RESUMO
BACKGROUND: Pemphigus vulgaris and pemphigus foliaceus are potentially life-threatening autoimmune disorders triggered by IgG autoantibodies against mucosal and epidermal desmogleins. There is an unmet need for fast-acting drugs that enable patients to achieve early sustained remission with reduced corticosteroid reliance. OBJECTIVES: To investigate efgartigimod, an engineered Fc fragment that inhibits the activity of the neonatal Fc receptor, thereby reducing serum IgG levels, for treating pemphigus. METHODS: Thirty-four patients with mild-to-moderate pemphigus vulgaris or foliaceus were enrolled in an open-label phase II adaptive trial. In sequential cohorts, efgartigimod was dosed at 10 or 25 mg kg-1 intravenously with various dosing frequencies, as monotherapy or as add-on therapy to low-dose oral prednisone. Safety endpoints comprised the primary outcome. The study is registered at ClinicalTrials.gov (identifier NCT03334058). RESULTS: Adverse events were mostly mild and were reported by 16 of 19 (84%) patients receiving efgartigimod 10 mg kg-1 and 13 of 15 (87%) patients receiving 25 mg kg-1 , with similar adverse event profiles between dose groups. A major decrease in serum total IgG and anti-desmoglein autoantibodies was observed and correlated with improved Pemphigus Disease Area Index scores. Efgartigimod, as monotherapy or combined with prednisone, demonstrated early disease control in 28 of 31 (90%) patients after a median of 17 days. Optimized, prolonged treatment with efgartigimod in combination with a median dose of prednisone 0·26 mg kg-1 per day (range 0·06-0·48) led to complete clinical remission in 14 of 22 (64%) patients within 2-41 weeks. CONCLUSIONS: Efgartigimod was well tolerated and exhibited an early effect on disease activity and outcome parameters, providing support for further evaluation as a therapy for pemphigus.
Assuntos
Anticorpos Monoclonais Humanizados , Pênfigo , Anticorpos Monoclonais Humanizados/efeitos adversos , Autoanticorpos , Desmogleína 1 , Estudos de Viabilidade , Antígenos de Histocompatibilidade Classe I , Humanos , Imunoglobulina G , Recém-Nascido , Pênfigo/tratamento farmacológico , Prednisona/administração & dosagem , Receptores FcRESUMO
There are several stratification scales of major cardiovascular events rate for patients have gone through acute coronary syndrome (ACS). None of them is perfect one. Arterial hypertension is included into some scales for post ACS patients but the features of it and its impact on coronary artery disease after ACS have never studied before. We studied the reasonability of Pulse Wave Velocity (PWV) measurement for fatal events rate in hypertensive patients have gone through ACS. 326 patients were examined. They were enrolled into the study in stable condition on 10th day after ACS has occurred. As a result of two years observation the increase PWV on carotid-femoral segment associated with the most negative (fatal) events in hypertensive patients have gone through ACS.
Assuntos
Síndrome Coronariana Aguda/etiologia , Artérias Carótidas/fisiopatologia , Doença da Artéria Coronariana/complicações , Vasos Coronários/fisiopatologia , Hipertensão , Síndrome Coronariana Aguda/fisiopatologia , Idoso , Velocidade do Fluxo Sanguíneo , Doença da Artéria Coronariana/fisiopatologia , Progressão da Doença , Feminino , Artéria Femoral/fisiopatologia , Seguimentos , Humanos , Hipertensão/complicações , Hipertensão/diagnóstico , Hipertensão/mortalidade , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Pulso Arterial/métodos , Medição de Risco/métodos , Medição de Risco/normas , Fatores de Risco , Taxa de SobrevidaRESUMO
We studied relation between cystatin C level and risk of unfavorable outcome (unstable angina, fatal and nonfatal myocardial infarction [MI], fatal and nonfatal stroke, and death) in patients stabilized after exacerbation of ischemic heart disease. Patients (n=272) were included on day 10 after onset of acute coronary syndrome. No relationship between studied outcomes and cystatin was found in a group as a whole. In patients with normal of slightly reduced renal function (glomerular filtration rate more or equal 60 ml/min/1.73 m2) unfavorable outcomes were independently associated with history of myocardial infarction and stroke, elevated levels of brain natriuretic peptide and cystatin. In subjects with moderately or severely reduced renal function elevation of cystatin level lost its significance. Risk of development of unfavorable outcomes among these subjects was independently related to history of MI and GFR <60 ml/min/1.73 m2 (OR 2.130, 95% CI 1.010-4,489; =0,047). Our data confirm possibility of use of cystatin C level measured early after ACS in patients with normal or slightly lowered renal function as a parameter characterizing risk of cardiovascular complications and death.
