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1.
Ann Rheum Dis ; 77(4): 563-570, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29306872

RESUMO

OBJECTIVES: Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). METHODS: The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). RESULTS: 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. CONCLUSIONS: Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. TRIAL REGISTRATION NUMBER: NCT02339441.


Assuntos
Esclerodermia Difusa/diagnóstico , Índice de Gravidade de Doença , Testes Cutâneos/estatística & dados numéricos , Adulto , Área Sob a Curva , Progressão da Doença , Diagnóstico Precoce , Feminino , Humanos , Modelos Logísticos , Masculino , Valor Preditivo dos Testes , Estudos Prospectivos , RNA Polimerase III/análise , Curva ROC , Esclerodermia Difusa/enzimologia , Esclerodermia Difusa/patologia , Pele/patologia
2.
Rheumatology (Oxford) ; 57(2): 370-381, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29207002

RESUMO

Objectives: Our aim was to describe the burden of early dcSSc in terms of disability, fatigue and pain in the European Scleroderma Observational Study cohort, and to explore associated clinical features. Methods: Patients completed questionnaires at study entry, 12 and 24 months, including the HAQ disability index (HAQ-DI), the Cochin Hand Function Scale (CHFS), the Functional Assessment of Chronic Illness Therapy-fatigue and the Short Form 36 (SF36). Associates examined included the modified Rodnan skin score (mRSS), current digital ulcers and internal organ involvement. Correlations between 12-month changes were also examined. Results: The 326 patients recruited (median disease duration 11.9 months) displayed high levels of disability [mean (s.d.) HAQ-DI 1.1 (0.83)], with 'grip' and 'activity' being most affected. Of the 18 activities assessed in the CHFS, those involving fine finger movements were most affected. High HAQ-DI and CHFS scores were both associated with high mRSS (ρ = 0.34, P < 0.0001 and ρ = 0.35, P < 0.0001, respectively). HAQ-DI was higher in patients with digital ulcers (P = 0.004), pulmonary fibrosis (P = 0.005), cardiac (P = 0.005) and muscle involvement (P = 0.002). As anticipated, HAQ-DI, CHFS, the Functional Assessment of Chronic Illness Therapy and SF36 scores were all highly correlated, in particular the HAQ-DI with the CHFS (ρ = 0.84, P < 0.0001). Worsening HAQ-DI over 12 months was strongly associated with increasing mRSS (ρ = 0.40, P < 0.0001), decreasing hand function (ρ = 0.57, P < 0.0001) and increasing fatigue (ρ = -0.53, P < 0.0001). Conclusion: The European Scleroderma Observational Study highlights the burden of disability in early dcSSc, with high levels of disability and fatigue, associating with the degree of skin thickening (mRSS). Impaired hand function is a major contributor to overall disability.


Assuntos
Avaliação da Deficiência , Fadiga/fisiopatologia , Dor/fisiopatologia , Esclerodermia Difusa/fisiopatologia , Índice de Gravidade de Doença , Adulto , Efeitos Psicossociais da Doença , Europa (Continente) , Fadiga/etiologia , Feminino , Dedos , Força da Mão , Inquéritos Epidemiológicos , Humanos , Masculino , Dor/etiologia , Estudos Prospectivos , Esclerodermia Difusa/complicações , Úlcera Cutânea/etiologia , Úlcera Cutânea/fisiopatologia
3.
Ann Rheum Dis ; 77(3): 412-416, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29275334

