Plasma GFAP: A Promising Biomarker for Disease Progression and Treatment Response in Secondary Progressive MS

Multiple sclerosis (MS) remains one of the most complex neurodegenerative diseases, particularly in its later stages. Secondary progressive multiple sclerosis (SPMS), which often follows an initial relapsing-remitting phase, is characterized by a gradual worsening of disability, often without clear relapses. Understanding and tracking this progression — especially in the absence of overt inflammatory activity — is one of the biggest challenges facing clinicians and researchers alike.

But a study presented at the 2020 AAN Annual Meeting (Abstract #1782) sheds new light on how plasma glial fibrillary acidic protein (GFAP) might help meet that challenge.

What is GFAP and Why Does It Matter?
GFAP is a structural protein expressed almost exclusively in astrocytes, a key glial cell type in the central nervous system (CNS). When the CNS undergoes injury or chronic stress — such as in neuroinflammatory conditions like MS — astrocytes become reactive, and GFAP expression tends to rise. Thus, plasma levels of GFAP could reflect ongoing CNS pathology, even when it’s not obvious on standard clinical assessments.

This study, led by Jens Kuhle and colleagues from the University of Basel and Novartis, explored whether GFAP could serve as a biomarker for both disease severity and treatment response in SPMS patients enrolled in the EXPAND trial, a large Phase 3 study of the oral S1P receptor modulator siponimod.

Study Design: A Deeper Look into EXPAND
The team analyzed plasma GFAP levels in 475 randomly selected SPMS patients from EXPAND. These levels were measured using the highly sensitive Single Molecule Array (Simoa) technology — capable of detecting GFAP concentrations in the picogram range.

Key evaluations included:

Baseline correlations between GFAP and clinical/radiologic measures of disease burden

Change in GFAP levels from baseline to the end of the study (~21 months) with siponimod vs. placebo

Subgroup analyses based on relapse history

Key Findings
1. GFAP Correlates with Disease Burden — But Not Relapse History
At baseline, higher GFAP levels were significantly associated with:

Older age and longer disease duration (p < 0.0001)

Higher EDSS scores (more disability) (p = 0.0003)

Lower cognitive performance (SDMT score) (p = 0.016)

Greater lesion burden on MRI — both more contrast-enhancing lesions (p = 0.0137) and higher T2 lesion volume (p < 0.0001)

However, a history of relapses in the two years prior did not correlate with baseline GFAP levels — suggesting GFAP reflects chronic disease activity and not just acute inflammation.

2. Siponimod Stabilizes or Lowers GFAP — Placebo Does Not
Over the course of the study:

GFAP levels increased by 7.0% in the placebo group (from 92.1 to 98.6 pg/mL)

GFAP levels decreased by 1.0% in the siponimod group (from 91.5 to 90.6 pg/mL)

The difference between groups was highly significant (p < 0.0001)

3. GFAP Response Seen in Both Relapsing and Non-Relapsing SPMS
In patients with recent relapses:

GFAP rose by 6.3% with placebo, but fell by 0.5% with siponimod (p = 0.0296)

In patients with no recent relapses:

GFAP rose by 7.3% with placebo, but fell by 1.5% with siponimod (p = 0.0004)

These subgroup findings are particularly compelling — they suggest that even in the absence of relapse, siponimod may slow underlying astrocytic activation and neurodegeneration.

Why This Matters: A Clinical Perspective
MS clinicians and researchers are increasingly turning to fluid biomarkers to get a clearer, real-time view of disease activity and treatment response. While neurofilament light chain (NfL) has garnered the most attention to date — primarily reflecting axonal damage — GFAP may offer complementary insights, especially into glial activity and chronic progression.

This study is one of the first to show that plasma GFAP not only correlates with disease severity but also responds to treatment. And importantly, the reduction in GFAP with siponimod treatment occurred even in patients without recent relapses, reinforcing the concept that SPMS is driven by more than just inflammation.

Caveats and Next Steps
While the findings are exciting, a few limitations are worth noting:

This was a post hoc analysis of a subset of patients from the EXPAND trial.

GFAP, though promising, is not yet a validated surrogate endpoint for clinical outcomes in MS.

Larger studies and real-world data will be needed to confirm whether GFAP can be used in routine practice to guide treatment decisions.

Final Thoughts
The potential of GFAP as a blood-based biomarker in SPMS represents a meaningful step forward. It gives researchers a valuable window into non-inflammatory pathology, and clinicians a possible tool for monitoring progression in a disease phase that has long been difficult to track.

In short: GFAP is more than just a research curiosity. It might soon be a practical marker of SPMS disease activity and treatment response — with real-world implications for personalized care.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Kuhle, J., Kropshofer, H., Maleska Maceski, A., et al. Plasma Glial Fibrillary Acidic Protein Correlates with Characteristics of Advanced Disease and Treatment Response in Secondary Progressive Multiple Sclerosis. Neurology. April 14, 2020; 94 (15_suppl): 1782.