Serum Neurofilament Light Level May Predict MS Progression

Erik Greb

October 26, 2021

Serum concentration of neurofilament light (NfL) may predict disease progression in patients with multiple sclerosis, new research suggests.

In an analysis of an international cohort, risk for disease progression at 2 years was 2.6 times greater in patients with high serum NfL concentrations at baseline, compared with patients with normal concentrations.

"Our study is, to our knowledge, the first to investigate the associations of serum NfL, clinical, MRI, and optical coherence tomography [OCT] measures with disease progression in a real-world MS patient population," investigator Synne Brune, MD, neurology trainee and doctoral student at Oslo University Hospital and the University of Oslo in Norway, told Medscape Medical News.

The data emphasize that serum NfL is a useful biomarker for disease progression in a real-world MS patient population, she added.

The findings were presented at the virtual 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2021.

Prognostic Challenges

MS has a heterogeneous clinical course, and predicting patients' clinical outcomes remains challenging. In recent years, serum NfL level has been found to reflect ongoing inflammatory neuroaxonal injury. Researchers have proposed it as an accessible biomarker of disease activity, disability progression, treatment response, and prognosis in MS.

Disease activity can also be detected on MRI and OCT. The researchers investigated the individual and collective value of clinical, serum NfL, MRI, and OCT measures as predictors of subsequent disease activity in patients with MS.

They examined participants in the Sys4MS cohort, which enrolled patients in Barcelona, Berlin, Genoa, and Oslo. Investigators in that study collected serum samples at baseline and at 2 years. These samples were analyzed at a single center using a single-molecule array assay.

The current researchers classified participants' serum NfL concentrations as high (>8 pg/mL) or normal (<8 pg/mL). They based this cutoff on the 75th percentile of reference values for serum NfL concentrations among healthy controls.

The study's primary outcome was disease progression at 2-year follow-up. The researchers defined disease progression as three or more new cerebral MRI lesions, confirmed Expanded Disability Status Scale (EDSS) progression, or new clinical relapse.

A Sensitive Biomarker

In all, 309 patients with MS and 59 age- and sex-matched healthy controls were enrolled in the study. At baseline, 83% of patients had relapsing-remitting MS, and approximately 70% of patients were female. Mean age at inclusion was 43 years, mean disease duration was 11 years, and median EDSS score was 2.5.

At baseline, patients with progressive MS had higher serum NfL concentrations, compared with healthy controls, after adjustment for age and sex (P = .03). At 2-year follow-up, 226 patients remained in the study.

At baseline and follow-up, a cross-sectional analysis confirmed previous observations that high serum NfL concentrations are associated with increased clinical disability, higher T2 lesion count and new T2 lesions, high T2 lesion volume, and retinal axonal loss.

The investigators also found that patients with high serum NfL concentrations at baseline had a 2.6-fold increased risk for disease progression at 2-year follow-up. Clinical, OCT, and MRI measures were not independently associated with risk for disease progression in univariable or multivariable models.

The findings suggest that serum NfL is a sensitive biomarker of ongoing neuroaxonal degeneration, even in early stages of the disease, whereas cerebral and retinal atrophy advance more slowly and are more pronounced in later stages of the disease course, said Brune.

"Further studies exploring sequential serum NfL concentrations are needed, including establishing serum NfL age-related reference values," she added.

Moving Toward Clinical Practice  

"To date, there's been a great deal of work on NfL, but it has not translated yet to regular use in clinical practice," said E. Ann Yeh, MD, director of the Pediatric MS and Neuroinflammatory Disorders Program at the Hospital for Sick Children in Toronto, Canada, who commented on the findings for Medscape Medical News. Yeh did not participate in the study.

"This study is adding to evidence that will allow us to move from NfL as a research test to one that could be used in clinical practice to predict outcomes," she added.

The large, multicenter cohort and the use of a control population are among the study's strong points, said Yeh. In terms of demographic and disease-related variables, the study population also seems representative of the broader population of patients with MS. The investigation is nevertheless subject to the limitations inherent to observational studies, Yeh cautioned.

It is possible that the treatments themselves influenced the findings. "In this era of highly effective medications being administered, it may very well be that we may run into more challenges with being able to detect disease progression with measures such as MRI and OCT," said Yeh.

But the consensus among MS specialists is that serum NfL is a good biomarker. "Being able to use a marker like this as a very sensitive indicator of whether a medication is working will make a big difference to clinical trials and to our ability to understand our therapeutic effect in clinical trials and daily practice," Yeh concluded.

The study was funded by the European Commission, Instituto de Salud Carlos III in Spain, the Italian Ministry of Health, the German Ministry of Science, the Norwegian Research Council, the South-Eastern Norway Regional Health Authority, and Biogen Norway. Brune has received honoraria for lecturing from Biogen and Novartis. Disclosures for the other co-authors can be found with the original abstract. Yeh has disclosed no relevant financial relationships.

37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2021: Abstract 157. Presented October 15, 2021.

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