Interleukin-6 Receptor Blockade in Treatment-Refractory MOG-IgG-Associated Disease and Neuromyelitis Optica Spectrum Disorders

被引：99

作者：

Ringelstein, Marius ^{[1
,2
]}

Ayzenberg, Ilya ^{[3
,4
]}

Lindenblatt, Gero ^{[5
]}

Fischer, Katinka ^{[1
]}

Gahlen, Anna ^{[3
]}

Novi, Giovanni ^{[6
]}

Hayward-Konnecke, Helen ^{[7
]}

Schippling, Sven ^{[7
]}

Rommer, Paulus S. ^{[8
]}

Kornek, Barbara ^{[8
]}

Zrzavy, Tobias ^{[8
]}

Biotti, Damien ^{[9
,10
]}

Ciron, Jonathan ^{[9
,10
]}

Audoin, Bertrand ^{[11
]}

Berthele, Achim ^{[12
]}

Giglhuber, Katrin ^{[12
]}

Zephir, Helene ^{[13
]}

Kuempfel, Tania ^{[14
]}

Berger, Robert ^{[15
]}

Roether, Joachim ^{[15
]}

Hauessler, Vivien ^{[16
,17
]}

Stellmann, Jan-Patrick ^{[18
,19
]}

Whittam, Daniel ^{[20
]}

Jacob, Anu ^{[20
,21
]}

Kraemer, Markus ^{[1
]}

Gueguen, Antoine ^{[23
]}

Deschamps, Romain ^{[23
]}

Bayas, Antonios ^{[24
]}

Hummert, Martin W. ^{[25
]}

Trebst, Corinna ^{[25
]}

Haarmann, Axel ^{[26
]}

Jarius, Sven ^{[27
]}

Wildemann, Brigitte ^{[27
]}

Grothe, Matthias ^{[28
]}

Siebert, Nadja ^{[29
,30
,31
,32
,33
,34
]}

Ruprecht, Klemens ^{[32
,33
,34
,35
]}

Paul, Friedemann ^{[29
,30
,31
,32
,33
,34
]}

Collongues, Nicolas ^{[36
]}

Marignier, Romain ^{[37
]}

Levy, Michael ^{[38
,39
]}

Karenfort, Michael ^{[22
,40
]}

Deppe, Michael ^{[41
]}

Albrecht, Philipp ^{[1
]}

Hellwig, Kerstin ^{[3
]}

Gold, Ralf ^{[3
]}

Hartung, Hans-Peter ^{[1
]}

Meuth, Sven G. ^{[1
]}

Kleiter, Ingo ^{[3
,42
]}

Aktas, Orhan ^{[1
]}

机构：

[1] Heinrich Heine Univ Dusseldorf, Med Fac, Dept Neurol, Dusseldorf, Germany

[2] Heinrich Heine Univ Dusseldorf, LVR Klinikum, Ctr Neurol & Neuropsychiat, Dept Neurol, Dusseldorf, Germany

[3] Ruhr Univ Bochum, St Josef Hosp, Dept Neurol, Bochum, Germany

[4] Sechenov First Moscow State Med Univ, Dept Neurol, Moscow, Russia

[5] Johanna Etienne Hosp, Dept Neurol, Neuss, Germany

[6] San Martino Hosp, Dept Neurol, Genoa, Italy

[7] Univ Hosp Zurich, Dept Neurol, Neuroimmunol & MS Res, Zurich, Switzerland

[8] Med Univ Vienna, Dept Neurol, Vienna, Austria

[9] Toulouse Purpan Univ Hosp, CRC SEP, B4 Unit, Dept Neurol, Toulouse, France

[10] Univ Toulouse 3, INSERM UMR1291 CNRS UMR5051, Inst Toulousain Malad Infect & Inflammatoires Inf, Toulouse, France

[11] Aix Marseille Univ, Hop La Timone, AP HM, Pole Neurosci Clin,Serv Neurol, Marseille, France

[12] Tech Univ Munich, Sch Med, Dept Neurol, Klinikum Rechts Isar, Munich, Germany

[13] Univ Lille, INSERM, CRC SEP, CHU Lille, Lille, France

[14] Ludwig Maximilians Univ Munchen, Fac Med, Inst Clin Neuroimmunol, Munich, Germany

[15] Asklepios Klin Altona, Dept Neurol, Hamburg, Germany

[16] Univ Med Ctr Hamburg Eppendorf, Dept Neurol, Hamburg, Germany

[17] Univ Med Ctr Hamburg Eppendorf, Inst Neuroimmunol & MS INIMS, Hamburg, Germany

