Serum neurofilament light chain levels at attack predict post-attack disability worsening and are mitigated by inebilizumab: analysis of four potential biomarkers in neuromyelitis optica spectrum disorder

ObjectiveTo investigate relationships between serum neurofilament light chain (sNfL), ubiquitin C-terminal hydrolase L1 (sUCHL1), tau (sTau) and glial fibrillary acidic protein (sGFAP) levels and disease activity/disability in neuromyelitis optica spectrum disorder (NMOSD), and the effects of inebil...

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Veröffentlicht in:Journal of Neurology, Neurosurgery & Psychiatry Jg. 94; H. 9; S. 757 - 768
Hauptverfasser: Aktas, Orhan, Hartung, Hans-Peter, Smith, Michael A, Rees, William A, Fujihara, Kazuo, Paul, Friedemann, Marignier, Romain, Bennett, Jeffrey L, Kim, Ho Jin, Weinshenker, Brian G, Pittock, Sean J, Wingerchuk, Dean M, Cutter, Gary, She, Dewei, Gunsior, Michele, Cimbora, Daniel, Katz, Eliezer, Cree, Bruce A
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England BMJ Publishing Group Ltd 01.09.2023
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Schriftenreihe:Original research
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ISSN:0022-3050, 1468-330X, 1468-330X
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Abstract ObjectiveTo investigate relationships between serum neurofilament light chain (sNfL), ubiquitin C-terminal hydrolase L1 (sUCHL1), tau (sTau) and glial fibrillary acidic protein (sGFAP) levels and disease activity/disability in neuromyelitis optica spectrum disorder (NMOSD), and the effects of inebilizumab on these biomarkers in N-MOmentum.MethodsN-MOmentum randomised participants to receive inebilizumab or placebo with a randomised controlled period (RCP) of 28 weeks and an open-label follow-up period of ≥2 years. The sNfL, sUCHL1, sTau and sGFAP were measured using single-molecule arrays in 1260 scheduled and attack-related samples from N-MOmentum participants (immunoglobulin G (IgG) autoantibodies to aquaporin-4-positive, myelin oligodendrocyte glycoprotein-IgG-positive or double autoantibody-negative) and two control groups (healthy donors and patients with relapsing–remitting multiple sclerosis).ResultsThe concentration of all four biomarkers increased during NMOSD attacks. At attack, sNfL had the strongest correlation with disability worsening during attacks (Spearman R2=0.40; p=0.01) and prediction of disability worsening after attacks (sNfL cut-off 32 pg/mL; area under the curve 0.71 (95% CI 0.51 to 0.89); p=0.02), but only sGFAP predicted upcoming attacks. At RCP end, fewer inebilizumab-treated than placebo-treated participants had sNfL>16 pg/mL (22% vs 45%; OR 0.36 (95% CI 0.17 to 0.76); p=0.004).ConclusionsCompared with sGFAP, sTau and sUCHL1, sNfL at attack was the strongest predictor of disability worsening at attack and follow-up, suggesting a role for identifying participants with NMOSD at risk of limited post-relapse recovery. Treatment with inebilizumab was associated with lower levels of sGFAP and sNfL than placebo.Trial registration number NCT02200770.
AbstractList ObjectiveTo investigate relationships between serum neurofilament light chain (sNfL), ubiquitin C-terminal hydrolase L1 (sUCHL1), tau (sTau) and glial fibrillary acidic protein (sGFAP) levels and disease activity/disability in neuromyelitis optica spectrum disorder (NMOSD), and the effects of inebilizumab on these biomarkers in N-MOmentum.MethodsN-MOmentum randomised participants to receive inebilizumab or placebo with a randomised controlled period (RCP) of 28 weeks and an open-label follow-up period of ≥2 years. The sNfL, sUCHL1, sTau and sGFAP were measured using single-molecule arrays in 1260 scheduled and attack-related samples from N-MOmentum participants (immunoglobulin G (IgG) autoantibodies to aquaporin-4-positive, myelin oligodendrocyte glycoprotein-IgG-positive or double autoantibody-negative) and two control groups (healthy donors and patients with relapsing–remitting multiple sclerosis).ResultsThe concentration of all four biomarkers increased during NMOSD attacks. At attack, sNfL had the strongest correlation with disability worsening during attacks (Spearman R2=0.40; p=0.01) and prediction of disability worsening after attacks (sNfL cut-off 32 pg/mL; area under the curve 0.71 (95% CI 0.51 to 0.89); p=0.02), but only sGFAP predicted upcoming attacks. At RCP end, fewer inebilizumab-treated than placebo-treated participants had sNfL>16 pg/mL (22% vs 45%; OR 0.36 (95% CI 0.17 to 0.76); p=0.004).ConclusionsCompared with sGFAP, sTau and sUCHL1, sNfL at attack was the strongest predictor of disability worsening at attack and follow-up, suggesting a role for identifying participants with NMOSD at risk of limited post-relapse recovery. Treatment with inebilizumab was associated with lower levels of sGFAP and sNfL than placebo.Trial registration numberNCT02200770.
