Serum Biomarker Profiles Discriminate AQP4 Seropositive and Double Seronegative Neuromyelitis Optica Spectrum Disorder

Abstract

Serum biomarker; Neuromyelitis optica spectrum disorder

Biomarcadores séricos; Trastorno del espectro de neuromielitis óptica

Biomarcadors sèrics; Trastorn de l'espectre de neuromielitis òptica

Background and Objectives Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) serum levels are useful to define disease activity in different neurologic conditions. These biomarkers are increased in patients with aquaporin-4 antibody–positive NMOSD (AQP4+NMOSD) during clinical attacks suggesting a concomitant axonal and glial damage. However, there are contradictory results in double seronegative NMOSD (DS-NMOSD). The aim of this study was to characterize the neuronal, axonal, and glial damage of DS-NMOSD in comparison with AQP4+NMOSD. Methods Patients with DS-NMOSD (i.e., for AQP4 and myelin oligodendrocyte glycoprotein antibodies—MOG-Abs) and age-matched AQP4+NMOSD diagnosed according to the latest diagnostic criteria and with available serum samples obtained within 3 months from onset/relapse were retrospectively enrolled from 14 international centers. Clinical and radiologic data were collected. Serum NfL, GFAP, tau, and UCH-L1 levels were determined using an ultrasensitive paramagnetic bead–based ELISA (SIMOA). Statistical analysis was performed using nonparametric tests and receiver-operating characteristic (ROC) curve analysis. Results We included 25 patients with AQP4+NMOSD and 26 with DS-NMOSD. The median age at disease onset (p = 0.611) and female sex predominance (p = 0.072) were similar in the 2 groups. The most common syndromes at sampling in both AQP4+NMOSD and DS-NMOSD were myelitis (56% vs 38.5%) and optic neuritis (34.6% vs 32%), with no statistical differences (p = 0.716). Median EDSS at sampling was 3.2 (interquartile range [IQR] 2–7.7) in the AQP4+NMOSD group and 4 (IQR [3–6]) in the DS-NMOSD group (p = 0.974). Serum GFAP, tau, and UCH-L1 levels were higher in patients with AQP4+NMOSD compared with those with DS-NMOSD (median 308.3 vs 103.4 pg/mL p = 0.001; median 1.2 vs 0.5 pg/mL, p = 0.001; and median 61.4 vs 35 pg/mL, p = 0.006, respectively). The ROC curve analysis showed that GFAP, tau, and UCH-L1, but not NfL, values were able to discriminate between AQP4+ and DS-NMOSD (area under the curve (AUC) tau: 0.782, p = 0.001, AUC GFAP: 0.762, p = 0.001, AUC UCH-L1: 0.723, p = 0.006). NfL levels were associated with EDSS at nadir only in patients with AQP4+NMOSD. Discussion Serum GFAP, tau, and UCH-L1 levels discriminate between AQP4+NMOSD and DS-NMOSD. The different biomarker profile of AQP4+NMOSD vs DS-NMOSD suggests heterogeneity of diseases within the latter category and provides useful data to improve our understanding of this disease.

H. Zéphir has no disclosure related to this work. Unrelated to this work, H. Zéphir received consulting fees from Alexion, Horizon Therapeutics, Roche, Merck, Biogen Idec, Sanofi, and Novartis. Georgina Arrambide has received speaking honoraria and compensation for consulting services or participation in advisory boards from Merck, Roche, and Horizon Therapeutics; travel support for scientific meetings from Novartis, Roche, and ECTRIMS; is the editor for Europe of the Multiple Sclerosis Journal - Experimental, Translational and Clinical; and is a member of the International Women in Multiple Sclerosis (iWiMS) Network executive committee and of the European Biomarkers in MS (BioMS-eu) Consortium steering committee; J. Villacieros-Álvarez has received a grant from Instituto de Salud Carlos III, Spain, FI21/00282; A. Cobo-Calvo has received a grant from Instituto de Salud Carlos III, Spain, JR19/00007; E.P. Flanagan has served on advisory boards for Alexion, Genentech, Horizon Therapeutics, and UCB. He has received speaker honoraria from Pharmacy Times. He received royalties from UpToDate. Dr. Flanagan was a site primary investigator in a randomized clinical trial on Inebilizumab in neuromyelitis optica spectrum disorder run by Medimmune/Viela-Bio/Horizon Therapeutics. Dr. Flanagan has received funding from the NIH (R01NS113828). Dr. Flanagan is a member of the medical advisory board of the MOG project. Dr. Flanagan is an editorial board member of the Journal of the Neurological Sciences and Neuroimmunology Reports. A patent has been submitted on DACH1-IgG as a biomarker of paraneoplastic autoimmunity. S. Mariotto received speaker honoraria from Novartis, Biogen, and Sanofi. Go to Neurology.org/NN for full disclosures.