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Objective:  To evaluate (1) the frequency of aquaporin-4 antibody (AQP4-ab)-seropositive cases among patients treated with natalizumab (NAT) and previously diagnosed with MS (MS NAT ) in a nationwide cohort, (2) the clinical course of NAT-treated AQP4-ab–seropositive neuromyelitis optica spectrum disorder (NMOSD) patients (NMO NAT ), (3) AQP4-ab titers in NMO NAT  and AQP4-ab–seropositive NMOSD treated with other immunotherapies (NMO IT ), and (4) immune mechanisms influencing disease activity in NMO NAT .    Methods:  MS NAT  serum samples were retrospectively screened with a cell-based assay for AQP4-IgG and titers determined by ELISA. The annualized relapse rate (ARR) and disability progression were assessed. Serum levels of proinflammatory cytokines (interleukin [IL]-1β, IL-4, IL-6, IL-8, IL-10, IL-17, IL-21, and interferon [IFN]-γ) and the chemokine CXCL-10 of NMO NAT  patients identified in this (n = 4) and a previous study (n = 5) were measured by cytometric bead array and ELISA.    Results:  Of the 1,183 MS NAT  patients (851 female, median 9 NAT infusions), only 4 (0.33%; 3 female, 1 male) had AQP4-IgG. Of these, 2 fulfilled the 2006 NMO criteria and all met the 2015 NMOSD criteria. The ARR was higher in NMO NAT  vs MS NAT  ( p  = 0.0182). All 4 NMO NAT  patients had relapses and 2 had an increase of disability. AQP4-ab titers were higher in NMO NAT  (n = 9) vs NMO IT  (n = 13;  p  = 0.0059). IL-8, IL-1β, and IFN-γ serum levels were significantly higher, and CXCL-10 was significantly lower in NMO NAT  vs NMO IT .    Conclusions:  Misdiagnosis of NMOSD with MS is rare. NAT was not able to control disease activity in NMO NAT  patients, who had higher serum levels of AQP4-IgG and proinflammatory cytokines than patients with NMOSD treated with other immunotherapies.

Aquaporin-4 antibodies in patients treated with natalizumab for suspected MS