OBJECTIVE: To investigate relationships between serum neurofilament light chain (sNfL), ubiquitin C-terminal hydrolase L1 (sUCHL1), tau (sTau) and glial fibrillary acidic protein (sGFAP) levels and disease activity/disability in neuromyelitis optica spectrum disorder (NMOSD), and the effects of inebilizumab on these biomarkers in N-MOmentum. METHODS: N-MOmentum randomised participants to receive inebilizumab or placebo with a randomised controlled period (RCP) of 28 weeks and an open-label follow-up period of ≥2 years. The sNfL, sUCHL1, sTau and sGFAP were measured using single-molecule arrays in 1260 scheduled and attack-related samples from N-MOmentum participants (immunoglobulin G (IgG) autoantibodies to aquaporin-4-positive, myelin oligodendrocyte glycoprotein-IgG-positive or double autoantibody-negative) and two control groups (healthy donors and patients with relapsing-remitting multiple sclerosis). RESULTS: The concentration of all four biomarkers increased during NMOSD attacks. At attack, sNfL had the strongest correlation with disability worsening during attacks (Spearman R2=0.40; p=0.01) and prediction of disability worsening after attacks (sNfL cut-off 32 pg/mL; area under the curve 0.71 (95% CI 0.51 to 0.89); p=0.02), but only sGFAP predicted upcoming attacks. At RCP end, fewer inebilizumab-treated than placebo-treated participants had sNfL>16 pg/mL (22% vs 45%; OR 0.36 (95% CI 0.17 to 0.76); p=0.004). CONCLUSIONS: Compared with sGFAP, sTau and sUCHL1, sNfL at attack was the strongest predictor of disability worsening at attack and follow-up, suggesting a role for identifying participants with NMOSD at risk of limited post-relapse recovery. Treatment with inebilizumab was associated with lower levels of sGFAP and sNfL than placebo. TRIAL REGISTRATION NUMBER: NCT02200770.

Brain and Mind Centre University of Sydney Sydney New South Wales Australia

Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle Service de Neurologie Sclérose en Plaques Pathologies de la Myéline et Neuro inflammation Hopital Neurologique et Neurochirurgical Pierre Wertheimer Centre de reference des syndromes neurologiques paraneoplasiques et encephalites auto immun Lyon Auvergne Rhône Alpes France

Department of Biostatistics University of Alabama at Birmingham Birmingham Alabama USA

Department of Multiple Sclerosis Therapeutics Fukushima Medical University Koriyama Fukushima Japan

Department of Neurology and Center for MS and Autoimmune Neurology Mayo Clinic Rochester Minnesota USA

Department of Neurology Mayo Clinic Scottsdale Arizona USA

Department of Neurology Medical Faculty Heinrich Heine University Düsseldorf Düsseldorf Germany

Department of Neurology Medical University Vienna Vienna Austria

Department of Neurology Palacky University in Olomouc Olomouc Czech Republic

Department of Neurology Research Institute and Hospital of National Cancer Center Goyang Republic of Korea

Department of Neurology UCSF Weill Institute for Neurosciences University California of San Francisco San Francisco California USA

Department of Neurology University of Virginia Charlottesville Virginia USA

Departments of Neurology and Ophthalmology Programs in Neuroscience and Immunology University of Colorado Anschutz Medical Campus Aurora Colorado USA

Experimental and Clinical Research Center Max Delbrück Center for Molecular Medicine and Charité Universitätsmedizin Berlin Berlin Germany

Horizon Therapeutics plc Gaithersburg Maryland USA

Multiple Sclerosis and Neuromyelitis Optica Center Southern Tohoku Research Institute for Neuroscience Koriyama Japan

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NCT02200770