Assuntos
Cistatina C/sangue , Isquemia Miocárdica , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/epidemiologia , Idoso , Biomarcadores , Comorbidade , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/sangue , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/fisiopatologia , Peptídeo Natriurético Encefálico/sangue , Prognóstico , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/fisiopatologia , Reprodutibilidade dos Testes , Fatores de Risco , Fatores de TempoRESUMO
Action of statins is characterized by pronounced variability what is caused by effects of a multitude of factors. Main of these factors appears to be genetic peculiarity of patients. We studied influence of polymorphic marker Trp719Arg of KIF6 gene on lipid and nonlipid effects of atorvastatin and simvastatin. The studied genetic marker is associated with risk of development of ischemic heart disease and myocardial infarction as well as efficacy of therapy with statins according to data of a number of large multicenter studies. We examined 60 men with ischemic heart disease which had manifested in young age when genetic factors were most expressed and had special significance. Efficacy of 40 mg/day simvastatin did not depend on genotypes of polymorphic marker Trp719Arg of KIF6. Therapy with 10 mg/day atorvastatin was more effective in carriers of polymorphic marker Trp719Arg of KIF6 gene by action on dynamics of changes of high sensitivity C-reactive protein and dispersion of high density lipoprotein response. Increase of atorvastatin dose to 80 mg/day abolished influence of genotypes. Thus for the first time we discovered influence of polymorphic marker Trp719Arg of KIF6 gene on individual response to therapy with 10 mg/day of atorvastatin, while and apoA1, structural protein of high density lipoproteins can be considered as a marker of "fast response".
Assuntos
Ácidos Heptanoicos , Cinesinas/genética , Isquemia Miocárdica , Pirróis , Sinvastatina , Idade de Início , Apolipoproteína A-I/metabolismo , Atorvastatina , Proteína C-Reativa/metabolismo , Relação Dose-Resposta a Droga , Ácidos Heptanoicos/administração & dosagem , Ácidos Heptanoicos/farmacocinética , Humanos , Hipolipemiantes/administração & dosagem , Hipolipemiantes/farmacocinética , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/genética , Farmacogenética , Polimorfismo Genético , Pirróis/administração & dosagem , Pirróis/farmacocinética , Sinvastatina/administração & dosagem , Sinvastatina/farmacocinética , Resultado do TratamentoRESUMO
Prognostication of the course of disease in patients with high risk of unfavorable outcome of ischemic heart disease (IHD) is of great importance for creation of individualized strategy of treatment. We have investigated contribution of levels of brain natriuretic peptide (BNP) and genetic factors in the risk of development of complications of atherosclerosis in patients who have had acute coronary syndrome. We started to follow 324 patients on day 10 of stable state after acute coronary syndrome (55.1% with Q-wave myocardial infarction, 18.5% with non-Q myocardial infarction, 25.5% with unstable angina, men BNP level 624.5+/-32.13 mol/ml [70.3 - 4276.6]). Duration of followup was 2 years. Baseline BNP level in patients with unfavorable outcome during followup (fatal and nonfatal myocardial infarction and stroke) was 872.47+/-91.42 compared with 592.45+/-35.97 mol/ml in patients without unfavorable outcome (p=0,001). Multifactorial Cox analysis showed that carriage of T allele of polymorphic marker (--1654) of protein C gene, elevated BNP level, symptomatic atherosclerosis of peripheral arteries, history of MI, and use of thiazide diuretics were independently associated with unfavorable outcomes (p=0.026, <0.0001, <0.0001, =0.001, =0.024, respectively). Thus genetic factors and study of BNP allow to improve prediction of unfavorable outcome after exacerbation of IHD.
