The clinical course of Duchenne muscular dystrophy in the corticosteroid treatment era: a systematic literature review

Abstract

Background Duchenne muscular dystrophy (DMD) is a severe rare progressive inherited neuromuscular disorder, leading to loss of ambulation (LOA) and premature mortality. The standard of care for patients with DMD has been treatment with corticosteroids for the past decade; however a synthesis of contemporary data describing the clinical course of DMD is lacking. The objective was to summarize age at key clinical milestones (loss of ambulation, scoliosis, ventilation, cardiomyopathy, and mortality) in the corticosteroid-treatment-era. Methods A systematic review was conducted using MEDLINE and EMBASE. The percentage experiencing key clinical milestones, and the mean or median age at those milestones, was synthesized from studies from North American populations, published between 2007 and 2018. Results From 5637 abstracts, 29 studies were included. Estimates of the percentage experiencing key clinical milestones, and age at those milestones, showed heterogeneity. Up to 30% of patients lost ambulation by age 10 years, and up to 90% by 15 years of age. The mean age at scoliosis onset was approximately 14 years. Ventilatory support began from 15 to 18 years, and up to half of patients required ventilation by 20 years of age. Registry-based estimates suggest that 70% had evidence of cardiomyopathy by 15 years and almost all by 20 years of age. Finally, mortality rates up to 16% by age 20 years were reported; among those surviving to adulthood mortality was up to 60% by age 30 years. Conclusions Contemporary natural history studies from North America report that LOA on average occurs in the early teens, need for ventilation and cardiomyopathy in the late teens, and death in the third or fourth decade of life. Variability in rates may be due to differences in study design, treatment with corticosteroids or other disease-modifying agents, variations in clinical practices, and dystrophin mutations. Despite challenges in synthesizing estimates, these findings help characterize disease progression among contemporary North American DMD patients.

Inhibition of PKCθ Improves Dystrophic Heart Phenotype and Function in a Novel Model of DMD Cardiomyopathy

“…Corticosteroids are effective in promoting muscle maintenance and, more importantly, in delaying both losses of ambulation and cardiomyopathy progression. Their beneficial effects are primarily due to their immunosuppressive action, supporting the notion that the immune system has a pivotal role in disease progression [19][20][21][22]. Indeed, several studies have shown that depletion of immune populations such as T cells and neutrophils, as well as genetic ablation or inhibition of inflammatory cytokines, ameliorated muscle phenotype and function in the murine model of DMD, the mdx mouse [23][24][25][26][27][28][29].…”

Multiomic Approaches to Uncover the Complexities of Dystrophin-Associated Cardiomyopathy

“…In the pre-steroid era DMD and BMD had a predictable disease projection with premature death in the early twenties or forties respectively. However, opportune treatment advances, e.g., nocturnal ventilation and corticosteroid regimens, opened a new era of treatment [6,7] which necessitates considerable planning particularly regarding cardiac care but also the choice of outcome measures for clinical studies or preclinical models.…”

“…Finding circulating biomarkers for identifying therapy-responsive patients is another important need that is particularly relevant due to the increasing number of candidate drugs entering clinical trials and the lack of optimal outcome measures adaptable to the contemporary natural history of MD [6,7]. In this context, two fragments of the myofibrillar structural protein myomesin-3 were identified to be abnormally increased in the serum of MD patients (DMD and limb-girdle MD type 2D) using a comprehensive high-resolution MS-based approach, and they are thus proposed as biomarkers for assessing experimental therapies for MD and other neuromuscular disorders [53].…”

Adeno-Associated Virus (AAV)-Mediated Gene Therapy for Duchenne Muscular Dystrophy: The Issue of Transgene Persistence

“…By the age of 2-3 years, DMD patients develop lower limb weakness, leading to the delay of motor milestones, walking disturbances, frequent falls and, in the second decade of life, loss of autonomous ambulation (2). During disease progression, patients show respiratory failure, which requires ventilatory support, and cardiomyopathy, which represents the leading cause of death in DMD (3,4). Almost one third of patients present neuropsychiatric disturbances, including intellectual disability, autistic spectrum disorders, hyperactivity and inattention (5).…”