Neurology, Odense Universitetshospital, Odense, Denmark
Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
J Neurol Neurosurg Psychiatry. 2019 Dec;90(12):1324-1330. doi: 10.1136/jnnp-2019-321321. Epub 2019 Oct 13.
In a prospective phase IV trial of the first-line oral treatment dimethyl fumarate (DMF), we examined dynamics of neurofilament light (NFL) chain in serum, plasma and cerebrospinal fluid (CSF) samples collected over 12 months from relapsing-remitting multiple sclerosis (RRMS) patients. NFL changes were related to disease activity.
We examined NFL levels by single-molecule array in 88 CSF, 348 plasma and 131 sera from treatment-naïve RRMS patients (n=52), healthy controls (n=23) and a placebo group matched by age, sex and NFL (n=52). Plasma/sera were collected at baseline, and 1, 3, 6 and 12 months after DMF. CSF samples were collected at baseline and 12 months after DMF.
NFL concentration in CSF, plasma and serum correlated highly (p<0.0001 for all), but plasma levels were only 76.9% of paired serum concentration. After 12 months of DMF treatment, NFL concentration decreased by 73%, 69% and 55% in the CSF, serum and plasma (p<0.0001, respectively). Significant reduction in blood was observed after 6 and 12 months treatment compared with baseline (p<0.01 and p<0.0001, respectively) and to placebo (p<0.0001). Patients with NFL above the 807.5 pg/mL cut-off in CSF had 5.0-times relative risk of disease activity (p<0.001).
This study provides Class II evidence that first-line DMF reduces NFL in both blood and CSF after 6 months and normalises CSF levels in 73% of patients. High NFL concentration in CSF after a year reflected disease activity. NFL levels were higher in serum than in plasma, which should be considered when NFL is used as a biomarker.
在一项关于一线口服药物富马酸二甲酯（DMF）的前瞻性 IV 期临床试验中，我们检测了复发缓解型多发性硬化症（RRMS）患者在 12 个月内采集的血清、血浆和脑脊液（CSF）样本中神经丝轻链（NFL）的动态变化，这些变化与疾病活动度相关。
我们使用单分子阵列法检测了 88 例 CSF、348 例血浆和 131 例血清中的 NFL 水平，这些样本均来自未经治疗的 RRMS 患者（n=52）、健康对照者（n=23）和年龄、性别及 NFL 相匹配的安慰剂组（n=52）。在 DMF 治疗前、1、3、6 和 12 个月时采集血浆/血清样本，在 DMF 治疗前和 12 个月时采集 CSF 样本。
CSF、血浆和血清中的 NFL 浓度高度相关（所有相关系数均<0.0001），但血浆水平仅为配对血清浓度的 76.9%。在 DMF 治疗 12 个月后，CSF、血清和血浆中的 NFL 浓度分别下降了 73%、69%和 55%（均<0.0001）。与基线相比，治疗 6 和 12 个月后血液中的 NFL 浓度明显下降（分别为 p<0.01 和 p<0.0001），与安慰剂相比也明显下降（均<0.0001）。CSF 中 NFL 高于 807.5 pg/mL 截点的患者发生疾病活动的相对风险为 5.0 倍（p<0.001）。
本研究提供了 II 级证据，表明一线 DMF 在 6 个月后可降低血液和 CSF 中的 NFL，使 73%的患者 CSF 中的 NFL 水平正常化。一年后 CSF 中 NFL 浓度较高反映了疾病活动度。血清中的 NFL 浓度高于血浆，在将 NFL 作为生物标志物时应考虑这一点。
