Disease-modifying therapies (DMTs) are widely used to manage multiple sclerosis (MS), but their effects on serum neurofilament light chain (sNfL), particularly in drug-naïve patients, remain underexplored. This study aimed to evaluate the effects of different DMT classes on sNfL level and compare these changes with clinical rating scales in drug-naïve MS patients.

In this prospective study, 85 drug-naïve MS patients completed 18-month follow-up after initiating DMTs (high-, moderate-, or first-line efficacy). Clinical assessments included EDSS, the 9-Hole Peg Test (9-HPT), the 25-Foot Walk Test (25-FWT), the MSIS-29, and the Hamilton Depression and Anxiety Scales. sNfL levels were measured via ELISA before and after treatment.

Baseline sNfL levels were significantly higher in MS patients than controls (66.36 ± 51.32 versus 10.55 ± 8.19 pg/mL, p < 0.001). High- and moderate-efficacy DMTs significantly reduced sNfL by 42.7% and 39.7%, respectively; first-line DMTs showed no significant reduction. Between-group differences were significant (p = 0.010). High-efficacy DMTs demonstrated the greatest reductions in EDSS (p = 0.001) and ARR (p < 0.001; large effect size), with moderate effects on motor performance. Changes in sNfL correlated with EDSS improvement (r = 0.383, p < 0.001) and 9-HPT (r = 0.258, p = 0.022), but not with psychiatric or quality-of-life measures. Age-adjusted analysis confirmed an independent association between sNfL reduction and EDSS change (p = 0.010).

High- and moderate-efficacy DMTs are associated with significant reductions in sNfL and improvements in clinical parameters in drug-naïve MS. Declines in sNfL parallel improvements in disability and motor function but not in psychiatric outcomes, supporting its role as a reliable biomarker of treatment response and neuroaxonal injury. Larger longitudinal studies are warranted to confirm its long-term prognostic and clinical utility.