Dimethyl fumarate decreases neurofilament light chain in CSF and blood of treatment naïve relapsing MS patients

Tobias Sejbaek*, Helle Hvilsted Nielsen, Natasha Penner, Tatiana Plavina, Jason P. Mendoza, Nellie Anne Martin, Maria Louise Elkjaer, Mads Henrik Ravnborg, Zsolt Illes

*Corresponding author for this work

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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.

Original languageEnglish
JournalJournal of Neurology, Neurosurgery and Psychiatry
Volume90
Issue number12
Pages (from-to)1324-1330
ISSN0022-3050
DOIs
Publication statusPublished - Dec 2019

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Intermediate Filaments
Cerebrospinal Fluid
Serum
Relapsing-Remitting Multiple Sclerosis
Dimethyl Fumarate
Placebos
Research Design
Age Groups

Keywords

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

Cite this

@article{ab8004451c064a3c823f9b8c77bd0ee6,
title = "Dimethyl fumarate decreases neurofilament light chain in CSF and blood of treatment na{\"i}ve relapsing MS patients",
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-na{\"i}ve 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.",
keywords = "biomarker, cerebrospinal fluid, dimethyl fumarate, disease modifying therapy, drug response, multiple sclerosis, neurofilament",
author = "Tobias Sejbaek and Nielsen, {Helle Hvilsted} and Natasha Penner and Tatiana Plavina and Mendoza, {Jason P.} and Martin, {Nellie Anne} and Elkjaer, {Maria Louise} and Ravnborg, {Mads Henrik} and Zsolt Illes",
year = "2019",
month = "12",
doi = "10.1136/jnnp-2019-321321",
language = "English",
volume = "90",
pages = "1324--1330",
journal = "Journal of Neurology, Neurosurgery and Psychiatry",
issn = "0022-3050",
publisher = "B M J Group",
number = "12",

}

Dimethyl fumarate decreases neurofilament light chain in CSF and blood of treatment naïve relapsing MS patients. / Sejbaek, Tobias; Nielsen, Helle Hvilsted; Penner, Natasha; Plavina, Tatiana; Mendoza, Jason P.; Martin, Nellie Anne; Elkjaer, Maria Louise; Ravnborg, Mads Henrik; Illes, Zsolt.

In: Journal of Neurology, Neurosurgery and Psychiatry, Vol. 90, No. 12, 12.2019, p. 1324-1330.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Dimethyl fumarate decreases neurofilament light chain in CSF and blood of treatment naïve relapsing MS patients

AU - Sejbaek, Tobias

AU - Nielsen, Helle Hvilsted

AU - Penner, Natasha

AU - Plavina, Tatiana

AU - Mendoza, Jason P.

AU - Martin, Nellie Anne

AU - Elkjaer, Maria Louise

AU - Ravnborg, Mads Henrik

AU - Illes, Zsolt

PY - 2019/12

Y1 - 2019/12

N2 - 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.

AB - 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.

KW - biomarker

KW - cerebrospinal fluid

KW - dimethyl fumarate

KW - disease modifying therapy

KW - drug response

KW - multiple sclerosis

KW - neurofilament

U2 - 10.1136/jnnp-2019-321321

DO - 10.1136/jnnp-2019-321321

M3 - Journal article

C2 - 31611264

AN - SCOPUS:85073548885

VL - 90

SP - 1324

EP - 1330

JO - Journal of Neurology, Neurosurgery and Psychiatry

JF - Journal of Neurology, Neurosurgery and Psychiatry

SN - 0022-3050

IS - 12

ER -