Monreal Enric, Fernández-Velasco José Ignacio, Álvarez-Lafuente Roberto, Sainz de la Maza Susana, García-Sánchez María Isabel, Llufriu Sara, Casanova Bonaventura, Comabella Manuel, Martínez-Yélamos Sergio, Galimberti Daniela, Ramió-Torrentà Lluís, Martínez-Ginés María Luisa, Aladro Yolanda, Ayuso Lucía, Martínez-Rodríguez José Enrique, Brieva Luis, Villarrubia Noelia, Eichau Sara, Zamora Javier, Rodero-Romero Alexander, Espiño Mercedes, Blanco Yolanda, Saiz Albert, Montalbán Xavier, Tintoré Mar, Domínguez-Mozo María Inmaculada, Cuello Juan Pablo, Romero-Pinel Lucía, Ghezzi Laura, Pilo de la Fuente Belén, Pérez-Miralles Francisco, Quiroga-Varela Ana, Rubio Lluïsa, Rodríguez-Jorge Fernando, Chico-García Juan Luís, Sainz-Amo Raquel, Masjuan Jaime, Costa-Frossard Lucienne, Villar Luisa M
Department of Neurology, Hospital Universitario Ramón y Cajal, Red Española de Esclerosis Múltiple (REEM), Red de Enfermedades Inflamatorias (REI), IRYCIS, Universidad de Alcalá, 28034 Madrid, Spain.
Department of Immunology, Hospital Universitario Ramón y Cajal, REEM, REI, IRYCIS, Universidad de Alcalá, 28034 Madrid, Spain.
Brain. 2024 Dec 3;147(12):4084-4093. doi: 10.1093/brain/awae260.
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.
血清神经丝轻链（sNfL）和胶质纤维酸性蛋白（sGFAP）水平联合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值是否能根据残疾恶化风险及其对疾病修饰治疗（DMTs）的反应来识别不同的患者亚组。这项多中心研究在13家欧洲医院开展，时间跨度从1994年7月15日至2022年8月18日，随访至2023年9月26日。我们纳入了在疾病发作12个月内且在开始DMTs之前采集了血清样本的多发性硬化症患者。使用多变量回归模型来估计复发相关恶化（RAW）、与复发活动无关的进展（PIRA）以及扩展残疾状态量表（EDSS）评分为3的风险。在纳入的725例患者中，中位年龄为34.2岁（四分位间距，27.6 - 42.4岁），509例患者（70.2%）为女性。中位随访时间为6.43年（四分位间距，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）以及达到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评分为3的风险较高相关（HR为1.36；95% CI 1.06 - 1.74；P = 0.02），并且在sNfL值较低的患者中与PIRA相关（HR为1.86；95% CI 1.01 - 3.45；P = 0.04）。我们还研究了sNfL和sGFAP水平的联合作用。sNfL和sGFAP值较低的患者所有结局风险均较低，并作为对照。未治疗的sNfL水平较高的患者RAW、PIRA以及达到EDSS为3的风险较高。注射或口服DMTs降低了这些患者的RAW风险，但未能减轻PIRA以及达到EDSS为3的风险。相反，高效DMTs抵消了这些结局的高风险，但sNfL和sGFAP水平较高的患者的PIRA风险除外。sNfL值较低且sGFAP值较高的患者PIRA以及达到EDSS为3 的风险增加, 高效或其他DMTs对此均无改变。总之，在多发性硬化症疾病发作时评估sNfL和sGFAP水平可能识别出与残疾获得和治疗反应的不同免疫途径相关的不同表型。
