interleukin-6 receptor blockade in treatment-refractory

$: Interleukin-6 Receptor Blockade in Treatment-Refractory$
ARTICLE OPEN ACCESS

Interleukin-6 Receptor Blockade in Treatment-Refractory MOG-IgGndashAssociated Disease andNeuromyelitis Optica Spectrum DisordersMarius Ringelstein MD Ilya Ayzenberg MD Gero Lindenblatt MD Katinka Fischer MSc Anna Gahlen MD

Giovanni Novi MD Helen Hayward-Konnecke MD Sven Schippling MD Paulus S Rommer MD

Barbara Kornek MD Tobias Zrzavy MD Damien Biotti MD Jonathan Ciron MD Bertrand Audoin MD

Achim Berthele MD Katrin Giglhuber MD Helene Zephir MD Tania Kumpfel MD Robert Berger MD

Joachim Rother MD Vivien Hauszligler MD Jan-Patrick Stellmann MD Daniel Whittam MD Anu Jacob MD

Markus Kraemer MD Antoine Gueguen MD Romain Deschamps MD Antonios Bayas MD

Martin W Hummert MD Corinna Trebst MD Axel Haarmann MD Sven Jarius MD Brigitte Wildemann MD

Matthias Grothe MD Nadja Siebert MD Klemens Ruprecht MD Friedemann Paul MD Nicolas Collongues MD

Romain Marignier MD Michael Levy MD Michael Karenfort MD Michael Deppe PhD Philipp Albrecht MD

Kerstin Hellwig MD Ralf Gold MD Hans-Peter Hartung MD Sven G Meuth MD Ingo Kleiter MD

Orhan Aktas MD on behalf of the Neuromyelitis Optica Study Group (NEMOS)

Neurol Neuroimmunol Neuroinflamm 20229e1100 doi101212NXI0000000000001100

Correspondence

Dr Ringelstein

mariusringelstein

meduni-duesseldorfde

or Dr Aktas

orhanaktasmeduni-duesseldorfde

AbstractBackground and ObjectivesTo evaluate the long-term safety and efficacy of tocilizumab (TCZ) a humanized antindashinterleukin-6 receptor antibody in myelin oligodendrocyte glycoproteinndashIgGndashassociated dis-ease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD)

MethodsAnnualized relapse rate (ARR) Expanded Disability Status Scale score MRI autoantibodytiters pain and adverse events were retrospectively evaluated in 57 patients withMOGAD (n =14) aquaporin-4 (AQP4)-IgG seropositive (n = 36) and seronegative NMOSD (n = 7 12)switched to TCZ from previous immunotherapies particularly rituximab

ResultsPatients received TCZ for 238 months (median interquartile range 130ndash511 months) withan IV dose of 80 mgkg (median range 6ndash12 mgkg) every 316 days (mean range 26ndash44

These authors contributed equally to this work

Department of Neurology (MR KF MKPA HPH SGM OA) Medical Faculty Heinrich Heine University Dusseldorf Department of Neurology (MR) Center for Neurologyand Neuropsychiatry LVR-Klinikum Heinrich Heine University Dusseldorf Department of Neurology (IA AG KH RG IK) St Josef-Hospital Ruhr University BochumGermany Department of Neurology (IA) Sechenov First Moscow State Medical University Russia Department of Neurology (GL) Johanna Etienne Hospital Neuss GermanyDepartment of Neurology (GN) San Martino Hospital Genova Italy Neuroimmunology and MS Research (HHK SS) Department of Neurology University Hospital ZurichSwitzerland Department of Neurology (PSR BK TZ) Medical University of Vienna Austria Department of Neurology (DB JC) B4 unit CRC-SEP Toulouse Purpan UniversityHospital France Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity) (DB JC) INSERM UMR1291-CNRS UMR5051 - Universite Toulouse III France AixMarseille University (BA) APHM Hopital de la Timone Pole de Neurosciences Cliniques Service de Neurologie Marseille France Technical University of Munich (AB KG)School of Medicine Department of Neurology Klinikum rechts der Isar Germany University of Lille (HZ) Inserm CRC-SEP CHU Lille France Institute of Clinical Neuro-immunology (TK) Faculty of Medicine Ludwig Maximilian University Munich Department of Neurology (RB JR) Asklepios Klinik Altona Hamburg Department of Neurologyand Institute of Neuroimmunology and MS (INIMS) (VH) University Medical Center Hamburg-Eppendorf Germany APHM Hopital de la Timone (JPS) CEMEREM Aix MarseilleUniv CNRS CRMBM (JPS) UMR 7339 Marseille France Department of Neurology (DW AJ) TheWalton Centre Liverpool United Kingdom the Cleveland Clinic Abu Dhabi (AJ)UAE Department of Neurology (MK) Alfried Krupp Hospital Essen Germany Department of Neurology (AGRD) Fondation Ophtalmologique Adolphe de Rothschild ParisFrance Department of Neurology (AB) Universitatsklinikum Augsburg Department of Neurology (MWH CT) Hannover Medical School Department of Neurology (AH)University of Wurzburg Molecular Neuroimmunology Group (SJ BW) Department of Neurology University of Heidelberg Department of Neurology (MG) University hospitalGreifswald NeuroCure Clinical Research Center and Experimental and Clinical Research Center (NS FP) Max Delbrueck Center for Molecular Medicine and Charite Uni-versitatsmedizin Berlin corporate member of Freie Universitat Berlin Humboldt Universitat zu Berlin and Berlin Institute of Health Department of Neurology (KR) ChariteUniversitatsmedizin Berlin corporate member of Freie Universitat Berlin Humboldt Universitat zu Berlin and Berlin Institute of Health Berlin Department of Neurology (NC)University Hospital Strasbourg Service de neurologie (RM) sclerose en plaques pathologies de la myeline et neuro-inflammation ndash Hopital Neurologique Pierre WertheimerHospices Civils de Lyon France Department of Neurology (ML) Massachusetts General Hospital and Harvard Medical School Boston Department of General Pediatrics (MK)Neonatology and Pediatric Cardiology University Childrenrsquos Hospital Medical Faculty Heinrich Heine University Dusseldorf Department of Neurology (MD) University HospitalMunster and Marianne-Strauszlig-Klinik (IK) Behandlungszentrum Kempfenhausen fur Multiple Sklerose Kranke Berg Germany

Go to NeurologyorgNN for full disclosures Funding information is provided at the end of the article

The Article Processing Charge was funded by Heinrich Heine University Dusseldorf Germany

Neuromyelitis Optica Study Group (NEMOS) coinvestigators are listed in the appendix at the end of the article

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

Copyright copy 2021 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 1

days) For MOGAD the median ARR decreased from 175 (range 05ndash5) to 0 (range 0ndash09 p = 00011) under TCZ A similareffect was seen for AQP4-IgG+ (ARR reduction from 15 [range 0ndash5] to 0 [range 0ndash42] p lt 0001) and for seronegativeNMOSD (from 30 [range 10ndash30] to 02 [range 0ndash20] p = 0031) During TCZ 60 of all patients were relapse free (79 forMOGAD 56 for AQP4-IgG+ and 43 for seronegative NMOSD) Disability follow-up indicated stabilization MRI in-flammatory activity decreased inMOGAD (p = 004 for the brain) and in AQP4-IgG+NMOSD (p lt 0001 for the spinal cord)Chronic pain was unchanged Regarding only patients treated with TCZ for at least 12 months (n = 44) ARR reductions wereconfirmed including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28) Similarly in the group of patientstreated with TCZ for at least 12 months 59 of them were relapse free with 73 for MOGAD 57 for AQP4-IgG+ and 40for patients with seronegative NMOSD No severe or unexpected safety signals were observed Add-on therapy showed noadvantage compared with TCZ monotherapy

DiscussionThis study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD andAQP4-IgG+ NMOSD

Myelin oligodendrocyte glycoprotein (MOG)-IgGndashassociateddisease (MOGAD) and neuromyelitis optica spectrum disor-der (NMOSD)with or without antindashaquaporin-4 (AQP4)-IgGare antibody-mediated chronic inflammatory CNS conditionsin most cases1-4 Although the clinical presentation with uni-lateral or bilateral optic neuritis (ON) longitudinally extensivetransverse myelitis or brain stem syndromes may be similar inMOGAD and NMOSD demographic clinical imaging andpathophysiologic findings strongly suggest the presence of 2distinct disease entities4-8 As MOGAD excluding acute dis-seminated encephalomyelitis (ADEM) and NMOSD typicallyfollow a relapsing course in adults39 attack prevention is key toavoid disability accumulation Recently a variety of therapeuticstrategies such as CD1920-mediated B-cell depletion1011

complement inhibition12 and interleukin-6 (IL-6) receptorblockade1314 were successfully investigated in pivotal NMOSDtrials particularly in AQP4-IgG+ patients Yet insights con-cerning the effectiveness and safety of such agents in MOGADare scarce

IL-6 plays an important role in the pathophysiology ofNMOSD15 Increased levels were detected in the serum andCSF particularly during attacks16 IL-6 promotes the dif-ferentiation of inflammatory Th17 cells17 and the pro-duction of AQP4-IgG by B cellndashderived plasmablasts inNMOSD18 and increases the permeability of the blood-brainbarrier19 facilitating CNS inflammation The efficacy of IL-6receptor blockade in AQP4-IgG+ NMOSD was suggestedby studies using tocilizumab (TCZ) in adults and children20-26 and demonstrated by 2 pivotal trials of satralizumab

whereas the effect in AQP4-IgGndashseronegative patients wasless evident1314 As AQP4-IgG+ NMOSD and MOGADboth display antibody- and complement-mediated CNS in-jury and similar inflammatory CSF profiles (with elevatedIL-6)2728 IL6-blockade may also be beneficial in MOGADsupported by recent case reports23252629-33 This retro-spective multicenter study explored the safety and efficacy ofTCZ in patients with MOGAD and is able to connect thesefindings with the effects of TCZ in classical (ie AQP4-IgG+) or double-seronegative NMOSD

Patients and Previous TreatmentsFifty-seven patients with relapsing MOGAD (n = 14)34 ex-cluding ADEM classical AQP4-IgG+ NMOSD (n = 36) ordouble-seronegative NMOSD (n = 7) mainly of Caucasiandescent (n = 50 Table 1) from neurologic departments of 23tertiary referral centers in Germany (n = 13 all members ofthe German Neuromyelitis Optica Study Group [NEMOS])France (n = 5 all members of the NOMADMUS cohort)Austria (1) Italy (1) Switzerland (1) United Kingdom (1)and United States of America (1) were retrospectively ana-lyzed The evaluated TCZ treatment period ranged fromDecember 2010 until November 2019 Regarding de-mographic parameters (Table 1) the mean age at diseasemanifestation was comparable for patients with MOGAD orAQP4-IgG+ NMOSD (355 or 361 years respectively p =089) as well as the age when TCZ was started (384 or 428years p = 035) Five patients were younger than 18 years atdisease manifestation and 3 of them younger than 18 years atinitiation of TCZ Of note patients with AQP4-IgG+

GlossaryADEM = acute disseminated encephalomyelitis AQP4 = aquaporin-4 ARR = annualized relapse rate AZA = azathioprineEDSS = Expanded Disability Status ScaleHDS = high-dose steroid IL-6 = interleukin-6 IQR = interquartile range IVIG = IVimmunoglobulin LDS = low-dose steroid MMF = mycophenolate mofetil MOG = myelin oligodendrocyte glycoproteinMOGAD = myelin oligodendrocyte glycoproteinndashIgGndashassociated disease MTX = methotrexate NMOSD = neuromyelitisoptica spectrum disorder ON = optic neuritis RTX = rituximab SLE = systemic lupus erythematosus TCZ = tocilizumabUTI = urinary tract infection

2 Neurology Neuroimmunology amp Neuroinflammation | Volume 9 Number 1 | January 2022 NeurologyorgNN

NMOSD were predominantly female in contrast to patientswithMOGAD(91 vs 35 female respectively) Patients withAQP4-IgG+ NMOSD tended to have a longer history of dis-ease (median 55 years) and were more severely affected atTCZ start (median Expanded Disability Status Scale [EDSS]score 625) than patients with MOGAD (median disease du-ration 22 years p = 013median EDSS score 275 plt 001) Inthe MOGAD group 7 patients (50) fulfilled the 2015 revisedinternational consensus diagnostic criteria for NMOSD35 Be-fore TCZ therapy patients with MOGAD had had a median of6 attacks (range 1ndash12 attacks) with 45 ON (median range1ndash10 ON) and 20 myelitis events (median range 1ndash5 myelitisevents) In the NMOSD group 57 double-seronegative(71) and 2736 AQP4-IgG+ (75) patients fulfilled the2006 NMO diagnostic criteria36 whereas all AQP4-IgG+ anddouble-seronegative patients fulfilled the 2015 NMOSD di-agnostic criteria35 Of note 4757 (83) patients were testedfor both antibodies and none was double positive Ten AQP4-IgG+ patients were not tested for MOG-IgG Before TCZ allpatients had been treated with different immunotherapies fol-lowing established recommendations and remarkably all hadreceived rituximab (RTX) (Table 1 Figures 1 and 2 for sero-positive patients) Within the last 24 12 and 6 months beforeTCZ switch 5357 (93) 4457 (77) and 3157 (54) ofthe patients were treated with RTX respectively B-cell countscollected briefly before the start of TCZ (median interval 09months interquartile range [IQR] 04ndash19 months) wereavailable for 3357 (58) patients (2536 [69] AQP4-IgG+NMOSD 614 [43] MOGAD and 27 [29] double-seronegative patients) Of these 33 patients 28 (85) patients(2125 [84] AQP4-IgG+ NMOSD 56 [83] MOGADand 22 [100] double-seronegative patients) showed mark-edly reduced or depleted B cells During the total pre-TCZtreatment phase (median duration of 29 years) patients had60 attacks (median range 1ndash30 attacks) Considering the last 2years before TCZ start 30 attacks (median range 0ndash10 at-tacks) were recorded (Table 1)

