Serum Neurofilament Light Adds Complimentary Value to Monitoring Disease Progression in Relapsing Multiple Sclerosis

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In patients with relapsing-remitting MS who achieved NEDA under highly effective DMT, sNfL concentrations were low and stable, suggesting a potential role for sNfL for long-term monitoring of inflammatory disease activity.

In a recently published, 48-week, single-center study, findings showed a robust correlation between disease activity and serum neurofilament light (sNfL) concentration in patients with relapsing multiple sclerosis (MS); however, some patients with relapse did not change significantly in post-baseline sNfL levels, suggesting that repeated sNfL to monitor disease activity is complementary rather than a substitute for clinical and MRI measures.

Published in the Multiple Sclerosis Journal, investigators aimed to evaluate the utility of sNfL for monitoring individual patients with active relapsing-remitting MS. The study, conducted at the MS center, Sahlgrenska University Hospital in Gothenburg, Sweden, included 44 patients, 40 with relapsing-remitting MS and 4 with clinically isolated syndrome (CIS), who were followed for 48 weeks.

Of the cohort, 13 patients had relapse but no contrast-enhancing lesions (30%), 27 had a relapse and CELs (61%), and 4 patients showed CELs but no relapse (9%). Led by Magnus Johnsson, a doctoral student at the University of Gothenburg, 9 patients had signs of new disease activity during follow-up: 3 patients with new CELs, 4 with new T2 lesions, and 2 with new sensory symptoms. A logistic regression was performed to determine how different sNfL variables (predictors, i.e, biomarkers) affected a patient’s odds ratio (OR) for having inflammatory disease activity and natalizumab-treated patients with relapsing-remitting MS (n = 66) from a previous study served as controls.

Overall, investigators observed median sNfL increase from 12.4 ng/L (IQR, 8.1-26.1) at baseline to 14.6 ng/L (IQR, 9.3-31.6) 2 weeks after baseline, followed by a slow but steady decrease until the end of the study. In patients with a clinical relapse (n = 40), the sNfL concentration peaked at median 5.5 weeks (IQR, 4-9) after the clinical onset of relapse symptoms. In addition, the delay in reaching peak sNfL was not significantly different (P = .866) when excluding patients with post-baseline inflammatory disease activity, or comparing patients with or without high-dose methylprednisolone (P = .939) or highly effective disease-modifying therapy (DMT) at baseline (P = .819).

The variability of sNfL was significantly higher in the study cohort than in stable controls, as the median individual sNfL range in patients sampled twice or more in the study cohort (n = 39) was 9.1 ng/L (IQR, 4.2-25.8) vs 3.6 ng/L (IQR, 2.3-4.9) in controls (n = 66; P <.001). The median baseline Z-score in active patients as compared with stable controls was 1.77 (IQR, 1.17-2.65) and 0.76 (IQR, 0.36-1.37; P <.001).

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The z-score, documented at 2.05 (IQR, 1.44-3.04) at 5.5 weeks after relapse, was considered the most accurate measure for assessing disease activity in sNfL. This value describes how an individual patient’s sNfL concentration is related to the age and body mass index-adjusted mean level in a large group of health controls, and is measured in terms of standard deviations from the mean.

"The advantage of sNfL range is the use of absolute raw sNfL concentrations, and our data show that a high range is very rare in stable RRMS patients,” Johnsson et al wrote. "Thus, the specificity of sNfL range is higher than for Z-score (93% vs. 70%) but at the expense of sensitivity (59% vs. 81%). Overall, the accuracy, the clinical applicability, and the possibility to compare populations accounting for confounding factors seem to be better with the use of Z-score compared to sNfL range."

Overall, ORs and area under the curve (AUC) values remained significant and similar in subgroups with or without high-dose methylprednisolone treatment or highly effective DMT at baseline, except for non-significant ORs for the predictor variable sNfL range in subgroups without steroid treatment (OR, 1.11; 95% CI, 0.99-1.25) or with DMT at baseline (OR, 1.13; 95% CI, 0.98-1.29). Investigators concluded that the accuracy, the clinical applicability, and the possibility to compare populations accounting for confounding factors seems to be better with the use of z-score compared with sNfL range.

"It is important to recognize the delay between relapse onset and the peak of sNfL concentration," study authors wrote. "The temporal change in sNfL is probably due to physiological metabolic and elimination processes and the extent, intensity, and length of relapses and MRI lesion activity. Suspect relapses with symptoms that are not confirmed in the neurological examination or with an increase of the functional score or EDSS may be supported by an increase in sNfL. However, this assumes that there is a baseline sNfL concentration and that repeated sampling is performed. According to our data, there is still a risk of false-negative results, but the chance of detecting ongoing axonal damage increases if sNfL determinations are performed 5.5 weeks (range 2–12) after relapse onset."

REFERENCE
1. Johnsson M, Stenberg YT, Novakova L, et al. Serum neurofilament light for detecting disease activity in individual patients with multiple sclerosis: a 48-week prospective single-center study. Mult Scler J.
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