Predictors of Loss of Ambulation in Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis.

Objective: The objective of this study was to describe predictors of loss of ambulation in Duchenne muscular dystrophy (DMD). Methods: This systematic review and meta-analysis included searches of MEDLINE ALL, Embase, and the Cochrane Database of Systematic Reviews from January 1, 2000, to December 31, 2022, for predictors of loss of ambulation in DMD. Search terms included "Duchenne muscular dystrophy" as a Medical Subject Heading or free text term, in combination with variations of the term "predictor". Risk of bias was assessed using the Newcastle-Ottawa Scale. We performed meta-analysis pooling of hazard ratios of the effects of glucocorticoids (vs. no glucocorticoid therapy) by fitting a common-effect inverse-variance model. Results: The bibliographic searches resulted in the inclusion of 45 studies of children and adults with DMD from 17 countries across Europe, Asia, and North America. Glucocorticoid therapy was associated with delayed loss of ambulation (overall meta-analysis HR deflazacort/prednisone/prednisolone: 0.44 [95% CI: 0.40-0.48]) (n = 25 studies). Earlier onset of first signs or symptoms, earlier loss of developmental milestones, lower baseline 6MWT (i.e.,<350 vs. ≥350 metres and <330 vs. ≥330 metres), and lower baseline NSAA were associated with earlier loss of ambulation (n = 5 studies). Deletion of exons 3-7, proximal mutations (upstream intron 44), single exon 45 deletions, and mutations amenable of skipping exon 8, exon 44, and exon 53, were associated with prolonged ambulation; distal mutations (intron 44 and downstream), deletion of exons 49-50, and mutations amenable of skipping exon 45, and exon 51 were associated with earlier loss of ambulation (n = 13 studies). Specific single-nucleotide polymorphisms in CD40 gene rs1883832, LTBP4 gene rs10880, SPP1 gene rs2835709 and rs11730582, and TCTEX1D1 gene rs1060575 (n = 7 studies), as well as race/ethnicity and level of family/patient deprivation (n = 3 studies), were associated with loss of ambulation. Treatment with ataluren (n = 2 studies) and eteplirsen (n = 3 studies) were associated with prolonged ambulation. Magnetic resonance biomarkers (MRI and MRS) were identified as significant predictors of loss of ambulation (n = 6 studies). In total, 33% of studies exhibited some risk of bias. Conclusion: Our synthesis of predictors of loss of ambulation in DMD contributes to the understanding the natural history of disease and informs the design of new trials of novel therapies targeting this heavily burdened patient population.

Factors Associated with Respiratory Health and Function in Duchenne Muscular Dystrophy: A Systematic Review and Evidence Grading.

BACKGROUND: Despite advances in the medical management of the disease, respiratory involvement remains a significant source of morbidity and mortality in children and adults with Duchenne muscular dystrophy (DMD). OBJECTIVE: The objective of this systematic literature review was to synthesize and grade published evidence of factors associated with respiratory health and function in DMD. METHODS: We searched MEDLINE, Embase, and the Cochrane Library for records of studies published from January 1, 2000 (to ensure relevance to current care practices), up until and including December 31, 2022, reporting evidence of prognostic indicators and predictors of disease progression in DMD. The quality of evidence (i.e., very low to high) was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. RESULTS: The bibliographic search strategy resulted in the inclusion of 29 articles. In total, evidence of 10 factors associated with respiratory health and function in patients with DMD was identified: glucocorticoid exposure (high- to very low-quality evidence), DMD mutations (low-quality evidence), DMD genetic modifiers (low-quality evidence), other pharmacological interventions (i.e., ataluren, eteplirsen, idebenone, and tamoxifen) (moderate- to very low-quality evidence), body mass index and weight (low-quality evidence), and functional ability (low-quality evidence). CONCLUSIONS: In conclusion, we identified a total of 10 factors associated with respiratory health in function in DMD, encompassing both pharmacological therapies, genetic mutations and modifiers, and patient clinical characteristics. Yet, more research is needed to further delineate sources of respiratory heterogeneity, in particular the genotype-phenotype association and the impact of novel DMD therapies in a real-world setting. Our synthesis and grading should be helpful to inform clinical practice and future research of this heavily burdened patient population.