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Aquaporin-4 Antibodies in Patients Treated with Natalizumab for Suspected MS

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Aquaporin-4 Antibodies in Patients Treated with Natalizumab for Suspected MS Aquaporin-4 antibodies in patients treated with natalizumab for suspected MS Anna Gahlen, MD ABSTRACT Anne-Kathrin Trampe, Objective: To evaluate (1) the frequency of aquaporin-4 antibody (AQP4-ab)-seropositive cases PhD among patients treated with natalizumab (NAT) and previously diagnosed with MS (MSNAT)in Steffen Haupeltshofer, a nationwide cohort, (2) the clinical course of NAT-treated AQP4-ab–seropositive neuromyelitis MSc optica spectrum disorder (NMOSD) patients (NMONAT), (3) AQP4-ab titers in NMONAT and AQP4- Marius Ringelstein, MD ab–seropositive NMOSD treated with other immunotherapies (NMOIT), and (4) immune mecha- Orhan Aktas, MD nisms influencing disease activity in NMONAT. Achim Berthele, MD Methods: MSNAT serum samples were retrospectively screened with a cell-based assay for AQP4- Brigitte Wildemann, MD IgG and titers determined by ELISA. The annualized relapse rate (ARR) and disability progression Ralf Gold, MD were assessed. Serum levels of proinflammatory cytokines (interleukin [IL]-1b, IL-4, IL-6, IL-8, IL- Sven Jarius, MD 10, IL-17, IL-21, and interferon [IFN]-g) and the chemokine CXCL-10 of NMONAT patients Ingo Kleiter, MD identified in this (n 5 4) and a previous study (n 5 5) were measured by cytometric bead array and ELISA. Correspondence to Results: Of the 1,183 MSNAT patients (851 female, median 9 NAT infusions), only 4 (0.33%; 3 Prof. Kleiter: female, 1 male) had AQP4-IgG. Of these, 2 fulfilled the 2006 NMO criteria and all met the 2015 [email protected] NMOSD criteria. The ARR was higher in NMONAT vs MSNAT (p 5 0.0182). All 4 NMONAT patients had relapses and 2 had an increase of disability. AQP4-ab titers were higher in NMONAT (n 5 9) vs NMOIT (n 5 13; p 5 0.0059). IL-8, IL-1b, and IFN-g serum levels were significantly higher, and CXCL-10 was significantly lower in NMONAT vs NMOIT. Conclusions: Misdiagnosis of NMOSD with MS is rare. NAT was not able to control disease activity in NMONAT patients, who had higher serum levels of AQP4-IgG and proinflammatory cytokines than patients with NMOSD treated with other immunotherapies. Neurol Neuroimmunol Neuroinflamm 2017;4:e363; doi: 10.1212/NXI.0000000000000363 GLOSSARY AQP4-ab 5 aquaporin-4 antibody; ARR 5 annualized relapse rate; CBA 5 cell-based assay; EAE 5 experimental autoim- mune encephalomyelitis; EDSS 5 expanded disability status scale; HEK 5 human embryonic kidney; JCV 5 JC virus; IL 5 interleukin; IFN 5 interferon; NAT 5 natalizumab; NMOSD 5 neuromyelitis optica spectrum disorder. Neuromyelitis optica (NMO) is a relapsing autoimmune CNS disease which mainly affects the optic nerves and spinal cord and often leads to severe disability.1 The detection of a serum antibody targeting the astrocytic water channel aquaporin-4 antibody (AQP4-ab)2 led to the definition of revised diagnostic criteria3 and to renaming of the entity as NMO spectrum disorder (NMOSD).4 Although distinction between MS and NMOSD was facilitated by AQP4-ab testing, there is a substantial overlap between clinical phenotypes of MS and NMOSD, which caused diagnostic uncertainty or misdiagnosis, in particular prior to the availability of AQP4-ab testing. Moreover, current AQP4-ab assays differ significantly with regard to sensitivity.1 Distinguishing MS and NMOSD is of high clinical relevance, since Supplemental data at Neurology.org/nn From the Department of Neurology (A.G., A.-K.T., S.H., R.G., I.K.), St. Josef-Hospital, Ruhr-University Bochum; Department of Neurology (M.R., O.A.), Medical Faculty, Heinrich-Heine-University Düsseldorf; Department of Neurology (A.B.), Klinikum Rechts der Isar, Technische Universität München; and Molecular Neuroimmunology Group (B.W., S.J.), Department of Neurology, University of Heidelberg, Germany. Funding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was funded by the authors. