Blood protein marker may predict hidden MS progression

Elevated levels of a blood protein called GFAP are associated with an increased risk of disease progression in the absence of relapse activity in people with multiple sclerosis (MS), according to a study.

The study also found that patients whose GFAP levels declined after starting MS treatment had a lower risk of future progression independent of relapse activity (PIRA), suggesting that changes in the biomarker may provide information about disease progression and treatment response.

The study, “Serum Glial Fibrillary Acidic Protein Dynamics, Disease Progression, and Therapy Response in Multiple Sclerosis,” was published in JAMA Neurology. The work was supported by the Swiss National Science Foundation, the Progressive MS Alliance, and grant funding from the pharma companies Novartis and Roche, and some of the authors are employees at these companies.

MS is an inflammatory disease that causes damage to the brain and spinal cord. In most cases, the disease is characterized by MS relapses, or periods when MS symptoms suddenly worsen, followed by periods in which symptoms ease and remain generally stable.

Until recently, researchers believed that people with relapsing forms of MS would only experience worsening disability as a result of poor recovery from relapses, in which some symptoms persisted after the relapse was controlled and contributed to long-term disability. But new evidence has consistently demonstrated that patients may experience gradual symptom worsening over time in the absence of relapses. This is known as PIRA, and it has been shown to be the main driver of long-term disability in most people with MS.

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Biomarker for relapse risk, but not for PIRA

Previous research has shown that high levels of neurofilament light chain (NfL), a biomarker of nerve damage, can indicate an increased risk of future relapses in people with MS. However, there isn’t a well-established marker that can identify people at greater risk of PIRA.

GFAP is found in astrocytes, cells that support and protect nerve cells in the brain and spinal cord. Increased GFAP levels can reflect astrocyte activation or injury, and they have been investigated as a marker of processes involved in MS progression.

“One of the key questions for us was whether progression leaves a different biological fingerprint than inflammation,” Jens Kuhle, MD, PhD, study co-author and research group leader at the University of Basel, said in a university news story. “If these processes are biologically distinct, we also need biomarkers that reflect different aspects of the disease rather than expecting a single marker to capture everything.”

To determine whether GFAP can serve as a biomarker of future PIRA risk, the researchers analyzed long-term data from two studies following people with MS over time. One study included 1,709 patients followed for a median of 6.9 years, and the other involved 620 patients followed for a median of 13.1 years.

In line with previous studies, elevated NfL levels were associated with a 69%-100% increased risk of relapses in the following year. GFAP, on the other hand, was not associated with relapse risk, but it did show significant correlations with both long-term and short-term PIRA risk.

Specifically, elevated GFAP levels were associated with 22%-31% higher risk of PIRA over the entire follow-up period. In short-term analyses, the researchers found that patients with GFAP levels above the 84th percentile at one clinical visit were 36%-45% more likely to have evidence of PIRA at their next clinical appointment.

“This study provides evidence for the combined use of NfL and GFAP to evaluate disease [activity] and their respective associations with future relapse activity and PIRA,” the researchers wrote.

The team investigated whether changes in GFAP after treatment initiation were associated with later PIRA risk. This analysis used data from 241 participants who started taking fingolimod (sold as Gilenya and Tascenso ODT, with generics also available) and 342 who started B-cell-depleting therapies such as Briumvi (ublituximab-xiiy), Kesimpta (ofatumumab), and Ocrevus (ocrelizumab).

Results showed that GFAP levels declined during the first two years of treatment in both groups. People who did not later develop PIRA tended to have a more pronounced decline in GFAP than those who did.

Among people receiving fingolimod, each one-unit reduction in normalized GFAP levels per year during the first two years was associated with a 54% lower risk of PIRA. For those receiving B-cell-depleting therapies, the corresponding reduction in risk was 67%.

“What was particularly noteworthy was not only that higher GFAP levels were associated with gradual disease progression,” said Maximilian Einsiedler, study co-author at Basel. “Changes in the biomarker during treatment were also associated with patients’ later risk of disability progression. This suggests that GFAP may capture more than a snapshot of disease activity and reflect biological processes that influence the future course of the disease.”