Longitudinal treatment responsiveness on plasma neurofilament light chain and glial fibrillary acidic protein levels in neuromyelitis optica spectrum disorder

Abstract

Background: Neurofilament light chain (NfL) and glial fibrilliary acidic protein (GFAP) have been suggested to be biomarkers of the pathophysiological process of neuromyelitis optica spectrum disorders (NMOSD), but the relationship between the plasma levels of these molecules with disease activity and treatment is incompletely understood. Objective: To investigate the treatment effects of disease-modifying drugs on plasma neurofilament light chain (pNfL) and plasma glial fibrillary acidic protein (pGFAP) and explore the predictive value of pNfL and pGFAP in the activity of NMOSD. Methods: pNfL and pGFAP levels were measured using single-molecule arrays in 72 patients with NMOSD and 38 healthy controls (HCs). Patients with NMOSD received tocilizumab ( n = 29), rituximab ( n = 23), oral prednisone ( n = 16), and oral azathioprine or mycophenolate mofetil ( n = 4). Results: NMOSD patients had significantly higher pNfL and pGFAP levels than HCs (pNfL, 18.3 (11.2–39.3) versus 11.5 (7.0–23.3) pg/mL; p = 0.001; pGFAP, 149.7 (88.6–406.5) versus 68.7 (59.4–80.8) pg/mL; p < 0.001). Multivariable regression analyses indicated that baseline pNfL concentration was associated with age ( p = 0.017), Expanded Disability Status Scale (EDSS) score ( p = 0.002), and recent relapses ( p < 0.001). Baseline pGFAP concentration was also associated with EDSS ( p < 0.001) and recent relapses ( p < 0.001). Compared with prednisone, tocilizumab and rituximab significantly reduced pNfL [tocilizumab, exp(β), 0.65; 95% confidence interval (CI), 0.56–0.75; p < 0.001; rituximab, exp(β), 0.79; 95% CI = 0.68–0.93; p = 0.005] and pGFAP levels [tocilizumab, exp(β), 0.64; 95% CI, 0.51–0.80; p < 0.001; rituximab, exp(β), 0.77; 95% CI, 0.61–0.98; p = 0.041] at the end of the study. The pNfL levels in the tocilizumab and rituximab groups were reduced to those of HCs [tocilizumab, 8.5 (7.06–17.90) pg/mL; p = 0.426; rituximab, 14.0 (9.94–21.80) pg/mL; p = 0.216]. However, the pGFAP levels did not decrease to those of HCs in NMOSD patients at the end of study [tocilizumab, 88.9 (63.4–131.8) pg/mL; p = 0.012; rituximab, 141.7 (90.8–192.7) pg/mL; p < 0.001]. Conclusion: pNfL and pGFAP may serve as biomarkers for NMOSD disease activity and treatment effects.

Glial Fibrillary Acidic Protein in Blood as a Disease Biomarker of Neuromyelitis Optica Spectrum Disorders

“…Remarkably, this performance was better than that of other blood biomarkers, such as NfL and the GFAP/NfL quotient ( 71 ). In line with this, another study on a longitudinal NMOSD cohort (median follow up: 12 months) showed that plasma GFAP levels were the most powerful contributor in a random forest model to differentiate relapses from remissions, compared to other biomarkers (NfL, GFAP, and GFAP/NfL) and clinical variables [age, annual relapse rates, expanded disability status scale (EDSS) score, disease duration, and treatment status] ( 78 ). After relapse, serum GFAP levels decrease over time, and most patients show reduced serum GFAP levels below the predefined cut-off value (≥3 standard deviations of mean levels in age-/sex-matched healthy controls) within 3 months ( 71 , 74 ).…”

“…Recently, several studies have demonstrated that blood GFAP levels measured by Simoa have potential as a useful NMOSD biomarker for ( 1 ) differentiating NMOSD from other demyelinating diseases, ( 2 ) identifying and predicting clinical attacks, ( 3 ) monitoring disease disability and progression, and ( 4 ) evaluating treatment effects ( 59 , 71 , 73 – 78 ) ( Table 1 ).…”

“…Serum GFAP levels could be used as a diagnostic marker for NMOSD, as they are significantly higher in NMOSD patients compared to those in healthy controls ( 59 , 71 , 75 , 77 , 78 ) and patients with other demyelinating diseases (MS or MOGAD) ( 59 , 73 , 75 , 77 ). These findings are in line with immunopathological studies which showed that GFAP-positive astrocytes are highly destroyed only in active lesions of NMOSD but not in those of MS ( 85 – 90 ).…”

“…These findings are in line with immunopathological studies which showed that GFAP-positive astrocytes are highly destroyed only in active lesions of NMOSD but not in those of MS ( 85 – 90 ). Neurofilament light chain (NfL), a scaffolding protein of the neuronal cytoskeleton that is released upon axonal damage, may represent another diagnostic biomarker because it is also elevated in the blood of NMOSD patients, compared to healthy controls ( 59 , 71 , 75 , 77 , 78 ). However, serum NfL levels do not differ between NMOSD patients and MS or MOGAD patients ( 59 , 73 , 77 ), suggesting that NfL lacks specificity as a biomarker for NMOSD.…”

“…Serum GFAP levels may help identify and predict clinical attacks in NMOSD patients, as they are higher in the attack state than in the remission state, and their elevation is associated with recent relapses ( 59 , 71 , 73 – 75 , 77 , 78 ). In a longitudinal NMOSD cohort (median follow up: 17 months), serum GFAP levels alone successfully discriminated clinical attacks from remission with a sensitivity of 94.7% and a specificity of 74.6% (area under the receiver characteristic curve = 0.876).…”