Multiple sclerosis (MS) is a disease that rarely plays by the rules. For some people, it moves slowly and quietly, while for others, it causes a rapid loss of function. Clinicians have long struggled with this unpredictability, especially when trying to choose the right treatment early on. A new multicenter study, published in Brain (Monreal et al., 2024), offers a promising way forward: using two simple blood biomarkers—serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP)—to predict how a person’s MS may progress and how well they might respond to therapy.

Why Biomarkers Matter in MS
Traditionally, neurologists rely on MRI scans and clinical symptoms to estimate how MS will behave. But these tools often catch the disease after damage is already done. The holy grail of MS research has been to find early warning signals—something measurable in the blood that could tell doctors whether a patient is at high risk of worsening disability.

sNfL reflects damage to nerve fibers, essentially serving as a “leakage signal” from injured neurons.

sGFAP is tied to activation of astrocytes (supporting cells in the brain), signaling a form of chronic inflammation that often underlies long-term progression.

Together, they provide a dual window into both acute damage and smoldering inflammation.

The Study at a Glance
Population: 725 patients, median age ~34 years, 70% women.

Setting: 13 European hospitals, with data spanning nearly three decades.

Timing: Blood samples taken within 12 months of disease onset and before treatment.

Follow-up: Median of 6.4 years.

Researchers tracked three key outcomes:

Relapse-associated worsening (RAW): disability increases linked to relapses.

Progression independent of relapse activity (PIRA): silent, gradual disability increase unrelated to relapses.

EDSS ≥ 3: a clinical marker of moderate disability.

What They Found
High sNfL = Higher Risk Across the Board

Patients with elevated sNfL were more likely to experience RAW, PIRA, and reach EDSS 3 sooner.

Think of sNfL as a warning flare for fast-moving disease activity.

High sGFAP = Hidden Risk

On its own, sGFAP mainly predicted reaching EDSS 3.

But in patients with low sNfL, high sGFAP strongly predicted PIRA—suggesting that even without much acute damage, “smoldering” inflammation was silently driving progression.

The Combination Tells the Full Story
Low sNfL + Low sGFAP: lowest risk—patients often remained stable.

High sNfL (with or without high sGFAP): high risk, especially for relapse-driven worsening.

Low sNfL + High sGFAP: risk of slow, relapse-independent progression.

Treatment Implications
The study also looked at how different disease-modifying therapies (DMTs) performed across biomarker groups:

Injectable/oral therapies (e.g., interferons, glatiramer acetate, fumarates) reduced relapse-related worsening but failed to prevent silent progression (PIRA).

High-efficacy DMTs (e.g., natalizumab, alemtuzumab, ocrelizumab, rituximab) effectively counteracted both RAW and PIRA risks—except in patients with both high sNfL and sGFAP, where PIRA risk remained stubbornly elevated.

In other words:
Patients with high sNfL benefit most from early, aggressive treatment.

Patients with high sGFAP but low sNfL may need different therapeutic strategies, since current drugs that mainly target adaptive immunity may not address “smoldering” brain inflammation.

Why This Matters
This study is a step toward personalized medicine in MS. Instead of a one-size-fits-all approach, clinicians may soon use a simple blood test at diagnosis to stratify patients into risk groups:

Stable group → may do well with lower-risk therapies.

High-inflammatory group (high sNfL) → needs early high-efficacy treatment.

Smoldering group (high sGFAP, low sNfL) → may require new drugs targeting CNS-resident inflammation.

By catching these patterns early, neurologists could prevent irreversible disability rather than just reacting to it later.

Looking Ahead
While promising, the authors note that more prospective trials are needed, especially to test how specific therapies work in biomarker-defined groups. Another challenge is that PIRA—the silent progression—remains resistant to most current drugs, highlighting the urgent need for treatments targeting innate immune mechanisms inside the brain.

Disclaimer: This blog post is based on the information provided in the cited scientific article. It aims to provide an accessible summary of the research findings and should not be considered as definitive medical advice. For any health concerns, please consult with a qualified healthcare professional.

Reference:
Monreal, E., Fernández-Velasco, J. I., Álvarez-Lafuente, R., Sainz de la Maza, S., García-Sánchez, M. I., Llufriu, S., Casanova, B., Comabella, M., Martínez-Yélamos, S., Galimberti, D., Ramió-Torrentà, L., Martínez-Ginés, M. L., Aladro, Y., Ayuso, L., Martínez-Rodríguez, J. E., Brieva, L., Villarrubia, N., Eichau, S., Zamora, J., Rodero-Romero, A., … Villar, L. M. (2024). Serum biomarkers at disease onset for personalized therapy in multiple sclerosis. Brain : a journal of neurology, 147(12), 4084–4093. https://doi.org/10.1093/brain/awae260