MethodsAll clinical and paraclinical data were analyzed retrospectively bychart review Patients were continuously treated at the contrib-uting centers specialized in clinical neuroimmunology withregular assessment of clinical (attacks EDSS score and painlevels) and paraclinical (MRI AQP4- and MOG-IgG and otherlaboratory tests) data AQP4-IgG and MOG-IgG antibodieswere exclusively measured by cell-based assays The primaryoutcome was the annualized relapse rate (ARR) An attack wasdefined as definitely new neurologic symptom or clear acuteworsening of previous neurologic deficits with objective clinicalsigns lasting for at least 24 hours and attributed to an in-flammatory CNS event confirmed by the treating physicianSafety aspects comprised infusion-related reactions infectionstumors cardiovascular events and standard laboratory testsAQP4-IgG titers EDSS score and chronic pain (occurrence andintensity classified asmild = 1moderate = 2 or severe = 3)were

assessed at TCZ start and if available at last follow-up duringTCZ MRI of the cervicothoracic spinal cord and the brainevaluated at TCZ onset and last available follow-up was classi-fied as nonactive or active indicated by the presence of new T2or contrast-enhancing lesions

Statistical AnalysisIn general the ARR was calculated by dividing the number ofattacks within the last 2 years before TCZ switch or duringTCZ treatment time by 2 However for 19 patients who hada TCZ pretreatment phase of lt2 years (median 11 years) wecategorically divided the total number of attacks by 2 and for13 patients with a follow-up period of lt1 year (median 05years) during TCZ treatment we divided the number of at-tacks by the concrete treatment duration and thus extrapo-lated this measure to 1 year To avoid possible overestimationof the relapse-free proportion in the latter group we excludedthose 13 patients with TCZ treatment durations of lt12months for subgroup analyses

In the descriptive analysis values are given as mean or medianwith the appropriate measures of dispersion (ie range SDor IQR) In all cases the assumption of normal distributioncould not be affirmed Therefore only nonparametrical testswere used To test for statistically significant differences be-tween 2 related samples like ARR before TCZ switch and ARRunder TCZ therapy theWilcoxon signed-rank test was used Incase of paired categorical data with a dichotomous trait theexact binomial test was used For count datandashlike relapses wealso applied an unconditional Poisson regression Statisticalresults are presented as p values and 95 confidence intervals pValues lt005 were considered to indicate statistically significantresults Because of the exploratory nature of the study noadjustment for multiple comparisons was made Version 363of the R statistics package was used for statistical analysis

Standard Protocol Approvals Registrationsand Patient ConsentsEthical approval was obtained from the Institutional ReviewBoard of the Heinrich Heine University Dusseldorf (3419)and from each participating center by their local institutionalreview boards according to ICHGCP All patients providedwritten informed consent

Data AvailabilityAnonymized data not published within this article will bemade available by request from any qualified investigator

ResultsTCZ Reduced ARRForty-five of 57 (79) patients switched to TCZ due to on-going disease activity 557 (9) due side effects of priorimmunotherapies (including allergic reactions on RTX in 3patients) and 657 (10) because of concomitant diseaseactivity and adverse events In 1 patient the detection of

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 9 Number 1 | January 2022 3

Table 1 Demographics and Disease Characteristics of Patients With MOGAD and NMOSD

CohortMOGAD(n = 14)

AQP4-IgG+ NMOSD(n = 36)

Double seronegatives(n = 7)

Total(N = 57)

Ethnicity n ()

Caucasian 13 (93) 30 (83) 7 (100) 50 (88)

African mdash 3 (8) mdash 3 (5)

Arabian 1 (7) 2 (6) mdash 3 (5)

Latin American mdash 1 (3) mdash 1 (2)

Sex n femalemale ( female) 59 (35) 333 (91) 61 (85) 4413 (77)

AQP4 serostatus n posneg ( positive) 014 (0) 3636 (100) 07 (0) 3621 (63)

MOG serostatus n posnegNAa ( positive) 1400 (100) 02610 (0) 070 (0) 143310 (25)

NMO based on 2006 criteria n yesno ( yes) 410 (28) 279 (75) 52 (71) 3621 (63)


Age at disease manifestation y mean (SD) 355 (147) 361 (152) 427 (115) 368 (146)

Disease duration before TCZ y median (IQR) 22 (12ndash34) 55 (12ndash90) 24 (23ndash51) 29 (13ndash82)

Relapses under last immunotherapy n median (IQR) 15 (10ndash20) 10 (10ndash20) 30 (15ndash3) 10 (10ndash20)

Relapses during last 2 y before TCZ n median (IQR) 35 (22ndash50) 30 (20ndash50) 60 (25ndash60) 30 (20ndash50)

Age at TCZ start y mean (SD) 384 (150) 428 (146) 465 (108) 422 (143)

Number of TCZ infusions n mean (SD) 269 (217) 376 (311) 284 (219) 340 (282)

TCZ intervals d mean (SD) 308 (46) 321 (46) 304 (08) 316 (43)

TCZ treatment duration mo median (IQR) 163 (142ndash446) 279 (129ndash532) 304 (103ndash381) 238 (130ndash511)

Relapses before TCZ n median (IQR) 60 (42ndash80) 50 (30ndash102) 60 (55ndash85) 60 (30ndash90)

Relapses under TCZ n median (IQR) 0 (0ndash0) 0 (0ndash10) 10 (0ndash20) 0 (0ndash10)

EDSS score before TCZ median (IQR) 275 (20ndash35) 625 (30ndash76) 50 (45ndash58) 45 (30ndash70)

EDSS score under TCZ median (IQR) 20 (12ndash29) 425 (25ndash70) 50 (35ndash68) 35 (20ndash65)

Immunotherapies before TCZ n ()

Rituximab 14 (100) 36 (100) 7 (100) 57 (100)

Azathioprine 3 (21) 13 (36) 2 (29) 18 (32)

Mycophenolate mofetil 3 (21) 7 (19) 1 (14) 11 (19)

Low-dose steroid monotherapy 4 (29) 7 (19) 0 (0) 11 (19)

Methotrexate 1 (7) 7 (19) 3 (43) 11 (19)

Cyclophosphamide 2 (14) 8 (22) 1 (14) 11 (19)

IVIG 3 (21) 4 (11) 0 (0) 7 (12)

Interferon-beta 0 (0) 5 (14) 1 (14) 6 (11)

Mitoxantrone 0 (0) 5 (14) 0 (0) 5 (9)

Glatiramer acetate 0 (0) 2 (6) 1 (14) 3 (5)

Natalizumab 0 (0) 1 (3) 1 (14) 2 (4)

Long-term plasma exchange 1 (7) 1 (3) 0 (0) 2 (4)

Alemtuzumab 0 (0) 1 (3) 0 (0) 1 (2)

Fingolimod 0 (0) 1 (3) 0 (0) 1 (2)

Cyclosporin A 0 (0) 1 (3) 0 (0) 1 (2)

Continued


neutralizing antibodies against RTX was the reason fortreatment switch TCZ was administered IV (mean 34 infu-sions range 3ndash109) in 56 patients (98) at a mean interval of316 days (range 261ndash442 days) and with a median dose of80 mgkg body weight (range 60ndash120 mgkg body weightTable 1) and subcutaneously in 1 patient (2) with weeklyinjections of 162 mg The interval from last relapse to initia-tion of TCZ was similar for all groups ie 22 months (me-dian IQR 11ndash51 months) for patients with AQP4-IgG+NMOSD 32 months (15ndash48 months) for the MOGADsubgroup and 24 months (17ndash62 months) for doubleseronegatives

The median treatment duration was 238 months (IQR130ndash511 months) with patients with AQP4-IgG+ NMOSD

showing the longest TCZ exposure (271 months) comparedwith MOGAD (163 months) and double-seronegative (304months) patients In one-third of patients (2057) TCZ wasgiven as an add-on treatment in 2 of them due to comorbidities(psoriasis cotreated with methotrexate [MTX] chronic poly-arthritis with oral low-dose steroids [LDSs]) Additional medi-cations included LDS (n = 10) MTX (n = 4) mycophenolatemofetil (MMF n = 2) azathioprine (AZA n = 1) IV immu-noglobulins (IVIG n = 1) RTX (n = 1) andmonthly high-dosesteroids (HDS n = 1) administered for lt6 months in 3 patientsand gt6 months in 17 patients during TCZ treatment

Initiation of TCZ was followed by a decrease of themedian ARR in patients with AQP4-IgG+ NMOSD from15 to 0 (p lt 0001 95 CI 0ndash02) compared with the last 2

Table 1 Demographics and Disease Characteristics of Patients With MOGAD and NMOSD (continued)

CohortMOGAD(n = 14)



Total(N = 57)

Belimumab 1 (7) 0 (0) 0 (0) 1 (2)

Etanercept 0 (0) 1 (3) 0 (0) 1 (2)

Abbreviations AQP4 = aquaporin-4 EDSS = Expanded Disability Status ScaleMOG =myelin oligodendrocyte glycoprotein MOGAD =MOG-IgGndashassociated disorder NMOSD = neuromyelitis optica spectrum disorder TCZ = tocilizumaba MOG-IgG ab not tested

Figure 1 Disease Courses and Individual Maintenance Immune Therapies of Patients With MOGAD

First attacks are indicated as red diamonds and further attacks as blue diamonds IVIG = IV immunoglobulin IVMP = IV methylprednisolone MOG = myelinoligodendrocyte glycoprotein MOGAD = MOG-IgGndashassociated disease


years before TCZ start Of note patients with MOGADshowed a similar median ARR reduction from 175 to 0(p = 00011 95 CI 13ndash26) For patients with double-seronegative NMOSD median ARR reduction was lessprominent but still significant (from 30 to 02 [p lt 003295 CI 03ndash28]) For the total cohort the median ARRdecreased from 15 to 0 (p lt 0001 95 CI 11ndash18Figure 3) Of note ARR reductions were also detectablewhen analysis was confined to those patients treated withTCZ for at least 12 months including MOGAD andAQP4-IgG+ NMOSD but not double-seronegative pa-tients (Figure 3)

Regarding individual patients 314 (214) patients withMOGAD (Figure 1) and 1436 (39) patients with AQP4-IgG+ NMOSD (Figure 2) had at least 1 attack during TCZtreatment and 214 (143) patients with MOGAD and 236 (56) patients with AQP4-IgG+ NMOSD showed 2 ormore attacks Sixty percent of all patients were relapse free(79 for MOGAD 56 for AQP4-IgG+ NMOSD and 43for double-seronegative NMOSD) When analyzing onlypatients treated with TCZ for at least 12 months 2644(59) of all patients 811 (73) MOGAD 1628 (57)AQP4-IgG+ and 25 (40) double-seronegative patientsremained relapse free

The median time to first relapse was 9 months (range 05ndash47months) for the whole group 94 months forMOGAD (range9ndash15 months) 44 months for AQP4-IgG+ NMOSD (range05ndash47 months) and 122 months for double-seronegativeNMOSD (range 26ndash189 months) An unconditionalPoisson regression analysis showed an average increasein relapses by 16 per year under TCZ therapy indicatingthat a relapse is not expected until after 5 years underTCZ in the total cohort (p lt 003) Moreover double-seronegative patients had average 26 times the relapsecounts compared with patients with AQP4-IgG+ NMOSD(p lt 003) and in the MOGAD subgroup relapses oc-curred 8 less than in AQP4-IgG+ NMOSD which wasnot significant (p = 086)

When comparing patients treated with TCZ plus add-ontreatment (2057) with those on TCZ monotherapy (3757) the ARR in the add-on group was higher in the 2 yearsbefore TCZ initiation (median 20 [IQR 1ndash3] vs 15 [IQR1ndash25]) as well as during TCZ treatment (02 [IQR 0ndash08] vs0 [IQR 0-0]) In line freedom from relapses was achieved in40 of patients in the add-on group and in 78 in themonotherapy group

By comparing the 2 groups of patients who switched to TCZdue to ongoing disease activity or side effects the medianARR in the first group was 20 (IQR 10ndash25) during the 2years prior TCZ and was 0 (IQR 0ndash02) during TCZ treat-ment whereas the median ARRs were 10 (IQR 05ndash10) and0 (IQR 0-0) respectively for both intervals in the secondsubgroup

Relapsing vs Nonrelapsing Patients DuringTCZ TreatmentWhen comparing patients who relapsed vs those who did notrelapse during TCZ treatment (across the different sub-groups) relapsing patients with AQP4-IgG+ NMOSD wereyounger at disease manifestation than nonrelapsing patients(years median relapsing vs nonrelapsing 314 vs 364 re-spectively) At TCZ start MOGAD and double-seronegativepatients who later relapsed were older than nonrelapsingpatients whereas relapsing and nonrelapsing AQP4-IgG+patients had comparable age (years median relapsing vsnonrelapsing AQP4-IgG+ 437 vs 436 MOGAD 485 vs412 double seronegatives 507 vs 378 respectively) Re-lapsing patients had a longer disease duration than non-relapsing in the AQP4-IgG+ and MOGAD groups (yearsmedian AQP4-IgG+ NMOSD 876 vs 293 MOGAD 333 vs211 respectively) Sex had no effect on relapses in all sub-groups Under TCZ therapy most of the myelitis and ONattacks occurred in AQP4-IgG+ NMOSD and double-seronegative patients (AQP4-IgG+ NMOSD myelitis [14]ON [4] MOGAD myelitis [2] ON + myelitis [1] doubleseronegatives myelitis [4])

