Refining Treatment Monitoring in Patients With Relapsing Multiple Sclerosis Based on Changes on Neurofilament Light Chain Z-Scores.
BACKGROUND AND OBJECTIVES Serum neurofilament light chain (sNfL) reflects inflammatory axonal damage in relapsing multiple sclerosis (RMS). Longitudinal sNfL dynamics may aid treatment response assessment, although data on expected changes under disease-modifying treatments remain limited, particularly in real-world practice. This study evaluated whether on-treatment changes in sNfL were associated with subsequent evidence of disease activity (EDA) and whether they provided complementary information to established treatment response scoring systems (TRSS). METHODS This prospective, real-world cohort study was conducted at the Multiple Sclerosis Center of Catalonia (Cemcat). Adult RMS patients initiating disease-modifying treatments (DMTs) with serum samples at treatment initiation (baseline) and after 1 year (Y1) were included. The primary exposure was change in sNfL z-scores (ΔzNfL = zNfLY1 - zNfL-baseline) analyzed using data-derived thresholds (ΔzNfL ≥0 and <0.5-point reduction). At Y1, Expanded Disability Status Scale progression, clinical/radiologic activity, and TRSS (Rio [RS], modified Rio [mRS], and MAGNIMS) were assessed. The primary outcome was EDA between years 1 and 2 (EDA-Y2). Multivariable logistic regression models evaluated associations between ΔzNfL and EDA-Y2, as well as the added value of ΔzNfL across TRSS strata. RESULTS A total of 329 patients (66.3% female; median age 39 years) initiated 352 DMTs; 342 remained on treatment for ≥1 year and 182 had complete EDA-Y2 data. Mean (SD) ΔzNfL at Y1 was -0.62 (1.2), with greater reductions in monoclonal antibody-treated and treatment-naïve patients. Lack of zNfL reduction over the first year (ΔzNfL ≥0) was associated with higher odds of EDA-Y2 in the overall cohort (OR [95% CI], p: 3.07 [1.47-6.39], 0.003), in treatment-naïve cases (14.04 [2.47-79.93], 0.003), and in those achieving No Evidence of Disease Activity (NEDA-3) at Y1 (4.54 [1.26-16.30], 0.02). Similar associations were observed for <0.5-point reductions. Adding ΔzNfL to TRSS showed persistent associations with EDA-Y2 despite otherwise favorable scores [e.g., RS: 2.26 (1.12-4.59), 0.024]. DISCUSSION Failure to reduce zNfL levels after 1 year of treatment was associated with subsequent disease activity, even in patients otherwise considered stable, providing complementary information to clinical and MRI-based monitoring. Limitations include incomplete follow-up and the modest discriminative performance of ΔzNfL, supporting a complementary rather than stand-alone role for zNfL dynamics.