JAMA Neurology | February 6, 2023

Stephanie Meier, MSc; Eline A.J. Willemse, PhD; Sabine Schaedelin, MSc; Johanna Oechtering, MD; Johannes Lorscheider, MD; Lester Melie-Garcia, PhD; Alessandro Cagol, MD; Muhamed Barakovic, PhD; Riccardo Galbusera, MD; Suvitha Subramaniam, MSc; Christian Barro, MD; Ahmed Abdelhak, MD; Simon Thebault, MD; Lutz Achtnichts, MD; Patrice Lalive, MD; Stefanie Müller, MD; Caroline Pot, MD; Anke Salmen, MD; Giulio Disanto, MD; Chiara Zecca, MD; Marcus D’Souza, MD; Annette Orleth, PhD; Michael Khalil, MD; Arabella Buchmann, MSc; Renaud Du Pasquier, MD; Özgür Yaldizli, MD; Tobias Derfuss, MD; Klaus Berger, MD; Marco Hermesdorf, MD; Heinz Wiendl, MD; Fredrik Piehl, MD; Marco Battaglini, PhD; Urs Fischer, MD; Ludwig Kappos, MD; Claudio Gobbi, MD; Cristina Granziera, MD; Claire Bridel, MD; David Leppert, MD; Aleksandra Maleska Maceski, MSc; Pascal Benkert, PhD; Jens Kuhle, MD

JAMA Neurol. Published online February 06, 2023.

https://doi.org/10.1001/jamaneurol.2022.5250

Abstract

Importance  There is a lack of validated biomarkers for disability progression independent of relapse activity (PIRA) in multiple sclerosis (MS).

Objective  To determine how serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) correlate with features of disease progression vs acute focal inflammation in MS and how they can prognosticate disease progression.

Design, Setting, and Participants  Data were acquired in the longitudinal Swiss MS cohort (SMSC; a consortium of tertiary referral hospitals) from January 1, 2012, to October 20, 2022. The SMSC is a prospective, multicenter study performed in 8 centers in Switzerland. For this nested study, participants had to meet the following inclusion criteria: cohort 1, patients with MS and either stable or worsening disability and similar baseline Expanded Disability Status Scale scores with no relapses during the entire follow-up; and cohort 2, all SMSC study patients who had initiated and continued B-cell–depleting treatment (ie, ocrelizumab or rituximab).

Exposures  Patients received standard immunotherapies or were untreated.

Main Outcomes and Measures  In cohort 1, sGFAP and sNfL levels were measured longitudinally using Simoa assays. Healthy control samples served as the reference. In cohort 2, sGFAP and sNfL levels were determined cross-sectionally.

Results  This study included a total of 355 patients (103 [29.0%] in cohort 1: median [IQR] age, 42.1 [33.2-47.6] years; 73 female patients [70.9%]; and 252 [71.0%] in cohort 2: median [IQR] age, 44.3 [33.3-54.7] years; 156 female patients [61.9%]) and 259 healthy controls with a median [IQR] age of 44.3 [36.3-52.3] years and 177 female individuals (68.3%). sGFAP levels in controls increased as a function of age (1.5% per year; P < .001), were inversely correlated with BMI (−1.1% per BMI unit; P = .01), and were 14.9% higher in women than in men (P = .004). In cohort 1, patients with worsening progressive MS showed 50.9% higher sGFAP levels compared with those with stable MS after additional sNfL adjustment, whereas the 25% increase of sNfL disappeared after additional sGFAP adjustment. Higher sGFAP at baseline was associated with accelerated gray matter brain volume loss (per doubling: 0.24% per year; P < .001) but not white matter loss. sGFAP levels remained unchanged during disease exacerbations vs remission phases. In cohort 2, median (IQR) sGFAP z scores were higher in patients developing future confirmed disability worsening compared with those with stable disability (1.94 [0.36-2.23] vs 0.71 [−0.13 to 1.73]; P = .002); this was not significant for sNfL. However, the combined elevation of z scores of both biomarkers resulted in a 4- to 5-fold increased risk of confirmed disability worsening (hazard ratio [HR], 4.09; 95% CI, 2.04-8.18; P < .001) and PIRA (HR, 4.71; 95% CI, 2.05-9.77; P < .001).

Conclusions and Relevance  Results of this cohort study suggest that sGFAP is a prognostic biomarker for future PIRA and revealed its complementary potential next to sNfL. sGFAP may serve as a useful biomarker for disease progression in MS in individual patient management and drug development.