To investigate relationships between serum neurofilament light chain (sNfL), ubiquitin C-terminal hydrolase L1 (sUCHL1), tau (sTau) and glial fibrillary acidic protein (sGFAP) levels and disease activity/disability in neuromyelitis optica spectrum disorder (NMOSD), and the effects of inebilizumab on these biomarkers in N-MOmentum. N-MOmentum randomised participants to receive inebilizumab or placebo with a randomised controlled period (RCP) of 28 weeks and an open-label follow-up period of ≥2 years. The sNfL, sUCHL1, sTau and sGFAP were measured using single-molecule arrays in 1260 scheduled and attack-related samples from N-MOmentum participants (immunoglobulin G (IgG) autoantibodies to aquaporin-4-positive, myelin oligodendrocyte glycoprotein-IgG-positive or double autoantibody-negative) and two control groups (healthy donors and patients with relapsing-remitting multiple sclerosis). The concentration of all four biomarkers increased during NMOSD attacks. At attack, sNfL had the strongest correlation with disability worsening during attacks (Spearman R =0.40; p=0.01) and prediction of disability worsening after attacks (sNfL cut-off 32 pg/mL; area under the curve 0.71 (95% CI 0.51 to 0.89); p=0.02), but only sGFAP predicted upcoming attacks. At RCP end, fewer inebilizumab-treated than placebo-treated participants had sNfL>16 pg/mL (22% vs 45%; OR 0.36 (95% CI 0.17 to 0.76); p=0.004). Compared with sGFAP, sTau and sUCHL1, sNfL at attack was the strongest predictor of disability worsening at attack and follow-up, suggesting a role for identifying participants with NMOSD at risk of limited post-relapse recovery. Treatment with inebilizumab was associated with lower levels of sGFAP and sNfL than placebo. NCT02200770.
To investigate relationships between serum neurofilament light chain (sNfL), ubiquitin C-terminal hydrolase L1 (sUCHL1), tau (sTau) and glial fibrillary acidic protein (sGFAP) levels and disease activity/disability in neuromyelitis optica spectrum disorder (NMOSD), and the effects of inebilizumab on these biomarkers in N-MOmentum.OBJECTIVETo investigate relationships between serum neurofilament light chain (sNfL), ubiquitin C-terminal hydrolase L1 (sUCHL1), tau (sTau) and glial fibrillary acidic protein (sGFAP) levels and disease activity/disability in neuromyelitis optica spectrum disorder (NMOSD), and the effects of inebilizumab on these biomarkers in N-MOmentum.N-MOmentum randomised participants to receive inebilizumab or placebo with a randomised controlled period (RCP) of 28 weeks and an open-label follow-up period of ≥2 years. The sNfL, sUCHL1, sTau and sGFAP were measured using single-molecule arrays in 1260 scheduled and attack-related samples from N-MOmentum participants (immunoglobulin G (IgG) autoantibodies to aquaporin-4-positive, myelin oligodendrocyte glycoprotein-IgG-positive or double autoantibody-negative) and two control groups (healthy donors and patients with relapsing-remitting multiple sclerosis).METHODSN-MOmentum randomised participants to receive inebilizumab or placebo with a randomised controlled period (RCP) of 28 weeks and an open-label follow-up period of ≥2 years. The sNfL, sUCHL1, sTau and sGFAP were measured using single-molecule arrays in 1260 scheduled and attack-related samples from N-MOmentum participants (immunoglobulin G (IgG) autoantibodies to aquaporin-4-positive, myelin oligodendrocyte glycoprotein-IgG-positive or double autoantibody-negative) and two control groups (healthy donors and patients with relapsing-remitting multiple