Serum neurofilament light chain and multiple sclerosis prognosis: a systematic review and meta-analysis

Abstract

Background: Serum neurofilament light chain (sNfL) has emerged as a promising biomarker of neuroaxonal injury in multiple sclerosis (MS), but its prognostic value for clinical and radiological outcomes requires comprehensive synthesis of available evidence. Methods: In this meta-analysis, we systematically searched PubMed, Embase, Ovid, and Cochrane databases from January 2015 to January 2026 for studies evaluating the association between baseline sNfL levels (high vs low) and MS progression outcomes. Primary outcomes were new clinical relapse (NCR) and ≥1 gadolinium-enhancing (Gd+) lesion. Secondary outcomes included relapse within 1 year (R1Y), new T2 lesions (NTL), and confirmed disease worsening. Random-effects models were used to pool risk ratios (RRs) with 95% CIs. Results: Among 3,281 identified records, 13 studies (n=12,513 patients) were included. Elevated sNfL was significantly associated with increased risk of NCR (6 studies; RR 1.42, 95% CI 1.30-1.54; P<0.01) and ≥1 Gd+ lesion (5 studies; RR 1.47, 1.39-1.56; P<0.01), with low heterogeneity (I²≤34.9%). Consistent associations were also observed for NTL (4 studies; RR 2.11, 95% CI 1.59-2.64; P<0.01) and disease worsening (5 studies; RR 2.10, 95% CI 1.57-2.63; P<0.01), although the latter showed moderate heterogeneity (I²=60.7%). An association was observed for R1Y (2 studies; RR 1.94, 95% CI 1.11-2.76; P<0.01), although the evidence for this outcome remains limited. No substantial publication bias was detected for the main outcomes, and leave-one-out sensitivity analyses confirmed the robustness of the results. Conclusion: Elevated sNfL concentrations are consistently associated with increased risks of clinical relapse, radiological activity, and disability progression in MS, supporting its utility as a prognostic biomarker for stratifying disease course and informing clinical trial design.