RESUMO

OBJECTIVES: To compare the effects of rituximab versus placebo on salivary gland ultrasound (SGUS) in primary Sjögren's syndrome (PSS) in a multicentre, multiobserver phase III trial substudy. METHODS: Subjects consenting to SGUS were randomised to rituximab or placebo given at weeks 0, 2, 24 and 26, and scanned at baseline and weeks 16 and 48. Sonographers completed a 0-11 total ultrasound score (TUS) comprising domains of echogenicity, homogeneity, glandular definition, glands involved and hypoechoic foci size. Baseline-adjusted TUS values were analysed over time, modelling change from baseline at each time point. For each TUS domain, we fitted a repeated-measures logistic regression model to model the odds of a response in the rituximab arm (≥1-point improvement) as a function of the baseline score, age category, disease duration and time point. RESULTS: 52 patients (n=26 rituximab and n=26 placebo) from nine centres completed baseline and one or more follow-up visits. Estimated between-group differences (rituximab-placebo) in baseline-adjusted TUS were -1.2 (95% CI -2.1 to -0.3; P=0.0099) and -1.2 (95% CI -2.0 to -0.5; P=0.0023) at weeks 16 and 48. Glandular definition improved in the rituximab arm with an OR of 6.8 (95% CI 1.1 to 43.0; P=0.043) at week 16 and 10.3 (95% CI 1.0 to 105.9; P=0.050) at week 48. CONCLUSIONS: We demonstrated statistically significant improvement in TUS after rituximab compared with placebo. This encourages further research into both B cell depletion therapies in PSS and SGUS as an imaging biomarker. TRIAL REGISTRATION NUMBER: 65360827, 2010-021430-64; Results.


Assuntos
Fatores Imunológicos/uso terapêutico , Rituximab/uso terapêutico , Glândulas Salivares/efeitos dos fármacos , Síndrome de Sjogren/tratamento farmacológico , Ultrassonografia/métodos , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Glândulas Salivares/diagnóstico por imagem , Síndrome de Sjogren/diagnóstico por imagem , Resultado do Tratamento
4.
Arthritis Rheumatol ; 69(7): 1440-1450, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28296257

RESUMO

OBJECTIVE: To investigate whether rituximab, an anti-B cell therapy, improves symptoms of fatigue and oral dryness in patients with primary Sjögren's syndrome (SS). METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial that included health economic analysis. Anti-Ro-positive patients with primary SS, symptomatic fatigue, and oral dryness were recruited from 25 UK rheumatology clinics from August 2011 to January 2014. Patients were centrally randomized to receive either intravenous (IV) placebo (250 ml saline) or IV rituximab (1,000 mg in 250 ml saline) in 2 courses at weeks 0, 2, 24, and 26, with pre- and postinfusion medication including corticosteroids. The primary end point was the proportion of patients achieving a 30% reduction in either fatigue or oral dryness at 48 weeks, as measured by visual analog scale. Other outcome measures included salivary and lacrimal flow rates, quality of life, scores on the European League Against Rheumatism (EULAR) Sjögren's Syndrome Patient Reported Index and EULAR Sjögren's Syndrome Disease Activity Index, symptoms of ocular and overall dryness, pain, globally assessed disease activity, and cost-effectiveness. RESULTS: All 133 patients who were randomized to receive placebo (n = 66) or rituximab (n = 67) were included in the primary analysis. Among patients with complete data, 21 of 56 placebo-treated patients and 24 of 61 rituximab-treated patients achieved the primary end point. After multiple imputation of missing outcomes, response rates in the placebo and rituximab groups were 36.8% and 39.8%, respectively (adjusted odds ratio 1.13 [95% confidence interval 0.50, 2.55]). There were no significant improvements in any outcome measure except for unstimulated salivary flow. The mean ± SD costs per patient for rituximab and placebo were £10,752 ± 264.75 and £2,672 ± 241.71, respectively. There were slightly more adverse events (AEs) reported in total for rituximab, but there was no difference in serious AEs (10 in each group). CONCLUSION: The results of this study indicate that rituximab is neither clinically effective nor cost-effective in this patient population.


Assuntos
Antirreumáticos/uso terapêutico , Fadiga/tratamento farmacológico , Rituximab/uso terapêutico , Síndrome de Sjogren/tratamento farmacológico , Xerostomia/tratamento farmacológico , Adulto , Idoso , Antirreumáticos/economia , Análise Custo-Benefício , Método Duplo-Cego , Fadiga/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Anos de Vida Ajustados por Qualidade de Vida , Rituximab/economia , Síndrome de Sjogren/complicações , Resultado do Tratamento , Reino Unido , Escala Visual Analógica , Xerostomia/etiologia
5.
Ann Rheum Dis ; 76(7): 1207-1218, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28188239

RESUMO

OBJECTIVES: The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches. METHODS: This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or 'no immunosuppressant'. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival. RESULTS: Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: -4.0 (-5.2 to -2.7) units for methotrexate, -4.1 (-5.3 to -2.9) for MMF, -3.3 (-4.9 to -1.7) for cyclophosphamide and -2.2 (-4.0 to -0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months. CONCLUSIONS: These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed. TRIAL REGISTRATION NUMBER: NCT02339441.


