RESUMO
OBJECTIVES: To evaluate the efficacy and safety of certolizumab pegol (CZP) after 24 weeks in RAPID-PsA (NCT01087788), an ongoing Phase 3 trial in patients with psoriatic arthritis (PsA). METHODS: Patients were randomised 1:1:1 to placebo, 200 mg CZP every 2 weeks (Q2W) or 400 mg CZP every 4 weeks (Q4W). Patients could have had exposure to one previous tumour necrosis factor (TNF) inhibitor therapy. Primary endpoints were American College of Rheumatology 20% (ACR20) response at week 12 and modified Total Sharp Score change from baseline at week 24. Secondary endpoints included; Psoriatic Arthritis Response Criteria (PsARC) score, Health Assessment Questionnaire Disability Index (HAQ-DI), Psoriasis Area and Severity Index, Leeds Enthesitis Index, Leeds Dactylitis Index, and Modified Nail Psoriasis Severity Index. RESULTS: Of 409 patients randomised, 368 completed 24 weeks of treatment. ACR20 response was significantly greater in CZP 200 mg Q2W and 400 mg Q4W-treated patients than placebo (58.0% and 51.9% vs 24.3% (p<0.001)) at week 12, with improvements observed by week 1. There was a statistically significant improvement in physical function from baseline, measured by HAQ-DI in CZP patients compared with placebo (-0.50 vs -0.19, p<0.001) and more patients treated with CZP 200 mg Q2W and CZP 400 mg achieved an improvement in PsARC at week 24 than placebo (78.3% and 77.0% vs 33.1% (p<0.001)). Sustained improvements were observed in psoriatic skin involvement, enthesitis, dactylitis and nail disease. Higher ACR20 response with CZP was independent of prior TNF inhibitor exposure. No new safety signals were observed. CONCLUSIONS: Rapid improvements in the signs and symptoms of PsA, including joints, skin, enthesitis, dactylitis and nail disease were observed across both CZP dosing regimens.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Artrite Psoriásica/tratamento farmacológico , Fragmentos Fab das Imunoglobulinas/administração & dosagem , Imunossupressores/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Artrite Psoriásica/diagnóstico , Certolizumab Pegol , Método Duplo-Cego , Feminino , Humanos , Fragmentos Fab das Imunoglobulinas/efeitos adversos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Placebos , Polietilenoglicóis/efeitos adversos , Resultado do TratamentoRESUMO
OBJECTIVES: To report the effect of different imputation methodologies on the assessment of radiographic progression in clinical trials. METHODS: The 216-week RAPID-psoriatic arthritis (PsA) (NCT01087788) trial of certolizumab pegol (CZP) in patients with active PsA was double-blind and placebo-controlled until week 24. A primary end point was change from baseline in modified Total Sharp Score(s) (mTSS). Prespecified imputation methodology in patients with fewer than two analysable mTSS used minimum observed baseline score for missing baseline values and maximum observed week 24 score for missing week 24 values. Post hoc analyses used alternative methods of imputation in patients with fewer than two analysable mTSS. mTSS non-progressors were defined as patients with ≤0 (predefined) or ≤0.5 (post hoc) change in mTSS from baseline to week 24. Baseline mTSS and C-reactive protein levels as predictors of radiographic progression were investigated. RESULTS: 409 patients were randomised. Baseline demographics were similar between groups. Prespecified imputation analysis inappropriately overestimated radiographic progression (least squares mean placebo, 28.9; CZP, 18.3; p≥0.05). Multiple post hoc analyses demonstrated that CZP inhibited radiographic progression compared with placebo, particularly in patients with high baseline mTSS and C-reactive protein levels. mTSS non-progression rate was higher in CZP than placebo groups in all analyses. CONCLUSIONS: Inappropriate prespecified imputation methodology resulted in an unrealistic assessment of progression in all arms. Methodologies for imputing missing radiographic data can greatly affect assessment and reporting of mTSS progression.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Artrite Psoriásica/diagnóstico por imagem , Artrite Psoriásica/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Fragmentos Fab das Imunoglobulinas/administração & dosagem , Imunossupressores/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Certolizumab Pegol , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Fragmentos Fab das Imunoglobulinas/efeitos adversos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Placebos , Polietilenoglicóis/efeitos adversos , Valor Preditivo dos Testes , Radiografia , Resultado do TratamentoRESUMO
