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Failure of Natalizumab to Prevent Relapses in Neuromyelitis Optica

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Failure of Natalizumab to Prevent Relapses in Neuromyelitis Optica ORIGINAL CONTRIBUTION Failure of Natalizumab to Prevent Relapses in Neuromyelitis Optica Ingo Kleiter, MD; Kerstin Hellwig, MD; Achim Berthele, MD; Tania Ku¨mpfel, MD; Ralf A. Linker, MD; Hans-Peter Hartung, MD; Friedemann Paul, MD; Orhan Aktas, MD; for the Neuromyelitis Optica Study Group Objective: To describe first experiences with the inte- with natalizumab before diagnosis of NMO was estab- grin inhibitor natalizumab, given to patients with sus- lished. Natalizumab was given as escalation therapy af- pected relapsing-remitting multiple sclerosis (MS) who ter failure of first- or second-line immunomodulatory were later diagnosed with aquaporin 4–positive neuro- therapies for MS. During natalizumab therapy (median myelitis optica (NMO). duration, 8 infusions; range, 2-11 infusions), all 5 pa- tients displayed persisting disease activity; a total of 9 re- Design: Retrospective case series. lapses occurred (median duration to relapse, 120 days; Setting: Neurology departments at tertiary referral cen- range, 45-230 days) after the start of treatment. Four pa- ters in Germany. tients had an accumulation of disability and 1 patient died 2 months after cessation of natalizumab treatment. Patients: Patients with NMO who tested positive for an- tibodies to aquaporin 4. Conclusions: Our results suggest that natalizumab fails Intervention: Treatment with natalizumab. to control disease activity in patients with NMO. Neu- romyelitis optica should be considered as a differential Main Outcome Measures: Relapses and accumula- diagnosis in patients with suspected MS who are unre- tion of disability. sponsive to natalizumab therapy. Results: We identified 5 patients (4 female; median age, 45 years) who were initially diagnosed with MS and treated Arch Neurol. 2012;69(2):239-245 EUROMYELITIS OPTICA of no proven efficacy or may even be harm- (NMO) is a disabling au- ful in NMO.11-16 toimmune central ner- Natalizumab is a monoclonal anti- vous system (CNS) dis- body against the adhesion molecule very order with clinical attacks late activation antigen 4, an ␣4␤1 integ- mainly involving the optic nerves and the rin expressed on leukocytes, and is ap- N1,2 spinal cord. The detection of a serum an- proved for treatment escalation in pa- tibody to the CNS water channel aquapo- tients with relapsing-remitting MS with rin 4 (AQP4) as a highly specific bio- breakthrough disease and patients with MS marker in most patients with NMO3-5 has with highly active disease.17 Interest- facilitated its distinction from multiple scle- ingly, natalizumab not only reduces the en- rosis (MS), which may be difficult solely on try of CD4ϩ and CD8ϩ T lymphocytes into the basis of clinical and neuroradiological the CNS but also decreases the number of findings. Thus, it is conceivable that a sub- CD19ϩ B cells and antibody-producing stantial number of patients with NMO have CD138ϩ plasma cells in the cerebrospi- been misdiagnosed with MS, in particular nal fluid (CSF) for at least 6 months after prior to the availability of AQP4 antibody infusion.18 Thus, interference with B-cell testing. While first-line therapy for MS com- invasion into the CNS may provide an im- prises disease-modifying drugs such as munological rationale for evaluation of na- Author Affiliations are listed at the end of this article. interferon beta and glatiramer acetate, NMO talizumab in NMO therapy. However, Group Information: The usually requires aggressive immunosup- clinical experience on natalizumab appli- Neuromyelitis Optica Study pression or a specific B-cell–targeted cation in NMO is lacking to date. Investigators are listed at the therapy.6-10 Treatment options that are ben- Here, we describe 5 patients who were end of this article. eficial in MS, especially interferon beta, are treated with natalizumab for suspected re- ARCH NEUROL / VOL 69 (NO. 2), FEB 2012 WWW.ARCHNEUROL.COM 239 ©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 lapsing-remitting MS, but were subsequently diagnosed tic neuritis was the initial clinical presentation in pa- with AQP4-positive NMO after experiencing severe re- tients 1, 2, and 4, diplopia and subsequent vomiting and lapses during natalizumab therapy. dysphagia in patient 3, and recurrent myelitis in patient 5. All patients had had at least 1 episode of myelitis and METHODS 3 patients had had 1 or more unusually severe relapses, including paraparesis during pregnancy (patient 1), brain- stem involvement (patient 3), and blindness and coma PATIENTS (patient 5). No patient had a concomitant overt autoim- mune disease. The extended medical history included py- To identify patients with NMO who were treated with natali- elonephritis in patient 2, elevation of transaminase lev- zumab, we used the network of the German Neuromyelitis Op- tica Study Group (http://www.nemos-net.de). This network is els during interferon beta therapy in patient 3, and Barrett a nationwide open association of neurological centers