Combo of Biomarkers Predict Future Disease Activity
In people with early-stage multiple sclerosis (MS), the presence of high levels of neurofilament light chain (sNfL) protein in the bloodstream combined with thinning of the retina is a strong indicator of future disease activity, a recent study demonstrates.
“Our findings encourage the application of both sNfL and retinal measurements for risk stratification [classification] in clinical routine and trials,” the researchers wrote.
The study, “Increased Serum Neurofilament Light and Thin Ganglion Cell–Inner Plexiform Layer Are Additive Risk Factors for Disease Activity in Early Multiple Sclerosis,” was published in the journal Neurology: Neuroimmunology & Neuroinflammation.
MS often starts as clinically isolated syndrome (CIS), which is the first episode of neurological symptoms that may or may not precede MS. The subsequent course of MS can show significant symptomatic variability among patients, in imaging and tissue analysis, and response to therapies.
That is why reliable biomarkers measured in the early stages of the disease are needed to predict future disease activity and identify those who would benefit most from disease-modifying therapies (DMTs).
Optical coherence tomography (OCT) is a noninvasive imaging technique that generates cross-sectional images of the layers within the retina at the back of the eye. It can be used to visualize the loss of optic nerve fibers (axons), nerve cell damage, and neuroinflammation caused by an altered immune response targeting the coating on axons (myelin), an underlying cause of MS.
sNfL protein is a potential biomarker for axonal damage. Increased levels of sNfL in the bloodstream have been associated with new or growing lesions in the brain, which reflect an ongoing loss of myelin and axons. Furthermore, patients with high levels of sNfL early in MS are more likely to progress to worse disability.
While OCT and sNfL each may be a valuable measure of future disease activity, the combined association of abnormal OCT findings and elevated sNfL levels in the early stages of MS has not been fully explored.
“In this study, we aimed at investigating the potentially additive value of sNfL and OCT measurements as markers for subsequent disease activity in patients with CIS or early MS,” the researchers wrote.
All patients in this study also participate in an ongoing observational study (NCT01371071) in Germany of patients with a CIS or early MS (up to 2 years since disease onset). The first (baseline) OCT measurements and sNfL samples were collected at the same clinic visit, and participants underwent yearly follow-up clinical assessments, along with blood sample collection, retinal OCT, and brain MRI imaging.
The primary outcome was evidence that contradicted, or violated, the status of no evidence of disease activity (NEDA-3) — defined as a combination of no new relapses or brain lesions on MRI and the absence of disease worsening, as determined by the expanded disability status scale (EDSS).
Of the 78 participants, 62 (79%) were diagnosed with relapsing-remitting MS (RRMS) and 16 (21%) with CIS. The mean age of the group was 33.7 years, and 64.1% were female.
At baseline, there was a significant correlation between elevated sNfL levels and the thickness of one retinal layer called the ganglion cell and inner plexiform layer (GCIP). No other baseline associations were seen in the other retinal layers measured, namely the peripapillary retinal nerve fiber layer (pRNFL) and the inner nuclear layer (INL).
During a median follow-up of 23.9 months (two years), 46 participants (59%) showed evidence of disease activity (violation of NEDA-3), 23 (29%) experienced a relapse, 38 (49%) developed new brain lesions on MRI, and nine (12%) had confirmed EDSS worsening.
An analysis of sNfL and OCT as separate biomarkers found patients with abnormal sNfL at baseline had a 2.28-fold higher risk of violating NEDA-3, and a 2.47-fold higher risk of developing new lesions, but not of experiencing a new relapse.
Thinner GCIP and pRNFL, or thicker INL, showed no significant association with future NEDA-3 violation. In contrast, a thinner GCIP was associated with a 2.88-times higher risk of a new relapse, but not for new lesions. The team found no associations between EDSS worsening and abnormal sNfL or OCT parameters.
A statistical analysis, which adjusted the data for established factors linked with future disease activity, including sNfL, GCIP thickness, as well as age, sex, lesion count, and the use of DMTs, showed abnormal sNfL was associated significantly with a 2.11-fold higher risk of NEDA-3 violation and a 2.04-fold higher risk of a new lesion. A higher lesion count also correlated with future lesion development.
A thinner GCIP had a higher risk of a new relapse than those with a thicker CGIP, but the association was not statistically significant. Greater lesion volume was associated with a future NEDA-3 violation and lesion development, but not age, sex, or DMT use at the time of study enrollment.
Combining the two
Next, the team examined whether sNfL and OCT parameters combined predicted future MS disease. Patients with abnormal sNfL plus thin GCIP had a 3.61-times higher risk of violating the NEDA-3 criteria, abnormal sNfL plus thin pRNFL had a 2.63-times higher risk, and those with abnormal sNfL plus a thicker INL were more than a threefold higher risk than those without these combined risk factors.
“Higher hazard [risk] ratios were observed when the sNfL and OCT measurements were combined than abnormal sNfL or thin GCIP/thin pRNFL/thick INL alone as a single risk factor,” the researchers wrote.
Regarding new relapses, there was a higher risk of new relapses with abnormal sNfL plus thin GCIP (5.38-fold), abnormal sNfL plus thin pRNFL (4.77-fold), or abnormal sNfL plus thick INL (3.26-fold). An increased risk also was seen for new lesion development when combining abnormal baseline sNfL levels with reduced GCIP thickness (3.19-fold). A combination of NfL with any of the three OCT parameters was not associated with EDSS worsening.
According to the team, an interaction effect was found between abnormal sNfL and thin GCIP for future NEDA-3 violation and new lesion development, but not further relapses. The proportion of the interaction of sNfL and thin GCIP added 75% to future NEDA-3 violation risk and 85% to new brain lesion risk.
“The most important finding of our study is that thinning of GCIP and pRNFL can both provide combined benefits to abnormal sNfL regarding their association with subsequent NEDA-3 violation,” the researchers wrote.
“In patients with early MS, the presence of both abnormal sNfL and thin GCIP is a stronger risk factor for future disease activity than the presence of each parameter alone,” the team concluded.