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Original research
Dimethyl fumarate decreases neurofilament light chain in CSF and blood of treatment naïve relapsing MS patients
  1. Tobias Sejbaek1,2,3,4,5,
  2. Helle Hvilsted Nielsen1,2,5,
  3. Natasha Penner6,
  4. Tatiana Plavina6,
  5. Jason P Mendoza6,
  6. Nellie Anne Martin2,
  7. Maria Louise Elkjaer1,2,
  8. Mads Henrik Ravnborg1,
  9. Zsolt Illes1,2,5
  1. 1 Neurology, Odense Universitetshospital, Odense, Denmark
  2. 2 Department of Clinical Research, University of Southern Denmark, Odense, Denmark
  3. 3 Neurology, Hospital of South West Jutland, Esbjerg, Denmark
  4. 4 The Department of Regional Health Research, University of Southern Denmark, Odense, Denmark
  5. 5 MS Alliance of Southern Denmark, Esbjerg, Denmark
  6. 6 Value Based Medicine, Biogen Idec Inc, Cambridge, Massachusetts, USA
  1. Correspondence to Dr Tobias Sejbaek, Neurology, Hospital of South West Jutland, Esbjerg 5000, Denmark; Tobias.Sejbaek.Mathiesen{at}rsyd.dk

Abstract

Objectives In a prospective phase IV trial of the first-line oral treatment dimethyl fumarate (DMF), we examined dynamics of neurofilament light (NFL) chain in serum, plasma and cerebrospinal fluid (CSF) samples collected over 12 months from relapsing-remitting multiple sclerosis (RRMS) patients. NFL changes were related to disease activity.

Methods We examined NFL levels by single-molecule array in 88 CSF, 348 plasma and 131 sera from treatment-naïve RRMS patients (n=52), healthy controls (n=23) and a placebo group matched by age, sex and NFL (n=52). Plasma/sera were collected at baseline, and 1, 3, 6 and 12 months after DMF. CSF samples were collected at baseline and 12 months after DMF.

Results NFL concentration in CSF, plasma and serum correlated highly (p<0.0001 for all), but plasma levels were only 76.9% of paired serum concentration. After 12 months of DMF treatment, NFL concentration decreased by 73%, 69% and 55% in the CSF, serum and plasma (p<0.0001, respectively). Significant reduction in blood was observed after 6 and 12 months treatment compared with baseline (p<0.01 and p<0.0001, respectively) and to placebo (p<0.0001). Patients with NFL above the 807.5 pg/mL cut-off in CSF had 5.0-times relative risk of disease activity (p<0.001).

Conclusions This study provides Class II evidence that first-line DMF reduces NFL in both blood and CSF after 6 months and normalises CSF levels in 73% of patients. High NFL concentration in CSF after a year reflected disease activity. NFL levels were higher in serum than in plasma, which should be considered when NFL is used as a biomarker.

  • multiple sclerosis
  • biomarker
  • dimethyl fumarate
  • neurofilament
  • disease modifying therapy
  • cerebrospinal fluid
  • drug response

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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Footnotes

  • Contributors TS contributed with: concept and design, acquisition, analysis and interpretation of data, drafting of the manuscript, revision of the manuscript, critical revision of the manuscript for important intellectual content, statistical analysis. HHN contributed with: analysis, acquisition, interpretation of data and revision of manuscript. NP contributed with: analysis, interpretation of data and revision of manuscript. TP contributed with: analysis, interpretation of data and revision of manuscript. JPM contributed with: analysis, interpretation of data and revision of manuscript. NAM contributed with: acquisition of data and manuscript. MLE contributed with: acquisition of data and manuscript. MHR contributed with concept and design, acquisition, analysis, interpretation, manuscript and revision of manuscript. ZI contributed with concept and design, writing the protocol of the trial, obtaining the necessary research grants, analysis and interpretation of data, drafting of the manuscript, revision of the manuscript, critical revision of the manuscript for important intellectual content, study supervisor.

  • Funding This trial was funded by research grants from Biogen (TREMEND to ZI and TS), University of Southern Denmark (14/24200 to TS and ZI), Odense University Hospital (5798002573633 to TS and ZI) and The Danish Multiple Sclerosis Society (R367-A25341 to ZI).

  • Competing interests TS has served on scientific advisory boards, received support for congress participation, received speaker honoraria and received research support from Biogen and Novartis. NP is employee of and holds stock/stock options in Biogen. TP is employee of and holds stock/stock options in Biogen. JPM is employee of and holds stock/stock options in Biogen. HHN has served on scientific advisory boards, received support for congress participation, received speaker honoraria and received research support from Biogen, Merck-Serono, Lundbeck and Novartis. ZI has served on scientific advisory boards, served as a consultant, received support for congress participation, received speaker honoraria and received research support from Biogen, Merck-Serono, Sanofi-Genzyme, Lundbeck and Novartis.

  • Patient consent for publication Obtained.

  • Ethics approval This study was approved by the regional Committee of Health Research Ethics (S-20140015HLP/csf), the Danish Health and Medicines Authority (2014013769) and the European Clinical Trials Database (2014-000254-11).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request.

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