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1.
Eur J Prev Cardiol ; : 2047487319880367, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610708

RESUMO

BACKGROUND: Narrower retinal arterioles and wider venules are linked to adverse cardiovascular outcomes. The mitochondrial adaptor p66Shc is a major source of ageing-induced generation of reactive oxygen species. Promoter DNA methylation inhibits p66Shc gene transcription. This cross-sectional study was designed to investigate the link between physical activity, retinal vessel diameters and p66Shc expression in active and sedentary ageing subjects. DESIGN/METHODS: Altogether 158 subjects were included in the study (mean age 59.4 ± 7.0 years). Thirty-eight subjects were healthy active, 36 were healthy sedentary and 84 were sedentary with ≥2 cardiovascular risk factors. Retinal arteriolar and venular diameters were measured by means of a retinal vessel analyser. As a marker of oxidative stress, plasma 3-nitrotyrosine was determined by enzyme-linked immunosorbent assay. Gene expression of p66Shc and DNA methylation were assessed in mononuclear cells by real-time quantitative polymerase chain reaction and methylated-DNA capture (MethylMiner Enrichment kit) coupled with quantitative polymerase chain reaction, respectively. RESULTS: Wider retinal arterioles (179 ± 14 vs 172 ± 11 and 171 ± 14 µm; p < 0.05 and narrower venules (204 ± 17 vs 209 ± 11 and 218 ± 16 µm; p < 0.001) were observed in healthy active subjects compared with healthy sedentary subjects and sedentary subjects with ≥2 cardiovascular risk factors, respectively. Furthermore, healthy active subjects had blunted p66Shc expression and lower 3-nitrotyrosine plasma levels compared with healthy sedentary and sedentary subjects with ≥2 cardiovascular risk factors. Accordingly, hypomethylation of p66Shc promoter observed in healthy sedentary and sedentary subjects with ≥2 cardiovascular risk factors was not found in healthy active subjects. CONCLUSION: Long-term physical activity-induced DNA methylation of p66Shc may represent a putative mechanistic link whereby active lifestyle promotes healthy microvascular ageing.

2.
Swiss Med Wkly ; 149: w20121, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31476243

RESUMO

OBJECTIVE: To characterise adherence and treat-to-target (T2T) strategy in gout patients within a Swiss tertiary hospital. METHODS: Consecutive presenting patients with proven gout were prospectively included in this cohort. Symptoms, comorbidities, medication and laboratory values were assessed (during hospitalisation and at planned 3- and 12-month follow-up assessments). RESULTS: 116 patients (98 men) with a mean age of 67 (range 23–94 years) were included, 74% of whom had active arthritis. Comorbidities were frequent: hypertension, renal impairment, and obesity were present in 72, 55 and 35% of patients, respectively. Thirty-five percent of patients received urate-lowering treatment at inclusion. Only 62 and 50% attended the 3- and 12-month follow-up. The target serum uric acid level of <360 μmol/l was achieved in 22 and 57% of patients by the 3- and 12-month follow-up visits, respectively. Patients followed up by rheumatologists reached the target serum uric acid at follow-up more often than those that were not (p = 0.033). Median daily allopurinol dose at 12-month follow-up was 300 mg in those achieving T2T and 100 mg in the others (p = 0.033). Flares occurred during the first 3 months in 52% and during the subsequent 9 months in 47% of patients. CONCLUSION: Only half of patients attended the planned follow-up visits, indicating low awareness for gout. Of those attending follow-up, only approximately 50% had achieved the serum urate target at 12 months. Although new treatments are available, care for gout patients remains insufficient, notably in difficult-to-treat multimorbid patient subsets as described in this cohort.

