Glucocorticoid corticosteroids for Duchenne muscular dystrophy.
ABSTRACT Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy of childhood. This incurable disease is characterised by muscle wasting and loss of walking ability leading to complete wheelchair dependence by 13 years of age. Prolongation of walking is one of the major aims of treatment.
The aim of this review was to assess whether glucocorticoid corticosteroids stabilize or improve muscle strength and walking in boys with DMD.
This is an update of the Cochrane systematic review first published in 2004 (Manzur 2004). We searched the Cochrane Neuromuscular Disease Group Trials Register (August 2006) using the term 'Duchenne muscular dystrophy'. We also searched MEDLINE (January 1966 to July 2007), EMBASE (January 1980 to August 2006), CINAHL and LILACS (January 1982 to August 2006). We wrote to authors of published studies and other experts in this disease to help identify other trials, checked the references in the identified trials and hand searched the abstracts of relevant journals.
Types of studies: randomised or quasi-randomised trials. Types of participants: all patients with a definite diagnosis of Duchenne muscular dystrophy. Types of interventions: glucocorticoids such as prednisone, prednisolone, deflazacort or others, with a minimum treatment period of three months. Primary outcome measure: prolongation of walking (independent walking without long leg calipers). Secondary outcome measures: strength outcome measures, manual muscle strength testing using Medical Research Council strength scores, functional outcome measures and adverse events.
We identified six randomised controlled trials that met the inclusion criteria for our review, and one of these (Beenakker 2005) is a new addition to this update, as it was published subsequent to our first review (Manzur 2004). Two review authors independently selected the trials for the review and assessed methodological quality. Data extraction and inputting were double-checked.
Primary outcome measure: data from one small study used prolongation of walking as an outcome measure and did not show significant benefit. Secondary outcome measures: The meta-analysis of the results from four randomised controlled trials with altogether 249 participants showed that glucocorticoid corticosteroids improved muscle strength and function over six months. Improvements were seen in time taken to rise from the floor (Gowers' time), nine metres walking time, four-stair climbing time, ability to lift weights, leg function grade and forced vital capacity. One randomised controlled trial with altogether 28 participants showed that glucocorticoid corticosteroids stabilize muscle strength and function for up to two years. The most effective prednisolone regime appears to be 0.75 mg/kg/day, given in a daily dose regime. Not enough data were available to compare efficacy of prednisone with deflazacort. Adverse effects: Excessive weight gain, behavioural abnormalities, cushingoid appearance and excessive hair growth were all more common with glucocorticoid corticosteroids than placebo. Long-term adverse effects of glucocorticoid therapy could not be evaluated because of the short-term duration of the randomised studies.Non-randomised studies: A number of non-randomised studies with important efficacy and adverse effects data are tabulated and discussed.
There is evidence from randomised controlled studies that glucocorticoid corticosteroid therapy in Duchenne muscular dystrophy improves muscle strength and function in the short-term (six months to two years). The most effective prednisolone regime appears to be 0.75 mg/kg/day, given daily. In the short term, adverse effects were significantly more common but not clinically severe. Long-term benefits and hazards of glucocorticoid treatment cannot be evaluated from the currently published randomised studies. Non-randomised studies support the conclusions of functional benefits but also identify clinically significant adverse effects of long-term treatment. These benefits and adverse effects have implications for future research studies and clinical practice.
- [Show abstract] [Hide abstract]
ABSTRACT: Congenital neuromuscular disorders, such as Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and Pompe disease (acid maltase deficiency, AMD) are candidates for universal newborn screening (NBS). In this paper, we discuss the future path of NBS for these disorders with particular emphasis on DMD-NBS, because of the likely approval of new gene modifying treatments, the possible benefits of earlier treatment with corticosteroids, and the recently demonstrated feasibility of a two tiered approach to NBS with screening by creatine kinase (CK) levels in dried blood spots followed by mutation detection in those with elevated CK.The cystic fibrosis newborn screening (CF-NBS) program is a successful model for NBS. Cystic fibrosis (CF) outcomes have consistently improved into adulthood following introduction of CF-NBS because considerable resources have been devoted to practices that include: attention to improving laboratory screening; consistent confirmatory testing and immediate referral of all newly diagnosed infants to designated CF care centers that follow established practice guidelines; and, ongoing evaluation of CF care centers via a centralized clinical database.Like CF, DMD, SMA, and infantile AMD are inexorably debilitating and require lifetime multidisciplinary clinical management. NBS would address the delays in diagnosis that prevent patients from receiving timely treatments. Standardized care following early diagnosis would reduce disparities in clinical care and outcomes. NBS in these neuromuscular disorders should be implemented, utilizing lessons learned from the past 20 years of CF-NBS: standardized protocols for all patients identified by DMD-NBS; longitudinal follow-up in multidisciplinary clinics; and coordinated oversight of these clinics. This article is protected by copyright. All rights reserved.Annals of Neurology 11/2014; 77(2). · 11.91 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Toll-like receptor 4 (TLR4) recognizes specific structural motifs associated with microbial pathogens and also responds to certain endogenous host molecules associated with tissue damage. In Duchenne muscular dystrophy (DMD), inflammation plays an important role in determining the ultimate fate of dystrophic muscle fibers. In this study, we used TLR4-deficient dystrophic mdx mice to assess the role of TLR4 in the pathogenesis of DMD. TLR4 expression was increased and showed enhanced activation following agonist stimulation in mdx diaphragm muscle. Genetic ablation of TLR4 led to significantly increased muscle force generation in dystrophic diaphragm muscle, which was associated with improved histopathology including decreased fibrosis, as well as reduced pro-inflammatory gene expression and macrophage infiltration. TLR4 ablation in mdx mice also altered the phenotype of muscle macrophages by inducing a shift toward a more anti-inflammatory (iNOS(neg) CD206(pos)) profile. In vitro experiments confirmed that lack of TLR4 is sufficient to influence macrophage activation status in response to classical polarizing stimuli such as IFN-gamma and IL-4. Finally, treatment of dystrophic mice with glycyrrhizin, an inhibitor of the endogenous TLR4 ligand, high mobility group box (HMGB1), also pointed to involvement of the HMGB1-TLR4 axis in promoting dystrophic diaphragm pathology. Taken together, our findings reveal TLR4 and the innate immune system as important players in the pathophysiology of DMD. Accordingly, targeting either TLR4 or its endogenous ligands may provide a new therapeutic strategy to slow disease progression. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: email@example.com.Human Molecular Genetics 12/2014; · 6.68 Impact Factor
Dataset: NSAA Rasch 2011