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1.
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
2.
Clin Immunol ; 173: 76-80, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27616458

RESUMO

Immune activation is a hallmark of systemic sclerosis (SSc). However, the immunological alterations that occur in preclinical and non-fibrotic SSc and that differentiate these subjects from those with primary Raynaud's phenomenon (PRP) or healthy controls (HC) are poorly defined. We isolated CD56+ (NK/NKT-like) cells from HC, patients with PRP, early SSc (EaSSc) and definite SSc without skin or lung fibrosis. Cytokine production upon different activating stimuli was measured via a multiplex immuno assay. Clearly discriminative patterns among the different stages of SSc were most markedly observed after TLR1/2 stimulation, with increased IL-6, TNF-α and MIP-1α/CCL3 production in definite SSc patients as compared to HC and/or PRP. Initial alterations were observed in EaSSc patients with an intermediate secretion pattern between HC/PRP and definite SSc. CD56+ cells from patients at different stages of SSc differentially respond to TLR stimulation, highlighting the relevance of natural immunity in the developmental and pre-fibrotic SSc.


Assuntos
Citocinas/imunologia , Escleroderma Sistêmico/imunologia , Adulto , Idoso , Antígeno CD56/imunologia , Feminino , Humanos , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Receptor 1 Toll-Like/imunologia , Receptor 2 Toll-Like/imunologia
3.
Ann Rheum Dis ; 75(8): 1521-6, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26338038

RESUMO

OBJECTIVES: TYK2 is a common genetic risk factor for several autoimmune diseases. This gene encodes a protein kinase involved in interleukin 12 (IL-12) pathway, which is a well-known player in the pathogenesis of systemic sclerosis (SSc). Therefore, we aimed to assess the possible role of this locus in SSc. METHODS: This study comprised a total of 7103 patients with SSc and 12 220 healthy controls of European ancestry from Spain, USA, Germany, the Netherlands, Italy and the UK. Four TYK2 single-nucleotide polymorphisms (V362F (rs2304256), P1104A (rs34536443), I684S (rs12720356) and A928V (rs35018800)) were selected for follow-up based on the results of an Immunochip screening phase of the locus. Association and dependence analyses were performed by the means of logistic regression and conditional logistic regression. Meta-analyses were performed using the inverse variance method. RESULTS: Genome-wide significance level was reached for TYK2 V362F common variant in our pooled analysis (p=3.08×10(-13), OR=0.83), while the association of P1104A, A928V and I684S rare and low-frequency missense variants remained significant with nominal signals (p=2.28×10(-3), OR=0.80; p=1.27×10(-3), OR=0.59; p=2.63×10(-5), OR=0.83, respectively). Interestingly, dependence and allelic combination analyses showed that the strong association observed for V362F with SSc, corresponded to a synthetic association dependent on the effect of the three previously mentioned TYK2 missense variants. CONCLUSIONS: We report for the first time the association of TYK2 with SSc and reinforce the relevance of the IL-12 pathway in SSc pathophysiology.


Assuntos
Interleucina-12/fisiologia , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/genética , TYK2 Quinase/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Mutação de Sentido Incorreto , Escleroderma Sistêmico/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia
4.
Rheumatology (Oxford) ; 55(6): 1112-6, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26989111

RESUMO

OBJECTIVE: To improve knowledge of vasculopathy in SSc through the assessment of serum levels of circulating angiogenetic and endothelial dysfunction markers in patients at different stages of the disease. METHODS: Sera from 224 subjects were obtained and concentrations of angiopoietin-2, chemokine (C-X-C motif) ligand (CXCL)-16 (CXCL16), E-selectin, soluble intercellular adhesion molecule-1, IL-8 (CXCL8), soluble vascular adhesion molecule-1 and VEGF were determined by a Luminex assay. Subjects included 43 healthy controls, 47 early SSc patients according to LeRoy and Medsger without other signs and symptoms of evolutive disease, 48 definitive SSc (defSSc) patients according to the 2013 ACR/EULAR criteria without skin or lung fibrosis, 51 lcSSc subjects and 35 dcSSc subjects. RESULTS: The four groups of patients showed well-distinct clinical and laboratory characteristics, with a linear decreasing trend in forced vital capacity and diffusing capacity for carbon monoxide % predicted values from early SSc to defSSc to lcSSc and to dcSSc, and a linear increasing trend in ESR, and in the prevalence of abnormal CRP, serum gamma globulins and lung fibrosis (all P < 0.0001). Highly significant linear trends pointing to an increase in angiopoietin-2 (P < 0.0001), CXCL16 (P < 0.0001), E-selectin (P = 0.001) and soluble intercellular adhesion molecule-1 (P = 0.002) in relation to the different disease subsets were observed. CONCLUSION: Markers characterizing vascular activation are found to be increased in SSc patients from the earliest stages of disease when clinical and laboratory findings of advanced disease cannot yet be detected. These abnormalities progress with the appraisal of the first sclerodermatous manifestation in defSSc and further increase with the onset of fibrotic manifestations.


