The potential for combining serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels to predict worsening disability in multiple sclerosis 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 13 European hospitals, spanned from 15 July 1994 to 18 August 2022, with follow-up until 26 September 2023. We enrolled patients with multiple sclerosis 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, the median age was 34.2 (interquartile range, 27.6–42.4) years, and 509 patients (70.2%) were female. The median follow-up duration was 6.43 (interquartile range, 4.65–9.81) years. Higher sNfL values were associated with an elevated risk of RAW [hazard ratio (HR) of 1.45; 95% confidence interval (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 also examined the combined effect of sNfL and sGFAP levels. Patients with low sNfL and sGFAP values exhibited a low risk of all outcomes and served as a 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 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 multiple sclerosis might identify distinct phenotypes associated with diverse immunological pathways of disability acquisition and therapeutic response.

中文翻译：

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发病时的血清生物标志物用于多发性硬化症的个性化治疗


结合血清神经丝轻链 （sNfL） 和神经胶质纤维酸性蛋白 （sGFAP） 水平来预测多发性硬化症残疾恶化的潜力仍未得到充分探索。我们旨在研究 sNfL 和 sGFAP 值是否根据残疾恶化的风险及其对疾病缓解治疗 （DMT） 的反应来识别不同的患者亚组。这项多中心研究在 13 家欧洲医院进行，时间跨度为 1994 年 7 月 15 日至 2022 年 8 月 18 日，随访至 2023 年 9 月 26 日。我们招募了多发性硬化症患者，这些患者在疾病发作后 12 个月内和开始 DMT 之前收集了血清样本。使用多变量回归模型来估计复发相关恶化 （RAW） 、独立于复发活动的进展 （PIRA） 和扩展残疾状况量表 （EDSS） 评分为 3 分的风险。在纳入的 725 名患者中，中位年龄为 34.2 岁 （四分位距，27.6-42.4） 岁，509 名患者 （70.2%） 为女性。中位随访时间为 6.43 （四分位距，4.65-9.81） 年。较高的 sNfL 值与 RAW 风险升高相关 [风险比 （HR） 为 1.45;95% 置信区间 （CI） 1.19-1.76;P < 0.001]，PIRA（HR 为 1.43;95% CI 1.13–1.81;P = 0.003）并达到 EDSS 为 3（HR 为 1.55;95% CI 1.29-1.85;P < 0.001）。此外，较高的 sGFAP 水平与达到 EDSS 评分 3 分的风险较高有关（HR 为 1.36;95% CI 1.06-1.74;P = 0.02），在 sNfL 值低的患者中，与 PIRA （HR 为 1.86;95% CI 1.01-3.45;P = 0.04）。我们还检查了 sNfL 和 sGFAP 水平的综合影响。sNfL 和 sGFAP 值低的患者所有结局的风险都较低，可作为参考。 sNfL 水平高的未经治疗的患者表现出更高的 RAW 、 PIRA 风险，EDSS 达到 3。注射或口服 DMT 降低了这些患者发生 RAW 的风险，但未能降低 PIRA 的风险并达到 EDSS 3。相反，高效 DMT 抵消了这些结果的增加风险，除了 sNfL 和 sGFAP 水平高的患者发生 PIRA 的风险。低 sNfL 和高 sGFAP 值的患者显示 PIRA 风险增加，EDSS 达到 3，而高效或其他 DMT 均保持不变。总之，评估多发性硬化症发病时的 sNfL 和 sGFAP 水平可能会识别与残疾获得和治疗反应的不同免疫途径相关的不同表型。