RESUMO
OBJECTIVES: Cardiovascular (CV) morbidity and mortality are significantly greater in SLE patients than in the general population. ASA is known to be associated with a decrease in the incidence of CV events in high-risk patients from the general population, but its efficacy as primary prophylaxis in SLE patients has not yet been investigated. METHODS: The clinical charts of SLE patients consecutively admitted to a tertiary centre who, at admission, satisfied 1992 ACR and/or 2012 SLICC classification criteria for SLE and had not experienced any CV event, were reviewed. The occurrence of any CV event was recorded at each visit. ASA was prescribed to all patients at first visit. The rate and reasons for ASA discontinuation were also recorded at each visit. RESULTS: One hundred and sixty-seven consecutive SLE patients were enrolled and followed up for a median of 8 years (range 1-14 years). Among them, 146 regularly took the medication (ASA-treated patients) and 21 refused to take or discontinued it (non-ASA-treated patients). Five CV events occurred in the 146 ASA-treated patients (4.2 per 1000 person-years) and four in the 21 non-ASA-treated patients (30 per 1000 person-years; P = 0.0007). The CV event-free rate was higher in ASA-treated than in non-ASA-treated patients (log-rank test χ(2) = 15.74; P = 0.0001). No relevant side-effect related to ASA was recorded. CONCLUSION: Low-dose ASA is a safe treatment and may be beneficial in the primary prophylaxis of CV events in SLE patients. Controlled, prospective studies are needed to provide a better definition of its role in these patients.
Assuntos
Aspirina/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Lúpus Eritematoso Sistêmico/complicações , Inibidores da Agregação Plaquetária/administração & dosagem , Adulto , Doenças Cardiovasculares/mortalidade , Causas de Morte , Feminino , Humanos , Incidência , Itália/epidemiologia , Estimativa de Kaplan-Meier , Lúpus Eritematoso Sistêmico/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
INTRODUCTION: We aimed to replicate a recent study which showed higher genetic risk load at 15 loci in men than in women with systemic lupus erythematosus (SLE). This difference was very significant, and it was interpreted as indicating that men require more genetic susceptibility than women to develop SLE. METHODS: Nineteen SLE-associated loci (thirteen of which are shared with the previous study) were analyzed in 1,457 SLE patients and 1,728 healthy controls of European ancestry. Genetic risk load was calculated as sex-specific sum genetic risk scores (GRS(s)). RESULTS: Our results did not replicate those of the previous study at either the level of individual loci or the global level of GRS(s). GRS(s) were larger in women than in men (4.20 ± 1.07 in women vs. 3.27 ± 0.98 in men). This very significant difference (P < 10(-16)) was more dependent on the six new loci not included in the previous study (59% of the difference) than on the thirteen loci that are shared (the remaining 41%). However, the 13 shared loci also showed a higher genetic risk load in women than in men in our study (P = 6.6 × 10(-7)), suggesting that heterogeneity of participants, in addition to different loci, contributed to the opposite results. CONCLUSION: Our results show the lack of a clear trend toward higher genetic risk in one of the sexes for the analyzed SLE loci. They also highlight several limitations of assessments of genetic risk load, including the possibility of ascertainment bias with loci discovered in studies that have included mainly women.