TCZ DiscontinuationTCZ therapy was discontinued in 2057 patients (3511536 [417] AQP4-IgG+ 214 [14] MOGAD and 37[429] double-seronegative patients) after 145 treatmentmonths (median range 29ndash539 treatment months) Of note45 (920) of them stopped TCZ for general reasons such aspregnancy plans for pregnancy and patientrsquos preference (egfor oral medications) and 2 patients were lost to follow-upHowever 6 of the 20 patients (2 AQP4-IgG+ 3 double se-ronegative and 1 MOGAD) presented ongoing MRI activityor attacks and 520 patients (all AQP4-IgG+) discontinueddue to suspected side effects such as ileus (n = 1) nephritisand urticaria in the context of systemic lupus erythematosus(SLE n = 1) psoriasis exacerbation (n = 1) and upper re-spiratory tract infections (n = 3) Two patients who stoppedTCZ restarted it after completion of pregnancy and ileustreatment Of the 11 patients with disease activity or sus-pected side effects 6 patients (55) received TCZ as add-ontherapy and 5 patients (45) showed relapse activity whichoccurred 256 days (median IQR 73ndash329 days) after TCZinitiation indicating that delayed onset of efficacy may havecontributed to early discontinuation

DisabilityThe median EDSS score significantly decreased in both se-ropositive groups in MOGAD from 275 to 20 (p lt 0031)and in AQP-IgG+ NMOSD from 625 to 425 (p lt 0003)The median EDSS score remained stable on 50 in 77double-seronegative patients (p lt 077 Table 1 Figure 4)

When including patients with TCZ treatment durationgt12 months only the EDSS score improvement was stillsignificant for AQP4-IgG+ NMOSD and the whole cohort(Figure 4) The EDSS score worsened in only 557 (9)


Figure 2Disease Courses and IndividualMaintenance Immune Therapies of PatientsWith AQP4-IgGndashSeropositive NMOSD

First attacks are indicated as red diamonds and further attacks as blue diamonds AQP4 = aquaporin-4 IVIG = IV immunoglobulin NMOSD = neuromyelitisoptica spectrum disorder IVMP = IV methylprednisolone PE = plasma exchange SLE = systemic lupus erythematosus (a) Twelve years before tocilizumab(TCZ) initiation (b) Twenty-four years before TCZ initiation (c) Therapy of chronic polyarthritis 2 and a half years before TCZ initiation (d) Fifteen years beforeTCZ initiation (e and f) Sixteen years before TCZ initiation (g) Ten and a half years before TCZ initiation (h) Twenty-two years before TCZ initiation (i) Elevenand a half years before TCZ initiation (j) Psoriasis therapy psoriasis flare-up finally remitted completely under rituximab loss to follow-up


patients of the entire cohort ie none of patients withMOGAD 336 (8) patients with AQP4-IgG+ NMOSDand 27 (29) double-seronegative patients

PainInitial disease-related chronic pain was reported in 2851patients (55) with a median pain intensity of 20 (IQR 1ndash3data from 27 patients) Presence and intensity of pain werenot modulated during TCZ treatment as 2552 patients(48) still had ongoing chronic pain with a median intensityof 20 (IQR 1ndash3 data available from 24 patients) at lastfollow-up regardless of the AQP4-IgGMOG-IgG serostatus

Antibody TitersRegarding AQP4-IgG immunoreactivity most patients (1216)showed decreased or stable titers after initiation of TCZ (Figure 5for individual courses) Longitudinally assessed MOG-IgG anti-body titers were available in only 2 of 14 patients and showed asimilar pattern as seen in AQP4-IgG+ NMOSD ie a decreasefrom 1320 to 132 and from 11280 to 110 respectively

Magnetic Resonance ImagingFor brain MRI the proportion of patients with active scans(presence of new T2 or contrast-enhancing lesions) signifi-cantly decreased from 435 at TCZ baseline (2046 patientswith available longitudinal data at TCZ onset and follow-up)to 152 (746 patients p = 0007) at last available scanwithin 316 months (mean range 42ndash958 months) Thisreduction was detectable for MOGAD (change from 713[538] to 113 patients [77] with active scans p = 0031)

but not for AQP4-IgG+ (926 [346] to 326 [115] p =0146) or seronegative (47 [571] to 37 [429] p = 1)subgroups

For spinal cord MRI the proportion of patients with activescans decreased from 714 (2535 patients) to 286 (1035 p = 000006) during TCZ (mean interval 405 monthsrange 37ndash1113) This effect was mainly driven by the AQP4-IgG+ group with a decrease from 741 (2027) to 259 (727) of patients during TCZ (p = 00002) For double-seronegative NMOSD and MOGAD the proportion of pa-tients with active scans was low and stable during TCZ

Safety Data

Clinical EventsInfusion-related reactions occurred in 757 (123) patientsand included headache abdominal pain vertigo nausea fa-tigue leg edema rash mild bruising and bloating (Table 2)Infections comprised recurrent urinary tract infections (UTIin 16 of patients) upper respiratory tract infections com-mon cold bronchitis and pneumonia (in 16) oral or lipinfections (in 7 including herpes simplex virus ulcers andcandidiasis) erysipelas and skin lesions compatible with SLE(in 5) and (pyelo)nephritis (in 35) In 1957 (33)patients 23 chronic underlying inflammatory diseases werereported including Hashimoto thyroiditis (N = 7) SLE (5)psoriasis (4) Sjogren syndrome (2) and vitiligo polyarthritisimmune thrombocytopenic purpura myasthenia gravis andCrohn disease (1 each) Exacerbation of SLE and psoriasis

Figure 3 ARR Before and During TCZ Treatment

Box-and-whisker plots showing the median IQR and range of the annualized relapse rate 2 years before and during TCZ treatment for the MOGAD (A) theAQP4-IgG+ NMOSD (B) and the double seronegative (C) subgroups of patients as well as for the total cohort (D) Each dot indicates 1 single patient Hatchedbars represent those patients who had been treated with TCZ for at least 12 months AQP4 = aquaporin-4 ARR = annualized relapse rate IQR = interquartilerange MOGAD = MOG-IgGndashassociated disease NMOSD = neuromyelitis optica spectrum disorder TCZ = tocilizumab


during TCZ occurred in 4 patients (2 from each) and led toTCZ discontinuation in 2 of these 19 (11) patients (bothAQP-IgG+ NMOSD) No new cancer occurred One case oftype 1 focal nodular hyperplasia of the liver was diagnosedduring TCZ Cardiovascular events occurred in 3 patientsincluding a non-ST elevation myocardial infarction after theinitial infusion a deep vein thrombosis and a slight increase inblood pressure One death due to recurrent pneumonia oc-curred 2 months after discontinuation of a 6-month TCZtreatment period but this was not regarded as treatment re-lated by the treating physician as the 58-year-old patient had ahistory of severe AQP4-IgG+ NMOSD with concomitantSLE and uterus carcinoma including surgery and radiation

TCZ-treated patients with additional immunotherapies suf-fered more frequently from pneumonia compared with themonotherapy group (18 vs 6) other side effects likereactivation of chronic latent infections (5 vs 6) wereequally distributed in both groups

Laboratory ChangesNeutropenia during TCZ treatment with a maximum cellcount reduction of 61 below the lower reference level oc-curred in 1057 (18) patients with 3 patients on a con-comitant immunotherapy (MTX RTX and LDS Table 2)However these 10 patients had no higher frequency ofcommon neutropenia-related conditions such as UTI pneu-monia and other (unspecific) infections Transient and mildto moderate increases of liver enzymes and lipase (2- to 3-foldabove the upper reference level) were reported in 2057

(351) patients In particular alanine aminotransferasewas elevated at least once in 1757 (298) patients duringTCZ and increased from 282 UL (mean range 8ndash90 ULat TCZ start) to 756 UL (range 21ndash179 UL p lt 0001)Mean total cholesterol levels increased slightly duringTCZ treatment from 1953 mgdL (n = 3757 range

Figure 5 Longitudinal Aquaporin-4-IgG Titers Before andDuring TCZ Treatment

Individual longitudinal courses of AQP4-IgG titers (assessed by cell-basedassays) for patients with AQP4-IgGndashseropositive NMOSD (n = 16) are shownMost patients (1216) showed decreased or stable titers on initiation of TCZin 416 patients the AQP4-IgG titer increased AQP4 = aquaporin-4 NMOSD= neuromyelitis optica spectrum disorder TCZ = tocilizumab

Figure 4 Level of Disability Measured as EDSS Score Before and During TCZ Treatment

Box-and-whisker plots showing the median IQR and range of the EDSS score 2 years before and during TCZ treatment for the MOGAD (A) the AQP4-IgG+NMOSD (B) and the double seronegative (C) subgroups of patients as well as for the total cohort (D) Each dot indicates 1 single patient Hatched barsrepresent those patients who had been treated with TCZ for at least 12 months AQP4 = aquaporin-4 EDSS = Expanded Disability Status Scale IQR =interquartile range MOGAD = MOG-IgGndashassociated disease NMOSD = neuromyelitis optica spectrum disorder TCZ = tocilizumab


59ndash311 mgdL) to 2038 mgdL (n = 4457 range85ndash372 mgdL p = 05554) with no changes within thesubgroups as well Similarly low- and high-density lipo-protein (LDLHDL) cholesterol levels were stable duringTCZ (Table 2)

DiscussionOur study designed as a multicenter real-world approachconfirms and extends existing evidence as it shows thatin MOG- or AQP4-IgGndashmediated inflammatory demyelinatingsyndromes IL-6 blockade offers a therapeutic perspectiveeven if patients were exposed to standard immunotherapiesbefore including targeted B-cell depletion by RTX Impor-tantly our data provide insights into therapeutic long-termmanagement of these diseases with a follow-up far beyondthe observation periods in existing pivotal trials

MOGAD in adults and NMOSD in general almost exclu-sively follow a relapsing disease course39 emphasizing therelevance of attack prevention for disease prognosis

Considering the long-term course MOGAD was assumedto have a less severe prognosis than NMOSD3738 How-ever recent studies indicate that retinal neuroaxonaldamage and visual impairment after ON are similar in bothdiseases suggesting that a higher attack rate in MOGADcompared with fewer but more severe ON episodes inAQP4-IgG+ NMOSD results in comparable tissuedamage39

Previous case series in NMOSD reported that IL-6R blockadewith TCZ confers beneficial effects for attack prevention inretrospective and 1 prospective case series in NMOSD20244041

Moreover the recent TANGO trial showed that TCZ (n = 56patients) better prevents NMOSD attacks than azathioprine(n = 52 patients)42 Finally 2 recent pivotal trials comparedsatralizumab with placebo either as a monotherapy (Sakur-aStar)14 or as an add-on therapy (SakuraSky)13 and revealedthat satralizumab reduces the relapse rate particularly inAQP4-IgG+ NMOSD However follow-up in these trialswas rather short with a range of 60ndash90 weeks42 and a mediantreatment duration in the double-blind period of 1074

Table 2 Safety Profile of Tocilizumab in Patients With MOGAD and NMOSD

CohortMOGAD(n = 14)



Total(N = 57)

Infusion-related reactions n () 1 (7) 6 (17) 0 (0) 7 (12)

Infections

Recurrent urinary tract infections 1 (7) 7 (19) 1 (14) 9 (16)

Viral upper respiratory tract infectionscommon coldbronchitispneumonia

2 (14) 5 (14) 2 (29) 9 (16)

Oral or lip infections 0 (0) 4 (11) 0 (0) 4 (7)

Erysipelas and skin lesions compatible with SLE 0 (0) 3 (8) 0 (0) 3 (5)

(Pyelo)nephritis 1 () 1 (3) 0 (0) 2 (4)

Reactivation of chronic latent infection n () 0 (0) 3 (8) 0 (0) 3 (5)

Tumor n () 0 (0) 1a (3) 0 (0) 1a (2)

Cardiovascular events n () 0 (0) 3 (8) 1 (14) 4 (7)

Neutropenia n () 2 (14) 8 (22) 0 (0) 10 (17)

Any liver enzyme changes n () 2 (14) 12 (33) 6 (86) 20 (35)

Cholesterol before TCZ mgdL mean (SD) 1958 (422) 1905 (650) 2203 (668) 1953 (585)

Cholesterol under TCZ mgdL mean (SD) 1996 (663) 1999 (462) 2352 (804) 2038 (566)

LDL before TCZ mgdL mean (SD) 1269 (500) 1140 (474) 1407 (545) 1210 (480)

LDL under TCZ mgdL mean (SD) 1298 (449) 1192 (433) 1663 (495) 1264 (449)

HDL before TCZ mgdL mean (SD) 606 (214) 594 (227) 663 (357) 605 (228)

HDL under TCZ mgdL mean (SD) 707 (403) 698 (419) 578 (385) 689 (402)

