Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2023 Sep;94(9):757-768.
doi: 10.1136/jnnp-2022-330412. Epub 2023 May 23.

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

Orhan Aktas  1 , Hans-Peter Hartung  2   3   4   5 , Michael A Smith  6 , William A Rees  6 , Kazuo Fujihara  7   8 , Friedemann Paul  9 , Romain Marignier  10 , Jeffrey L Bennett  11 , Ho Jin Kim  12 , Brian G Weinshenker  13 , Sean J Pittock  14 , Dean M Wingerchuk  15 , Gary Cutter  16 , Dewei She  6 , Michele Gunsior  6 , Daniel Cimbora  6 , Eliezer Katz  6 , Bruce A Cree  17 ; N-MOmentum study investigators
Affiliations
Randomized Controlled Trial

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

Orhan Aktas et al. J Neurol Neurosurg Psychiatry. 2023 Sep.

Abstract

Objective: 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.

Methods: 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).

Results: 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).

Conclusions: 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.

Trial registration number: NCT02200770.

Keywords: CLINICAL NEUROLOGY; RANDOMISED TRIALS.

PubMed Disclaimer

Conflict of interest statement

Competing interests: OA reports grants from the German Ministry of Education and Research (BMBF) and the German Research Foundation (DFG); grants and personal fees from Biogen and Novartis; and travel support and personal fees from Alexion, Almirall, MedImmune, Merck Serono, Roche, Sanofi, Viela Bio/Horizon Therapeutics and Zambon. OA is a member of the European Reference Network for Rare Eye Diseases (ERN-EYE), co-funded by the Health Program of the European Union under the Framework Partnership Agreement No 739534 'ERN-EYE. H-PH has received fees for consulting, speaking and serving on steering committees from Bayer Healthcare, Biogen Idec, Celgene Receptos, CSL Behring, GeNeuro, Genzyme, MedDay, MedImmune, Merck Serono, Novartis, Roche, Sanofi, TG Therapeutics and Viela Bio/Horizon Therapeutics, with approval by the Rector of Heinrich Heine University Düsseldorf. KF has received fees for consulting, speaking and serving on steering committees from AbbVie, Alexion, Asahi Kasei Medical, Biogen, Chugai/Roche, Eisai, Japan Tobacco, MedImmune/Viela Bio, Merck, Merck Biopharma, Mitsubishi-Tanabe, Novartis, Takeda, Teijin and UCB, and has received Grant-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan. FP has received research support, speaker fees and travel reimbursement from Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme and Teva; is supported by the German Competence Network for Multiple Sclerosis and the German Research Council (DFG Exc 257); has received travel reimbursement from the Guthy–Jackson Charitable Foundation; and serves on the steering committee of the OCTIMS study sponsored by Novartis. RM serves on scientific advisory boards for Alexion, Roche and Viela Bio/Horizon Therapeutics; and has received funding for travel and fees from Alexion, Biogen, Merck, Novartis, Roche and Viela Bio/Horizon Therapeutics. JLB reports payment for study design/consultation from MedImmune/Viela Bio/Horizon Therapeutics; reports personal fees from AbbVie, Alexion, Beigene, Chugai, Clene Nanomedicine, Genentech, Genzyme, Mitsubishi Tanabe Pharma, Reistone Biopharma and Roche; reports grants and personal fees from EMD Serono and Novartis; reports grants from Alexion, Mallinckrodt and the National Institutes of Health; and has a patent for Aquaporumab issued. HJK has received a grant from the National Research Foundation of Korea; consultancy/speaker fees or research support from Alexion, AprilBio, ALTOS Biologics, Biogen, Celltrion, Daewoong, Eisai, GC Pharma, HanAll BioPharma, Handok, Horizon Therapeutics (formerly Viela Bio), Kolon Life Science, MDimune, Mitsubishi Tanabe Pharma, Merck Serono, Novartis, Roche, Sanofi Genzyme, Teva-Handok and UCB; and is a co-editor for the Multiple Sclerosis Journal and an associated editor for the Journal of Clinical Neurology. BGW receives payments for serving as chair of attack adjudication committees for clinical trials in NMOSD for Alexion, MedImmune, UCB Bioscience and Viela Bio/Horizon Therapeutics; has consulted with Chugai, Genentech, Horizon Pharmaceuticals, Mitsubishi Tanabe Pharma and Roche; has received payments for speaking for Genentech and Roche; and has a patent for NMO-IgG for diagnosis of neuromyelitis optica, with royalties paid by Hospices Civils de Lyon, MVZ Labor PD Dr Volkmann und Kollegen GbR, RSR and the University of Oxford. SJP has received personal compensation for serving as a consultant for Astellas, Genentech and Sage Therapeutics; has received personal compensation for serving on scientific advisory boards or data safety monitoring boards for F. Hoffman-La Roche AG, Genentech and UCB; has received research support from Alexion, Roche/Genentech and Viela Bio/MedImmune/Horizon; has a Patent# 8,889,102 (Application#12-678350, Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia)—issued; has a patent, Patent# 9,891,219B2 (Application#12-573942, Methods for Treating Neuromyelitis Optica [NMO] by Administration of Eculizumab to an individual that is Aquaporin-4 (AQP4)-IgG Autoantibody positive)—issued; and his institution has received compensation for serving as a consultant for Alexion, Astellas and Viela Bio/MedImmune/Horizon. DMW reports personal fees from Biogen, Genentech, Horizon, Mitsubishi Tanabe, Roche, UCB Pharma and Viela Bio; and research support paid to Mayo Clinic by Alexion Pharmaceuticals. GC has received personal fees for participation on data and safety monitoring boards from AI Therapeutics, AMO Pharma, AstraZeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Green Valley Pharma, Horizon Pharmaceuticals, Immunic, Karuna Therapeutics, Mapi Pharmaceuticals, Merck, Mitsubishi Tanabe Pharma Holdings, NHLBI (Protocol Review Committee), Novartis, Opko Biologics, Prothena Biosciences, Regeneron, Sanofi-Aventis, Reata Pharmaceuticals, University of Texas Southwestern, University of Pennsylvania and Visioneering Technologies; has received personal fees for consulting or advisory board participation from Alexion, Antisense Therapeutics, Biogen, Clinical Trial Solutions, Entelexo Biotherapeutics, Genentech, Genzyme, GW Pharmaceuticals, Immunic, Klein-Buendel Incorporated, Merck/Serono, Novartis, Osmotica Pharmaceuticals, Perception Neurosciences, Protalix Biotherapeutics, Recursion/Cerexis Pharmaceuticals, Regeneron, Roche, SAB Biotherapeutics; and is employed by the University of Alabama at Birmingham and President of Pythagoras, a private consulting company located in Birmingham, Alabama. BAC reports personal compensation for consulting from Alexion, Atara Biotherapeutics, Autobahn, Avotres, Biogen, EMD Serono, Gossamer Bio, Horizon, Neuron23, Novartis, Sanofi, TG Therapeutics and Therini Bio; and has received research support from Genentech. MAS, WAR, DS and DC are employees of Horizon Therapeutics and own stock. MG and EK are former employees of Horizon Therapeutics and own stock.

