VIEWS amp REVIEWS OPEN ACCESS

Interleukin-6 in neuromyelitis optica spectrumdisorder pathophysiologyKazuo Fujihara MD Jeffrey L Bennett MD PhD Jerome de Seze MD PhD Masayuki Haramura PhD

Ingo Kleiter MD Brian G Weinshenker MD Delene Kang Tabasum Mughal PhD and

Takashi Yamamura MD PhD

Neurol Neuroimmunol Neuroinflamm 20207e841 doi101212NXI0000000000000841

Correspondence

Dr Fujihara

fujikazumedtohokuacjp

AbstractNeuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder that prefer-entially affects the spinal cord and optic nerve Most patients with NMOSD experience severerelapses that lead to permanent neurologic disability therefore limiting frequency and severity ofthese attacks is the primary goal of disease management Currently patients are treated withimmunosuppressants Interleukin-6 (IL-6) is a pleiotropic cytokine that is significantly elevated inthe serum and the CSF of patients with NMOSD IL-6 may have multiple roles in NMOSDpathophysiology by promoting plasmablast survival stimulating the production of antibodiesagainst aquaporin-4 disrupting blood-brain barrier integrity and functionality and enhancingproinflammatory T-lymphocyte differentiation and activation Case series have shown decreasedrelapse rates following IL-6 receptor (IL-6R) blockade in patients with NMOSD and 2 recentphase 3 randomized controlled trials confirmed that IL-6R inhibition reduces the risk of relapsesin NMOSD As such inhibition of IL-6 activity represents a promising emerging therapy for themanagement of NMOSD manifestations In this review we summarize the role of IL-6 in thecontext of NMOSD

From the Department of Multiple Sclerosis Therapeutics (KF) Fukushima Medical University School of Medicine and Multiple Sclerosis and Neuromyelitis Optica Center SouthernTOHOKU Research Institute for Neuroscience Koriyama Japan Departments of Neurology and Ophthalmology (JLB) Programs in Neuroscience and Immunology School ofMedicine University of Colorado Aurora Department of Neurology (JS) Hopital de Hautepierre Strasbourg Cedex France Chugai Pharmaceutical Co (MH) Ltd Tokyo JapanDepartment of Neurology (IK) St Josef Hospital Ruhr University BochumMarianne-Strauszlig-Klinik (IK) Behandlungszentrum Kempfenhausen fur Multiple Sklerose Kranke gGmbHBerg Germany Department of Neurology (BGW) Mayo Clinic Rochester MN ApotheCom (DK TM) London UK and Department of Immunology (TY) National Institute ofNeuroscience National Center of Neurology and Psychiatry Tokyo Japan

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

The Article Processing Charge was funded by Chugai Pharmaceutical

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 2020 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 1

Interleukin-6 (IL-6) is a soluble pleiotropic cytokine thatplays a key part in many biologic processes1 It is a primaryregulator of acute and chronic inflammation and hemato-poiesis contributing to the onset and maintenance of variousautoimmune and inflammatory disorders1

Neuromyelitis optica spectrum disorder (NMOSD) is anuncommon often debilitating inflammatory condition of theCNS2 Neuromyelitis optica (NMO) was previously consid-ered a rare severe variant of multiple sclerosis (MS) howeverit is now recognized as a distinct autoimmune disorder2 AnInternational Panel for NMO Diagnosis codified clinical ra-diologic and laboratory features collectively distinguishingNMOSD from MS and other CNS inflammatory disorders2

Left untreated patients with NMOSD experience new attacksor relapses often leading to permanent disability3

The pathophysiologic processes and inflammatory cascade inNMOSD are complex and not fully understood Circulatingimmunoglobulin G (IgG) 1 antibodies targeting the astrocytewater channel aquaporin-4 (AQP4) have been found almostexclusively in patients with NMOSD3 AQP4-IgG binding toastrocytic AQP4 leads to classical complement cascade acti-vation and granulocyte and lymphocyte infiltration thatcombine to damage neural tissues45

IL-6 may drive disease activity in NMOSD by promotingplasmablast survival stimulating AQP4-IgG secretion re-ducing blood-brain barrier (BBB) integrity and functionalityand enhancing proinflammatory T-lymphocyte differentia-tion and activation (figure A) CSF and serum IL-6 levels aresignificantly elevated in patients with NMOSD and IL-6 in-hibition has been shown to improve disease control (table 1)Therefore the IL-6 receptor (IL-6R) represents a promisingtherapeutic target for NMOSD relapse prevention This re-view summarizes the role of IL-6 in NMOSD

Interleukin-6Biological activitiesIL-6 is produced by diverse cell types such as T cells B cellsmonocytes fibroblasts keratinocytes endothelial cells and

mesangial cells6 IL-6 is involved inmany physiologic processesincluding inflammation antigen-specific immune responseshost defense mechanisms hematopoiesis and production ofacute phase proteins6 Outside the immune system IL-6 canpromote angiogenesis osteoclast differentiation and kerati-nocyte and mesangial cell proliferation7 Within the immunesystem IL-6 plays a key part in the adaptive immune responseby stimulating antibody production and effector T-cell de-velopment7 Furthermore IL-6 has an important role in regu-lating the balance between proinflammatory T helper (Th) 17cells and regulatory T cells (Treg)7

IL-6 binds to the IL-6 receptor (IL-6R) which is expressed asmembrane-bound (mIL-6R) and soluble (sIL-6R) forms8 ThesIL-6R binds to IL-6with a similar affinity as themIL-6R and bothreceptors interact with glycoprotein 130 (gp130 also known as IL-6R subunit β) to initiate cellular signaling through the Src ho-mology region 2-containing protein tyrosine phosphatase-2mitogen-activated protein kinase and Janus kinasesignal trans-ducer and activator of transcription 3 protein pathways (figureB)8

Importantly cells that do not express IL-6R and are therefore notresponsive to IL-6 can be stimulated by the complex of sIL-6RndashIL-6 (IL-6 trans-signaling) IL-6 trans-signaling can be selectivelyblocked by the soluble form of gp130 (sgp130Fc)mdashwhich isdimerized by a human immunoglobulin IgG1-Fcmdashwithout af-fecting IL-6 signaling via the membrane-bound IL-6R8

Pathogenic roleDysregulation of IL-6 expression or signaling contributes to thepathogenesis of various human diseases and is linked to in-flammatory andor lymphoproliferative disorders such as rheu-matoid arthritis Castleman disease multiple myeloma giant cellarteritis and systemic lupus erythematosus (SLE)8 The path-ways driving IL-6 secretion fromCNS-resident cells are complexNeurons astrocytes microglia and endothelial cells produce IL-6following injury and CSF IL-6 levels are elevated in multipleneuroinflammatory diseases9

