New AAN Practice Guideline Update Backs Use of Corticosteroids for Duchenne Muscular Dystrophy
ARTICLE IN BRIEF
A new practice guideline looks at the effectiveness and side effect profile of long-term use of corticosteroids for Duchenne muscular dystrophy. The guideline replaces an earlier version published in 2005.
Nearly 10 years after the publication of a practice guideline on corticosteroids for Duchenne muscular dystrophy (DMD), the AAN has provided an updated review of the evidence on their effectiveness for delaying and lessening the effects of certain symptoms and enhancing quality of life and survival.
The practice parameter replaces a practice guideline published in 2005, when there was little published research on the long-term use of corticosteroids for DMD.
“Research has suggested that there is wide variation in corticosteroid use to treat patients with Duchenne muscular dystrophy,” said Richard T. Moxley III, MD, FAAN, a coauthor of the new guideline and lead author of the previous one. He said some practitioners have been hesitant to prescribe corticosteroids long-term because they worry that “when you continue treatment, the boys are going to have all these side effects.”
The new guideline, published in the February 2 issue of Neurology, is based on a review of 63 articles from 2004-2014 on the use of prednisone or deflazacort for DMD, including a few related studies on bone health interventions. Deflazacort is currently not available on the US market, but Marathon Pharmaceuticals hopes to gain Food and Drug Administration approval to market the drug for DMD, Dr. Moxley said.
“It is timely to provide care providers, patients, and their families with updated published information about the effectiveness of corticosteroid treatment, the treatment regimens that have received careful assessment, the side effects during short-term and long-term treatment, and the future challenges and opportunities ahead for corticosteroid therapy in these patients,” Dr. Moxley, the Helen Aresty Fine and Irving Fine professor of neurology at the University of Rochester, told Neurology Today.
Dr. Moxley discussed some of the guideline's recommendations and others that may be coming along to enhance treatment for DMD patients.
WHY WAS THE GUIDELINE UPDATED NOW?
Approximately 10 years has passed since the initial practice parameter on corticosteroid treatment of DMD, and the information that served as the basis for those recommendations largely involved treatment trials of less than two years duration. This update allows a presentation of information gathered during the intervening years, including more recently published studies of long-term treatment with either prednisone or deflazacort.
WHAT ARE SOME OF THE KEY POINTS?
Prednisone treatment reduces the need for scoliosis surgery (Level C) and delays the onset of cardiomyopathy by 18 years of age (Level C). Deflazacort treatment reduces the need for scoliosis surgery, delays the onset of cardiomyopathy, and increases survival at five to 15 years of follow-up (Level C for each). But the optimal dosing of deflazacort is unclear, and the treatment may cause a greater risk of cataracts than prednisone. Prednisone therapy may cause greater weight gain than deflazacort in the first years of treatment.
WHAT DOSE OF PREDNISONE IS RECOMMENDED FOR DMD?
A dose of 0.75 mg/kg daily is the most efficacious over a period of years (Level B). A 2011 study, published in Neurology, indicated that 12 months of high-dose weekend prednisone treatment (Saturday 5 mg/kg and Sunday 5 mg/kg) gives comparable benefit to prednisone 0.75 mg/kg daily, but no long-term data are available yet to evaluate efficacy and side effects of high-dose weekend prednisone. There is an ongoing study to assess the effectiveness of intermittent prednisone treatment by comparing three treatment regimens. The results are not expected until after 2019.
SYMPTOM CONTROL IS ONE ISSUE. BUT DO CORTICOSTEROIDS IMPROVE QUALITY OF LIFE AND SURVIVAL?
Based upon the limited information available my answer is ‘yes.’ However, there are an insufficient number of controlled prospective studies to confirm my bias. More studies are needed. For example, it is important to determine if the beneficial effects on improving quality of life and on extending longevity depend upon the age at which corticosteroid treatment is initiated. To obtain a clear answer will require evaluation of a large group of DMD patients who have received many years of corticosteroid therapy.
HOW DOES PREDNIZONE COMPARE WITH DEFLAZACORT?
There is no clearly established set of criteria to indicate whether prednisone or deflazacort is preferable. Based upon current information, both treatments are similarly effective in prolonging ambulation, extending effective pulmonary and cardiac function, delaying the need for scoliosis surgery, and prolonging life with a higher quality of life as well.