Assuntos
Inibidores da Angiogênese/sangue , Mediadores da Inflamação/sangue , Escleroderma Sistêmico/sangue , Adulto , Idoso , Amina Oxidase (contendo Cobre)/sangue , Angiopoietina-2/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Moléculas de Adesão Celular/sangue , Quimiocina CXCL16 , Quimiocinas CXC/sangue , Selectina E/sangue , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Molécula 1 de Adesão Intercelular/sangue , Interleucina-8/sangue , Masculino , Pessoa de Meia-Idade , Receptores Depuradores/sangue , Escleroderma Sistêmico/fisiopatologia , Índice de Gravidade de Doença , Fator A de Crescimento do Endotélio Vascular/sangue
5.
BMC Med Inform Decis Mak ; 16 Suppl 3: 74, 2016 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-27454392

RESUMO

BACKGROUND: Nearest neighbor (NN) imputation algorithms are efficient methods to fill in missing data where each missing value on some records is replaced by a value obtained from related cases in the whole set of records. Besides the capability to substitute the missing data with plausible values that are as close as possible to the true value, imputation algorithms should preserve the original data structure and avoid to distort the distribution of the imputed variable. Despite the efficiency of NN algorithms little is known about the effect of these methods on data structure. METHODS: Simulation on synthetic datasets with different patterns and degrees of missingness were conducted to evaluate the performance of NN with one single neighbor (1NN) and with k neighbors without (kNN) or with weighting (wkNN) in the context of different learning frameworks: plain set, reduced set after ReliefF filtering, bagging, random choice of attributes, bagging combined with random choice of attributes (Random-Forest-like method). RESULTS: Whatever the framework, kNN usually outperformed 1NN in terms of precision of imputation and reduced errors in inferential statistics, 1NN was however the only method capable of preserving the data structure and data were distorted even when small values of k neighbors were considered; distortion was more severe for resampling schemas. CONCLUSIONS: The use of three neighbors in conjunction with ReliefF seems to provide the best trade-off between imputation error and preservation of the data structure. The very same conclusions can be drawn when imputation experiments were conducted on the single proton emission computed tomography (SPECTF) heart dataset after introduction of missing data completely at random.


Assuntos
Algoritmos , Interpretação Estatística de Dados , Modelos Estatísticos , Doença da Artéria Coronariana/diagnóstico por imagem , Humanos , Tomografia Computadorizada de Emissão de Fóton Único/estatística & dados numéricos
6.
Rheumatology (Oxford) ; 54(4): 707-11, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25231181

RESUMO

OBJECTIVE: HLAs have been extensively associated with SSc susceptibility but their role in the progression of the disease is poorly understood. In 2013 the ACR and European League Against Rheumatism (EULAR) jointly defined criteria for the classification of SSc that allow the early identification of definite SSc patients. In this study we investigated the role of HLA class II antigens in the progression from early to definite SSc. METHODS: One hundred and fifty-eight subjects with early SSc according to LeRoy and Medsger criteria and no other manifestation indicative of definite SSc at referral were considered. All the patients underwent high-resolution HLA class II typing and the appraisal of definite SSc was retrospectively conducted in a prospective manner. Lifetime analysis was conducted to gauge the effect of genetic and clinical characteristics on progression of the disease. RESULTS: The median estimated time to progression was 45 months from referral; the 5 and 10 year estimates of progression were 59.8% and 80%, respectively. ACAs were associated with a reduced risk of progression [median survival 55 vs 23 months for ACA-positive vs ACA-negative patients, P = 0.035; hazard ratio (HR) 0.67 (95% CI 0.458, 0.979)]. HLA alleles within the HLA DQ5-DR1 haplotype [HLA-DRB1*0101-HLA-DQA1*0101(4)-HLA-DQB1*0501] reduced the risk of progression of the disease [median survival 108 vs 44 months for DQ5-DR1 carriers vs DQ5-DR1 non-carriers; HR 0.388 (CI 0.211, 0.712), P = 0.001, corrected P = 0.014]. In multivariate models, the effect of genetics was found to be independent of ACA positivity or other baseline factors; additive risks were observed when the DQ5-DR1 haplotype and ACA were jointly considered. CONCLUSION: HLA class II alleles within the HLA DQ5-DR1 haplotype are associated with lower rates of progression from early to definite SSc.


