Pretreatment Neurofilament Light Chain Serum Levels, Early Disease Severity, and Treatment Response in Pediatric Multiple Sclerosis

Abstract

Background and objectives: High disease activity and frequent therapy failure in pediatric multiple sclerosis (MS) make prognostic biomarkers urgently needed. We investigated whether serum neurofilament light chain (sNfL) levels in treatment-naive pediatric patients with MS are associated with early disease severity and indicate treatment outcomes.

Methods: A retrospective cohort study of patients seen in the Göttingen Center for MS in Childhood and Adolescence, Germany. Inclusion criteria were MS diagnosis according to the McDonald criteria, MS onset <18 years, and available pretreatment serum sample. sNfL levels were analyzed using a single-molecule array assay. Associations with clinical and MRI evidence of disease severity at sampling were evaluated using the Spearman correlations and nonparametric tests for group comparisons. Correlations between pretreatment sNfL and annualized relapse and new T2 lesion rate on first-line therapy, and odd ratios for switch to high-efficacy therapy were assessed.

Results: A total of 178 patients (116 women [65%]) with a mean sampling age of 14.3 years were included in the study. Pretreatment sNfL levels were above the ≥90th percentile reported for healthy controls in 80% of patients (median 21.1 pg/mL) and correlated negatively with age, but no correlation was seen with sex, oligoclonal band status, or body mass index. High pretreatment sNfL levels correlated significantly with a high number of preceding relapses, a shorter first interattack interval, a high T2 lesion count, and recent gadolinium-enhancing lesions. Of interest, sNfL levels reflected more strongly MRI activity rather than clinical activity. Pretreatment sNfL levels also correlated significantly with the relapse rate and occurrence of new/enlarging T2 lesions while on first-line injectable therapy. Odds of future therapy escalation increased from 0.14 for sNfL below 7.5 pg/mL to 6.38 for sNfL above 15 pg/mL. In patients with a recent relapse, higher sNfL levels were associated with poorer recovery 3 months after attack.

Discussion: The results of this study have 3 important implications: First, pretreatment sNfL levels are a valuable biomarker for underlying disease activity in pediatric patients with MS. Second, pretreatment sNfL levels in pediatric patients with MS have a predictive value for the response to first-line therapy and the necessity of future therapy escalation. Third, high sNfL levels during a relapse are associated with poor recovery in this age group.

Figure 1. Influence of Age and Recent Disease Activity on sNfL Levels in Treatment-Naive Pediatric Patients With MS

A positive correlation between age at sampling and sNfL is shown in graph (A). Line indicates linear fit to the observed data and 95% confidence bands. Positive associations between sNfL and recent clinical and MRI activity before sampling are shown as boxplots in graph (B), (C), and (D). Boxes depict median and interquartile range with whiskers extending to minimum and maximum values. Gd+ = gadolinium-enhanced; MS = multiple sclerosis; sNfL = serum neurofilament light chain.

Figure 2. Associations Between sNfL Levels Recent Attack Severity and Clinical and Subclinical Disease at Sampling in Treatment-Naive Pediatric Patients With MS

In patients with a recent relapse (≤90 days) before serum sampling, higher sNfL levels were associated with (A) polyfocal symptoms during the attack and (B) incomplete recovery 3 months after the attack. Both clinical (C, D) and subclinical disease (E, F) in the untreated patients showed associations with sNfL. Boxplots depict median and interquartile range with whiskers extending to minimum and maximum values. MS = multiple sclerosis; sNfL = serum neurofilament light chain.

Figure 3. Associations Between Pretreatment sNfL Levels and Clinical and Subclinical Disease Activity on the First-Line Therapy, Need for Second-Line Therapy, and EDSS 2 Years After MS Onset

Higher pretreatment sNfL levels up to 3 months before therapy initiation in patients ≥11 years were associated with a relapse (A) or new T2 lesion development (B) within the first 12 months of first-line therapy with IFN-β/GA. Patients with a clinical onset ≥2009 who had higher pretreatment sNfL levels were more likely to receive a high-efficacy therapy during the follow-up (C). Although most patients had no disability 2 years after onset, EDSS 2–4 was associated with higher pretreatment NfL concentrations (D). Boxplots depict median and interquartile range with whiskers extending to minimum and maximum values. EDSS = Expanded Disability Status Scale; GA = glatiramer acetate; IFN-β = interferon-beta; MS = multiple sclerosis; sNfL = serum neurofilament light chain.