Assuntos
Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Metotrexato/uso terapêutico , Ácido Micofenólico/uso terapêutico , Esclerodermia Difusa/tratamento farmacológico , Adulto , Anticorpos Antinucleares/imunologia , Autoanticorpos/imunologia , Estudos de Coortes , Intervenção Médica Precoce , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/imunologia , Estudos Prospectivos , RNA Polimerase III/imunologia , Esclerodermia Difusa/imunologia , Índice de Gravidade de Doença , Taxa de Sobrevida , Resultado do Tratamento
6.
J Am Heart Assoc ; 5(2)2016 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-26896473

RESUMO

BACKGROUND: Rheumatoid arthritis is a systemic inflammatory condition associated with increased cardiovascular risk that may be due to underlying endothelial dysfunction and subsequent aortic stiffening. We hypothesized that supplementation with tetrahydrobiopterin (BH4) would recouple endothelial nitric oxide synthase and thus improve endothelial function and consequently reduce aortic stiffness. METHODS AND RESULTS: We conducted 2 randomized, double-blinded, placebo-controlled crossover studies examining 2 separate regimens: an acute regimen, with a single dose of BH4 400 mg versus placebo (n=18), and a short-term regimen, composed of a 1-week treatment with BH4 400 mg once daily versus placebo (n=15). Flow-mediated dilatation and aortic pulse wave velocity were studied 4 times, before and after each treatment phase. Acute BH4 supplementation led to an improvement of flow-mediated dilatation, whereas placebo had no effect (mean±SD of effect difference 2.56±4.79%; P=0.03). Similarly, 1-week treatment with BH4 improved endothelial function, but there was no change with placebo (mean±SD of effect difference 3.50±5.05%; P=0.02). There was no change in aortic pulse wave velocity following acute or short-term BH4 supplementation or placebo (mean±SD of effect difference: acute 0.09±0.67 m/s, P=0.6; short-term 0.03±1.46 m/s, P=0.9). CONCLUSION: Both acute and short-term supplementation with oral BH4 improved endothelial function but not aortic stiffness. This result suggests that BH4 supplementation may be beneficial for patients with rheumatoid arthritis by improving endothelial dysfunction and potentially reducing risk of cardiovascular disease. There appears to be no causal relationship between endothelial function and aortic stiffness, suggesting that they occur in parallel, although they may share common risk factors such as inflammation.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Biopterina/análogos & derivados , Fármacos Cardiovasculares/administração & dosagem , Suplementos Nutricionais , Endotélio Vascular/efeitos dos fármacos , Doenças Vasculares/prevenção & controle , Rigidez Vascular/efeitos dos fármacos , Administração Oral , Adulto , Idoso , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/fisiopatologia , Biomarcadores/sangue , Biopterina/administração & dosagem , Biopterina/efeitos adversos , Fármacos Cardiovasculares/efeitos adversos , Estudos Cross-Over , Suplementos Nutricionais/efeitos adversos , Método Duplo-Cego , Esquema de Medicação , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Inglaterra , Feminino , Humanos , Mediadores da Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo III/metabolismo , Projetos Piloto , Análise de Onda de Pulso , Fatores de Tempo , Resultado do Tratamento , Doenças Vasculares/diagnóstico , Doenças Vasculares/fisiopatologia , Vasodilatação/efeitos dos fármacos , Adulto Jovem
8.
Circulation ; 126(21): 2473-80, 2012 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-23095282