3.
Eur Heart J ; 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-31323685

RESUMO

AIMS: Impairments of retinal vessel diameter are associated with major adverse cardiovascular (CV) events. Promoter DNA methylation is a repressor of the mitochondrial adaptor p66Shc gene transcription, a key driver of ageing-induced reactive oxygen species. The study aimed to investigate whether high-intensity interval training (HIIT) affects retinal microvascular phenotype as well as p66Shc expression and oxidative stress in ageing subjects with increased CV risk from the EXAMIN AGE cohort. METHODS AND RESULTS: Eighty-four sedentary subjects (mean age 59.4 ± 7.0 years) with ≥2 CV risk factors were randomized into either a 12-week HIIT or standard physical activity recommendations. Retinal arteriolar and venular diameters were measured by use of a retinal vessel analyser. As a marker of oxidative stress plasma 3-nitrotyrosine (3-NT) level was determined by ELISA. Gene expression of p66Shc and DNA methylation were assessed in mononuclear cells by RT-qPCR and methylated-DNA capture (MethylMiner Enrichment Kit) coupled with qPCR, respectively. High-intensity interval training reduced body mass index, fat mass, low-density lipoprotein and increased muscle mass, as well as maximal oxygen uptake (VO2max). Moreover, HIIT restored microvascular phenotype by inducing retinal arteriolar widening (pre: 175 ± 14 µm vs. post: 181 ± 13 µm, P = 0.001) and venular narrowing (pre: 222 ± 14 µm vs. post: 220 ± 14 µm, P = 0.007). After HIIT, restoration of p66Shc promoter methylation (P = 0.034) reduced p66Shc gene expression (P = 0.037) and, in turn, blunted 3-NT plasma levels (P = 0.002). CONCLUSION: High-intensity interval training rescues microvascular dysfunction in ageing subjects at increased CV risk. Exercise-induced reprogramming of DNA methylation of p66Shc gene may represent a putative mechanistic link whereby exercise protects against age-related oxidative stress. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02796976 (https://clinicaltrials.gov/ct2/show/NCT02796976).

4.
Arthritis Res Ther ; 21(1): 175, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31319889

RESUMO

OBJECTIVE: Primary Sjögren syndrome (pSS) is characterized by T and B cell infiltration of exocrine glands. The cysteine protease cathepsin S (CatS) is crucially involved in MHCII processing and T cell stimulation, and elevated levels have been found in patients with RA, psoriasis and pSS. However, little is known about the functional characteristics and mechanisms of SS-A- and SS-B-specific T cells in pSS patients. We herein investigated the inhibition of CatS activity in different biocompartments of pSS patients including antigen-specific T cell responses. METHODS: Ex vivo CatS activity was assessed in tears, plasma and saliva of 15 pSS patients and 13 healthy controls (HC) and in the presence or absence of the specific CatS inhibitor RO5459072. In addition, antigen (SS-A (60kD), SS-B, influenza H3N2, tetanus toxoid and SEB)-specific T cell responses were examined using ex vivo IFN-γ/IL-17 Dual ELISPOT and Bromdesoxyuridin (BrdU) proliferation assays in the presence or absence of RO5459072. Supernatants were analysed for IL-1ß, IL-6, IL-10, TNF-α, IL-21, IL-22 and IL-23, using conventional ELISA. RESULTS: CatS activity was significantly elevated in tear fluid, but not other biocompartments, was inversely associated with exocrinic function in pSS patients and could significantly be suppressed by RO5459072. Moreover, CatS inhibition by RO5459072 led to strong and dose-dependent suppression of SS-A/SS-B-specific T cell effector functions and cytokine secretion by CD14+ monocytes. However, RO5459072 was incapable of suppressing SS-A/SS-B-induced secretion of cytokines in CD14+ monocytes when T cells were absent, confirming a CatS/MHCII-mediated mechanism of suppression. CONCLUSION: CatS activity in tear fluid seems to be a relevant biomarker for pSS disease activity. Conversely, CatS inhibition diminishes T cell and associated monokine responses towards relevant autoantigens in pSS. Thus, CatS inhibition may represent a promising novel treatment strategy in pSS.

