The impact of glucocorticoids in Duchenne muscular dystrophy throughout the lifespan:implications for clinical care and clinical trial design

Abstract

This publication-based PhD analysed two large databases of genetically confirmed individuals with Duchenne muscular dystrophy (DMD) treated with glucocorticoids to inform clinical care and trial design. The paediatric database included longitudinal data on boys with DMD (4-<8 years old) from the Finding the Optimum Corticosteroid Regime for Duchenne Muscular Dystrophy study (FOR-DMD, 2013-2016), a randomized, parallel-group, doubleblind clinical trial comparing the benefits and side effects of the three most prescribed glucocorticoid regimens: daily prednisone, daily deflazacort, and prednisone 10 days off/10 days on. The adult database contained retrospective data from individuals with DMD (>16 years old) followed at the John Walton Muscular Dystrophy Research Centre (JWMDRC, 1986-2022) according to evolving Standards of Care. Using the FOR-DMD database, I investigated the effect of genotype on motor performance in young glucocorticoid-naïve boys, the clinical factors influencing early motor trajectories after glucocorticoid initiation, time to motor performance peak, and the short- and long-term correlation between anthropometric measures and motor performance. This data provides important considerations for clinical trials randomization, and analysis adjustments, while also supporting clinical care decisions for glucocorticoid initiation. Using the adult JWMDRC database, I explored the effect of glucocorticoid on long-term motor, respiratory, and cardiac outcomes when glucocorticoids are continued after loss of ambulation (LOA), investigate DMD-related comorbidities and predictive factors and the correlation between age at LOA and cardiac function in adults with DMD. I described the current practice regarding glucocorticoid use in adults with DMD in a highly specialised neuromuscular centre. These findings support clinical care discussion on glucocorticoid prescription after LOA, guide clinicians on minimal glucocorticoid dose in adults and inform adult clinical service requirements. Finally, the PhD included a lab-based project investigating for the first time the novel biomarker Chitinase-3-like-1 protein in serum samples from individuals with DMD to better understand its role in DMD pathophysiology