Dysregulation of IL-6 signaling may aggravate the inflammatoryresponse in some CNS diseases however intrathecal IL-6 pro-ductionmay have variable effects Because the IL-6R is expressedon both oligodendrocyte progenitor cells andmicroglia CNS IL-6 signaling may have both direct and indirect effects on

GlossaryADEM = acute disseminated encephalomyelitis AQP4 = aquaporin-4 ARR = annualized relapse rate BBB = blood-brainbarrier CD59 = complement regulatory protein CDC = complement-dependent cytotoxicity CDCC = complement-dependent cellular cytotoxicity EDSS = Expanded Disability Status Scale GFAP = glial fibrillary acidic protein GRP78 = 78-kDa glucose-regulated protein HR = hazard ratio ICAM-1 = intracellular adhesion molecule 1 IgG = immunoglobulin GIL-6 = interleukin-6 IL-6R = interleukin-6 receptor IPND = International Panel for NMO Diagnosis LETM = longitudinalextensive transverse myelitis MAC = membrane attack complex mIL-6R = membrane-bound IL-6R MOG = myelinoligodendrocyte glycoproteinMS = multiple sclerosisNF-κB = nuclear factor kappa-light-chain-enhancer of activated B cellsNMO = neuromyelitis optica NMOSD = neuromyelitis optica spectrum disorder ON = optic neuritis SE = standard errorSEM = standard error of the mean sgp130 = soluble glycoprotein 130 sIL-6R = soluble IL-6R SLE = systemic lupuserythematosus TGF-β1 = transforming growth factor beta 1 Th = T helper cell Treg = regulatory T cell

2 Neurology Neuroimmunology amp Neuroinflammation | Volume 7 Number 5 | September 2020 NeurologyorgNN

microglial andmacroglial survival In rat cerebral ischemic injuryit was shown that IL-6 modulates a decrease in neuronal andBBB integrity in the CNS10 In addition intrathecal IL-6 pro-duction during CNS inflammation has been demonstrated toaffect BBB permeability11 How these roles interact to promoteCNS injury in autoimmune disease requires further research

Neuromyelitis opticaspectrum disorderOverviewNMOSD is a rare debilitating autoimmune conditionof the CNS characterized by inflammatory lesions

predominantly in the spinal cord and optic nerves4 Pa-tients with NMOSD may present with a variety of symp-toms but most commonly with optic neuritis and myelitisOptic neuritis or the inflammation of the contiguous opticchiasm causes acute visual impairment and eye pain My-elitis causes varying degrees of motor paralysis sensoryloss pain or bladder and bowel dysfunction associated withMRI evidence of longitudinal extensive transverse myelitis(LETM) lesions NMOSD may also lead to intractablehiccups nausea or vomiting due to area postrema lesioninflammation brainstem dysfunction or encephalopa-thy12 Most patients with NMOSD experience a more se-vere disease course than do patients with MS due to

Figure Potential roles of IL-6 signaling and inhibition in NMOSD pathophysiology and treatment

(A)Potential roles for IL-6 signaling inNMOSDpathophysiology IL-6 inducesdifferentiationof inflammatoryTh17cells fromnaiveTcellswhich in turnprovidesupport toAQP4-dependentactivatedBcells IL-6alsopromotesdifferentiationofBcells intoplasmablasts inducingproductionofpathogenicAQP4-IgGTheseeventsare followedby increased BBB permeability to antibodies and proinflammatory cell infiltration into the CNS leading to binding of AQP4-IgG to AQP4 channels on the astrocytes Inresponse to stimulation by proinflammatory cytokines astrocytes produce IL-6 which promotes demyelination and contributes to oligodendrocyte and axon damage(B) Schematic of IL-6 signaling with potential modes of therapeutic inhibition IL-6 can bind either to the membrane-bound (classic signaling) or soluble form (trans-signaling) of the IL-6R α receptor IL-6 trans-signaling allows for the activation of cells that do not express the IL-6R α receptor Classic signaling may be blocked byantibodiesagainst IL-6and IL-6RTrans-signalingmaybeblockedbyantibodiesagainst IL-6Ror thesoluble formofglycoprotein130 (sgp130) IL-6signaling ismediatedatthe plasmamembrane through the homodimerization of gp130 which activates the intracellular JAK-STAT and SHP2-MAPK signaling pathways AQP4 = aquaporin-4AQP4-IgG = aquaporin-4 immunoglobulin G BBB = blood-brain barrier CDC = complement-dependent cytotoxicity CDCC = complement-dependent cellular cyto-toxicity D1-D3 = subdomain of IL-6Rα IL-1β = interleukin-1β IL-6 = interleukin-6 JAKSTAT = Janus kinasesignal transducers and activators of transcription MAC =membrane attack complex mAbs = monoclonal antibodies MAPK = mitogen-activated protein kinase NMOSD = neuromyelitis optica spectrum disorder sgp130 =soluble glycoprotein 130 SHP2MAPK = Src homology region 2 domain-containing phosphatase-2mitogen-activated protein kinase STAT3 = signal transducers andactivators of transcription 3 Th = T helper cell TNF-α = tumor necrosis factor α Treg = regulatory T cell

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frequent and severe relapses that lead to early and in-cremental disability A benign disease course of NMOSD israre13 Limiting frequency and severity of relapses repre-sents a primary goal in NMOSD management14

If patients are not treated 49 and 70 of patients relapsewithin 1 and 2 years respectively15 The mean annualizedrelapse rate (ARR) in patient cohorts ranges from 082 to134 with a median time to first relapse of 14 months15

The mortality rate without treatment ranges from 9 to

32 depending on age relapse rate and recovery fromattacks16

In 2004 the identification of AQP4-IgG greatly facili-tated differentiation of NMO from MS17 and in 2006AQP4-IgG serology was incorporated into the revisedNMO diagnostic criteria18 An international expert panelin 2015 proposed a unifying term for the disease asNMOSD with further stratification by AQP4-IgG sero-logic status2

Table 1 Clinical case reports on IL-6R blockade in the treatment of patients with NMOSDa

Case No Age (y)sex DD (y)ARR (IL-6 block)beforeduring Other effects of antindashIL-6 AEs associated with antindashIL-6

154 31F 121 1605 No new or active SL (47 months) Transient diarrhea deep venousthrombosis

254 18F 88 2103 No new or active SL (33 months) R-UTI during self-catheterization

354 30F 55 250 No new or active SL (41 months) None

454 37F 28 1806 No new or active SL (34 months) Headache fatigue

554 22F 89 120 No new or SL (28 months) None

654 24F 24 070 No new but still active SL (14 months) Transient mild fatigue

754 24F 09 5508 No new or active SL (12 months) Mild post-infusion nausea transientgastritis R-UTI