sclerosis).The concentration of all four biomarkers increased during NMOSD attacks. At attack, sNfL had the strongest correlation with disability worsening during attacks (Spearman R2=0.40; p=0.01) and prediction of disability worsening after attacks (sNfL cut-off 32 pg/mL; area under the curve 0.71 (95% CI 0.51 to 0.89); p=0.02), but only sGFAP predicted upcoming attacks. At RCP end, fewer inebilizumab-treated than placebo-treated participants had sNfL>16 pg/mL (22% vs 45%; OR 0.36 (95% CI 0.17 to 0.76); p=0.004).RESULTSThe concentration of all four biomarkers increased during NMOSD attacks. At attack, sNfL had the strongest correlation with disability worsening during attacks (Spearman R2=0.40; p=0.01) and prediction of disability worsening after attacks (sNfL cut-off 32 pg/mL; area under the curve 0.71 (95% CI 0.51 to 0.89); p=0.02), but only sGFAP predicted upcoming attacks. At RCP end, fewer inebilizumab-treated than placebo-treated participants had sNfL>16 pg/mL (22% vs 45%; OR 0.36 (95% CI 0.17 to 0.76); p=0.004).Compared with sGFAP, sTau and sUCHL1, sNfL at attack was the strongest predictor of disability worsening at attack and follow-up, suggesting a role for identifying participants with NMOSD at risk of limited post-relapse recovery. Treatment with inebilizumab was associated with lower levels of sGFAP and sNfL than placebo.CONCLUSIONSCompared with sGFAP, sTau and sUCHL1, sNfL at attack was the strongest predictor of disability worsening at attack and follow-up, suggesting a role for identifying participants with NMOSD at risk of limited post-relapse recovery. Treatment with inebilizumab was associated with lower levels of sGFAP and sNfL than placebo.NCT02200770.TRIAL REGISTRATION NUMBERNCT02200770.
ObjectiveTo investigate relationships between serum neurofilament light chain (sNfL), ubiquitin C-terminal hydrolase L1 (sUCHL1), tau (sTau) and glial fibrillary acidic protein (sGFAP) levels and disease activity/disability in neuromyelitis optica spectrum disorder (NMOSD), and the effects of inebilizumab on these biomarkers in N-MOmentum.MethodsN-MOmentum randomised participants to receive inebilizumab or placebo with a randomised controlled period (RCP) of 28 weeks and an open-label follow-up period of ≥2 years. The sNfL, sUCHL1, sTau and sGFAP were measured using single-molecule arrays in 1260 scheduled and attack-related samples from N-MOmentum participants (immunoglobulin G (IgG) autoantibodies to aquaporin-4-positive, myelin oligodendrocyte glycoprotein-IgG-positive or double autoantibody-negative) and two control groups (healthy donors and patients with relapsing–remitting multiple sclerosis).ResultsThe concentration of all four biomarkers increased during NMOSD attacks. At attack, sNfL had the strongest correlation with disability worsening during attacks (Spearman R2=0.40; p=0.01) and prediction of disability worsening after attacks (sNfL cut-off 32 pg/mL; area under the curve 0.71 (95% CI 0.51 to 0.89); p=0.02), but only sGFAP predicted upcoming attacks. At RCP end, fewer inebilizumab-treated than placebo-treated participants had sNfL>16 pg/mL (22% vs 45%; OR 0.36 (95% CI 0.17 to 0.76); p=0.004).ConclusionsCompared with sGFAP, sTau and sUCHL1, sNfL at attack was the strongest predictor of disability worsening at attack and follow-up, suggesting a role for identifying participants with NMOSD at risk of limited post-relapse recovery. Treatment with inebilizumab was associated with lower levels of sGFAP and sNfL than placebo.Trial registration number NCT02200770.
