Blood neurofilament light chain as a biomarker of MS disease activity and treatment response

Abstract

Objective: To assess the value of blood neurofilament light chain (NfL) as a biomarker of recent, ongoing, and future disease activity and tissue damage and its utility to monitor treatment response in relapsing-remitting multiple sclerosis.

Methods: We measured NfL in blood samples from 589 patients with relapsing-remitting multiple sclerosis (from phase 3 studies of fingolimod vs placebo, FREEDOMS and interferon [IFN]-β-1a, TRANSFORMS) and 35 healthy controls and compared NfL levels with clinical and MRI-related outcomes.

Results: At baseline, NfL levels (pg/mL) were higher in patients than in healthy controls (30.5 and 27.0 vs 16.9, p = 0.0001) and correlated with T2 lesion load and number of gadolinium-enhancing T1 lesions (p < 0.0001, both). Baseline NfL levels, treatment, and number of new or enlarging T2 lesions during the studies predicted NfL levels at the end of study (all p < 0.01). High vs low baseline NfL levels were associated (estimate [95% confidence interval]) with an increased number of new or enlarging T2 lesions (ratio of mean: 2.64 [1.51-4.60]; p = 0.0006), relapses (rate ratio: 2.53 [1.67-3.83]; p < 0.0001), brain volume loss (difference in means: -0.78% [-1.02 to -0.54]; p < 0.0001), and risk of confirmed disability worsening (hazard ratio: 1.94 [0.97-3.87]; p = 0.0605). Fingolimod significantly reduced NfL levels already at 6 months (vs placebo 0.73 [0.656-0.813] and IFN 0.789 [0.704-0.884]), which was sustained until the end of the studies (vs placebo 0.628 [0.552-0.714] and IFN 0.794 [0.705-0.894]; p < 0.001, both studies at all assessments).

Conclusions: Blood NfL levels are associated with clinical and MRI-related measures of disease activity and neuroaxonal damage and have prognostic value. Our results support the utility of blood NfL as an easily accessible biomarker of disease evolution and treatment response.

Figure 1. Baseline NfL concentrations in patients with relapsing-remitting multiple sclerosis and healthy controls

The box represents the interquartile range, with the median represented by the line in the center; n = number of patients with evaluable data. The black dot represents the GeoMean value and the whiskers indicate the 10^th and 90^th percentiles. Dotted line represents plasma NfL (pg/mL, median) concentrations in healthy controls. The p Values are based on a Wilcoxon rank sum test. GeoMean = geometric mean; Max = maximum; Min = minimum; NfL = neurofilament light chain.

Figure 2. Blood NfL levels by T2 lesion volume (mm³) at baseline: (A) FREEDOMS, (B) TRANSFORMS

The box represents the interquartile range, with the median represented by the line in the center; n = number of patients with evaluable data. The black dot represents the geometric mean value and the whiskers indicate the 10^th and 90^th percentiles. Dotted line represents plasma NfL (pg/mL, median) concentrations in healthy controls. NfL = neurofilament light chain.

Figure 3. Blood NfL levels by Gd+ T1 lesion count at baseline: (A) FREEDOMS, (B) TRANSFORMS

The box represents the interquartile range, with the median represented by the line in the center; n = number of patients with evaluable data. The black dot represents the geometric mean value and the whiskers indicate the 10^th and 90^th percentiles. Dotted line represents plasma NfL (pg/mL, median) concentrations in healthy controls. Gd+ = gadolinium-enhancing; NfL = neurofilament light chain.

Figure 4. Effect of fingolimod on NfL levels in blood, (A) compared with placebo, FREEDOMS study; (B) compared with interferon-β-1a, TRANSFORMS study

The figure shows geometric means of NfL with 95% confidence intervals and statistical tests from mixed models for repeated measurements of postbaseline NfL. Dotted line represents plasma NfL (pg/mL, geometric mean) concentrations in healthy controls. ***p < 0.0001. n = number of patients with evaluable data. NfL = neurofilament light chain.