Abbreviations AQP4 = aquaporin-4 HDL = high-density lipoprotein cholesterol LDL = low-density lipoprotein cholesterol MOG = myelin oligodendrocyteglycoprotein MOGAD = MOG-IgGndashassociated disorder NMOSD = neuromyelitis optica spectrum disorder SLE = systemic lupus erythematosus TCZ =tocilizumabSI conversion factors to convert cholesterol LDL and HDL to mmolL multiply values by 00259a FNH (focal nodular hyperplasia)


and 923 weeks respectively1314 Moreover real-worldNMOSD patient cohorts on TCZ covered a limited num-ber of patients (ranging from 3 to 19)20244041 and did notinvestigate the effects of IL-6R blockade in MOGAD Ofnote 1236 patients with AQP4-IgG+ NMOSD from thiswork were previously reported in 4 TCZ-specificstudies21222526

In our study on 57 patients including 14 individuals withMOGAD and 36 individuals with AQP4-IgG+ NMOSDwe provide real-world data with a mean and maximumtreatment duration of nearly 3 and 9 years respectivelywith 65 of patients receiving TCZ as monotherapy Themean ARR as a primary outcome measure significantlydecreased during TCZ treatment by 80 in the total cohortand by 76 in the AQP4-IgG+ subgroup Of note our mainresultsmdashARR reductions in MOGAD and AQP4-IgG+NMOSD subgroups and the whole cohortmdashremainedstable when the analysis was restricted to patients receivingTCZ for at least 12 months Our findings confirm the re-cent pivotal trials on the beneficial effects of IL-6 blockadeby satralizumab in NMOSD particularly for AQP4-IgGndashseropositive patients We also observed clinical sta-bilization and reduced spinal cord MRI activity in AQP4-IgG+ patients along with decreased or stable AQP4-IgGtiters in most of them whereas pain remained constantduring TCZ The decrease of the EDSS score spinal cordMRI activity and AQP4-IgG titers could at least in part beexplained by fact that baseline values were ascertainedduring the acute phase and follow-up measures mainlyduring remission phase while TCZ treatment Beyond thatthe AQP4-IgG titer decreasestabilization may also be anindirect effect of the IL-6 blockade by TCZ as IL-6 sig-naling promotes the autoantibody production from plas-mablasts in NMOSD18 Our clinical and imaging findingsare in line with those in smaller retrospective case series andthe TANGO trial22234142 The effect on pain remainsambiguous as it was reported in smaller case series2022 butwas not confirmed in our study or the satralizumabSakuraSky trial13

Regarding the patients with double-seronegative NMOSDwe observed a significant ARR reduction when consideringall 7 patients independently of the treatment durationwhich was not reported in the pivotal trials for satralizumaband could be explained by the heterogeneity of this less-defined patient group hampering direct comparisons1314

In line with the satralizumab studies no effect on EDSS scorepain and furthermore on MRI activity was detectable inAQP4-IgG+ NMOSD in this study

For MOGAD treatment recommendations are scarce andapproaches well established for AQP4-IgG+ NMOSD suchas CD20-mediated B-cell depletion have shown limitedefficacy in MOGAD43-45 Another MOGAD treatmentstudy showed that under azathioprine therapy 14 of 17

MOG-IgG+ patients (82) had at least 1 attack particu-larly during the first 6 months and in patients withoutconcomitant steroid therapy3 Reports on IVIG or MTXtreatment in MOGAD are so far rather anecdotal346however recent data revealed the lowest ARR being asso-ciated with an IVIG maintenance therapy (n = 10 patients)compared with RTX MMF and AZA45 Of note recentfindings in a Chinese MOGAD cohort indicate that MMFmay prevent relapses particularly with concomitant oralprednisolone47 Compared with untreated adult patientswith MOGAD AZA MMF and RTX but not MTXmitoxantrone and cyclophosphamide significantly re-duced the risk of new relapses and the ARR in a cohort of125 patients48 So far only 14 different MOGAD patientstreated IV andor subcutaneously with TCZ were reportedin 7 small case reportsseries232629-33 6 of these 14patients were included in the present cohort

Here in our series of 14 patients with MOGAD the ARRdecreased by 93 the median EDSS score was reducedfrom 275 to 20 over a mean TCZ treatment duration of31 months and an anti-inflammatory effect was obviousalso on brain MRI Notably the ARR reduction persistedwhen considering only those patients who were treated formore than 12 months Again the effect on EDSS score andMRI activity was mainly driven by the fact of high diseaseactivity at baseline and remission phase at follow-up as-sessment Most patients with MOGAD (79 and 73for the patients treated for gt12 months respectively)remained relapse free and in 57 of them TCZ was usedas monotherapy The remaining 6 patients were cotreatedwith LDS (n = 4) monthly HDS plus IVIG (n = 1) orMTX (due to psoriasis n = 1) No effects were found onpain which is a common symptom in MOGAD49 andspinal cord MRI activity A single attack during TCZtreatment occurred in 21 of patients with MOGAD 2 or4 attacks in 14 and 7 of patients respectively Ourfindings are in line with those of a recent study whichshowed that TCZ therapy was associated with clinical andradiographic relapse freedom resolution of eye pain andability to discontinue corticosteroids in a cohort of 10patients with MOGAD over an average treatment durationof 286 months33 Overall when considering disease ac-tivity including ARR as well as suspected side effectsduring TCZ therapy we did not observe a clear advantageof add-on treatments supporting the use of TCZ asmonotherapy

Considering safety adverse events occurred within theexpected range based on the established use of TCZ in clinicalpractice Infusion-related reactions appeared in 12 of allpatients and infections of the urinary or respiratory tract werereported with similar frequency Of note (re)activation orworsening of chronic latent inflammatory diseases was ob-served in patients with already established SLE (n = 2) andpsoriasis (n = 2) indicating that these patients should beparticularly monitored Laboratory changes included mild to


moderate neutropenia in 18 and liver enzyme changes in35 of patients Total cholesterol as well as HDL and LDLcholesterol levels did not change during TCZ treatment asexpected22

An obvious limitation of this study is the retrospective mul-ticenter design resulting in heterogeneity of TCZ treatmentregimens andMRI protocols as well as missing data eg thelack of MOG-IgG testing in 1036 (28) AQP4-IgG+ pa-tients However the latter issue may not be a serious limi-tation as co-occurrence of AQP4- and MOG-IgG atsignificant titers is extremely rare50 Another constraint is therelatively small sample size which is justifiable by the rarityof NMOSD and MOGAD on a concomitant rare andoff-label treatment with TCZ Nevertheless we attemptedto enroll all of these seldom patients from 2 of the largestcohorts in Europe NEMOS in Germany and NOMADMUSin France and additional patients from other countriesMoreover because of the lack of a control cohort and thetiming of the switch to TCZ (ie during a phase of activedisease) we have to consider regression to the mean asan important limitation of our study design as mean dis-ease activity could decrease spontaneously even withouttreatment

Despite these limitations this largest real-world studysupports the long-term safety and therapeutic relevance ofthe IL-6 pathway in RTX-refractory AQP4-IgG+ NMOSDfor up to 9 years Moreover our findings suggest a similarrole for MOGAD pointing toward the need for random-ized controlled trials to evaluate the efficacy of IL-6blockade in patients with MOGAD This study providesClass III evidence that TCZ decreases the probability ofrelapses in patients with refractory MOGAD and NMOSD

AcknowledgmentThe authors thank all patients and their families for con-tributing to our study Contributing members of the Neuro-myelitis Optica Study Group are listed in Appendix 2 MR IAGL IK and OA had full access to all of the data in the studyand take responsibility for the integrity of the data and theaccuracy of the data analysis

Study FundingThe Neuromyelitis Optica Study Group (NEMOS) is par-tially funded by the German Ministry for Education and Re-search (BMBF) as part of the German Competence NetworkMultiple Sclerosis (KKNMS for NEMOS NationNMO FKZ01GI1602)

DisclosureM Ringelstein received speaker honoraria from NovartisBayer Vital GmbH Roche Alexion and Ipsen and travelreimbursement from Bayer Schering Biogen Idec MerzGenzyme Teva Roche and Merck I Ayzenberg receivedpersonal fees from Roche Alexion and Merck and receivedresearch support from Diamed none related to this study

G Lindenblatt received travel reimbursement from BayerHealthCare not related to this study K Fischer A Gahlenand G Novi report no disclosures relevant to the manu-script H Hayward-Konnecke received compensation foradvice lecturing or travel support from Biogen GenzymeMerck Novartis and Teva S Schippling received consul-ting and speaker fees and travel grants from Biogen IdecBayer Merck Sanofi GenzymeSanofi Aventis Novartisand Teva and research grants from Bayer Biogen IdecMerck Serono Sanofi GenzymeSanofi Aventis andNovartis He is currently an employee at Roche Pharma-ceutical Research and Development Neuroscience andRare Diseases P Rommer received speaker or consultancyhonoraria from AbbVie Alexion Almirall Biogen DaiichiSankyo Merck Novartis Sanofi Genzyme Sandoz andRoche and research funding from Biogen Merck Rocheand Austrian Science Funds (KLI 837-8) none related tothis study B Kornek received speaker honoraria fromBayer Biogen Celgene-BMS Merck Novartis RocheSanofi Genzyme and Teva and participated in advisoryboards from Celgene-BMS Merck Novartis Sanofi Gen-zyme and Roche No COIs related to this study T Zrzavyhas participated in meetings sponsored by or receivedtravel funding from Biogen Merck Novartis Roche SanofiGenzyme and Teva D Biotti reports no disclosures rele-vant to the manuscript J Ciron received personal com-pensation for consulting serving on a scientific advisoryboard speaking or other activities with Biogen NovartisMerck Genzyme and Roche none related to this study BAudoin reports no disclosures relevant to the manuscriptA Berthele has received speaker and consulting honorariafrom Alexion Biogen Bayer HealthCare Celgene MerckNovartis Pharma and Roche all outside the submittedwork K Giglhuber reports no disclosures relevant to themanuscript H Zephir reports speaker honoraria travelreimbursement and consulting fees from Biogen IdecMerck Novartis Roche Teva Genzyme and BayerPharma and research grants from Roche Teva ARSEP andLFSEP not relevant to the manuscript T Kumpfel hasreceived speaker honoraria andor personal fees for advi-sory boards from Bayer HealthCare Teva Pharma MerckNovartis Pharma Sanofi AventisGenzyme RochePharma and Biogen and grant support from Novartis andChugai Pharma in the past R Berger reports no disclosuresrelevant to the manuscript J Rother received speakerhonoraria from Bayer Vital GmbH Bristol Myers SquibbPfizer AstraZeneca Portola Daiichi Sankyo and Serviernone related to this study V Hauszligler reports no disclo-sures relevant to the manuscript J-P Stellmann receivedresearch grants and speaker honoraria from Biogen Gen-zyme and Alexion D Whittam and A Jacob report nodisclosures relevant to the manuscript M Kramer receivedhonoraria for teaching and scientific activities from ChugaiPharma Janssen-Cilag and Roche Pharma A Gueguenserved as an editorial board member of Biogen IdecNovartis and Teva and received consulting fees fromBiogen Idec Novartis and Teva he received funding for


travel from Biogen Idec Novartis and Teva Pharma RDeschamps reports no disclosures relevant to the manu-script A Bayas has received personal compensation fromMerck Serono Biogen Novartis Teva Roche SanofiGenzyme Alexion and Celgene and grants for congresstrips and participation from Biogen Teva Novartis SanofiGenzyme Merck Serono and Celgene MW Hummertreports no disclosures relevant to the manuscript C Trebsthas received honoraria for consultation and expert testi-mony from Biogen IdecGmbH Genzyme GmbH NovartisPharma GmbH Merck Chugai Pharma Germany GmbHand Roche Pharma GmbH None of this interfered with thecurrent report A Haarmann and S Jarius report no dis-closures relevant to the manuscript B Wildemann receivedgrants from the German Ministry of Education and Re-search Deutsche Forschungsgemeinschaft Dietmar HoppFoundation and Klaus Tschira Foundation grants andpersonal fees from Merck Serono Sanofi Genzyme andNovartis Pharmaceuticals and personal fees from BayerHealthCare Biogen and Teva Pharma M Grothe receivedhonoraria and travel reimbursements for attending meetingsfrom Biogen Celgene Merck Serono Novartis RocheSanofi-Genzyme and Teva and research grants from theGerman Ministry for Education and Research (BMBF)Merck Serono and Novartis None of this interfered withthe current report N Siebert received travel funding fromSanofi AventisGenzyme and speaker honoraria from BayerAG K Ruprecht received research support from NovartisMerck Serono German Ministry of Education and Re-search European Union (821283-2) Stiftung Charite (BIHClinical Fellow Program) and Arthur Arnstein Foundationreceived speaker honoraria and travel grants from BayerBiogen Idec Merck Serono Sanofi AventisGenzyme TevaRoche Novartis and The Guthy-Jackson CharitableFoundation F Paul serves as Academic Editor PLoS ONEand Associate Editor Neurology Neuroimmunology andNeuroinflammation is member of Novartis OCTIMS studysteering committee and MedImmuneViela Bio steeringcommittee reports speaker honoraria and travel grants fromBayer Novartis Biogen Idec Teva Sanofi-AventisGenzyme Merck Serono Alexion Chugai MedImmuneShire Roche Actelion and Celgene and consultancies forSanofi Genzyme Biogen Idec MedImmune Shire andAlexion and received research support from BayerNovartis Biogen Idec Teva Sanofi-AventisGenzymeAlexion and Merck Serono German Research Council(DFG Exc 257) Werth Stiftung of the City of CologneGerman Ministry of Education and Research (BMBFCompetence Network Multiple Sclerosis) Arthur ArnsteinStiftung Berlin EU FP7 Framework Program (combim-seu) Arthur Arnstein Foundation Berlin The Guthy-Jackson Charitable Foundation and National MultipleSclerosis Society of the United States N Collongues reportsno disclosures relevant to the manuscript R Marignier re-ports personal fees and nonfinancial support from Viela Biononfinancial support from Merck nonfinancial supportfrom Biogen personal fees and nonfinancial support from

