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1.
Australas J Dermatol ; 65(4): 350-357, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38509804

RESUMO

BACKGROUND: Drug survival, which refers to the time from treatment initiation to discontinuation, provides a surrogate measure of the effectiveness of a biologic in a real-world setting (J Invest Dermatol, 2015, 135, 1). The aim of this study was to determine the drug survival of biologics that are currently available in Australia. We also analysed the treatment efficacy of these biologics and reasons for discontinuation. METHODS: Retrospective data from outpatient Dermatology biologic clinics in Westmead Hospital and Royal Prince Alfred Hospital (Sydney, Australia) from April 2006 to December 2020 were collected. Kaplan-Meier analysis was used to calculate drug survival. RESULTS: A total of 306 patients who underwent 566 treatment courses were analysed. Guselkumab was observed to have the longest drug survival, with cumulative drug survival rates of 94.2% ± 4.0 at 1- and 5-years. This was followed by ixekizumab which had a 1-year survival rate of 87.2% ± 4.5 and 5-year survival rate of 59.4% ± 9.5. Ixekizumab and guselkumab were also noted to have superior treatment efficacy compared with other biologics, with PASI-75 rates of 94.9% and 93.8%, respectively. The most common reasons for treatment discontinuation were a lack of initial efficacy to treatment and a loss of efficacy over time despite an initial response, respectively. CONCLUSION: To our knowledge, this is the first Australian study to report on outcomes of multiple new biologics that are currently in use for the treatment of chronic plaque psoriasis. Overall, this study provides insight into patterns of care from a local experience that may help guide the management of moderate-to-severe psoriasis.


Assuntos
Anticorpos Monoclonais Humanizados , Produtos Biológicos , Psoríase , Humanos , Psoríase/tratamento farmacológico , Psoríase/mortalidade , Estudos Retrospectivos , Masculino , Feminino , Pessoa de Meia-Idade , Austrália , Produtos Biológicos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Adulto , Fármacos Dermatológicos/uso terapêutico , Idoso , Resultado do Tratamento , Índice de Gravidade de Doença , Ustekinumab/uso terapêutico
4.
Am J Pathol ; 183(3): 745-57, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23886890

RESUMO

Friedreich ataxia (FA) is a neurodegenerative and cardiodegenerative disease resulting from marked frataxin deficiency. The condition is characterized by ataxia with fatal cardiomyopathy, but the pathogenic mechanisms are unclear. We investigated the association between gene expression and progressive histopathological and functional changes using the muscle creatine kinase conditional frataxin knockout (KO) mouse; this mouse develops a severe cardiac phenotype that resembles that of FA patients. We examined KO mice from 3 weeks of age, when they are asymptomatic, to 10 weeks of age, when they die of the disease. Positive iron staining was identified in KO mice from 5 weeks of age, with markedly reduced cardiac function from 6 weeks. We identified an early and marked up-regulation of a gene cohort responsible for stress-induced amino acid biosynthesis and observed markedly increased phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α), an activator of the integrated stress response, in KO mice at 3 weeks of age, relative to wild-type mice. Importantly, the eIF2α-mediated integrated stress response has been previously implicated in heart failure via downstream processes such as autophagy and apoptosis. Indeed, expression of a panel of autophagy and apoptosis markers was enhanced in KO mice. Thus, the pathogenesis of cardiomyopathy in FA correlates with the early and persistent eIF2α phosphorylation, which precedes activation of autophagy and apoptosis.


Assuntos
Fator de Iniciação 2 em Eucariotos/metabolismo , Ataxia de Friedreich/genética , Ataxia de Friedreich/patologia , Transdução de Sinais , Estresse Fisiológico , Fator 4 Ativador da Transcrição/metabolismo , Aminoácidos/biossíntese , Animais , Apoptose , Autofagia , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Feminino , Ataxia de Friedreich/diagnóstico por imagem , Ataxia de Friedreich/fisiopatologia , Perfilação da Expressão Gênica , Testes de Função Cardíaca , Humanos , Proteínas de Ligação ao Ferro/metabolismo , Masculino , Camundongos , Camundongos Knockout , Modelos Biológicos , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Fenótipo , Fosforilação , Proteínas Quinases/metabolismo , Transdução de Sinais/genética , Estresse Fisiológico/genética , Ultrassonografia , Frataxina
5.
Biochem J ; 453(3): 321-36, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23849057

RESUMO

FRDA (Friedreich's ataxia) is a debilitating mitochondrial disorder leading to neural and cardiac degeneration, which is caused by a mutation in the frataxin gene that leads to decreased frataxin expression. The most common cause of death in FRDA patients is heart failure, although it is not known how the deficiency in frataxin potentiates the observed cardiomyopathy. The major proposed biochemical mechanisms for disease pathogenesis and the origins of heart failure in FRDA involve metabolic perturbations caused by decreased frataxin expression. Additionally, recent data suggest that low frataxin expression in heart muscle of conditional frataxin knockout mice activates an integrated stress response that contributes to and/or exacerbates cardiac hypertrophy and the loss of cardiomyocytes. The elucidation of these potential mechanisms will lead to a more comprehensive understanding of the pathogenesis of FRDA, and will contribute to the development of better treatments and therapeutics.


Assuntos
Cardiomiopatias/metabolismo , Ataxia de Friedreich/metabolismo , Doenças Mitocondriais/metabolismo , Animais , Apoptose/fisiologia , Cardiomiopatias/fisiopatologia , Ataxia de Friedreich/fisiopatologia , Humanos , Proteínas de Ligação ao Ferro/metabolismo , Doenças Mitocondriais/fisiopatologia , Estresse Oxidativo/fisiologia , Frataxina
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