5.
Acta Radiol ; : 284185119854200, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31169411

RESUMO

BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging has the potential to show disease activity of rheumatoid arthritis even in complex anatomic areas as the atlantodental region. PURPOSE: To demonstrate the technical feasibility of measuring synovial volume and perfusion characteristics with dynamic contrast-enhanced magnetic resonance imaging of the atlantodental region in patients with rheumatoid arthritis. MATERIAL AND METHODS: Ten patients with rheumatoid arthritis and cervical spine involvement underwent dynamic contrast-enhanced magnetic resonance imaging of the cervical spine at 1.5 T. For each patient, 80 3D datasets were acquired using the commercialized Time Resolved Imaging of Contrast KineticS (TRICKS) sequence. Volumes of synovia with active synovitis on anatomical and parametric images were segmented. Synovial tissue perfusion parameters, namely plasma flow (Fp), relative plasma volume (vp), and the permeability-surface area product (PS), were calculated using a two-compartment uptake model. Statistical analysis included calculation of intra- and inter-reader agreement and a correlation of perfusion parameters with Outcome Measures in Rheumatology Clinical Trials (OMERACT) criteria. RESULTS: Dynamic contrast-enhanced magnetic resonance imaging as well as quantification of volume and perfusion characteristics of synovia was successful in most patients (80%). Intra- and inter-reader agreement was excellent (0.89-0.99). There was a positive correlation between OMERACT score and the permeability-surface product. CONCLUSION: Dynamic contrast-enhanced magnetic resonance imaging using a 4D angiography sequence for the atlantodental region in patients with rheumatoid arthritis for quantitative and qualitative assessment of synovial volume and perfusion characteristics is technically feasible.

6.
Br J Haematol ; 186(1): 101-112, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30941747

RESUMO

Anaemia affects quality of life and radiographic outcome in rheumatoid arthritis (RA). In a cross-sectional study with 779 patients, we assessed the prognostic potential of the major haematopoietic regulators, hepcidin and erythropoietin, comparing their serum concentrations with respect to different anaemia types, inflammatory activity, anti-cytokine-specific treatment effects and iron deficiency (ID) indices. The results showed that clinical disease activity was more closely associated with haemoglobin levels than with anti-tumour necrosis factor-alpha or interleukin 6 receptor effects. In ID, hepcidin was suppressed, independently of inflammation. Erythropoietin levels were inappropriately low in relation to the degree of anaemia, but, in contrast to low haemoglobin, not directly associated with joint damage progression. Hepcidin and erythropoietin levels are intimately connected with inflammation and ID. Interventional studies on these important targets are already in progress.

7.
Rheumatology (Oxford) ; 58(9): 1585-1596, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30877773

RESUMO

OBJECTIVES: We aimed to assess the safety and immunogenicity of a diphtheria/tetanus vaccine booster dose in three different patient groups with rheumatic diseases on a variety of immunosuppressive/immunomodulatory medications compared with healthy controls (HCs). METHODS: We conducted a multi-centre prospective cohort study in Switzerland. We enrolled patients with RA, axial SpA/PsA, vasculitis (Behçet's disease, ANCA-associated vasculitis) and HCs. Diphtheria/tetanus vaccination was administered according to the Swiss vaccination recommendations. Blood samples were drawn before vaccination, and 1 month and 3 months afterwards. Antibody concentrations against vaccine antigens were measured by ELISA. Immunogenicity was compared between patient and medication groups. A mixed model was applied for multivariate analysis. Missing data were dealt with using multiple imputation. RESULTS: Between January 2014 and December 2015, we enrolled 284 patients with rheumatic diseases (131 RA, 114 SpA/PsA, 39 vasculitis) and 253 HCs. Of the patients, 89% were on immunosuppressive/immunomodulatory medication. Three months post-vaccination 100% of HCs vs 98% of patients were protected against tetanus and 84% vs 73% against diphtheria. HCs and SpA/PsA patients had significantly higher responses than RA and vasculitis patients. Assessing underlying diseases and medications in a multivariate model, rituximab was the only factor negatively influencing tetanus immunogenicity, whereas only MTX treatment had a negative influence on diphtheria antibody responses. No vaccine-related serious adverse events were recorded. CONCLUSION: Diphtheria/tetanus booster vaccination was safe. Tetanus vaccination was immunogenic; the diphtheria component was less immunogenic. Vaccine responses were blunted by rituximab and MTX. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, Identifier: NCT01947465.

