Alemtuzumab exerts its clinical efficacy by its specific pattern of depletion and repopulation of different immune cell subsets. Recently, single cases of multiple sclerosis patients who developed severe exacerbation after the first alemtuzumab application, accompanied by re-appearance of peripheral B cells, were reported. Here we present a case with underlying B cell-driven multiple sclerosis that impressively improves after alemtuzumab, although peripheral B cell repopulation took place. Our detailed clinical, histopathological, imaging and immunological data suggest that alemtuzumab can act as an effective rescue treatment in highly active B cell-driven and antibody/complement-mediated multiple sclerosis type II patients

Hagen H. Kitzler

Imke Metz

Katja Akgün

Tjalf Ziemssen

Wolfgang Brück

Therapeutic Advances in Neurological Disorders

Akgün, Katja

Metz, Imke

Kitzler, Hagen H.

Brück, Wolfgang

Ziemssen, Tjalf

Technische Universität Dresden: Qucosa

     Dieses Dokument ist eine Zweitveröffentlichung (Verlagsversion) / This is a self-archiving document (published version):            Diese Version ist verfügbar / This version is available on:  https://nbn-resolving.org/urn:nbn:de:bsz:14-qucosa2-355436    „Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFGgeförderten) Allianz- bzw. Nationallizenz frei zugänglich.“  This publication is openly accessible with the permission of the copyright owner. The permission is granted within a nationwide license, supported by the German Research Foundation (abbr. in German DFG). www.nationallizenzen.de/    Katja Akgün, Imke Metz, Hagen H. Kitzler, Wolfgang Brück, Tjalf Ziemssen Rescue therapy with alemtuzumab in B cell/antibody-mediated  multiple sclerosis  Erstveröffentlichung in / First published in: Therapeutic Advances in Neurological Disorders. 2018, 11, S. 1 – 4 [Zugriff am: 13.08.2019]. SAGE journals. ISSN 1756-2864. DOI: https://doi.org/10.1177/1756286418759895   https://doi.org/10.1177/1756286418759895 https://doi.org/10.1177/1756286418759895journals.sagepub.com/home/tan 1Ther Adv Neurol Disord2018, Vol. 11: 1–4DOI: 10.1177/ 17562856 8759895© The Author(s), 2018.  Reprints and permissions:  http://www.sagepub.co.uk/journalsPermissions.navCreative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License  (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Therapeutic Advances in Neurological DisordersIntroductionThe monoclonal anti-CD52 antibody alemtu-zumab mediates its efficacy by antibody and com-plement-dependent cytotoxicity and results in depletion of CD52-positive cells and an altered dis-tribution of different peripheral T and B immune cell subtypes in multiple sclerosis patients.1,2 In post-marketing experience, single cases of severe clinical exacerbation with respective development of tumefactive lesions after alemtuzumab use were reported.3,4 In addition, alemtuzumab has failed in several cases of neuromyelitis optica.5 For these cases, the authors suggested a B cell-mediated pro-cess causing the clinical and MRI exacerbation, since the clinical exacerbation was paralleled by the re-appearance of B cells in the periphery. This is of special interest as B cells seem to play a significant role in multiple sclerosis pathogenesis. B cell-depleting therapies have been extensively and suc-cessfully tested in relapsing, remitting and primary progressive multiple sclerosis and have already been approved with ocrelizumab.Case reportWe report a patient with histopathologically proven antibody/complement mediated pattern type II multiple sclerosis, in which alemtuzumab has been successfully applied as rescue therapy. After multiple sclerosis diagnosis in 2006, a 34-year-old female started interferon-beta treat-ment. Because of high disease activity she was escalated to natalizumab treatment in 2008. The JC virus antibody status was positive in December 2014, and thus therapy was changed to fingoli-mod in March 2015 because of the high risk of developing progressive multifocal leukencepha-lopathy. One month later she suffered a severe relapse with headache, and an MRI presented a novel subset of large ring-enhancing lesions among otherwise typical multiple sclerosis lesions (Figure 1(a), first row). Additional evaluation of cerebrospinal fluid (CSF) was negative for JC virus DNA testing. A first brain biopsy was per-formed to exclude opportunistic infections and confirmed multiple sclerosis typical lesions with signs of active demyelination, allowing this case to be classified as multiple sclerosis pattern II (antibody/complement mediated). The patient was treated with steroids, and fingolimod was continued. After an additional relapse, fingoli-mod was stopped in September 2015 and the patient was treated with steroids again. Due to vaccination, alemtuzumab initiation was delayed. Rescue therapy with alemtuzumab in B  cell/antibody-mediated multiple sclerosisKatja Akgün, Imke Metz, Hagen H. Kitzler, Wolfgang Brück and Tjalf ZiemssenAbstract: Alemtuzumab exerts its clinical efficacy by its specific pattern of depletion and repopulation of different immune cell subsets. Recently, single cases of multiple sclerosis patients who developed severe exacerbation after the first alemtuzumab application, accompanied by re-appearance of