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Carga Genética , Predisposição Genética para Doença/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Medição de Risco/métodos , Alelos , Estudos de Casos e Controles , Europa (Continente) , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Humanos , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Razão de Chances , Medição de Risco/estatística & dados numéricos , Fatores de Risco , Fatores Sexuais , População Branca/genéticaRESUMO
INTRODUCTION: Systemic Lupus Erythematosus (SLE) shows a spectrum of clinical manifestations that complicate its diagnosis, treatment and research. This variability is likely related with environmental exposures and genetic factors among which known SLE susceptibility loci are prime candidates. The first published analyses seem to indicate that this is the case for some of them, but results are still inconclusive and we aimed to further explore this question. METHODS: European SLE patients, 1444, recruited at 17 centres from 10 countries were analyzed. Genotypes for 26 SLE associated SNPs were compared between patients with and without each of 11 clinical features: ten of the American College of Rheumatology (ACR) classification criteria (except ANAs) and age of disease onset. These analyses were adjusted for centre of recruitment, top ancestry informative markers, gender and time of follow-up. Overlap of samples with previous studies was excluded for assessing replication. RESULTS: THERE WERE THREE NEW ASSOCIATIONS: the SNPs in XKR6 and in FAM167A-BLK were associated with lupus nephritis (OR=0.76 and 1.30, P(corr)â=0.007 and 0.03, respectively) and the SNP of MECP2, which is in chromosome X, with earlier age of disease onset in men. The previously reported association of STAT4 with early age of disease onset was replicated. Some other results were suggestive of the presence of additional associations. Together, the association signals provided support to some previous findings and to the characterization of lupus nephritis, autoantibodies and age of disease onset as the clinical features more associated with SLE loci. CONCLUSION: Some of the SLE loci shape the disease phenotype in addition to increase susceptibility to SLE. This influence is more prominent for some clinical features than for others. However, results are only partially consistent between studies and subphenotype specific GWAS are needed to unravel their genetic component.
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Loci Gênicos , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , População Branca , Adolescente , Adulto , Idade de Início , Autoanticorpos/imunologia , Europa (Continente)/epidemiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/imunologia , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/imunologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/imunologia , Fenótipo , Fator de Transcrição STAT4/genética , Fator de Transcrição STAT4/imunologiaRESUMO
INTRODUCTION: We aimed to investigate whether the effect size of the systemic lupus erythematosus (SLE) risk alleles varies across European subpopulations. METHODS: European SLE patients (n = 1,742) and ethnically matched healthy controls (n = 2,101) were recruited at 17 centres from 10 different countries. Only individuals with self-reported ancestry from the country of origin were included. In addition, participants were genotyped for top ancestry informative markers and for 25 SLE associated SNPs. The results were used to compare effect sizes between the Central Eureopan and Southern European subgroups. RESULTS: Twenty of the 25 SNPs showed independent association with SLE, These SNPs showed a significant bias to larger effect sizes in the Southern subgroup, with 15/20 showing this trend (P = 0.019) and a larger mean odds ratio of the 20 SNPs (1.46 vs. 1.34, P = 0.02) as well as a larger difference in the number of risk alleles (2.06 vs. 1.63, P = 0.027) between SLE patients and controls than for Central Europeans. This bias was reflected in a very significant difference in the cumulative genetic risk score (4.31 vs. 3.48, P = 1.8 × 10-32). Effect size bias was accompanied by a lower number of SLE risk alleles in the Southern subjects, both patients and controls, the difference being more marked between the controls (P = 1.1 × 10-8) than between the Southern and Central European patients (P = 0.016). Seven of these SNPs showed significant allele frequency clines. CONCLUSION: Our findings showed a bias to larger effect sizes of SLE loci in the Southern Europeans relative to the Central Europeans together with clines of SLE risk allele frequencies. These results indicate the need to study risk allele clines and the implications of the polygenic model of inheritance in SLE.
Assuntos
Alelos , Loci Gênicos/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/genética , Viés , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Systemic Lupus Erythematosus (SLE) is an autoimmune disease with a very varied spectrum of clinical manifestations that could be partly determined by genetic factors. We aimed to determine the relationship between prevalence of 11 clinical features and age of disease onset with European population genetic substructure. Data from 1413 patients of European ancestry recruited in nine countries was tested for association with genotypes of top ancestry informative markers. This analysis was done with logistic regression between phenotypes and genotypes or principal components extracted from them. We used a genetic additive model and adjusted for gender and disease duration. Three clinical features showed association with ancestry informative markers: autoantibody production defined as immunologic disorder (Pâ=â6.8×10(-4)), oral ulcers (Pâ=â6.9×10(-4)) and photosensitivity (Pâ=â0.002). Immunologic disorder was associated with genotypes more common in Southern European ancestries, whereas the opposite trend was observed for photosensitivity. Oral ulcers were specifically more common in patients of Spanish and Portuguese self-reported ancestry. These results should be taken into account in future research and suggest new hypotheses and possible underlying mechanisms to be investigated. A first hypothesis linking photosensitivity with variation in skin pigmentation is suggested.
