A blood test that measures elevations in neurofilament light chain (NfL) levels in patients with multiple sclerosis (MS) could warn of worsening disability up to 2 years before it occurs, a new study suggests.
Rising NfL levels are a known indicator of neuroaxonal injury and correlate with MS disease activity. Levels rise in the presence of an MS relapse or MRI activity and fall following treatment with disease-modifying therapies. But the link between NfL levels and worsening disability was less understood.
This new analysis of NfL in two large MS cohorts found that elevated levels of the neuronal protein at baseline were associated with large increases in future disability risk, even in patients with no clinical relapse.
“This rising of NfL up to two years before signs of disability worsening, represents the window when interventions may prevent worsening,” lead investigator Ahmed Abdelhak, MD, Department of Neurology, University of California, San Francisco, said in a press release.
The findings were published online November 6 in JAMA Neurology.
Early Warning System?
The study included data on 1899 patients with nearly 13,000 patient visits from two observational, long-term, real-world cohorts: the US-based Expression, Proteomics, Imaging, Clinical (EPIC) study (n = 609 patients), and the Swiss Multiple Sclerosis Cohort trial (SMSC; n = 1290 patients).
Investigators analyzed longitudinal serum NfL measurements in conjunction with clinical disability worsening, defined as 6 months or more of increased impairment as measured by the Expanded Disability Status Scale.
Researchers also assessed the temporal association between NfL measurements and the risk of increased disability and distinguished between disability with and without relapse.
Worsening disability was reported in 227 patients in the EPIC group and 435 in the SMSC trial.
Elevated NfL at baseline was associated with a 70% higher risk for worsening disability with relapse about 11 months later in the SMSC study (hazard ratio [HR], 1.70; P = .02). In the EPIC trial, there was trend toward a 91% higher risk for worsening disability with relapse at 12.6 months, although the findings did not meet statistical significance (HR, 1.91; P = .07).
The risk of future disability progression independent of clinical relapse was 40% higher in those with high NfL at baseline in the EPIC study 12 months after baseline (HR, 1.40; P = .02) and 49% higher in the SMSC trial 21 months later (HR, 1.49; P < .001).
The early elevation of NfL levels suggests a slower degradation of nerve cells and could be a possible early warning system of future progression of disability, allowing time for interventions that could slow or even halt further disability.
“Monitoring NfL levels might be able to detect disease activity with higher sensitivity than clinical exam or conventional imaging,” senior author Jens Kuhle, MD, PhD, leader of the Swiss cohort and head of the Multiple Sclerosis Center at University Hospital and University of Basel, Switzerland, said in a statement.
Challenges for Clinicians
Commenting on the findings for Medscape Medical News, Robert Fox, MD, staff neurologist at the Mellen Center for MS and vice chair for research, Neurological Institute, Cleveland Clinic, Ohio, said that while there is a clinical test to measure NfL levels, incorporating that test into standard of care isn’t straightforward.
“The challenge for the practicing clinician is to translate these population-level studies to individual patient management decisions,” said Fox, who was not a part of the study.
“The published prediction curves corrected for age, sex, disease course, disease-modifying treatment, relapse within the past 90 days, and current disability status, the combination of which makes it rather challenging to calculate and interpret adjusted z-score NfL levels in routine practice and then use it in clinical decision-making.”
Investigators say the study underscores the importance of NfL as an MS biomarker and “points to the existence of different windows of dynamic central nervous system pathology” that precedes worsening disability with or without relapse. But there may be a simpler explanation, Fox suggests.
“We know MRI activity occurs five to 10 times more frequently than relapses, and we know that MRI activity is associated with both NfL increases and future disability progression,” Fox said. “It is quite likely that the elevations in NfL seen here are reflective of new MRI disease activity, which frequently is seen without symptoms of an MS relapse,” he said
The study was funded by the Westridge Foundation, F. Hoffmann-La Roche, the Fishman Family, the Swiss National Research Foundation, the National Institutes of Health/National Institute of Neurological Disorders and Stroke, and the Valhalla Foundation. Abdelhak reported receiving grants from the German Multiple Sclerosis Society and the Weill Institute for Neurosciences outside the submitted work. Kuhle has received grants from Swiss MS Society, the Swiss National Research Foundation, the Progressive MS Alliance, Biogen, Merck, Celgene, Bristol-Myers Squibb, Novartis, Octave Bioscience, Roche, Sanofi, Alnylam, Bayer, Immunic, Quanterix, Neurogenesis, Stata DX, and the University of Basel outside the submitted work. Fox reported receiving consulting fees from Siemens and Roche.
Kelli Whitlock Burton is a reporter for Medscape Medical News covering neurology and psychiatry.
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