854 49F 05 624 No new or active SL (3 months) R-UTI

955 32F 88 13b0 EDSS score 90 to 25 AntindashAQP4-Abtiter dropped from 1800 to 120

None

1056 37F 14 315b Oral PSL and AZA were tapered URIs AEC acute pyelonephritis LKPandor LPP

1156 38F 11 20 NA NA

1256 26F 5 20 Oral PSL was tapered Anemia

1356 31M 19 20 Oral PSL and AZA were tapered AEC LKP andor LPP

1456 55F 17 3077b NA NA

1556 62F 2 30 NA NA

1656 23F 2 50 Oral PSL was tapered URIs LKP andor LPP anemia

1757 36F 17 43b0 EDSS score 80 to 25 MRI hasremained free of Gd activity

No safety signals have occurred

18cd58 40F 94 2606 EDSS score 65 to 65 No newlesions no contrast enhancement

No serious AEs were observed

19cd58 26F 82 270 EDSS score 50 to 40 No newlesions no contrast enhancement

No serious AEs were observed

20cd58 39F 25 1713 No new lesions no contrastenhancement

UTI Mild oral mucosis Noserious AEs

21c59 36F 14 53b2b EDSS score improved from 35 to 20No significant changes of lesions on MRI

Decline in systolic blood pressure LPPEnteritis caused by a norovirus A URI

Abbreviations AE = adverse event AEC = acute enterocolitis AZA = azathioprine CS = corticosteroids DD = disease duration Gd = gadolinium LKP =leukocytopenia LPP = lymphocytopenia NA = not applicable PSL = prednisolone RTX = rituximab R-UTI = recurrent urinary tract infectionSL = spinal lesions URI = upper respiratory infectionAll patients are serum AQP4-IgG positivea Please see the supplemental table (linkslwwcomNXIA288) for full version of the tableb Calculated from the number of relapses please see the supplemental tablec No oligoclonal IgG bands foundd No concomitant autoimmune diseases

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PathophysiologyNMOSD is recognized as a humoral immune disease driven inmost patients by the presence of AQP4-IgG19 As a resultinitial attention has focused on B-cell autoimmunity inNMOSD However polymorphonuclear infiltration into theCNS is a prominent feature of active disease and is charac-teristic of Th17-mediated pathology20 Furthermore clinicalworsening in response to interferon-β therapy in patients withNMOSD is also characteristic of Th17-mediated in-flammatory processes Thus T-cell autoimmunity may alsoplay a part in disease pathogenesis20

Role of AQP4AQP4 is the most abundant water channel in the CNS and hasa key role in transcellular water transport21 AQP4 functionmay also affect neuroinflammation astrocyte migration andneuroexcitation Within the CNS AQP4 is expressed in theendfeet of astrocytes that surround the blood vessels andsubarachnoid space and in retinal Mueller cells It is particu-larly enriched in brain parenchyma interfacing with the CSF21

AQP4-IgG has a critical role in mediating CNS injury inNMOSD AQP4-IgG is detected in 70 of patients withNMOSD but not in patients with MS or other neurologicdiseases22 In AQP4-IgGndashseropositive patients with NMOSDCNS injury initiates with the binding of AQP4-IgG to AQP4 onperivascular astrocyte endfeet4 Autoantibody binding results inactivation of the classical complement cascade granulocyte andmacrophage infiltration secondary oligodendrocyte damageand neuronal death4 CSF analysis of patients with NMOSDsuggests that the majority of AQP4-IgG may transit passively tothe CNS through an open BBB22 However molecular tech-niques show that AQP4-IgG is also produced intrathecallyduring acute NMOSD exacerbations23

Whether AQP4-IgGndashseronegative patients with NMOSD havethe same disease as AQP4-IgGndashseropositive patients remainscontroversial The demographics clinical presentation andprognosis differ between AQP4-IgGndashseropositive and AQP4-IgGndashseronegative patients24 Some AQP4-IgGndashseronegativepatients are seropositive for myelin oligodendrocyte glyco-protein (MOG)ndashIgG however MOG-IgGndashseropositive pa-tients show differences in natural history neuroimagingand lesion histopathology from AQP4-IgGndashseropositive pa-tients supporting a distinct pathophysiology between thesedisorders25

Role of the BBBDisruption of the BBB is important in the pathophysiology ofNMOSD and correlates modestly with disease activity In-trathecal production of AQP4-IgG23 may initiate disease ac-tivity by causing focal BBB breakdown and precipitating alarge influx of serum AQP4-IgG and serum complement intothe CNS compartment Alternatively systemic inflammationmay disrupt the BBB allowing entry of serum AQP4-IgG andautoreactive B cells into the CNS and subsequent lesionformation19

A recent study demonstrated that some serum samples takenfrom patients with NMOSD and SLE harbor autoantibodiesagainst the 78-kDa glucose-regulated protein (GRP78-IgG)These autoantibodies bind to brain microvascular endothelialcells resulting in nuclear factor kappa-light-chain-enhancer ofactivated B-cell nuclear translocation intercellular adhesionmolecule 1 induction reduced tight junction expression andbarrier permeability26 Peripheral administration of recombi-nant GRP78-IgG to mice resulted in increased BBB perme-ability suggesting that GRP78 autoantibodies may induceBBB permeability and may contribute to disease activity insome patients26 Further research is needed to confirmwhether GRP78-IgG has a role in NMOSD pathogenesis

Role of complementComplement activation plays an essential part in NMOSDlesion formation4 Activation of the classical complementcascade is thought to result from engagement of complementcomponent C1q with AQP4-IgG bound to perivascular as-trocyte endfeet4 This leads to classical complement cascadeactivation and membrane attack complex formation4

Nytrova et al showed that levels of the complement com-ponent C3a were higher in patients with NMO than inhealthy control subjects and that C3a levels in these patientsalso correlated with disease activity neurologic disability andAQP4-IgG27

Recent in vitro studies have identified alternative complementpathways such as the bystander mechanism where followingAQP4-IgG binding to astrocyte AQP4 activated solublecomplement proteins were implicated in early oligodendrocyteinjury in NMOSD28 In addition complement regulatoryprotein (CD59) may confer a protective role in AQP4-IgGndashseropositiveNMOSD tissues outside of the CNS and thusexplain why peripheral AQP4-expressing cells in NMOSD re-main mostly unaffected29

