Abstract
BackgroundOne-off serum levels of neurofilament light chain (sNfL) is an established predictor of emerging disease activity in multiple sclerosis (MS). However, the importance of longitudinal increases in sNfL is yet to be enumerated, an important consideration as this test is translated for serial monitoring. Glial Fibrillary Acidic Protein (sGFAP) is another biomarker of predictive interest. Our objective was to assess the association between longitudinal changes sNfL and prediction of future relapses, as well as a possible role for sGFAP. MethodsParticipants with active MS were prospectively monitored for one year as part of a clinical trial testing mesenchymal stem cells. Visits every three months or less included clinical assessments, MRI scans and serum draws. sNfL and sGFAP concentrations were quantified with Single Molecule Array immunoassay. We used Kaplan-Meier estimates and Anderson-Gill Cox regression models with and without adjustment for age, sex, disease subtype, disease duration and expanded disability status score (EDSS) to estimate the rate of relapse predicted by baseline and longitudinal changes in biomarker. Results58 Canadian and Italian participants with MS were enrolled in this study. Higher baseline sNfL was future relapse (Log-rank p = 0.0068), MRI lesions (p=0.0096), composite-relapse associated worsening (p=0.01) and progression independent of relapse activity (p=0.0096). Conversely, baseline sGFAP was only weakly associated with MRI lesions (0.044). Cross-sectional analyses of baseline sNfL revealed that a two-fold difference in baseline sNfL, e.g. from 10 to 20 pg/mL, was associated with a 2.3-fold increased risk of relapse during follow-up (95% confidence interval 1.65–3.17). Longitudinally, a two-fold increase in sNfL level from the first measurement was associated with an additional 1.46 times increased risk of relapse (1.07–2.00). The impact of longitudinal increases in sNfL on the risk of relapse were most pronounced for patients with lower baseline values of sNfL (<10 pg/mL: HR = 1.54, 1.06–2.24). These associations remained significant after adjustment for potential confounders. ConclusionWe enumerate the risk of relapse associated with dynamic changes in sNfL. Both baseline and longitudinal change in sNfL may help identify patients who would benefit from early treatment optimisation. Trial registrationsCanada:NCT02239393, Italy:NCT01854957&EudraCT, 2011–001295-19 Classification of evidenceThis study provides class 1 evidence that high baseline and longitudinal increases in sNfL are predictive of impending relapses in patients with active MS.
Highlights
With an expanding spectrum of disease-modifying treatments (DMTs) for patients with multiple sclerosis (MS), the need for biomarkers that can identify patients at risk of impending disease activity who might benefit from pro-active treatment optimization has never been more urgent
Baseline com parisons of log-normalized serum levels of neurofilament light chain (sNfL)/sGFAP concentrations and disease subtype, relapses, MRI lesions and disability worsening were performed with t-tests or one-way ANOVA
We compared the time to the first event for each outcome according to baseline sNfL or sGFAP using log-rank tests
Summary
With an expanding spectrum of disease-modifying treatments (DMTs) for patients with MS, the need for biomarkers that can identify patients at risk of impending disease activity who might benefit from pro-active treatment optimization has never been more urgent. While cross-sectional correlates include clinical severity, progressive disease subtypes, disease duration and MRI lesion load(Abdelhak et al, 2019, 2018; Ayrignac et al, 2020; Hogel et al, 2020), the predictive utility of sGFAP has not known. The impact of longitudinal in creases in sNfL on the risk of relapse were most pronounced for patients with lower baseline values of sNfL (
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