诺西那生钠治疗脊髓性肌萎缩症患儿临床疗效的meta分析

doi:10.12372/jcp.2023.23e0303

摘要/Abstract

摘要：

目的采用meta分析方法评估诺西那生钠治疗儿童脊髓性肌萎缩症（SMA）患者的临床疗效。方法通过检索Cochrane Library、Embase、PubMed、Web of Science、ClinicalTrial.gov、CBM、CNKI、万方和VIP数据库，检索时限为建库至2022年12月31日。由2名研究者独立筛选文献、提取资料并评价纳入研究的偏倚风险后，采用Stata 14.0进行meta分析。结果共纳入14篇队列研究，1 274例年龄<18岁SMA患者。治疗期间，运动功能指标费城儿童医院神经肌肉障碍婴儿测试评分（CHOP-INTEND）、Hammersmith婴儿神经病学检查第2部分（HINE-2）评分、Hammersmith运动功能（HFMSE）评分、上肢运动功能（RULM）评分均有显著改善，合并均数差分别为9.08（95%CI：7.17~10.99)、2.08（95%CI：1.26~2.90)、3.83（95%CI：2.15~5.50)、2.42（95%CI：1.33~3.52)；临床改善率分别为0.77（95%CI：0.71~0.82)、0.39（95%CI：0.31~0.48)、0.53（95%CI：0.33~0.72)、0.56（95%CI：0.49~0.63)。结论诺西那生钠对SMA 1、2、3型患儿的运动功能有较大改善，受纳入研究质量和样本量的限制，上述结论尚待更多高质量研究予以验证。

关键词: 脊髓性肌萎缩症, 诺西那生钠, 运动功能, meta分析, 儿童

Abstract:

Objective Meta-analysis was used to evaluate clinical efficacy in children with spinal muscular atrophy treated with nusinersen. Methods Cochrane Library, Embase, PubMed, Web of Science, ClinicalTrial.gov, CBM, CNKI, Wanfang and VIP databases were searched from inception to December 31, 2022. Stata 14.0 was used for meta-analysis after two researchers independently screened the literature, extracted data, and evaluated the risk of bias in the included studies. Results A total of 14 cohort studies were included, involving 1274 SMA patients <18 years of age. During therapy, motor function indicators showed significant improvement in the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), Hammersmith Infant Neurological Examination Part 2 (HINE-2) score, Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) score, and combined mean differences were 9.08(95%CI: 7.17-10.99), 2.08(95%CI: 1.26-2.90), 3.83(95%CI: 2.15-5.50) and 2.42(95%CI: 1.33-3.52), respectively. The clinical improvement rates were 0.77(95%CI: 0.71-0.82), 0.39(95%CI: 0.31-0.48), 0.53(95%CI: 0.33-0.72), and 0.56(95%CI: 0.49-0.63), respectively. Conclusions The motor function of children with SMA type 1, 2, and 3 was significantly improved by nusinersen. Limited by the quality and sample size of the included studies, the above conclusions need to be verified by more high-quality studies.

Key words: spinal muscular atrophy, nusinersen, motor function, meta-analysis, child

何冠兰, 韦秋芬, 李娜, 陈少萍, 刘云媛, 廖莎莎, 唐秀能. 诺西那生钠治疗脊髓性肌萎缩症患儿临床疗效的meta分析[J]. 临床儿科杂志, 2023, 41(12): 946-954.

HE Guanlan, WEI Qiufen, LI Na, CHEN Shaoping, LIU Yunyuan, LIAO Shasha, TANG Xiuneng. Meta-analysis of clinical efficacy of nusinersen in the treatment of children with spinal muscular atrophy[J]. Journal of Clinical Pediatrics, 2023, 41(12): 946-954.

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步骤	检索式
#1	"Muscular Atrophy, Spinal"[Mesh]
#2	"Spinal Muscular atrophy"[Text Word]
#3	SMA[Text Word]
#4	#1 OR #2 OR #3
#5	"Oligonucleotides, Antisense"[Mesh]
#6	nusinersen[Text Word]
#7	spinraza[Text Word]
#8	#5 OR #6 OR #7
#9	"treatment,outcome"[Mesh]
#10	"treatment outcome*[Text Word]"
#11	efficacy[Text Word]
#12	#9 OR #10 OR #11
#13	#4 AND #8 AND #12

作者	年份	患者例数	人群来源	SMA分型	随访时间/月	结局指标
Tscherter^[13]	2022	11	瑞士	1	>6	①
Pechmann^[14]	2022	256	德国	2、3	14	②③
Pane^[15]	2022	73	意大利	2、3	24	②③
Kotulska^[16]	2022	298	波兰	1、2、3	12	①②
Pera^[17]	2021	77	美国、英国、意大利	3	>6	②③
Pane^[18]	2021	122	意大利	1	12	①④
Modrzejewska^[19]	2021	26	波兰	1	18-26	①
Mendonca^[20]	2021	21	巴西	1	>6	①④
Konersman^[21]	2021	19	美国	1、2、3	22	①②
Coratti^[22]	2021	77	美国、英国、意大利	2	12	②③
Szabo^[23]	2020	57	匈牙利	1、2、3	10	①②③
Audic^[24]	2020	123	法国	1、2	12	①④
Aragon-Gawinska^[25]	2020	53	法国、比利时	1	14	①④
Pechmann^[26]	2018	61	德国	1	>6	①④

作者	年份	研究人群选择（0~4分）	组间可比性（0~2分）	结果测量（0~3分）	总分
Tscherter^[13]	2022	3	2	3	8
Pechmann^[14]	2022	3	2	2	7
Pane^[15]	2022	3	2	3	8
Kotulska^[16]	2022	3	2	3	8
Pera^[17]	2021	3	2	3	8
Pane^[18]	2021	3	2	3	8
Modrzejewska^[19]	2021	3	2	3	8
Mendonca^[20]	2021	3	2	3	8
Konersman^[21]	2021	3	2	3	8
Coratti^[22]	2021	3	2	3	8
Szabo^[23]	2020	3	2	3	8
Audic^[24]	2020	3	2	3	8
Aragon-Gawinska^[25]	2020	3	2	3	8
Pechmann^[26]	2018	3	2	3	8
总分		42/56	28/28	41/42

结局指标	纳入研究数	质量升级因素			结果汇总
结局指标	纳入研究数	效应值是否很大	存在剂量- 效应关系	存在降低疗效的混杂因素	研究对象 /例	MD/改善率（95%CI）	证据质量
CHOP INTEND评分	8	效应值较大	否	否	369	9.08(7.17~10.99)	中
CHOP INTEND临床改善率	3	效应值较大	否	否	242	0.77(0.71~0.82)	中
HINE-2评分	6	否	否	否	219	2.08(1.26~2.90)	低
HINE-2临床改善率	4	否	否	否	131	0.39(0.31~0.48)	低
HFMSE评分	7	否	否	否	508	3.83(2.15~5.50)	低
HFMSE临床改善率	4	否	否	否	354	0.53(0.33~0.72)	低
RULM评分	6	否	否	否	306	2.42(1.33~3.52)	低
RULM临床改善率	3	否	否	否	205	0.56(0.49~0.63)	低