Reliability of serum neurofilament light and glial fibrillary acidic protein for detecting disease activity upon discontinuation of first-line disease-modifying therapy in stable multiple sclerosis (DOT-MS)

Background: Neurofilament light(NfL) and glial fibrillary acidic protein(GFAP) are associated with disease activity in multiple sclerosis(MS), however use in monitoring remains limited. The ability of these biomarkers to detect disease activity upon treatment discontinuation was studied. Methods: Long-term stable relapse-onset MS patients were to continue or discontinue their first-line disease-modifying therapy(DMT) to study the safety of DMT discontinuation(DOT-MS trial NCT04260711). “Significant” disease activity was defined as clinical relapse, ≥3 new lesions or ≥2 contrast-enhancing lesions. MRI and sampling were performed at baseline, month 3, 6, 12, 18 and 24. Associations of delta biomarker levels and NfL z-score(age and body mass index derived) with “significant” disease activity were tested. Cut-off values for biomarkers to detect disease activity were calculated. Results: 45(50.5%) participants discontinued their DMT. Eight(all discontinued DMT) had “significant” disease activity, which was associated with an increase in NfL levels(OR:1.13 [1.03–1.33], p = 0.04) and NfL z-scores(OR:2.17 [0.98–5.22], p = 0.06), but not with GFAP(p = 0.52). Delta NfL had the highest ability to detect “significant” disease activity(AUC:0.88 [0.76–0.99]), with the best calculated cut-off of 46.4% increase(AUC:0.68, sensitivity 0.57, specificity 0.96). Discussion: NfL may be useful to identify, but not predict, disease activity after DMT discontinuation in MS. GFAP levels were not discriminatory for disease activity.