Of 4 markers, NfL best at predicting worse disability in NMOSD: Study

Blood levels of NfL at attack onset may help in prognosis, treatment

Patricia Inacio, PhD avatar

by Patricia Inacio, PhD |

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Out of four markers of nervous system cell injury, blood levels of neurofilament light chain (NfL) were found to best predict disability worsening in people with neuromyelitis optica spectrum disorder (NMOSD), a study showed.

Measures of blood NfL levels at the time of an NMOSD attack were the only ones significantly associated with muscle weakness and movement difficulty — and the sole marker for determining those patients experiencing disability worsening after an attack.

Conversely, the risk of future attacks was better predicted by blood levels of another marker, called glial fibrillary acidic protein, or GFAP.

The study, “Serum neurofilament light chain levels at attack predict post-attack disability worsening and are mitigated by inebilizumab: analysis of four potential biomarkers in neuromyelitis optica spectrum disorder,” was published in the Journal of Neurology, Neurosurgery and Psychiatry.

“This analysis provides valuable insights into how we can improve care for people with NMOSD by integrating easily accessible serum [blood] biomarker assessments into treatment decision-making,” Orhan Aktas, MD, the study’s first author and professor at the Medical Faculty at Heinrich-Heine-University, in Düsseldorf, Germany, said in a press release from Horizon Therapeutics, which funded the study.

“Conducting assessments of the sNfL biomarker during an attack can inform clinicians about the attack severity and the likelihood of residual disability in the patient, and therefore may guide therapeutic interventions to help preserve their long-term outcomes. Combination with other select serum biomarkers such as sGFAP may further increase prediction of clinical activity and, thus, prognosis in this devastating disorder,” said Aktas.

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N-MOmentum trial used to investigate blood levels of 4 disability markers

NMOSD is caused by the immune system abnormally producing self-reactive antibodies that attack healthy nervous system cells. Such attacks cause inflammation and damage to the spinal cord and the optic nerves, which connect the eyes to the brain.

The inflammatory response to an attack leads to disease relapses that are associated with worsening disability and disease progression. As such, identifying markers that can help predict the course of NMOSD and guide treatment is an active research field.

With this in mind, an international team of researchers investigated potential links between four markers of nervous system cell damage and disease activity or disability. Their study involved NMOSD patients who participated in the Phase 2/3 N-MOmentum trial (NCT02200770), which wrapped up in November 2020.

The N-MOmentum study had enrolled 230 patients who were first given either Uplizna (inebilizumab-cdon) or a placebo for six months. After that period, all were treated with Uplizna for up to three years. Most of the participants (nearly 93%) had antibodies against AQP4 — the most common target of NMOSD-driving self-reactive antibodies.

The study results showed that Uplizna, developed by Horizon Therapeutics, was superior to a placebo at reducing disease attacks and slowing disability progression, supporting the therapy’s approvals for NMOSD patients positive for anti-AQP4 antibodies.

In the new analysis, researchers analyzed blood levels of NfL, ubiquitin C-terminal hydrolase L1 (UCHL1), and tau — all markers of nerve cell damage — and GFAP, a marker of injury to astrocytes, the cells that are mainly attacked in NMOSD.

In total, 1,260 serial and NMOSD attack-related blood samples were used to measure the four putative markers. The samples came from 215 NMOSD patients, 90% of whom were women and 51% of whom were white individuals.

Two additional groups were included in the analysis to serve as controls. One comprised patients with relapsing-remitting multiple sclerosis (RRMS), another neurodegenerative disease, and the other was composed of healthy people.

The results showed that NMOSD patients positive for anti-AQP4 antibodies tended to show higher blood levels of NfL and GFAP than RRMS patients and healthy controls.

Also, NfL and GFAP levels were pronouncedly increased during the week following attack onset relative to those seen in healthy controls. In turn, tau and UCHL1 levels “remained below elevated levels at all time points assessed,” the team wrote.

In the seven days or more after the attack, only the mean NfL levels remained elevated, a pattern specifically seen in patients positive for anti-AQP4 antibodies, but not in those with other types of self-reactive antibodies or none.

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Only blood GFAP levels shown to predict future attacks

Statistical analysis showed that GFAP, NfL, and tau levels were significantly associated with NMOSD attacks.

However, only GFAP levels were predictive of future attacks in AQP4-NMOSD patients. Specifically, higher-than-normal levels at study’s start were significantly associated with a 2.5 times higher risk of relapse during the trial’s placebo-controlled phase.

The researchers then analyzed how the concentrations of each biomarker in AQP4-NMOSD patients correlated with three measures of disability: the Expanded Disability Status Scale (EDSS), Opticospinal Impairment Scale (OSIS), and the modified Rankin Scale (mRS).

NfL was the marker that correlated best with changes in EDSS scores during attacks, and it was the only one linked to changes in mRS scores. Regarding EDSS subscales, NfL was significantly associated with changes in walking skills, as well as muscle weakness or difficulty moving the legs during attack assessments.

In addition, an NfL cut-off value of 32 picograms per mL (pg/mL) at time of the attack allowed the researchers to accurate discriminate patients positive for anti-AQP4 antibodies who experienced disability worsening during follow-up from those who did not.

The other biomarkers “were not significantly associated with EDSS score changes during attack or follow-up after controlling for [blood] NfL changes,” the researchers wrote.

[NfL] measured at attack, is the best predictor among the [nerve system tissue] damage biomarkers studied here for disability worsening during and after attacks.

The team then assessed the effects of Uplizna in these markers’ levels. They found that NfL levels were significantly lower in AQP4-NMOSD patients treated with the therapy than in those in the placebo group.

Also, fewer Uplizna-treated patients had NfL levels higher than 16 pg/mL (22% vs. 45%), supporting the therapy’s effectiveness in easing disability.

Overall, these findings show that despite being inferior to GFAP at predicting future attacks, NfL “measured at attack, is the best predictor among the [nerve system tissue] damage biomarkers studied here for disability worsening during and after attacks,” the team wrote.