Assuntos
Síndrome Coronariana Aguda/sangue , DNA/genética , Peptídeo Natriurético Encefálico/sangue , Polimorfismo Genético , Proteína C/genética , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/genética , Alelos , Angiografia Coronária , Eletrocardiografia , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prognóstico , Proteína C/metabolismo , Fatores de TempoRESUMO
We investigated the association of gene IL6 G(-174)C polymorphism and gene IL10 G(-1082)A polymorphism with coronary artery disease (CAD) in the Russian population. A total of 1145 patients with CAD diagnose on the basis of clinical studies in cardiological hospitals of Moscow, St -Petersburg, Kazan, Chelyabinsk, Perm, Stavropol and Rostov-on-Don. Supervision term was 9.10 +/- 5.03 months (the maximum term 18 months). In case of gene IL10 G(-1082)A polymorphism we determined that patients with CAD diagnose and A alleles gene IL10 had unfavorable outcome more often than patients with homozygous G alleles. Survival time from end point from carrier genotype GA and AA is 11.68 +/- 0.67 months against 12.69 +/- 0.65 months from carrier phenotype GG gene IL10 (chi2 = 4.13, p = 0.042). The group studied do not differ significantly with respect to the distributions of gene IL6 G(-174)C alleles and genotypes. However in case combined group studies of gene IL10 G(-1082)A polymorphism and IL6 G(-174)C polymorphism we determined that patients with CAD diagnose and carrier genotype GG gene IL6 and genotype GA and AA gene IL10 had unfavorable outcome more often (survival time 11.01 +/- 1.24 months) than patients with genotype CC and CG gene IL6 and genotype GG gene IL10 (survival time 13.28 +/- 0.83 months) chi2 = 10.23, p = 0.017. The obtained data allows assuming the important role of the IL6 and IL10 genes which are responsible for functioning of inflammation system, in the accelerated formation of failures at the patients who had a coronary syndrome.
Assuntos
Síndrome Coronariana Aguda/genética , Síndrome Coronariana Aguda/mortalidade , Alelos , Interleucina-10/genética , Interleucina-6/genética , Polimorfismo de Nucleotídeo Único , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/metabolismo , Idoso , Feminino , Genótipo , Humanos , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos TestesRESUMO
We investigated the association of polymorphisms of genes FGB G(-455)A and PROCC(-1654)T with coronary artery disease (CAD) in the Russian population. A total of 1145 patients with CAD diagnose on the basis of clinical studies in cardiological hospitals of Moscow, St. Petersburg, Kazan, Chelyabinsk, Perm, Stavropol and Rostov-on-Don. Supervision term was 1.14 +/- +/- 0.33 years (the maximum term 3.2 years). The group studied do not differ significantly with respect to the distributions of G(-455)A alleles and genotypes. However in case of gene PROC C(-1654)T polymorphism we determined that patients with CAD diagnose and Talleles of PROC gene had unfavorable outcome more often than patients with homozygous C alleles. Survival time from end point from carrier phenotype TT and CTis 2.19 +/- 0.18 r. years against 2.46 +/- 0.16 from carrier phenotype CCgene PROC. The obtained data allows to assume the important role of the genes which are responsible for functioning of system of a hemostasis, in the accelerated formation of failures at the patients who had a coronary syndrome.
Assuntos
Síndrome Coronariana Aguda/genética , Síndrome Coronariana Aguda/mortalidade , Fibrinogênio/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Proteína C/genética , Alelos , Intervalo Livre de Doença , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Federação Russa/epidemiologia , Taxa de SobrevidaRESUMO
For the study of contribution of atrial fibrillation (AF) during acute coronary syndrome (ACS) in long-term prognosis after clinical stabilization we examined 453 patients admitted to Moscow hospitals and followed them for 2.07 +/- 0.48 years. The following events were registered: fatal and nonfatal myocardial infarction (MI), unstable angina (UA), fatal and nonfatal stroke, death of other causes. At ACS onset sinus rhythm was noted in 419 (92.5%), permanent or persistent AF-in 16 (3.5%), attack (paroxysm) of AF - in 18 (4.0%) patients. Mean length of life before end point was 884.9 +/- 23.4, 827.3 +/- 123.3 and 514.0 +/- 111.3 days in patients with sinus rhythm, permanent/persistent AF, and attack of AF during first 10 days of ACS, respectively (p<0.001). Compared with patients in sinus rhythm in patients with attack of AF relative risk (RR) of occurrence of any end point was 1.75 (95% confidence interval [CI] 1.284 to 2.873, p< 0.001), of fatal MI - 1.72 (95% CI 1.026 to 2.873, p=0.040), of UA - 2.116 (95% CI 1.249 to 3.585, p=0.005), of stroke - 2.863 (95% CI 1.300 to 6.301, p=0.009). Multifactorial analysis selected history of MI and attack of AF during first 10 days of ACS as independent predictors of unfavorable outcome. Thus paroxysmal form of AF during hospital stay because of ACS is associated with higher probability of development of unfavorable events in the next 1-2 years.