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1.
PLoS One ; 14(8): e0220531, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31381601

RESUMO

OBJECTIVES: Patients with rheumatoid arthritis (RA) have an increased mortality and morbidity due to cardiovascular disease (CVD). In this prospective 5-year follow up of patients with RA, we analysed several biomarkers, known to be associated with atherosclerosis and/or inflammation in the general population. The aim of this study was to find out whether the RA-disease per se affect these biomarkers and if those could be associated with the progression of atherosclerosis, as measured by intima media thickness (IMT) among patients with early RA. METHODS: Patients from northern Sweden diagnosed with early RA, are consecutively recruited into an ongoing prospective study on CVD comorbidity. A subgroup of patients, aged ≤60 years (n = 71) was included for ultrasound measurements of IMT at inclusion (T0) and after 5 years (T5) together with age-sex-matched controls (n = 40). The patients were clinically assessed. Blood was analysed for lipids, ESR and CRP and several biomarkers known to be associated with atherosclerosis in the general population. RESULTS: At T0, the patients with RA had significantly lower levels of MIF and significantly higher levels of interleukin (IL)-18 and MIC-1 compared with controls. At T5, the patients with RA had significantly higher levels of pentraxin3, MIC-1, TNF-R2, ICAM-1, VCAM-1 and endostatin compared with controls. At T0 the levels of MPO correlated with DAS28, sCD40L with CRP and IL-18 with systolic blood pressure and Reynolds risk score. Using PLSR on a CVD-panel analysed with multiplex immunoassay, the patients with RA could be correctly classified into those who had a worsening in their IMT over the five years or not. Here, MMP3 was identified as influential. CONCLUSIONS: This study indicates that the RA disease itself could affect several of the biomarkers in this study, and possibly also the processes involved in the development of atherosclerosis.

2.
Ann Rheum Dis ; 77(7): 1063-1069, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29514802

RESUMO

OBJECTIVES: Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have increased risk of cardiovascular disease (CVD). We investigated whether single nucleotide polymorphisms (SNPs) at autoimmunity risk loci were associated with CVD in SLE and RA. METHODS: Patients with SLE (n=1045) were genotyped using the 200K Immunochip SNP array (Illumina). The allele frequency was compared between patients with and without different manifestations of CVD. Results were replicated in a second SLE cohort (n=1043) and in an RA cohort (n=824). We analysed publicly available genetic data from general population, performed electrophoretic mobility shift assays and measured cytokine levels and occurrence of antiphospholipid antibodies (aPLs). RESULTS: We identified two new putative risk loci associated with increased risk for CVD in two SLE populations, which remained after adjustment for traditional CVD risk factors. An IL19 risk allele, rs17581834(T) was associated with stroke/myocardial infarction (MI) in SLE (OR 2.3 (1.5 to 3.4), P=8.5×10-5) and RA (OR 2.8 (1.4 to 5.6), P=3.8×10-3), meta-analysis (OR 2.5 (2.0 to 2.9), P=3.5×10-7), but not in population controls. The IL19 risk allele affected protein binding, and SLE patients with the risk allele had increased levels of plasma-IL10 (P=0.004) and aPL (P=0.01). An SRP54-AS1 risk allele, rs799454(G) was associated with stroke/transient ischaemic attack in SLE (OR 1.7 (1.3 to 2.2), P=2.5×10-5) but not in RA. The SRP54-AS1 risk allele is an expression quantitative trait locus for four genes. CONCLUSIONS: The IL19 risk allele was associated with stroke/MI in SLE and RA, but not in the general population, indicating that shared immune pathways may be involved in the CVD pathogenesis in inflammatory rheumatic diseases.

