诺西那生钠对2型和非行走型3型脊髓性肌萎缩症儿科患者呼吸进展的治疗作用
Therapeutic Role of Nusinersen on Respiratory Progression in Pediatric Patients With Spinal Muscular Atrophy Type 2 and Nonambulant Type 3.
作者信息
Trucco Federica, Ridout Deborah, Weststrate Harriet, Scoto Mariacristina, Rohwer Annemarie, Coratti Giorgia, Main Marion L, Mayhew Anna G, Montes Jacqueline, De Sanctis Roberto, Pane Marika, Pera Maria Carmela, Sansone Valeria A, Albamonte Emilio, D'Amico Adele, Bruno Claudio, Messina Sonia S, Childs Anne-Marie, Willis Tracey, Ong Min T, Servais Laurent, Majumdar Anirban, Hughes Imelda, Marini-Bettolo Chiara, Parasuraman Deepak, Gowda Vasantha L, Baranello Giovanni, Bertini Enrico S, De Vivo Darryl C, Darras Basil T, Day John W, Mayer Oscar, Zolkipli-Cunningham Zarazuela, Finkel Richard S, Mercuri Eugenio, Muntoni Francesco
机构信息
Dubowitz Neuromuscular Centre (FT, HW, MS, AR, MLM, GB, FM), UCL Institute of Child Health & Great Ormond Street Hospital, London; Department Paediatric Neuroscience Evelina London Children's Hospital and Department Paediatric Respiratory Medicine (FT), Royal Brompton Hospital, Guy's and St Thomas NHS Trust London, United Kingdom; Pediatric Neurology and Muscular Diseases Unit (FT), IRCCS Istituto Giannina Gaslini, Genova and Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Italy; Population (DR), Policy and Practice Programme, UCL GOS Institute of Child Health, London; Paediatric Neurology (GC, RDS, MP, MCP, EM), Università Cattolica del Sacro Cuore; Centro Clinico Nemo (GC, RDS, MP, MCP, EM), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Newcastle University and Newcastle Hospitals NHS Foundation Trust (AGM, CM-B), Newcastle Upon Tyne, United Kingdom; Department of Rehabilitation and Regenerative Medicine (JM), Columbia University Irving Medical Center, New York; Neurorehabilitation Unit (VAS, EA), University of Milan, Neuromuscular Omnicentre Clinical Center, Niguarda Hospital; Unit of Neuromuscular and Neurodegenerative Disorders (ADA, ESB), Bambino Gesù Children's Hospital IRCCS, Rome; Center of Experimental and Translational Myology (CB), IRCCS Istituto Giannina Gaslini, Genoa and Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa; Department of Clinical and Experimental Medicine and Centro Clinico Nemo Sud (SSM), University of Messina, Italy; Leeds Children Hospital (A-MC); The Robert Jones and Agnes Hunt Orthopaedic Hospital (TW), Oswestry; Sheffield Children's Hospital (MTO, LS); MDUK Oxford Neuromuscular Centre & NIHR Oxford Biomedical Research Centre (LS), University of Oxford, United Kingdom; Neuromuscular Reference Center, Department of Paediatrics, University and University Hospital of Liege, Belgium; Royal Hospital for Children (AM), Bristol; Royal Manchester Children's Hospital (IH); University Hospitals Birmingham (DP), United Kingdom; Evelina London Children's Hospital (VLG), London, UK; Departments of Neurology and Pediatrics (DCDV), Columbia University Irving Medical Center, New York; Department of Neurology (BTD), Boston Children's Hospital, Harvard Medical School, Boston, MA; Department of Neurology (JWD), Stanford University, Palo Alto, CA; Department of Paediatrics The Children's Hospital of Philadelphia (OM, ZZ-C), Philadelphia, PA; Nemours Children's Hospital (RSF), University of Central Florida College of Medicine, Orlando; St. Jude Children's Research Hospital (RSF), Memphis, TN; and NIHR Great Ormond Street Hospital Biomedical Research Centre (FM), London, United Kingdom.
出版信息
Neurol Clin Pract. 2024 Jun;14(3):e200298. doi: 10.1212/CPJ.0000000000200298. Epub 2024 May 17.
BACKGROUND AND OBJECTIVES
Nusinersen has shown significant functional motor benefit in the milder types of spinal muscular atrophy (SMA). Less is known on the respiratory outcomes in patients with nusinersen-treated SMA. The aim of this study was to describe changes in respiratory function in pediatric patients with SMA type 2 and 3 on regular treatment with nusinersen within the iSMAc international cohort and to compare their trajectory with the natural history (NH) data published by the consortium in 2020.
