Craig M McDonald1, Erik K Henricson2, Richard T Abresch2, Tina Duong3, Nanette C Joyce2, Fengming Hu4, Paula R Clemens5, Eric P Hoffman6, Avital Cnaan4, Heather Gordish-Dressman4. 1. University of California Davis School of Medicine, Sacramento, CA, USA. Electronic address: cmmcdonald@ucdavis.edu. 2. University of California Davis School of Medicine, Sacramento, CA, USA. 3. Stanford University, Stanford, CA, USA. 4. Center for Genetic Medicine, Children's National Health System and the George Washington University School of Medicine and Health Sciences, Washington, DC, USA. 5. University of Pittsburgh, Pittsburgh, PA, USA. 6. Binghamton University's School of Pharmacy and Pharmaceutical Sciences, Binghamton, NY, USA.
Abstract
BACKGROUND: Glucocorticoid treatment is recommended as a standard of care in Duchenne muscular dystrophy; however, few studies have assessed the long-term benefits of this treatment. We examined the long-term effects of glucocorticoids on milestone-related disease progression across the lifespan and survival in patients with Duchenne muscular dystrophy. METHODS: For this prospective cohort study, we enrolled male patients aged 2-28 years with Duchenne muscular dystrophy at 20 centres in nine countries. Patients were followed up for 10 years. We compared no glucocorticoid treatment or cumulative treatment duration of less than 1 month versus treatment of 1 year or longer with regard to progression of nine disease-related and clinically meaningful mobility and upper limb milestones. We used Kaplan-Meier analyses to compare glucocorticoid treatment groups for time to stand from supine of 5 s or longer and 10 s or longer, and loss of stand from supine, four-stair climb, ambulation, full overhead reach, hand-to-mouth function, and hand function. Risk of death was also assessed. This study is registered with ClinicalTrials.gov, number NCT00468832. FINDINGS: 440 patients were enrolled during two recruitment periods (2006-09 and 2012-16). Time to all disease progression milestone events was significantly longer in patients treated with glucocorticoids for 1 year or longer than in patients treated for less than 1 month or never treated (log-rank p<0·0001). Glucocorticoid treatment for 1 year or longer was associated with increased median age at loss of mobility milestones by 2·1-4·4 years and upper limb milestones by 2·8-8·0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones by 2·1-2·7 years in comparison with prednisone or prednisolone (log-rank p<0·012). 45 patients died during the 10-year follow-up. 39 (87%) of these deaths were attributable to Duchenne-related causes in patients with known duration of glucocorticoids usage. 28 (9%) deaths occurred in 311 patients treated with glucocorticoids for 1 year or longer compared with 11 (19%) deaths in 58 patients with no history of glucocorticoid use (odds ratio 0·47, 95% CI 0·22-1·00; p=0·0501). INTERPRETATION: In patients with Duchenne muscular dystrophy, glucocorticoid treatment is associated with reduced risk of losing clinically meaningful mobility and upper limb disease progression milestones across the lifespan as well as reduced risk of death. FUNDING: US Department of Education/National Institute on Disability and Rehabilitation Research; US Department of Defense; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases; and Parent Project Muscular Dystrophy.
