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

多发性硬化症 (MS) 是一种免疫介导的中枢神经系统炎症性疾病。尽管 典型地被认为是一种脱髓鞘疾病，已证明会发生神经轴突损伤 病程早期，是永久性神经功能障碍的病理基础 多发性硬化症 (PwMS) 患者。在临床实践中，PwMS 中的疾病监测是通过临床评估和 使用传统的磁共振成像 (MRI) 测量，包括新的 T2 病变和/或存在 T1 后钆 (Gd) 增强病变。值得注意的是，这些传统的 MRI 测量方法可以评估是否存在 炎症性疾病活动而不是神经轴突损失，并且与临床仅适度相关 MS 残疾的衡量标准，这种现象被称为“临床放射学悖论”。有一个未满足的 MS 需要一种生物标志物，可以在 PwMS 发生之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细胞骨架蛋白，在神经轴突释放后释放 损坏。血液和脑脊液中神经丝轻链 (NfL) 水平增加 (CSF) 治疗多种神经系统疾病，包括多发性硬化症。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测量相关， 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，影响因素包括 MS 中 sNfL 水平的人口统计学、疾病亚型和共病状况仍知之甚少。 目前还不清楚 sNfL 水平是否可用于监测治疗反应、指导决策 关于免疫疗法的效力，并预测长期结果。同时，考虑到这些新出现的证据， 人们对 sNfL 作为神经轴突损伤的预后和监测生物标志物非常感兴趣 在多发性硬化症中，需要在更大的、人口多样化的、临床上进行进一步的临床验证 异质、多中心队列。此外，最重要的是验证 利用可以在临床领域快速实施的稳健、可扩展的测定来进行。 我们计划利用新型自动免疫测定法（Siemens Healthineers；执行）来测量 sNfL 在现有的临床可用平台上）来自两项大型多中心研究的血清样本：1）MS PATHS （多发性硬化症合作伙伴推进技术和健康解决方案）是一个由 10 个医疗保健机构组成的网络 美国和欧洲的机构，通过收集数据将研究与持续的患者护理结合起来 在常规医疗就诊期间标准化临床/影像数据和生物样本。截至2019年2月1日， > 15,000 名患者选择参加 MS PATHS，生物样本已可供 > 5,000 名患者使用 患者。 2) TREAT-MS（多发性硬化症的传统疗法与早期积极疗法）是一项持续的、 务实的随机对照试验，旨在评估未接受治疗的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 个月时）。 TREAT-MS 预计在约 45 个地点招募 900 名受试者 在美国（截至 2019 年 2 月 1 日已登记 83 名受试者），预计生物样本库将登记 700 名受试者 子研究。 我们预计 sNfL 在 MS 中作为预后和监测的大规模临床验证 本研究中的工具将导致向 FDA 提交完整的资格包，并将导致 第一个基于血液的多发性硬化症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.