From the Department of Neurology (G.B., B.C.H., S.S., F.S., B.I.G., R.B., H.L.W., T.C.), Brigham and Women's Hospital, Boston, MA; Harvard Medical School (G.B., B.C.H., B.I.G., R.B., H.L.W., T.C.), Boston, MA; The University of Ottawa and Ottawa Hospital Research Institute (G.B.), Ottawa, Canada.
Neurol Neuroimmunol Neuroinflamm. 2023 Oct 9;10(6). doi: 10.1212/NXI.0000000000200167. Print 2023 Nov.
Stable patients with multiple sclerosis (MS) may discontinue treatment, but the risk of disease activity is unknown. Serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) are biomarkers of subclinical disease activity and may help risk stratification. In this study, sNfL and sGFAP levels in stable patients were evaluated before and after treatment discontinuation to determine association with disease activity.
This observational study included patients enrolled in the Comprehensive Longitudinal Investigation in MS at the Brigham and Women's Hospital who discontinued treatment after >2 years disease activity-free. Two serum samples within 2 years, before and after treatment stop, were sent for sNfL and sGFAP measurements by single-molecule array. Biannual neurologic examinations and yearly MRI scans determined disease activity by 3 time-to-event outcomes: 6-month confirmed disability worsening (CDW), clinical attacks, and MRI activity (new T2 or contrast-enhancing lesions). Associations between each outcome and log-transformed sNfL and sGFAP levels pretreatment stop and posttreatment stop and the percent change were estimated using multivariable Cox regression analysis adjusting for age, disability, disease duration, and duration from attack before treatment stop.
Seventy-eight patients (92% female) discontinued treatment at a median (interquartile range) age of 48.5 years (39.0-55.7) and disease duration of 12.3 years (7.5-18.8) and were followed up for 6.3 years (4.2-8.5). CDW occurred in 27 patients (35%), new attacks in 19 (24%), and new MRI activity in 26 (33%). Higher posttreatment stop sNfL level was associated with CDW (adjusted hazard ratio (aHR) 2.80, 95% CI 1.36-5.76, = 0.005) and new MRI activity (aHR 3.09, 95% CI 1.42-6.70, = 0.004). Patients who had >100% increase in sNfL level from pretreatment stop to posttreatment stop had greater risk of CDW (HR 3.87, 95% CI 1.4-10.7, = 0.009) and developing new MRI activity (HR 4.02, 95% CI 1.51-10.7, = 0.005). Patients who had >50% increase in sGFAP level also had greater risk of CDW (HR 5.34, 95% CI 1.4-19.9, = 0.012) and developing new MRI activity (HR 5.16, 95% CI 1.71-15.6, = 0.004).
Stable patients who discontinue treatment may be risk stratified by sNfL and sGFAP levels measured before and after discontinuing treatment. Further studies are needed to validate findings and determine whether resuming treatment in patients with increasing biomarker levels reduces risk of subsequent disease activity.
多发性硬化症（MS）稳定期患者可能会停止治疗，但疾病活动的风险尚不清楚。血清神经丝轻链（sNfL）和血清神经胶质纤维酸性蛋白（sGFAP）是亚临床疾病活动的生物标志物，可能有助于风险分层。本研究旨在评估稳定期患者在停止治疗前后 sNfL 和 sGFAP 水平，以确定其与疾病活动的相关性。
本观察性研究纳入了在布莱根妇女医院接受全面纵向 MS 研究的患者，这些患者在疾病无活动 2 年以上后停止治疗。在停止治疗前和停止治疗后 2 年内，分别采集两份血清样本，用于通过单分子阵列法测量 sNfL 和 sGFAP。通过 6 个月确认残疾恶化（CDW）、临床发作和 MRI 活动（新 T2 或对比增强病变）这 3 个时间事件结局来确定疾病活动。使用多变量 Cox 回归分析，调整年龄、残疾、疾病持续时间和停止治疗前发作的持续时间，估计每个结局与治疗前停止治疗和治疗后停止治疗时的 log 转化 sNfL 和 sGFAP 水平以及百分比变化之间的相关性。
78 名患者（92%为女性）在中位（四分位间距）年龄 48.5 岁（39.0-55.7）、疾病持续时间 12.3 年（7.5-18.8）时停止治疗，并随访了 6.3 年（4.2-8.5）。27 名患者（35%）出现 CDW，19 名（24%）出现新发作，26 名（33%）出现新的 MRI 活动。治疗后停止时较高的 sNfL 水平与 CDW（调整后的危险比（aHR）2.80，95%CI 1.36-5.76， = 0.005）和新的 MRI 活动（aHR 3.09，95%CI 1.42-6.70， = 0.004）相关。从治疗前停止到治疗后停止时 sNfL 水平增加＞100%的患者发生 CDW（HR 3.87，95%CI 1.4-10.7， = 0.009）和出现新的 MRI 活动（HR 4.02，95%CI 1.51-10.7， = 0.005）的风险更大。sGFAP 水平增加＞50%的患者发生 CDW（HR 5.34，95%CI 1.4-19.9， = 0.012）和出现新的 MRI 活动（HR 5.16，95%CI 1.71-15.6， = 0.004）的风险也更大。
停止治疗的稳定期患者可通过测量停止治疗前后的 sNfL 和 sGFAP 水平进行风险分层。需要进一步研究来验证这些发现，并确定在生物标志物水平升高的患者中恢复治疗是否可以降低随后疾病活动的风险。
