Abstract：
The potential of combining serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels to predict disability worsening in multiple sclerosis (MS) remains underexplored. We aimed to investigate whether sNfL and sGFAP values identify distinct subgroups of patients according to the risk of disability worsening and their response to disease-modifying treatments (DMTs). This multicentre study, conducted across thirteen European hospitals, spanned from July 15, 1994, to August 18, 2022, with follow-up until September 26, 2023. We enrolled MS patients who had serum samples collected within 12 months from disease onset and before initiating DMTs. Multivariable regression models were used to estimate the risk of relapse-associated worsening (RAW), progression independent of relapse activity (PIRA), and Expanded Disability Status Scale (EDSS) score of 3. Of the 725 patients included, median age was 34.2 years (IQR, 27.6-42.4), and 509 patients (70.2%) were female. Median follow-up duration was 6.43 years (IQR, 4.65-9.81). Higher sNfL values associated with an elevated risk of RAW (HR of 1.45; 95% CI 1.19-1.76; P < 0.001), PIRA (HR of 1.43; 95% CI 1.13-1.81; P = 0.003), and reaching an EDSS of 3 (HR of 1.55; 95% CI 1.29-1.85; P < 0.001). Moreover, higher sGFAP levels were linked to a higher risk of achieving an EDSS score of 3 (HR of 1.36; 95% CI 1.06-1.74; P = 0.02) and, in patients with low sNfL values, to PIRA (HR of 1.86; 95% CI 1.01-3.45; P = 0.04). We further examined the combined effect of sNfL and sGFAP levels. Patients with low sNfL and sGFAP values (NLGL) exhibited a low risk of all outcomes and served as reference. Untreated patients with high sNfL levels showed a higher risk of RAW, PIRA, and reaching an EDSS of 3. Injectable or oral DMTs reduced the risk of RAW in these patients but failed to mitigate the risk of PIRA and reaching an EDSS of 3. Conversely, high-efficacy DMTs counteracted the heightened risk of these outcomes, except for the risk of PIRA in patients with high sNfL and sGFAP levels. Patients with low sNfL and high sGFAP values (NLGH) showed an increased risk of PIRA and achieving an EDSS of 3, which remained unchanged with either high-efficacy or other DMTs. In conclusion, evaluating sNfL and sGFAP levels at disease onset in MS may identify distinct phenotypes associated with diverse immunological pathways of disability acquisition and therapeutic response.
摘要：
结合血清神经丝轻链（sNfL）和神经胶质纤维酸性蛋白（sGFAP）水平预测多发性硬化症（MS）残疾恶化的潜力仍未得到充分研究。我们旨在调查sNfL和sGFAP值是否根据残疾恶化的风险及其对疾病改善治疗（DMT）的反应来识别患者的不同亚组。这项多中心研究，在13家欧洲医院进行，从1994年7月15日至2022年8月18日，随访至2023年9月26日。我们招募了在疾病发作后12个月内和开始DMT之前收集血清样本的MS患者。多变量回归模型用于估计复发相关恶化（RAW）的风险，独立于复发活动（PIRA）的进展，扩展残疾状况量表(EDSS)得3分。在这725名患者中,中位年龄为34.2岁（IQR，27.6-42.4),509例（70.2%）为女性。中位随访时间为6.43年(IQR，4.65-9.81)。较高的sNfL值与RAW风险升高相关（HR为1.45;95％CI1.19-1.76;P<0.001），PIRA（HR为1.43；95%CI1.13-1.81；P=0.003），EDSS为3（HR为1.55；95%CI1.29-1.85；P<0.001）。此外，较高的sGFAP水平与实现EDSS评分3的较高风险相关(HR为1.36;95%CI1.06-1.74;P=0.02),在sNfL值较低的患者中，至PIRA（HR为1.86；95%CI1.01-3.45；P=0.04）。我们进一步检查了sNfL和sGFAP水平的联合作用。具有低sNfL和sGFAP值(NLGL)的患者表现出所有结果的低风险并作为参考。高sNfL水平的未经治疗的患者显示出更高的RAW风险，PIRA,并达到3的EDSS。注射或口服DMT降低了这些患者的RAW风险，但未能减轻PIRA的风险并达到3的EDSS。相反，高效DMT抵消了这些结果的高风险，除了高sNfL和sGFAP水平患者的PIRA风险。具有低sNfL和高sGFAP值（NLGH）的患者显示出PIRA的风险增加，并达到3的EDSS，这与高疗效或其他DMT保持不变。总之,在MS发病时评估sNfL和sGFAP水平,可以确定与残疾获得和治疗反应的不同免疫途径相关的不同表型.
