Levels of GFAP protein in blood may predict ‘silent progression’ of MS

Measuring levels of the protein GFAP in blood can help to predict disability progression that occurs without relapses — so-called silent progression — in people with multiple sclerosis (MS), a new study reports.

These findings may have “clinical implications for patient management and development of novel drugs,” the researchers wrote, noting the ongoing “lack of validated biomarkers for disability progression independent of relapse activity” in MS.

The study, “Serum Glial Fibrillary Acidic Protein Compared With Neurofilament Light Chain as a Biomarker for Disease Progression in Multiple Sclerosis,” was published in JAMA Neurology.

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GFAP blood levels linked to MS progression

MS is caused by inflammation that damages the nervous system. In most patients, the disease is marked by relapses — flares where symptoms suddenly worsen — followed by periods of remission during which symptoms ease.

While relapse activity can be a substantial driver of disability, many patients experience worsening disability even in the absence of new relapses. This type of disability worsening is referred to as progression independent of relapse activity or PIRA, sometimes colloquially called silent progression.

With a lack of biological markers, or biomarkers, it now is difficult for clinicians to predict which patients will experience PIRA. In this study, a team led by scientists in Switzerland conducted a series of analyses aiming to identify a biomarker that could be measured to predict PIRA risk.

“The need for a biomarker that specifically reflects current and prognosticates future disability due to pure progression/PIRA has become urgent [because] disability worsening often continues despite almost complete suppression of acute disease activity under high-efficacy therapies,” the researchers wrote.

The team specifically focused on levels of two proteins in the blood: neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP).

NfL is a structural protein inside nerve cells that gets released into the spinal fluid and blood when nerves are damaged. It is a well-established marker of nerve damage in MS and other diseases, and prior research has suggested that NfL levels tend to spike during MS relapse.

GFAP also is a structural protein, serving a similar function to NfL but in a different type of cell. This protein impacts astrocytes, star-shaped cells in the nervous system that play a variety of roles in supporting neuronal function.

“This study attempted a direct comparison of [blood GFAP and NfL] levels: how they reflect acute disease activity vs the identification and prognostication of future disease progression and whether their combination provides added value,” the researchers wrote.

In a first analysis, the team examined data from 103 people with MS who were divided into three groups. One group had stable MS, while a second included patients who experienced relapse activity. The third group comprised patients who experienced PIRA. At the initial assessment (baseline), all three groups were generally comparable for demographic and clinical data.

In line with prior data, analyses of patients who experienced relapses showed that NfL levels increased during relapses, by 53.2% compared with remission. However, GFAP levels changed by less than 5% between relapse and remission.

Conversely, GFAP levels were 57.5% higher in patients with PIRA compared with those with stable MS, while the difference in NfL was 24.8%. When the researchers adjusted for GFAP levels, the difference in NfL between the groups was no longer statistically significant, whereas the increase in GFAP levels in patients who experienced PIRA was significant even after adjusting for NfL.

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Examing MS progression in patients on relapse-reducing meds

In a second analysis, the scientists examined data for 252 people with MS who were on treatment with B-cell-depleting therapies, namely Ocrevus (ocrelizumab) or rituximab. These medications can substantially reduce the risk of MS relapse.

Over the course of follow-up, 17.1% of these patients experienced a confirmed worsening in disability. About 90% of those progression events were attributable to PIRA, while the rest were related to relapse activity.

The need for a biomarker that specifically reflects current and prognosticates future disability … has become urgent [because] disability worsening often continues despite almost complete suppression of acute disease activity under high-efficacy therapies.

In statistical models, GFAP levels showed strongly significant associations with the risk of PIRA, whereas NfL levels showed less strong associations.

Further models suggested that high levels of GFAP were associated with a roughly threefold higher risk of disability worsening, while high NfL levels were linked to a roughly doubled risk of worsening. In turn, high levels of both GFAP and NfL were associated with a more than fourfold risk of disability worsening, compared with low levels of both proteins.

Collectively, the researchers said these data support GFAP as a good biomarker for predicting the risk of PIRA, while also supporting NfL as a marker of relapse activity. As such, looking at both markers gives “comprehensive coverage of biological processes leading to disability worsening.”

“GFAP and NfL thus complement each other,” Jens Kuhle, MD, PhD, a professor at the University of Basel and co-author of the study, said in a university press release. Kuhle added that these findings “can help us in making MS therapy more individually tailored and forward-looking.”

The researchers noted that further research will be needed to validate these findings. In particular, they highlighted a need to assess whether GFAP can predict PIRA in MS patients on other therapies.