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.

FIGURE 1

(A) Brooke upper extremity grade. (B) Vignos lower extremity grade. Percent study population at each grade by year of age (number of participants noted in bars).

FIGURE 2

Ability to perform functional milestones by glucocorticoid status for: (A) standing from supine; (B) climbing stairs; (C) rising from a chair; (D) walking independently; and (E) raising a hand to the mouth. Numbers of participants (denominator) by age cohort in (A)–(E) who were GC-naive, current GC users, and past GC users (respectively) are as follows: 4–6 years (N = 26, 27, 0); 7–9 years (N = 8, 68, 2); 10–12 years (N = 6, 47, 9); 13–15 years (N = 9, 30, 12); 16–18 years (N = 4, 15, 10); >18 years (N = 16, 19, 15).

FIGURE 3

Timed function tests by age group for: (A) 10-m walk/run; (B) climb 4 stairs, and (C) stand from supine. The boxand-whisker figures show velocity; a velocity of 0 is imputed for all participants who could not perform the test. The limits of the box are the 25th and 75th percentile. The median (middle line) and mean (“1”) are shown within the box. The whiskers are 1.5 times the interquartile length, starting from the edge of the boxes; asterisks indicate data values of outliers beyond the whiskers. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

FIGURE 4

Percent predicted forced vital capacity by age and GC treatment groups. The limits of the box are the 25th and 75th percentile. The median (middle line) and mean (1) are shown within the box. The whiskers are 1.5 times the interquartile length starting from the edge of the boxes; the asterisks are data values of outliers beyond the whiskers. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]