sNfL Levels Linked to Relapse-free Disability Progression, Move to SPMS

Measuring levels of the protein serum neurofilament light chain (NfL) can help to identify people with relapsing-remitting multiple sclerosis (RRMS) at higher risk of relapse-free disability progression or conversion to secondary-progressive disease, according to a study from Germany.

The study, “NfL predicts relapse-free progression in a longitudinal multiple sclerosis cohort study: Serum NfL predicts relapse-free progression,” was published in EBioMedicine.

Most people with multiple sclerosis (MS) are first diagnosed with RRMS, a disease form characterized by periods of worsening symptoms (relapses) followed by times when symptoms ease (remission). However, RRMS almost always evolves into secondary-progressive multiple sclerosis (SPMS), a form where symptoms gradually get worse over time, with or without relapses.

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The distinction between RRMS and SPMS is largely considered a convenience of medical labeling. It is possible for someone with RRMS to experience worsening disability without having a relapse while still not qualifying for a diagnosis of SPMS. Little is known about what factors affect such disease worsening, or the conversion from RRMS to SPMS.

This makes it harder for doctors to accurately predict a person’s likely disease course (prognosis), which can be anxiety-inducing for patients and complicate treatment decisions.

NfL is a structural protein found in neurons (nerve cells). When neurons are damaged, as occurs in MS, NfL can be released into the blood. As such, measuring blood levels of this protein may be a useful prognostic tool in MS.

Researchers enrolled 196 people with RRMS or clinically isolated syndrome (CIS) in a study at the University Medicine Mainz from 2010 to 2016. Their median age at study entry was 35, and over two-thirds were female. Blood NfL levels — termed serum NfL or sNfL — were measured at the study’s start (baseline), and at follow-up after a median of six years.

“In this study, we prospectively evaluated the temporal development of sNfL in a six-year longitudinal cohort study and examined the ability of sNfL to predict later disability progression and SPMS conversion,” the researchers wrote.

Over the course of follow-up, 34 patients experienced confirmed relapse-free disability worsening, and 27 converted to SPMS (some patients were in both groups).

Statistical analyses demonstrated that the risk of relapse-free disability progression at one year was significantly increased in individuals with abnormally high baseline sNfL levels. In particular, sNfL levels higher than 7.3 pg/ml (picograms per milliliter) were associated with a greater risk, though the researchers noted that the optimal cut-off value may vary depending on methods used to measure the protein and a patient’s age.

These results support “the application of sNfL as a biomarker for patient-individualized treatment decisions in clinical practice,” the team concluded. “In a next step, this patient-individualized treatment approach and the proposed age-dependent sNfL cut-off needs to be validated in prospective studies.”

sNfL levels at baseline were not significantly different among patients who did or did not convert to SPMS. However, those who converted tended to have a higher ratio of sNfL at follow-up compared with sNfL at baseline — in other words, a more drastic increase in levels of this protein over time, the researchers found.

“This indicates that longitudinal assessment of sNfL levels might be helpful in shortening the time necessary to diagnose SPMS as early as possible,” they wrote, noting that diagnostic delays for SPMS are commonplace.

Additional analyses indicated that high sNfL levels at follow-up were associated with increased inflammation in the brain at baseline, independent of disability progression. This suggests that measuring this protein’s levels may help to “identify those early inflammatory processes resulting in later axonal [nerve fiber] loss associated with [disability]-progression in the long run,” the researchers wrote.

Overall similar results were found in a comparable group of 204 RRMS and CIS patients followed at separate institutions in Germany, further supporting these findings.

“sNfL measurements are capable of predicting disability progression at 12 months prior to six-year follow-up, due to their ability to reflect disability relevant neuronal damage and are able to discriminate SPMS patients thereby facilitating an earlier diagnosis of patients at risk,” the researchers concluded.