Serum Neurofilament Identifies Patients With Multiple Sclerosis With Severe Focal Axonal Damage in a 6-Year Longitudinal Cohort.

BACKGROUND AND OBJECTIVES: Immunomodulatory therapies reduce the relapse rate but only marginally control disability progression in patients with MS. Although serum neurofilament light chain (sNfL) levels correlate best with acute signs of inflammation (e.g., relapses and gadolinium-enhancing [Gd+] lesions), their role in predicting progressive biology and irreversible axonal damage is less clear. We aimed to determine the ability of sNfL to dissect distinct measures of disease severity and predict future (no) evidence of disease activity (EDA/no evidence of disease activity [NEDA]). METHODS: One hundred fifty-three of 221 patients with relapsing-remitting MS initially enrolled in the Neurofilament and longterm outcome in MS cohort at the MS outpatient clinic of the University Medical Center Mainz (Germany) met the inclusion criteria for this prospective observational cohort study with a median follow-up of 6 years (interquartile range 4-7 years). Progressive disease forms were excluded. Inclusion criteria consisted of Expanded Disability Status Scale (EDSS) assessment within 3 months and MRI within 12 months around blood sampling at baseline (y0) and follow-up (y6). EDSS progression at y6 had to be confirmed 12 weeks later. sNfL was measured by single-molecule array, and the following additional variables were recorded: therapy, medical history, and detailed MRI parameters (T2 hyperintense lesions, Gd+ lesions, and new persistent T1 hypointense lesions). RESULTS: Patients experiencing EDSS progression or new persistent T1 lesions at y6 showed increased sNfL levels at y0 compared with stable patients or patients with inflammatory activity only. As a potential readily accessible marker of neurodegeneration, we incorporated the absence of persistent T1 lesions to the NEDA-3 concept (NEDA-3T1: n = 54, 35.3%; EDAT1: n = 99, 64.7%) and then evaluated a risk score with factors that distinguish patients with and without NEDA-3T1 status. Adding sNfL to this risk score significantly improved NEDA-3T1 prediction (0.697 95% CI 0.616-0.770 vs 0.819 95% CI 0.747-0.878, p < 0.001). Patients with sNfL values ≤8.6 pg/mL showed a 76% risk reduction for EDAT1 at y6 (hazard ratio 0.244, 95% CI 0.142-0.419, p < 0.001). DISCUSSION: sNfL levels associate with severe focal axonal damage as reflected by development of persistent T1 lesions. Baseline sNfL values predicted NEDA-3T1 status at 6-year follow-up.

NfL predicts relapse-free progression in a longitudinal multiple sclerosis cohort study.

BACKGROUND: Easily accessible biomarkers enabling the identification of those patients with multiple sclerosis (MS) who will accumulate irreversible disability in the long term are essential to guide early therapeutic decisions. We here examine the utility of serum neurofilament light chain (sNfL) for forecasting relapse-free disability progression and conversion to secondary progressive MS (SPMS) in the prospective Neurofilamentandlongtermoutcome inMS (NaloMS) cohort. METHODS: The predictive ability of sNfL at Baseline and sNfL follow-up (FU)/ Baseline (BL) ratio with regard to disability progression was assessed within a development cohort (NaloMS, n=196 patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome) and validated with an external independent cohort (Düsseldorf, Essen, n=204). Both relapse-free EDSS-progression (RFP: inflammatory-independent EDSS-increase 12 months prior to FU) and SPMS-transition (minimum EDSS-score of 3.0) were investigated. FINDINGS: During the study period, 17% (n=34) of NaloMS patients suffered from RFP and 14% (n=27) converted to SPMS at FU (validation cohort RFP n=42, SPMS-conversion n=24). sNfL at BL was increased in patients with RFP (10.8 pg/ml (interquartile range (IQR) 7.7-15.0) vs. 7.2 pg/ml (4.5-12.5), p<0.017). In a multivariable logistic regression model, increased sNfL levels at BL (Odds Ratio (OR) 1.02, 95% confidence interval (CI) 1.01-1.04, p=0.012) remained an independent risk factor for RFP and predicted individual RFP risk with an accuracy of 82% (NaloMS) and 83% (validation cohort) as revealed by support vector machine. In addition, the sNfL FU/BL ratio was increased in SPMS-converters (1.16 (0.89-1.70) vs. 0.96 (0.75-1.23), p=0.011). This was confirmed by a multivariable logistic regression model, as sNfL FU/BL ratio remained in the model (OR 1.476, 95%CI 1.078-2,019, p=0.015) and individual sNfL FU/BL ratios showed a predictive accuracy of 72% in NaloMS (63% in the validation cohort) as revealed by machine learning. INTERPRETATION: sNfL levels at baseline predict relapse-free disability progression in a prospective longitudinal cohort study 6 years later. While prediction was confirmed in an independent cohort, sNfL further discriminates patients with SPMS at follow-up and supports early identification of patients at risk for later SPMS conversion. FUNDING: This work was supported by the German Research Council (CRC-TR-128), Else Kröner Fresenius Foundation and Hertie-Stiftung.