Neutrophil Markers Distinguish MS From NMOSD

Erik Greb

October 22, 2020

Neutrophil granulocyte biomarkers can distinguish between neuromyelitis optica spectrum disorders (NMOSD) and anti-MOG antibody–associated disease (MOGAD) on one hand and multiple sclerosis (MS) on the other hand, researchers reported. If current findings are replicated, these biomarkers will help neurologists distinguish between these disorders in the future, even in cases that are negative for autoantibodies, they said.

The sensitivity and specificity profile of neutrophil granulocyte biomarkers is not as good as that for cell-based assays for AQP4 and anti-MOG antibodies when it comes to distinguishing between acute NMOSD or MOGAD versus acute relapsing-remitting MS, said David Leppert, MD, of University Hospital Basel (Switzerland) and the University of Basel. But the sensitivity and specificity of neutrophil granulocyte biomarkers are "even with" those of referring ELISA tests, he added. Furthermore, the evaluation of these biomarkers can be completed within hours, thus providing the potential for timely support for therapeutic decisions about patients with acute NMOSD.

It can be difficult to distinguish between NMOSD, MOGAD, and MS using a clinical examination and MRI scans alone. Assays for AQP4 and anti-MOG antibodies are the standard for refining the diagnosis, but obtaining the results of these assays takes 1-2 weeks. This time frame may delay the administration of urgently needed treatment.

Neutrophil granulocytes have various components that carry molecules that, although they are secreted to defend the host, also can damage tissue. These cells are common in brain tissue and CSF among patients with NMOSD. Patients with MOGAD often have neutrophil granulocytes as well, but the latter are rare in MS.

Biomarkers Had High AUC

Leppert and colleagues conducted a study to evaluate whether these cells can distinguish NMOSD or MOGAD from MS. The investigators specifically examined the following neutrophil granule products: elastase, myeloperoxidase (MPO), matrix metalloproteinase-8 (MMP-8), and neutrophil gelatinase-associated lipocalin (NGAL). Leppert's group evaluated CSF samples from 42 patients with NMOSD, 6 patients with MOGAD, and 41 patients with relapsing-remitting MS for these potential biomarkers. They also examined the samples for neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and S100B by conventional ELISA or single-molecule array assay. The investigators examined CSF samples from 25 healthy controls as a reference group.

Linear models allowed Leppert and colleagues to assess the association between biomarkers and disease groups. The investigators modeled the change of biomarker levels over time. They calculated receiver operating characteristic (ROC) curves and area under the curve (AUC) to estimate the potential to distinguish NMOSD and MOGAD from relapsing-remitting MS in acute disease phase (i.e., at 20 or fewer days after relapse), as well as between acute NMOSD and MOGAD. Finally, they assessed the association of biomarkers with Expanded Disability Status Scale (EDSS) score in acute NMOSD and relapsing-remitting MS using linear models and Spearman correlation.

Leppert and colleagues found that levels of NfL were increased among patients, compared with healthy controls. GFAP levels were increased in patients with NMOSD, compared with controls.

Among patients with NMOSD, all four neutrophil granulocyte markers were significantly increased, compared with healthy controls and patients with acute relapsing-remitting MS. Among patients with MOGAD, elastase, MPO, and MMP-8 were increased, compared with healthy controls and patients with acute relapsing-remitting MS. In ROC analyses comparing patients with acute NMOSD or MOGAD against those with acute RRMS, the AUC of elastase and NGAL was 0.91, the AUC of MPO was 0.82, and the AUC of MMP-8 was 0.81.

Levels of S100B were increased in 89% of patients with acute NMOSD (AUC = 0.82), and levels of GFAP were increased in 83% of patients with acute NMOSD (AUC = 0.80), compared with median values of MOGAD. Among patients with acute NMOSD, EDSS scores correlated with all four neutrophil granulocyte markers and GFAP, but not with NfL and S100B. The neutrophil granulocyte markers in acute NMOSD are likely drivers of tissue damage, said Leppert. "We may end up in the future with an algorithm that combines several markers into one score to optimize the differentiating power." The next step will be to validate these findings in a larger sample set, he said at the Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

Biomarkers May Predict Attacks

Granulocyte markers may provide support for a diagnosis of NMOSD over MS even in the small subgroup of patients who are seronegative for AQP4-IgG and MOG-IgG, said Brian G. Weinshenker, MD, a neurology consultant at Mayo Clinic in Rochester, Minn. In the study by Leppert and colleagues, granulocyte markers did not appear able to distinguish patients with AQP4-IgG–associated NMOSD from those with MOG-IgG–associated NMOSD, although astrocyte markers did in previous studies. "Granulocyte markers are primarily effective when studied in the context of an acute attack, unlike the antibody biomarkers," said Weinshenker.

"Perhaps the most promising aspect of these new biomarkers is the fact that they are biomarkers for important mediators of tissue toxicity and seemed to correlate with attack-related disability," he added. "They may prove to be prognostic indicators of attacks, and might influence the aggressiveness of acute management of attacks, although, in practice, all patients with NMOSD attacks, especially those associated with AQP4-IgG, should be managed aggressively."

The current results will need independent confirmation before these biomarkers can be integrated into clinical practice, said Weinshenker. Studies should include patients with other diseases that can cause inflammation in the spinal cord and optic nerve (e.g., acute disseminated encephalomyelitis, infectious myelitis, and parainfectious myelitis) as relevant controls to determine whether granulocyte markers can distinguish these conditions effectively.

In addition, patients with discrepant values for elevations of granulocyte markers and serological indicators of NMOSD should be followed to determine the markers' significance in this population, as well as to understand the value that measuring neutrophil markers provides. "Further studies of how these markers might herald attacks and predict disability might render these tests useful in monitoring patients and potentially intervening early in the attack process before attacks are fully manifest clinically."

Leppert did not report any disclosures or any outside funding for the study. Weinshenker receives royalties from RSR, Oxford University, Hospices Civil de Lyon, and MVZ Labor PD Volkmann und Kollegen for a patent on NMO-IgG as a diagnostic test for NMOSD. He has served on an adjudication committee for clinical trials in NMOSD being conducted by MedImmune/VielaBio and Alexion, and consulted for Chugai/Roche/Genentech and Mitsubishi-Tanabe regarding a clinical trial for NMOSD.

SOURCE: Leppert D et al. MSVirtual2020. Abstract LB01.03.

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