Relationship between gut microbiota andhumoral and cellular immunityThe AQP4 epitope p63-76 displays sequence homology withp204-217 of Clostridium perfringens a ubiquitous Gram-positive bacterium found in the human gut30 This observa-tion provided new perspectives for investigating NMOSDpathogenesis Gut microbiome analysis of patients with NMOidentified an overabundance of C perfringens30 Because spe-cific gut clostridia can regulate Treg and Th17 cell balance31

an excess of C perfringens could theoretically evoke proin-flammatory AQP4-specific T- and B-cell responses drivingNMOSD development C perfringensmay also enhance Th17differentiation by promoting the secretion of IL-6 by antigen-presenting cells in the gut30

Pathophysiologic role of IL-6IL-6 levels are associated with key NMOSD diseasemarkers3233 Studies have shown that CSF and serum levels ofIL-6 correlatewithCSF cell counts and the ExpandedDisability

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Table 2 Spearman rank correlation coefficient (ρ) of the association among IL-6 levels CSF cell count and disability

Reference N Female nCSF cell countcellsmm3

Mean (SD) CSF IL-6levels pgmL

ρ (p value) betweenIL-6 levels and CSF cell count

Mean (SD) serumIL-6 levels pgmL

Baseline EDSSscore mean (SD)

ρ (p value) correlation betweenIL-6 levels and EDSS score

Wang et al33 22 16 NR 2495 (2557) NR NR 35 (10ndash85)a 0372 (0088)b

Uzawa et al34 31 31 268 7573 (11796) 0638 (lt0001) NR 75 (20ndash90)a 0258 (0161)b

Uchida et al35 29 27 8 (120)ac 893 (7377)a 04497 (0021) 232 (000)d 60 (3)a NR

Matsushita et al36 20 17 115 (153)e NR 075 (0012) NR 56 (25) 072 (0012)b

Icoz et al37 23 17

AQP4ndashIgG+ 12 10 12f (363)g 781f (20798)g NR 48f (944)g 6f (073)g NR

AQP4ndashIgGndash 11 7 18f (341)g 39f (1564)g NR 11f (411)g 4f (059)g NR

Barros et al38 20 16 NR NR NR 5141 (2131)h

8984 (411)k493 (191)i 05880 (00064)j

Uzawa et al39 17 17 95 2810 (2124)g 05 (0002) NR NR NR

Abbreviations AQP4-IgG = aquaporin-4-immunoglobulin G EDSS = Expanded Disability Status Scale IL-6 = interleukin-6 NMOSD = neuromyelitis optica spectrum disorder NR = not reporteda Median (interquartile range)b In CSFc μLd n = 29e n = 19f Meanmedian not specifiedg Mean (standard error)h Patients who did not relapsei The EDSS score was determined either at the time the blood was analyzed or after 2 years of follow-upj In plasmak Patients who relapsed

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Status Scale (EDSS) score (table 2)33ndash39 CSF levels of IL-6 areshown to correlate with AQP4-IgG levels and glial fibrillaryacidic protein levels an indicator of astrocyte damage34 CSFand serum IL-6 concentrations are significantly elevated inpatients with NMOSD and are higher than in healthy indi-viduals and patients with MS or other noninflammatory neu-rologic disorders34ndash37 In 1 study an IL-6 CSF concentration of78 pgmL was proposed as an optimal cutoff value for di-agnosing NMOSD32 Furthermore CSF IL-6 levels are alsosignificantly elevated in the acute phase of NMOSD comparedwith MS myelitis ON and other inflammatory and non-inflammatory neurologic disorders40 IL-6 levels may be in-dicative of NMOSD relapse because IL-6 serum and CSFconcentrations in patients with NMOSD are significantlyhigher during relapse than in periods of remission3638

Barros et al also demonstrated a relationship between serumIL-6 levels with occurrence of clinical relapses in patients withNMO38 Furthermore during a 2-year disease follow-up inthese patients baseline IL-6 levels correlated with the risk ofclinical relapses and severity An 8-fold increase in relapse riskwas observed in patients with IL-6 serum concentrations abovethe baseline median value of 585 pgmL during remissions38

Higher IL-6 levels are also associated with greater disability inNMOSD following relapse One study evaluated recovery fromrelapse-related impairment in patients with NMOSD anddemonstrated that patients with NMOSD and higher CSF IL-6levels experienced more modest improvements than did pa-tients with lower IL-6 levels41 Furthermore elevated IL-6levels have been linked with short relapse-free durations inNMOSD after relapse Uzawa et al41 evaluated the relapse-freeduration after relapse in patients with NMOSD and found thatpatients with high CSF IL-6 levels tended to have shorterrelapse-free durations than did those with low IL-6 levels fol-lowing relapse (p = 0079)

Effect of IL-6 on B cellsB cells appear to have a central proinflammatory role inNMOSD immunopathology19 This is mediated throughseveral proposed mechanisms including production ofAQP4-IgG antigen presentation increased B-cell and plas-mablast activity and reduced regulatory function of B cells19

IL-6 was originally identified as B cell stimulatory factor-2 whichinduced activated B cells into antibody-producing cells7 Indeedcirculating short-lived CD19intCD27high CD38highCD180minus

plasmablasts may be increased in the peripheral blood of somepatients with NMOSD and are capable of producing AQP4-IgGwhen stimulated with IL-642However these activated antibody-secreting cells may not play a major part in the maintenance ofcirculating serum AQP4-IgG Detailed molecular studies havedemonstrated that AQP4-specific peripheral blood B cells in theCD27+ classical and CD27minus IgD memory compartments showthe closest lineal relationship to AQP4-IgGndashsecreting cells in theCSF43 In addition human cell culture experiments showed thatAQP4-IgGndashsecreting cells were readily generated from

pregerminal centerndashnaive and postgerminal center memoryB cells but not the circulating plasmablast compartment IL-6Rblockade may act indirectly to modulate AQP4-IgG productionand relapse risk through its effects on T-cell development44

Further immunologic studies of serum AQP4-IgG titers andcirculating B-cell profiles via T-cell development in patients withNMOSD receiving IL-6R inhibitors are needed

Effect of IL-6 on T cellsNaive T cells are differentiated into Th17 cells through thecombination of transforming growth factor beta 1 (TGF-β1)IL-6 and IL-2345 Th17 cells mediate disruption of the BBB andsubsequent CNS inflammation45 Levels of Th17-related cyto-kines IL-17 IL-21 and IL-23 are increased in NMOSD as is thelevel of IL-6 particularly in AQP4-IgGndashseropositive patientswith NMOSD46 AQP4-specific T cells in AQP4-IgGndashseropositive patients with NMO exhibit Th17 polariza-tion47 In addition levels of Th17-related cytokines including IL-6 are significantly elevated in the CSF and peripheral blood ofpatients with NMOSD during relapse34 The release of IL-6 andother Th17-related cytokines by activated T lymphocytes frompatients with NMOSD was also found to directly correlate withneurologic disability and risk of relapse3438

