Université Claude Bernard Lyon 1, Faculté de Médecine Lyon Est, Lyon, France.
Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-Inflammation, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon/Bron, France.
JAMA Neurol. 2020 Jan 1;77(1):94-102. doi: 10.1001/jamaneurol.2019.2670.
Risk of developing progressive multifocal leukoencephalopathy (PML) is the major barrier to using natalizumab for patients with multiple sclerosis (MS). To date, the association of risk stratification with PML incidence has not been evaluated.
To describe the temporal evolution of PML incidence in France before and after introduction of risk minimization recommendations in 2013.
DESIGN, SETTING, AND PARTICIPANTS: This observational study used data in the MS registry OFSEP (Observatoire Français de la Sclérose en Plaques) collected between April 15, 2007, and December 31, 2016, by participating MS expert centers and MS-dedicated networks of neurologists in France. Patients with an MS diagnosis according to current criteria, regardless of age, were eligible, and those exposed to at least 1 natalizumab infusion (n = 6318) were included in the at-risk population. A questionnaire was sent to all centers, asking for a description of their practice regarding PML risk stratification. Data were analyzed in July 2018.
Time from the first natalizumab infusion to the occurrence of PML, natalizumab discontinuation plus 6 months, or the last clinical evaluation.
Incidence was the number of PML cases reported relative to the person-years exposed to natalizumab. A Poisson regression model for the 2007 to 2016 period estimated the annual variation in incidence and incidence rate ratio (IRR), adjusted for sex and age at treatment initiation and stratified by period (2007-2013 and 2013-2016).
In total, 6318 patients were exposed to natalizumab during the study period, of whom 4682 (74.1%) were female, with a mean (SD [range]) age at MS onset of 28.5 (9.1 [1.1-72.4]) years; 45 confirmed incident cases of PML were diagnosed in 22 414 person-years of exposure. The crude incidence rate for the whole 2007 to 2016 period was 2.00 (95% CI, 1.46-2.69) per 1000 patient-years. Incidence significantly increased by 45.3% (IRR, 1.45; 95% CI, 1.15-1.83; P = .001) each year before 2013 and decreased by 23.0% (IRR, 0.77; 95% CI, 0.61-0.97; P = .03) each year from 2013 to 2016.
The results of this study suggest, for the first time, a decrease in natalizumab-associated PML incidence since 2013 in France that may be associated with a generalized use of John Cunningham virus serologic test results; this finding appears to support the continuation and reinforcement of educational activities and risk-minimization strategies in the management of disease-modifying therapies for multiple sclerosis.
进展性多灶性白质脑病（PML）的风险是使用那他珠单抗治疗多发性硬化症（MS）患者的主要障碍。迄今为止，风险分层与 PML 发病率的关联尚未得到评估。
描述 2013 年引入风险最小化建议前后法国 PML 发病率的时间演变。
设计、设置和参与者：本观察性研究使用了 2007 年 4 月 15 日至 2016 年 12 月 31 日期间在法国通过参与 MS 专家中心和 MS 专用神经病学家网络收集的 OFSEP（法国多发性硬化症观察站）MS 注册表中的数据。根据当前标准诊断为 MS 的患者，无论年龄大小，均符合条件，且至少接受过 1 次那他珠单抗输注（n=6318）的患者被纳入高危人群。向所有中心发送了一份问卷，要求他们描述其 PML 风险分层实践情况。数据于 2018 年 7 月进行了分析。
从第一次那他珠单抗输注到发生 PML、那他珠单抗停药加 6 个月或最后一次临床评估的时间。
发病率是报告的 PML 病例数与接受那他珠单抗治疗的人年数之比。2007 年至 2016 年期间的泊松回归模型估计了发病率的年度变化和发病率比（IRR），调整了性别和治疗开始时的年龄，并按时期分层（2007-2013 年和 2013-2016 年）。
在研究期间，共有 6318 名患者接受了那他珠单抗治疗，其中 4682 名（74.1%）为女性，MS 发病时的平均（SD[范围]）年龄为 28.5（9.1[1.1-72.4]）岁；在 22414 人年的暴露中，确诊了 45 例确诊的 PML 病例。整个 2007 年至 2016 年期间的粗发病率为 2.00（95%CI，1.46-2.69）/1000 人年。2013 年前，发病率每年显著增加 45.3%（IRR，1.45；95%CI，1.15-1.83；P=.001），2013 年至 2016 年期间每年降低 23.0%（IRR，0.77；95%CI，0.61-0.97；P=.03）。
这项研究的结果首次表明，自 2013 年以来，法国那他珠单抗相关 PML 发病率有所下降，这可能与更广泛使用约翰·坎宁安病毒血清学检测结果有关；这一发现似乎支持继续加强多发性硬化症疾病修饰疗法管理中的教育活动和风险最小化策略。
