The cooperative international neuromuscular research group Duchenne natural history study: Glucocorticoid treatment preserves clinically meaningful functional milestones and reduces rate of disease progression as measured by manual muscle testing and other commonly used clinical trial outcome measures

Abstract

Introduction Glucocorticoid (GC) therapy in Duchenne muscular dystrophy (DMD) has altered disease progression, necessitating contemporary natural history studies. Methods The Cooperative Neuromuscular Research Group (CINRG) DMD Natural History Study (DMD-NHS) enrolled 340 DMD males, ages 2–28 years. A comprehensive battery of measures was obtained. Results A novel composite functional “milestone” scale scale showed clinically meaningful mobility and upper limb abilities were significantly preserved in GC-treated adolescents/young adults. Manual muscle test (MMT)-based calculations of global strength showed that those patients <10 years of age treated with steroids declined by 0.4±0.39 MMT unit/year, compared with −0.4±0.39 MMT unit/year in historical steroid-naive subjects. Pulmonary function tests (PFTs) were relatively preserved in steroid-treated adolescents. The linearity and magnitude of decline in measures were affected by maturational changes and functional status. Conclusions In DMD, long-term use of GCs showed reduced strength loss and preserved functional capabilities and PFTs compared with previous natural history studies performed prior to the widespread use of GC therapy.

Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy

“…Based on the documented effect of corticosteroids on disease progression,3 only patients treated with corticosteroids were included in the current analyses.…”

“…Pulmonary function data were not available for the matched historical control patients, and therefore comparison can only be made to published natural history. Pulmonary function data from recent natural history studies in patients with DMD suggest that %pMEP and %pMIP decline at a rate of 4% per year for patients in the age range of 6 to 19 years, and %pFVC declines at a rate of 5% per year for patients in the age range of 5 to 24 years 3, 31. Thus, over a period of 36 months, patients not receiving eteplirsen might be expected to show declines in MEP and MIP of approximately 11.5% and declines in FVC of approximately 14.3%.…”

“…The etiology of this rare but devastating disease, the eteplirsen mode of action, and the course of the clinical studies (studies 201/202) have been described in detail in an earlier publication1 and in several reviews 2, 3, 4. Briefly, DMD is caused by deletions and other mutations in the dystrophin (also known as DMD ) gene that abrogate the mRNA reading frame and prevent expression of dystrophin protein.…”

“…Briefly, DMD is caused by deletions and other mutations in the dystrophin (also known as DMD ) gene that abrogate the mRNA reading frame and prevent expression of dystrophin protein. As a result, affected newborn boys experience severe, progressive neuromuscular impairment starting in early childhood,5 typically lose ambulation in their midteens, and succumb to respiratory failure or cardiomyopathy by their mid‐20s 3, 6, 7, 8. Eteplirsen‐induced skipping of exon 51 restores the mRNA reading frame, allowing production of an internally deleted but functional dystrophin protein.…”

Respiratory magnetic resonance imaging biomarkers in Duchenne muscular dystrophy

“…Respiratory failure is inevitable in DMD 1. Multidisciplinary care and ventilatory support have increased longevity,2, 3 and corticosteroids and idebenone may stabilize the respiratory function in nonambulatory patients 4, 5. Restoration of the diaphragm function alone prevented cardiomyopathy in mice 6.…”