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

多发性硬化（MS）是一种免疫介导的中枢神经系统炎症性疾病。尽管 传统上认为是一种脱髓鞘疾病，已经证明， 在病程的早期，并代表永久性神经功能障碍的病理基础， MS患者（PwMS）在临床实践中，PwMS中的疾病监测通过临床评价进行， 使用常规磁共振成像（MRI）测量，包括新发T2病变和/或存在 T1钆（Gd）后增强病变。值得注意的是，这些常规MRI测量评估了 炎症性疾病活动而不是神经轴突损失，并且仅与临床 MS的残疾指标，一种被称为“临床放射学悖论”的现象。存在未满足的 MS需要一种生物标志物，可以在PwMS发生前识别出持续的神经轴突损伤。 永久性临床残疾的累积，以便及时干预。 神经丝是神经元特异性的细胞骨架蛋白， 损害在血液和脑脊液中发现神经丝轻链（NfL）水平升高 (CSF)在MS中，有证据表明血清NfL（sNfL）水平 与CSF NfL水平密切相关，与疾病活动的临床放射学指标相关， 通过疾病修饰疗法（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， 人口统计学、疾病亚型和共病状况对MS中sNfL水平的影响仍然没有得到很好的表征。 目前还不清楚sNfL水平是否可用于监测对治疗的反应，指导决策， 关于免疫疗法的效力，并预测长期结果。同时，鉴于这一新出现的证据， sNfL作为神经轴索损伤的预后和监测生物标志物， 在MS中，需要在更大的、人口统计学上多样化的、临床上 异质性、多中心队列。此外，最重要的是， 利用可以在临床领域中快速实施的稳健的、可扩展的测定来进行。 我们计划利用新的自动化免疫测定法（Siemens Healthineers;进行了2009年10月至2009年12月的研究）来测量sNfL。 在现有的临床可用平台上）在来自两项大型多中心研究的血清样品中：1）MS PATHS （多发性硬化症合作伙伴推进技术和健康解决方案）是一个网络的10个医疗保健 美国和欧洲的研究机构，通过收集 常规医疗访视期间的标准化临床/成像数据和生物标本。截至2019年2月1日， > 15，000名患者选择参与MS PATHS，生物标本已经超过5，000 患者2)多发性硬化症的传统疗法与早期积极疗法（Traditional versus Early aggressive therapy for multiple sclerosis）是一项正在进行的研究， 一项实用的随机对照试验，旨在评估初治MS患者中是否存在"早期 与传统的一线治疗方法相比，"积极"治疗方法影响了 长期残疾风险（48个月）。ESSE-MS在约45个研究中心前瞻性招募了900名受试者 在美国（截至2019年2月1日入组83例），生物库预计入组700例受试者 子研究。 我们预计，sNfL在MS中作为预后和监测指标的大规模临床验证， 本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.