Brazilian consensus on Duchenne muscular dystrophy. Part 1: diagnosis, steroid therapy and perspectives

Abstract

Significant advances in the understanding and management of Duchenne muscular dystrophy (DMD) took place since international guidelines were published in 2010. Our objective was to provide an evidence-based national consensus statement for multidisciplinary care of DMD in Brazil. A combination of the Delphi technique with a systematic review of studies from 2010 to 2016 was employed to classify evidence levels and grade of recommendations. Our recommendations were divided in two parts. We present Part 1 here, where we describe the guideline methodology and overall disease concepts, and also provide recommendations on diagnosis, steroid therapy and new drug treatment perspectives for DMD. The main recommendations: 1) genetic testing in diagnostic suspicious cases should be the first line for diagnostic confirmation; 2) patients diagnosed with DMD should have steroids prescribed; 3) lack of published results for phase 3 clinical trials hinders, for now, the recommendation to use exon skipping or read-through agents.Keywords: muscular dystrophy, Duchenne; practice guideline; consensus; diagnosis; genetic testing; drug therapy; glucocorticoids; utrophin. RESUMOAvanços na compreensão e no manejo da distrofia muscular de Duchenne (DMD) ocorreram desde a publicação de diretrizes internacionais em 2010. Nosso objetivo foi elaborar um consenso nacional baseado em evidências de cuidado multidisciplinar dos pacientes com DMD no Brasil. Utilizamos a técnica de Delphi combinada com revisão sistemática da literatura de 2010 a 2016 classificando níveis de evidência e graus de recomendação. Nossas recomendações foram divididas em duas partes. Apresentamos aqui a parte 1, descrevendo a metodologia utilizada e conceitos gerais da doença, e fornecemos recomendações sobre diagnóstico, tratamento com corticosteroides e novas perspectivas de tratamentos medicamentosos. As principais recomendações: 1) testes genéticos deveriam ser a primeira linha para confirmação de casos suspeitos; 2) pacientes com diagnóstico de DMD devem receber corticosteroides; 3) por enquanto, a falta de publicações de resultados dos ensaios clínicos de fase 3, dificulta recomendações de uso medicamentos que "saltam exons" ou "passam" por código de parada prematura.

Muscular Dystrophy: A Retrospective Evaluation of 15 Cases

“…The standard treatment for DMD includes the use of corticosteroids and ataluren. [2][3][4] The aim of this study was to investigate the clinical and laboratory findings of patients followed up with a diagnosis of DMD.…”

Duchenne muscular dystrophy: classical and new therapeutic purposes and future perspectives

“…prednisolone, deflazacort, or prednisone), most desirably as early as possible 2,4,8 ; and (iii) reaffirm the importance of special caution before the adoption of the new current therapeutic purposes by the using of exon-skipping ( for the most common genetic situations) and read through agents(in the case of premature stop codon), since most of the results in the studies of such therapies (e.g. Ataluren, Drisapersen, Eteplirsen) still have an unknown impact in the long term for patients and most emerged from studies limited to initial clinical phases 1 and 2 3,4 , being essential to extend such randomized clinical trials to phase 3 with a large number of patients.It is believed that through the results from this consensus clinicians and neuropediatricians can improve their care for patients with dystrophinopathies from the appropriate diagnostic process to the possibility of offering proper drug therapy based on current scientific evidence. …”

“…looking for DMD exon deletion/duplication by techniques such as Multiplex Ligation-dependent Probe Amplification/MLPA or Comparative Genomic Hybridizationmicroarray/aCGH, and if necessary next-generation sequencing of DMD gene 4,7 ), in such a way that muscle biopsy with immunohistochemistry evaluation, classically used as a diagnostic tool by many centers, should be performed in cases in which genetic testing is unavailable or in cases with high suspicion index with undetermined or non-definite diagnostic criteria by prior genetic testing; (ii) the recommendation of using cortico steroids since the diagnosis (e.g. prednisolone, deflazacort, or prednisone), most desirably as early as possible 2,4,8 ; and (iii) reaffirm the importance of special caution before the adoption of the new current therapeutic purposes by the using of exon-skipping ( for the most common genetic situations) and read through agents(in the case of premature stop codon), since most of the results in the studies of such therapies (e.g. Ataluren, Drisapersen, Eteplirsen) still have an unknown impact in the long term for patients and most emerged from studies limited to initial clinical phases 1 and 2 3,4 , being essential to extend such randomized clinical trials to phase 3 with a large number of patients.…”

“…The advent of neurogenetics, new diagnostic methods and emerging therapeutic proposals makes extremely necessary the review of the main consolidated topics on DMD, as well as making guidelines and the adoption of a Brazilian consensus among experts in neuromuscular diseases as a reference for the proper practice of the general neurologist and neuropediatrician. The study provided by Araújo et al, 4 presented at this issue of Arquivos de Neuro-Psiquiatria represents the most recent attempt of classifying evidence levels and recommendation degrees for different diagnostic and therapeutic aspects related to DMD using a systematic review approach of the current medical literaturesince2010, year of publishing of the last international guideline of DMD 5,6 . Authors have proposed as their main results of the consensus: (i) the formal recommendation of genetic testing as the first-line exam to provide diagnosis in suspected cases of dystrophinopathies (e.g.…”

>b<Avaliação de Pericitos no modelo GRMD (>i<Golden Retriever Muscular Dystrophy>/i<)>/b<

“…No homem, os sintomas clínicos são demonstrados de forma dinâmica, afetando o músculo estriado esquelético, músculo liso e músculo cardíaco (BROLIO et al, 2014;MARKHAM et al, 2017). Por se tratar de uma doença de caráter congênito, as manifestações clínicas da doença aparecem desde o início da infância e surgem com maior evidência entre três e cinco anos de idade (ARAUJO et al, 2017 (ROBRIQUET et al, 2016;SCHNEIDER et al, 2018).…”