Validation of Serum Neurofilament Light Chain as a Prognostic and Monitoring Biomarker in Multiple Sclerosis

多发性硬化症(MS)是一种免疫调节的中枢神经系统炎症性疾病。尽管 被经典地认为是一种脱髓鞘障碍，已经证明会发生神经轴突损伤。 在病程的早期，代表了永久性神经功能障碍的病理基础 多发性硬化症患者(PWMS)。在临床实践中，PWMS的疾病监测是通过临床评估和 使用常规磁共振成像(MRI)措施，包括新的T2病变和/或存在 T1期Gd增强后病变。值得注意的是，这些常规的MRI测量方法评估是否存在 炎症性疾病的活动性，而不是神经轴突的丧失，仅与临床略有关联 多发性硬化症的残疾测量，一种被称为“临床放射学悖论”的现象。有一个未满足的人 多发性硬化症需要一种生物标记物来识别PWMS在发病前持续的神经轴突损害 应计永久临床残疾，以便及时干预。 神经丝是神经元特有的细胞骨架蛋白，在神经轴突后释放。 损坏。在血液和脑脊液中发现神经丝轻链(NFL)水平增加 (CSF)在包括MS在内的几种神经系统疾病中，有证据表明，MS患者血清NFL(SNFL)水平 与脑脊液NFL水平密切相关，与疾病活动性的临床放射学指标相关，是 由疾病修正疗法(DMT)调节，并预测残疾恶化和脑萎缩。然而， 这些数据主要来自小型、单中心研究，影响因素包括 人口统计学、疾病亚型和共病条件对多发性硬化症患者SNFL水平的描述仍然很差。 目前还不清楚SNFL水平是否可用于监测治疗反应、指导决策。 关于免疫治疗的效力，并预测长期结果。同时，考虑到这些新出现的证据， SNFL作为一种预测和监测神经轴突损伤的生物标志物引起了极大的兴趣。 在多发性硬化症中，需要在更大的、人口统计学上不同的临床上进行进一步的临床验证 异质的、多中心的队列。此外，最重要的是验证是 利用可在临床领域快速实施的健壮的、可扩展的检测来执行。 我们计划使用一种新的自动免疫分析方法(西门子医疗集团；已执行)来测量SNFL。 在现有的临床可用平台上)来自两个大型多中心研究的血清样本：1)MS路径 (多发性硬化症合作伙伴推进技术和健康解决方案)是一个由10名医疗保健人员组成的网络 美国和欧洲的机构，将研究与持续的患者护理相结合，通过收集 标准化的临床/影像数据和常规就诊期间的生物检材。截至2019年2月1日， 已有15,000名患者选择参加多发性硬化症治疗路径，其中5,000名患者已有生物制剂可用。 病人。2)Treat-MS(多发性硬化症的传统与早期积极治疗)是一项持续的、 一项务实的随机对照试验，旨在评估治疗幼稚多发性硬化症患者是否“早期” 与从传统的一线治疗方法开始相比，“积极”的治疗方法会影响 长期残疾风险(48个月)。Treat-MS计划在大约45个地点招募900名受试者 在美国(截至2019年2月1日登记了83人)，预计将有700名受试者进入生物银行 分组研究。 我们期望大规模临床验证SNFL对多发性硬化患者的预后和监测作用。 这项研究中的工具将导致向FDA提交完整的资格认证包，并将导致 第一个基于血液的MS生物标志物的可用性。

Multiple sclerosis (MS) is an immune-mediated, inflammatory disorder of the central nervous system. Despite being classically considered a demyelinating disorder, it has been demonstrated that neuro-axonal injury occurs early in the disease course and represents the pathologic substrate for permanent neurological disability in people with MS (PwMS). In clinical practice, disease monitoring in PwMS is performed by clinical evaluation and use of conventional magnetic resonance imaging (MRI) measures, including new T2 lesions and/or presence of T1 post-gadolinium (Gd) enhancing lesions. Notably, these conventional MRI measures assess for the presence of inflammatory disease activity rather than neuro-axonal loss and are only modestly associated with clinical measures of disability in MS, a phenomenon known as the “clinico-radiological paradox”. There is an unmet need in MS for a biomarker that may identify PwMS with ongoing neuro-axonal damage prior to the accrual of permanent clinical disability, in order to allow for timely intervention. Neurofilaments are neuron-specific cytoskeletal proteins that are released following neuro-axonal damage. Increased neurofilament light chain (NfL) levels have been found in the blood and cerebrospinal fluid (CSF) in several neurological disorders, including MS. In MS, there is evidence that serum NfL (sNfL) levels correlate closely with CSF NfL levels, are associated with clinico-radiological measures of disease activity, are modulated by disease modifying therapies (DMTs), and predict disability worsening and brain atrophy. However these data are derived mainly from small, single-center studies, and the influence of factors including demographics, disease subtype, and co-morbid conditions on sNfL levels in MS remains poorly characterized. It is also remains unclear if sNfL levels may be used to monitor response to therapy, guide decision-making regarding potency of immunotherapy, and predict long-term outcomes. While, given this emerging evidence, there is great interest in sNfL for use as a prognostic and monitoring biomarker of neuro-axonal injury in MS, further clinical validation is necessary in larger, demographically diverse, clinically heterogeneous, multi-center cohorts. Furthermore, it is of utmost importance that validation is performed utilizing a robust, scalable assay that may be rapidly implemented in the clinical realm. We plan to measure sNfL utilizing a novel automated immunoassay (Siemens Healthineers; performed on an existing clinically available platform) in serum samples from two large multi-center studies: 1) MS PATHS (Multiple Sclerosis Partners Advancing Technology and Health Solutions) is a network of 10 healthcare institutions in the United States and Europe, merging research with ongoing patient care by collecting standardized clinical/imaging data and biospecimens during routine medical visits. As of February 1st, 2019, >15,000 patients have opted to participate in MS PATHS with biospecimens already available for >5,000 patients. 2) TREAT-MS (Traditional versus Early Aggressive Therapy for Multiple Sclerosis) is an ongoing, pragmatic, randomized controlled trial, designed to evaluate in treatment naïve MS patients whether an “early aggressive” therapy approach, versus starting with a traditional, first-line therapy approach, influences the longer-term risk of disability (at 48 months). TREAT-MS is prospectively recruiting 900 subjects across ~45 sites in the US (83 enrolled as of February 1st, 2019) with anticipated enrollment of 700 subjects in the bio-banking sub-study. We anticipate that large-scale clinical validation of sNfL in MS as a prognostic and monitoring tool in this study will lead to submission to the FDA of a full qualification package and will lead to availability of the first blood-based biomarker of MS.