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. 2019 Nov 1;76(11):1359-1366.
doi: 10.1001/jamaneurol.2019.2137.

Association Between Serum Neurofilament Light Chain Levels and Long-term Disease Course Among Patients With Multiple Sclerosis Followed up for 12 Years

Ester Cantó  1 , Christian Barro  2 , Chao Zhao  1 , Stacy J Caillier  1 , Zuzanna Michalak  2 , Riley Bove  1 , Davorka Tomic  3 , Adam Santaniello  1 , Dieter A Häring  3 , Jill Hollenbach  1 , Roland G Henry  1 , Bruce A C Cree  1 , Ludwig Kappos  2   4 , David Leppert  2 , Stephen L Hauser  1 , Pascal Benkert  5 , Jorge R Oksenberg  1 , Jens Kuhle  2
Affiliations

Association Between Serum Neurofilament Light Chain Levels and Long-term Disease Course Among Patients With Multiple Sclerosis Followed up for 12 Years

Ester Cantó et al. JAMA Neurol. .

Abstract

Importance: Blood sample-based biomarkers that are associated with clinically meaningful outcomes for patients with multiple sclerosis (MS) have not been developed.

Objective: To evaluate the potential of serum neurofilament light chain (sNFL) measurements as a biomarker of disease activity and progression in a longitudinal MS data set.

Design, setting, and participants: Single-center, ongoing, prospective observational cohort study of 607 patients with MS from the longitudinal EPIC (Expression, Proteomics, Imaging, Clinical) study at the University of California, San Francisco from July 1, 2004, through August 31, 2017. Clinical evaluations and sample collection were performed annually for 5 years, then at different time points for up to 12 years, with a median follow-up duration of 10 (interquartile range, 7-11) years. Serum NFL levels were measured using a sensitive single molecule array platform and compared with clinical and magnetic resonance imaging variables with the use of univariable and multivariable analyses.

Main outcomes and measures: The main outcomes were disability progression defined as clinically significant worsening on the Expanded Disability Status Scale (EDSS) score and brain fraction atrophy.

Results: Mean (SD) age of the 607 study participants at study entry was 42.5 (9.8) years; 423 (69.7%) were women; and all participants were of non-Hispanic European descent. Of 3911 samples sequentially collected, 3904 passed quality control for quantification of sNFL. Baseline sNFL levels showed significant associations with EDSS score (β, 1.080; 95% CI, 1.047-1.114; P < .001), MS subtype (β, 1.478; 95% CI, 1.279-1.707; P < .001), and treatment status (β, 1.120; 95% CI, 1.007-1.245; P = .04). A significant interaction between EDSS worsening and change in levels of sNFL over time was found (β, 1.015; 95% CI, 1.007-1.023; P < .001). Baseline sNFL levels alone were associated with approximately 11.6% of the variance in brain fraction atrophy at year 10. In a multivariable analysis that considered sex, age, and disease duration, baseline sNFL levels were associated with 18.0% of the variance in brain fraction atrophy at year 10. After 5 years' follow-up, active treatment was associated with lower levels of sNFL, with high-potency treatments associated with the greater decreases in sNFL levels compared with platform therapies (high-potency vs untreated: β, 0.946; 95% CI, 0.915-0.976; P < .001; high-potency vs platform: β, 0.972; 95% CI, 0.948-0.998; P = .04).

Conclusions and relevance: This study found that statistically significant associations of sNFL with relevant clinical and neuroimaging outcomes in MS were confirmed and extended, supporting the potential of sNFL as an objective surrogate of ongoing MS disease activity. In this data set of patients with MS who received early treatment, the prognostic power of sNFL for relapse activity and long-term disability progression was limited. Further prospective studies are necessary to assess the assay's utility for decision-making in individual patients.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Barro reported receiving a conference travel grant from Novartis. Dr Bove reported receiving personal fees from Roche-Genentech, personal fees from Genzyme Sanofi, grants from Akili Interactive, and personal fees from Biogen IDEC outside the submitted work. Dr Tomic reported receiving a salary from Novartis during the conduct of the study outside the submitted work, and employment with Novartis Pharma AG. Dr Henry reported receiving grants and personal fees from Roche-Genentech, personal fees from Novartis, and personal fees from Sanofi outside the submitted work. Dr Cree reported receiving personal fees from AbbVie, Akili, Alexion, Biogen, EMD Serono, GeNeuro, Novartis, Sanofi Genzyme outside the submitted work. Dr Kappos reported receiving research support from Actelion, Almirall, Allergan, Baxalta, Bayer, Biogen, Celgene/Receptos, CSL Behring, Desitin, df-mp, Excemed, Genzyme, Japan Tobacco, Merck, Minoryx, Mitsubishi Pharma, Novartis, Pfizer, Roche, Sanofi, Teva, and Vianex; and grants from Bayer, Biogen, Novartis, Swiss MS Society, Swiss National Research Foundation, Merck, and CSL Behring outside the submitted work. Dr Leppert reported receiving a salary from Novartis during the conduct of the study and being a Novartis employee until January 31, 2019. Dr Hauser reported receiving personal fees from Bionure, Symbiotix, Annexon, Molecular Stethoscope, Alector, and Neurona Therapeutics outside the submitted work; and receiving travel reimbursement and writing assistance from F. Hoffman–La Roche Ltd for CD20-related meetings and presentations. Dr Kuhle reported receiving research support from Novartis during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Change Over Time of Serum Neurofilament Light Chain (sNFL) Levels in Patients With Multiple Sclerosis (MS) in Different Treatment Groups
The graphs represent the group means of sNFL over time. Levels of sNFL show a different rate of change over time in patients treated with high-potency therapies compared with those receiving platform therapy or those who were untreated during a period of 3 and 5 years. The analysis includes patients with relapsing-remitting multiple sclerosis, clinically isolated syndrome, secondary progressive MS, and primary progressive MS, analyzed as a single group. Dashed lines represent 95% CIs.
Figure 2.
Figure 2.. Association of Serum Neurofilament Light Chain (sNFL) Level at Baseline With Percentage of Brain Fraction Change Over Time
In a multivariable model including age, disease duration, and sex, baseline sNFL levels were significantly associated with the percentage of brain fraction change across time.
See this image and copyright information in PMC

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