Author Marignier, Romain
Weinshenker, Brian G
Cree, Bruce A
Aktas, Orhan
Gunsior, Michele
Fujihara, Kazuo
Rees, William A
Pittock, Sean J
Cutter, Gary
Bennett, Jeffrey L
Wingerchuk, Dean M
Paul, Friedemann
She, Dewei
Katz, Eliezer
Hartung, Hans-Peter
Smith, Michael A
Cimbora, Daniel
Kim, Ho Jin
AuthorAffiliation 5 Horizon Therapeutics plc , Gaithersburg , Maryland , USA
10 Departments of Neurology and Ophthalmology, Programs in Neuroscience and Immunology , University of Colorado - Anschutz Medical Campus , Aurora , Colorado , USA
9 Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle (MIRCEM), Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-inflammation , Hopital Neurologique et Neurochirurgical Pierre Wertheimer Centre de reference des syndromes neurologiques paraneoplasiques et encephalites auto-immun , Lyon , Auvergne-Rhône-Alpes , France
16 Department of Neurology , UCSF, Weill Institute for Neurosciences, University California of San Francisco , San Francisco , California , USA
7 Multiple Sclerosis and Neuromyelitis Optica Center , Southern Tohoku Research Institute for Neuroscience , Koriyama , Japan
1 Department of Neurology, Medical Faculty , Heinrich Heine University Düsseldorf , Düsseldorf , Germany
11 Department of Neurology , Re
AuthorAffiliation_xml – name: 14 Department of Neurology , Mayo Clinic , Scottsdale , Arizona , USA
– name: 2 Brain and Mind Centre , University of Sydney , Sydney , New South Wales , Australia
– name: 3 Department of Neurology , Medical University Vienna , Vienna , Austria
– name: 10 Departments of Neurology and Ophthalmology, Programs in Neuroscience and Immunology , University of Colorado - Anschutz Medical Campus , Aurora , Colorado , USA
– name: 11 Department of Neurology , Research Institute and Hospital of National Cancer Center , Goyang , Republic of Korea
– name: 8 Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité , Universitätsmedizin Berlin , Berlin , Germany
– name: 9 Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle (MIRCEM), Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-inflammation , Hopital Neurologique et Neurochirurgical Pierre Wertheimer Centre de reference des syndromes neurologiques paraneoplasiques et encephalites auto-immun , Lyon , Auvergne-Rhône-Alpes , France
– name: 6 Department of Multiple Sclerosis Therapeutics , Fukushima Medical University , Koriyama , Fukushima , Japan
– name: 1 Department of Neurology, Medical Faculty , Heinrich Heine University Düsseldorf , Düsseldorf , Germany
– name: 7 Multiple Sclerosis and Neuromyelitis Optica Center , Southern Tohoku Research Institute for Neuroscience , Koriyama , Japan
– name: 5 Horizon Therapeutics plc , Gaithersburg , Maryland , USA
– name: 13 Department of Neurology and Center for MS and Autoimmune Neurology , Mayo Clinic , Rochester , Minnesota , USA
– name: 4 Department of Neurology , Palacky University in Olomouc , Olomouc , Czech Republic
– name: 15 Department of Biostatistics , University of Alabama at Birmingham , Birmingham , Alabama , USA
– name: 16 Department of Neurology , UCSF, Weill Institute for Neurosciences, University California of San Francisco , San Francisco , California , USA
– name: 12 Department of Neurology , University of Virginia , Charlottesville , Virginia , USA
Author_xml – sequence: 1
  givenname: Orhan
  orcidid: 0000-0002-2020-9210
  surname: Aktas
  fullname: Aktas, Orhan
  email: orhan.aktas@uni
  organization: Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
– sequence: 2
  givenname: Hans-Peter
  surname: Hartung
  fullname: Hartung, Hans-Peter
  organization: Department of Neurology, Palacky University in Olomouc, Olomouc, Czech Republic
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  organization: Horizon Therapeutics plc, Gaithersburg, Maryland, USA
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  organization: Horizon Therapeutics plc, Gaithersburg, Maryland, USA
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  surname: Paul
  fullname: Paul, Friedemann
  organization: Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité, Universitätsmedizin Berlin, Berlin, Germany
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  givenname: Romain
  surname: Marignier
  fullname: Marignier, Romain