[18] Hop La Timone, AP HM, CEMEREM, Marseille, France

[19] Aix Marseille Univ, CNRS, CRMBM, UMR 7339, Marseille, France

[20] Walton Ctr, Dept Neurol, Liverpool, Merseyside, England

[21] Cleveland Clin Abu Dhabi, Abu Dhabi, U Arab Emirates

[22] Alfried Krupp Hosp, Dept Neurol, Essen, Germany

[23] Fdn Ophtalmol Adolphe de Rothschild, Dept Neurol, Paris, France

[24] Univ Klinikum Augsburg, Dept Neurol, Augsburg, Germany

[25] Hannover Med Sch, Dept Neurol, Hannover, Germany

[26] Univ Wurzburg, Dept Neurol, Wurzburg, Germany

[27] Heidelberg Univ, Dept Neurol, Mol Neuroimmunol Grp, Heidelberg, Germany

[28] Univ Hosp Greifswald, Dept Neurol, Greifswald, Germany

[29] Max Delbrueck Ctr Mol Med, NeuroCure Clin Res Ctr, Berlin, Germany

[30] Max Delbrueck Ctr Mol Med, Expt & Clin Res Ctr, Berlin, Germany

[31] Charite Univ Med Berlin, Berlin, Germany

[32] Free Univ Berlin, Berlin, Germany

[33] Humboldt Univ, Berlin, Germany

[34] Berlin Inst Hlth, Berlin, Germany

[35] Charite Univ Med Berlin, Dept Neurol, Berlin, Germany

[36] Univ Hosp Strasbourg, Dept Neurol, Strasbourg, France

[37] Hosp Civils Lyon, Hop Neurol Pierre Wertheimer, Sclerose Plaques Pathol Myeline & Neuroinflammat, Serv Neurol, Lyon, France

[38] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

[39] Harvard Med Sch, Boston, MA 02115 USA

[40] Heinrich Heine Univ Dusseldorf, Med Fac, Univ Childrens Hosp, Neonatol & Pediat Cardiol,Dept Gen Pediat, Dusseldorf, Germany

[41] Univ Hosp, Dept Neurol, Munster, Germany

[42] Behandlungszentrum Kempfenhausen Multiple Skleros, Marianne Strauss Klin, Berg, Germany

来源：

NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION | 2022年 / 9卷 / 01期

关键词：

DIAGNOSTIC-CRITERIA; CLINICAL-COURSE; DOUBLE-BLIND; TOCILIZUMAB; MULTICENTER; EFFICACY; SAFETY; SATRALIZUMAB; RITUXIMAB; AQP4-IGG;

D O I：

10.1212/NXI.0000000000001100

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Background and ObjectivesTo evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized anti-interleukin-6 receptor antibody in myelin oligodendrocyte glycoprotein-IgG-associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD).MethodsAnnualized relapse rate (ARR), Expanded Disability Status Scale score, MRI, autoantibody titers, pain, and adverse events were retrospectively evaluated in 57 patients with MOGAD (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 23.8 months (median; interquartile range 13.0-51.1 months), with an IV dose of 8.0 mg/kg (median; range 6-12 mg/kg) every 31.6 days (mean; range 26-44 days). For MOGAD, the median ARR decreased from 1.75 (range 0.5-5) to 0 (range 0-0.9; p = 0.0011) under TCZ. A similar effect was seen for AQP4-IgG+ (ARR reduction from 1.5 [range 0-5] to 0 [range 0-4.2]; p < 0.001) and for seronegative NMOSD (from 3.0 [range 1.0-3.0] to 0.2 [range 0-2.0]; p = 0.031). During TCZ, 60% of all patients were relapse free (79% for MOGAD, 56% for AQP4-IgG+, and 43% for seronegative NMOSD). Disability follow-up indicated stabilization. MRI inflammatory activity decreased in MOGAD (p = 0.04; for the brain) and in AQP4-IgG+ NMOSD (p < 0.001; for the spinal cord). Chronic pain was unchanged. Regarding only patients treated with TCZ for at least 12 months (n = 44), ARR reductions were confirmed, including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28). Similarly, in the group of patients treated with TCZ for at least 12 months, 59% of them were relapse free, with 73% for MOGAD, 57% for AQP4-IgG+, and 40% for patients with seronegative NMOSD. No severe or unexpected safety signals were observed. Add-on therapy showed no advantage compared with TCZ monotherapy.DiscussionThis study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD.

引用

页数：18

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[1] Transcriptomics and proteomics reveal a cooperation between interferon and T-helper 17 cells in neuromyelitis optica [J].

Agasing, Agnieshka M. ;

Wu, Qi ;

Khatri, Bhuwan ;

Borisow, Nadja ;

Ruprecht, Klemens ;

Brandt, Alexander Ulrich ;

Gawde, Saurabh ;

Kumar, Gaurav ;

Quinn, James L. ;

Ko, Rose M. ;

Mao-Draayer, Yang ;

Lessard, Christopher J. ;

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Axtell, Robert C. .