Roche and personal fees from UCB outside the submittedwork M Levy received consulting fees from Alexion VielaBio GenentechRocheChugai Quest Diagnostics Mitsu-bishi Pharma and UCB Pharmaceuticals M Karenfort re-ceived board honoraria from Novartis not related to thecontent of this manuscript M Deppe reports no disclosuresrelevant to the manuscript P Albrecht received compen-sation for serving on scientific advisory boards for IpsenNovartis and Biogen he received speaker honoraria andtravel support from Novartis Teva Biogen Merz Pharma-ceuticals Ipsen Allergan Bayer HealthCare Esai UCB andGlaxoSmithKline he received research support fromNovartis Biogen Teva Merz Pharmaceuticals Ipsen andRoche All not related to the content of this manuscript KHellwig received speakerrsquos board honoraria and researchsupport from Bayer Schering Biogen Idec Genzyme MerckSerono Novartis and Teva His department received grantsupport from Bayer Schering Biogen Idec Genzyme MerckSerono Novartis Roche and Teva R Gold receivedspeakerrsquos and board honoraria from Baxter Bayer ScheringBiogen Idec CLB Behring Genzyme Merck SeronoNovartis Stendhal Talecris and Teva His department re-ceived grant support from Bayer Schering Biogen IdecGenzyme Merck Serono Novartis and Teva All not relatedto the content of this manuscript H-P Hartung receivedwith approval of the Rector of Heinrich Heine Universityand the CEO of University of Dusseldorf Hospital honorariafor consulting serving on steering committees and speakingfrom Bayer Biogen GeNeuro Genzyme MedImmuneMerck Novartis Receptos Celgene Roche Sanofi andTeva SG Meuth receives honoraria for lecturing and travelexpenses for attending meetings from Almirall AmicusTherapeutics Germany Bayer HealthCare Biogen Cel-gene Diamed Genzyme MedDay Pharmaceuticals MerckSerono Novartis Novo Nordisk ONO Pharma RocheSanofi-Aventis Chugai Pharma QuintilesIMS and TevaHis research is funded by the German Ministry for Educa-tion and Research (BMBF) Bundesinstitut fur Ris-ikobewertung (BfR) Deutsche Forschungsgemeinschaft(DFG) Else Kroner Fresenius Foundation GemeinsamerBundesausschuss (G-BA) German Academic ExchangeService Hertie Foundation Interdisciplinary Center forClinical Studies (IZKF) Muenster German FoundationNeurology and Alexion Almirall Amicus TherapeuticsGermany Biogen Diamed Fresenius Medical Care Gen-zyme HERZ Burgdorf Merck Serono Novartis ONOPharma Roche and Teva I Kleiter has received personal feesfrom Alexion Biogen Celgene Chugai Novartis Merck andRoche and received research support from Chugai and DiamedO Aktas has received personal fees from Alexion BayerHealthCare Biogen Celgene Merck Serono MedImmuneNovartis Roche Teva and Zambon outside the submittedwork Go to NeurologyorgNN for full disclosures

Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationFebruary 8 2021 Accepted in final form August 25 2021


Appendix 1 Authors

Name Location Contribution

MariusRingelsteinMD

Heinrich Heine UniversityDusseldorf Germany

Designed andconceptualized the studymajor role in the acquisitionof data analyzed the dataand drafted the manuscriptfor intellectual content

IlyaAyzenbergMD

Ruhr University BochumGermany Sechenov FirstMoscow State MedicalUniversity Russia

Designed andconceptualized the studymajor role in the acquisitionof data analyzed thedata and drafted themanuscript for intellectualcontent

GeroLindenblattMD

Johanna Etienne HospitalNeuss Germany

Major role in the statisticalanalysis and drafted themanuscript for intellectualcontent

KatinkaFischerMSc



AnnaGahlen MD

Ruhr University BochumGermany

Major role in the acquisitionof data and revised themanuscript for intellectualcontent

GiovanniNovi MD

San Martino HospitalGenova Italy


HelenHayward-KonneckeMD

University Hospital ZurichSwitzerland


SvenSchipplingMD



PaulusRommerMD

Medical University of ViennaAustria


BarbaraKornek MD



TobiasZrzavy MD



DamienBiotti MD

Universite de ToulouseFrance


JonathanCiron MD



BertrandAudoin MD

Aix Marseille UniversityFrance


Appendix 1 (continued)


AchimBertheleMD

Technical University ofMunich Germany


KatrinGiglhuberMD



HeleneZephir MD

University of Lille France Major role in the acquisitionof data and revised themanuscript for intellectualcontent

TaniaKumpfelMD

Ludwig-MaximiliansUniversityMunich Germany


RobertBerger MD

Asklepios Klinik AltonaHamburg Germany


JoachimRother MD



VivienHauszligler MD

University Medical CenterHamburg-EppendorfGermany


Jan-PatrickStellmannMD

Hopital de la Timone and AixMarseille France


DanielWhittamMD

The Walton CentreLiverpool United Kingdom


Anu JacobMD

The Walton CentreLiverpool United Kingdomand the Cleveland Clinic AbuDhabi UAE


MarkusKraemerMD

Department of NeurologyAlfried Krupp HospitalEssen Germany


AntoineGueguenMD

Fondation OphtalmologiqueAdolphe de Rothschild ParisFrance


RomainDeschampsMD



AntoniosBayas MD

UniversitatsklinikumAugsburg AugsburgGermany


Martin WHummertMD

Hannover Medical SchoolHannover Germany





CorinnaTrebst MD



AxelHaarmannMD

University HospitalWurzburg Germany


Sven JariusMD

University of HeidelbergGermany


BrigitteWildemannMD



MatthiasGrothe MD

University hospitalGreifswald Germany

Analyzed the data andrevised the manuscript forintellectual content

NadjaSiebert MD

Charite UniversitatsmedizinBerlin Germany


KlemensRuprechtMD



FriedemannPaul MD



NicolasCollonguesMD

University HospitalStrasbourg France


RomainMarignierMD

Pierre Wertheimer HospicesCivils de Lyon France


MichaelLevy MDPhD

Massachusetts GeneralHospital and HarvardMedical School Boston MAUSA


MichaelKarenfortMD


Designed andconceptualized the studyanalyzed the data anddrafted the manuscript forintellectual content

MichaelDeppe PhD

University Hospital MunsterGermany


PhilippAlbrechtMD



KerstinHellwig MD



Ralf Gold Ruhr University BochumGermany


Appendix 2 Coinvestigators

Name Location Role Contribution

KlemensAngstwurmMD

University HospitalRegensburg Germany

Coinvestigator Organizationalsupport

SusannaAsseyer MD

Charite -UniversitatsmedizinBerlin Germany


JudithBellmann-Strobl MD



Felix BischofMD

University HospitalTubingen andNervenarztlicheGemeinschaftspraxisBoblingen Germany


StefanBittner MD

University MedicalCenter of the JohannesGutenberg UniversityMainz Germany


TobiasBottcher MD

Johanna-Odebrecht-Stiftung GreifswaldGermany


MathiasButtmannMD

University of WurzburgGermany


AnkelienDuchow

Charite UniversityMedicine BerlinGermany


BarbaraEttrich MD

University HospitalLeipzig Germany


Jurgen FaissMD

Asklepios Klinik TeupitzGermany


BenediktFrank MD

University HospitalEssen Germany


Continued



Hans-PeterHartung MD



Sven GMeuth



Ingo KleiterMD

Marianne-Strauszlig-KlinikBerg Germany


OrhanAktas MD






Achim GassMD

University HospitalMannheim Germany


ChristianGeis MD

Department ofNeurology JenaUniversity HospitalGermany


KerstinGuthke MD

Klinikum GorlitzGermany


BernhardHemmer MD

Technical UniversityMunich Germany


FrankHoffmannMD

Krankenhaus Martha-Maria Halle Germany


OlafHoffmannMD

St Josefs-KrankenhausPotsdam Germany


UlrichHofstadt-vanOy MD

Klinikum WestfalenDortmund Germany


JuttaJunghans MD



MatthiasKaste MD

Nordwest HospitalSanderbusch SandeGermany


BarbaraKaulen MD

University HospitalHamburg Germany


Peter KernMD



PawelKermer MD



ChristophKleinschnitzMD



Luisa KlotzMD

University HospitalMunster Germany


WolfgangKohler MD



MelanieKorsen MD

University HospitalDusseldorf Germany


MarkusKowarik MD

University HospitalTubingen Germany


MarkusKrumbholzMD



Stefan LangelMD

LandeskrankenhausRheinhessen Germany


MartinLiebetrauMD

St Josefs-HospitalWiesbaden Germany


Ralf LinkerMD



De-HyungLee MD

University HospitalRegensburgGermany




Felix LuessiMD



MartinMarziniakMD

Isar-Amper Klinik OstMunich Germany


ChristophMayer MD

NeurologischenGemeinschaftspraxis imBienenkorbhausFrankfurt Germany


StefanieMeister MD

University HospitalRostock Germany


ArthurMelms MD

Facharztpraxis furNeurologie undPsychiatrie StuttgartGermany


Imke MetzMD

University HospitalGottingen Germany


OliverNeuhaus MD

SRH KrankenhausSigmaringen Germany


SabineNiehaus MD

Klinikum DortmundGermany


FlorencePache MD



MarcPawlitzki MD



HannahPellkofferMD

Ludwig-MaximiliansUniversity MunichGermany


Hans-UlrichPuhlmannMD

Schlosspark-KlinikBerlin Germany


Refik Pul MD University HospitalEssen Germany


KevinRostasy MD

Vestische Caritas-Kliniken GmbH DattelnGermany


LiobaRuckriemMD

MediClin Hedon-KlinikLingen (Ems) Germany


ChristophRuschil MD



MatthiasSchwab MD

University HospitalJena Germany


MakbuleSenel MD

University Hospital UlmGermany


Jorn PeterSieb MD

Helios HanseklinikumStralsund Germany


ClaudiaSommer MD



AnnetteSpreer MD




References1 Wingerchuk DM Weinshenker BG Neuromyelitis optica (Devicrsquos syndrome)

Handb Clin Neurol 2014122581-5992 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositive

and seronegative neuromyelitis optica a multicentre study of 175 patientsJ Neuroinflammation 2012914

3 Jarius S Ruprecht K Kleiter I et al MOG-IgG in NMO and related disorders amulticenter study of 50 patients Part 2 epidemiology clinical presentation radio-logical and laboratory features treatment responses and long-term outcomeJ Neuroinflammation 201613(1)280

4 Cobo-Calvo A Ruiz A Maillart E et al Clinical spectrum and prognostic value ofCNSMOG autoimmunity in adults the MOGADOR studyNeurology 201890(21)e1858-e1869

5 Salama S Khan M Shanechi A Levy M Izbudak I MRI differences between MOGantibody disease and AQP4 NMOSD Mult Scler 202026(14)1854-1865

6 Hacohen Y Palace J Time to separate MOG-Ab-associated disease from AQP4-Ab-positive neuromyelitis optica spectrum disorder Neurology 201890(21)947-948

7 Mader S Kumpfel T Meinl E Novel insights into pathophysiology and therapeuticpossibilities reveal further differences between AQP4-IgG- and MOG-IgG-associateddiseases Curr Opin Neurol 202033(3)362-371

8 Hoftberger R Guo Y Flanagan EP et al The pathology of central nervous systeminflammatory demyelinating disease accompanying myelin oligodendrocyte glyco-protein autoantibody Acta Neuropathol 2020139(5)875-892

9 Wingerchuk DM Pittock SJ Lucchinetti CF Lennon VA Weinshenker BG A sec-ondary progressive clinical course is uncommon in neuromyelitis optica Neurology200768(8)603-605

10 Cree BAC Bennett JL Kim HJ et al Inebilizumab for the treatment of neuromyelitisoptica spectrum disorder (N-MOmentum) a double-blind randomised placebo-controlled phase 23 trial Lancet 2019394(10206)1352-1363

11 Tahara M Oeda T Okada K et al Safety and efficacy of rituximab in neuromyelitisoptica spectrum disorders (RIN-1 study) a multicentre randomised double-blindplacebo-controlled trial Lancet Neurol 202019(4)298-306

12 Pittock SJ Berthele A Fujihara K et al Eculizumab in aquaporin-4-positive neuro-myelitis optica spectrum disorder N Engl J Med 2019381(7)614-625

13 Yamamura T Kleiter I Fujihara K et al Trial of satralizumab in neuromyelitis opticaspectrum disorder N Engl J Med 2019381(22)2114-2124

14 Traboulsee A Greenberg BM Bennett JL et al Safety and efficacy of satralizumabmonotherapy in neuromyelitis optica spectrum disorder a randomised double-blindmulticentre placebo-controlled phase 3 trial Lancet Neurol 202019(5)402-412