Assuntos
Antígenos HLA-D/genética , Escleroderma Sistêmico/genética , Adulto , Alelos , Progressão da Doença , Feminino , Antígenos HLA-D/imunologia , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/imunologia , Cadeias alfa de HLA-DQ/genética , Cadeias alfa de HLA-DQ/imunologia , Cadeias beta de HLA-DQ/genética , Cadeias beta de HLA-DQ/imunologia , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia , Antígenos de Histocompatibilidade Classe II , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Escleroderma Sistêmico/imunologia
7.
Clin Exp Rheumatol ; 33(4 Suppl 91): S31-5, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26314374

RESUMO

OBJECTIVES: The current knowledge of the influence of systemic sclerosis (SSc) risk loci in the clinical sub-phenotypes is still limited. The main limitation lies in the low frequency of some sub-phenotypes which could be solved by replication studies in independent cohorts and meta-analysis between studies. In this regard, CCR6 gene variants have been recently associated with anti-topoisomerase I positive (ATA+) production in SSc patients in a candidate gene study. This gene has been proposed to have a critical role in IL-17-driven autoimmunity in human diseases. METHODS: In order to confirm the association between CCR6 and ATA+ SSc patients, we performed an independent replication study in populations of European ancestry. We studied two CCR6 genetic variants (rs968334 and rs3093024) in a total of 901 ATA+ SSc cases, 3,258 ATA- SSc cases and 7,865 healthy controls and compared allelic frequencies for those SNPs in ATA+ SSc with healthy controls and also with ATA- SSc patients. RESULTS: The comparison performed between ATA+ SSc patients and healthy controls showed significant association with SNP rs968334 (p=4.88x10(-2), OR=1.11). When we compared ATA+ SSc cases with ATA- SSc, both SNPs, rs3093024 and rs968334, showed significant associations (p=2.89x10(-2), OR=1.13; p=1.69x10(-2), OR=1.15). Finally, in order to increase even more sample size and statistical power, we meta-analysed our study with the previous reported and found a significant association between SNP rs3093024 and ATA+ SSc patients (p=1.00x10(-4), OR=1.16) comparing with healthy controls. CONCLUSIONS: Our work confirms the association of CCR6 gene and ATA+ SSc patients.


Assuntos
Autoanticorpos/sangue , DNA Topoisomerases Tipo I/imunologia , Polimorfismo de Nucleotídeo Único , Receptores CCR6/genética , Escleroderma Sistêmico/genética , Biomarcadores/sangue , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Europa (Continente) , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Razão de Chances , Fenótipo , Fatores de Risco , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/etnologia , Estados Unidos/epidemiologia , População Branca/genética
8.
Clin Exp Rheumatol ; 31(2 Suppl 76): 135-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23295023

RESUMO

OBJECTIVES: Scleroderma renal crisis (SRC) is a relative rare yet dramatic event in the history of systemic sclerosis (SSc). Several factors that may precipitate or protect from the development of SRC have been described in previous case-control studies. To date, no attempt has been made to evaluate these factors in an observational fashion. METHODS: Retrospective data from 410 SSc patients with disease duration <5 years at referral were evaluated in an observational fashion for the development of hypertensive or normotensive SRC within 5 years from the first visit at our centre. Baseline characteristics as well as the use of steroids or dhiydropyridine calcium-channel blockers (CCB) were analysed via the Cox regression method with time-dependent covariates. RESULTS: In the multivariate model the diffuse subset the disease (HR=5.728 CI(95)=2.199-14.918, p<0.001) and the use of prednisone (HR=1.015, CI(95)=1.004-1.026, p=0.006) resulted to be predictors for the development of SRC, with a risk to develop SRC increased by 1.5% for every mg of prednisone/day consumed the trimester prior SRC. Contrariwise, the risk to develop SRC was highly reduced in those who were prescribed CCBs (HR=0.094, CI(95)=0.038-0.236, p<0.001). CONCLUSIONS: Steroids exhibits a weak effect on the risk to progress toward SRC in our case series, whilst dhyidrophyridines CCB appeared to be protective against that. Further larger prospective studies are warranted to better define the role of CCB in this setting or as a background therapy for SSc.


Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo L/metabolismo , Nefropatias/prevenção & controle , Prednisolona/uso terapêutico , Escleroderma Sistêmico/tratamento farmacológico , Adulto , Feminino , Glucocorticoides/uso terapêutico , Humanos , Iloprosta/uso terapêutico , Itália/epidemiologia , Nefropatias/epidemiologia , Nefropatias/metabolismo , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/metabolismo , Vasodilatadores/uso terapêutico
9.
J Biomed Inform ; 46(1): 174-80, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23153648

RESUMO

BACKGROUND: The discovery and the description of the genetic background of common human diseases is hampered by their complexity and dynamic behavior. Appropriate bioinformatic tools are needed to account all the facets of complex diseases and to this end we recently described the survival dimensionality reduction (SDR) algorithm in the effort to model gene-gene interactions in the context of survival analysis. When one event precludes the occurrence of another event under investigation in the 'competing risk model', survival algorithms require particular adjustment to avoid the risk of reporting wrong or biased conclusions. METHODS: The SDR algorithm was modified to incorporate the cumulative incidence function as well as an adapted version of the Brier score for mutually exclusive outcomes, to better search for epistatic models in the competing risk setting. The applicability of the new SDR algorithm (SDR-CR) was evaluated using synthetic lifetime epistatic datasets with competing risks and on a dataset of scleroderma patients. RESULTS/CONCLUSIONS: The SDR-CR algorithms retains a satisfactory power to detect the causative variants in simulated datasets under different scenarios of sample size and degrees of type I or type II censoring. In the real-world dataset, SDR-CR was capable of detecting a significant interaction between the IL-1α C-889T and the IL-1ß C-511T single-nucleotide polymorphisms to predict the occurrence of restrictive lung disease vs. isolated pulmonary hypertension. We provide an useful extension of the SDR algorithm to analyze epistatic interactions in the competing risk settings that may be of use to unveil the genetic background of complex human diseases. AVAILABILITY: http://sourceforge.net/projects/sdrproject/files/.


Assuntos
Algoritmos , Epistasia Genética , Modelos Teóricos , Análise de Sobrevida , Feminino , Humanos , Masculino , Risco , Esclerodermia Difusa/genética , Esclerodermia Difusa/fisiopatologia
10.
Optom Vis Sci ; 90(6): 576-86, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23670123

RESUMO

PURPOSE: To study, by a new, integrated, laser scanning confocal microscopy approach, the ocular surface morpho-functional unit in patients with primary Sjogren syndrome (SSI), non-Sjogren syndrome dry eye (non-SSDE), and meibomian gland disease (MGD). METHODS: Patients and age- and sex-matched control subjects (N = 60; 15 each) were consecutively enrolled in a prospective case-control study. Laser scanning confocal microscopy was used to obtain simultaneous optical sampling of the ocular surface components: cornea, bulbar and tarsal conjunctiva, MGs, and eyelid margin. RESULTS: For all superficial epithelia, except eyelid margins, there were reduced cell densities in each group compared with that in controls (p < 0.001). The lowest cell densities were in the SSI group (p < 0.001). Eyelid margin superficial cell density was decreased only in MGD (p < 0.001). Basal epithelial cell density at the corneal apex was increased in both SSI and non-SSDE compared with that in controls (p < 0.01). In the conjunctiva, it was decreased in each group compared with that in controls (p < 0.01). Subbasal dendritic cell density was significantly increased in both SSI and MGD compared with that in controls (p < 0.01). Conjunctival inflammatory cell density and MG inflammation were increased in each group compared with those in controls (p < 0.001), with the highest values in SSI. Subbasal nerve plexi had fewer fibers and higher bead density in each group compared with those in controls (p < 0.001). There was increased tortuosity in both SSI and MGD (p < 0.001). Patients with MGD had the lowest MG acinar density, the largest diameter of acini and acinar orifices, and the highest secretion reflectivity (p < 0.001). CONCLUSIONS: Laser scanning confocal microscopy can provide an in vivo, noninvasive, high-resolution overview of the ocular surface morpho-functional unit. This confocal integrated approach may be useful in both research and clinical settings.