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Estudos de Associação Genética , Predisposição Genética para Doença , Genética Populacional , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , População Branca/genética , Adulto , Feminino , Frequência do Gene/genética , Marcadores Genéticos , Geografia , Humanos , Masculino , Filogenia , Análise de Componente PrincipalRESUMO
INTRODUCTION: We aimed to replicate association of newly identified systemic lupus erythematosus (SLE) loci. METHODS: We selected the most associated SNP in 10 SLE loci. These 10 SNPs were analysed in 1,579 patients with SLE and 1,726 controls of European origin by single-base extension. Comparison of allele frequencies between cases and controls was done with the Mantel-Haenszel approach to account for heterogeneity between sample collections. RESULTS: A previously controversial association with a SNP in the TYK2 gene was replicated (odds ratio (OR) = 0.79, P = 2.5 x 10-5), as well as association with the X chromosome MECP2 gene (OR = 1.26, P = 0.00085 in women), which had only been reported in a single study, and association with four other loci, 1q25.1 (OR = 0.81, P = 0.0001), PXK (OR = 1.19, P = 0.0038), BANK1 (OR = 0.83, P = 0.006) and KIAA1542 (OR = 0.84, P = 0.001), which have been identified in a genome-wide association study, but not found in any other study. All these replications showed the same disease-associated allele as originally reported. No association was found with the LY9 SNP, which had been reported in a single study. CONCLUSIONS: Our results confirm nine SLE loci. For six of them, TYK2, MECP2, 1q25.1, PXK, BANK1 and KIAA1542, this replication is important. The other three loci, ITGAM, STAT4 and C8orf13-BLK, were already clearly confirmed. Our results also suggest that MECP2 association has no influence in the sex bias of SLE, contrary to what has been proposed. In addition, none of the other associations seems important in this respect.
Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Lúpus Eritematoso Sistêmico/genética , Estudos de Casos e Controles , Bases de Dados Genéticas/normas , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/epidemiologia , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genéticaRESUMO
OBJECTIVE: To develop valid instruments for the assessment of disease-related damage and disease activity in Sjögren's syndrome (SS). METHODS: Data on 206 patients with primary SS were collected in 12 Italian centers. Each patient was scored by 1 investigator, on the basis of a global assessment of the degree of disease damage and disease activity. Patients judged to have active disease at the time of enrollment underwent a second evaluation after 3 months. Univariate and multivariate analyses were performed to select the clinical and serologic variables that were the best predictors of damage and of disease activity, and these variables were used to construct the Sjögren's Syndrome Disease Damage Index (SSDDI) and the Sjögren's Syndrome Disease Activity Index (SSDAI). The weight of each variable in the index was determined by the beta coefficients in multivariate regression models. Scores obtained using the SSDDI and the SSDAI were compared with scores initially given by the investigators. Finally, a receiver operating characteristic (ROC) curve was used to determine the cutoff value in the SSDAI with the highest level of accuracy in identifying patients with a significant level of disease activity. RESULTS: A multivariate model with 9 variables was the best predictor of investigator scores of damage. The scores obtained using the SSDDI were closely correlated with investigator ratings (R = 0.760, P < 0.0001). A model composed of 11 variables was the best predictor of investigator scores of disease activity. The scores obtained using the SSDAI were strongly correlated with the investigator ratings both at the time of enrollment and 3 months after enrollment (R = 0.872, P < 0.0001, and R = 0.817, P < 0.0001, respectively). The differences between scores given by investigators at study enrollment and after 3 months, a measure of variation of disease activity over time, were also closely correlated with the differences calculated using the SSDAI (R = 0.683, P < 0.0001). The ROC curve analysis showed that patients with the highest level of disease activity could be identified on the basis of an SSDAI score of >or=5. CONCLUSION: Our findings indicate that the SSDDI is an adequate instrument to objectively measure damage in patients with SS, and that the SSDAI is a valid tool to measure disease activity when used either as a single-state index or as a transition index.