peripheral B cells, were reported. Here we present a case with underlying B cell-driven multiple sclerosis that impressively improves after alemtuzumab, although peripheral B cell repopulation took place. Our detailed clinical, histopathological, imaging and immunological data suggest that alemtuzumab can act as an effective rescue treatment in highly active B cell-driven and antibody/complement-mediated multiple sclerosis type II patients.Keywords: alemtuzumab, B cell-mediated multiple sclerosis, multiple sclerosis exacerbation, rescue treatment in highly active multiple sclerosisReceived: 23 August 2017; revised manuscript accepted: 19 December 2017.Correspondence to: Tjalf Ziemssen Department of Neurology, University Hospital of Dresden, Fetscherstraße 74, 01307, Dresden, Germany Tjalf.Ziemssen@uniklinikum-dresden.deKatja Akgün Center of Clinical Neuroscience, University Hospital Dresden, Dresden, GermanyHagen H. Kitzler Department of Neuroradiology, University Hospital Dresden, Dresden, GermanyImke Metz Wolfgang Brück Department of Neuropathology, University Medical Centre, Goettingen, Germany759895 TAN0010.1177/1756286418759895Therapeutic Advances in Neurological DisordersK Thomas, I Metzcase-report20182018Case ReportTherapeutic Advances in Neurological Disorders 112 journals.sagepub.com/home/tanSubsequently, in October 2015 she suffered another severe relapse with hemiparesis and apha-sia unresponsive to steroids, and plasmapheresis necessitating intensive care with intubation. MRI revealed an increasing number of contrast-enhancing lesions in cerebral and spinal MRI Figure 1. (a) MRI data. First row: initial MRI 4 months before alemtuzumab revealed inhomogeneous lesions pattern including large ring-enhancing lesions in juxtacortical white matter admixed with smaller lesions of infrequent nodular enhancement. Second row: MRI prior to alemtuzumab administration revealed new enhancing lesions and now extensive brainstem involvement. Third row: MRI 6 months after alemtuzumab treatment revealed reduction in lesion size as well as perifocal edema and gadolinium enhancement disappearance. Fourth row: 12 months after alemtuzumab, lesion consolidation was found. Formerly acute lesions revealed progressive T1 hypointensity.(b) Biopsy was taken from the subcortical right middle frontal gyrus before alemtuzumab application (pre). Multiple sclerosis lesion with involvement of the humoral immune system (type II pattern): HE staining shows a macrophage-rich lesion with perivascular inflammation and a reactive gliosis. The lesion is demyelinated (LFB/PAS stain with missing blue myelin). Numerous macrophages with myelin degradation products in their cytoplasm are present, indicating an active demyelinating lesion (anti-proteolipid protein). Within the lesion, T cells are located in the perivascular space and within the parenchyma (anti-CD3). Activated complement components (anti-C9neo) and immunoglobulins (anti-immunoglobulin G) are present with macrophages, indicating a complement/immunoglobulin mediated demyelination (pattern II; arrows indicate complement and IgG-laden macrophages). Scale bar: 100 µm for HE, LFB/PAS and anti-CD3. 50 µm for anti-PLP, anti-c9neo and anti-IgG.(c) Analysis of peripheral immune cell subtypes and CSF markers: peripheral blood immune cell subtypes including CD19+ B cells and CD3+ T cells were evaluated prior to and after alemtuzumab infusion. One month before alemtuzumab administration (–1M) lymphocyte counts were still decreased due to previous but interrupted fingolimod treatment and were normalized directly before alemtuzumab initiation (pre). CD19+ B cells were markedly decreased after the first alemtuzumab cycle but demonstrated an overshooting repopulation before the second alemtuzumab cycle (12M). Arrows indicate first and second alemtuzumab application. CSF was investigated directly before (pre) and one month (1M) after alemtuzumab. Intrathecal inflammation and damage of the blood–brain barrier were markedly decreased after alemtuzumab. Q, quotient. Reference values: CD19+ B cell in peripheral blood 0.175–0.575 GPt/L; CD3+ T cell in peripheral blood 1.5–4.0 GPt/L; CSF cell count <5 MPt/L; total protein 150–450 m/L; QAlbumin 6.5; intrathecal IgG, IgM or IgA synthesis 0%.K Thomas, I Metz et al.journals.sagepub.com/home/tan 3(Figure 1(a), second row). The MRI at this stage revealed numerous new acute inflammatory lesions of similar pattern as in the initial relapse. At this stage, multifocal lesions in the brainstem were detectable in the MRI. Inadequate response toward the intensive anti-inflammatory therapy led to another brain biopsy to rule out other dif-ferential pathologies than ongoing acute demyeli-nation. This second biopsy confirmed the highly inflammatory, active demyelinating multiple scle-rosis lesions with antibody/complement deposits (multiple sclerosis pattern II) (Figure 1(b)).The first course of alemtuzumab was performed in the intensive care unit. Therapy was well toler-ated. The clinical condition stabilized rapidly and the patient was extubated a few days after alemtu-zumab treatment. After the second alemtuzumab cycle in October 2016 the patient had recovered, with an EDSS score of 3.5. MRI demonstrated lesion regression with resolved blood–brain