Assuntos
Túnica Conjuntiva/patologia , Síndromes do Olho Seco/patologia , Epitélio Corneano/patologia , Pálpebras/patologia , Microscopia Confocal , Adulto , Idoso , Estudos de Casos e Controles , Contagem de Células , Células Epiteliais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
11.
Arthritis Res Ther ; 25(1): 15, 2023 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-36707842

RESUMO

BACKGROUND: The study of molecular mechanisms characterizing disease progression may be relevant to get insights into systemic sclerosis (SSc) pathogenesis and to intercept patients at very early stage. We aimed at investigating the proteomic profile of preclinical systemic sclerosis (PreSSc) via a discovery/validation two-step approach. METHODS: SOMAcan aptamer-based analysis was performed on a serum sample of 13 PreSSc (discovery cohort) according to 2001 LeRoy and Medsger criteria (characterized solely by Raynaud phenomenon plus a positive nailfold capillaroscopy and SSc-specific antibodies without any other sign of definite disease) and 8 healthy controls (HCs) age, gender, and ethnicity matched. Prospective data were available up to 4±0.6 years to determine the progression to definite SSc according to the EULAR/ACR 2013 classification criteria. In proteins with relative fluorescence units (RFU) > |1.5|-fold vs HCs values, univariate analysis was conducted via bootstrap aggregating models to determine the predicting accuracy (progression vs non-progression) of categorized baseline protein values. Gene Ontologies (GO terms) and Reactome terms of significant proteins at the adjusted 0.05 threshold were explored. Significant proteins from the discovery cohort were finally validated via ELISAs in an independent validation cohort of 50 PreSSc with clinical prospective data up to 5 years. Time-to-event analysis for interval-censored data was used to evaluate disease progression. RESULTS: In the discovery cohort, 286 out of 1306 proteins analyzed via SomaScan, were differentially expressed versus HCs. Ten proteins were significantly associated with disease progression; analysis through GO and Reactome showed differentially enriched pathways involving angiogenesis, endothelial cell chemotaxis, and endothelial cell chemotaxis to fibroblast growth factor (FGF). In the validation cohort, endostatin (HR=10.23, CI95=2.2-47.59, p=0.003) was strongly associated with disease progression, as well as bFGF (HR=0.84, CI95=0.709-0.996, p=0.045) and PAF-AHß (HR=0.372, CI95=0.171-0.809, p=0.013) CONCLUSIONS: A distinct protein profile characterized PreSSc from HCs and proteins associated with hypoxia, vasculopathy, and fibrosis regulation are linked with the progression from preclinical to definite SSc. These proteins, in particular endostatin, can be regarded both as markers of severity and molecules with pathogenetic significance as well as therapeutic targets.


Assuntos
Proteômica , Escleroderma Sistêmico , Humanos , Biomarcadores , Progressão da Doença , Endostatinas , Angioscopia Microscópica , Estudos Prospectivos , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia
12.
Rheumatology (Oxford) ; 51(1): 52-9, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22087014