3.
Sci Rep ; 7(1): 6236, 2017 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-28740209

RESUMO

Genome-wide association studies have identified risk loci for SLE, but a large proportion of the genetic contribution to SLE still remains unexplained. To detect novel risk genes, and to predict an individual's SLE risk we designed a random forest classifier using SNP genotype data generated on the "Immunochip" from 1,160 patients with SLE and 2,711 controls. Using gene importance scores defined by the random forest classifier, we identified 15 potential novel risk genes for SLE. Of them 12 are associated with other autoimmune diseases than SLE, whereas three genes (ZNF804A, CDK1, and MANF) have not previously been associated with autoimmunity. Random forest classification also allowed prediction of patients at risk for lupus nephritis with an area under the curve of 0.94. By allele-specific gene expression analysis we detected cis-regulatory SNPs that affect the expression levels of six of the top 40 genes designed by the random forest analysis, indicating a regulatory role for the identified risk variants. The 40 top genes from the prediction were overrepresented for differential expression in B and T cells according to RNA-sequencing of samples from five healthy donors, with more frequent over-expression in B cells compared to T cells.

4.
Semin Arthritis Rheum ; 45(6): 684-90, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26743074

RESUMO

OBJECTIVES: The main objectives of this study were to calculate total costs of illness and cost-driving disease features among patients with systemic lupus erythematosus (SLE) in Sweden. METHODS: Five cohorts of well-defined SLE patients, located in different parts of the country were merged. Incident and prevalent cases from 2003 through 2010 were included. The American College of Rheumatology (ACR) classification criteria was used. From the local cohorts, data on demographics, disease activity (SLEDAI 2K), and organ damage (SDI) were collected. Costs for inpatient care, specialist outpatient care and drugs were retrieved from national registries at the National Board of Health and Welfare. Indirect costs were calculated based on sickness leave and disability pensions from the Swedish Social Insurance Agency. RESULTS: In total, 1029 SLE patients, 88% females, were included, and approximately 75% were below 65 years at the end of follow-up, and thus in working age. The mean number of annual specialist physician visits varied from six to seven; mean annual inpatient days were 3.1-3.6, and mean annual sick leave was 123-148 days, all per patient. The total annual cost was 208,555 SEK ($33,369 = 22,941€), of which direct cost was 63,672kr ($10,188 = 7004€) and the indirect cost was 144,883 SEK ($23,181 = 15,937€), all per patient. The costs for patients with short disease duration were higher. Higher disease activity as measured by a SLEDAI 2K score > 3 was associated with approximately 50% increase in both indirect and direct costs. Damage in the neuropsychiatric and musculoskeletal domains were also linked to higher direct and indirect costs, while organ damage in the renal and ocular systems increased direct costs. CONCLUSION: Based on this study and an estimate of slightly more than 6000 SLE patients in Sweden, the total annual cost for SLE in the country is estimated at $188 million (=129.5 million €). Both direct (30%) and indirect costs (70%) are substantial. Medication accounts for less than 10% of the total cost. The tax paid national systems for health care and social security in Sweden ensure equal access to health care, sick leave reimbursements, and disability pensions nationwide. Our extrapolated annual costs for SLE in Sweden are therefore the best supported estimations thus far, and they clearly underline the importance of improved management, especially to reduce the indirect costs.


Assuntos
Assistência Ambulatorial/economia , Custos de Medicamentos , Hospitalização/economia , Lúpus Eritematoso Sistêmico/economia , Sistema de Registros , Reumatologia/economia , Licença Médica/economia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Custos de Cuidados de Saúde , Humanos , Lúpus Eritematoso Sistêmico/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Suécia , Adulto Jovem
5.
Biomed Res Int ; 2015: 673018, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26504820

