The pathogenesis of multiple sclerosis (MS) involves both adaptive and innate immune disease mechanisms. There is a lack of validated biomarkers for disability progression independent of relapse activity (PIRA) in multiple sclerosis (MS).
A recent study in JAMA Neurology, Stephanie Meier, MSc and team reported that serum biomarkers can predict disability progression that will occur years later. This study showed that serum neurofilament light chain (NfL) was better correlated with relapse activity. In contrast, serum glial fibrillary acidic protein (GFAP) level was correlated with disease progression. However, the combination of these values was the strongest predictor of future disability, and this finding points toward the combined role of inflammation and neurodegeneration in MS.
The study is a prospective, multicenter study performed in 8 centers in Switzerland. For the 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 study patients who had initiated and continued B-cell–depleting treatment (ie, ocrelizumab or rituximab).
The cohort study of 355 patients and 259 healthy controls,they found that elevated sGFAP z scores identified current disease progression and were associated with future disease progression but not with acute inflammation. In addition, the association of sNfL levels with progression was less pronounced, whereas sNfL levels were strongly increased during relapse activity.
The key findings of the study are
• 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. I
• n 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).
The researchers concluded that 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.
Reference: Meier S, Willemse EA, Schaedelin S, et al. Serum Glial Fibrillary Acidic Protein Compared With Neurofilament Light Chain as a Biomarker for Disease Progression in Multiple Sclerosis. JAMA Neurol. Published online February 06, 2023. doi:10.1001/jamaneurol.2022.5250.