Figures

Figure 1
Figure 1
Boxplots displaying (A) sGFAP, (B) sNfL, (C) sTau, (D) sUCHL1 and (E) serum GFAP:NfL ratio in samples drawn during the lead-up to an NMOSD attack and in day1/RCP samples drawn >5 weeks from the attack in participants who experienced an NMOSD attack during the RCP. Horizontal dotted lines show 2 SDs from the mean of the HD control cohort; sGFAP, 170 pg/mL; sNfL, 16 pg/mL; sTau, 1.3 pg/mL; sUCHL1, 53 pg/mL; sGFAP:sNfL ratio, 33. Note the differing y-axis scales, particularly the logarithmic scale for sGFAP. Median (IQR) attack follow-up was at 108 (27–124) days. ▲p<0.10; *p<0.05; **p<0.01; ***p<0.001, Wilcoxon signed-rank test, samples drawn at baseline versus 1 week until attack. AQP4+, seropositive for immunoglobulin G autoantibodies to aquaporin-4; AQP4−, seronegative for immunoglobulin G autoantibodies to aquaporin-4; DN, double-negative; GFAP, glial fibrillary acidic protein; HD, healthy donor; MOG+, seropositive for myelin oligodendrocyte glycoprotein-immunoglobulin G; NfL, neurofilament light chain; NMOSD, neuromyelitis optica spectrum disorder; RCP, randomised controlled period; sGFAP, serum glial fibrillary acidic protein; sNfL, serum neurofilament light chain; sTau, serum tau; sUCHL1, serum ubiquitin C-terminal hydrolase L1.
Figure 2
Figure 2
Boxplots of day 1/RCP serum CNS damage biomarkers relative to HDs. (A) sGFAP, (B) sNfL, (C) sTau, (D) sUCHL1 and (E) serum GFAP:NfL ratio. Patients were determined to be ‘high’ for each cut-off based on levels being higher than two SDs from the mean of the HD cohort. Horizontal dotted line in each case represents the threshold for 2 SDs from the HD mean; sGFAP, 170 pg/mL; sNfL, 16 pg/mL; sTau, 1.3 pg/mL; sUCHL1, 53 pg/mL; sGFAP:sNfL ratio, 33. (F) Forest plot of Cox regression coefficients from model fit using day 1/RCP CNS damage biomarker concentrations as predictors of RCP attack risk in AQP4+ participants. Note the differing logarithmic y-axis scales, particularly the scale for sGFAP. HR for sGFAP, *p<0.05. AB, antibody; AQP4+, seropositive for immunoglobulin G autoantibodies to aquaporin-4; CNS, central nervous system; DN, double-negative; GFAP, glial fibrillary acidic protein; HD, healthy donor; MOG+, seropositive for myelin oligodendrocyte glycoprotein-immunoglobulin G; NfL, neurofilament light chain; NMOSD, neuromyelitis optica spectrum disorder; RCP, randomised controlled period; RRMS, relapsing–remitting multiple sclerosis; sGFAP, serum glial fibrillary acidic protein; sNfL, serum neurofilament light chain; sTau, serum tau; sUCHL1, serum ubiquitin C-terminal hydrolase L1.
Figure 3
Figure 3
(A) Heatmap displaying concentration of CNS damage markers relative to HD reference cohort in samples drawn most proximal (+/− 7 days) to NMOSD attack in placebo-treated participants (left) and inebilizumab-treated participants (right). Heatmaps ordered by sGFAP concentration. (B) Mean ROC curves for out-of-fold predictions from 10 iterations of fivefold cross validation for mixed-effect logistic regression model fit to identify 37 attack samples versus remaining samples drawn during the study using sGFAP alone (red) versus all four CNS markers (blue) as predictors. (C) Sensitivity analysis displaying mean (+/− SEM) AUC from out-of-fold predictions for both models for all samples, samples drawn from the inebilizumab cohort and placebo cohort separately, then for those samples drawn from participants who experienced attacks during the RCP. One participant had a missing attack sample. AQP4+, seropositive for immunoglobulin G autoantibodies to aquaporin-4; AQP4−, seronegative for immunoglobulin G autoantibodies to aquaporin-4; AUC, area under the curve; CNS, central nervous system; CV, coefficient of variation; HD, healthy donor; NMOSD, neuromyelitis optica spectrum disorder; OSIS, Opticospinal Impairment Scale; RCP, randomised controlled period; ROC, receiver operator curve; sGFAP, serum glial fibrillary acidic protein; sNfL, serum neurofilament light chain; sTau, serum tau; sUCHL1, serum ubiquitin C-terminal hydrolase L1.
