Integration of retinal layer thinning into NEDA-3 predicts disability progression in multiple sclerosis

INTRODUCTION: Retinal layer thinning is associated with disability progression and treatment failure in relapsing multiple sclerosis (RMS). However, the systematic integration of optical coherence tomography (OCT)-derived metrics into a composite measure of treatment response has not yet been evaluated. METHODS: We analyzed two observational cohorts of patients with RMS who newly initiated DMT, received an MRI and OCT at baseline and 12 months, and had ≥ 24 months of clinical follow-up. No evidence of disease activity (NEDA-3/NEDA-3 + OCT) status was assigned at 12 months after DMT. Retinal thinning was defined as a reduction of ≥ 1.0 µm/year peripapillary retinal nerve fiber layer or ≥ 0.5 µm/year ganglion-cell/inner plexiform layer. The primary endpoint was confirmed disability progression occurring after the 12 month NEDA assessment. Both low-efficacy DMT and high-efficacy were included and analyzed jointly, with treatment class entered as a covariate in all models. RESULTS: Overall, 124 individuals (72% female, mean age 33.1 [SD ± 7.7] years, median EDSS of 2.0 [IQR 0.0-2.5]) were included. Over a median follow-up period of 3.4 years, disability progression was observed in 28 (23%) individuals. Time to and risk of disability progression did not significantly differ between EDA-3 and NEDA-3 (restricted mean survival time [RMST]: 43.4 [SE ± 2.8] vs. 48.1 [SE ± 1.3] months, p = 0.067; adjusted hazard ratio [aHR] 1.52, 95% LL-CI 0.64, p = 0.173). When retinal layer thinning was incorporated, EDA-3 + OCT was associated with a higher risk of future progression (aHR 6.59, 95% LL-CI 2.38, p = 0.005) and shorter time to progression (RMST: 41.9 [SE ± 2.1] vs. 51.9 [SE ± 0.9] months, p < 0.001). CONCLUSION: Incorporating retinal layer thinning into the NEDA-3 framework substantially improves prediction of subsequent disability progression compared with conventional NEDA-3 alone, identifying a subgroup of patients in whom ongoing neurodegeneration appears to drive disability accumulation despite suppressed inflammatory activity.