RESUMO

OBJECTIVE: To determine the role of Class II HLAs in SSc patients from Italy and Spain and in SSc patients of Caucasian ancestry. METHODS: Nine hundred and forty-four SSc patients (Italy 392 patients; Spain 452 patients) and 1320 ethnically matched healthy controls (Italy 398 patients; Spain 922 patients) were genotyped up to the fourth digit by PCR with sequence-specific oligonucleotides for HLA-DRB1, DQA1 and DQB1 loci. Patients included 390 ACA-positive and 254 anti-topo I-positive subjects. Associations between SSc or SSc-specific antibodies and HLA alleles or HLA haplotypes were sought via the chi-square test after 10 000-fold permutation testing. A meta-analysis including this study cohort and other Caucasoids samples was also conducted. RESULTS: In both the cohorts, the strongest association was observed between the HLA-DRB1*1104 allele and SSc or anti-topo I antibodies. The HLA-DRB1*1104 -DQA1*0501 -DQB1*0301 haplotype was overrepresented in Italian [odds ratio (OR) = 2.069, 95% asymptotic CIs (CI(95)) 1.486, 2.881; P < 0.001] and in Spanish patients (OR = 6.707, CI(95) 3.974, 11.319; P < 0.001) as well as in anti-topo-positive patients: Italy (OR = 2.642, CI(95) 1.78, 3.924; P < 0.001) and Spain (OR = 20.625, CI(95) 11.536, 36.876; P < 0.001). In both the populations we also identified an additional risk allele (HLA-DQB1*03) and a protective allele (HLA-DQB1*0501) in anti-topo-positive patients. The meta-analysis showed different statistically significant associations, the most interesting being the differential association between HLA-DRB1*01 alleles and ACAs (OR = 1.724, CI(95) 1.482, 2.005; P < 0.001) or topo I antibodies (OR = 0.5, CI(95) 0.384, 0.651; P < 0.001). CONCLUSIONS: We describe multiple robust associations between SSc and HLA Class II antigens in Caucasoids that may help to understand the genetic architecture of SSc.


Assuntos
Antígenos HLA-D/genética , Escleroderma Sistêmico/genética , Autoanticorpos/análise , Estudos de Casos e Controles , Predisposição Genética para Doença , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Teste de Histocompatibilidade/métodos , Humanos , Itália/epidemiologia , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/imunologia , Espanha/epidemiologia
13.
J Biomed Inform ; 44(2): 361-9, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21168527

RESUMO

BACKGROUND: The analysis of survival data allows to evaluate whether in a population the genetic exposure is related to the time until an event occurs. Owing to the complexity of common human diseases, there is the incipient need to develop bioinformatics tools to properly model non-linear high-order interactions in lifetime datasets. These tools, such as the survival dimensionality reduction algorithm, may suffer from extreme computational costs in large-scale datasets. Herein, we address the problem of estimating the quality of attributes, so as to extract relevant features from lifetime datasets and to scale down their size. METHODS: The ReliefF algorithm was modified and adjusted to compensate for the loss of information due to censoring, introducing reclassification and weighting schemes. Synthetic lifetime two-locus epistatic datasets of 500 attributes, 400-800 individuals and different degrees of cumulative heritability and censorship were generated. The capability of the survival ReliefF algorithm (sReliefF) and of a tuned sReliefF approach to properly select the causative pair of attributes was evaluated and compared to univariate selection based on Cox scores. RESULTS/CONCLUSIONS: sReliefF methods efficiently scaled down the simulated datasets, whilst univariate selection performed no better than random choice. These approaches may help to reduce the computational cost and to improve the classification task of algorithms that model high-order interactions in presence of right-censored data. AVAILABILITY: http://sourceforge.net/projects/sdrproject/files/sReliefF/.


Assuntos
Algoritmos , Biologia Computacional/métodos , Bases de Dados Genéticas , Epistasia Genética , Perfilação da Expressão Gênica/métodos , Software , Análise de Sobrevida
14.
BMC Bioinformatics ; 11: 416, 2010 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-20691091

RESUMO

BACKGROUND: Epistasis is recognized as a fundamental part of the genetic architecture of individuals. Several computational approaches have been developed to model gene-gene interactions in case-control studies, however, none of them is suitable for time-dependent analysis. Herein we introduce the Survival Dimensionality Reduction (SDR) algorithm, a non-parametric method specifically designed to detect epistasis in lifetime datasets. RESULTS: The algorithm requires neither specification about the underlying survival distribution nor about the underlying interaction model and proved satisfactorily powerful to detect a set of causative genes in synthetic epistatic lifetime datasets with a limited number of samples and high degree of right-censorship (up to 70%). The SDR method was then applied to a series of 386 Dutch patients with active rheumatoid arthritis that were treated with anti-TNF biological agents. Among a set of 39 candidate genes, none of which showed a detectable marginal effect on anti-TNF responses, the SDR algorithm did find that the rs1801274 SNP in the Fc gamma RIIa gene and the rs10954213 SNP in the IRF5 gene non-linearly interact to predict clinical remission after anti-TNF biologicals. CONCLUSIONS: Simulation studies and application in a real-world setting support the capability of the SDR algorithm to model epistatic interactions in candidate-genes studies in presence of right-censored data. AVAILABILITY: http://sourceforge.net/projects/sdrproject/.