Figure 4
Figure 4
(A-C) Forest plots displaying strength of correlation between change from baseline in concentration of CNS damage biomarkers and change from baseline in (A) EDSS component scores, (B) the OSIS components scores and (C) mRS scores in AQP4+ participants. (D) Scatterplot displaying correlation between changes from baseline to attack in sNfL and EDSS scores during attack assessments. (E) Box and whisker plot displaying distribution of sNfL changes from baseline in participants who displayed EDSS score worsening at attack follow-up versus those who did not experience EDSS score change at follow-up. Optimal cut-off point determined using Youden’s index. Attack follow-up was (median (±IQR)) 108 (27–124) days. AUC, area under the curve; CNS, central nervous system; EDSS, Expanded Disability Status Scale; GFAP, glial fibrillary acidic protein; mRS, modified Rankin Scale; OSIS, Opticospinal Impairment Scale; sGFAP, serum glial fibrillary acidic protein; sNfL, serum neurofilament light chain; sTau, serum tau; sUCHL1, serum ubiquitin C-terminal hydrolase L1.
Figure 5
Figure 5
(A) Median (+/− IQR) fold change from baseline of sNfL in inebilizumab-treated and placebo-treated participants. Significance of changes between treatment groups assessed using Mann-Whitney U test. Boxplots of sNfL concentrations in (B) participants who did not experience RCP attacks and (C) those who did experience RCP attacks. Dashed vertical lines show when all participants received inebilizumab therapy at the end of the RCP and start of the OLP. Dashed horizontal lines show the threshold for elevated sNfL concentrations. Significance of changes from baseline in each treatment group was assessed using the Wilcoxon-signed rank test; *p<0.05; **p<0.01; ***p<0.001. FC, fold change; OLP, open-label period; RCP, randomised controlled period; sNfL, serum neurofilament light chain; W, week.
See this image and copyright information in PMC

References

    1. Cree BA, Bennett JL, Sheehan M, et al. Placebo-controlled study in neuromyelitis optica—ethical and design considerations. Mult Scler 2016;22:862–72. 10.1177/1352458515620934 - DOI - PMC - PubMed
    1. Fujihara K, Misu T, Nakashima I, et al. Neuromyelitis optica should be classified as an astrocytopathic disease rather than a demyelinating disease. Clin Exp Neuroimmunol 2012;3:58–73. 10.1111/j.1759-1961.2012.00030.x Available: http://doi.wiley.com/10.1111/cen3.2012.3.issue-2 - DOI
    1. Wingerchuk DM, Pittock SJ, Lucchinetti CF, et al. A secondary progressive clinical course is uncommon in neuromyelitis optica. Neurology 2007;68:603–5. 10.1212/01.wnl.0000254502.87233.9a - DOI - PubMed
    1. Jarius S, Paul F, Weinshenker BG, et al. Neuromyelitis optica. Nat Rev Dis Primers 2020;6:85. 10.1038/s41572-020-0214-9 - DOI - PubMed
    1. Li J, Bazzi SA, Schmitz F, et al. Molecular level characterization of circulating aquaporin-4 antibodies in neuromyelitis optica spectrum disorder. Neurol Neuroimmunol Neuroinflamm 2021;8:e1034. 10.1212/NXI.0000000000001034 - DOI - PMC - PubMed

Publication types

MeSH terms

Associated data