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Síndrome de Sjogren/patologia , Síndrome de Sjogren/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Sistema Nervoso Central/patologia , Sistema Nervoso Central/fisiopatologia , Estudos de Coortes , Demografia , Feminino , Nível de Saúde , Humanos , Itália , Idioma , Masculino , Pessoa de Meia-Idade , Atividade Motora , Glândulas Salivares , Síndrome de Sjogren/psicologia , XeroftalmiaRESUMO
OBJECTIVE: To compare the SDAI values to DAS28 scores in RA patients undergoing different DMARD regimens. METHODS: The SDAI is an unweighted numerical sum of five outcome parameters: tender and swollen joint count (based on 28-joint assessment), patient and physician global assessment of disease activity (visual analogue scale: 0-10 cm) and level of C-reactive protein (mg/dl). 80 patients (F/M 68/12; age between 20-68 years, median 52) with active rheumatoid arthritis were prospectively enrolled in the study. The patients were randomly assigned to one of four groups according to the therapeutic regimens: group I: Methotrexate (MTX) 15 mg/weekly + salazopyrin 2 g/daily; group II: MTX 15 mg/weekly + infliximab 3 mg/Kg at time 0, 2, 4 and every 8 weeks; group III: MTX 15 mg/weekly + etanercept 25 mg/twice weekly; group IV: MTX 15 mg/weekly + adalimumab 40 mg/every other week. SDAI and DAS28 were determined at baseline and after 6 months in each patient. Mean changes in SDAI values were compared to those detected in DAS 28 at baseline and after 6 months. RESULTS: SDAI and DAS 28 were found to be significantly correlated at baseline. Moreover, changes in SDAI over time paralleled those in DAS, and were found to be significantly correlated. CONCLUSIONS: SDAI is a valid measure of response to treatment in RA patients undergoing different therapeutic regimens.
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Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Glucosamina/análogos & derivados , Imunoglobulina G/uso terapêutico , Metotrexato/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Índice de Gravidade de Doença , Sulfassalazina/uso terapêutico , Resultado do Tratamento , Adalimumab , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Proteína C-Reativa/análise , Combinação de Medicamentos , Etanercepte , Feminino , Glucosamina/uso terapêutico , Humanos , Infliximab , Masculino , Pessoa de Meia-Idade , Medição da Dor , Estudos ProspectivosRESUMO
BACKGROUND: Some patients with cryoglobulinemic syndrome (CS) develop frank non-Hodgkin lymphoma (NHL), but the incidence and timing of this event are still poorly defined. METHODS: A retrospective multicenter study was performed of hepatitis C virus-positive patients with CS observed in 11 Italian centers belonging to the Italian Group for the Study of Cryoglobulinemia. RESULTS: The inclusion criteria were satisfied by 1,255 patients. During a cumulative follow-up of 8,928 patient-years, 59 cases of NHL were diagnosed, for an estimated rate of 660.8 new cases per 100,000 patient-years with 224.1 new cases of aggressive NHL subtypes per 100,000 patient-years. More than 90% of the patients developing NHLs had type II cryoglobulins. The NHLs were classified as nonaggressive in 31 cases (53%), aggressive in 20 (34%), and mucosa-associated lymphoid tissue lymphomas in 6 (10%); 2 cases were unclassifiable. The median time from the diagnosis of CS to the clinical onset of NHL was 6.26 years (range, 0.81-24 years). The clinical course and response to chemotherapy in the patients with CS who had NHL were similar to those usually described in patients with NHL without CS; the course of the CS only marginally benefited from chemotherapy. CONCLUSIONS: The overall risk of NHL in patients with CS is about 35 times higher than in the general population (12 times higher if nonaggressive lymphomas are excluded). The presence of CS did not significantly affect the treatment of newly diagnosed lymphomas.