The objective of this study was to investigate patients' perceptions of the acceptability of two devices delivering etanercept for rheumatoid arthritis (RA) treatment and to explore whether specific patients' attributes are associated with device preferences. Two similar multicenter, open-label, randomised, parallel-design studies were conducted in a total of 13 European countries. A total of 640 adult patients with RA were randomised to receive etanercept 50 mg once-weekly subcutaneously for 12 weeks in either a pre-filled syringe (PFS) or a pre-filled pen (PFP). Patient satisfaction at week 12 was measured on a 0- to 10-point Likert scale (primary endpoint). The study was powered to demonstrate non-inferiority of a PFP over PFS for the primary endpoint. At week 12, mean patient satisfaction was 8.3 (± 2.4) points in the pen group and 7.2 (± 2.6) points in the syringe group. Non-inferiority and even superiority of the pen over the syringe was demonstrated. In conclusion, this study showed higher patient satisfaction in the group of patients injecting etanercept with a PFP compared with the group of patients using a PFS.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologia , Imunoglobulina G/administração & dosagem , Satisfação do Paciente/estatística & dados numéricos , Receptores do Fator de Necrose Tumoral/administração & dosagem , Autoadministração/instrumentação , Autoadministração/estatística & dados numéricos , Seringas/estatística & dados numéricos , Antirreumáticos/administração & dosagem , Artrite Reumatoide/diagnóstico , Etanercepte , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Prevalência , Seringas/classificação , Resultado do TratamentoRESUMO
BACKGROUND: There is limited information regarding the acceptability of injection devices for biological agents. OBJECTIVES: The primary objective of the study was to investigate patients' perceptions on the acceptability of two devices delivering etanercept. The secondary objectives of the study were to explore whether patients' attributes are associated with preferences. METHODS: This was a multicentre, open-label, randomized, parallel-design study. Adult patients with psoriasis were randomized to receive etanercept 50 mg twice-weekly subcutaneously for 12 weeks, either as a pre-filled syringe or as a pre-filled pen. The primary outcome was the patient satisfaction at week 12 with the injection device, as measured on a 0-10-point Likert scale. The study was powered to demonstrate non-inferiority of a pen over a syringe for the primary endpoint. RESULTS: A total of 421 patients were randomized. Mean patient satisfaction at week 12 was 8.9 (±1.9) points in the pen group and 7.6 (±2.6) points in the syringe group. There was a statistically significant advantage for the pen compared with the syringe. Multiple correspondence analysis showed that very satisfied patients were the oldest and had had psoriasis for a longer duration, while less satisfied patients were the most anxious and depressed. PASI 75 response was achieved by 61% of patients in the pen group and 57% in the syringe group at week 12. CONCLUSIONS: This study showed higher patient satisfaction when injecting etanercept with a pen compared with a syringe. Factors associated with lower satisfaction are younger age, anxiety and depression.
Assuntos
Imunoglobulina G/uso terapêutico , Imunossupressores/uso terapêutico , Psoríase/tratamento farmacológico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Adulto , Etanercepte , Feminino , Humanos , Imunoglobulina G/administração & dosagem , Imunoglobulina G/efeitos adversos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Receptores do Fator de Necrose Tumoral/administração & dosagem , Índice de Gravidade de DoençaRESUMO
BACKGROUND: The ABCA1 gene encodes for a member of subfamily A of the ATP-binding cassette transporters that plays an important role in cellular export of cholesterol and phospholipids; therefore, quantification of the ABCA1 mRNA is critical in many studies related to its expression and regulation by metabolic factors, nutritional status, and new antiatherogenic drug candidates. We developed a rapid, sensitive, specific, and reproducible real-time reverse transcription-PCR (RT-PCR) method for detection and quantification of ABCA1 transcripts in total RNA isolated from cultured human cells and tissues. METHODS: To quantify ABCA1 mRNA, we generated a calibration curve from serial dilutions of in vitro-transcribed RNA corresponding to an amplified ABCA1 cDNA 205-bp fragment (homologous calibrator). Two pairs of fluorescent hybridization probes were used to detect the ABCA1 and porphobilinogen deaminase (PBGD) mRNAs; the latter served as an internal control. PCR was performed as real-time amplification of ABCA1 mRNA in 100 ng of total RNA isolated from various human tissues, and cultured cells were calculated from the calibration curve. In addition, normalized values of target (ABCA1/PBGD ratio) were calculated. RESULTS: Using this method, we quantified ABCA1 transcripts in various human tissue samples as well as in monocytes, THP-1 cells, fibroblasts, and adipocytes. We demonstrated ABCA1 mRNA up-regulation during human adipocyte and monocyte differentiation. In addition, we examined the effect of cholesterol loading and deloading on ABCA1 expression in monocytes, THP-1 cells, and fibroblasts. CONCLUSIONS: Our RT-PCR assay allows the specific and highly reproducible detection and quantification of minute amounts of human ABCA1 mRNA. This new method is more accurate, more informative, and less laborious than the classic RT-PCR methods and Northern blot; it therefore could simplify all studies on ABCA1 mRNA expression.