetic) and 2UV% and 2LV%, (vagal). The %∆ORT was calculated from the differences between HRV in ORT and SUP, normalized (%) by the HRV values at rest. RESULTS: SSc as a whole had higher markers of sympathetic (LF, 0 V%) and lower markers of vagal modulation (HR, 2UV%, 2LV%) compared to HCs. In addition, %∆LFnu, %∆HFnu, %∆0 V, %∆2UV and %∆2LV were lower in SSc than HC. dcSSc and lcSSc were dissimilar to HC as far as rest indexes were concerned (↑LF/HF, ↑LFnu, ↓HFnu, ↑0 V% and ↓2UV%) while no differences could be detected between HC and EaSSc. CONCLUSION: SSc showed a reduced vagal and increased sympathetic modulation at rest and a blunted autonomic response to ORT in comparison to HC. These alterations were mostly detectable in the advanced and fibrotic forms of SSc (dcSSc and lcSSc), while EaSSc were similar to HC.


Assuntos
Sistema Nervoso Autônomo/fisiologia , Frequência Cardíaca , Postura , Escleroderma Sistêmico/fisiopatologia , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Cardiovasculares , Escleroderma Sistêmico/classificação , Decúbito Dorsal
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