BACKGROUND: Glucocorticoid treatment is recommended as a standard of care in Duchenne muscular dystrophy; however, few studies have assessed the long-term benefits of this treatment. We examined the long-term effects of glucocorticoids on milestone-related disease progression across the lifespan and survival in patients with Duchenne muscular dystrophy. METHODS: For this prospective cohort study, we enrolled male patients aged 2-28 years with Duchenne muscular dystrophy at 20 centres in nine countries. Patients were followed up for 10 years. We compared no glucocorticoid treatment or cumulative treatment duration of less than 1 month versus treatment of 1 year or longer with regard to progression of nine disease-related and clinically meaningful mobility and upper limb milestones. We used Kaplan-Meier analyses to compare glucocorticoid treatment groups for time to stand from supine of 5 s or longer and 10 s or longer, and loss of stand from supine, four-stair climb, ambulation, full overhead reach, hand-to-mouth function, and hand function. Risk of death was also assessed. This study is registered with ClinicalTrials.gov, number NCT00468832. FINDINGS: 440 patients were enrolled during two recruitment periods (2006-09 and 2012-16). Time to all disease progression milestone events was significantly longer in patients treated with glucocorticoids for 1 year or longer than in patients treated for less than 1 month or never treated (log-rank p<0·0001). Glucocorticoid treatment for 1 year or longer was associated with increased median age at loss of mobility milestones by 2·1-4·4 years and upper limb milestones by 2·8-8·0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones by 2·1-2·7 years in comparison with prednisone or prednisolone (log-rank p<0·012). 45 patients died during the 10-year follow-up. 39 (87%) of these deaths were attributable to Duchenne-related causes in patients with known duration of glucocorticoids usage. 28 (9%) deaths occurred in 311 patients treated with glucocorticoids for 1 year or longer compared with 11 (19%) deaths in 58 patients with no history of glucocorticoid use (odds ratio 0·47, 95% CI 0·22-1·00; p=0·0501). INTERPRETATION: In patients with Duchenne muscular dystrophy, glucocorticoid treatment is associated with reduced risk of losing clinically meaningful mobility and upper limb disease progression milestones across the lifespan as well as reduced risk of death. FUNDING: US Department of Education/National Institute on Disability and Rehabilitation Research; US Department of Defense; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases; and Parent Project Muscular Dystrophy.
Authors: Utkarsh J Dang; Michael Ziemba; Paula R Clemens; Yetrib Hathout; Laurie S Conklin; Eric P Hoffman Journal: Hum Mol Genet Date: 2020-08-29 Impact factor: 6.150
Authors: Laurie S Conklin; Jesse M Damsker; Eric P Hoffman; William J Jusko; Panteleimon D Mavroudis; Benjamin D Schwartz; Laurel J Mengle-Gaw; Edward C Smith; Jean K Mah; Michela Guglieri; Yoram Nevo; Nancy Kuntz; Craig M McDonald; Mar Tulinius; Monique M Ryan; Richard Webster; Diana Castro; Richard S Finkel; Andrea L Smith; Lauren P Morgenroth; Adrienne Arrieta; Maya Shimony; Mark Jaros; Phil Shale; John M McCall; Yetrib Hathout; Kanneboyina Nagaraju; John van den Anker; Leanne M Ward; Alexandra Ahmet; Michaelyn R Cornish; Paula R Clemens Journal: Pharmacol Res Date: 2018-09-13 Impact factor: 7.658
Authors: Panteleimon D Mavroudis; John van den Anker; Laurie S Conklin; Jesse M Damsker; Eric P Hoffman; Kanneboyina Nagaraju; Paula R Clemens; William J Jusko Journal: J Clin Pharmacol Date: 2019-02-11 Impact factor: 3.126
Authors: Daniela J Conrado; Jane Larkindale; Alexander Berg; Micki Hill; Jackson Burton; Keith R Abrams; Richard T Abresch; Abby Bronson; Douglass Chapman; Michael Crowther; Tina Duong; Heather Gordish-Dressman; Lutz Harnisch; Erik Henricson; Sarah Kim; Craig M McDonald; Stephan Schmidt; Camille Vong; Xiaoxing Wang; Brenda L Wong; Florence Yong; Klaus Romero Journal: J Pharmacokinet Pharmacodyn Date: 2019-05-24 Impact factor: 2.745
Authors: Mattia Quattrocelli; Aaron S Zelikovich; Zhen Jiang; Clara Bien Peek; Alexis R Demonbreun; Nancy L Kuntz; Grant D Barish; Saptarsi M Haldar; Joseph Bass; Elizabeth M McNally Journal: JCI Insight Date: 2019-12-19
Authors: J Spencer Hauck; Jeovanna Lowe; Neha Rastogi; Kevin E McElhanon; Jennifer M Petrosino; Kyra K Peczkowski; Ashlee N Chadwick; Jonathan G Zins; Federica Accornero; Paul M L Janssen; Noah L Weisleder; Jill A Rafael-Fortney Journal: Hum Mol Genet Date: 2019-06-15 Impact factor: 6.150
Authors: Xiaonan Li; Laurie S Conklin; John van den Anker; Eric P Hoffman; Paula R Clemens; William J Jusko Journal: J Clin Pharmacol Date: 2020-05-20 Impact factor: 3.126