Glial Fibrillary Acidic Protein Represents Valuable Biomarker for MS Disease Progression

Using phenotypically “extreme” MS groups, annualized brain volume loss was higher in progressors vs non-progressors and was predicted by baseline GFAP and NfL levels.

Jens Kuhle, MD, PhD, head, MS Center, and senior physician, University Hospital Basel

Jens Kuhle, MD, PhD

Data presented at the 38th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), October 26-28, in Amsterdam, Netherlands, suggest that glial fibrillary acidic protein (GFAP) is a more useful biomarker for progression in multiple sclerosis (MS) compared with neurofilament light (NfL), as NfL increases disappeared after additional GFAP adjustment.1

To better understand the effects of both biomarkers on MS disease progression, senior investigator Jens Kuhle, MD, PhD, head, MS Center, and senior physician, University Hospital Basel, and colleagues assessed 4 phenotypically “extreme” MS groups. The groups included (1) progressors (n = 18; median Expanded Disability Status Scale [EDSS] baseline [BL], 4.0 and last visit, 6.0), (2) non-progressors (n = 19; EDSS, 3.0 and 2.5), (3) those with focal inflammation (n = 66) during relapse and/or contrast enhancing lesions, and (4) the same patients during remission (n = 66). Additionally, there were 485 samples from health controls (HC).

Multivariable mixed models were used to longitudinally compared log-transformed GFAP vs NfL between either group. Brain volume (BV) loss was measured with SIENA combined in both groups 1 and 2 and analyzed in adjusted linear models to perform a preliminary assessment of the associations with BL GFAP/NfL. Kuhle et al used adjusted Cox regression models to understand the association between BL GFAP and NfL levels and time to confirmed disability progression by EDSS (CDP).

All told, GFAP in HC were influence by age (1.5%/y; P <.001), higher in women (15%; P = .004) and inversely correlated with body mass index (–1.1%/unit; P = .015). While there was 57% higher GFAP levels found in progressors vs non progressors (P = .006; 51%; P = .010 after additional NfL adjustment in the model), the 25% increase in NfL between the groups (P = .046) disappeared after additional GFAP adjustment.

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Focal inflammation had no effect on GFAP, while it increased NfL levels by 53% (P <.001). Between progressors and non-progressors, the annualized BV loss was 0.43% higher in those who progressed (estimate, –0.43; P = .0069) and was predicted by BL GFAP (estimate per doubling, –0.31; P = .0025) and NfL (estimate, –0.35; P = .0024). In contrast to BL NfL (hazard ratio [HR] per doubling, 1.9; P = .112), BL GFAP was significantly associated with time to CDP (GFAP: HR, 3.6; P = .005).

Kuhle has previously researched the impacts of GFAP on MS disease progression. Using the EXPAND study (NCT01665144), findings from a 2021 study suggested that lowering plasma GFAP early leads to reduced risk of disability worsening in those with secondary progressive MS on siponimod (Mayzent; Novartis). Altogether, samples from 1453 of 1651 randomized patients were analyzed. In patients treated with siponimod with plasma GFAP levels over 75 pg/mL, a decrease in plasma GFAP levels after 3 months was associated with a reduced risk of disability worsening. Time to 1-point sustained EDSS worsening had a HR of 0.68 (P = .0543) and time to 3-month CDW had an HR of 0.66 (P = .0053). Time to sustained EDSS score of 7 had an HR of 0.79 (P = .4470) from month 3 to end of study.2

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REFERENCES
1. Meier S, Benkert P, Maceski A, et al, Serum glial fibrillary acidic protein compared with neurofilament light chain as biomarker for multiple sclerosis disease progression. Presented at: ECTRIMS Congress 2022; October 26-28; Amsterdam, Netherlands. Abstract O166
2. Akinsanya J, Absinta M, Dargah-zade N, et al. Toward the use of paramagnetic rim lesions in proof-of-concept clinical trials for treating chronic inflammation in multiple sclerosis. Presented at ACTRIMS Annual Forum; February 25-27, 2021. Poster P126.
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