Effect of IL-6 in the BBBProinflammatory cytokines including IL-6 increase the per-meability of the BBB allowing antibodies and proin-flammatory cells to infiltrate the CNS leading to binding ofAQP4-IgG to AQP4 channels on the astrocytes In responseto stimulation by proinflammatory cytokines astrocytesproduce IL-6 which promotes demyelination and contributesto oligodendrocyte and axon damage (figure A) In vitro BBBmodels including cocultures of human brain microvascularendothelial cells and human astrocyte cell lines with orwithout AQP4 expression showed that AQP4-IgG inducedIL-6 production by AQP4-positive astrocytes and IL-6 sig-naling to endothelial cells impaired BBB function increasedproduction of other chemokines and enhanced flow-basedleukocyte transmigration48 These effects were reversed withan IL-6R-neutralizing antibody48

MOG-IgG-seropositive patients and IL-6MOG is a glycoprotein localized on the surface of the myelinsheath and represents a potential target for the treatment ofdemyelinating diseases Mice immunized with MOG peptidesmay develop experimental autoimmune encephalomyelitis withan NMO phenotype MOG-IgG is found in a subset of patientswith optic neuritis acute disseminated encephalomyelitismultiphasic disseminated encephalomyelitis myelitis AQP4-IgGndashseronegative NMOSD or encephalitis49 Although MOG-IgGndashseropositive and AQP4-IgGndashseropositive NMOSD share asimilar serum and CSF cytokine profile characterized by thecoordinated upregulation of multiple cytokines especially Th17-related these diseases have different pathologies50 AQP4-IgGndashseropositive NMOSD is primarily an astrocytopathic dis-ease whereas MOG-IgGndashseropositive NMOSD is a de-myelinating disease50

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 7 Number 5 | September 2020 7

Therapeutic approachesCurrent clinical practice involves treatment of exacerba-tions with high-dose corticosteroids apheresis therapiesand off-label use of immunotherapies for relapse pre-vention particularly with azathioprine methotrexateand prednisone (immunosuppressants) mycophenolatemofetil (inhibits lymphocyte proliferation) anti-CD20monoclonal antibody and antindashIL-6R monoclonal anti-body Until recently NMONMOSD treatment studieswere mostly retrospective

There is a need for alternative therapeutic options for pa-tients with NMOSDwho do not respond to first-line therapyand for treatments that manage other manifestations of thedisease including pain and fatigue Different therapeutictargets have been investigated in international randomizedcontrolled trials These include monoclonal antibodies tar-geting the B-cell antigen CD19 (inebilizumab)51 CD20(rituximab) the complement component 5 (eculizumab)52

and IL-6R (satralizumab)53

IL-6 blockade in the treatment of NMOSDTargeting the IL-6 signaling pathway inhibits both the hu-moral immune response as well as T-cell pathway and dys-function of the BBB providing a comprehensive treatment forthe different NMOSD manifestations Several case reportsshowed decreased relapse rate and reduced neurologic dis-ability following off-label treatment with an anti-IL-6R anti-body in patients with NMOSD (table 1)54ndash59

Araki et al56 reported that the mean (standard error of themean [SEM]) ARR decreased from 29 (11) to 04 (08p lt 0005) and mean EDSS scores (SEM range) from 51 (1730ndash65) to 41 (16 20ndash60) following 12-month treatmentwith an antindashIL-6R antibody as add-on therapy to eitherprednisolone or immunosuppressants in 7 patients withNMOSD In the same report mean (SEM) pain decreasedfrom 30 (15) at baseline to 09 (12) at 12 months and mean(SEM) general fatigue decreased from 61 (20) at baseline to30 (14) at 12 months respectively Adverse events in thisreport included upper respiratory infections (2 patients) acuteenterocolitis (2 patients) acute pyelonephritis (1 patient)leukocytopenia andor lymphocytopenia (3 patients) anemia(2 patients) and a slight decline in systolic blood pressure (1patient) However none of the events were severe

Ringelstein et al54 reported that patients with NMOSD whowere not responsive to rituximab and other immunosup-pressants experienced significant improvements in the me-dian ARR (from 40 at baseline to 04 at the end of the studyp = 0008) EDSS score (from 73 at baseline to 55 at the endof the study p = 003) and pain scores (from 65 at baselineto 25 at the end of the study p = 002) following treatmentwith an antindashIL-6R antibody No major adverse events orlaboratory abnormalities were reported except for elevationof cholesterol levels in 6 patients and neutropenia in1 patient54 Similarly Ayzenberg et al reported that 3

AQP4-positive female patients with NMO and a history oftreatment with rituximab and other immunosuppressive andimmunomodulating agents experienced a reduction in me-dian ARR (from 30 at baseline to 06 at the end of thestudy) but not in impairment scores after switching to anantindashIL-6R antibody58 There was no serious infectionmalignancy hypersensitivity reaction or elevation of trans-aminase levels One patient experienced urinary tract in-fection in the fourth month and mild oral mycosis in theseventh month of therapy58

Harmel et al60 reported favorable outcomes following treat-ment with an antindashIL-6R antibody after inadequate responseto interferon-β therapy in a patient misdiagnosed with MSUnder interferon-β treatment the patient showed persistingrelapse activity Treatment with rituximab was initiated butsevere LETM attacks occurred shortly after Following switchto an anti-IL-6R antibody the patient experienced no furtherrelapses for the following 12 months Other single patientreports included no adverse events during treatment

Satralizumab is a novel humanized IgG2 recycling mono-clonal antibody targeting the IL-6R It has been investigatedin 2 phase 3 studies for the treatment of NMOSD5361 Bothresults from the monotherapy trial (no other chronic base-line immunosuppression allowed) and data from the add-onto other immunosuppressive therapy trial were recentlypublished5361 Satralizumab as an add-on to baseline treat-ment significantly reduced the risk of protocol-defined re-lapse by 62 vs placebo hazard ratio (HR) 038 95 CI016ndash088 p = 002 Prespecified additional analyses showeda 79 relapse risk reduction with satralizumab vs placebo inAQP4-IgGndashseropositive patients (n = 55 HR 021 95 CI006ndash075) and 34 in AQP4-IgGndashseronegative patients(HR 066 95 CI 020ndash224) In the overall study pop-ulation the ARR was 011 (95 CI 005ndash021) when treatedwith satralizumab vs 032 (95 CI 019ndash051) with placeboThere were no deaths or anaphylactic reactions in eithergroup during the double-blind period The rate of seriousadverse events and infections did not differ between thesatralizumab and placebo groups (table 3)53 The results ofthe monotherapy trial were similar to the results of the add-on therapy trial (table 3)61 These results further support animportant role of IL-6 in NMOSD pathophysiology