8.
Arthritis Rheumatol ; 2018 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-30073800

RESUMO

OBJECTIVE: DIP joints are commonly considered to be unaffected by RA. Despite synovitis and bone marrow edema being associated with radiographic progression in hand OA and RA, radiographic courses differ substantially. We analyzed radiographic incidence and progression of distal DIP-OA in RA patients, considering RA activity and patient characteristics. METHODS: In sequential radiographs of 1988 RA patients in the Swiss rheumatic disease registry, we scored 15904 DIP joints for the presence of central erosions and subchondral sclerosis, and for the severity of osteophytes and joint-space narrowing according to the modified Kellgren-Lawrence grade (KLG). Presence of DIP-OA was defined as ≥one joint with KLG≥2, and progression was defined as an increase in summed KLG. RESULTS: Median follow-up time was 4.5 years (IQR 3.1-7.0), and patients averaged 56.1 years (SD 11.1) old. DIP-OA was present in 60% of patients at baseline. Age (OR=1.09, 95%CI=1.08-01), female sex (OR=1.37, 95%CI=1.08-1.74), and greater BMI (OR=1.03, 95%CI=1.00-1.06), but neither ACPA (OR=0.72, 95%CI=0.50-1.03) nor RF (OR=1.01, 95%CI=0.74-1.38), were associated with the presence of DIP-OA. DAS28-ESR and MCP erosions were not associated with DIP-OA progression (OR=1.02, 95%CI=0.94-1.11; and OR[10-20]=0.82, 95%CI=0.60-1.13; OR[30-70]=0.86, 95%CI=0.59-1.26; and OR[80-800]=0.84, 95%CI=0.53-1.33, all vs. no erosions, respectively). RA duration had no relevant effect size associated with DIP-OA progression (OR=0.97, 95%CI=0.96-0.99). CONCLUSION: Known risk factors for DIP-OA were replicated in patients with RA. The observation that RA activity, autoantibody status, and MCP erosions were not associated with the prevalence or progression of DIP-OA indicates the distinct roles of inflammation in the pathogenesis of RA and DIP-OA. This article is protected by copyright. All rights reserved.

9.
Front Physiol ; 9: 176, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29593551

RESUMO

Objectives: Low-grade systemic inflammation is responsible for atherosclerotic lesions in patients with rheumatic diseases. Vascular dysfunction is a precursor of atherosclerosis and can be improved by physical activity (PA). Our aim was to asses micro- and macrovascular function as well as PA and cardiorespiratory fitness (CRF) in patients with rheumatic diseases in the absence of cardiovascular (CV) comorbidities compared to controls. Methods: Fifty-one patients without CV comorbidities were compared to 35 controls. Retinal microvascular diameters were assessed using a Retinal Vessel Analyzer. Arterial stiffness (AST) was measured by applanation tonometry. CRF was assessed as peak oxygen consumption and PA was assessed with a questionnaire. Results: Retinal venular diameters were significantly wider in patients [median 221 µm (interquartile range (IQR) 211, 231)] compared to controls [median 215 µm (IQR 196, 223); p = 0.01]. One hour increase of PA per week led to a venular constriction of -0.56 µm (95%CI -1.09, -0.03; p = 0.04). In our patients with low disease activity (median DAS28 1.9; median BASDAI 2.8), no differences in AST were evident compared to controls. The association of PA and CRF with AST was not independent of blood pressure. Conclusions: Patients with rheumatic disease and mild-to-moderate disease activity show an impairment of the retinal microvasculature but not of large artery stiffness. Retinal vessel analysis seems to be a sensitive biomarker to unmask vascular impairments even in the absence of classic CV risk factors. PA may have the potential to counteract the development of small artery disease at early stages of rheumatic disease.