Assuntos
Algoritmos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Epistasia Genética , Adulto , Antirreumáticos/uso terapêutico , Estudos de Casos e Controles , Simulação por Computador , Perfilação da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/antagonistas & inibidores
15.
Clin Exp Rheumatol ; 28(2 Suppl 58): S18-27, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20804663

RESUMO

OBJECTIVES: Systemic sclerosis (SSc) is a multiorgan disease with high mortality rates. Several clinical features have been associated with poor survival in different populations of SSc patients, but no clear and reproducible prognostic model to assess individual survival prediction in scleroderma patients has ever been developed. METHODS: We used Cox regression and three data mining-based classifiers (Naïve Bayes Classifier [NBC], Random Forests [RND-F] and logistic regression [Log-Reg]) to develop a robust and reproducible 5-year prognostic model. All the models were built and internally validated by means of 5-fold cross-validation on a population of 558 Italian SSc patients. Their predictive ability and capability of generalisation was then tested on an independent population of 356 patients recruited from 5 external centres and finally compared to the predictions made by two SSc domain experts on the same population. RESULTS: The NBC outperformed the Cox-based classifier and the other data mining algorithms after internal cross-validation (area under receiving operator characteristic curve, AUROC: NBC=0.759; RND-F=0.736; Log-Reg=0.754 and Cox= 0.724). The NBC had also a remarkable and better trade-off between sensitivity and specificity (e.g. Balanced accuracy, BA) than the Cox-based classifier, when tested on an independent population of SSc patients (BA: NBC=0.769, Cox=0.622). The NBC was also superior to domain experts in predicting 5-year survival in this population (AUROC=0.829 vs. AUROC=0.788 and BA=0.769 vs. BA=0.67). CONCLUSIONS: We provide a model to make consistent 5-year prognostic predictions in SSc patients. Its internal validity, as well as capability of generalisation and reduced uncertainty compared to human experts support its use at bedside. Available at: http://www.nd.edu/~nchawla/survival.xls.


Assuntos
Modelos Estatísticos , Esclerodermia Difusa/mortalidade , Esclerodermia Limitada/mortalidade , Adulto , Mineração de Dados , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Esclerodermia Difusa/diagnóstico , Esclerodermia Limitada/diagnóstico , Taxa de Sobrevida
16.
Front Neurol ; 11: 269, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32411070

RESUMO

Background: Microscopic polyangiitis (MPA) is a necrotizing vasculitis that affects predominantly small-sized vessels in many organ systems. The disease generally causes glomerulonephritis, pulmonary damage, arthritis, and neuropathy. An exclusive involvement of both central nervous system (CNS) and peripheral nervous system (PNS) is extremely rare. Case Presentation: A 62-year-old woman was admitted to our hospital with a 3 months history of right foot drop, recently complicated by intense myalgia, arthralgia, and allodynia to tactile, vibratory, and pressure stimuli. Since blood tests revealed elevated inflammatory indexes, we suspected either infectious or immune-mediated disorders. Chest radiograph, blood culture series, and echocardiogram revealed normal findings, while urinalysis showed a bacterial infection that was successfully treated. The neurophysiological findings were compatible with multiple mononeuritis, and a brain MRI evidenced ischemic lesions of both basal ganglia and thalamus. A wide-spectrum autoantibody assay revealed the presence of high-titer perinuclear anti-neutrophil cytoplasmic antibodies specific for myeloperoxidase (MPO-ANCA). According to these findings, the diagnosis of MPA was made, and the patient was successfully treated with intravenous (IV) methylprednisolone, followed by two doses of rituximab. Conclusions: An assessment of both CNS and PNS should be included in the diagnostic evaluation of MPA. The involvement of the PNS may raise the risk of a relapsing course and treatment failure, therefore it should be considered in the choice of induction and maintenance therapy.

17.
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
18.
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.