15 Fujihara K Bennett JL de Seze J et al Interleukin-6 in neuromyelitis optica spectrumdisorder pathophysiology Neurol Neuroimmunol Neuroinflamm 20207(5)e841

16 Uzawa A Mori M Arai K et al Cytokine and chemokine profiles in neuromyelitisoptica significance of interleukin-6 Mult Scler 201016(12)1443-1452

17 Agasing AM Wu Q Khatri B et al Transcriptomics and proteomics reveal a co-operation between interferon and T-helper 17 cells in neuromyelitis optica NatCommun 202011(1)2856

18 Chihara N Aranami T Sato W et al Interleukin 6 signaling promotes anti-aquaporin4 autoantibody production from plasmablasts in neuromyelitis optica Proc Natl AcadSci U S A 2011108(9)3701-3706

19 Takeshita Y Obermeier B Cotleur AC et al Effects of neuromyelitis optica-IgG at theblood-brain barrier in vitro Neurol Neuroimmunol Neuroinflamm 20174(1)e311

20 Araki M Matsuoka T Miyamoto K et al Efficacy of the anti-IL-6 receptor antibodytocilizumab in neuromyelitis optica a pilot study Neurology 201482(15)1302-1306

21 Ayzenberg I Kleiter I Schroder A et al Interleukin 6 receptor blockade in patientswith neuromyelitis optica nonresponsive to anti-CD20 therapy JAMA Neurol 201370(3)394-397

22 Ringelstein M Ayzenberg I Harmel J et al Long-term therapy with interleukin 6receptor blockade in highly active neuromyelitis optica spectrum disorder JAMANeurol 201572(7)756-763

23 Lotan I Charlson RW Ryerson LZ Levy M Kister I Effectiveness of subcutaneoustocilizumab in neuromyelitis optica spectrum disordersMult Scler Relat Disord 201939101920

24 Carreon GE Hernandez CR Castillo TT et al Experience with tocilizumab inpatients with neuromyelitis optica spectrum disorders Neurologia 2019S0213-4853(19)30033-7

25 Breu M Glatter S Hoftberger R et al Two cases of pediatric AQP4-antibody positiveneuromyelitis optica spectrum disorder successfully treated with tocilizumab Neu-ropediatrics 201950(3)193-196

26 Rigal J Pugnet G Ciron J Lepine Z Biotti D Off-label use of tocilizumab in neu-romyelitis optica spectrum disorders and MOG-antibody-associated diseases a case-series Mult Scler Relat Disord 202046102483

27 Kaneko K Sato DK Nakashima I et al CSF cytokine profile in MOG-IgG+ neu-rological disease is similar to AQP4-IgG+ NMOSD but distinct from MS a cross-sectional study and potential therapeutic implications J Neurol Neurosurg Psychiatry201889(9)927-936

28 Kothur K Wienholt L Tantsis EM et al B cell Th17 and neutrophil related cere-brospinal fluid cytokinechemokines are elevated in MOG antibody associated de-myelination PLoS One 201611(2)e0149411

29 Hayward-Koennecke H Reindl M Martin R Schippling S Tocilizumab treatment insevere recurrent anti-MOG-associated optic neuritis Neurology 201992(16)765-767

30 Novi G Gastaldi M Franciotta D Pesce G Benedetti L Uccelli A Tocilizumab inMOG-antibody spectrum disorder a case report Mult Scler Relat Disord 201927312-314



MartinStangel MD

Hannover MedicalSchool HannoverGermany


AndreaSteinbrecherMD

Helios Klinikum ErfurtGermany


HeikeStephanikMD

University HospitalMagdeburg Germany


MurielStoppe MD



Marie SuszligeMD

University HospitalGreifswald Germany


BjornTackenbergMD

University HospitalMarburg Germany


Florian ThenBergh MD

University of LeipzigGermany


JohannesTunnerhoffMD



HayrettinTumani MD



AnnetteWalter MD

Klinikum HerfordHerford Germany


Klaus-PeterWandingerMD

University MedicalCenter Schleswig-Holstein CampusLubeck Germany


ClemensWarnke MD

University HospitalKoln Germany


Martin SWeber MD



RobertWeissert MD



Heinz WiendlMD



ChristianWilke MD

NervenzentrumPotsdam Germany


AlexanderWinkelmannMD



YavorYalachkovMD

University HospitalFrankfurt Germany


Lena ZeltnerMD



Uwe Zettl University HospitalRostock Germany


Ulf ZiemannMD



Frauke ZippMD




31 Schwake C Hellwig K Gold R Ayzenberg I Reader response comparison of theresponse to rituximab between myelin oligodendrocyte glycoprotein and aquaporin-4antibody diseases Ann Neurol 202088(2)430

32 Masuccio FG Lo Re M Bertolotto A Capobianco M Solaro C Benign SARS-CoV-2infection in MOG-antibodies associated disorder during tocilizumab treatmentMultScler Relat Disord 202046102592

33 Elsbernd PMHoffmanWR Carter JLWingerchukDM Interleukin-6 inhibition withtocilizumab for relapsing MOG-IgG associated disorder (MOGAD) a case-series andreview Mult Scler Relat Disord 202148102696

34 Jarius S Paul F Aktas O et al MOG encephalomyelitis international recommen-dations on diagnosis and antibody testing J Neuroinflammation 201815(1)134

35 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnosticcriteria for neuromyelitis optica spectrum disorders Neurology 201585(2)177-189

36 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF Weinshenker BG Reviseddiagnostic criteria for neuromyelitis optica Neurology 200666(10)1485-1489

37 Jurynczyk M Messina S Woodhall MR et al Clinical presentation and prognosis inMOG-antibody disease a UK study Brain 2017140(12)3128-3138

38 Lopez-Chiriboga S Sechi E Buciuc M et al Long-term outcomes in patients withmyelin oligodendrocyte glycoprotein immunoglobulin G-associated disorder JAMANeurol 202077(12)1575-1577

39 Pache F Zimmermann H Mikolajczak J et al MOG-IgG in NMO and relateddisorders a multicenter study of 50 patients Part 4 afferent visual system damageafter optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patientsJ Neuroinflammation 201613(1)282

40 Lotan I McGowan R Levy M Anti- IL-6 therapies for neuromyelitis optica spectrum dis-orders a systematic review of safety and efficacy Curr Neuropharmacol 202119(2)220-232

41 Araki M Blockade of IL-6 signaling in neuromyelitis opticaNeurochem Int 2019130104315

42 Zhang C ZhangM QiuW et al Safety and efficacy of tocilizumab versus azathioprinein highly relapsing neuromyelitis optica spectrum disorder (TANGO) an open-labelmulticentre randomised phase 2 trial Lancet Neurol 202019(5)391-401

43 Durozard P Rico A Boutiere C et al Comparison of the response to rituximabbetween myelin oligodendrocyte glycoprotein and aquaporin-4 antibody diseasesAnn Neurol 202087(2)256-266

44 Whittam DH Cobo-Calvo A Lopez-Chiriboga AS et al Treatment of MOG-IgG-associated disorder with rituximab an international study of 121 patients Mult SclerRelat Disord 202044102251

45 Chen JJ Flanagan EP Bhatti MT et al Steroid-sparing maintenance immunotherapyfor MOG-IgG associated disorder Neurology 202095(2)e111-e120

46 Ramanathan S Mohammad S Tantsis E et al Clinical course therapeutic responsesand outcomes in relapsing MOG antibody-associated demyelination J Neurol Neu-rosurg Psychiatry 201889(2)127-137

47 Li S Ren H Xu Y et al Long-term efficacy of mycophenolate mofetil in myelinoligodendrocyte glycoprotein antibody-associated disorders a prospective studyNeurol Neuroimmunol Neuroinflamm 20207(3)e705

48 Cobo-Calvo A Sepulveda M Rollot F et al Evaluation of treatment response inadults with relapsing MOG-Ab-associated disease J Neuroinflammation 201916(1)134

49 Asseyer S Henke E Trebst C et al Pain depression and quality of life in adults withMOG-antibody-associated disease Eur J Neurol 202128(5)1645-1658

50 Jarius S Ruprecht K Kleiter I et al MOG-IgG in NMO and related disorders amulticenter study of 50 patients Part 1 frequency syndrome specificity influence ofdisease activity long-term course association with AQP4-IgG and originJ Neuroinflammation 201613(1)279


DOI 101212NXI000000000000110020229 Neurol Neuroimmunol Neuroinflamm

Marius Ringelstein Ilya Ayzenberg Gero Lindenblatt et al Disease and Neuromyelitis Optica Spectrum Disorders

AssociatedminusInterleukin-6 Receptor Blockade in Treatment-Refractory MOG-IgG

This information is current as of November 16 2021

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days) For MOGAD the median ARR decreased from 175 (range 05ndash5) to 0 (range 0ndash09 p = 00011) under TCZ A similareffect was seen for AQP4-IgG+ (ARR reduction from 15 [range 0ndash5] to 0 [range 0ndash42] p lt 0001) and for seronegativeNMOSD (from 30 [range 10ndash30] to 02 [range 0ndash20] p = 0031) During TCZ 60 of all patients were relapse free (79 forMOGAD 56 for AQP4-IgG+ and 43 for seronegative NMOSD) Disability follow-up indicated stabilization MRI in-flammatory activity decreased inMOGAD (p = 004 for the brain) and in AQP4-IgG+NMOSD (p lt 0001 for the spinal cord)Chronic pain was unchanged Regarding only patients treated with TCZ for at least 12 months (n = 44) ARR reductions wereconfirmed including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28) Similarly in the group of patientstreated with TCZ for at least 12 months 59 of them were relapse free with 73 for MOGAD 57 for AQP4-IgG+ and 40for patients with seronegative NMOSD No severe or unexpected safety signals were observed Add-on therapy showed noadvantage compared with TCZ monotherapy

DiscussionThis study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD andAQP4-IgG+ NMOSD

Myelin oligodendrocyte glycoprotein (MOG)-IgGndashassociateddisease (MOGAD) and neuromyelitis optica spectrum disor-der (NMOSD)with or without antindashaquaporin-4 (AQP4)-IgGare antibody-mediated chronic inflammatory CNS conditionsin most cases1-4 Although the clinical presentation with uni-lateral or bilateral optic neuritis (ON) longitudinally extensivetransverse myelitis or brain stem syndromes may be similar inMOGAD and NMOSD demographic clinical imaging andpathophysiologic findings strongly suggest the presence of 2distinct disease entities4-8 As MOGAD excluding acute dis-seminated encephalomyelitis (ADEM) and NMOSD typicallyfollow a relapsing course in adults39 attack prevention is key toavoid disability accumulation Recently a variety of therapeuticstrategies such as CD1920-mediated B-cell depletion1011

complement inhibition12 and interleukin-6 (IL-6) receptorblockade1314 were successfully investigated in pivotal NMOSDtrials particularly in AQP4-IgG+ patients Yet insights con-cerning the effectiveness and safety of such agents in MOGADare scarce

IL-6 plays an important role in the pathophysiology ofNMOSD15 Increased levels were detected in the serum andCSF particularly during attacks16 IL-6 promotes the dif-ferentiation of inflammatory Th17 cells17 and the pro-duction of AQP4-IgG by B cellndashderived plasmablasts inNMOSD18 and increases the permeability of the blood-brainbarrier19 facilitating CNS inflammation The efficacy of IL-6receptor blockade in AQP4-IgG+ NMOSD was suggestedby studies using tocilizumab (TCZ) in adults and children20-26 and demonstrated by 2 pivotal trials of satralizumab

whereas the effect in AQP4-IgGndashseronegative patients wasless evident1314 As AQP4-IgG+ NMOSD and MOGADboth display antibody- and complement-mediated CNS in-jury and similar inflammatory CSF profiles (with elevatedIL-6)2728 IL6-blockade may also be beneficial in MOGADsupported by recent case reports23252629-33 This retro-spective multicenter study explored the safety and efficacy ofTCZ in patients with MOGAD and is able to connect thesefindings with the effects of TCZ in classical (ie AQP4-IgG+) or double-seronegative NMOSD

Patients and Previous TreatmentsFifty-seven patients with relapsing MOGAD (n = 14)34 ex-cluding ADEM classical AQP4-IgG+ NMOSD (n = 36) ordouble-seronegative NMOSD (n = 7) mainly of Caucasiandescent (n = 50 Table 1) from neurologic departments of 23tertiary referral centers in Germany (n = 13 all members ofthe German Neuromyelitis Optica Study Group [NEMOS])France (n = 5 all members of the NOMADMUS cohort)Austria (1) Italy (1) Switzerland (1) United Kingdom (1)and United States of America (1) were retrospectively ana-lyzed The evaluated TCZ treatment period ranged fromDecember 2010 until November 2019 Regarding de-mographic parameters (Table 1) the mean age at diseasemanifestation was comparable for patients with MOGAD orAQP4-IgG+ NMOSD (355 or 361 years respectively p =089) as well as the age when TCZ was started (384 or 428years p = 035) Five patients were younger than 18 years atdisease manifestation and 3 of them younger than 18 years atinitiation of TCZ Of note patients with AQP4-IgG+

GlossaryADEM = acute disseminated encephalomyelitis AQP4 = aquaporin-4 ARR = annualized relapse rate AZA = azathioprineEDSS = Expanded Disability Status ScaleHDS = high-dose steroid IL-6 = interleukin-6 IQR = interquartile range IVIG = IVimmunoglobulin LDS = low-dose steroid MMF = mycophenolate mofetil MOG = myelin oligodendrocyte glycoproteinMOGAD = myelin oligodendrocyte glycoproteinndashIgGndashassociated disease MTX = methotrexate NMOSD = neuromyelitisoptica spectrum disorder ON = optic neuritis RTX = rituximab SLE = systemic lupus erythematosus TCZ = tocilizumabUTI = urinary tract infection