inter- esophagus, hepatitis C, myocardial infarction, and hy- ested in NMO/NMO spectrum disorders. It collects clinical fea- pertension in patient 4. tures of such patients in a retrospective and prospective fash- Brain MRI performed prior to starting treatment with ion approved by the institutional review boards of the natalizumab showed supratentorial lesions in patients 1, participating academic centers and in accordance with the Ger- 2, and 5 and had normal findings in patient 4 (Table). man data protection law. At the time of analysis, 153 patients Patient 3 initially presented with a large bithalamic le- with NMO or NMO spectrum disorders according to the re- sion extending to the mesencephalon and the brain- 19 vised 2006 criteria by Wingerchuk et al had been captured. stem. Although the distribution and appearance of the In the present retrospective approach, we included all pa- lesions were unspecific according to established crite- tients with confirmed NMO and IgG antibodies to AQP4 (AQP4- 23 Abs) who had a history of treatment with natalizumab. We iden- ria, MRI findings were regarded to be consistent with tified 5 patients at 4 university medical centers (Ruhr University MS by the local evaluating radiologists in 4 of 5 cases. Bochum, Ludwig-Maximilians-University Munich, Technische Four patients (2-5) underwent spinal cord MRI before Universita¨t Mu¨ nchen, Munich, and University Medical Center they started receiving natalizumab, which showed lon- Regensburg). All patients had initially been diagnosed with re- gitudinally extensive lesions in the cervical and thoracic lapsing-remitting MS, according to the McDonald criteria re- myelon in patients 2, 3, and 4 and several small lesions vised in 2005,20 before receiving natalizumab as an escalation in the thoracic cord in patient 5. Only patients 2 and 4 therapy after failure of first- or second-line MS therapies. were suspected to have NMO prior to initiation of na- Medical records were retrospectively assessed for disease du- talizumab, but this diagnosis was not favored by the sub- ration, previous treatments, total number of relapses, exacer- sequent treating neurologist. Cerebrospinal fluid analy- bations before, during, and after cessation of natalizumab, dis- ability scored by the Expanded Disability Status Scale,21 duration sis was performed in all patients. Patient 1 had persistent until NMO diagnosis, and anti-AQP4 antibody titers. Brain and oligoclonal bands; patient 3 initially tested negative for spinal cord magnetic resonance imaging (MRI) findings dur- oligoclonal bands but tested positive 5 years later at di- ing and after therapy with natalizumab were reevaluated for agnosis of NMO. The remaining 3 patients tested posi- MS- or NMO-typical lesions in the brain and spinal cord, in tive for oligoclonal bands during relapses but negative particular for longitudinally extensive spinal cord lesions ex- during remissions. Testing for AQP4 was not per- tending over 3 vertebral segments. Furthermore, detailed clini- formed when natalizumab therapy was started. For pa- cal information was obtained with regard to the period of na- tients 3 and 4, AQP4-Ab testing was not yet available when talizumab treatment, cessation of natalizumab, and diagnosis the initial diagnosis of MS was made. For the other pa- of NMO. Clinical, radiological, and histopathological features tients, AQP4-Ab serology was not performed because the of patient 5 have been described elsewhere in detail.22 clinical presentation was initially assessed to be compat- ible with MS. AQP4 SEROLOGY Previous treatments included steroids for relapses (n=5) and azathioprine (n=1), interferon beta (n=4), mi- A recently described cell-based flow cytometry assay was used toxantrone (n=2), and rituximab (n=1) for long-term for quantification of serum AQP4-Abs by detection of the dif- therapy. Owing to ongoing disease activity despite pre- ference in median fluorescence intensity (⌬MFI).5 vious disease-modifying therapies, all patients were switched to natalizumab therapy (300 mg intrave- RESULTS nously every 4 weeks) as escalation therapy. DEMOGRAPHICS AND CLINICAL FEATURES TREATMENT RESPONSE PRIOR TO NATALIZUMAB THERAPY TO NATALIZUMAB We identified 5 patients (4 female, 1 male) who had ini- Natalizumab was given for a median of 8 infusions (range, tially been treated with natalizumab for suspected re- 2-11 infusions) at monthly intervals except for 1 patient lapsing-remitting MS but were subsequently diagnosed with repeated infections who received only 8 infusions with AQP4-Abs–positive NMO (Table). The median dis- over 10 months (Table). During natalizumab therapy, all ease duration at initiation of natalizumab was 9 years 5 patients experienced at least 1 clinical relapse (Figure). (range, 4-31 years) and the median age was 45 years The median time from the start of natalizumab to the first (range, 35-56 years). All patients had experienced pro- relapse was 120 days (range, 45-230 days). Two pa- nounced disease activity (median, 12 relapses; range, 6-40 tients had 1 relapse, 2 patients had 2, and another pa- relapses) prior to receiving natalizumab.
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