bar-rier disruption, although peripheral B cells dem-onstrated an overshooting repopulation (Figure 1(a) third and fourth rows; Figure 1(c)).DiscussionCharacterizing the histopathology of early multi-ple sclerosis lesions, type II pattern multiple scle-rosis has been described, involving antibodies and complement in lesion formation.6,7 This pat-tern is often associated with ring-enhancing MRI lesions as described in the published cases.3,4,8 Disease exacerbations in patients with antibody-mediated central nervous system demyelination such as multiple sclerosis pattern II or neuromy-elitis optica spectrum disorders are known for mainly T cell directed multiple sclerosis thera-pies such as interferon-beta, natalizumab or fin-golimod.6,9 The exact pathophysiological mechanisms for these observations are not yet clear, but might have also played a role in the three cases reported by Haghikia and colleagues and Barton and colleagues.3,4 Due to its mecha-nism of action, repopulation of distinct B cell subtypes is seen even 6 months after alemtu-zumab application, whereas T cell subtype repopulation is delayed and decreased even after 12 months. Based on the different distribution of B and T cells after alemtuzumab, Barton and colleagues and Haghikia and colleagues sup-posed B cell-mediated severe clinical exacerba-tion. After initial depletion, they documented re-appearance of peripheral B cells and con-cluded relation to clinical disease activity and development of tumefactive lesions in MRI, especially in B cell-driven multiple sclerosis sub-types. Here we present a case with underlying B cell-driven multiple sclerosis that impressively improves after alemtuzumab, although periph-eral B cell repopulation took place. Although it cannot be excluded that disease exacerbation during alemtuzumab therapy may occur in single patients with a suggested underlying B cell-driven autoimmunity, our case proves that alem-tuzumab may act as an effective rescue treatment in highly active antibody/complement-mediated multiple sclerosis type II patients.FundingThis research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.Conflict of interest statementK. Akgün received personal compensation from Novartis, Biogen Idec, Sanofi Genzyme and Roche for consulting services. Imke Metz reports personal fees from BiogenIdec, Bayer Healthcare, Teva, Novartis, Genzyme and Roche, as well as grants from BiogenIdec, out-side the submitted work. W. Brück has received honoraria for lectures by Bayer Vital, Biogen, Merck Serono, Teva, Genzyme, Roche and Novartis. He is a member of scientific advisory boards for Teva, Biogen, Novartis and Genzyme, and receives research support from Teva, Biogen, Genzyme and Novartis. H. Kitzler has received travel grants, speaker’s honoraria, financial research support, consul-tancy fees from Bayer, Biogen Idec, Novartis and Teva. He served on advisory boards for Novartis and Biogen Idec. He received a research grant from Novartis. T. Ziemssen received personal compensation from Biogen Idec, Bayer, Novartis, Sanofi, Teva and Synthon for consulting services. Ziemssen received additional financial support for research activities from Bayer, Biogen Idec, Novartis, Teva and Sanofi Aventis.ConsentThe authors confirm that any aspect of the work covered in this manuscript that has involved human patients has been conducted with the ethi-cal approval of all relevant bodies (institutional review board of the University Hospital of Dresden, EK348092014). The patient provided written informed consent for publishing this case report in an international medical journal.Therapeutic Advances in Neurological Disorders 114 journals.sagepub.com/home/tanReferences1.  Ziemssen, T., & Thomas, K.  Alemtuzumab in the long-term treatment of relapsing-remitting multiple sclerosis: an update on the clinical trial evidence and data from the real world. Ther Adv Neurol Disord 2017; 10(10): 343–359. 2.  Hassoun L, Eisele J, Thomas K, et al. Hands on alemtuzumab-experience from clinical practice: whom and how to treat. Mult Scler Demyelinating Disord 2016; 1: 1–10.3.  Haghikia A, Dendrou CA, Schneider R, et al. Severe B-cell-mediated CNS disease secondary to alemtuzumab therapy. Lancet Neurol 2017; 16: 104–106.4.  Barton J, Hardy TA, Riminton S, et al. Tumefactive demyelination following treatment for relapsing multiple sclerosis with alemtuzumab. Neurology 2017; 88: 1004–1006.5.  Azzopardi L, Cox AL, McCarthy CL, et al. Alemtuzumab use in neuromyelitis optica spectrum disorders: a brief case series. J Neurol 2016; 263: 25–29.6.  Haupts MR, Schimrigk SK, Brune N, et al. Fulminant tumefactive multiple sclerosis: therapeutic implications of histopathology. J Neurol 2008; 255: 1272–1273.7.  Lucchinetti C, Bruck W, Parisi J, et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000; 47:  707–717.8.  Luchineti CF, Altintas A, Wegner C, et al. Magnetic resonance imaging correlates  of multiple sclerosis pathologic subtypes.  Ann Neurol 2003; 54(Suppl. 7): S37.9.  Visser F, Wattjes MP, Pouwels PJW, et al. Tumefactive multiple sclerosis lesions under fingolimod treatment. Neurology 2012; 79: 2000–2003.Visit SAGE journals online journals.sagepub.com/home/tanSAGE journals

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