Summary and future directionsNMOSD is recognized as a B- and T-cellndashmediated immunedisease IL-6 appears to have a key role in the immune re-sponse by stimulating antibody production in B cells and thedevelopment of effector T cells by disruption of BBBfunction and by regulating the balance between Th17 andTreg cells Inhibition of IL-6 activity was shown to be ef-fective in 2 phase 3 clinical trials particularly in AQP4-IgGndashseropositive individuals and represents a promisingemerging therapy for the management of NMOSD

8 Neurology Neuroimmunology amp Neuroinflammation | Volume 7 Number 5 | September 2020 NeurologyorgNN

Table 3 Summary of phase 3 add-on therapy and monotherapy clinical trial of satralizumab in NMOSD

Product name Satralizumab

Mode of action IL-6 inhibition (antindashIL-6 receptor monoclonal antibody)

Study name SAkuraSky (NCT02028884) SAkuraStar (NCT02073279)

Study design Add-on therapy to baselinetreatment azathioprinemycophenolate mofetilandor OCs compared with placebo

Monotherapy compared with placebo

Administration

Every 4 wk subcutaneously Every 4 wk subcutaneously

Satralizumab(n = 41)

Placebo(n = 42)

Satralizumab(n = 63)

Placebo(n = 32)

Characteristics of the patientat baseline

Mean age y (range) 408 plusmn 161 (13ndash73) 434 plusmn 120 (14ndash65) 453 plusmn 120 (21ndash70) 405 plusmn 105 (20ndash56)

Female sex n () 37 (90) 40 (95) 46 (73) 31 (97)

AQP4-IgGndashseropositivestatus n ()

27 (66) 28 (67) 41 (65) 23 (72)

Annualized relapse rate inprevious 2 y

15 plusmn 05 14 plusmn 05 14 plusmn 06 15 plusmn 07

Annualized relapse rateduring the double-blind period

011 (005ndash021) 032 (019ndash051) 017 (010ndash026) 041 (024ndash067)

Relapse prevention efficacy (vs placebo)

AQP4-IgG (+ and 2) HR = 038 (016ndash088) HR = 045 (023ndash089)

AQP4-IgG (+) HR = 021 (006ndash075) HR = 026 (011ndash063)

AQP4-IgG (2) HR = 066 (020ndash224) HR = 119 (030ndash478)

AEs in the double-blind period(safety population)

Patientsn ()

Events (95 CI)n100 pt-y

Patientsn ()

Events (95 CI)n100 pt-y

Patients n () Events (95 CI)n100 pt-y

Patients n () Events (95 CI)n100 pt-y

Infection 28 (68) 1325(1082ndash1605)

26 (62) 1496 (1201ndash1841) 34 (54) 998 (824ndash1198) 14 (44) 1626 (1258ndash2069)

Serious infection 2 (5) 26 (03ndash92) 3 (7) 50 (10ndash147) 6 (10) 52 (19ndash113) 3 (9) 99 (27ndash252)

Injection-related reaction 5 (12) 217 (126ndash347) 2 (5) 34 (04ndash121) 8 (13) 139 (79ndash226) 5 (16) 173 (69ndash355)

Anaphylactic reaction 0 0 0 0 0 0 (NEndash32) 0 0 (NEndash91)

Abbreviations AE = adverse event AQP4-IgG = aquaporin-4-immunoglobulin G HR = hazard ratio IgG = immunoglobulin G IL-6 = interleukin-6 NMOSD = neuromyelitis optica spectrum disorders OC = oral corticosteroidpt-y = patient-year

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Study fundingThis studywas funded byChugai Pharmaceutical Co LtdMedicaland medical writing support was provided by ApotheCom UKand was funded by Chugai Pharmaceutical Co Ltd

DisclosureK Fujihara has received grants from the Ministry of Edu-cation of Japan Ministry of Health Welfare and Labor ofJapan Alexion Pharmaceuticals Chemo-Sero-TherapeuticResearch Institute Teva Teijin and Genzyme Japan re-ceived grants and personal fees from Chugai PharmaceuticalCo Ltd Bayer Biogen Mitsubishi Tanabe Ono NihonPharmaceutical and Asahi Kasei and received personal feesfrom Novartis Merck Serono MedImmune Eisai AstellasTakeda Daiichi Sankyo and Cosmic Corporation JLBennett holds patents for compositions and methods for thetreatment of neuromyeltis optica and novel blockingmonoclonal therapy for neuromyelitis optica has consultedfor Frequency Therapeutics Roche Viela Bio AbbVieClene Nanomedicine Alexion Pharmaceuticals EMD-Serono Chugai Pharmaceutical Co Ltd Reistone andGenentech received research support from MallinckrodtPharmaceuticals NIH Novartis and Guthy-Jackson Foun-dation and receives license fee and royalty payments foraquaporumab J de Seze has received grants and personalfees from Roche received personal fees from Chugai Phar-maceutical Co Ltd and served on advisory boards and ex-pert committees for the clinical trial conducted by ChugaiPharmaceutical Co Ltd M Haramura is an employee ofChugai Pharmaceutical Co Ltd I Kleiter has receivedpersonal fees from Alexion Pharmaceuticals Bayer BiogenCelgene IQVIA Novartis Merck Mylan Roche SanofiGenzyme grants and personal fees from Chugai Pharma-ceutical Co Ltd and grants fromDiamed BGWeinshenkerholds a patent for and receives royalties from an NMO-IgGfor diagnosis of neuromyelitis optica from RSR Ltd OxfordUniversity Hospices Civil de Lyon and MVZ Labor PD DrVolkmann und Kollegen GbR is an adjudication committeemember of MedImmune Pharmaceuticals and AlexionPharmaceuticals consults for Chugai Pharmaceutical CoLtd and Mitsubishi Tanabe and served on the editorialboard of the Canadian Journal of Neurological Sciences andTurkish Journal of Neurology T Yamamura has served onscientific advisory boards for Biogen Takeda Ono Sumi-tomo Dainippon Novartis and Chugai Pharmaceutical CoLtd received research grants from Chugai PharmaceuticalCo Ltd Biogen Novartis Takeda Teva and Nihon Phar-maceutical and received speaker honoraria from ChugaiPharmaceutical Co Ltd Ono Takeda Biogen SumitomoDainippon Mitsubishi Tanabe Human MetabolomeTechnologies Bayer Japan Blood Products OrganizationOtsuka Kissei Novartis and Daiichi Sankyo Go to Neu-rologyorgNN for full disclosures

Publication historyReceived by Neurology Neuroimmunology amp NeuroinflammationApril 1 2020 Accepted in final form June 5 2020

References1 Tanaka T Narazaki M Kishimoto T IL-6 in inflammation immunity and disease