10.
Eur Heart J Cardiovasc Imaging ; 19(8): 933-940, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29126277

RESUMO

Aims: The usefulness of [18F] fluorodeoxyglucose-positron emission tomography/computed tomography ([18F]FDG-PET/CT) for diagnosing giant cell arteritis (GCA) has been previously reported. Yet, the interpretation of PET scans is not clear-cut. The present study aimed at determining the best method to analyse PET/CT in a large, real-life cohort of patients presenting with suspicion of GCA. Methods and results: One hundred and three patients with clinical suspicion of GCA undergoing PET/CT between 2006 and 2012 were included. Clinical data were retrieved from patients' charts. PET/CT was categorized by visual scoring of the uptake and by the artery/liver standardized uptake values (SUV) ratios. Diagnosis of GCA was confirmed in 68 patients and excluded in 35 patients, which served as the controls. GCA patients were older (median age 75 vs. 68 years), and presented more often with ischaemic symptoms. The best discrimination between GCA patients and controls was achieved for PET/CT findings within the supra-aortic arteries (sensitivity 0.71, specificity 0.91 for a SUV/LE cut-off value of 1.0). Specificity of PET/CT for the aorta and the iliofemoral arteries was lower (<0.34). Visual scoring correlated poorly to SUV measurements (Kendall Tau-b 0.13-0.55) and had a lower diagnostic accuracy (sensitivity 0.77, specificity 0.75). Prednisone treatment for ≥10 days significantly reduced PET/CT sensitivity (P = 0.009). Conclusion: SUV based analysis of PET/CT enhances diagnostic accuracy with best discrimination in the supra-aortic region, particularly in steroid naïve patients. For discrimination based on the aorta and the iliofemoral region, higher cut-off values have to be applied, resulting in lower sensitivities for diagnosing GCA.

12.
Arthritis Res Ther ; 19(1): 245, 2017 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-29096690

RESUMO

BACKGROUND: Toll-like receptors (TLRs) and macrophages play an important role in rheumatoid arthritis (RA). Currently, it is not clear whether inflammatory M1 or anti-inflammatory M2 predominate among the resident macrophages in the synovium. In the present study, we set out to investigate the impact of TLR stimulation on monocyte-derived M1 and M2 macrophage function and phenotype by mimicking the exposure to abundant TLR agonists as occurs in the context of RA. The response of macrophage subsets to TLR2 and TLR4 activation was evaluated on cluster of differentiation (CD) marker profile; cytokine secretion; gene expression; and NF-κB, interferon regulatory factors 3 and 7 (IRF3/7), and mitogen-activated protein kinase (MAPK) activation. METHODS: Human monocytes were isolated from peripheral blood of healthy individuals and patients with RA and differentiated into M1-like and M2-like macrophages by granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF), respectively. Cells were either (1) stimulated with TLR ligands Pam3 or lipopolysaccharide (LPS) or (2) classically activated via interferon (IFN)-γ/LPS. Cytokine production was measured by enzyme-linked immunosorbent assay, and gene expression was measured by qPCR. Cells were stained for CD markers and analyzed by fluorescence-activated cell sorting. NF-κB, IRF3/7, and MAPKs were detected by Western blotting. RESULTS: Monocyte-derived macrophages of healthy donors (HD) or patients with RA displayed comparable subset-specific phenotypes upon exposure to TLR agonists. CD14 and CD163 marker expression on M2 macrophages did not change upon TLR2 and TLR4 engagement. By contrast, M2 gene markers HMOX1, FOLR2, and SLC40A1 were decreased. Importantly, M2 macrophages derived from HD or patients with RA showed both a decreased ratio of interleukin (IL)-10/IL-6 and IL-10/IL-8 upon stimulation with TLR2 ligand Pam3 compared with TLR4 ligand LPS. Gene expression of TLR2 was increased, whereas TLR4 expression was decreased, by TLR ligand stimulation. MAPKs p38, extracellular signal-regulated kinase 1/2, and c-Jun N-terminal kinase were activated more strongly in M2 than in M1 macrophages by Pam3 or LPS. CONCLUSIONS: We show that the anti-inflammatory activity of M2 macrophages is reduced in the presence of abundant TLR2 ligands without significant changes in cell surface markers. Thus, the classical M1/M2 paradigm based on cellular markers does not apply to macrophage functions in inflammatory conditions such as RA.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Receptor 2 Toll-Like/agonistas , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Western Blotting , Diferenciação Celular/genética , Células Cultivadas , Citocinas/metabolismo , Expressão Gênica/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Lipopolissacarídeos/farmacologia , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos/classificação , Macrófagos/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Monócitos/citologia , Monócitos/metabolismo , NF-kappa B/metabolismo , Fenótipo , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismo
14.
Rheumatology (Oxford) ; 56(9): 1579-1585, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28859327