  organization: Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle (MIRCEM), Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-inflammation, Hopital Neurologique et Neurochirurgical Pierre Wertheimer Centre de reference des syndromes neurologiques paraneoplasiques et encephalites auto-immun, Lyon, Auvergne-Rhône-Alpes, France
– sequence: 8
  givenname: Jeffrey L
  surname: Bennett
  fullname: Bennett, Jeffrey L
  organization: Departments of Neurology and Ophthalmology, Programs in Neuroscience and Immunology, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, USA
– sequence: 9
  givenname: Ho Jin
  orcidid: 0000-0002-8672-8419
  surname: Kim
  fullname: Kim, Ho Jin
  organization: Department of Neurology, Research Institute and Hospital of National Cancer Center, Goyang, Republic of Korea
– sequence: 10
  givenname: Brian G
  surname: Weinshenker
  fullname: Weinshenker, Brian G
  organization: Department of Neurology, University of Virginia, Charlottesville, Virginia, USA
– sequence: 11
  givenname: Sean J
  orcidid: 0000-0002-6140-5584
  surname: Pittock
  fullname: Pittock, Sean J
  organization: Department of Neurology and Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota, USA
– sequence: 12
  givenname: Dean M
  surname: Wingerchuk
  fullname: Wingerchuk, Dean M
  organization: Department of Neurology, Mayo Clinic, Scottsdale, Arizona, USA
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  fullname: Cutter, Gary
  organization: Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, USA
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  givenname: Dewei
  surname: She
  fullname: She, Dewei
  organization: Horizon Therapeutics plc, Gaithersburg, Maryland, USA
– sequence: 15
  givenname: Michele
  surname: Gunsior
  fullname: Gunsior, Michele
  organization: Horizon Therapeutics plc, Gaithersburg, Maryland, USA
– sequence: 16
  givenname: Daniel
  surname: Cimbora
  fullname: Cimbora, Daniel
  organization: Horizon Therapeutics plc, Gaithersburg, Maryland, USA
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  fullname: Katz, Eliezer
  organization: Horizon Therapeutics plc, Gaithersburg, Maryland, USA
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  givenname: Bruce A
  surname: Cree
  fullname: Cree, Bruce A
  email: bruce.cree@ucsf.edu
  organization: Department of Neurology, UCSF, Weill Institute for Neurosciences, University California of San Francisco, San Francisco, California, USA
BackLink https://cir.nii.ac.jp/crid/1870865117725611008$$DView record in CiNii
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Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. 2023
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DOI 10.1136/jnnp-2022-330412
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Keywords RANDOMISED TRIALS
CLINICAL NEUROLOGY
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Snippet ObjectiveTo investigate relationships between serum neurofilament light chain (sNfL), ubiquitin C-terminal hydrolase L1 (sUCHL1), tau (sTau) and glial...
To investigate relationships between serum neurofilament light chain (sNfL), ubiquitin C-terminal hydrolase L1 (sUCHL1), tau (sTau) and glial fibrillary acidic...
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StartPage 757
SubjectTerms Alzheimer's disease
Antibodies, Monoclonal, Humanized - therapeutic use
Aquaporin 4
Autoantibodies
Biomarkers
CLINICAL NEUROLOGY
Double-Blind Method
Function and Dysfunction of the Nervous System
General Neurology
Humans
Immunoglobulin G
Integrative Biomedicine [Topic 3]
Intermediate Filaments
Mann-Whitney U test
Monoclonal antibodies
Neurology
Neuromyelitis Optica
Neuromyelitis Optica - blood
Neuromyelitis Optica - drug therapy
Proteins
RANDOMISED TRIALS
Statistical significance
Title Serum neurofilament light chain levels at attack predict post-attack disability worsening and are mitigated by inebilizumab: analysis of four potential biomarkers in neuromyelitis optica spectrum disorder
URI https://jnnp.bmj.com/content/94/9/757.full
https://cir.nii.ac.jp/crid/1870865117725611008
https://www.ncbi.nlm.nih.gov/pubmed/37221052
https://www.proquest.com/docview/2819110774
https://www.proquest.com/docview/2851145586
https://www.proquest.com/docview/2818749840
https://pubmed.ncbi.nlm.nih.gov/PMC10447388
Volume 94
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