Cold Spring Harb Perspect Biol 20146a0162952 Wingerchuk DM Banwell B Bennett JL et al International consensus diagnostic

criteria for neuromyelitis optica spectrum disorders Neurology 201585177ndash1893 Zekeridou A Lennon VA Aquaporin-4 autoimmunity Neurol Neuroimmunol

Neuroinflamm 20152e110 doi 101212NXI00000000000001104 Papadopoulos MC Bennett JL Verkman AS Treatment of neuromyelitis optica

state-of-the-art and emerging therapies Nat Rev Neurol 201410493ndash5065 Duan T Smith AJ Verkman AS Complement-independent bystander injury in

AQP4-IgG seropositive neuromyelitis optica produced by antibody-dependent cel-lular cytotoxicity Acta Neuropathol Commun 20197112

6 Ataie-Kachoie P Pourgholami MH Morris DL Inhibition of the IL-6 signalingpathway a strategy to combat chronic inflammatory diseases and cancer CytokineGrowth Factor Rev 201324163ndash173

7 Tanaka T Kishimoto T Targeting interleukin-6 all the way to treat autoimmune andinflammatory diseases Int J Biol Sci 201281227ndash1236

Appendix Authors

Name Location Contribution

KazuoFujihara MD

Department of MultipleSclerosis TherapeuticsFukushima MedicalUniversity School ofMedicine and MultipleSclerosis andNeuromyelitis OpticaCenter SouthernTOHOKU ResearchInstitute forNeuroscience KoriyamaJapan

Design andconceptualization of thereview manuscriptdrafting and criticalrevision of themanuscriptfor important intellectualcontent

Jeffrey LBennett MDPhD

Departments ofNeurology andOphthalmologyPrograms inNeuroscience andImmunology School ofMedicine University ofColorado Aurora

Design of the review andcritical revision of themanuscript for importantintellectual content

Jerome deSeze MD PhD

Department ofNeurology Hopital deHautepierre StrasbourgCedex France

Design of the review andcritical revision of themanuscript for importantintellectual content

MasayukiHaramuraPhD

Chugai PharmaceuticalCo Ltd Tokyo Japan

Design of the review andcritical revision of themanuscript for importantintellectual content

Ingo KleiterMD

Department ofNeurology St JosefHospital Ruhr-UniversityBochum Germany

Design of the review andcritical revision of themanuscript for importantintellectual content

Brian GWeinshenkerMD

Department ofNeurology Mayo ClinicRochester MN

Design of the review andcritical revision of themanuscript for importantintellectual content

Delene Kang ApotheCom London UK Critical revision of themanuscript for importantintellectual content

TabasumMughal PhD

ApotheCom London UK Critical revision of themanuscript for importantintellectual content

TakashiYamamuraMD PhD

Department ofImmunology NationalInstitute of NeuroscienceNational Center ofNeurology and PsychiatryTokyo Japan

Design of the review andcritical revision of themanuscript for importantintellectual content

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 7 Number 5 | September 2020 NeurologyorgNN

8 Garbers C Heink S Korn T Rose-John S Interleukin-6 designing specific thera-peutics for a complex cytokine Nat Rev Drug Discov 201817395ndash412

9 Erta M Quintana A Hidalgo J Interleukin-6 a major cytokine in the central nervoussystem Int J Biol Sci 201281254ndash1266

10 Feng Q Wang YI Yang Y Neuroprotective effect of interleukin-6 in a rat model ofcerebral ischemia Exp Ther Med 201591695ndash1701

11 Zhang J Sadowska GB Chen X et al Anti-IL-6 neutralizing antibody modulatesblood-brain barrier function in the ovine fetus FASEB J 2015291739ndash1753

12 Weinshenker BG Wingerchuk DM Neuromyelitis spectrum disorders Mayo ClinProc 201792663ndash679

13 Uzawa A Mori M Muto M et al Benign neuromyelitis optica is rare in Japanesepatients Mult Scler 2015211204ndash1208

14 Wingerchuk DM Lennon VA Lucchinetti CF Pittock SJ Weinshenker BG Thespectrum of neuromyelitis optica Lancet Neurol 20076805ndash815

15 Kitley J Leite MI Nakashima I et al Prognostic factors and disease course inaquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorderfrom the United Kingdom and Japan Brain 20121351834ndash1849

16 Mealy MA Kessler RA Rimler Z et al Mortality in neuromyelitis optica is stronglyassociated with African ancestry Neurol Neuroimmunol Neuroinflamm 20185e468doi 101212NXI0000000000000468

17 Lennon VA Wingerchuk DM Kryzer TJ et al A serum autoantibody marker ofneuromyelitis optica distinction from multiple sclerosis Lancet 20043642106ndash2112

18 Wingerchuk DM Lennon VA Pittock SJ Lucchinetti CF Weinshenker BG Reviseddiagnostic criteria for neuromyelitis optica Neurology 2006661485ndash1489

19 Kowarik MC Dzieciatkowska M Wemlinger S et al The cerebrospinal fluid im-munoglobulin transcriptome and proteome in neuromyelitis optica reveals centralnervous system-specific B cell populations J Neuroinflammation 20151219

20 Mitsdoerffer M Kuchroo V Korn T Immunology of neuromyelitis optica a T cell-Bcell collaboration Ann N Y Acad Sci 2013128357ndash66

21 Day RE Kitchen P Owen DS et al Human aquaporins regulators of transcellularwater flow Biochim Biophys Acta 201418401492ndash1506

22 Jarius S Franciotta D Paul F et al Cerebrospinal fluid antibodies to aquaporin-4 inneuromyelitis optica and related disorders frequency origin and diagnostic rele-vance J Neuroinflammation 2010752

23 Bennett JL Lam C Kalluri SR et al Intrathecal pathogenic anti-aquaporin-4 anti-bodies in early neuromyelitis optica Ann Neurol 200966617ndash629

24 Jarius S Ruprecht K Wildemann B et al Contrasting disease patterns in seropositiveand seronegative neuromyelitis optica a multicentre study of 175 patientsJ Neuroinflammation 2012914

25 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 201613280

26 Shimizu F Schaller KL Owens GP et al Glucose-regulated protein 78 autoantibodyassociates with blood-brain barrier disruption in neuromyelitis optica Sci Transl Med20179eaai9111

27 Nytrova P Potlukova E Kemlink D et al Complement activation in patients withneuromyelitis optica J Neuroimmunol 2014274185ndash191

28 Tradtrantip L Yao X Su T Smith AJ Verkman AS Bystander mechanism forcomplement-initiated early oligodendrocyte injury in neuromyelitis optica ActaNeuropathol 201713435ndash44