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is a systemic inflammatory condition associated with increased cardiovascular risk. This is not fully explained by traditional risk factors, but direct vascular inflammation and aortic stiffening may play a role. We hypothesized that patients with RA exhibit aortic inflammation, which can be reversed with anti-tumor necrosis factor-α therapy and correlates with aortic stiffness reduction. METHODS AND RESULTS: Aortic inflammation was quantified in 17 patients with RA, before and after 8 weeks of anti-tumor necrosis factor-α therapy by using (18)F-fluorodeoxyglucose positron emission tomography with computed tomography coregistration. Concomitantly, 34 patients with stable cardiovascular disease were imaged as positive controls at baseline. Aortic fluorodeoxyglucose target-to-background ratios (TBRs) and aortic pulse wave velocity were assessed. RA patients had higher baseline aortic TBRs in comparison with patients who have cardiovascular disease (2.02±0.22 versus 1.74±0.22, P=0.0001). Following therapy, aortic TBR fell to 1.90±0.29, P=0.03, and the proportion of inflamed aortic slices (defined as TBR >2.0) decreased from 50±33% to 33±27%, P=0.03. Also, TBR in the most diseased segment of the aorta fell from 2.51±0.33 to 2.05±0.29, P<0.0001. Treatment also reduced aortic pulse wave velocity significantly (from 9.09±1.77 to 8.63±1.42 m/s, P=0.04), which correlated with the reduction of aortic TBR (R=0.60, P=0.01). CONCLUSIONS: This study demonstrates that RA patients have increased aortic (18)F-fluorodeoxyglucose uptake in comparison with patients who have stable cardiovascular disease. Anti-tumor necrosis factor-α therapy reduces aortic inflammation in patients with RA, and this effect correlates with the decrease in aortic stiffness. These results suggest that RA patients exhibit a subclinical vasculitis, which provides a mechanism for the increased cardiovascular disease risk seen in RA.


Assuntos
Aorta Torácica/patologia , Aorta/patologia , Artrite Reumatoide/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Rigidez Vascular/fisiologia , Vasculite/tratamento farmacológico , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Aorta/efeitos dos fármacos , Aorta Torácica/efeitos dos fármacos , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/patologia , Etanercepte , Feminino , Humanos , Imunoglobulina G/farmacologia , Imunoglobulina G/uso terapêutico , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Receptores do Fator de Necrose Tumoral/uso terapêutico , Tomografia Computadorizada por Raios X/métodos , Vasculite/epidemiologia , Vasculite/patologia
9.
Practitioner ; 256(1747): 21-6, 3, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22720456

RESUMO

Chronic inflammatory rheumatological conditions are associated with an increased burden of cardiovascular disease (CVD). In both rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) most excess mortality is cardiovascular. Increased CVD risk is also associated with psoriatic arthritis, ankylosing spondylitis, antiphospholipid syndrome and systemic sclerosis. Several studies report that CVD mortality increases early in disease in RA, with increased risk of MI within one year and increased risk of hospital admission for CVD within seven years of diagnosis. A linear association has been demonstrated between subclinical carotid atherosclerosis and raised inflammatory markers. SLE is associated with 2-10 times the risk of a CVD event compared with the general population. CVD is now a leading cause of morbidity and mortality in SLE. Antiphospholipid antibodies are associated with accelerated atherosclerosis, as well as thromboses. Atherogenesis in the context of autoimmune disease results from a complex interplay between traditional risk factors, disease-specific factors and drug-related adverse effects. Chronic inflammation itself modifies the lipid profile.


Assuntos
Doenças Cardiovasculares/etiologia , Doenças do Tecido Conjuntivo/complicações , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/prevenção & controle , Doenças do Tecido Conjuntivo/patologia , Doenças do Tecido Conjuntivo/terapia , Humanos , Fatores de Risco
10.
Curr Pharm Biotechnol ; 13(10): 2009-21, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22208658

RESUMO

T cells are implicated in both local and systemic pathophysiology of primary Sjögren's syndrome (PSS). Lymphocytic infiltrates in exocrine glands are dominated by CD4+ T cells, some contributing to ectopic lymphoid tissue, others, unusually, exhibiting cytotoxic potential. Cytokine secretion patterns are complex, with Th1 and Th17 components implicated in pathology. Circulating T cells exhibit phenotypes consistent with hyperactivation, cytokine imbalance, and homeostatic alterations; CD4 lymphopenia is recognized as a risk factor for developing lymphoma. Evidence of oligoclonal expansion is found locally and systemically. Functional alterations (e.g. cytokine secretion profile, migratory potential, target cell interactions) are less clearly defined. Attempts at T cell-targeted therapy of PSS have been limited, although therapy targeted at other arms of the immune response may also affect T cells. A better understanding of T-cell dysregulation in PSS is required in order to understand its contribution to disease, aid prognosis, and improve therapeutic interventions aimed at this aspect of the disease.