RESUMO

Objectives: To analyse the association between female hormonal factors and the development of systemic autoimmunity associated with RA in women at increased risk for RA, namely first-degree relatives of patients with RA (RA-FDRs). Methods: In an ongoing cohort study of RA-FDRs, we analysed all women with available ACPA status. The primary outcome was ACPA positivity. The predictors of interest were female hormonal factors, such as oral contraceptives, breastfeeding, post-menopausal status, early post-menopausal period and total number of ovulatory years. Results: A total of 768 female RA-FDRs were analysed, of which 42 (5%) had developed ACPA positivity. ACPA-positive women were older (52 vs 44 years, P = 0.001). Hormonal factors significantly and independently associated with the presence of ACPA were the post-menopausal (P < 0.001) and the early post-menopausal periods (P = 0.040). Conclusions: In women at increased risk of RA, characteristic systemic autoimmunity was associated with menopause, suggesting that the acute decline in ovarian function might contribute to the development of autoimmunity associated with RA and potentially to the increased risk of RA in women.


Assuntos
Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Peptídeos Cíclicos/imunologia , História Reprodutiva , Adulto , Autoimunidade , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paridade , Pós-Menopausa/imunologia , Fatores de Risco
15.
Rheumatology (Oxford) ; 56(10): 1707-1712, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28957553

RESUMO

Objectives: The aim was to evaluate patient self-assessment of RA disease activity in terms of Routine Assessment of Patient Index Data (RAPID) scores via a Web-based smartphone application (WebApp). Methods: In this prospective, multicentre study, adult RA patients were examined by a rheumatologist at baseline and after 3 months. Patients were asked to complete WebApp questionnaires weekly. The time course of patient-assessed RAPID3/4 scores and their correlations with rheumatologist-assessed DAS28, as well as Clinical and Simplified Disease Activity Indices (CDAI/SDAI), were evaluated. Results: Eighty patients were included in the analysis (median RA duration, 4.5 years; age, 57 years; 59% female). At baseline, there was a moderate to strong correlation between RAPID3 and DAS28 (r = 0.63), CDAI (r = 0.65) and SDAI (r = 0.61) scores. Similar or stronger correlations were seen at the 3-month follow-up visit (DAS28 r = 0.66, CDAI r = 0.71 and SDAI r = 0.61). Similar correlations were seen between RAPID4 and rheumatologist assessments. Correlations were not influenced by demographics or RA treatment. In the 3-month period, the RAPID3 score changed into a higher severity category than the category at baseline at least once in 47% of patients. When DAS28 scores were predicted from the RAPID3, 11% of patients had an increase of > 1 DAS28 unit during the 3-month observation period. Conclusion: Web-based patient assessments were strongly correlated with rheumatologist assessments of RA activity and showed considerable variation during follow-up. This provides a rationale for further exploration of their use as cost-effective tools to monitor RA activity between outpatient visits and to optimize tight control strategies.


Assuntos
Artrite Reumatoide/patologia , Autoavaliação Diagnóstica , Aplicativos Móveis , Índice de Gravidade de Doença , Avaliação de Sintomas/métodos , Adulto , Idoso , Avaliação da Deficiência , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Smartphone
16.
Clin Rheumatol ; 36(3): 677-682, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28110385