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[2] Long-term Outcomes in Patients With Myelin Oligodendrocyte Glycoprotein Immunoglobulin G-Associated Disorder [J].

不详 .

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[3] Blockade of IL-6 signaling in neuromyelitis optica [J].

Araki, Manabu .

NEUROCHEMISTRY INTERNATIONAL, 2019, 130

[4] Efficacy of the anti-IL-6 receptor antibody tocilizumab in neuromyelitis optica A pilot study [J].

Araki, Manabu ;

Matsuoka, Takako ;

Miyamoto, Katsuichi ;

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Okamoto, Tomoko ;

Murata, Miho ;

Miyake, Sachiko ;

Aranami, Toshimasa ;

Yamamura, Takashi .

NEUROLOGY, 2014, 82 (15) :1302-1306

[5] Pain, depression, and quality of life in adults with MOG-antibody-associated disease [J].

Asseyer, Susanna ;

Henke, Eugenia ;

Trebst, Corinna ;

Hummert, Martin W. ;

Wildemann, Brigitte ;

Jarius, Sven ;

Ringelstein, Marius ;

Aktas, Orhan ;

Pawlitzki, Marc ;

Korsen, Melanie ;

Klotz, Luisa ;

Siebert, Nadja ;

Ruprecht, Klemens ;

Bellmann-Strobl, Judith ;

Wernecke, Klaus-Dieter ;

Haussler, Vivien ;

Havla, Joachim ;

Gahlen, Anna ;

Gold, Ralf ;

Paul, Friedemann ;

Kleiter, Ingo ;

Ayzenberg, Ilya .

EUROPEAN JOURNAL OF NEUROLOGY, 2021, 28 (05) :1645-1658

[6] Interleukin 6 Receptor Blockade in Patients With Neuromyelitis Optica Nonresponsive to Anti-CD20 Therapy [J].

Ayzenberg, Ilya ;

Kleiter, Ingo ;

Schroeder, Alexandra ;

Hellwig, Kerstin ;

Chan, Andrew ;

Yamamura, Takashi ;

Gold, Ralf .

JAMA NEUROLOGY, 2013, 70 (03) :394-397

[7] Diagnosis and Treatment of NMO Spectrum Disorder and MOG-Encephalomyelitis [J].

Borisow, Nadja ;

Mori, Masahiro ;

Kuwabara, Satoshi ;

Scheel, Michael ;

Paul, Friedemann .

FRONTIERS IN NEUROLOGY, 2018, 9

[8] Two Cases of Pediatric AQP4-Antibody Positive Neuromyelitis Optica Spectrum Disorder Successfully Treated with Tocilizumab [J].

Breu, Markus ;

Glatter, Sarah ;

Hoeftberger, Romana ;

Freilinger, Michael ;

Kircher, Karl ;

Kasprian, Gregor ;

Seidl, Rainer ;

Kornek, Barbara .

NEUROPEDIATRICS, 2019, 50 (03) :193-196

[9] Experience with tocilizumab in patients with neuromyelitis optica spectrum disorders [J].

Carreon Guarnizo, E. ;

Hernandez Clares, R. ;

Castillo Trivino, T. ;

Meca Lallana, V ;

Arocas Casan, V ;

Iniesta Martinez, F. ;

Olascoaga Urtaza, J. ;

Meca Lallana, J. E. .

NEUROLOGIA, 2022, 37 (03) :178-183

[10] Steroid-sparing maintenance immunotherapy for MOG-IgG associated disorder [J].

Chen, John J. ;

Flanagan, Eoin P. ;

Bhatti, M. Tariq ;

Jitprapaikulsan, Jiraporn ;

Dubey, Divyanshu ;

Lopez Chiriboga, Alfonso S. ;

Fryer, James P. ;

Weinshenker, Brian G. ;

McKeon, Andrew ;

Tillema, Jan-Mendelt ;

Lennon, Vanda A. ;

Lucchinetti, Claudia F. ;

Kunchok, Amy ;

McClelland, Collin M. ;

Lee, Michael S. ;

Bennett, Jeffrey L. ;

Pelak, Victoria S. ;

Van Stavern, Gregory ;

Adesina, Ore-Ofe O. ;

Eggenberger, Eric R. ;

Acierno, Marie D. ;

Wingerchuk, Dean M. ;

Lam, Byron L. ;

Moss, Heather ;

Beres, Shannon ;

Gilbert, Aubrey L. ;

Shah, Veeral ;

Armstrong, Grayson ;

Heidary, Gena ;

Cestari, Dean M. ;

Stiebel-Kalish, Hadas ;

Pittock, Sean J. .

NEUROLOGY, 2020, 95 (02) :E111-E120

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