ECTRIMS 2023: Blood biomarker may help to predict disability in MS

Blood levels of neurofilament light chain (NfL), a marker of nerve damage, were seen to increase about a year or two prior to disability worsening in people with multiple sclerosis (MS), particularly among patients whose disease progressed without any relapse activity.

That’s according to new data presented at the joint meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), held last week in Italy.

The researchers said these blood biomarker findings — presented in a talk titled “Elevated Serum Neurofilament Light Chain Precedes and Predicts Disease Progression in Multiple Sclerosis” — could prove pivotal both in the clinic and in trials.

“This work documents the occurrence of [nerve fiber damage] in advance of, not co-incident with, clinical worsening, particularly in subjects with silent progression [or] progression independent of relapse activity,” the researchers wrote in their abstract.

These findings “could define a therapeutic window for intervention in the clinical setting and have significant implication for the design of clinical trials,” they wrote.

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Investigating the link between disease progression and NfL levels

The symptoms of MS are driven by inflammation in the brain and spinal cord, which causes damage to axons, the long wire-like fibers that nerve cells use to connect with each other.

NfL, short for neurfilament light chain, is a protein that normally helps provide structural support to axons. When these nerve fibers are damaged, however, NfL is released into blood and other bodily fluids. As such, NfL can be a useful marker of axon damage.

The researchers now sought to better understand how the timing of axon damage, as assessed by NfL changes, relates to disability progression in people with MS.

“One big question that remains is how NfL is associated with disease progression,” said Ahmed Abdelhak, MD, a professor at the University of California San Francisco, who presented the findings at the meeting.

Most people with MS experience relapses, or flares, where symptoms suddenly worsen. Symptoms usually ease once the relapse is over, but sometimes they can persist, resulting in long-term disability. This is sometimes referred to as confirmed disability worsening with relapse, or CDWR.

It’s also possible for people with MS to experience worsening disability in the absence of any relapse activity. Often called CDWNR, for confirmed disability worsening without relapse (or with no relapse), it’s also known as progression independent of relapse activity, or PIRA. In some case, this is simply known as silent progression.

According to a recent review paper, silent progression is the most common driver of disability worsening across all types of MS.

Here, the team analyzed blood samples from patients included in two large databases, the Expression, Proteomics, Imaging, Clinical study (EPIC) and the Swiss Multiple Sclerosis Cohort (SMSC). Collectively these studies covered nearly 2,000 people with MS.

Confirmed worsening of disability was defined as a clinically meaningful increase in Expanded Disability Status Scale (EDSS) scores that was confirmed in another visit at least six months later.

The patients who experienced such events of disability progression were divided into CDWR and CDWNR groups based on whether or not they’d experienced a relapse in the year before the score worsened.

Abdelhak noted that, in line with other studies, silent progression was “way more common” than relapse-associated worsening.

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Possible window may exist before worse MS disability is seen

The scientists used statistical models to compare blood NfL levels in these two groups against levels in patients who did not experience any worsening in disability scores.

The results showed that, for both CDWR and CDWNR, blood NfL levels were significantly elevated compared with patients who didn’t experience disability worsening. The specific timing did vary a bit between the two types of disability worsening.

Specifically, for relapse-associated worsening, NfL levels tended to spike high about one year before the worse disability score was confirmed. In the silent progression group, blood NfL levels tended to be chronically increased between one and two years before disability scores worsened.

“The time-to-event analysis confirmed the prognostic value of NfL for future CDWNR within 1-2 years and CDWR in [approximately] 1 year,” the researchers wrote in their abstract.

These data imply that patients have detectable nerve damage quite a while before they start to experience substantial symptoms.

The time-to-event analysis confirmed the prognostic value of [the biomarker neurofilament light chain] NfL.

This finding has implications for MS clinical trials, Abdelhak said, as it implies that disability worsening occurring fairly early in trials, such as in the first year after starting an experimental treatment. It also implies that the worsening of disability likely was caused by nerve damage that had already happened before the treatment was started. Longer-term events are more likely to be affected by treatment, the researchers noted.

According to the team, these results also suggest that there may be a window where nerve damage has happened, but hasn’t yet caused notable symptoms. If that’s indeed the case, then tracking NfL levels may help to guide decisions about treatment, the scientists said.

A notable limitation of this analysis, according to Abdelhak, is that disability in this study was measured using the EDSS scale. This is a well-validated tool to measure overall disability in MS, but isn’t very sensitive to small changes, so it may not detect disability worsening until fairly late after it happens. Abdelhak noted that other analyses of the data are ongoing.

Note: The Multiple Sclerosis News Today team is providing in-depth coverage of the 9th joint ECTRIMS-ACTRIMS meeting Oct. 11–13. Go here to see the latest stories from the conference.