RESUMO

Transition from genetic risk to the development of systemic autoimmunity associated with rheumatoid arthritis (RA) is considered a key step for the development of RA and often referred to as the immune onset of the disease. The aim of this study is to identify predictors for the presence of anticitrullinated protein antibodies (ACPA) as a marker of systemic autoimmunity associated with RA in a high-risk population, an ongoing cohort of first-degree relatives of patients with RA. We assessed the presence of ACPA in individuals without clinical evidence of RA. We examined characteristics associated with ACPA positivity using general estimation equations to account for multiple observations per individual. A total of 1159 serum samples from 1025 subjects were analyzed, 69 samples (6%) were ACPA-positive, and 227 (20%) positive for rheumatoid factor. Participants had a median age of 45 years (interquartile range (IQR): 33-55) at baseline and 76% were women. Overall, ACPA positivity increased with age (p < 0.001). Among women, ACPA positivity was particularly associated with the age group 45 to 55 years (p = 0.003), but not among men (p = 0.7). In multivariable adjusted analyses, age older than 45, female sex and tobacco smoking were independently associated with ACPA positivity. In our cohort, the presence of ACPA was associated with older age and peaked in women around age 45 to 55 years, the perimenopausal period, suggesting that the development of ACPA may be favored by the decline in ovarian function.


Assuntos
Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Peptídeos Cíclicos/imunologia , Adulto , Fatores Etários , Idoso , Artrite Reumatoide/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fator Reumatoide/sangue , Fatores de Risco
17.
J Autoimmun ; 77: 55-66, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27793425

RESUMO

B-cells are pivotal to the pathogenesis of rheumatoid arthritis and tofacitinib, a JAK inhibitor, is effective and safe in its treatment. Tofacitinib interferes with signal transduction via cytokine receptors using the common γ-chain. Despite extensive data on T-lymphocytes, the impact of tofacitinib on B-lymphocytes is poorly understood. In this study we assessed the effect of tofacitinib on B-lymphocyte differentiation and function. Tofacitinib treatment strongly impaired in vitro plasmablast development, immunoglobulin secretion and induction of B-cell fate determining transcription factors, Blimp-1, Xbp-1, and IRF-4, in naïve B-cells. Interestingly, class switch and activation-induced cytidine deaminase (AICDA) induction was only slightly reduced in activated naïve B-cells. The effect of tofacitinib on plasmablast formation, immunoglobulin secretion and proliferation was less profound, when peripheral blood B-cells, including not only naïve but also memory B-cells, were stimulated. In line with these in vitro results, the relative distribution of B-cell populations remained stable in tofacitinib treated patients. Nevertheless, a temporary increase in absolute B-cell numbers was observed 6-8 weeks after start of treatment. In addition, B-cells isolated from tofacitinib treated patients responded rapidly to in vitro activation. We demonstrate that tofacitinib has a direct impact on human naïve B-lymphocytes, independently from its effect on T-lymphocytes, by impairing their development into plasmablasts and immunoglobulin secretion. The major effect of tofacitinib on naïve B-lymphocyte development points to the potential inability of tofacitinib-treated patients to respond to novel antigens, and suggests planning vaccination strategies prior to tofacitinib treatment.


Assuntos
Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Formação de Anticorpos/efeitos dos fármacos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Linfócitos B/metabolismo , Células Cultivadas , Citidina Desaminase/metabolismo , Humanos , Switching de Imunoglobulina/efeitos dos fármacos , Imunomodulação , Subunidade gama Comum de Receptores de Interleucina/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Piperidinas/uso terapêutico , Plasmócitos/efeitos dos fármacos , Plasmócitos/imunologia , Plasmócitos/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
18.
Pulm Pharmacol Ther ; 37: 24-9, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26869014

