Digital signatures of fatigue and wearing-off symptoms in patients with multiple sclerosis under natalizumab

Wearing-off symptoms (WoS) during natalizumab (NTZ) treatment are frequently interpreted as subclinical disease activity in patients with multiple sclerosis (PwMS), but their significance remains uncertain. In the prospective single-center SATURATE study (NCT05701423), we investigated whether WoS were associated with inflammatory or neurodegenerative damage and whether wearable monitoring captures related motor changes. Thirty-four NTZ-treated participants were enrolled; 28 completed 6-month follow-up and 21 provided analyzable smartwatch data. Clinical assessments were performed at baseline, month 3, and month 6; serum NTZ, soluble vascular cell adhesion molecule-1, neurofilament light chain, glial fibrillary acidic protein, and diffusion-weighted magnetic resonance imaging were assessed at baseline and month 6. Before each NTZ administration, participants completed a WoS questionnaire. WoS occurred in 19/28 analyzed participants (67.9%) and 63/177 of observed questionnaires (35.6%). WoS rate was associated with fatigue, but not with dosing interval, diffusion changes, or serum biomarkers. The adjusted subcutaneous-versus-intravenous coefficient was -0.296 (HC3-robust 95% CI, -0.649 to 0.056; p = 0.100; conventional OLS 95% CI, -0.575 to -0.018; p = 0.038). Wearable data showed a subtle end-of-cycle decline in afternoon steps (within-subject z-score difference, -0.130; 95% CI, -0.229 to -0.004; Holm-adjusted p = 0.015). Dynamic activity features, including morning-to-afternoon step ratios and reduced peak step variability, correlated with fatigue scores and WoS rate. These exploratory findings indicate that, in this clinically stable cohort, WoS under NTZ do not reflect ongoing inflammatory or neurodegenerative disease activity, but rather align with fatigue-related motor changes detectable by high-adherence passive wearables. Dynamic wearable activity metrics warrant evaluation as digital endpoints for fatigue-focused interventions and clinical care.