29 Yao X Verkman AS Complement regulator CD59 prevents peripheral organ injury inrats made seropositive for neuromyelitis optica immunoglobulin G Acta NeuropatholCommun 2017557

30 Zamvil SS Spencer CM Baranzini SE Cree BAC The gut microbiome in neuro-myelitis optica Neurotherapeutics 20181592ndash101

31 Omenetti S Pizarro TT The TregTh17 Axis a dynamic balance regulated by the gutmicrobiome Front Immunol 20156639

32 Uzawa A Mori M Masuda H et al Interleukin-6 analysis of 572 consecutive CSFsamples from neurological disorders a special focus on neuromyelitis optica ClinChim Acta 2017469144ndash149

33 Wang H Wang K Zhong X et al Notable increased cerebrospinal fluid levels ofsoluble interleukin-6 receptors in neuromyelitis optica Neuroimmunomodulation201219304ndash308

34 Uzawa A Mori M Arai K et al Cytokine and chemokine profiles in neuromyelitisoptica significance of interleukin-6 Mult Scler 2010161443ndash1452

35 Uchida T Mori M Uzawa A et al Increased cerebrospinal fluid metalloproteinase-2and interleukin-6 are associated with albumin quotient in neuromyelitis optica theirpossible role on blood-brain barrier disruption Mult Scler 2017231072ndash1084

36 Matsushita T Tateishi T Isobe N et al Characteristic cerebrospinal fluid cytokinechemokine profiles in neuromyelitis optica relapsing remitting or primary progressivemultiple sclerosis PLoS One 20138e61835

37 Icoz S Tuzun E Kurtuncu M et al Enhanced IL-6 production in aquaporin-4 anti-body positive neuromyelitis optica patients Int J Neurosci 201012071ndash75

38 Barros PO Cassano T Hygino J et al Prediction of disease severity in neuromyelitisoptica by the levels of interleukin (IL)-6 produced during remission phase Clin ExpImmunol 2016183480ndash489

39 Uzawa A Mori M Ito M et al Markedly increased CSF interleukin-6 levels inneuromyelitis optica but not in multiple sclerosis J Neurol 20092562082ndash2084

40 Uzawa A Mori M Sawai S et al Cerebrospinal fluid interleukin-6 and glial fibrillaryacidic protein levels are increased during initial neuromyelitis optica attacks ClinChim Acta 2013421181ndash183

41 Uzawa A Mori M Sato Y Masuda S Kuwabara S CSF interleukin-6 level predicts recoveryfrom neuromyelitis optica relapse J Neurol Neurosurg Psychiatry 201283339ndash340

42 Chihara N Aranami T Sato W et al Interleukin 6 signaling promotes anti-aquaporin4 autoantibody production from plasmablasts in neuromyelitis optica Proc Natl AcadSci USA 20111083701ndash3706

43 Kowarik MC Astling D Gasperi C et al CNS Aquaporin-4-specific B cells connectwith multiple B-cell compartments in neuromyelitis optica spectrum disorder AnnClin Transl Neurol 20174369ndash380

44 Dienz O Eaton SM Bond JP et al The induction of antibody production by IL-6 isindirectly mediated by IL-21 produced by CD4+ T cells J Exp Med 200920669ndash78

45 Dos Passos GR Sato DK Becker J Fujihara K Th17 cells pathways in multiplesclerosis and neuromyelitis optica spectrum disorders pathophysiological and ther-apeutic implications Mediators Inflamm 201620165314541

46 Wang HH Dai YQ Qiu W et al Interleukin-17-secreting T cells in neuromyelitisoptica and multiple sclerosis during relapse J Clin Neurosci 2011181313ndash1317

47 Varrin-Doyer M Spencer CM Schulze-TopphoffU et al Aquaporin 4-specific T cellsin neuromyelitis optica exhibit a Th17 bias and recognize Clostridium ABC trans-porter Ann Neurol 20127253ndash64

48 Takeshita Y Obermeier B Cotleur AC et al Effects of neuromyelitis optica-IgG at theblood-brain barrier in vitro Neurol Neuroimmunol Neuroinflamm 20174e311 doi101212NXI0000000000000311

49 Fujihara K Sato DK Nakashima I et al Myelin oligodendrocyte glycoprotein im-munoglobulin G-associated disease an overview Clin Exp Neuroimmunol 2018948ndash55

50 Kaneko K Sato DK Nakashima I et al Myelin injury without astrocytopathy inneuroinflammatory disorders with MOG antibodies J Neurol Neurosurg Psychiatry2016871257ndash1259

51 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 20193941352ndash1363

52 Pittock SJ Berthele A Fujihara K et al Eculizumab in aquaporin-4-positive neuro-myelitis optica spectrum disorder N Engl J Med 2019381614ndash625

53 Yamamura T Kleiter I Fujihara K et al Trial of satralizumab in neuromyelitis opticaspectrum disorder N Engl J Med 20193812114ndash2124

54 Ringelstein M Ayzenberg I Harmel J et al Long-term therapy with interleukin 6receptor blockade in highly active neuromyelitis optica spectrum disorder JAMANeurol 201572756ndash763

55 Lauenstein AS Stettner M Kieseier BC Lensch E Treating neuromyelitis optica withthe interleukin-6 receptor antagonist tocilizumab BMJ Case Rep 20142014bcr2013202939

56 Araki M Matsuoka T Miyamoto K et al Efficacy of the anti-IL-6 receptor antibodytocilizumab in neuromyelitis optica a pilot study Neurology 2014821302ndash1306

57 Kieseier BC Stuve O Dehmel T et al Disease amelioration with tocilizumab in atreatment-resistant patient with neuromyelitis optica implication for cellular immuneresponses JAMA Neurol 201370390ndash393

58 Ayzenberg I Kleiter I Schroder A et al Interleukin 6 receptor blockade in patientswith neuromyelitis optica nonresponsive to anti-CD20 therapy JAMA Neurol 201370394ndash397

59 Araki M Aranami T Matsuoka T Nakamura M Miyake S Yamamura T Clinicalimprovement in a patient with neuromyelitis optica following therapy with the anti-IL-6 receptor monoclonal antibody tocilizumab Mod Rheumatol 201323827ndash831

60 Harmel J Ringelstein M Ingwersen J et al Interferon-beta-related tumefactive brainlesion in a Caucasian patient with neuromyelitis optica and clinical stabilization withtocilizumab BMC Neurol 201414247

61 Traboulsee A Greenberg B 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 202019402ndash412

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 7 Number 5 | September 2020 11

DOI 101212NXI000000000000084120207 Neurol Neuroimmunol Neuroinflamm

Kazuo Fujihara Jeffrey L Bennett Jerome de Seze et al Interleukin-6 in neuromyelitis optica spectrum disorder pathophysiology

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