19.
Clin Exp Med ; 19(3): 357-366, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30989453

RESUMO

Vasculopathy is a crucial feature of systemic sclerosis (SSc), and Raynaud's phenomenon (RP) and digital ulcers (DU) have a deep impact on the quality of patients' life. The management of vascular disease can be challenging for the clinician because of the suboptimal tolerability of the treatments and lack of consensus on the best therapeutic approach. Intravenous iloprost, a synthetic analogue of prostacyclin, is broadly used for the treatment of RP and ischemic ulcers secondary to SSc. However, no standardized protocol on iloprost use is currently available and, consequently, the management of this treatment is largely based on the experience of each single center. The PROSIT project is an observational, multicenter study aiming to investigate the current treatments for SSc vasculopathy, the use of prostanoids, with special regard to iloprost, and the perception of the treatment from a patient's perspective. The study was conducted on a cohort of 346 patients from eight Italian centers and included a structured survey addressed to physicians, data collected from patient's medical records and two patient-administered questionnaires assessing the level of satisfaction, tolerability and perception of the efficacy of Iloprost. PROSIT data confirmed that in the contest of SSc iloprost represents the first-line choice for the management of severe RP and DU. Moreover, it is a well-tolerated treatment as reported by patients' experience. Although a standard protocol for the treatment of SSc-related vasculopathy is lacking, PROSIT study identified different therapeutic approaches largely supported by tertiary Italian centers. Further studies are needed in order to optimize the best treatment for SSc vascular diseases, in particular to improve the best iloprost schedule management.


Assuntos
Gerenciamento Clínico , Iloprosta/uso terapêutico , Doenças Vasculares Periféricas/tratamento farmacológico , Doenças Vasculares Periféricas/patologia , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Vasodilatadores/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Centros de Atenção Terciária , Resultado do Tratamento , Adulto Jovem
20.
Clin Ther ; 30(5): 924-9, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18555939

RESUMO

BACKGROUND: Vasculopathy is one of the hallmarks of systemic sclerosis (SSc), characterized by endothelial activation and over expression of adhesion molecules. A preliminary in vitro study has suggested that aminaftone, a naphtohydrochinone used in the treatment of capillary disorders, may downregulate the expression of adhesion molecules in endothelial cells. OBJECTIVE: This study investigated the ex vivo effects of aminaftone on soluble adhesion molecule concentrations in patients with SSc. METHODS: This randomized, open-label pilot study was conducted in patients with SSc. Patients received baseline treatment for Raynaud's phenomenon (eg, calcium channel blockers and IV cyclic iloprost) with (test) or without (control) aminaftone 75 mg or placebo TID for 12 weeks. Standard treatment for Raynaud's phenomenon was allowed as long as the dose was stable for >or=3 months prior to randomization. Concentrations of soluble E-selectin adhesion molecule 1 (sELAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), and soluble intracellular adhesion molecule 1 (sICAM-1) were measured at baseline and 12 weeks, and their variation was tested using the analysis of variance for repeated measures with statistical correction. Laboratory analyses were performed by experienced personnel blinded to treatment assignment. RESULTS: A total of 24 patients were enrolled (21 women, 3 men; mean age, 53.4 years; aminaftone, 12 patients; control, 12 patients). Decreases in mean (SD) sELAM-1 and sVCAM-1 concentrations were significantly greater in treated patients (sELAM-1, from 17.0 [7.8] to 11.9 [9.0] pg/mL; sVCAM-1, from 51.2 [12.9] to 40.8 [13.8] ng/mL) compared with controls (sELAM-1, from 20.3 [9.9] to 20.4 [10.5] pg/mL; sVCAM-1, from 56.8 [49.6] to 62.7 [40.6] ng/mL) (both, P < 0.05 [analysis of variance or repeated measures after Bonferroni correction]). No significant changes in sICAM-1 concentrations versus controls were observed. CONCLUSIONS: In this small pilot study in this select group of patients with SSc, aminaftone was associated with downregulation of sELAM-1 and sVCAM-1 concentrations. Studies evaluating the potential role of aminaftone in the treatment of vascular sclerodermal disease and SSc are warranted.


Assuntos
Moléculas de Adesão Celular/biossíntese , Escleroderma Sistêmico/metabolismo , para-Aminobenzoatos , Ácido 4-Aminobenzoico/administração & dosagem , Ácido 4-Aminobenzoico/farmacologia , Selectina E/biossíntese , Feminino , Humanos , Molécula 1 de Adesão Intercelular/biossíntese , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Solubilidade , Molécula 1 de Adesão de Célula Vascular/biossíntese
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