From the Mellen Center for Multiple Sclerosis (R.J.F.), Neurological Institute, Cleveland Clinic, OH; Department of Neurology (B.A.C.C.), Weill Institute for Neurosciences, University of California San Francisco; Department of Neurology (J.S.), Hôpital Civil, Strasbourg, France; Department of Neurology (R.G.), St. Josef Hospital, Ruhr University, Bochum, Germany; Department of Neurology (H.-P.H.), Heinrich Heine University, Düsseldorf, Germany; Brain and Mind Center, University of Sydney, Australia; Department of Neurology, Palacky University Olomouc, Czech Republic; Piedmont HealthCare (D.J.), Mooresville, NC; Research Center for Clinical Neuroimmunology and Neuroscience and MS Center (L.K.); Departments of Head, Spine and Neuromedicine, Clinical Research and Biomedical Engineering, University Hospital and University of Basel, Switzerland; Vall d'Hebron University Hospital (X.M.), Barcelona, Spain; Jacobs Multiple Sclerosis Center and Pediatric Multiple Sclerosis Center of Excellence (B.W.-G.), Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY; and Biogen (C.M.S., A.A., N.B., R.L.A., P.-R.H., R.S., R.E., D.S., C.M., E.F., B.C.K., R.A.R.), Cambridge, MA.
Neurology. 2024 May 14;102(9):e209357. doi: 10.1212/WNL.0000000000209357. Epub 2024 Apr 22.
Serum neurofilament light chain (sNfL) levels correlate with multiple sclerosis (MS) disease activity, but the dynamics of this correlation are unknown. We evaluated the relationship between sNfL levels and radiologic MS disease activity through monthly assessments during the 24-week natalizumab treatment interruption period in RESTORE (NCT01071083).
In the RESTORE trial, participants with relapsing forms of MS who had received natalizumab for ≥12 months were randomized to either continue or stop natalizumab and followed with MRI and blood draws every 4 weeks to week 28 and again at week 52 The sNfL was measured, and its dynamics were correlated with the development of gadolinium-enhancing (Gd+) lesions. Log-linear trend in sNfL levels were modeled longitudinally using generalized estimating equations with robust variance estimator from baseline to week 28.
Of 175 patients enrolled in RESTORE, 166 had serum samples for analysis. Participants with Gd+ lesions were younger (37.7 vs 43.1, = 0.001) and had lower Expanded Disability Status Scale scores at baseline (2.7 vs 3.4, = 0.017) than participants without Gd+ lesions. sNfL levels increased in participants with Gd+ lesions (n = 65) compared with those without (n = 101, mean change from baseline to maximum sNfL value, 12.1 vs 3.2 pg/mL, respectively; = 0.003). As the number of Gd+ lesions increased, peak median sNfL change also increased by 1.4, 3.0, 4.3, and 19.6 pg/mL in the Gd+ lesion groups of 1 (n = 12), 2-3 (n = 18), 4-9 (n = 21), and ≥10 (n = 14) lesions, respectively. However, 46 of 65 (71%) participants with Gd+ lesions did not increase above the 95th percentile threshold of the group without Gd+ lesions. The initial increase of sNfL typically trailed the first observation of Gd+ lesions, and the peak increase in sNfL was a median [interquartile range] of 8 [0, 12] weeks after the first appearance of the Gd+ lesion.
Although sNfL correlated with the presence of Gd+ lesions, most participants with Gd+ lesions did not have elevations in sNfL levels. These observations have implications for the use and interpretation of sNfL as a biomarker for monitoring MS disease activity in controlled trials and clinical practice.
血清神经丝轻链（sNfL）水平与多发性硬化症（MS）疾病活动相关，但这种相关性的动态变化尚不清楚。我们通过评估 RESTORE 研究中断纳立珠单抗治疗 24 周期间每月评估的 sNfL 水平与影像学 MS 疾病活动之间的关系来研究这一问题（NCT01071083）。
在 RESTORE 试验中，接受纳立珠单抗治疗 12 个月以上的复发型 MS 患者被随机分配至继续或停止纳立珠单抗治疗，并在第 4 周、第 8 周、第 12 周、第 16 周、第 20 周、第 24 周、第 28 周和第 52 周时进行 MRI 和血液采集。测定 sNfL，并将其动态变化与钆增强（Gd+）病变的发展相关联。使用广义估计方程和稳健方差估计器，从基线到第 28 周对 sNfL 水平的对数线性趋势进行纵向建模。
在 RESTORE 研究中，175 名患者中有 166 名患者的血清样本可供分析。与无 Gd+病变的患者相比，有 Gd+病变的患者更年轻（37.7 岁比 43.1 岁，P=0.001），基线时扩展残疾状态量表评分也更低（2.7 分比 3.4 分，P=0.017）。与无 Gd+病变的患者相比（n=101），有 Gd+病变的患者（n=65）sNfL 水平升高（从基线到 sNfL 值最高时的平均变化分别为 12.1 pg/ml 比 3.2 pg/ml，P=0.003）。随着 Gd+病变数量的增加，Gd+病变组中第 1 组（n=12）、第 2-3 组（n=18）、第 4-9 组（n=21）和≥10 组（n=14）的峰值中位数 sNfL 变化分别增加了 1.4、3.0、4.3 和 19.6 pg/ml。然而，在有 Gd+病变的 65 名患者中，有 46 名（71%）未超过无 Gd+病变患者组的第 95 百分位阈值。sNfL 的最初升高通常滞后于首次出现 Gd+病变，sNfL 的峰值升高中位数[四分位距]为首次出现 Gd+病变后 8[0，12]周。
尽管 sNfL 与 Gd+病变的存在相关，但大多数有 Gd+病变的患者 sNfL 水平并未升高。这些观察结果对使用和解释 sNfL 作为监测临床试验和临床实践中 MS 疾病活动的生物标志物具有重要意义。
