An ever-expanding number of disease-modifying drugs for multiple sclerosis have become available in recent years, after demonstrating efficacy in clinical trials. In the real-world setting, however, disease-modifying drugs are prescribed in patient populations that differ from those included in pivotal studies, where extreme age patients are usually excluded or under-represented. In this multicentre, observational, retrospective Italian cohort study, we evaluated treatment exposure in three cohorts of patients with relapsing-remitting multiple sclerosis defined by age at onset: paediatric-onset (≤18 years), adult-onset (18–49 years) and late-onset multiple sclerosis (≥50 years). We included patients with a relapsing-remitting phenotype, ≥5 years follow-up, ≥3 Expanded Disability Status Scale (EDSS) evaluations and a first neurological evaluation within 3 years from the first demyelinating event. Multivariate Cox regression models (adjusted hazard ratio with 95% confidence intervals) were used to assess the risk of reaching a first 12-month confirmed disability worsening and the risk of reaching a sustained EDSS of 4.0. The effect of disease-modifying drugs was assessed as quartiles of time exposure. We found that disease-modifying drugs reduced the risk of 12-month confirmed disability worsening, with a progressive risk reduction in different quartiles of exposure in paediatric-onset and adult-onset patients [adjusted hazard ratios in non-exposed versus exposed >62% of the follow-up time: 8.0 (3.5–17.9) for paediatric-onset and 6.3 (4.9–8.0) for adult-onset, P < 0.0001] showing a trend in late-onset patients [adjusted hazard ratio = 1.9 (0.9–4.1), P = 0.07]. These results were confirmed for a sustained EDSS score of 4.0. We also found that relapses were a risk factor for 12-month confirmed disability worsening in all three cohorts, and female sex exerted a protective role in the late-onset cohort. This study provides evidence that sustained exposure to disease-modifying drugs decreases the risk of disability accumulation, seemingly in a dose-dependent manner. It confirms that the effectiveness of disease-modifying drugs is lower in late-onset patients, although still detectable.

中文翻译：

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缓解疾病的药物可以减少复发性多发性硬化症中的残疾进展。

在临床试验中证明了疗效之后，近年来用于多发性硬化症的疾病改善药物的数量正在不断增加。然而，在现实世界中，疾病治疗药物的处方人群不同于关键研究中的患者人群，而关键研究中极端年龄患者通常被排除或代表性不足。在这项多中心，观察性，回顾性意大利队列研究中，我们评估了三组根据发作年龄定义的复发缓解型多发性硬化症患者的治疗暴露：儿科发作（≤18岁），成人发作（18-49岁）和迟发性多发性硬化症（≥50岁）。我们纳入了复发缓解型患者，随访≥5年，在第一次脱髓鞘事件发生后的三年内，≥3扩展的残疾状态量表（EDSS）评估和首次神经系统评估。使用多变量Cox回归模型（具有95％置信区间的调整风险比）评估达到最初12个月确认的残疾加重的风险和达到EDSS持续4.0的风险。疾病缓解药物的效果被评估为时间暴露的四分位数。我们发现，改变疾病的药物降低了12个月证实的残疾加重的风险，儿科和成人患者不同四分位数的暴露风险逐渐降低[未暴露与暴露的经调整的危险比> 62％随访时间：儿童发病为8.0（3.5–17.9），成人发病为6.3（4.9–8.0），使用多变量Cox回归模型（具有95％置信区间的调整风险比）评估达到最初12个月确认的残疾加重的风险和达到EDSS持续4.0的风险。疾病缓解药物的效果被评估为时间暴露的四分位数。我们发现，改变疾病的药物降低了12个月证实的残疾加重的风险，儿科和成人患者不同四分位数的暴露风险逐步降低[未暴露与暴露的经调整的危险比> 62％随访时间：儿童发病为8.0（3.5–17.9），成人发病为6.3（4.9–8.0），使用多变量Cox回归模型（具有95％置信区间的调整风险比）评估达到最初12个月确认的残疾加重的风险和达到EDSS持续4.0的风险。疾病缓解药物的效果被评估为时间暴露的四分位数。我们发现，改变疾病的药物降低了12个月证实的残疾加重的风险，儿科和成人患者不同四分位数的暴露风险逐步降低[未暴露与暴露的经调整的危险比> 62％随访时间：儿童发病为8.0（3.5–17.9），成人发病为6.3（4.9–8.0），疾病缓解药物的效果被评估为时间暴露的四分位数。我们发现，改变疾病的药物降低了12个月证实的残疾加重的风险，儿科和成人患者不同四分位数的暴露风险逐渐降低[未暴露与暴露的经调整的危险比> 62％随访时间：儿童发病为8.0（3.5–17.9），成人发病为6.3（4.9–8.0），疾病改善药物的效果被评估为时间暴露的四分位数。我们发现，改变疾病的药物降低了12个月证实的残疾加重的风险，儿科和成人患者不同四分位数的暴露风险逐渐降低[未暴露与暴露的经调整的危险比> 62％随访时间：儿童发病为8.0（3.5–17.9），成人发病为6.3（4.9–8.0），P  <  0.0001]显示了晚期患者的趋势[校正后的危险比= 1.9（0.9-4.1），P  =  0.07]。EDSS持续得分为4.0证实了这些结果。我们还发现，复发是所有三个队列中12个月证实的残疾加重的危险因素，而女性在迟发队列中起保护作用。这项研究提供的证据表明，持续接触改善疾病的药物似乎可以剂量依赖性地降低残疾累积的风险。它证实，尽管仍可检出，但在晚期患者中，疾病缓解药物的有效性较低。