Assuntos
Crioglobulinemia/complicações , Hepatite C Crônica/complicações , Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/epidemiologia , Idoso , Feminino , Humanos , Incidência , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Fatores de RiscoRESUMO
A retrospective study was performed on 27 patients with hepatitis C (HCV)-related mixed cryoglobulinemia (purpura, arthralgia, hepatitis, glomerulonephritis, peripheral neuropathy) to assess peripheral nerve involvement during follow-up of up to 8 years. All patients had the same degree of organ/system involvement initially and were clinically evaluated at least annually. All 27 patients received steroids; 15 also received recombinant interferon-alpha 2b (rIFN-alpha 2b). At first examination, neurological signs and electrodiagnostic findings consistent with peripheral neuropathy were found in 20 (74%) and in 24 (88.8%) patients, respectively. Neurological evaluation and electrodiagnostic data at 3 and 8 years revealed worsening of neuropathy, whereas the other manifestations of mixed cryoglobulinemia (MC) were stable. At the last examination, clinical and electrodiagnostic signs of neuropathy were found in 25 patients (92.5%), occurring in 1 of 3 patients with normal initial findings, and worsened in 8. A more severe neuropathy was observed in 3 (25%) of the patients treated with prednisone alone and in 6 (40%) of the patients additionally treated with rIFN-alpha 2b. Our data confirm that in patients with HCV-related MC, peripheral nerve involvement is frequent, is progressive, and does not seem to benefit by addition of rIFN-alpha 2b to steroid treatment.
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Crioglobulinemia/virologia , Hepatite C/sangue , Hepatite C/complicações , Doenças do Sistema Nervoso Periférico/virologia , Adulto , Idoso , Antivirais/uso terapêutico , Complemento C4/análise , Estudos Transversais , Quimioterapia Combinada , Eletrofisiologia , Feminino , Seguimentos , Hepatite C/tratamento farmacológico , Humanos , Imunoglobulina M/sangue , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neurite (Inflamação)/fisiopatologia , Neurite (Inflamação)/virologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Proteínas Recombinantes , Estudos Retrospectivos , Fator Reumatoide/sangue , Esteroides/uso terapêuticoRESUMO
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against intracellular components, the formation of immune complexes, and inflammation in various organs, typically the skin and kidney glomeruli. The etiology of the disease is not well understood but is most likely the result of the interaction between genetic and environmental factors. In order to identify susceptibility loci for SLE, we have performed genome scans with microsatellite markers covering the whole genome in families from Argentina, Italy, and Europe. The results reveal a heterogeneous disease with different susceptibility loci in different family sets. We have found significant linkage to chromosome 17p12-q11 in the Argentine set of families. The maximum LOD score was given by marker D17S1294 in combination with D17S1293, when assuming a dominant inheritance model (Z = 3.88). We also analyzed a repeat in the promoter region of the NOS2A gene, a strong candidate gene in the region, but no association was found. The locus on chromosome 17 has previously been identified in genetic studies of multiple sclerosis families. Several other interesting regions were found at 1p35, 1q31, 3q26, 5p15, 11q23 and 19q13, confirming previously identified loci for SLE or other autoimmune diseases.
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Cromossomos Humanos Par 17/genética , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Adulto , Idoso , Argentina/epidemiologia , Mapeamento Cromossômico , Europa (Continente)/epidemiologia , Feminino , Genótipo , Humanos , Itália/epidemiologia , Lúpus Eritematoso Sistêmico/epidemiologia , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Linhagem , Regiões Promotoras GenéticasRESUMO
To assess the presence of viral ribonucleic acid (RNA) in nerve tissues of 15 patients with hepatitis C virus (HCV) infection and peripheral neuropathy with (11) or without (4) mixed cryoglobulinemia, nested reverse transcription-polymerase chain reaction (RT-PCR) was performed. Amplification of HCV-RNA was successful in 7 patients with and 3 without mixed cryoglobulinemia. This study demonstrates that the nested RT-PCR technique is a sensitive method to detect viral RNA in nerve tissue, and offers further evidence that in patients with HCV infection peripheral neuropathy can occur in the absence of mixed cryoglobulinemia.