Assuntos
Ativação Linfocitária/imunologia , Síndrome de Sjogren/imunologia , Linfócitos T/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Autoanticorpos/imunologia , Quimiotaxia de Leucócito/imunologia , Glândulas Exócrinas/efeitos dos fármacos , Glândulas Exócrinas/imunologia , Glândulas Exócrinas/patologia , Humanos , Imunidade Inata/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Terapia de Alvo Molecular , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
12.
Int J Cardiol ; 129(3): 399-405, 2008 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-18571252

RESUMO

BACKGROUND: Recent in vitro studies suggest that inducible nitric oxide synthase (iNOS) activity mediates endothelial dysfunction. Rheumatoid arthritis (RA) is a chronic inflammatory condition and is associated with endothelial dysfunction and increased risk of cardiovascular disease. The aim of the study was to establish the contribution of iNOS to endothelial function. METHODS: Forearm blood flow (FBF) was measured during intra-arterial infusions of acetylcholine (ACh), sodium nitroprusside (SNP), N(G)-monomethyl-l-arginine (l-NMMA) and aminoguanidine (AG) in 12 RA patients and 13 healthy control subjects. Levels of C-reactive protein (CRP) and myeloperoxidase (MPO) were assessed. FBF data are presented as mean percentage changes in the ratio (infused/control arm) of FBF + or - SEM. RESULTS: FBF response to ACh was reduced in patients with RA compared to controls (179 + or - 29 v. 384 + or - 72%, respectively; P=0.01), but SNP response was not (P=0.5). FBF response to AG differed between patients and controls (-15 + or - 2% v. 13 + or - 4%, respectively; P<0.001), whereas the response to l-NMMA did not (P=0.4). In a multiple regression model log CRP, AG response and LDL were found to be independent predictors of endothelial function (R(2)=0.617, P<0.001). CONCLUSION: RA patients have endothelial dysfunction and increased iNOS activity in comparison to controls. Furthermore, CRP and iNOS activity were independently associated with endothelial function. Our data demonstrates that inflammation is a key mediator in a process of endothelial dysfunction possibly via activation of iNOS and increased production of MPO.


Assuntos
Artrite Reumatoide/enzimologia , Artrite Reumatoide/fisiopatologia , Endotélio Vascular/enzimologia , Endotélio Vascular/fisiopatologia , Óxido Nítrico Sintase Tipo II/metabolismo , Ativação Enzimática/fisiologia , Feminino , Antebraço/irrigação sanguínea , Humanos , Mediadores da Inflamação/metabolismo , Mediadores da Inflamação/fisiologia , Masculino , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Fluxo Sanguíneo Regional/fisiologia , ômega-N-Metilarginina/farmacologia
13.
J Am Coll Cardiol ; 50(9): 852-8, 2007 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-17719471

RESUMO

OBJECTIVES: The aim of this study was to investigate the effect of simvastatin and ezetimibe on inflammation, disease activity, endothelial dysfunction, and arterial stiffness in a cohort of rheumatoid arthritis (RA) patients. BACKGROUND: Rheumatoid arthritis is a chronic inflammatory condition associated with increased cardiovascular risk. Statins reduce inflammation and disease activity in RA patients, but whether this is due to pleiotropism or cholesterol lowering per se is unclear. METHODS: Twenty patients received 20 mg simvastatin or 10 mg ezetimibe each for 6 weeks in a randomized double-blind crossover study. Disease activity, blood pressure, aortic pulse wave velocity (PWV), brachial artery flow-mediated dilation (FMD), and serum inflammatory markers were measured before and after each treatment. RESULTS: Both ezetimibe and simvastatin significantly reduced total cholesterol (-0.62 +/- 0.55 mmol/l and -1.28 +/- 0.49 mmol/l, respectively; p < 0.001), low-density lipoprotein cholesterol (-0.55 +/- 0.55 mmol/l and -1.28 +/- 0.49 mmol/l; p < 0.0001), and C-reactive protein (-5.35 +/- 9.25 mg/l and -5.05 +/- 6.30 mg/l; p < 0.001). Concomitantly, Disease Activity Score (-0.55 +/- 1.01 and -0.67 +/- 0.91; p = 0.002), aortic PWV (-0.69 +/- 1.15 m/s and -0.71 +/- 0.71 m/s; p = 0.001), and FMD (1.37 +/- 1.17% and 2.51 +/- 2.13%; p = 0.001) were significantly improved by both drugs. CONCLUSIONS: This study demonstrates that both ezetimibe and simvastatin reduce disease activity and inflammatory markers to a similar extent in patients with RA. Therapy is also associated with a concomitant reduction in aortic PWV and improvement in endothelial function. This suggests that cholesterol lowering per se has anti-inflammatory effects and improves vascular function in RA.


