Serum Glial Fibrillary Acidic Protein and Neurofilament Light Chain Levels Reflect Different Mechanisms of Disease Progression under B-Cell Depleting Treatment in Multiple Sclerosis

Abstract

Objective: To investigate the longitudinal dynamics of serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) levels in people with multiple sclerosis (pwMS) under B-cell depleting therapy (BCDT) and their capacity to prognosticate future progression independent of relapse activity (PIRA) events.

Methods: A total of 362 pwMS (1,480 samples) starting BCDT in the Swiss Multiple Sclerosis (MS) Cohort were included. sGFAP levels in 2,861 control persons (4,943 samples) provided normative data to calculate adjusted Z scores.

Results: Elevated sGFAP levels (Z score >1) at 1 year were associated with a higher hazard for PIRA (hazard ratio [HR]: 1.80 [95% CI: 1.17-2.78]; p = 0.0079) than elevated sNfL levels (HR, 1.45 [0.95-2.24], p = 0.0886) in a combined model. Independent of PIRA events, sGFAP levels longitudinally increased by 0.49 Z score units per 10 years follow-up (estimate, 0.49 [0.29, 0.69], p < 0.0001). In patients experiencing PIRA, sGFAP Z scores were 0.52 Z score units higher versus stable patients (0.52 [0.22, 0.83], p = 0.0009). Different sNfL Z score trajectories were found in pwMS with versus without PIRA (interaction p = 0.0028), with an average decrease of 0.92 Z score units per 10 years observed without PIRA (-0.92 [-1.23, -0.60], p < 0.0001), whereas levels in patients with PIRA remained high.

Interpretation: Elevated sGFAP and lack of drop in sNfL after BCDT start are associated with increased risk of future PIRA. These findings provide a rationale for combined monitoring of sNfL and sGFAP in pwMS starting BCDT to predict the risk of PIRA, and to use sGFAP as an outcome in clinical trials aiming to impact on MS progressive disease biology. ANN NEUROL 2024.

FIGURE 1

sGFAP (A) and sNfL (B) Z scores in samples from RMS and PMS patients under B‐cell depleting therapy. In RMS and PMS, sGFAP (A) and sNfL (B) levels were increased compared to control persons (ie, Z = 0, solid line; all p < 0.0001 in Wilcoxon rank sum test as indicated below). Both sGFAP and sNfL levels were elevated in PMS compared to RMS (both p < 0.0001 above square brackets). Furthermore, the proportion of samples with Z score >1 (>84.1st percentile; dashed line) was considerably higher (vertically written percentages) than expected in control persons (15.9% according to a standard normal distribution): sGFAP: 41.4% in PMS and 24.8% in RMS (A); sNfL: 37.6% in PMS and 22.3% in RMS (B). A total of 2,212 longitudinal samples from all 362 patients were included. MS, multiple sclerosis; n, number; PMS, progressive MS; RMS, relapsing MS; sGFAP, serum glial fibrillary acidic protein; sNfL, serum neurofilament light chain. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 2

Kaplan–Meier curves showing the proportion of patients experiencing future PIRA when having high (Z score > 1) versus low (Z score ≤ 1) biomarker levels of sGFAP (A) and sNfL (B) at index sample. Patients with a sGFAP Z score > 1 (≥84.1st percentile) at index sample (median 1 year after BCDT start) were at 2.1‐fold risk of a future PIRA event versus those with sGFAP Z score of ≤1 (HR: 2.1 [1.4–3.1], p = 0.0005); accordingly, patients with a sNfL Z score >1 showed 1.8‐fold increased risk to develop PIRA compared to patients with a sNfL Z score ≤1 (HR: 1.8 [CI: 1.2–2.6], p = 0.0058). HR, hazard ratio; PIRA, progression independent of relapse activity; sGFAP, serum glial fibrillary acidic protein; sNfL, serum neurofilament light chain. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 3

Longitudinal dynamics of sGFAP (A,C) and sNfL (B,D) Z scores under BCDT in relation to PIRA. A and B show estimates (dots) with 95% CI (error bars) from multivariable mixed models with sGFAP and sNfL Z score, respectively, as outcome variable. C and D show marginal effects on predicted biomarker Z scores over time. Statistical significance indicated as **p < 0.01 or ***p < 0.001. Z score: 0 represents the mean biomarker concentration in control persons. Models are adjusted for age and EDSS at BCDT start and for recent relapse (<90 days before sampling). (A + C): sGFAP Z scores steadily increased over time by 0.49 Z score units/10 years (p < 0.0001) in both PIRA and non‐PIRA patients, whereas there was no difference in slopes between the 2 groups (p _{interaction PIRA*follow‐up time} = 0.44), and therefore, the interaction term was excluded from the statistical model (see Table S2 for model details including 95% CI). However, Z scores were 0.52 units higher in patients developing PIRA during follow‐up (p = 0.0009). sGFAP levels were lower in older patients and higher with higher EDSS and recent relapse. (B + D): No difference in sNfL Z scores was observed in patients with versus those without PIRA at start of BCDT (p = 0.38; Table S2). However, the dynamics of sNfL over time differed between these groups (p _{interaction PIRA*follow‐up time} = 0.0028 in model B where time is approximated by a linear term; p _{interaction PIRA*follow‐up time} = 0.0092 in model D in which a spline term for time was used): in patients without PIRA, sNfL strongly decreased by 0.92 Z score units/10 years (p < 0.0001), whereas in those with PIRA, Z scores remained stable over time. BCDT, B‐cell depleting therapy; CI, confidence interval; EDSS, expanded disability disease score; PIRA, progression independent of relapse activity; sGFAP, serum glial fibrillary acidic protein; sNfL, serum neurofilament light chain. [Color figure can be viewed at www.annalsofneurology.org]