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Neurology.org/nn Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1 optimum treatments for the 2 diseases differ. NAT treatment time in years) in MSNAT and NMONAT patients; Most treatments found to be beneficial in MS the ARR prior NAT, calculated as the number of attacks within the last 12 months before start of NAT; and the expanded have been suggested to be ineffective or even disability status scale (EDSS) score in NMONAT patients during to cause disease exacerbation in NMOSD.5 and after NAT treatment. The clinical course of NMONAT pa- Previously, we have shown that natalizu- tients was further evaluated by a standardized questionnaire and mab (NAT), a very effective therapy for relaps- telephone interview of treating neurologists. The latter included detailed data about immunotherapies, MRI presentation, ing MS, had detrimental effects in 5 patients relapses, and disability progression before, during, and after who had been misdiagnosed with MS and NAT treatment. were treated with NAT prior to establishment As control group for studies of AQP4-ab titers, a prospective – cohort of AQP4-ab–seropositive NMOSD patients not treated of the correct diagnosis of AQP4-ab with NAT was tested. That cohort was matched for age, sex, 6 seropositive NMOSD. Although this study disease duration, and disease activity (acute disease vs remission) suggested treatment failure, it could not rule against the identified cohort of NMONAT patients. Patients with out that other patients with known or unde- an apheresis therapy in the last 60 days were excluded. Active disease was defined as relapse 660 days from the day of serum 7 tected NMOSD might benefit from NAT. sampling. To rule out the influence of immunotherapies when In the current study, we investigated a large testing antibodies and cytokines, we divided the control group set of serum samples from NAT-treated pa- into NMOSD without immunotherapy (NMOno IT) and IT tients with the diagnosis of MS (MSNAT) for NMOSD with immunotherapy (NMO ). the presence of AQP4-IgG to identify AQP4- Serological studies. The presence of serum AQP4-IgG was – evaluated by a standardized immunohistochemical cell-based ab seropositive patients with NMOSD ’ NAT assay (CBA) according to the manufacturer s protocol (AQP4- (NMO ). We hypothesized that some CBA; Euroimmun, Lübeck, Germany).10 Staining of each sample NAT AQP4-ab–seropositive NMO patients was evaluated with a fluorescence microscope (EuroStar; Euro- might have been misdiagnosed with MS and immun) at 3200 magnification and 1,000 ms exposure time in that NAT might turn out to be unable to comparison with appropriate negative and positive controls. Positive and ambiguous samples were sent in a masked fashion for control disease activity in those patients. In confirmation to 2 independent reference laboratories (Euro- addition, we investigated immune mecha- immun; Molecular Neuroimmunology Group, University nisms possibly underlying disease activity in Hospital Heidelberg, Germany). NAT Serum AQP4-ab concentrations were evaluated by a human NMO patients and compared serologic M23-AQP4–based ELISA according to the manufacturer’s markers with control NMOSD patients not protocol (anti-AQP4-Ab ELISA version 2; RSR, Cardiff, UK). treated with NAT. The cut-off for positive values was 3.0 U/mL. To evaluate the presence of AQP4-IgG reactive only with the M1 isoform of – METHODS Standard protocol approvals, registrations, human AQP4, additionally, a second, M1-AQP4 based ELISA was used (anti-AQP4-ELISA version 1; RSR; cut-off 3.0 and patient consents. Ethical approval was obtained from the U/mL).11 Absorbance was read at 450 and 405 nm by an ELISA institutional ethics review boards of the Universities of Bochum plate reader (Emax; Molecular Devices, Sunnyvale, CA). (no. 4390-12) and Düsseldorf (nos. 3419 and 3738). Prospec- Cytokines (interleukin [IL]-1b, IL-4, IL-6, IL-8, IL-10, IL- tively evaluated patients provided written informed consent. A 17, IL-21, and interferon [IFN]-g) and the chemokine CXCL-10 waiver for retrospective analysis of serum samples and unblinding were evaluated by a multiplex bead-based immunoassay (cyto- of NMONAT patients to get further clinical information from metric bead array) according to the manufacturer’s protocol treating doctors was issued by the institutional ethics review (BD Biosciences, Heidelberg, Germany). Samples were acquired board, since previous data suggested deleterious effects of NAT on a flow cytometer, and data were analyzed using FCAP Array treatment in AQP4-ab–seropositive NMO patients.6,8 software v3 (both BD Biosciences, Franklin Lakes, NJ). IL-8 and Patients. We retrospectively evaluated blinded frozen serum CXCL-10 additionally were evaluated by ELISA according to the samples from MSNAT patients stored in a serum depository at manufacturer’s protocol (IL-8 Quantikine ELISA, CXCL-10 the St. Josef Hospital Bochum.9 The sera were initially sent for Quantikine ELISA; both R&D, Minneapolis, MN). For IL-8, analysis of anti-NAT-abs with neutralizing activity. The study serum was diluted 1:10, and for CXCL-10, serum was diluted population consisted of a nationwide cohort of patients with 1:2. Absorbance was read at 650 and 450 nm. All samples were relapsing-remitting
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