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , RNA Mensageiro/análise , Transportador 1 de Cassete de Ligação de ATP , Adipócitos/química , Northern Blotting , Células Cultivadas , Fibroblastos/química , Humanos , Monócitos/química , Especificidade de Órgãos , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e EspecificidadeRESUMO
Familial high-density lipoprotein (HDL)-deficiency syndromes are caused by mutations of the ABCA1 gene, coding for the ATP-binding cassette transporter 1. We have developed a homogeneous assay based on 52 primer sets to amplify all 50 ABCA1 exons and approximately 1 kb of its promoter. The assay allows for convenient amplification of the gene from genomic DNA and easy mutational analysis through automatic sequencing. It obviates the need to use mRNA preparations, which were difficult to handle and posed a risk to miss splice junction or promoter mutations. The application of the test to the molecular analysis of a new patient with familial HDL-deficiency (Tangier disease) led to a discovery of two novel ABCA1 mutations: C2665del and C4457T.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Hipolipoproteinemias/genética , Lipoproteínas HDL/sangue , Mutação , Transportador 1 de Cassete de Ligação de ATP , Adulto , Primers do DNA , Humanos , Hipolipoproteinemias/sangue , Masculino , Linhagem , Reação em Cadeia da Polimerase/métodos , SíndromeRESUMO
HDL cholesterol (HDL-C) deficiency is the most common lipid abnormality observed in patients with premature coronary heart disease (CHD). Recently, our laboratory and others demonstrated that mutations in the ATP-binding cassette transporter 1 (ABCA1) gene are responsible for Tangier disease, a rare genetic disorder characterized by severely diminished plasma HDL-C concentrations and a predisposition for CHD. To address the question of whether common variants within the coding sequence of ABCA1 may affect plasma HDL-C levels and CHD risk in the general population, we determined the frequencies of three common ABCA1 variants (G596A, A2589G and G3456C) in men participating in the Veterans Affairs Cooperative HDL Cholesterol Intervention Trial (VA-HIT), a study designed to examine the benefits of HDL raising in men having low HDL-C (< or =40 mg/dl) and established CHD, as well as in CHD-free men from the Framingham Offspring Study (FOS). Allele frequencies (%) in VA-HIT were 31, 16, and 4 for the G596A, A2589G, and G3456C variants, respectively, versus 27, 12, and 2 in FOS (P<0.03). None of the variants were significantly associated with plasma HDL-C concentrations in either population; however, in VA-HIT, the G3456C variant was associated with a significantly increased risk for CHD end points, suggesting a role for this variant in the premature CHD observed in this population.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , HDL-Colesterol/sangue , Doença das Coronárias/sangue , Doença das Coronárias/genética , Variação Genética , Transportador 1 de Cassete de Ligação de ATP , Idoso , Alelos , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Leptin and its structural gene, Ob, are exclusively expressed in adipose tissue. Leptin is secreted into the blood and is responsible for fat mass regulation via leptin receptors in the hypothalamus. This has been considered the major role of leptin, but leptin receptor isoforms are expressed not only in the brain but also in most other tissues in humans and rodents: heart, placenta, lung, liver, muscle, kidney, pancreas, spleen, thymus, prostate, testes, ovary, small intestine, and colon. This implicates leptin regulation in other systems apart from fat mass regulation, and leptin action has been demonstrated in human fetal development and reproductive development, liver metabolism, hematopoiesis, and insulin secretion. Four splice variants of the leptin receptor have been identified in humans: the long isoform huOb-R and the shorter isoforms B219.1 to B219.3. It is known that the long isoform has full intracellular signaling capacity, and is responsible for anorectic action in the hypothalamus. The roles of the other isoforms are yet to be elucidated. Here, we report the identification by reverse transcriptase-polymerase chain reaction (RT-PCR) of three leptin receptor isoforms coexpressed in human visceral adipose tissue: the long isoform huOb-R and the short isoforms huB219.1 and huB219.3. The possible roles of these isoforms are discussed.