RESUMO

BACKGROUND: Rituximab (RTX), a B-cell depleting monoclonal antibody is increasingly used in several antibody-mediated diseases. It has been reported to cause pulmonary toxicity, though mainly during polychemotherapy of malignant lymphoma. Prospective data on RTX-induced pulmonary complications in patients with rheumatoid arthritis (RA) are lacking. METHODS AND METHODS: Serial spirometries and measurements of diffusion capacity of the lung for carbon monoxide (DLCO) in patients with RA before and 2, 4, 8, and 26 weeks after treatment with RTX were performed. A reduction from baseline of forced vital capacity (FVC) of ≥10%, or ≥15% of DLCO was defined as indicative for pulmonary toxicity. RESULTS: Thirty-three patients (mean (SD) age 59 (12) years, 27% males) were included. Mean (SD) FVC predicted and DLCO predicted at baseline were 108% (18%) and 88% (18%), respectively. In contrast to FVC, DLCO showed a progressive decline during follow-up with a maximum reduction of 6.1% (95%CI 2.5%, 9.7%; p = 0.001) at 26 weeks compared with baseline. After 26 weeks, 22% of the patients had a ≥15% DLCO decline. None of the patients reported increased dyspnea during follow-up. Risk factors for pulmonary function changes after treatment with RTX were cigarette smoking, repeated administration of the drug, and co-medication with Prednisone. CONCLUSION: Although no cases of symptomatic lung injury were observed, the progressive DLCO decline seems to indicate the presence of subclinical RTX-induced pulmonary toxicity.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Pneumopatias/induzido quimicamente , Rituximab/uso terapêutico , Idoso , Antirreumáticos/efeitos adversos , Artrite Reumatoide/fisiopatologia , Monóxido de Carbono/metabolismo , Feminino , Seguimentos , Humanos , Pneumopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Estudos Prospectivos , Testes de Função Respiratória , Fatores de Risco , Rituximab/efeitos adversos , Fumar/epidemiologia , Espirometria , Fatores de Tempo , Capacidade Vital
19.
J Ultrason ; 15(60): 29-44, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26674725

RESUMO

OBJECTIVE: High resolution ultrasonography is a non-painful and non-invasive imaging technique which is useful for the assessment of shoulder pain causes, as clinical examination often does not allow an exact diagnosis. The aim of this study was to compare the findings of clinical examination and high resolution ultrasonography in patients presenting with painful shoulder. METHODS: Non-interventional observational study of 100 adult patients suffering from unilateral shoulder pain. Exclusion criteria were shoulder fractures, prior shoulder joint surgery and shoulder injections in the past month. The physicians performing the most common clinical shoulder examinations were blinded to the results of the high resolution ultrasonography and vice versa. RESULTS: In order to detect pathology of the m. supraspinatus tendon, the Hawkins and Kennedy impingement test showed the highest sensitivity (0.86) whereas the Jobe supraspinatus test showed the highest specificity (0.55). To identify m. subscapularis tendon pathology the Gerber lift off test showed a sensitivity of 1, whereas the belly press test showed the higher specificity (0.72). The infraspinatus test showed a high sensitivity (0.90) and specificity (0.74). All AC tests (painful arc II(a), AC joint tenderness(b), cross body adduction stress test(c)) showed high specificities ((a)0.96, (b)0.99, (c)0.96). Evaluating the long biceps tendon, the palm up test showed the highest sensitivity (0.47) and the Yergason test the highest specificity (0.88). CONCLUSION: Knowledge of sensitivity and specificity of various clinical tests is important for the interpretation of clinical examination test results. High resolution ultrasonography is needed in most cases to establish a clear diagnosis.

20.
Swiss Med Wkly ; 145: w14192, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26376442

RESUMO

Small noncoding RNAs (snRNAs) were discovered more than two decades ago, yet it was not until relatively recently that their important role in genome regulation was recognised. With such a substantial role in genome regulation, it is not surprising that snRNAs are crucial contributors to an ever-increasing number of diseases, as evidenced by the long list of published studies. Currently, microRNAs (miRNAs) represent the most intensively studied snRNAs. Dysregulation of miRNAs has been confirmed in numerous diseases, and changes in their levels could play an essential role in disease onset and progression and could be used for prognosis and potential therapy. Indeed, disease-altered miRNAs may either signify a direct trigger or a consequence of the disease. Therefore, miRNAs represent unique targets for disease intervention through their down- or up-regulation. Importantly, miRNAs may facilitate disease monitoring by detection of disease-altered miRNAs in easily accessible bodily fluids, such as blood or cerebrospinal fluid. Therefore, study of these events is of utmost importance for understanding the molecular mechanisms that drive disease, as well as for diagnosis and therapy. Here we attempted to synthesise a large number of studies to highlight the crucial role of miRNAs in the pathogenesis of neurodegenerative, muscle, cardiovascular and inflammatory diseases.


Assuntos
Doenças Cardiovasculares/genética , Inflamação/genética , MicroRNAs/fisiologia , Doenças Musculares/genética , Doenças Neurodegenerativas/genética , Humanos
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