CohortMOGAD(n = 14)



Total(N = 57)

Ethnicity n ()

Caucasian 13 (93) 30 (83) 7 (100) 50 (88)


Arabian 1 (7) 2 (6) mdash 3 (5)




















Rituximab 14 (100) 36 (100) 7 (100) 57 (100)

Azathioprine 3 (21) 13 (36) 2 (29) 18 (32)



Methotrexate 1 (7) 7 (19) 3 (43) 11 (19)


IVIG 3 (21) 4 (11) 0 (0) 7 (12)

Interferon-beta 0 (0) 5 (14) 1 (14) 6 (11)

Mitoxantrone 0 (0) 5 (14) 0 (0) 5 (9)


Natalizumab 0 (0) 1 (3) 1 (14) 2 (4)


Alemtuzumab 0 (0) 1 (3) 0 (0) 1 (2)

Fingolimod 0 (0) 1 (3) 0 (0) 1 (2)

Cyclosporin A 0 (0) 1 (3) 0 (0) 1 (2)

Continued







CohortMOGAD(n = 14)



Total(N = 57)

Belimumab 1 (7) 0 (0) 0 (0) 1 (2)

Etanercept 0 (0) 1 (3) 0 (0) 1 (2)
























Safety Data





















CohortMOGAD(n = 14)



Total(N = 57)


Infections



2 (14) 5 (14) 2 (29) 9 (16)



(Pyelo)nephritis 1 () 1 (3) 0 (0) 2 (4)


Tumor n () 0 (0) 1a (3) 0 (0) 1a (2)


Neutropenia n () 2 (14) 8 (22) 0 (0) 10 (17)































Appendix 1 Authors


MariusRingelsteinMD



IlyaAyzenbergMD



GeroLindenblattMD



KatinkaFischerMSc



AnnaGahlen MD



GiovanniNovi MD






SvenSchipplingMD



PaulusRommerMD



BarbaraKornek MD



TobiasZrzavy MD



DamienBiotti MD



JonathanCiron MD



BertrandAudoin MD





AchimBertheleMD



KatrinGiglhuberMD



HeleneZephir MD


TaniaKumpfelMD



RobertBerger MD



JoachimRother MD









DanielWhittamMD



Anu JacobMD



MarkusKraemerMD



AntoineGueguenMD



RomainDeschampsMD



AntoniosBayas MD



Martin WHummertMD






CorinnaTrebst MD



AxelHaarmannMD



Sven JariusMD



BrigitteWildemannMD



MatthiasGrothe MD



NadjaSiebert MD



KlemensRuprechtMD



FriedemannPaul MD



NicolasCollonguesMD



RomainMarignierMD



MichaelLevy MDPhD



MichaelKarenfortMD



MichaelDeppe PhD



PhilippAlbrechtMD



KerstinHellwig MD







KlemensAngstwurmMD



SusannaAsseyer MD






Felix BischofMD



StefanBittner MD



TobiasBottcher MD



MathiasButtmannMD



AnkelienDuchow



BarbaraEttrich MD



Jurgen FaissMD



BenediktFrank MD



Continued






Sven GMeuth



Ingo KleiterMD



OrhanAktas MD






Achim GassMD



ChristianGeis MD



KerstinGuthke MD



BernhardHemmer MD



FrankHoffmannMD



OlafHoffmannMD






JuttaJunghans MD



MatthiasKaste MD



BarbaraKaulen MD



Peter KernMD



PawelKermer MD






Luisa KlotzMD



WolfgangKohler MD



MelanieKorsen MD



MarkusKowarik MD



MarkusKrumbholzMD



Stefan LangelMD



MartinLiebetrauMD



Ralf LinkerMD



De-HyungLee MD





Felix LuessiMD



MartinMarziniakMD



ChristophMayer MD



StefanieMeister MD



ArthurMelms MD



Imke MetzMD



OliverNeuhaus MD



SabineNiehaus MD



FlorencePache MD



MarcPawlitzki MD



HannahPellkofferMD








KevinRostasy MD



LiobaRuckriemMD



ChristophRuschil MD



MatthiasSchwab MD



MakbuleSenel MD



Jorn PeterSieb MD



ClaudiaSommer MD



AnnetteSpreer MD





































MartinStangel MD






HeikeStephanikMD



MurielStoppe MD



Marie SuszligeMD



BjornTackenbergMD









HayrettinTumani MD



AnnetteWalter MD






ClemensWarnke MD



Martin SWeber MD



RobertWeissert MD



Heinz WiendlMD



ChristianWilke MD






YavorYalachkovMD



Lena ZeltnerMD





Ulf ZiemannMD



Frauke ZippMD












































Reprints














CohortMOGAD(n = 14)



Total(N = 57)

Ethnicity n ()

Caucasian 13 (93) 30 (83) 7 (100) 50 (88)


Arabian 1 (7) 2 (6) mdash 3 (5)




















Rituximab 14 (100) 36 (100) 7 (100) 57 (100)

Azathioprine 3 (21) 13 (36) 2 (29) 18 (32)



Methotrexate 1 (7) 7 (19) 3 (43) 11 (19)


IVIG 3 (21) 4 (11) 0 (0) 7 (12)

Interferon-beta 0 (0) 5 (14) 1 (14) 6 (11)

Mitoxantrone 0 (0) 5 (14) 0 (0) 5 (9)


Natalizumab 0 (0) 1 (3) 1 (14) 2 (4)


Alemtuzumab 0 (0) 1 (3) 0 (0) 1 (2)

Fingolimod 0 (0) 1 (3) 0 (0) 1 (2)

Cyclosporin A 0 (0) 1 (3) 0 (0) 1 (2)

Continued







CohortMOGAD(n = 14)



Total(N = 57)

Belimumab 1 (7) 0 (0) 0 (0) 1 (2)

Etanercept 0 (0) 1 (3) 0 (0) 1 (2)
























Safety Data





















CohortMOGAD(n = 14)



Total(N = 57)


Infections



2 (14) 5 (14) 2 (29) 9 (16)



(Pyelo)nephritis 1 () 1 (3) 0 (0) 2 (4)


Tumor n () 0 (0) 1a (3) 0 (0) 1a (2)


Neutropenia n () 2 (14) 8 (22) 0 (0) 10 (17)































Appendix 1 Authors


MariusRingelsteinMD



IlyaAyzenbergMD



GeroLindenblattMD



KatinkaFischerMSc



AnnaGahlen MD



GiovanniNovi MD






SvenSchipplingMD



PaulusRommerMD



BarbaraKornek MD



TobiasZrzavy MD



DamienBiotti MD



JonathanCiron MD



BertrandAudoin MD





AchimBertheleMD



KatrinGiglhuberMD



HeleneZephir MD


TaniaKumpfelMD



RobertBerger MD



JoachimRother MD









DanielWhittamMD



Anu JacobMD



MarkusKraemerMD



AntoineGueguenMD



RomainDeschampsMD



AntoniosBayas MD



Martin WHummertMD






CorinnaTrebst MD



AxelHaarmannMD



Sven JariusMD



BrigitteWildemannMD



MatthiasGrothe MD



NadjaSiebert MD



KlemensRuprechtMD



FriedemannPaul MD



NicolasCollonguesMD



RomainMarignierMD



MichaelLevy MDPhD



MichaelKarenfortMD



MichaelDeppe PhD



PhilippAlbrechtMD



KerstinHellwig MD







KlemensAngstwurmMD



SusannaAsseyer MD






Felix BischofMD



StefanBittner MD



TobiasBottcher MD



MathiasButtmannMD



AnkelienDuchow



BarbaraEttrich MD



Jurgen FaissMD



BenediktFrank MD



Continued






Sven GMeuth



Ingo KleiterMD



OrhanAktas MD






Achim GassMD



ChristianGeis MD



KerstinGuthke MD



BernhardHemmer MD



FrankHoffmannMD



OlafHoffmannMD






JuttaJunghans MD



MatthiasKaste MD



BarbaraKaulen MD



Peter KernMD



PawelKermer MD






Luisa KlotzMD



WolfgangKohler MD



MelanieKorsen MD



MarkusKowarik MD



MarkusKrumbholzMD



Stefan LangelMD



MartinLiebetrauMD



Ralf LinkerMD



De-HyungLee MD





Felix LuessiMD



MartinMarziniakMD



ChristophMayer MD



StefanieMeister MD



ArthurMelms MD



Imke MetzMD



OliverNeuhaus MD



SabineNiehaus MD



FlorencePache MD



MarcPawlitzki MD



HannahPellkofferMD








KevinRostasy MD



LiobaRuckriemMD



ChristophRuschil MD



MatthiasSchwab MD



MakbuleSenel MD



Jorn PeterSieb MD



ClaudiaSommer MD



AnnetteSpreer MD





































MartinStangel MD






HeikeStephanikMD



MurielStoppe MD



Marie SuszligeMD



BjornTackenbergMD









HayrettinTumani MD



AnnetteWalter MD






ClemensWarnke MD



Martin SWeber MD



RobertWeissert MD



Heinz WiendlMD



ChristianWilke MD






YavorYalachkovMD



Lena ZeltnerMD





Ulf ZiemannMD



Frauke ZippMD












































Reprints









CohortMOGAD(n = 14)



Total(N = 57)

Belimumab 1 (7) 0 (0) 0 (0) 1 (2)

Etanercept 0 (0) 1 (3) 0 (0) 1 (2)
























Safety Data





















CohortMOGAD(n = 14)



Total(N = 57)


Infections



2 (14) 5 (14) 2 (29) 9 (16)



(Pyelo)nephritis 1 () 1 (3) 0 (0) 2 (4)


Tumor n () 0 (0) 1a (3) 0 (0) 1a (2)


Neutropenia n () 2 (14) 8 (22) 0 (0) 10 (17)































Appendix 1 Authors


MariusRingelsteinMD



IlyaAyzenbergMD



GeroLindenblattMD



KatinkaFischerMSc



AnnaGahlen MD



GiovanniNovi MD






SvenSchipplingMD



PaulusRommerMD



BarbaraKornek MD



TobiasZrzavy MD



DamienBiotti MD



JonathanCiron MD



BertrandAudoin MD





AchimBertheleMD



KatrinGiglhuberMD



HeleneZephir MD


TaniaKumpfelMD



RobertBerger MD



JoachimRother MD









DanielWhittamMD



Anu JacobMD



MarkusKraemerMD



AntoineGueguenMD



RomainDeschampsMD



AntoniosBayas MD



Martin WHummertMD






CorinnaTrebst MD



AxelHaarmannMD



Sven JariusMD



BrigitteWildemannMD



MatthiasGrothe MD



NadjaSiebert MD



KlemensRuprechtMD



FriedemannPaul MD



NicolasCollonguesMD



RomainMarignierMD



MichaelLevy MDPhD



MichaelKarenfortMD



MichaelDeppe PhD



PhilippAlbrechtMD



KerstinHellwig MD







KlemensAngstwurmMD



SusannaAsseyer MD






Felix BischofMD



StefanBittner MD



TobiasBottcher MD



MathiasButtmannMD



AnkelienDuchow



BarbaraEttrich MD



Jurgen FaissMD



BenediktFrank MD



Continued






Sven GMeuth



Ingo KleiterMD



OrhanAktas MD






Achim GassMD



ChristianGeis MD



KerstinGuthke MD



BernhardHemmer MD



FrankHoffmannMD



OlafHoffmannMD






JuttaJunghans MD



MatthiasKaste MD



BarbaraKaulen MD



Peter KernMD



PawelKermer MD






Luisa KlotzMD



WolfgangKohler MD



MelanieKorsen MD



MarkusKowarik MD



MarkusKrumbholzMD



Stefan LangelMD



MartinLiebetrauMD



Ralf LinkerMD



De-HyungLee MD





Felix LuessiMD



MartinMarziniakMD



ChristophMayer MD



StefanieMeister MD



ArthurMelms MD



Imke MetzMD



OliverNeuhaus MD



SabineNiehaus MD



FlorencePache MD



MarcPawlitzki MD



HannahPellkofferMD








KevinRostasy MD



LiobaRuckriemMD



ChristophRuschil MD



MatthiasSchwab MD



MakbuleSenel MD



Jorn PeterSieb MD



ClaudiaSommer MD



AnnetteSpreer MD





































MartinStangel MD






HeikeStephanikMD



MurielStoppe MD



Marie SuszligeMD



BjornTackenbergMD









HayrettinTumani MD



AnnetteWalter MD






ClemensWarnke MD



Martin SWeber MD



RobertWeissert MD



Heinz WiendlMD



ChristianWilke MD






YavorYalachkovMD



Lena ZeltnerMD





Ulf ZiemannMD



Frauke ZippMD












































Reprints























Safety Data





















CohortMOGAD(n = 14)



Total(N = 57)


Infections



2 (14) 5 (14) 2 (29) 9 (16)



(Pyelo)nephritis 1 () 1 (3) 0 (0) 2 (4)


Tumor n () 0 (0) 1a (3) 0 (0) 1a (2)


Neutropenia n () 2 (14) 8 (22) 0 (0) 10 (17)































