Serum neurofilament light chain (NfL) elevation -- a sign of accelerated neuroaxonal injury -- appeared about 1 year before disability worsening events associated with relapses in multiple sclerosis (MS) patients, longitudinal data showed.
NfL also was elevated 1 to 2 years before worsening independent of clinical relapses, reported Ari Green, MD, of the University of California San Francisco, and co-authors in .
The pattern indicates that nerve cell death is a slow process and suggests that interventions could potentially protect nerve cells to prevent permanent MS disability, the researchers noted.
The study is the first to quantify the timeframe when injury to the central nervous system takes place in MS before disability worsening, they added.
"The data on NfL as a predictor of long-term outcome in MS gets more robust with time and supports the position that NfL will become [the field's] C-reactive protein," noted Gavin Giovannoni, MBBCh, PhD, of Queen Mary University of London in England, who wasn't involved with the study.
"Hopefully, regulators will now adopt NfL as a surrogate outcome for MS and allow registration trials of combination or add-on therapies using the area-under-the-NfL-curve as the primary outcome," Giovannoni told 乌鸦传媒. "This will transform drug development and MS outcomes in the future."
Green and colleagues tracked MS patients in two real-world prospective MS cohorts: the U.S.-based study and the multicenter Swiss Multiple Sclerosis Cohort (). EPIC samples were obtained from July 2004 to December 2016, and SMSC samples were from June 2012 to September 2021. All participants in both cohorts with NfL results were included in the study.
Confirmed disability worsening (CDW) was defined as worse scores on the Expanded Disability Status Scale () that were confirmed after 6 or more months. Worsening was classified into CDW associated with clinical relapses (CDW-R) or independent of clinical relapses (CDW-NR).
The analysis included 3,906 EPIC visits and 8,901 SMSC visits. Median baseline age in the EPIC study was 42, and 70% were women. Median baseline age in SMSC was 41, and 66% were women.
Overall, 129 CDW-R events and 533 CDW-NR events occurred in the two cohorts. Most CDW events were sustained; longitudinal EDSS scores remained higher than reference EDSS scores 75% to 90% of the time.
At the last visit preceding the CDW-R event, NfL z scores were 0.71 units higher in EPIC and 0.32 units higher in SMSC, compared with stable MS samples.
At the two visits preceding a CDW-NR event, NfL z scores were 0.23 units higher in EPIC and 0.28 units higher in SMSC. At the last visit preceding a CDW-NR event, NfL z scores were 0.27 units higher in EPIC and showed a nonsignificant trend that was 0.09 units higher in SMSC.
Time-to-event analyses confirmed the relationship between NfL levels and future CDW-R within approximately 1 year and CDW-NR in about 1 to 2 years.
An NfL z score greater than 1.0 was tied to a 70% (P=0.02) higher risk for diagnosing CDW-R at the subsequent visit approximately 11 months later in SMSC and showed a trend for a 91% (P=0.07) higher risk at 12.6 months later in EPIC. A NfL z score over 1.0 was associated with a 40% (P=0.02) and 49% (P<0.001) higher risk of diagnosing CDW-NR in roughly 12 months in EPIC and 21 months in SMSC, respectively.
"The reported NfL elevation preceding CDW events highlights the value of NfL as an early biomarker of disability worsening and points to the existence of different windows of dynamic central nervous system pathology preceding CDW-R and CDW-NR," Green and co-authors observed.
"Furthermore, our findings hint to the necessity for optimized terms to describe CDW in MS depending on its temporal association with any detectable focal inflammatory disease activity," they added. "That includes relapses (regardless of the outcome), MRI activity, and/or potentially significant NfL surge beyond a yet-to-define cutoff."
This study had several limitations, the researchers acknowledged. More frequent NfL assessments -- every 3 months, for example -- might give a more tightly focused time window of NfL changes, they noted. In addition, CDW was based on EDSS, whereas other disability measures might be more sensitive.
Disclosures
This study was supported by Westridge Foundation, Hoffmann-La Roche, the Fishman Family, the Swiss National Research Foundation, the NIH, and the Valhalla Foundation. The UCSF MS biorepository was supported by the National Multiple Sclerosis Society.
Green reported relationships with F. Hoffmann La Roche, the Fishman Family, Westridge Foundation, and Pipeline Therapeutics outside the submitted work. Co-authors reported numerous relationships with nonprofit groups and pharmaceutical companies.
Primary Source
JAMA Neurology
Abdelhak A, et al "Neurofilament light chain elevation and disability progression in multiple sclerosis" JAMA Neurol 2023; DOI: 10.1001/jamaneurol.2023.3997.