Prednisone is more readily available and less costly compared to deflazacort. In the United States, there have been more studies of prednisone treatment in DMD, and many clinicians in the US have experience in using prednisone to treat a wide spectrum of more common medical disorders. Use of deflazacort to treat DMD is more common in Canada compared with prednisone.
WHAT ARE THE DOWNSIDES TO LONG-TERM CORTICOSTEROIDS?
There are a number of side effects, such as, excessive weight gain, hirsutism, cushingoid appearance, cataracts, susceptibility to spinal fractures, short stature, mood and sleep disturbances, and behavior problems High-dose corticosteroid replacement treatment is needed for patients undergoing major surgery or prolonged stress from an acute medical problem.
CAN SIDE EFFECTS BE MANAGED?
Yes, all of these side effects can be managed. It helps, if possible, for patients to be followed by a multidisciplinary team. While we often focus on the side effects, I worry that we are forgetting that regular dosing with corticosteroids may be accomplishing something that we can't measure. I like the analogy of cancer care, where children receive all kinds of medications with some big-league side effects. However, treatments can prolong and extend quality of life of these children, and, in some cases, these treatments produce cures. We hope to accomplish a cure for our patients with DMD. But before the cure is obtained, corticosteroids, despite sometimes difficult side effects, can lead to more functional capabilities in life.
DO THE GUIDELINES RECOMMEND TREATMENTS FOR KEEPING BONES HEALTHY?
No. There is insufficient evidence at present to determine all the specific factors that contribute to bone alterations in DMD; and, that there is insufficient evidence to support recommending specific medications and other interventions.
WHAT ARE SOME UNANSWERED QUESTIONS ABOUT LONG-TERM CORTICOSTEROID USE?
Research needs to focus on several questions. What is the earliest age at which we can safely initiate corticosteroid treatment, the best dosage, and the best measures to use to assess efficacy and side effects? What is the biological mechanism responsible for the beneficial effects and side effects of corticosteroids on skeletal muscle in patients with DMD? What dosing regimen is optimal for DMD patients once they are non-ambulatory? What is the optimal stress dosing for patients on chronic corticosteroid therapy who undergo major surgery or have severe acute medical illness?
HOW WOULD YOU CHARACTERIZE THE STATE OF DMD RESEARCH?
I would say it's very promising. The improvements in respiratory care, cardiac care, physical therapy, occupational therapy and speech therapy are remarkable. The use of corticosteroid therapy has extended motor function, cardiorespiratory function, delayed or obviated the need for scoliosis surgery, and is allowing higher quality of life as well as extending the life span and career opportunities.
Another important area of research is the development of more detailed knowledge of the progression of the different manifestations of DMD over time in boys receiving long-term corticosteroid therapy. This information will allow researchers to determine if new treatments produce benefits that are superior to those that occur with long-term corticosteroids. There also needs to be continued refinement and validation of the optimal, most patient-meaningful measures of efficacy of corticosteroid treatment and of detection of significant side effects. There is no shortage of opportunities and challenges to consider as we make progress in helping our DMD patients enjoy a higher quality of life.
ARE THERE ANY PROMISING THERAPIES ON THE HORIZON?
There is the possibility of identifying a “corticosteroid like” drug without the usual side effects that may produce the same beneficial effects of prednisone and deflazacort. There also are strategies being evaluated to correct the (DMD) gene defect and the tissue changes that occur as a result. There are hopes that the new CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat) gene editing methodology can be applied to animal models of DMD and eventually be appropriate to treat patients.
CLASSIFICATION REQUIREMENTS FOR THERAPEUTIC QUESTIONS
- Class 1: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.
- Class II: A randomized, controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criterion a-e in class 1 or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b-e in class I. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.
- Class III. All other controlled trials (including well-defined nature history controls or patients serving as their own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurements.
- Class IV. Studies not meeting class I, II, or III criteria including consensus or expert opinion.
AAN CLASSIFICATION OF RECOMMENDATIONS
- A: Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent class 1 studies.)
- B: Probably effective, ineffective, or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one class I study or two consistent class II studies.)
- C: Probably effective, ineffective, or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one class II study or two consistent class III studies.)