Cyclosporine A for Duchenne Muscular Dystrophy

Abstract & Commentary

By Michael Rubin, MD, Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Rubin reports no financial relationships relevant to this field of study.

Synopsis: Unfortunately, cyclosporine treatment had no effect on muscle power in children with Duchenne muscular dystrophy.

Source: Kirschner J, Schessl J, Schara U, et al. Treatment of Duchenne muscular dystrophy with ciclosporin A: A randomised, double-blind, placebo-controlled multicentre trial. Lancet Neurol 2010;9:1053-1059.

Duchenne muscular dystrophy (DMD), an x-linked disease affecting 1 in 3,500 newborn boys, causes progressive skeletal muscle weakness, cardiomyopathy, and ventilatory failure, resulting in wheelchair-dependence by age 12 years and death by age 35 years in virtually all. Glucocorticoids improve muscle strength and have extended the expected lifespan past 20 years, but side effects limit their long-term use. Might lifespan be improved by administering cyclosporine?

Between January 2004 and 2007, DMD ambulatory patients, 5 years of age or older, followed through the German Muscular Dystrophy Network, were recruited into a multicenter, randomized, double-blinded, placebo- controlled trial comparing 3 months of oral cyclosporine A (3.5–4.0 mg/kg per day) vs. placebo. Following 3 months of treatment, prednisone, 0.75 mg/kg, was added, administered orally in an alternating fashion, 10 days on, followed by 10 days off, for an additional 12 months. DMD diagnosis was based on the clinical picture, elevated serum creatine kinase level, and results of muscle biopsy or genetic testing. Patients were excluded if they were previously treated with steroids, or had received clenbuterol or other sympathomimetics in the previous 3 months. Outcome measures, performed at baseline and at months 3, 9, and 15, included manual muscle testing as measured by the extended version of the Medical Research Council (MRC) score, and quantitative muscle testing using the Citec handheld dynamometer. Functional outcome measures included the time to stand up from a supine position, and the time to walk 10 m independently. Statistical analysis used a linear regression model with baseline value, treatment group, age, and trial site as covariates, and an additional posthoc supportive analysis, using a mixed regression model. Kaplan-Meier estimation and log-rank tests, and Cox proportional hazards regression models were applied where indicated. Though Novartis Pharma AG provided funding, they played no role in study design, data collection, analysis, or interpretation, or in writing the paper.

Among 77 patients who received cyclosporine A and 76 placebo patients, no improvement in muscle strength was appreciated in the treatment group over placebo. Nor did the addition of intermittent prednisone to cyclosporine for 1 year prove beneficial. None of the outcome measures was shown to be significantly different between treatment groups. Adverse events were seen in the same frequency in both groups. Cyclosporine A is safe but provides no tangible clinical benefit in DMD.

Commentary

Focusing on cardiac function may provide an alternate avenue for improving life expectancy in DMD. Usually evident after the first decade, the incidence of conduction defects, and dilated and hypertrophic cardiomyopathy, increases with age, as do arrhythmias including atrial flutter, frequent premature atrial and ventricular beats, and ventricular arrhythmias, which itself may be a risk factor for sudden death. Up to 20% of DMD patients experience a cardiac death, a number expected to rise as respiratory complications are being more successfully managed. ACE inhibitors delay the onset and progression of ventricular dysfunction and, in the DMD mouse model, appear to bulk up muscle. Research in this direction is clearly warranted.