Assuntos
Anticolesterolemiantes/farmacologia , Aorta/fisiopatologia , Artrite Reumatoide/sangue , Artrite Reumatoide/fisiopatologia , Azetidinas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Sinvastatina/farmacologia , Idoso , Anticolesterolemiantes/uso terapêutico , Azetidinas/uso terapêutico , Velocidade do Fluxo Sanguíneo , Proteína C-Reativa/análise , Colesterol/sangue , Estudos Cross-Over , Método Duplo-Cego , Elasticidade , Ezetimiba , Feminino , Humanos , Inflamação/tratamento farmacológico , Lipoproteínas LDL/sangue , Masculino , Pessoa de Meia-Idade , Sinvastatina/uso terapêutico , Estresse Mecânico
16.
Circulation ; 114(11): 1185-92, 2006 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-16952987

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is associated with increased cardiovascular risk, which is not explained by traditional cardiovascular risk factors but may be due in part to increased aortic stiffness, an independent predictor of cardiovascular mortality. In the present study, our aim was to establish whether aortic stiffness is increased in RA and to investigate the relationship between inflammation and aortic stiffness. In addition, we tested the hypothesis that aortic stiffness could be reduced with anti-tumor necrosis factor-alpha (TNF-alpha) therapy. METHODS AND RESULTS: Aortic pulse-wave velocity (PWV), augmentation index, and blood pressure were measured in 77 patients with RA and in 142 healthy individuals. Both acute and chronic inflammatory measures and disease activity were determined. The effect of anti-TNF-alpha therapy on PWV and endothelial function was measured in 9 RA patients at 0, 4, and 12 weeks. Median (interquartile range) aortic PWV was significantly higher in subjects with RA than in control subjects (8.35 [7.14 to 10.24] versus 7.52 [6.56 to 9.18] m/s, respectively; P = 0.005). In multiple regression analyses, aortic PWV correlated independently with age, mean arterial pressure, and log-transformed C-reactive protein (R2 = 0.701; P < 0.0001). Aortic PWV was reduced significantly by anti-TNF-alpha therapy (8.82+/-2.04 versus 7.94+/-1.86 versus 7.68+/-1.56 m/s at weeks 0, 4, and 12, respectively; P < 0.001); concomitantly, endothelial function improved. CONCLUSIONS: RA is associated with increased aortic stiffness, which correlates with current but not historical measures of inflammation, suggesting that increased aortic stiffness may be reversible. Indeed, anti-TNF-alpha therapy reduced aortic stiffness to a level comparable to that of healthy individuals. Therefore, effective control of inflammation may be of benefit in reducing cardiovascular risk in patients with RA.


Assuntos
Aorta/fisiopatologia , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Aterosclerose/fisiopatologia , Proteínas de Neoplasias/uso terapêutico , Receptores Tipo II do Fator de Necrose Tumoral/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antirreumáticos/uso terapêutico , Aorta/efeitos dos fármacos , Artrite Reumatoide/fisiopatologia , Aterosclerose/etiologia , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Pressão Sanguínea , Suscetibilidade a Doenças/fisiopatologia , Elasticidade , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Etanercepte , Feminino , Humanos , Imunoglobulina G/uso terapêutico , Inflamação/complicações , Inflamação/fisiopatologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/farmacologia , Receptores do Fator de Necrose Tumoral/uso terapêutico , Análise de Regressão , Fatores de Risco , Receptores Chamariz do Fator de Necrose Tumoral
18.
Eur J Immunol ; 35(10): 2896-908, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16180249

