sGFAP May Predict Progression Independent of Relapse in BCDT-Treated MS

New study findings provide indications that a certain biomarker measured at any point in time may offer help to predict worsening disability among patients with multiple sclerosis (MS) receiving certain treatment for their disease.¹

The findings, published in Annals of Neurology, showed that increases in serum glial fibrillary acidic protein (sGFAP) throughout the course of B-cell depletion therapy (BCDT) are associated with disability worsening despite not relapsing—known as progression independent of relapse activity (PIRA). Previous research has suggested that PIRA is the most common driver of disability worsening across MS phenotypes.²

“Because BCDT leads to an almost complete suppression of focal inflammatory activity, the focus shifts to how disability worsening (independent of focal inflammatory activity) can be controlled therapeutically and how this can be anticipated with biomarkers,” the researchers of this new study explained.¹ “The increase of sGFAP may result from a disturbed astrocyte homeostasis and is, therefore, a plausible biomarker to reflect the scaring of neural tissue (i.e., ‘sclerosis’) and its clinical correlate progression in its strict sense (i.e., PIRA).”

Across 362 patients, accounting for nearly 1500 samples, data consistently showed higher sGFAP scores among patients with PIRA. After 1 year of treatment, those with sGFAP levels of greater than 1 had an 80% (hazard ratio [HR], 1.80; 95% CI, 1.17-2.78; P = .0079) increased risk of PIRA. While having high serum neurofilament light chain (sNfL) Z scores showed initial signals of carrying a higher risk of PIRA, no association was seen in a Cox model accounting for both sNfL and sGFAP.

Previous research has found similar patterns, suggesting that sGFAP is more strongly associated with disease progression than sNfL levels. For example, a study published in 2023 in JAMA Neurology found that while patients with worsening progressive MS (PMS) had sGFP levels that were 50.9% higher than those of patients with stable disease after adjusting for sNfL, a 25% increase in sNfL among patients with PMS was lost after adjusting for sGFAP.³

In this most recent study, patients who experienced PIRA were older, had higher Neurostatus-Expanded Disability Status Scale scores at the start of the study, experienced fewer relapses prior to BCDT, and were more likely to have primary PMS.¹

Looking at the 26.2% of patients who experienced PIRA throughout the study follow-up over a median of 4.8 years, sGFAP Z scores were higher than for those with stable disease, up by 0.52 Z score units (range, 0.22-0.83). Notably, sGFAP levels continued to increase over time (0.49; 95% CI, 0.29-0.69 Z score units/10 years; P < .0001) throughout BCDT treatment, suggesting the treatment approach has a limited effect on mechanisms underlying MS progression.

Meanwhile, levels of sNfL decreased throughout BCDT treatment in certain patients. Among patients not experiencing PIRA, sNfL levels decreased among the 274 patients with relapsing MS (RMS) once treatment was initiated, while levels increased in the 88 patients with PMS.

“The decrease of sNfL after BCDT start in RMS patients without PIRA confirms that this biomarker reflects the modification of disease processes by this therapy,” the researchers wrote. “In return, the sustained elevation of sNfL in PMS suggests that neuro-axonal degeneration is also an essential aspect of progressive disease biology that is not equally addressed by BCDT. Although current results support the concept that sGFAP and sNfL reflect largely orthogonal pathomechanisms (i.e., smoldering neurodegeneration and acute inflammation, respectively), it is evident that both mechanisms of neural damage represent a spectrum that, to a variable degree, occur interdependently and at all stages of MS.”

The researchers noted the potential impact of having no comparison group in the study on their findings, particularly when comparing the effect of BCDT on sGFAP levels with other treatments or with no treatment.

References

1. Benkert P, Maceski AM, Schaedelin S, et al. Serum glial fibrillary acidic protein and neurofilament light chain levels reflect different mechanisms of disease progression under B-cell depleting treatment in multiple sclerosis. Ann Neurol. Published online October 16, 2024. doi:10.1002/ana.27096.

2. Müller J, Cagol A, Lorscheider J, et al. Harmonizing definitions for progression independent of relapse activity in multiple sclerosis: a systematic review. JAMA Neurol 2023;80(11):1232-1245. doi:10.1001/jamaneurol.2023.3331

3. Meier S, Willemse EAJ, 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. 2023;80(3):287-297. doi:10.1001/jamaneurol.2022.5250