Center for Neuroinflammation and Experimental Therapeutics, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
F. Hoffmann-La Roche Ltd., Basel, Switzerland.
EBioMedicine. 2023 Jul;93:104662. doi: 10.1016/j.ebiom.2023.104662. Epub 2023 Jun 22.
Neurofilament light chain (NfL), a neuronal cytoskeletal protein that is released upon neuroaxonal injury, is associated with multiple sclerosis (MS) relapsing activity and has demonstrated some prognostic ability for future relapse-related disease progression, yet its value in assessing non-relapsing disease progression remains unclear.
We examined baseline and longitudinal blood NfL levels in 1421 persons with relapsing MS (RMS) and 596 persons with primary progressive MS (PPMS) from the pivotal ocrelizumab MS trials. NfL treatment-response and risk for disease worsening (including disability progression into the open-label extension period and slowly expanding lesions [SELs] on brain MRI) at baseline and following treatment with ocrelizumab were evaluated using time-to-event analysis and linear regression models.
In persons from the RMS control arms without acute disease activity and in the entire PPMS control arm, higher baseline NfL was prognostic for greater whole brain and thalamic atrophy, greater volume expansion of SELs, and clinical progression. Ocrelizumab reduced NfL levels vs. controls in persons with RMS and those with PPMS, and abrogated the prognostic value of baseline NfL on disability progression. Following effective suppression of relapse activity by ocrelizumab, NfL levels at weeks 24 and 48 were significantly associated with long-term risk for disability progression, including up to 9 years of observation in RMS and PPMS.
Highly elevated NfL from acute MS disease activity may mask a more subtle NfL abnormality that reflects underlying non-relapsing progressive biology. Ocrelizumab significantly reduced NfL levels, consistent with its effects on acute disease activity and disability progression. Persistently elevated NfL levels, observed in a subgroup of persons under ocrelizumab treatment, demonstrate potential clinical utility as a predictive biomarker of increased risk for clinical progression. Suppression of relapsing biology with high-efficacy immunotherapy provides a window into the relationship between NfL levels and future non-relapsing progression.
F. Hoffmann-La Roche Ltd.
神经丝轻链（NfL）是一种神经元细胞骨架蛋白，在神经轴突损伤时释放，与多发性硬化症（MS）的复发活动有关，并显示出一些对未来复发相关疾病进展的预后能力，但它在评估非复发疾病进展中的价值尚不清楚。
我们检查了来自关键奥瑞珠单抗 MS 试验的 1421 例复发型 MS（RMS）患者和 596 例原发性进展型 MS（PPMS）患者的基线和纵向血 NfL 水平。使用时间事件分析和线性回归模型评估基线和奥瑞珠单抗治疗后 NfL 治疗反应和疾病恶化风险（包括残疾进展到开放标签扩展期和脑 MRI 上的缓慢扩展病变[SELs]）。
在 RMS 对照臂中无急性疾病活动的患者和整个 PPMS 对照臂中，较高的基线 NfL 与更大的全脑和丘脑萎缩、更大的 SEL 体积扩张以及临床进展相关。与对照相比，奥瑞珠单抗降低了 RMS 和 PPMS 患者的 NfL 水平，并消除了基线 NfL 对残疾进展的预后价值。在奥瑞珠单抗有效抑制复发活动后，第 24 周和第 48 周的 NfL 水平与残疾进展的长期风险显著相关，包括 RMS 和 PPMS 长达 9 年的观察。
来自急性 MS 疾病活动的高度升高的 NfL 可能掩盖了更微妙的反映潜在非复发进展生物学的 NfL 异常。奥瑞珠单抗显著降低 NfL 水平，与其对急性疾病活动和残疾进展的影响一致。在接受奥瑞珠单抗治疗的患者亚组中观察到持续升高的 NfL 水平，表明其作为增加临床进展风险的预测生物标志物具有潜在的临床效用。高效免疫疗法抑制复发生物学为 NfL 水平与未来非复发进展之间的关系提供了一个窗口。
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