Assuntos
Tecido Adiposo/metabolismo , Proteínas de Transporte/biossíntese , Proteínas/metabolismo , Receptores de Superfície Celular , Adulto , Idoso , Proteínas de Transporte/genética , Feminino , Expressão Gênica , Humanos , Isomerismo , Leptina , Leucócitos/metabolismo , Pessoa de Meia-Idade , Obesidade/metabolismo , Reação em Cadeia da Polimerase , Proteínas/genética , Receptores para LeptinaRESUMO
Glucose uptake into brown adipose tissue has been shown to be enhanced directly by noradrenaline (norepinephrine) released from sympathetic nerves. In this study we characterized the glucose transport system in cultured brown adipocytes, which responds to noradrenaline as well as insulin, and analysed the mechanism underlying the noradrenaline-induced increase in glucose transport. Insulin increased 2-deoxyglucose (dGlc) uptake progressively at concentrations from 10(-11) to 10(-6) M, with maximal stimulation at 10(-7) M. Noradrenaline concentrations ranging from 10(-8) to 10(-6) M also enhanced dGlc uptake, even in the absence of insulin. The effects of noradrenaline and insulin on dGlc uptake were additive. The stimulatory effect of noradrenaline was mimicked by the beta3-adrenergic agonist, BRL37344, at concentrations two orders lower than noradrenaline. Dibutyryl cyclic AMP also mimicked the stimulatory effect of noradrenaline, and the antagonist of cyclic AMP, cyclic AMP-S Rp-isomer, blocked the enhancement of glucose uptake due to noradrenaline. Furthermore Western blot analysis with an anti-phosphotyrosine antibody revealed that, in contrast with insulin, noradrenaline apparently does not stimulate intracellular phosphorylation of tyrosine, suggesting that the noradrenaline-induced increase in dGlc uptake depends on elevation of the intracellular cyclic AMP level and not on the signal chain common to insulin. When cells were incubated with insulin, the content of the muscle/adipocyte type of glucose transporter (GLUT4) in the plasma membrane increased, with a corresponding decrease in the amount in the microsomal membrane. In contrast, noradrenaline did not affect the subcellular distribution of GLUT4 or that of the HepG2/erythrocyte type of glucose transporter. Although insulin increased Vmax. and decreased the Km value for glucose uptake, the effect of noradrenaline was restricted to a pronounced decrease in Km. These results suggest that the mechanism by which noradrenaline stimulates glucose transport into brown adipocytes is not due to translocation of GLUT but is probably due to an increase in the intrinsic activity of GLUT, which is mediated by a cyclic AMP-dependent pathway.
Assuntos
Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Insulina/fisiologia , Proteínas Musculares , Norepinefrina/fisiologia , Animais , Transporte Biológico , Células Cultivadas , AMP Cíclico/fisiologia , Desoxiglucose/metabolismo , Glucose/metabolismo , Transportador de Glucose Tipo 1 , Transportador de Glucose Tipo 4 , Cinética , Proteínas de Transporte de Monossacarídeos/metabolismo , Fosforilação , Ratos , Frações Subcelulares/metabolismo , Tirosina/metabolismoRESUMO
Glucose uptake into brown adipose tissue is enhanced directly by norepinephrine released from the sympathetic nerves. In the present study, we tried to establish culture conditions for brown adipocytes which are favorable for investigation of this unique glucose transport. Stromal-vascular cells isolated from the interscapular brown adipose tissue of newborn rats differentiated into brown adipocytes expressing the uncoupling protein, when the cells were maintained on collagen-coated dishes. These cells, however, did not show an increase in 2-[3H]deoxyglucose transport in response to insulin or norepinephrine, nor did they exhibit expression of the GLUT4 glucose transporter, whereas GLUT1 was present, as judged on Western blotting. Pre-treatment of confluent cells with dexamethasone induced a response of glucose transport to either insulin or norepinephrine, and the expression of GLUT4, together with notable accumulation of lipid droplets. The induction of GLUT4 expression by dexamethasone was dose-dependent and potentiated by insulin. These results indicate that treatment of cultured brown adipocytes with dexamethasone makes it feasible to analyze the mechanism underlying the enhancement of glucose transport induced by norepinephrine.