Cladribina oral para o tratamento da esclerose múltipla remitente-recorrente altamente ativa: análise de impacto orçamentário sob a perspectiva do sistema brasileiro de saúde suplementar / Cladribine tablets for the treatment of highly active recurrent multiple sclerosis: budget impact analysis from the perspective of the Brazilian supplementary health system

Objetivo: Avaliar o impacto orçamentário da inclusão da cladribina oral no tratamento de esclerose múltipla remitente-recorrente em alta atividade da doença (EMRR HDA) no Sistema de Saúde Suplementar (SSS). Métodos: Foi conduzida uma análise de impacto orçamentário, sob a perspectiva do SSS, com horizonte temporal de quatro anos, considerando a abordagem de coorte aberta na qual o número de pacientes elegíveis para tratamento varia em cada ano com a introdução de novos pacientes diagnosticados de EMRR HDA e a retirada de indivíduos prevalentes devido a morte ou progressão secundária. Foram considerados custos médicos diretos, incluindo a aquisição e administração de medicamentos, monitoramento, eventos adversos e surtos. Os comparadores utilizados na análise foram: alentuzumabe, fingolimode, natalizumabe e ocrelizumabe. Os custos foram apresentados em real brasileiro (BRL). Resultados: O custo incremental da inclusão da cladribina oral para o SSS foi estimado em 463.265 BRL, 739.691 BRL, -1.414.963 BRL, -3.719.007 BRL, nos anos 1, 2, 3 e 4, respectivamente. Isso resultou em um custo incremental total de -3.931.015 BRL no período analisado, representando 1,5% da redução orçamentária total no tratamento de EMRR HDA. Conclusão: A inclusão da cladribina oral para o tratamento de pacientes com diagnóstico de EMRR HDA poderia gerar uma economia substancial para o sistema brasileiro de saúde suplementar, atingindo um valor de cerca de 3,9 milhões de BRL em um período de quatro anos

Objective: To evaluate the budget impact of adopting cladribine tablets as a treatment strategy for relapsing remitting multiple sclerosis with high disease activity (RRMS HDA), from the Brazilian private healthcare system perspective. Methods: A budget impact analysis, under private healthcare system perspective, with a 4-years time horizon was conducted, considering the open cohort approach in which the number of patients eligible for treatment varies each year with the introduction of newly diagnosed RRMS HDA patients and the drop out of prevalent individuals due to death or secondary progression. Direct medical costs, including acquisition, drug administration, monitoring, adverse events and relapses were considered. Comparators used in the analysis were: alentuzumab, fingolimod, natalizumab and ocrelizumab. Costs were presented in Brazilian real (BRL). Results: The incremental cost of incorporating cladribine tablets into the private healthcare system was estimated at 463,265BRL, 739,961BRL, -1,414,963 BRL, -3,716,007 BRL, in years 1, 2, 3 and 4, respectively. This resulted in a total incremental cost of -3,931,015 BRL over the period analyzed, representing 1.5% of the total budget reduction in the treatment of RRMS HDA. Conclusion: Incorporation of cladribine tablets for the management of RRMS HDA could generate substantial savings for the private healthcare system, reaching a value of approximately 3.9 million BRL in a 4-years period

Clinical, Histological, and Immunohistochemical Findings in Inclusion Body Myositis.

Sporadic inclusion body myositis (sIBM) is considered the most common acquired myopathy aged over 50 years. The disease is characterized by a particular process of muscle degeneration characterized by abnormal deposit of protein aggregates in association with inflammation. The aim of this study was to present clinical and muscle histopathological findings, including immunostaining for LC3B, p62, α-synuclein, and TDP-43, in 18 patients with sIBM. The disease predominated in males (61%) and European descendants, with onset of clinical manifestations around 59 years old. The most common symptoms were muscle weakness, falls, dysphagia, and weight loss. Hypertension was the main comorbidity. Most of the cases presented with paresis predominantly proximal in lower limbs and distal in upper limbs. Immunosuppressive treatment showed to be not effective. Muscle histological findings included dystrophic changes, endomysial inflammation, increased lysosomal activity, and presence of rimmed vacuoles and of beta-amyloid accumulation, in addition to high frequency of mitochondrial changes. There was increased expression of LC3B, p62, α-synuclein, and TDP-43 in muscle biopsies. The sIBM has characteristic clinical and histological findings, and the use of degeneration and autophagic markers can be useful for the diagnosis.

Rare variants in SQSTM1 and VCP genes and risk of sporadic inclusion body myositis.