RESUMO

OBJECTIVE: Lipoprotein-associated phospholipase A2 (Lp-PLA2), a marker of vascular inflammation, is associated with cardiovascular disease. This prospective study of an inception cohort aimed to investigate whether the level of Lp-PLA2 is associated with subclinical atherosclerosis in patients with rheumatoid arthritis (RA). METHODS: Patients from northern Sweden diagnosed with early RA were consecutively recruited into an ongoing prospective study. From these, all patients ≤60 years (n = 71) were included for measurements of subclinical atherosclerosis at inclusion (T0) and five years later (T5). Forty age- and sex-matched controls were included. The patients were clinically assessed, SCORE, Reynolds Risk Score, and Larsen score were calculated, and blood samples were drawn from all individuals at T0 and T5. RESULTS: There was no significant difference in the level of Lp-PLA2 between patients with RA and controls (p > 0.05). In simple linear regression models among patients with RA, Lp-PLA2 at T0 was significantly associated with intima media thickness (IMT) at T0 and T5, flow mediated dilation (FMD) at T0 and T5, ever smoking, male sex, HDL-cholesterol (inversely), non-HDL-cholesterol, SCORE, Reynolds Risk Score, and Larsen score (p < 0.05). CONCLUSION. In this cohort of patients with early RA, the concentration of Lp-PLA2 was associated with both subclinical atherosclerosis and disease severity.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Artrite Reumatoide/enzimologia , Aterosclerose/enzimologia , Inflamação/enzimologia , Artrite Reumatoide/epidemiologia , Aterosclerose/epidemiologia , Feminino , Humanos , Inflamação/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
6.
J Rheumatol ; 42(6): 935-42, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25877503

RESUMO

OBJECTIVE: This prospective followup study investigated subclinical atherosclerosis in relation to traditional cardiovascular disease (CVD) risk factors and inflammation in patients with rheumatoid arthritis (RA) recruited at diagnosis compared with controls. METHODS: Patients diagnosed with early RA were consecutively recruited into a prospective study. From these, a subgroup aged ≤ 60 years (n = 71) was consecutively included for ultrasound measurement of intima-media thickness (IMT) and flow-mediated dilation (FMD) at inclusion (T0) and after 5 years (T5). Age- and sex-matched controls (n = 40) were also included. RESULTS: In the Wilcoxon signed-rank test, both IMT and FMD were significantly aggravated at T5 compared to baseline in patients with RA, whereas only IMT was significantly increased in controls. In univariate linear regression analyses among patients with RA, the IMT at T5 was significantly associated with age, systolic blood pressure (BP), cholesterol, triglycerides, Systematic Coronary Risk Evaluation (SCORE), and Reynolds Risk Score at baseline (p < 0.05). Similarly, FMD at T5 was significantly inversely associated with age, smoking, systolic BP, SCORE, and Reynolds Risk Score (p < 0.05). A model with standardized predictive value from multiple linear regression models including age, smoking, BP, and blood lipids at baseline significantly predicted the observed value of IMT after 5 years. When also including the area under the curve for the 28-joint Disease Activity Score over 5 years, the observed value of IMT was predicted to a large extent. CONCLUSION: This prospective study identified an increased subclinical atherosclerosis in patients with RA. In the patients with RA, several traditional CVD risk factors at baseline significantly predicted the extent of subclinical atherosclerosis 5 years later. The inflammatory load over time augmented this prediction.


Assuntos
Artrite Reumatoide/diagnóstico , Artrite Reumatoide/epidemiologia , Aterosclerose/diagnóstico , Aterosclerose/epidemiologia , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Adulto , Área Sob a Curva , Artrite Reumatoide/tratamento farmacológico , Aterosclerose/tratamento farmacológico , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças das Artérias Carótidas/diagnóstico , Doenças das Artérias Carótidas/tratamento farmacológico , Doenças das Artérias Carótidas/epidemiologia , Espessura Intima-Media Carotídea , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Suécia
7.
Circ Cardiovasc Genet ; 6(3): 255-63, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23661672