RESUMO

Despite substantial advances in our understanding of CD4+ CD25+ regulatory T cells, a possible equivalent regulatory subset within the CD8+ T cell population has received less attention. We now describe novel human CD8+/TCR alphabeta+ T cells that have a regulatory phenotype and function. We expanded and cloned these cells using autologous LPS-activated dendritic cells. The clones were not cytolytic, but responded in an autoreactive HLA class I-restricted fashion, by proliferation and production of IL-4, IL-5, IL-13 and TGFbeta1, but not IFN-gamma. They constitutively expressed CD69 and CD25 as well as molecules associated with CD4+ CD25+ regulatory T cells, including cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and Foxp3. They suppressed IFN-gamma production and proliferation by CD4+ T cells in vitro in a cell contact-dependent manner, which could be blocked using a CTLA-4-specific mAb. They were more readily isolated from patients with ankylosing spondylitis and may therefore be up-regulated in response to inflammation. We suggest that they are the CD8+ counterparts of CD4+ CD25+ regulatory T cells. They resemble recently described CD8+ regulatory cells in the rat that were able to abrogate graft-versus-host disease. Likewise, human HLA-restricted CD8+ regulatory T cells that can be cloned and expanded in vitro may have therapeutic applications.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Antígenos CD , Antígenos de Diferenciação/imunologia , Western Blotting , Antígeno CTLA-4 , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Fatores de Transcrição Forkhead/imunologia , Humanos , Fenótipo , Receptores de Interleucina-2/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
20.
Arthritis Rheum ; 48(8): 2375-85, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12905493

RESUMO

OBJECTIVE: To explore the cytokine responses associated with T cell epitopes from human cartilage glycoprotein 39 (HC gp-39) and the potential for modifying cytokine secretion using altered peptide ligands (APLs). METHODS: Draining lymph node cells were harvested from HLA-DR*0401 transgenic mice that had been immunized with HC gp-39. Cytokine responses to 5 previously identified HLA-DR*0401-restricted HC gp-39 T cell epitopes were studied in vitro. The anchor and T cell receptor (TCR) contact residues of peptide 322-337 were identified, and this information was used to design alanine-substituted APLs. T cells were primed in vivo with wild-type peptide 322-337, restimulated with wild-type peptide or APLs, and the cytokine profiles were compared. RESULTS: Restimulation with individual peptides elicited distinct cytokine profiles. HC gp-39 (peptide 322-337) elicited a dominant interferon-gamma (IFNgamma) response. Residues within the core (positions P1-P9) 322-337 peptide sequence were critical for T cell recognition. Surprisingly, the N-terminal flanking region was also important for recognition by 6 of 10 specific T cell hybridomas. Substitutions of charged TCR contact residues in the 322-337 core epitope (E332A and K335A) were associated with a significant reduction in the IFNgamma and interleukin-10 (IL-10) stimulation indices. Restimulation with peptides W325A and V326A was also associated with a trend toward reduced IFNgamma and IL-10 secretion. In contrast, restimulation with peptide D330N elicited cytokine profiles more comparable with those resulting from restimulation with wild-type peptide. CONCLUSION: This study indicates that APLs of a proinflammatory HC gp-39 T cell epitope may be used to alter the cytokine response from a memory T cell population.


Assuntos
Autoantígenos/imunologia , Epitopos de Linfócito T/imunologia , Glicoproteínas/imunologia , Interferon gama/biossíntese , Interleucina-10/biossíntese , Membrana Sinovial/imunologia , Adipocinas , Animais , Células Cultivadas , Proteína 1 Semelhante à Quitinase-3 , Epitopos de Linfócito T/metabolismo , Glicoproteínas/farmacologia , Antígenos HLA-DR/genética , Antígenos HLA-DR/imunologia , Humanos , Imunização , Memória Imunológica/imunologia , Técnicas In Vitro , Interferon gama/metabolismo , Interleucina-10/metabolismo , Lectinas , Ligantes , Linfonodos/citologia , Linfonodos/imunologia , Camundongos , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/farmacologia , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
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