Annual 12-Week Dosing Gap of Natalizumab: Clinical Efficacy, Blood Biomarkers, and CSF Cell Composition.

IF 3.9 2区 医学 Q1 CLINICAL NEUROLOGY
Regina Berkovich, Tilman Schneider-Hohendorf, Eric Baetscher, Evan L Riddle, Marie Deffner, Emily Katsnelson, Janine Ferrant-Orgettas, Julie Czerkowicz, John Anderson, Susan E Goelz, Nicholas Schwab
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Abstract

Objective: Natalizumab (NTZ) is a highly effective therapy for multiple sclerosis (MS); however, its use is limited by the risk of a rare potentially severe opportunistic brain infection, progressive multifocal leukoencephalopathy (PML). Alternative dosing strategies are evaluated to reduce PML risk while still maintaining efficacy, which include extending the dosing interval (EID) or a lesser-known annual dosing gap (aGAP), which is the focus of this prospective observational single-site cohort study. We evaluated whether aGAP affects the efficacy of NTZ, which biomarkers could be useful for a personalized dosing strategy, and potential cellular mechanisms that might contribute to reducing the risk of PML during aGAP.

Methods: Clinical assessments, quantifications of NTZ, neurofilament light chain (NfL), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were performed for ten study participants of a clinical trial (NCT04048577); CSF single-cell RNA-sequencing data from nine participants (15 samples) were analyzed together with 48 healthy and 35 MS controls.

Results: Although NTZ serum levels were decreased below EID levels and sVCAM-1 levels were increased, aGAP was not associated with MS activity as measured by EDSS and MRI. After aGAP, while CSF cell counts remained stable, the CSF immune cell composition changed and NfL values were increased 3 months post gap. CSF proportions of CD4, CD8, and natural killer cell subsets increased towards levels of untreated MS patients, while B-cell proportions remained unchanged.

Interpretation: The differential CSF composition associated with sVCAM-1 serum level changes suggests that selective immune cell trafficking may occur during aGAP, potentially contributing to PML prevention.

每年12周给药间隔:临床疗效、血液生物标志物和脑脊液细胞组成
目的:Natalizumab (NTZ)是一种治疗多发性硬化症(MS)的高效药物;然而,它的使用受到罕见的潜在严重的机会性脑感染,进行性多灶性脑白质病(PML)的风险的限制。评估替代给药策略,以降低PML风险,同时仍保持疗效,包括延长给药间隔(EID)或鲜为人知的年度给药间隔(aGAP),这是本前瞻性观察性单点队列研究的重点。我们评估了aGAP是否会影响NTZ的疗效,该生物标志物可用于个性化给药策略,以及可能有助于降低aGAP期间PML风险的潜在细胞机制。方法:对临床试验(NCT04048577)的10名研究参与者进行临床评估、NTZ、神经丝轻链(NfL)和可溶性血管细胞粘附分子-1 (sVCAM-1)的定量分析;9名参与者(15份样本)的脑脊液单细胞rna测序数据与48名健康和35名MS对照进行了分析。结果:尽管NTZ血清水平低于EID水平,sVCAM-1水平升高,但EDSS和MRI测量的aGAP与MS活动无关。aGAP后,虽然脑脊液细胞计数保持稳定,但脑脊液免疫细胞组成发生变化,NfL值在间隔3个月后升高。脑脊液中CD4、CD8和自然杀伤细胞亚群的比例向未治疗的MS患者水平升高,而b细胞比例保持不变。解释:脑脊液成分的差异与sVCAM-1血清水平变化相关,表明aGAP期间可能发生选择性免疫细胞运输,可能有助于预防PML。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Annals of Clinical and Translational Neurology
Annals of Clinical and Translational Neurology Medicine-Neurology (clinical)
CiteScore
9.10
自引率
1.90%
发文量
218
审稿时长
8 weeks
期刊介绍: Annals of Clinical and Translational Neurology is a peer-reviewed journal for rapid dissemination of high-quality research related to all areas of neurology. The journal publishes original research and scholarly reviews focused on the mechanisms and treatments of diseases of the nervous system; high-impact topics in neurologic education; and other topics of interest to the clinical neuroscience community.
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