Genetic factors have been suggested to be involved in the pathogenesis of sporadic inclusion body myositis (sIBM). Sequestosome 1 (SQSTM1) and valosin-containing protein (VCP) are 2 key genes associated with several neurodegenerative disorders but have yet to be thoroughly investigated in sIBM. A candidate gene analysis was conducted using whole-exome sequencing data from 181 sIBM patients, and whole-transcriptome expression analysis was performed in patients with genetic variants of interest. We identified 6 rare missense variants in the SQSTM1 and VCP in 7 sIBM patients (4.0%). Two variants, the SQSTM1 p.G194R and the VCP p.R159C, were significantly overrepresented in this sIBM cohort compared with controls. Five of these variants had been previously reported in patients with degenerative diseases. The messenger RNA levels of major histocompatibility complex genes were upregulated, this elevation being more pronounced in SQSTM1 patient group. We report for the first time potentially pathogenic SQSTM1 variants and expand the spectrum of VCP variants in sIBM. These data suggest that defects in neurodegenerative pathways may confer genetic susceptibility to sIBM and reinforce the mechanistic overlap in these neurodegenerative disorders.

Estudo clínico, histológico, imunoistoquímico e da função lisossomal na miosite por corpos de inclusão / Clinical, histological, immunohistochemical and lysosomal function study in inclusion body myositis

A miosite por corpos de inclusão (inclusion body myositis - IBM), na sua forma esporádica, é considerada a miopatia adquirida mais comum após os 50 anos de idade. Embora seja incluída no grupo das miopatias inflamatórias, estudos recentes mostram um processo particular de degeneração muscular caracterizado por deposição anormal de agregados de proteínas nas fibras musculares e funcionamento anormal dos principais sistemas de degradação proteica. O objetivo deste estudo foi o de avaliar os aspectos clínicos, histológicos e imunoistoquímicos de pacientes com IBM. Avaliamos 18 casos com diagnóstico de IBM de dois dos principais centros de doenças neuromusculares do Brasil (25 biópsias musculares). Na tentativa de diferenciar os casos de IBM das outras miopatias inflamatórias, determinamos o padrão de expressão tecidual da p-tau (p62), alfa-sinucleína e TDP-43. Também foi avaliada a função lisossomal através da reação da fosfatase ácida (marcação da atividade lisossomal global) e determinação da marcação para LC3B (marcador de autofagia). Foi observado que a IBM predominou no sexo masculino (61% dos casos), da cor branca, com início das manifestações clínicas ao redor dos 59 anos de idade e os sintomas mais frequentes foram fraqueza muscular, instabilidade postural com quedas da própria altura, disfagia e perda ponderal, podendo ainda apresentar dispneia. O diagnóstico demorou em média 7,4 anos após o início dos sintomas e frequentemente esteve associada às seguintes comorbidades: hipertensão arterial sistêmica, diabetes mellitus tipo 2, osteopenia / osteoporose, dislipidemia e hiperuricemia / gota. O padrão de comprometimento muscular na IBM foi caracterizado por tetraparesia de predomínio proximal em membros inferiores e distal em membros superiores. Os valores séricos da creatinofosfoquinase em pelo menos uma das medições foram elevados em todos os pacientes, porém sem ultrapassar 10 vezes o limite superior da normalidade. O uso de...

Sporadic inclusion body myositis (sIBM) is considered the most common acquired myopathy affecting adults aged over 50 years. Although included in the group of inflammatory myopathies, recent studies show a particular process of muscle degeneration characterized by abnormal deposit of protein aggregates in muscle fibers and abnormal operation of the main protein degradation systems. The aim of this study was to evaluate the clinical, histological and immunohistochemical patients with IBM. We evaluated 18 cases with IBM diagnostic of two of the main centers of neuromuscular diseases in Brazil (25 muscle biopsies). In an attempt to differentiate the IBM cases of other inflammatory myopathies, we determined the pattern of tissue expression of p-tau (p62), alfa-synuclein and TDP-43. Also evaluated the lysosomal function by acid phosphatase reaction (marking global lysosomal activity) and determining the markup for LC3B (autophagy marker). It was observed that IBM was predominant in males (61% of cases), white colored, with onset of clinical manifestations around 59 years old and the most common symptoms are muscle weakness, postural instability with high falls, dysphagia and weight loss, and may also present dyspnea. The diagnosis took an average of 7.4 years after the onset of symptoms and was often associated with the following comorbidities: hypertension, type 2 diabetes mellitus, osteopenia / osteoporosis, dyslipidemia and hyperuricemia / gout. The muscular damage pattern at IBM was characterized by tetraparesis predominantly proximal lower limbs and distal upper limbs. Serum creatine kinase levels in at least one of the measurements were elevated in all patients, but not exceeding 10 times normal. Immunosuppression was not effective in patients with IBM. The IBM histological findings included diversify dystrophic changes, endomysial inflammation, as well as the occurrence of rimmed vacuoles, in addition to high frequency of mitochondrial changes. Other...

Functional mapping of the motor cortex of the rat using transdural electrical stimulation.

Motor cortex stimulation oriented by functional cortical mapping is used mainly for treating otherwise intractable neurological disorders, however, its mechanism of action remains elusive. Herein, we present a new method for functional mapping of the rat motor cortex using non-invasive transdural electrical stimulation. This method allows a non-invasive mapping of the surface of the neocortex providing a differentiation of representative motor areas. This study may facilitate further investigation about the mechanisms mediating the effects of electrical stimulation, possibly benefiting patients who do not respond to this neuromodulation therapy.