Among people with secondary progressive multiple sclerosis (SPMS) without active disease, high blood levels of the proteins neurofilament light chain, known as NfL, and glial fibrillary acidic protein, or GFAP, are associated with an increased risk of worsening disability, new research shows.
The findings were presented at the 2021 annual meeting of the American Academy of Neurology, in a talk titled “Plasma Neurofilament Light Chain and Glial Fibrillary Acidic Protein Levels Are Prognostic of Disability Worsening: A Biosignature That Helps Differentiating Active From Non-active SPMS.”
Measuring levels of certain proteins in the blood can provide important information about a person’s health. NfL is released into the blood when neurons or nerve cells are damaged or destroyed. As such, levels of NfL in the blood are indicative of injury in the nervous system. GFAP, meanwhile, is associated with the activity of star-shaped neural support cells called astrocytes, and also is a marker of nervous system injury.
Prior research has suggested that both NfL and GFAP have prognostic utility in multiple sclerosis. This led researchers to hypothesize that combining the two markers could provide additional useful information.
EXPAND included a total of 1,651 patients, who were randomly assigned to receive Mayzent or a placebo, taken by mouth once a day, for up to three years. Following the trial’s conclusion, participants could then enter an extension study and receive Mayzent for up to 10 years.
Now, researchers conducted a post-hoc analysis of EXPAND and its extension to determine if the NfL and GFAP proteins could be used to identify patients more likely to experience disability progression. Of note, a post-hoc analysis is one that was not initially planned and is conducted after data have been collected.
The team examined samples for 1,369 SPMS patients, including 665 with active disease — meaning they experienced relapses and/or evidence of new disease activity on an MRI scan in the two years prior to the trial. The remaining 704 SPMS patients had non-active disease.
Based on testing at the start of the trial, the researchers determined whether each participant had high or low levels of NfL and GFAP. Using the results of prior research, “high” levels were considered to be 30 picograms (pg) per mL or higher for NfL, and 130 pg/mL or higher for GFAP.
Statistical analyses then were used to assess whether these levels were significantly associated with disability-related outcomes later on, as measured using the Expanded Disability Status Scale, or EDSS. These analyses took into account various relevant factors, including age, gender, disease duration, treatment, and disability prior to the start of the trial.
Among individuals with non-active SPMS, those with high levels of both NfL and GFAP had significantly worse disability-related outcomes than those with low levels of both proteins. For example, time to reach a score of 7.0 on the EDSS — meaning that a person is essentially dependent on a wheelchair to get around — was significantly shorter among those with high levels of NfL and GFAP.
Two other disability measurements — time-to-one-point-sustained EDSS worsening and time-to-three-month confirmed disability worsening — also were significantly shorter among those with high levels of both proteins.
Among those with non-active SPMS, high levels of NfL, but not GFAP, also were associated with significantly shorter times to worsening disability, as compared with low levels of both proteins. In contrast, high levels of GFAP, but not NfL, were not significantly linked with disability progression.
“So, high plasma NfL seems to be more important than high plasma GFAP in non-active SPMS,” said Jens Kuhle, MD, of the University Hospital and University of Basel, in Switzerland, who presented the findings. Plasma is the non-cellular part of blood.
While high NfL and GFAP together were effective at predicting disability in non-active SPMS, for those with active disease, levels of these proteins showed “no consistent trends across disability outcomes,” according to Kuhle.
Also of note, the combination of the two markers was generally better at predicting disability than either protein alone for people with non-active disease. This trend was not seen in active SPMS. The results showed that for some disability measurements, high levels of just one protein were more closely associated with greater disability than high levels of both.
“The signature of high plasma NfL in combination with high plasma GFAP … was most consistently associated with a higher risk of worse disability outcomes in non-active SPMS,” Kuhle concluded.
“In people with non-active SPMS, identifying those with a higher risk of progression who might benefit from treatment is especially difficult because by definition, they are lacking the established signs of relapse and MRI activity seen in active SPMS, while still experiencing disability worsening,” Ludwig Kappos, MD, the principal investigator of the EXPAND trial and a professor at University Hospital Basel, said in a press release.
“These encouraging data indicate that a combination of blood biomarkers may increase sensitivity in detecting the early signs of progression in non-active SPMS, allowing for intervention when treatment could be most effective in delaying further progression,” Kappos added.
The researchers are currently conducting further analyses to investigate the effect of using different cut-off values for the two markers. They also are testing how these markers may change over time or with treatment.
Kuhle noted that these data come from a trial that was not designed to evaluate these markers, which is a limitation of the analysis.
“These results need further exploration,” Kuhle said, noting a need for “validation in real-world practice or other progressive MS trials.”
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