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Page 6 Bozzetti et al. Neuroimmunol Neuroinflammation 2021;8:1-13 I http://dx.doi.org/10.20517/2347-8659.2020.26

concentration measured at year 2 from the beginning of the trial and EDSS changes, as well as brain
atrophy, expressed by brain parenchymal fraction (BPF) change at 8 years follow-up. Similarly, serum NfL
levels at 3 years displayed a correlation with both BPF and EDSS changes at 8 years follow-up, whereas
[47]
NfL values at 4 years showed a significant association with EDSS changes over 15 years . CSF NfL
concentrations at year 2 and serum NfL levels at year 3 in the upper tertile predicted an increased risk of
[47]
reaching an EDSS score of 6.0 or higher at 8 years follow-up . During the last years, a composite clinical
and paraclinical definition of “no disease activity” (NEDA) that includes the absence of relapses, disability
[55]
worsening, and new or enlarging MRI lesions was proposed as the main target of MS treatment . Several
studies have reported that NfL levels at baseline are significantly lower in patients with no evidence of
activity during the subsequent follow-up [25,48] , therefore showing an accuracy of 85% in correctly classifying
[25]
NEDA3 cases over the following 2 years . These findings have led to the proposal of expanding the
concept of NEDA, taking into consideration also the assessment of brain atrophy and the evaluation of
[56]
serum and CSF biomarkers, including NfL . Finally, a recent longitudinal study in a Norwegian cohort of
44 patients with newly diagnosed MS and a long-term follow-up of 10 years demonstrated that CSF NfL
values were significantly higher in patients evolving from RRMS to secondary progressive multiple sclerosis
(SPMS) over 5 years, suggesting a possible role of NfL in predicting the risk of a secondary progressive
[54]
disease course .
NfL levels as a measure of treatment response
Besides the role as a diagnostic and disease activity biomarker, one of the most attractive applications of
NfL is their possible use in monitoring therapeutic response. The evidence that serum NfL levels are lower
in patients under DMT [9,49] and that initiation and escalation of such therapies significantly decrease NfL
[49]
concentrations has further confirmed this hypothesis. In particular, starting on an IFNB-1a therapy
[20]
led to a sustained reduction of serum NfL levels over the following 12 and 24 months . Natalizumab
initiation resulted in a 3-fold reduction in CSF NfL values, which reached levels compatible with those
measured in healthy controls . The efficacy of fingolimod in reducing NfL concentration in serum and
[38]
[39]
[38]
[42]
CSF has been demonstrated, also in comparison with IFN , in a phase 3 placebo-controlled clinical
trial (FREEDOMS) [38,42] and in a phase 3 active-controlled vs. IFN trial (TRANSFORMS) . NfL levels
[38]
have been reported to be significantly reduced by 73% in CSF, 69% in serum, and 55% in plasma 1 year
after dimethyl fumarate initiation in a prospective open-label phase 4 clinical trial designed to evaluate
the effect of dimethyl fumarate in a cohort of newly-diagnosed RRMS patients (TREMEND). NfL values
were similar to those measured in healthy controls in all serum samples, in 96% of plasma samples, and in
[46]
72% of CSF samples of treated patients 1 year after treatment initiation . Finally, the therapeutic switch
from IFNB or glatiramer acetate to rituximab has been demonstrated to produce a significant (i.e., 21%)
[53]
reduction of CSF NfL values during the subsequent year in a cohort of 75 patients with RRMS . The role
of NfL as drug-response markers has recently been confirmed in a study analyzing the distribution of NfL
in RRMS patients starting DMTs and the evolution of NfL values over time. The authors observed that
the reduction in plasma NfL concentrations under DMT differed according to specific drugs, although
levels were also influenced by baseline characteristics, clinical improvement, and possibly NfL kinetics. In
particular, the largest reduction in NfL values was noted on treatment with alemtuzumab and the lowest on
teriflunomide, while reduced NfL levels similar to that observed under treatment with alemtuzumab were
noted under dimethyl fumarate, fingolimod, and natalizumab. However, groups were not homogeneous
for characteristics influencing NfL levels, including age, disease duration, and disease severity, potentially
resulting in an indication bias, which the authors tried to overcome with statistical adjustments for baseline
[57]
characteristics .
Taken together, these data led to serum NfL being proposed as a candidate and useful biomarker for
surveilling subclinical activity in clinically stable RRMS patients and for measuring and predicting
[49]
disease activity and treatment response, although commonly accepted cut-off values are still lacking and
NfL concentrations are not comparable between different studies.