Neuroaxonal pathology occurred in advance of -- not coincident with -- clinical worsening in multiple sclerosis (MS), particularly in patients with "silent progression" or progression independent of relapse activity (PIRA), longitudinal data showed.
In MS patients with no recent relapses, neurofilament light (NfL) levels rose 1 to 2 years before confirmed disability worsening was identified, reported Ahmed Abdelhak, MD, of the University of California San Francisco, 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).
The study used data from about 13,000 patient visits to track the link between serum NfL, a marker of axonal injury, and MS progression, Abdelhak said.
"This is the largest and most detailed study to evaluate neuroaxonal injury before progression so far in two very unique long-term prospective world cohorts," Abdelhak told 鶹ý. "It shows that NfL can be used to predict disease progression."
"It's also the first to document neuroaxonal damage in a particular timeframe preceding progression and demonstrate that this timeframe of NfL elevation differs based on the pattern of disability," he added. "This has very relevant implications, particularly for designing clinical trials."
Mechanisms contributing to disability accumulation in MS are poorly understood, he noted. Serum NfL correlates with disease activity in people with MS, but the occurrence and timing of NfL elevation relative to disability worsening isn't clear.
"NfL is a very promising biomarker," Abdelhak noted in his presentation. Some current assays can detect neurodegeneration-related epitopes, he added.
Abdelhak and colleagues analyzed longitudinal data from 609 participants (3,900 patient visits) in the study at the University of California San Francisco and validated findings in 1,290 participants (8,900 patient visits) in the Swiss MS Cohort (). Both groups had a mean age of about 42 and two-thirds were women.
Mean Expanded Disability Scale Status () scores were 1.5 in the EPIC study and 2.0 in SMSC. In the EPIC study, 87% had relapsing MS; in SMSC, that figure was 90%. Mean follow-up was 10 years in EPIC and 7 years in SMSC.
The study aimed to identify the relationship between confirmed disability worsening (CDW) and NfL. CDW, defined as confirmed worsening on EDSS scores, was classified into two groups: worsening with relapse since the last visit, or worsening with no relapse since the last visit. All other participants were assigned to a control group of stable MS patients.
Confirmed disability worsening-related visits were examined at several time points, from first diagnosis of EDSS increase (CDW event) to two visits preceding diagnosis. Data were adjusted for age at sampling, sex, treatment category, disease course (relapsing versus progressive MS), EDSS scores, and relapses in the last 90 days.
In people with CDW and relapse, one event occurred in 5.3% of the EPIC cohort and 6.4% of SMSC; recurrent events occurred in 0.3% and 0.4%, respectively. NfL elevation was apparent about 12 months before diagnosing CDW in this group; a higher NfL Z score was tied to about 70% to 90% higher CDW risk in the next year.
In people with CDW and no relapses, however, one event occurred in 22.8% of the EPIC cohort and 20.8% of SMSC. Two events occurred in 3.3% and 2.6%, respectively, and more than two events occurred in 0.7% and 0.2.
Among people with no relapses, NfL elevation emerged about 12 to 26 months before CDW diagnosis. A higher NfL Z score was associated with about 40% to 50% higher CDW risk in the next 1 to 2 years.
The findings may define a therapeutic intervention window, Abdelhak observed, but it still needs refinement. Larger samples at earlier timepoints may be needed to see patterns. "We are now also evaluating the application on an individual level, since all the differences we have seen are at group levels," he added.
An important limitation is the use of EDSS to assess progression. Some newer disability tools might be more sensitive, Abdelhak pointed out. "Are we measuring progression late?" he asked. "That's something we need to know in other studies."
Disclosures
Abdelhak received research funding from DMSG, AMSEL, Bavarian MS Trust, the Department of Defense, and UCSF Weill Institute for Neurosciences, all not related to this work.
Co-authors reported multiple relationships with industry.
Primary Source
European Committee for Treatment and Research in Multiple Sclerosis
Abdelhak A "Elevated serum neurofilament light chain precedes and predicts disease progression in multiple sclerosis" ECTRIMS 2023; abstract 1014/O125.