RESUMO

BACKGROUND: Patients with systemic lupus erythematosus have increased morbidity and mortality in coronary heart disease (CHD). We asked whether there was a genetic influence on CHD in systemic lupus erythematosus. METHODS AND RESULTS: The association between single-nucleotide polymorphisms (SNPs) and CHD in 2 populations of patients with systemic lupus erythematosus was assessed. Patients were genotyped on a custom 12k Illumina Array. The allele frequencies were compared between patients with (n=66) and without (n=509) CHD. We found 61 SNPs with an association (P<0.01) to CHD, with the strongest association for 3 SNPs located in the interferon regulatory factor-8 (IRF8) gene. Comparison of the allele frequencies of these 61 SNPs in patients with (n=27) and without (n=212) CHD in the second study population revealed that 2 SNPs, rs925994 and rs10514610 in IRF8 (linkage disequilibrium, r²=0.84), were associated with CHD in both study populations. Meta-analysis of the SNP rs925994 gave an odds ratio of 3.6 (2.1-6.3), P value 1.9×10⁻6. The identified IRF8 allele remained as a risk factor for CHD after adjustment for traditional CHD risk factors. The IRF8 risk allele was associated with the presence of carotid plaques (P<0.001) and increased intima-media thickness (P=0.01). By electrophoretic mobility shift assays, we show weaker binding of protein to the risk allele of the highly linked SNP rs11117415, and by flow cytometry, a reduced frequency of circulating B cells was detected in patients with the IRF8 risk allele. CONCLUSIONS: There is a considerable genetic component for CHD in systemic lupus erythematosus, with IRF8 as a strong susceptibility locus.


Assuntos
Doença das Coronárias/genética , Variação Genética , Fatores Reguladores de Interferon/genética , Lúpus Eritematoso Sistêmico/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Suécia , Adulto Jovem
8.
Basic Clin Pharmacol Toxicol ; 107(6): 919-24, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20560926

RESUMO

The aim of this study was to investigate the microvascular responses in the skin, to local heat, iontophoretically administered acetylcholine and to sodium nitroprusside in relation to cardiovascular damage in patients with systemic lupus erythematosus (SLE) and matched controls. We also wanted to examine if the ongoing medication in SLE patients influenced this vascular response. We investigated 30 women with SLE and compared them with 20 age and sex-matched controls. The cutaneous blood flow response to local heat (+44°C), iontophoretically administered endothelium-dependent (acetylcholine), as well as independent (sodium nitroprusside) vasodilatation, was measured by laser Doppler flowmetry. Clinical data and medication were retrieved from the clinical database and patient records. The cutaneous microvascular reactivity did not differ between SLE patients and a group of matched controls nor did it correlate with cardiovascular damage [assessed by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR-DI)]. However, patients on antimalarial drugs (hydroxychloroquine n = 8 and chloroquine diphosphate n = 3) responded more strongly to sodium nitroprusside (endothelium-independent vasodilatation) compared with those without antimalarial drugs (p < 0.01). The response to acetylcholine was higher among patients on warfarin compared with those without (p < 0.05), whereas glucocorticoid use (≥5 mg daily) was associated with reduced response to acetylcholine (p < 0.05). Smokers in general tended to have a lower response to acetylcholine (p = 0.064). Smoking SLE patients versus non-smoking SLE patients had a significantly lower response to acetylcholine (p = 0.01). Medication with antimalarial drugs-enhanced endothelium-independent vasodilatation, while glucocorticoid use was associated with reduction and warfarin-treatment with enhancement of endothelium-dependent vasodilatation. Therefore, despite there is no difference in microvascular endothelium-dependent vasodilatation, other factors such as medication and smoking may affect vasodilatation in SLE patients.


Assuntos
Acetilcolina/efeitos adversos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Nitroprussiato/análogos & derivados , Vasodilatação/efeitos dos fármacos , Vasodilatadores/efeitos adversos , Acetilcolina/administração & dosagem , Idoso , Antimaláricos/administração & dosagem , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/tratamento farmacológico , Estudos de Casos e Controles , Interações de Medicamentos , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Fluxometria por Laser-Doppler , Lúpus Eritematoso Sistêmico/complicações , Pessoa de Meia-Idade , Nitroprussiato/administração & dosagem , Pele/irrigação sanguínea , Pele/metabolismo , Fumar/efeitos adversos , Vasodilatadores/administração & dosagem
9.
Autoimmunity ; 38(7): 531-40, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16373258

