利司扑兰单药治疗儿童脊髓性肌萎缩症随访1年的病例系列报告

One year follow-up of Risdiplam monotherapy in children with spinal muscular atrophy:A case series report

背景利司扑兰服用1个月内对不同类型脊髓性肌萎缩症(SMA)患儿均有疗效,由于利司扑兰治疗获取的便捷性等原因复诊随访率较低,缺乏中国长期应用该药治疗的真实世界数据。目的观察不同类型SMA患儿利司扑兰单药治疗≥12个月的效果。设计病例系列报告。方法纳入2021年8月至2023年3月山东大学附属儿童医院神经内科门诊或住院、接受了利司扑兰初始和随访期间单药治疗的、治疗年龄≥16 d的、治疗开始和随访期间接受了运动功能评估的不同类型SMA的连续病例。依据利司扑兰说明书推荐的方法以年龄和体重计算口服剂量服药,观察随访≥6个月,由有评估资质的医生行运动功能评估,评估量表如下:费城儿童医院神经肌肉评估量表(CHOP INTEND)、修订的上肢模块测试(RULM)、汉默史密斯运动功能扩展量表(HFMSE)、6 min步行试验(6MWT),观察不良事件和发生率。主要结局指标运动功能改善水平(最后一次随访的运动功能评分-基线运动功能评分,或切换量表后最后一次随诊时运动功能评分)。结果14例SMA患儿进入本文分析,男9例(64.3%),女5例。除1例症状前患儿外,余13例患儿的平均起病年龄为9.0(3.0,12.0)月龄;14例SMA患儿接受利司扑兰治疗的平均年龄为19.5(6.5,39.5)月龄。1例SMN1拷贝数为1,存在点突变,余13例SMN1拷贝数均为0;SMN2拷贝数为1、2、3和4的患儿分别有1例、3例、9例和1例。症状前1例,1型6例,2型5例,3型2例。末次随访与首次给药时间间隔为20(11.8,25.5)个月。13例SMA患儿的运动功能改善具有临床意义,1例运动功能评分有提升,但改善尚不具临床意义。9例SMA患儿有基线及随访血常规、肝功能和肾功能结果;血常规均正常;2例基线时肝功能异常,随访中恢复正常;部分患儿血肌酐水平异常,与SMA疾病本身相关,随访中未见血肌酐水平增高。随访期间可能与药物无关的不良事件包括上呼吸道感染11例次,肺炎4例次,腹泻1例次,除1例肺炎为2型SMA,其余不良事件均发生于1型SMA;可能与药物相关的不良反应包括皮肤颜色改变12例(85.7%),皮疹2例(14.3%),便秘1例(7.1%)。未发现严重不良反应。本文报告了1例SMA患儿在出现症状前接受利司扑兰治疗可维持正常的运动功能发育的病例,也报告了SMN2单拷贝患儿接受利司扑兰同样具有良好效果。结论中国不同类型的SMA患儿长期接受利司扑兰单药治疗疗效尚好,常见不良事件为呼吸道感染和皮肤颜色改变。

Background Risdiplam has showed efficacy in Chinsese children with different types of spinal muscular atrophy(SMA)for one-month treatment.However,there is still a lack of real-world data on long-term use of Risdiplam due to the low follow-up visit rates which may caused by the convenience of Risdiplam obtaining and other reasons.Objective To observe the efficacy of Risdiplam monotherapy in children with different types of SMA treated for more than 12 months.Design Case series report.Methods Continuous cases with different types of SMA who were treated with Risdiplam as a monotherapy during the initial and follow-up periods from August 2021 to March 2023 in outpatient or hospital settings were enrolled.The enrolled cases with the age≥16 days when the treatment was initiated were assessed by motor function scales at the beginning of the treatment and during their follow-ups.The oral dose of Risdiplam was calculated based on the patient's age and weight referred to the drug instructions.Patients were followed for at least 6 months and assessed by the qualified doctors with different motor scales.The outcomes of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders(CHOP INTEND),the Revised Upper Limb Module Test(RULM),the Hammersmith Functional Motor Scale Expanded(HFMSE)and the 6-Minute Walk Test(6MWT)were recorded.The adverse events(AEs)and the rate of AEs were reported.Main outcome measures Improvement level of motor function score:last follow-up motor function score-baseline motor function score;or motor function score at the last follow-up after switching scales.Results In total,14 SMA pediatric patients were enrolled in this study,including 9 boys(64.3%)and 5 girls.Except for 1 presymptomatic patient,the median age of disease onset of the remaining 13 patients was 9.0(3.0,12.0)months;the median age of the 14 patients receiving Risdiplam treatment was 19.5(6.5,39.5)months.One patient had one copy number of SMN1 with a point mutation,and the remaining 13 patients occupied 0 copy of SMN1.The nubmer of atients with 1,2,3 and 4 copy numbers of SMN2 was 1,3,9 and 1,respectively.The case number of presymptomatic,type 1,type 2 and type 3 was 1,6,5 and 2,respectively.The interval between the last follow-up and the first drug administration was 20(11.8,25.5)months.The improvement in motor function reached clinical significance in 13 SMA patients,and the remained 1 patient also showed improved motor function score scale,but the improvement was not clinically significant.Nine patients had the results of blood routine,liver function and renal function at the baseline and during the follow-ups.The blood routine were normal.Two patients showed abnormal liver function at baseline but with normal results during the follow-ups,and some patients showed abnormal serum creatinine levels,which were caused by the SMA disease itself,and no increase in serum creatinine levels was found during follow-ups.Adverse events that may not be related to the treatment during follow-ups included 11 case of upper respiratory tract infection,4 case of pneumonia,and 1 case of diarrhea.Except for pneumonia occurred in a child with type 2,the rest of the adverse events occurred in children with type 1.Adverse events that may be related to the treatment included skin color changes in 12 cases(85.7%),rash in 2 cases(14.3%),and constipation in 1 case(7.1%).No serious adverse reactions were found.This article reports one case who maintained normal motor function development after receiving Risdiplam treatment before symptom onset and one case who showed good efficacy of Risdiplam with one copy of SMN2.Conclusion Long-term monotherapy of Risdiplam has shown good efficacy in Chinese children with different subtypes of SMA and the most common adverse drug reaction are respiratory tract infections and the change of skin color.