Neurofilament light chain as a surrogate candidate for disease activity in multiple sclerosis (LUMINOUS)—A meta-regression of randomized controlled trials

Background/Objectives: Neurofilament light chain (NfL) is a promising biomarker for monitoring disease activity and treatment response in multiple sclerosis (MS). This meta-regression assesses the relationship between treatment effects on serum/plasma NfL (s/pNfL) and clinical and radiological endpoints in randomized controlled trials (RCTs). Methods: A systematic PubMed search identified RCTs in MS (1999–2023) with ⩾24 months’ duration and s/pNfL data. Extracted outcomes included treatment effects on s/pNfL, annualized relapse rate (ARR), confirmed disability worsening (CDW), magnetic resonance imaging (MRI) new/enlarging T2 lesions, and percentage brain volume change (PBVC). We evaluated the association of treatment effect on the selected outcomes at the trial level by a meta-regression, weighted by trial size and duration. Results: Fifteen RCTs (n = 6814) were included, nine in relapsing MS (RMS, n = 5221), and six in progressive MS (PMS, n = 1593). Treatment effects on s/pNfL showed a moderate association with treatment effects on MRI new/enlarging T2 lesions (R2 = 0.42, p = 0.01), ARR (R2= 0.33, p = 0.03) and CDW (R2= 0.30, p = 0.04), but not with PBVC. In RMS-only trials, association with ARR (R2= 0.45, p = 0.05) and CDW (R2= 0.50, p = 0.03) was more pronounced. Conclusion: In MS, treatment effects on s/pNfL are moderately associated with therapeutic effects on ARR, MRI new/enlarging T2 lesions, and CDW, whereas no consistent association was observed with PBVC.