High-efficacy disease-modifying therapies have been proven to slow disability accrual in adults with relapsing–remitting multiple sclerosis. However, their impact on disability worsening in paediatric-onset multiple sclerosis, particularly during the early phases, is not well understood. We evaluated how high-efficacy therapies influence transitions across five disability states, ranging from minimal disability to gait impairment and secondary progressive multiple sclerosis, in people with paediatric-onset multiple sclerosis. Longitudinal data were obtained from the international MSBase registry, containing data from people with multiple sclerosis from 151 centres across 41 countries, and the Italian Multiple Sclerosis and Related Disorders Register, containing data from people with multiple sclerosis from 178 Italian multiple sclerosis centres. People younger than 18 years at the onset of multiple sclerosis symptoms were included, provided they had a confirmed diagnosis of relapsing–remitting multiple sclerosis and at least four Expanded Disability Status Scale (EDSS) scores recorded within 12-month intervals. The primary outcome was the time to change in disability state: minimal disability (EDSS scores 0, 1·0, and 1·5), mild disability (EDSS scores 2·0 and 2·5), moderate disability (EDSS scores 3·0 and 3·5), gait impairment (EDSS scores ≥4·0), and clinician diagnosed secondary progressive multiple sclerosis. A multi-state model was constructed to simulate the natural course of multiple sclerosis, modelling the probabilities of both disability worsening and improvement simultaneously. The impact of high-efficacy disease-modifying therapies (alemtuzumab, cladribine, daclizumab, fingolimod, mitoxantrone, natalizumab, ocrelizumab, rituximab, or autologous haematopoietic stem cell transplantation) and low-efficacy disease-modifying therapies (dimethyl fumarate, glatiramer acetate, interferon beta, or teriflunomide), compared with no treatment, on the course of disability was assessed. Apart from recruitment, individuals with lived experience of multiple sclerosis were not involved in the design and conduct of this study. A total of 5224 people (3686 [70·6%] female and 1538 [29·4%] male) with mean age at onset of multiple sclerosis 15·24 years (SD 2·52) were included. High-efficacy therapies reduced the hazard of disability worsening across the disability states. The largest reduction (hazard ratio 0·41 [95% CI 0·31–0·53]) was observed in participants who were treated with high-efficacy therapies while in the minimal disability state, compared with those remained untreated. The benefit of high-efficacy therapies declined with increasing disability. Young people with minimal disability who received low-efficacy therapy also experienced a reduced hazard (hazard ratio 0·65 [95% CI 0·54–0·77]) of transitioning to mild disability, in contrast to those who remained untreated. Treatment of paediatric-onset relapsing−remitting multiple sclerosis with high-efficacy therapy substantially reduces the risk of reaching key disability milestones. This reduction in risk is most pronounced among young people with minimal or mild disability when treatment began. Children with relapsing−remitting multiple sclerosis should be treated early with high-efficacy therapy, before developing significant neurological impairments, to better preserve their neurological capacity. National Health and Medical Research Council, Australia; MSBase Foundation Fellowship; MS Australia Postdoctoral Fellowship.

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控制儿童多发性硬化症残疾恶化的疾病修饰疗法：全球和国家登记的纵向分析

高效的疾病缓解疗法已被证明可以减缓患有复发缓解型多发性硬化症的成人的残疾累积。然而，它们对儿童发病的多发性硬化症残疾恶化的影响，特别是在早期阶段，尚不清楚。我们评估了高效疗法如何影响儿科发病的多发性硬化症患者五种残疾状态的转变，从轻微残疾到步态障碍和继发性进行性多发性硬化症。纵向数据来自国际 MSBase 登记处（包含来自 41 个国家 151 个中心的多发性硬化症患者的数据）和意大利多发性硬化症及相关疾病登记处（包含来自 178 个意大利多发性硬化症中心的多发性硬化症患者的数据）。多发性硬化症症状发作时年龄小于 18 岁的人也被包括在内，前提是他们已确诊为复发缓解型多发性硬化症，并且至少在 12 个月的时间间隔内记录了四项扩展残疾状态量表 (EDSS) 评分。主要结局是残疾状态改变的时间：轻微残疾（EDSS 评分 0、1·0 和 1·5）、轻度残疾（EDSS 评分 2·0 和 2·5）、中度残疾（EDSS 评分 3·5） 0和3·5），步态障碍（EDSS评分≥4·0），临床医生诊断为继发性进行性多发性硬化症。构建了多状态模型来模拟多发性硬化症的自然病程，同时对残疾恶化和改善的概率进行建模。高效疾病缓解疗法（阿仑单抗、克拉屈滨、达克珠单抗、芬戈莫德、米托蒽醌、那他珠单抗、奥瑞珠单抗、利妥昔单抗或自体造血干细胞移植）和低效疾病缓解疗法（富马酸二甲酯、醋酸格拉替雷、干扰素）的影响β或特立氟胺）与不治疗相比，对残疾过程进行了评估。除了招募之外，具有多发性硬化症生活经历的个人没有参与本研究的设计和实施。共纳入 5224 人（3686 [70·6%] 女性和 1538 [29·4%] 男性），多发性硬化症平均发病年龄为 15·24 岁（SD 2·52）。高效疗法降低了残疾状态下残疾恶化的风险。与未接受治疗的参与者相比，在最低程度残疾状态下接受高效治疗的参与者观察到最大程度的降低（风险比 0·41 [95% CI 0·31–0·53]）。高效疗法的益处随着残疾的增加而下降。与未接受治疗的年轻人相比，接受低效治疗的轻度残疾年轻人转变为轻度残疾的风险也降低（风险比 0·65 [95% CI 0·54–0·77]）。采用高效疗法治疗儿科发作的复发缓解型多发性硬化症可大大降低达到关键残疾里程碑的风险。这种风险的降低在治疗开始时患有轻微或轻度残疾的年轻人中最为明显。患有复发缓解型多发性硬化症的儿童应在出现明显的神经功能障碍之前尽早接受高效治疗，以更好地保留其神经功能。澳大利亚国家健康和医学研究委员会； MSBase 基金会奖学金；澳大利亚女士博士后奖学金。