Serum neurofilament light chain predicts long term clinical outcomes in multiple sclerosis

Abstract

Serum neurofilament light chain (NfL) is emerging as an important biomarker in multiple sclerosis (MS). Our objective was to evaluate the prognostic value of serum NfL levels obtained close to the time of MS onset with long-term clinical outcomes. In this prospective cohort study, we identified patients with serum collected within 5 years of first MS symptom onset (baseline) with more than 15 years of routine clinical follow-up. Levels of serum NfL were quantified in patients and matched controls using digital immunoassay (SiMoA HD-1 Analyzer, Quanterix). Sixty-seven patients had a median follow-up of 18.9 years (range 15.0–27.0). The median serum NfL level in patient baseline samples was 10.1 pg/mL, 38.5% higher than median levels in 37 controls (7.26 pg/mL, p = 0.004). Baseline NfL level was most helpful as a sensitive predictive marker to rule out progression; patients with levels less 7.62 pg/mL were 4.3 times less likely to develop an EDSS score of ≥ 4 (p = 0.001) and 7.1 times less likely to develop progressive MS (p = 0.054). Patients with the highest NfL levels (3rd-tertile, > 13.2 pg/mL) progressed most rapidly with an EDSS annual rate of 0.16 (p = 0.004), remaining significant after adjustment for sex, age, and disease-modifying treatment (p = 0.022). This study demonstrates that baseline sNfL is associated with long term clinical disease progression. sNfL may be a sensitive marker of subsequent poor clinical outcomes.

Serum Neurofilament Light Chain Measurement in MS: Hurdles to Clinical Translation

“…In clinically isolated syndromes, higher sNfL independently predicted faster conversion to clinically definite MS (Disanto et al, 2016). Following diagnosis, higher sNfL has been associated with short and long term poorer outcomes, including relapses, EDSS score progression including progression independent of relapse-activity, clinical conversion to a progressive phenotype, poorer cognitive measures as well as both MRI lesion activity and atrophy (Disanto et al, 2017;Barro et al, 2018;Chitnis et al, 2018;Siller et al, 2018;Cantó et al, 2019;Lorscheider and Benkert, 2020;Thebault et al, 2020a). Some experts consider this test to be on the cusp of widespread clinical adoption (Leppert and Kuhle, 2019), while others remain skeptical (Javed and Stankiewicz, 2020).…”

Longitudinal Serum Neurofilament Levels of Multiple Sclerosis Patients Before and After Treatment with First-Line Immunomodulatory Therapies

“…In most studies, group effects of treatments on neurofilaments are investigated, which already indicate the applicability of serum NfL as a therapy response marker [22,24] and as a prognostic marker for long-term clinical outcomes in MS [25]. However, longitudinal data of intraindividual NfL levels over disease course under immunomodulatory therapies in well-characterized MS patients are widely missing and only described rarely [26,27].…”

Should We Use Clinical Tools to Identify Disease Progression?

“…Progressively, active inflammatory lesions may account for a degenerative axonopathy, which would clinically lead to disability progression ( 24 ). Damage assessed by NfL is observed already in early stages of RRMS patients who develop secondary disability progression in the disease course ( 25 ). Likewise, it has been suggested in a French cohort that the onset of disability is at a great part an age-related process as the onset age of the PPMS and the diagnosis of SPMS are done at a very similar age ( 22 , 26 ).…”

“…The identification of NfL could play an interesting role in detecting disease activity and further neurological damage as already stated above ( 40 ). A recent study correlated high sNfL at early stages of the disease with an increased risk of disability progression in the next 15 years ( 25 ).…”

“…Beyond imaging, other structural biomarkers are under development and validation in progressive MS. Neurofilament light chain (Nfl) is a novel marker that can be detected in serum or in cerebrospinal fluid with a good correlation between both measures ( 40 , 53 , 54 ). This non-specific biomarker serves as evidence of neuronal destruction and has a good correlation with MRI measures and possible with the risk of developing SPMS ( 25 , 55 , 56 ). However, technical methods for the analysis and Nfl concentrations in healthy subjects and at early phases of the disease should be addressed ( 56 ).…”