RESUMO

The objective of this study was to evaluate the efficacy of low dose dehydroepiandrosterone (DHEA) on health-related quality of life (HRQOL) in glucocorticoid treated female patients with systemic lupus erythematosus (SLE). Forty one women ( >or= 5 mg prednisolone/day) were included in a double-blind, randomized, placebo-controlled study for 6 months where DHEA was given at 30 mg/20 mg ( or= 46 years) daily, or placebo, followed by 6 months open DHEA treatment to all patients. HRQOL was assessed at baseline, 6 and 12 months, using four validated questionnaires and the patients' partners completed a questionnaire assessing mood and behaviour at 6 months. DHEA treatment increased serum levels of sulphated DHEA from subnormal to normal. The DHEA group improved in SF-36 "role emotional" and HSCL-56 total score (both p<0.05). During open DHEA treatment, the former placebo group improved in SF-36 "mental health" (p<0.05) with a tendency for improvement in HSCL-56 total score (p=0.10). Both groups improved in McCoy's Sex Scale during active treatment (p<0.05). DHEA replacement decreased high-density lipoprotein (HDL) cholesterol and increased insulin-like growth factor I (IGF-I) and haematocrit. There were no effects on bone density or disease activity and no serious adverse events. Side effects were mild. We conclude that low dose DHEA treatment improves HRQOL with regard to mental well-being and sexuality and can be offered to women with SLE where mental distress and/or impaired sexuality constitutes a problem.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Desidroepiandrosterona/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/fisiopatologia , Prednisolona/uso terapêutico , Qualidade de Vida , Adjuvantes Imunológicos/farmacologia , Hormônio Adrenocorticotrópico/sangue , Adulto , Idoso , Androgênios/sangue , Desidroepiandrosterona/farmacologia , Método Duplo-Cego , Feminino , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Pessoa de Meia-Idade , Prednisolona/farmacologia , Caracteres Sexuais , Globulina de Ligação a Hormônio Sexual/metabolismo
10.
J Rheumatol ; 29(7): 1398-400, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12136895

RESUMO

OBJECTIVE: We previously reported high Systemic Lupus International Collaborating Clinics (SLICC) scores in fatal cases of systemic lupus erythematosus (SLE) from our inception cohort. This study was done to clarify if the SLICC damage scores 5 years after diagnosis predicted the outcome. METHODS: We studied 80 patients with SLE (70 women, 10 men), all enrolled and diagnosed during the years 1981 through 1991 in our inception cohort, and all alive 5 years after inclusion into the cohort. In all patients the SLICC/American College of Rheumatology (ACR) damage index (DI) was scored at 5 years after SLE diagnosis, and these scores were tested for predictive value. The outcomes were survival or late mortality within the following median observation period of 7 years. All surviving patients were followed through 1999, and no patient was lost to followup. RESULTS: At study entry, 5 years after the diagnosis of SLE, 37 patients had no damage to score with SLICC. Of the remaining 43 patients, 25 had a score of 1 and 18 had a score of 2 or more. In total, 14 fatalities occurred within 7 years after study entry, 7 among the 18 with initial SLICC/ACR DI of 2 or more compared with 7 fatalities among the 62 with less or no damage (p < 0.01). Cardiovascular or cerebrovascular SLICC/ACR DI items were more common in fatal cases than in survivors (p < 0.001). A SLICC score at 5 years of 2 or more increased the relative risk for fatality by 3.4 (95% CI 1.5-14.4), and had a predictive value of 38%. A SLICC score of 0 at 5 years gave an odds ratio in favor of survival of 0.06 (95% CI 0.0-0.5) and had a predictive value for survival of 97%. During an extended followup for one more year the predictive value of damage for fatalities was even more pronounced (p = 0.003, log-rank). CONCLUSION: SLICC damage scores registered 5 years after SLE diagnosis have a high predictive value for survival during the following median observation time of 7 years. These data provide strong evidence that the items included in the SLICC score are clinically relevant.


Assuntos
Idade de Início , Causas de Morte , Indicadores Básicos de Saúde , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/mortalidade , Adulto , Distribuição por Idade , Idoso , Estudos de Coortes , Intervalos de Confiança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Valor Preditivo dos Testes , Probabilidade , Estudos Retrospectivos , Índice de Gravidade de Doença , Distribuição por Sexo , Análise de Sobrevida , Suécia/epidemiologia
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