Appendix 1 Authors


MariusRingelsteinMD



IlyaAyzenbergMD



GeroLindenblattMD



KatinkaFischerMSc



AnnaGahlen MD



GiovanniNovi MD






SvenSchipplingMD



PaulusRommerMD



BarbaraKornek MD



TobiasZrzavy MD



DamienBiotti MD



JonathanCiron MD



BertrandAudoin MD





AchimBertheleMD



KatrinGiglhuberMD



HeleneZephir MD


TaniaKumpfelMD



RobertBerger MD



JoachimRother MD









DanielWhittamMD



Anu JacobMD



MarkusKraemerMD



AntoineGueguenMD



RomainDeschampsMD



AntoniosBayas MD



Martin WHummertMD






CorinnaTrebst MD



AxelHaarmannMD



Sven JariusMD



BrigitteWildemannMD



MatthiasGrothe MD



NadjaSiebert MD



KlemensRuprechtMD



FriedemannPaul MD



NicolasCollonguesMD



RomainMarignierMD



MichaelLevy MDPhD



MichaelKarenfortMD



MichaelDeppe PhD



PhilippAlbrechtMD



KerstinHellwig MD







KlemensAngstwurmMD



SusannaAsseyer MD






Felix BischofMD



StefanBittner MD



TobiasBottcher MD



MathiasButtmannMD



AnkelienDuchow



BarbaraEttrich MD



Jurgen FaissMD



BenediktFrank MD



Continued






Sven GMeuth



Ingo KleiterMD



OrhanAktas MD






Achim GassMD



ChristianGeis MD



KerstinGuthke MD



BernhardHemmer MD



FrankHoffmannMD



OlafHoffmannMD






JuttaJunghans MD



MatthiasKaste MD



BarbaraKaulen MD



Peter KernMD



PawelKermer MD






Luisa KlotzMD



WolfgangKohler MD



MelanieKorsen MD



MarkusKowarik MD



MarkusKrumbholzMD



Stefan LangelMD



MartinLiebetrauMD



Ralf LinkerMD



De-HyungLee MD





Felix LuessiMD



MartinMarziniakMD



ChristophMayer MD



StefanieMeister MD



ArthurMelms MD



Imke MetzMD



OliverNeuhaus MD



SabineNiehaus MD



FlorencePache MD



MarcPawlitzki MD



HannahPellkofferMD








KevinRostasy MD



LiobaRuckriemMD



ChristophRuschil MD



MatthiasSchwab MD



MakbuleSenel MD



Jorn PeterSieb MD



ClaudiaSommer MD



AnnetteSpreer MD





































MartinStangel MD






HeikeStephanikMD



MurielStoppe MD



Marie SuszligeMD



BjornTackenbergMD









HayrettinTumani MD



AnnetteWalter MD






ClemensWarnke MD



Martin SWeber MD



RobertWeissert MD



Heinz WiendlMD



ChristianWilke MD






YavorYalachkovMD



Lena ZeltnerMD





Ulf ZiemannMD



Frauke ZippMD












































Reprints




















CohortMOGAD(n = 14)



Total(N = 57)


Infections



2 (14) 5 (14) 2 (29) 9 (16)



(Pyelo)nephritis 1 () 1 (3) 0 (0) 2 (4)


Tumor n () 0 (0) 1a (3) 0 (0) 1a (2)


Neutropenia n () 2 (14) 8 (22) 0 (0) 10 (17)































Appendix 1 Authors


MariusRingelsteinMD



IlyaAyzenbergMD



GeroLindenblattMD



KatinkaFischerMSc



AnnaGahlen MD



GiovanniNovi MD






SvenSchipplingMD



PaulusRommerMD



BarbaraKornek MD



TobiasZrzavy MD



DamienBiotti MD



JonathanCiron MD



BertrandAudoin MD





AchimBertheleMD



KatrinGiglhuberMD



HeleneZephir MD


TaniaKumpfelMD



RobertBerger MD



JoachimRother MD









DanielWhittamMD



Anu JacobMD



MarkusKraemerMD



AntoineGueguenMD



RomainDeschampsMD



AntoniosBayas MD



Martin WHummertMD






CorinnaTrebst MD



AxelHaarmannMD



Sven JariusMD



BrigitteWildemannMD



MatthiasGrothe MD



NadjaSiebert MD



KlemensRuprechtMD



FriedemannPaul MD



NicolasCollonguesMD



RomainMarignierMD



MichaelLevy MDPhD



MichaelKarenfortMD



MichaelDeppe PhD



PhilippAlbrechtMD



KerstinHellwig MD







KlemensAngstwurmMD



SusannaAsseyer MD






Felix BischofMD



StefanBittner MD



TobiasBottcher MD



MathiasButtmannMD



AnkelienDuchow



BarbaraEttrich MD



Jurgen FaissMD



BenediktFrank MD



Continued






Sven GMeuth



Ingo KleiterMD



OrhanAktas MD






Achim GassMD



ChristianGeis MD



KerstinGuthke MD



BernhardHemmer MD



FrankHoffmannMD



OlafHoffmannMD






JuttaJunghans MD



MatthiasKaste MD



BarbaraKaulen MD



Peter KernMD



PawelKermer MD






Luisa KlotzMD



WolfgangKohler MD



MelanieKorsen MD



MarkusKowarik MD



MarkusKrumbholzMD



Stefan LangelMD



MartinLiebetrauMD



Ralf LinkerMD



De-HyungLee MD





Felix LuessiMD



MartinMarziniakMD



ChristophMayer MD



StefanieMeister MD



ArthurMelms MD



Imke MetzMD



OliverNeuhaus MD



SabineNiehaus MD



FlorencePache MD



MarcPawlitzki MD



HannahPellkofferMD








KevinRostasy MD



LiobaRuckriemMD



ChristophRuschil MD



MatthiasSchwab MD



MakbuleSenel MD



Jorn PeterSieb MD



ClaudiaSommer MD



AnnetteSpreer MD





































MartinStangel MD






HeikeStephanikMD



MurielStoppe MD



Marie SuszligeMD



BjornTackenbergMD









HayrettinTumani MD



AnnetteWalter MD






ClemensWarnke MD



Martin SWeber MD



RobertWeissert MD



Heinz WiendlMD



ChristianWilke MD






YavorYalachkovMD



Lena ZeltnerMD





Ulf ZiemannMD



Frauke ZippMD












































Reprints

























Appendix 1 Authors


MariusRingelsteinMD



IlyaAyzenbergMD



GeroLindenblattMD



KatinkaFischerMSc



AnnaGahlen MD



GiovanniNovi MD






SvenSchipplingMD



PaulusRommerMD



BarbaraKornek MD



TobiasZrzavy MD



DamienBiotti MD



JonathanCiron MD



BertrandAudoin MD





AchimBertheleMD



KatrinGiglhuberMD



HeleneZephir MD


TaniaKumpfelMD



RobertBerger MD



JoachimRother MD









DanielWhittamMD



Anu JacobMD



MarkusKraemerMD



AntoineGueguenMD



RomainDeschampsMD



AntoniosBayas MD



Martin WHummertMD






CorinnaTrebst MD



AxelHaarmannMD



Sven JariusMD



BrigitteWildemannMD



MatthiasGrothe MD



NadjaSiebert MD



KlemensRuprechtMD



FriedemannPaul MD



NicolasCollonguesMD



RomainMarignierMD



MichaelLevy MDPhD



MichaelKarenfortMD



MichaelDeppe PhD



PhilippAlbrechtMD



KerstinHellwig MD







KlemensAngstwurmMD



SusannaAsseyer MD






Felix BischofMD



StefanBittner MD



TobiasBottcher MD



MathiasButtmannMD



AnkelienDuchow



BarbaraEttrich MD



Jurgen FaissMD



BenediktFrank MD



Continued






Sven GMeuth



Ingo KleiterMD



OrhanAktas MD






Achim GassMD



ChristianGeis MD



KerstinGuthke MD



BernhardHemmer MD



FrankHoffmannMD



OlafHoffmannMD






JuttaJunghans MD



MatthiasKaste MD



BarbaraKaulen MD



Peter KernMD



PawelKermer MD






Luisa KlotzMD



WolfgangKohler MD



MelanieKorsen MD



MarkusKowarik MD



MarkusKrumbholzMD



Stefan LangelMD



MartinLiebetrauMD



Ralf LinkerMD



De-HyungLee MD





Felix LuessiMD



MartinMarziniakMD



ChristophMayer MD



StefanieMeister MD



ArthurMelms MD



Imke MetzMD



OliverNeuhaus MD



SabineNiehaus MD



FlorencePache MD



MarcPawlitzki MD



HannahPellkofferMD








KevinRostasy MD



LiobaRuckriemMD



ChristophRuschil MD



MatthiasSchwab MD



MakbuleSenel MD



Jorn PeterSieb MD



ClaudiaSommer MD



AnnetteSpreer MD





































MartinStangel MD






HeikeStephanikMD



MurielStoppe MD



Marie SuszligeMD



BjornTackenbergMD









HayrettinTumani MD



AnnetteWalter MD






ClemensWarnke MD



Martin SWeber MD



RobertWeissert MD



Heinz WiendlMD



ChristianWilke MD






YavorYalachkovMD



Lena ZeltnerMD





Ulf ZiemannMD



Frauke ZippMD












































Reprints






CorinnaTrebst MD



AxelHaarmannMD



Sven JariusMD



BrigitteWildemannMD



MatthiasGrothe MD



NadjaSiebert MD



KlemensRuprechtMD



FriedemannPaul MD



NicolasCollonguesMD



RomainMarignierMD



MichaelLevy MDPhD



MichaelKarenfortMD



MichaelDeppe PhD



PhilippAlbrechtMD



KerstinHellwig MD







KlemensAngstwurmMD



SusannaAsseyer MD






Felix BischofMD



StefanBittner MD



TobiasBottcher MD



MathiasButtmannMD



AnkelienDuchow



BarbaraEttrich MD



Jurgen FaissMD



BenediktFrank MD



Continued






Sven GMeuth



Ingo KleiterMD



OrhanAktas MD






Achim GassMD



ChristianGeis MD



KerstinGuthke MD



BernhardHemmer MD



FrankHoffmannMD



OlafHoffmannMD






JuttaJunghans MD



MatthiasKaste MD



BarbaraKaulen MD



Peter KernMD



PawelKermer MD






Luisa KlotzMD



WolfgangKohler MD



MelanieKorsen MD



MarkusKowarik MD



MarkusKrumbholzMD



Stefan LangelMD



MartinLiebetrauMD



Ralf LinkerMD



De-HyungLee MD





Felix LuessiMD



MartinMarziniakMD



ChristophMayer MD



StefanieMeister MD



ArthurMelms MD



Imke MetzMD



OliverNeuhaus MD



SabineNiehaus MD



FlorencePache MD



MarcPawlitzki MD



HannahPellkofferMD








KevinRostasy MD



LiobaRuckriemMD



ChristophRuschil MD



MatthiasSchwab MD



MakbuleSenel MD



Jorn PeterSieb MD



ClaudiaSommer MD



AnnetteSpreer MD





































MartinStangel MD






HeikeStephanikMD



MurielStoppe MD



Marie SuszligeMD



BjornTackenbergMD









HayrettinTumani MD



AnnetteWalter MD






ClemensWarnke MD



Martin SWeber MD



RobertWeissert MD



Heinz WiendlMD



ChristianWilke MD






YavorYalachkovMD



Lena ZeltnerMD





Ulf ZiemannMD



Frauke ZippMD












































Reprints






Achim GassMD



ChristianGeis MD



KerstinGuthke MD



BernhardHemmer MD



FrankHoffmannMD



OlafHoffmannMD






JuttaJunghans MD



MatthiasKaste MD



BarbaraKaulen MD



Peter KernMD



PawelKermer MD






Luisa KlotzMD



WolfgangKohler MD



MelanieKorsen MD



MarkusKowarik MD



MarkusKrumbholzMD



Stefan LangelMD



MartinLiebetrauMD



Ralf LinkerMD



De-HyungLee MD





Felix LuessiMD



MartinMarziniakMD



ChristophMayer MD



StefanieMeister MD



ArthurMelms MD



Imke MetzMD



OliverNeuhaus MD



SabineNiehaus MD



FlorencePache MD



MarcPawlitzki MD



HannahPellkofferMD








KevinRostasy MD



LiobaRuckriemMD



ChristophRuschil MD



MatthiasSchwab MD



MakbuleSenel MD



Jorn PeterSieb MD



ClaudiaSommer MD



AnnetteSpreer MD





































MartinStangel MD






HeikeStephanikMD



MurielStoppe MD



Marie SuszligeMD



BjornTackenbergMD









HayrettinTumani MD



AnnetteWalter MD






ClemensWarnke MD



Martin SWeber MD



RobertWeissert MD



Heinz WiendlMD



ChristianWilke MD






YavorYalachkovMD



Lena ZeltnerMD





Ulf ZiemannMD



Frauke ZippMD












































Reprints





































MartinStangel MD






HeikeStephanikMD



MurielStoppe MD



Marie SuszligeMD



BjornTackenbergMD









HayrettinTumani MD



AnnetteWalter MD






ClemensWarnke MD



Martin SWeber MD



RobertWeissert MD



Heinz WiendlMD



ChristianWilke MD






YavorYalachkovMD



Lena ZeltnerMD





Ulf ZiemannMD



Frauke ZippMD












































Reprints












































Reprints




interleukin-6 receptor blockade in treatment-refractory

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