Neurofilament light levels are associated with long-term outcomes in multiple sclerosis

Jens Kuhle, Tatiana Plavina, Christian Barro, Giulio Disanto, Dipen Sangurdekar, Carol M Singh, Carl de Moor, Bob Engle, Bernd C Kieseier, Elizabeth Fisher, Ludwig Kappos, Richard A Rudick, Jaya Goyal, Jens Kuhle, Tatiana Plavina, Christian Barro, Giulio Disanto, Dipen Sangurdekar, Carol M Singh, Carl de Moor, Bob Engle, Bernd C Kieseier, Elizabeth Fisher, Ludwig Kappos, Richard A Rudick, Jaya Goyal

Abstract

Background: Neurofilament light chain (NfL) is a promising marker of disease activity/treatment response in multiple sclerosis (MS), although its predictive value for long-term clinical outcomes remains unclear.

Objective: We measured NfL from a phase 3 trial in relapsing-remitting MS and investigated its association with outcomes after 8 and 15 years.

Methods: NfL concentrations were measured by single molecule array assay in cerebrospinal fluid (CSF) from MS patients (n = 235) in a 2-year randomized clinical trial (RCT) of intramuscular interferon β-1a, and in serum (n = 164) from the extension study.

Results: Year 2 CSF and Year 3 serum NfL were associated with brain parenchymal fraction (BPF) change over 8 years (p < 0.0001, r = -0.46; p < 0.05. r = -0.36, respectively) and were predictive of reaching Expanded Disability Status Scale (EDSS) ⩾ 6.0 at Year 8 (odds ratio (OR) (upper vs lower tertile) = 3.4; 95% confidence interval (CI) = 1.2-9.9, p < 0.05; OR = 11.0, 95% CI = 2.0-114.6; p < 0.01, respectively). Serum NfL concentration (Year 4) was predictive of reaching EDSS score ⩾6.0 at 15 years (OR (upper vs lower tertile) = 4.9; 95% CI = 1.4-20.4; p < 0.05). NfL concentrations were complementary to 2-year BPF change in predicting long-term outcomes.

Conclusion: Serum and CSF NfL concentrations were associated with long-term clinical outcomes in MS patients and are promising biomarkers for disease severity stratification supporting treatment decisions.

Keywords: MRI; Neurofilament; multiple sclerosis.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J.K.’s institution (University Hospital Basel) received and used exclusively for research support consulting fees from Biogen, Novartis, Protagen AG, Roche, and Teva; speaker fees from Biogen, Genzyme, Novartis, Roche, and the Swiss Multiple Sclerosis Society; travel expenses from Merck Serono, Novartis, and Roche; grants from Bayer AG, Biogen, the ECTRIMS Research Fellowship Programme, Genzyme, Merck, Novartis, Roche, the Swiss Multiple Sclerosis Society, the Swiss National Research Foundation (320030_160221), and the University of Basel. T.P., D.S., C.M.S., C.d.M., B.E., B.C.K., E.F., and R.A.R. are employees of and hold stock/stock options in Biogen. C.B. has received travel support by Teva and Novartis. G.D. has nothing to disclose. L.K.’s institution (University Hospital Basel) received in the last 3 years and used exclusively for research support at the Department: steering committee, advisory board, and consultancy fees from Actelion, Alkermes, Almirall, Bayer, Biogen, Celgene/Receptos, df-mp, EXCEMED, GeNeuro SA, Genzyme, Japan Tobacco, Merck, Minoryx, Mitsubishi Pharma, Novartis, Roche, Sanofi-Aventis, Santhera, Teva, Vianex, and royalties for Neurostatus-UHB products. J.G. was employed at Biogen at the time of the analysis and holds stock/stock options in Biogen.

Figures

Figure 1.
Figure 1.
Schematic diagram of the study and available data points and samples. Values indicate the number of available data points or samples at each time point. CSF samples were available from 235 patients: 172 at baseline and 107 at Year 2; 44 had CSF samples available from Year 0 to Year 2. Serum samples were available from 164 patients: 101 at Year 3 and 136 at Year 4; 73 had serum samples available from Year 3 to Year 4. BL: baseline; BPF: brain parenchymal fraction; CSF: cerebrospinal fluid; EDSS: Expanded Disability Status Scale; IFN: interferon; IM: intramuscular; MSCRG: Multiple Sclerosis Collaborative Research Group; MSFC: Multiple Sclerosis Functional Composite; Y: year. aSelf-reported.
Figure 2.
Figure 2.
Correlation between CSF concentration at Year 2 and serum NfL concentration at Year 3 with 8-year outcomes. (a) CSF NfL and BPF change. (b) CSF NfL and EDSS change. (c) Serum NfL and BPF change. (d) Serum NfL and EDSS change. Scatterplots (log base 2) were used to depict the association between NfL and clinical and radiological parameters; r and p values were computed to characterize the association between NfL levels and clinical and radiological assessments. BPF: brain parenchymal fraction; CSF: cerebrospinal fluid; EDSS: Expanded Disability Status Scale; NfL: neurofilament light; r: Spearman’s rank correlation coefficient.
Figure 3.
Figure 3.
ORs for reaching an EDSS score of 6.0. (a) After 8 years of follow-up. (b) After 15 years of follow-up. For the purpose of illustration, the range of NfL assessments was broken down into tertiles; n indicates the total for each category. Hypothesis testing of the association of NfL levels with cumulative incidence of progression to EDSS score ⩾6.0 was conducted using Fisher’s exact test, as well as Wald chi-square test based on Firth’s penalized univariate logistic regression. OR are shown relative to the lowest tertile. EDSS: Expanded Disability Status Scale; NfL: neurofilament light chain; NS: not significant; OR: odds ratio.
Figure 4.
Figure 4.
Proportion of patients reaching EDSS score ⩾6.0 at Year 8 stratified by BPF change and NfL levels. (a) CSF: the proportion of patients reaching an EDSS ⩾6.0 at Year 8 was stratified by BPF change from Year 0 to Year 2 and mean (Year 0 and Year 2) CSF NfL levels (below or above median). (b) Serum: the proportion of patients reaching an EDSS ⩾6.0 at Year 8 was stratified by BPF change from Year 0 to Year 2 and mean (Year 3 and Year 4) serum NfL levels (below or above median). Hypothesis testing of the association of NfL levels with cumulative incidence of progression to an EDSS score ⩾6.0 was conducted using Fisher’s exact test. Mean NfL levels represent the mean of two time points when both measurements were available, and a single value when only one measurement was available. Light gray bars indicate NfL below median; dark gray bars indicate NfL above median. BPF: brain parenchymal fraction; CSF: cerebrospinal fluid; EDSS: Expanded Disability Status Scale; NfL: neurofilament light.

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