More Evidence for Neurofilament Light Chain as MS Biomarker

Damian McNamara

August 22, 2019

Serum levels of the biomarker neurofilament light chain (sNfL) increased significantly faster among people with multiple sclerosis (MS) who experienced worsening of their disability compared with others who were clinically stable over time in a large study.

At a median 10 years of follow-up, sNfL levels also were significantly associated with age, score on the Expanded Disability Status Scale (EDSS), MS disease subtype, and treatment with high potency medications.

In addition, investigators linked increased sNfL levels to greater brain fraction loss when they followed more than 600 adults with MS.

"While neurofilament light levels in the blood and CSF are consistently shown to serve as a drug response marker and a predictor of measures related to long-term disability outcome and disease acuity in MS, all published results so far are based on group comparisons," study author David Leppert, MD, Neurologic Clinic and Policlinic and Departments of Medicine, Biomedicine, and Clinical Research at the University Hospital Basel, University of Basel, Switzerland, told Medscape Medical News.

"In other words," he added, "this test is not yet validated for use in individual patients to monitor treatment, predict disease progression, or response to treatment." He also cautioned that increased NfL levels reflect neuronal damage, which is not exclusive to MS.

The study was published online August 12 in JAMA Neurology.

Addressing an Unmet Need

Lack of sensitive laboratory measures of MS worsening, progression, and treatment response are an important unmet need, the researchers note. They point out that the two markers considered clinically meaningful — cerebrospinal fluid oligoclonal bands and measurements of intrathecal IgG synthesis — date back more than 50 years.

A blood-based biomarker for MS would be ideal, the researchers note, because "the use of repeated lumbar punctures for assessment of biomarkers is impractical." Although lab assays to measure sNfL from peripheral blood exist..."long-term studies of sNfL concentrations and association with disease outcomes are lacking."

To learn more, Leppert and colleagues evaluated data from 607 people with MS from the University of California, San Francisco EPIC (Expression, Proteomics, Imaging, Clinical) dataset. Enrollment started in July 2004. The sNfL concentrations were measured at regular intervals up to 12 years (mean, 10 years).

The study included 93 people with clinically isolated syndrome, 435 with relapsing-remitting MS, 25 with primary progressive MS, and 54 with secondary progressive MS. Mean age was 43 years and 70% were women.

Significant Associations

Leppert and colleagues found significantly higher baseline concentrations of sNfL among people who then experienced one or more relapses in the first 5 years of the study compared with those who did not (P < .001).

The investigators also found a significant interaction between worsening EDSS values and changes in sNfL concentrations over time when they compared 159 "progressors" to another 248 "nonprogressors" in the study (P < .001). The steeper trajectory of sNfL levels among progressors remained significant after controlling for age, sex, and disease duration.

In contrast, sNfL levels at different time points were not associated with long-term disability progression.

To evaluate the role of treatment on sNfL levels, the researchers compared untreated participants to those treated with platform therapies or with intermediate or high-potency therapies. Treatment with high potency therapies was associated with a more significant decrease in sNfL concentrations compared with no treatment in the first 3 years.

In addition, the same observation emerged at 5 years versus both platform and untreated patients, "suggesting that drugs with greater effectiveness produced more robust changes for sNfL levels."

Leppert and colleagues also evaluated clinical progression according to annual MRI findings in a subset of 372 participants with clinically isolated syndrome or relapsing-remitting MS. They found T2 lesion volume was associated with sNfL levels over time, and there was an association between sNfL levels and brain fraction. These associations remained significant when adjusted for covariates.

"Our work adds to the large evidence that increased NfL levels represent a relevant and tangible treatment target in a variety of neurological diseases," Leppert said.

When asked if the current findings are sufficient to encourage more widespread longitudinal monitoring of sNfL levels in individuals, Leppert replied, "Not yet. NfL is validated as a measure for three clinical features, but only on the group level."

"The community is working hard to bring this biomarker to the next development steps after which it is fit for use in individual persons," he added.

'Good News for MS Patients'

"This study illustrates that although sNfL correlates with disease severity and disease activity, it doesn't predict long-term course very well — probably because MS therapies can alter that course. That's good news for MS patients," Robert J. Fox, MD, FAAN, staff neurologist at the Mellen Center for MS and vice-chair of research at the Neurologic Institute, Cleveland Clinic, Ohio, told Medscape Medical News when asked for comment.

"Additionally, the utility of sNfL in individual patient management remains unknown," he said, "and will be important to understand before we can consider utilizing this test in everyday patient management."

The study was supported by grants from the National Institutes of Health, US National Multiple Sclerosis Society, and Swiss National Research Foundation. Novartis provided additional funding to purchase reagents for the single molecule array assay. Leppert has reported receiving a salary from Novartis during the conduct of the study and being a Novartis employee until January 31, 2019. Fox has reported no relevant financial relationships.

JAMA Neurol. Published online August 12, 2019. Article

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