METHODS
This is a 5-year retrospective observational study of pediatric SMA type 2 and nonambulant type 3 (age ≤18 years) treated with nusinersen. The primary objective was to compare the slopes of decline in forced vital capacity % predicted (FVC% pred.), FVC, and age when FVC dropped below 60% between the treated patients and a control group from the natural history cohort. Data on peak cough flow and the use of noninvasive ventilation (NIV) and cough assist were collected.
RESULTS
Data were available for 69 treated patients, 53 were SMA type 2 and 16 type 3. The mean (SD) age at first injection was 8.5 (3.2) and 9.7 (3.7) years, respectively. The median (interquartile range) treatment duration was 1 (0.7; 1.9) and 1.2 (0.9; 1.9) years, respectively. At the time of the first nusinersen injection, 24 of 52 (46%) patients with SMA type 2 and 2 of 16 (13%) patients with SMA type 3 were on NIV. Forty-three of 53 (81%) and 4 of 16 (25%) patients used cough device. FVC% pred. in treated patients with SMA type 2 declined annually by 2.3% vs 3.9% in NH ( = 0.08) and in treated patients with type 3 by 2.6% vs 3.4% NH ( = 0.59). Patients treated reached FVC <60% later than untreated (12.1 vs 10 years, = 0.05). A higher percentage of treated vs untreated patients maintained FVC% pred. equal/above their baseline after 12 (65% vs 36%) and 24 (50% vs 24%) months, respectively. NIV use among treated did not significantly change throughout 1-year follow-up.
DISCUSSION
This study included the largest real-world cohort of pediatric patients with milder SMA types. The results suggest a positive role of nusinersen in delaying the respiratory decline in patients treated longer than 1 year when compared with natural history. Larger cohorts and longer observation are planned.
CLASSIFICATION OF EVIDENCE
This study provided Class III evidence that nusinersen slows progression for patients with SMA types 2 and 3 compared with a natural history cohort.
背景与目的
在症状较轻的脊髓性肌萎缩症（SMA）类型中，诺西那生已显示出显著的运动功能改善效果。关于接受诺西那生治疗的SMA患者的呼吸结局，人们了解较少。本研究的目的是描述国际SMA队列研究（iSMAc）中接受诺西那生常规治疗的2型和3型小儿SMA患者的呼吸功能变化，并将其轨迹与该联盟2020年公布的自然史（NH）数据进行比较。
方法
这是一项对接受诺西那生治疗的2型小儿SMA和非行走型3型小儿SMA（年龄≤18岁）进行的为期5年的回顾性观察研究。主要目的是比较治疗组患者与自然史队列中的对照组在预测的用力肺活量百分比（FVC%pred.）、FVC以及FVC降至60%以下时的年龄下降斜率。收集了关于峰值咳嗽流量以及无创通气（NIV）和咳嗽辅助使用的数据。
结果
有69例接受治疗的患者的数据可用，其中53例为2型SMA，16例为3型SMA。首次注射时的平均（标准差）年龄分别为8.5（3.2）岁和9.7（3.7）岁。治疗持续时间的中位数（四分位间距）分别为1（0.7；1.9）年和1.2（0.9；1.9）年。在首次注射诺西那生时，52例2型SMA患者中有24例（46%）和16例3型SMA患者中有2例（13%）正在接受NIV治疗。53例患者中有43例（81%）和16例患者中有4例（25%）使用了咳嗽装置。接受治疗的2型SMA患者的FVC%pred.每年下降2.3%，而自然史队列中为3.9%（P = 0.08）；接受治疗的3型患者的FVC%pred.每年下降2.6%，而自然史队列中为3.4%（P = 0.59）。接受治疗的患者达到FVC<60%的时间比未治疗的患者晚（12.1岁对10岁，P = 0.05）。在12个月（65%对36%）和24个月（50%对24%）后，接受治疗的患者中维持FVC%pred.等于/高于其基线的比例高于未治疗的患者。在1年的随访期间，接受治疗的患者中NIV的使用没有显著变化。
讨论
本研究纳入了最大的现实世界中症状较轻的小儿SMA患者队列。结果表明，与自然史相比，诺西那生在延迟接受治疗超过1年的患者的呼吸功能下降方面具有积极作用。计划开展更大规模的队列研究和更长时间的观察。
证据分级
本研究提供了III级证据，表明与自然史队列相比，诺西那生可减缓2型和3型SMA患者的疾病进展。
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