Patients with neuromyelitis optica spectrum disorder display hallmarks of systemic autoimmunity: broad serum autoreactivity to nuclear antigens and elevated interferon-inducible gene expression

INTRODUCTION: Neuromyelitis optica spectrum disorder (NMOSD) is a primary astrocytopathy often characterized by high aquaporin‐4 (AQP4) autoantibody titers. Patients with NMOSD produce interferogenic anti‐nuclear autoantibodies and tend to develop systemic autoimmunity. OBJECTIVE: Profile serum autoreactivity and type1 interferoninducible gene signatures (IFNGSs) in blood to characterize the relationship with disease activity in NMOSD. METHODS: Serum samples were obtained from 220/230 patients with NMOSD randomized in N‐MOmentum and from 25 healthy controls (HCs). Baseline samples were profiled for serum immunoglobulin (Ig)G, IgM, IgA, and IgE autoreactivity by hybridizing samples to microarrays of 122 autoantigens (excluding AQP4) implicated in human autoimmune diseases (e.g. systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome). Autoreactivity was confirmed by a signal >5 standard deviations above HC mean. Baseline IFNGS were analyzed in blood RNA samples from 219 participants and 10 HCs. Those with >4‐fold change in signal above HC mean were IFNGS‐positive. Possible associations of baseline autoreactivity and IFNGS‐positivity with pre‐study NMOSD disease activity (annualized attack rate or mean annual disability worsening on Expanded Disability Status Scale between diagnosis and baseline, in patients with >4 years of medical history) were studied by negative binomial regression. RESULTS: At baseline, HCs did not display autoreactivity to any antigens studied, while 90% of patients with NMOSD (n=197) had autoreactivity to ≥1 autoantigen, mostly in IgG subclass (83% [n=183]), but also in IgA (41% [n=90]), IgM (25% [n=56]), and IgE (6% [n=14]) subclasses. In total, 27% of patients (n=59) were IFNGS‐positive at baseline and 4% (n=8) had a prior diagnosis of a systemic autoimmune disease. Serum autoreactivity against nuclear antigens (NAs) was greater than that against other antigens. Proportionally more IFNGS‐positive than IFNGSnegative patients were reactive to NAs (68% [40/59] vs 46% [71/153]; area under the ROC curve, 0.63; p = 0.002). Neither serum autoreactivity nor IFNGS‐positivity at baseline were associated with increased risk of pre‐study NMOSD disease activity. CONCLUSIONS: Patients with NMOSD show greater serum autoreactivity than do healthy controls to autoantibodies known to be associated with other systemic autoimmune diseases. However, this autoreactivity does not appear to be associated with increased NMOSD disease activity.