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Progressive Multifocal Leukoencephalopathy Incidence and Risk Stratification Among Natalizumab Users in France.
JAMA Neurology ( IF 29.0 ) Pub Date : 2020-01-01 , DOI: 10.1001/jamaneurol.2019.2670
Sandra Vukusic 1, 2, 3 , Fabien Rollot 1, 4, 5, 6 , Romain Casey 1, 4, 5, 6 , Julie Pique 1, 2 , Romain Marignier 1, 2, 7 , Guillaume Mathey 8, 9 , Gilles Edan 10 , David Brassat 11 , Aurélie Ruet 12, 13, 14 , Jérôme De Sèze 15 , Elisabeth Maillart 16 , Hélène Zéphir 17 , Pierre Labauge 18, 19 , Nathalie Derache 20 , Christine Lebrun-Frenay 21 , Thibault Moreau 22 , Sandrine Wiertlewski 23, 24 , Eric Berger 25 , Xavier Moisset 26 , Audrey Rico-Lamy 27, 28 , Bruno Stankoff 29, 30 , Caroline Bensa 31 , Eric Thouvenot 32, 33 , Olivier Heinzlef 34 , Abdullatif Al-Khedr 35 , Bertrand Bourre 36 , Mathieu Vaillant 37 , Philippe Cabre 38 , Alexis Montcuquet 39 , Abir Wahab 40 , Jean-Philippe Camdessanché 41 , Ayman Tourbah 42, 43 , Anne-Marie Guennoc 44 , Karolina Hankiewicz 45 , Ivania Patry 46 , Chantal Nifle 47 , Nicolas Maubeuge 48 , Céline Labeyrie 49 , Patrick Vermersch 17 , David-Axel Laplaud 23, 24 ,
Affiliation  

Importance 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.

Objective 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.

Exposures Time from the first natalizumab infusion to the occurrence of PML, natalizumab discontinuation plus 6 months, or the last clinical evaluation.

Main Outcomes and Measures 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).

Results 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.

Conclusions and Relevance 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.



中文翻译:

法国那他珠单抗使用者中进行性多灶性白质脑病的发病率和风险分层。

发生进行性多灶性白质脑病(PML)的重要性风险是将那他珠单抗用于多发性硬化症(MS)患者的主要障碍。迄今为止,尚未评估风险分层与PML发生率的关联。

目的 描述2013年引入风险最小化建议前后法国PML发病率的时间变化。

设计,设置和参与者 这项观察性研究使用了MS专家注册中心和MS专用的神经科医生网络收集的2007年4月15日至2016年12月31日期间MS注册表OFSEP(弗兰克·德拉·斯科拉罗斯·弗拉瓦斯天文台)中的数据。在法国。根据目前的标准,无论年龄大小,均具有MS诊断的患者均符合条件,并且至少接受过1次那他珠单抗输注(n = 6318)的患者包括在高危人群中。向所有中心发送了一份问卷,要求其描述有关PML风险分层的实践。数据于2018年7月进行了分析。

暴露 时间:从首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。

主要结果和措施 发病率是报告的PML病例数相对于那他珠单抗暴露的人年数。2007年至2016年期间的Poisson回归模型估算了发病率和发病率比率(IRR)的年度变化,并根据治疗开始时的性别和年龄进行了调整,并按时期(2007-2013年和2013-2016年)进行了分层。

结果 在研究期间,共有6318例患者暴露于那他珠单抗,其中4682例女性(74.1%)为女性,MS发病的平均年龄(SD [范围])为28.5(9.1 [1.1-72.4])岁;在22 414人年期间,诊断出45例确诊的PML事件。整个2007年至2016年期间的原始发病率是每1000个患者-年2.00(95%CI,1.46-2.69)。 在2013年之前,每年的发病率显着上升45.3%(IRR,1.45; 95%CI,1.15-1.83; P = .001),而下降了23.0%(IRR,0.77; 95%CI,0.61-0.97; P  = .03 )从2013年到2016年每年。

结论与相关性 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的PML发病率下降,这可能与普遍使用John Cunningham病毒血清学检测结果有关。这一发现似乎支持在多发性硬化症的疾病缓解疗法管理中继续开展和加强教育活动和风险最小化策略。

更新日期:2020-01-13
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