Dataset Information

Serum glial fibrillary acidic protein and disability progression in progressive multiple sclerosis.

ABSTRACT:

Objective

Progression prediction is a significant unmet need in people with progressive multiple sclerosis (pwPMS). Studies on glial fibrillary acidic protein (GFAP) have either been limited to single center with relapsing MS or were based solely on Expanded Disability Status Scale (EDSS), which limits its generalizability to state-of-the-art clinical settings and trials applying combined outcome parameters.

Methods

Serum GFAP and NfL (neurofilament light chain) were investigated in EmBioProMS participants with primary (PP) or secondary progressive MS. Six months confirmed disability progression (CDP) was defined using combined outcome parameters (EDSS, timed-25-foot walk test (T25FW), and nine-hole-peg-test (9HPT)).

Results

243 subjects (135 PPMS, 108 SPMS, age 55.5, IQR [49.7-61.2], 135 female, median follow-up: 29.3 months [17.9-40.9]) were included. NfL (age-) and GFAP (age- and sex-) adjusted Z scores were higher in pwPMS compared to HC (p < 0.001 for both). 111 (32.8%) CDP events were diagnosed in participants with ≥3 visits (n = 169). GFAP Z score >3 was associated with higher risk for CDP in participants with low NfL Z score (i.e., ≤1.0) (HR: 2.38 [1.12-5.08], p = 0.025). In PPMS, GFAP Z score >3 was associated with higher risk for CDP (HR: 2.88 [1.21-6.84], p = 0.016). Risk was further increased in PPMS subjects with high GFAP when NfL is low (HR: 4.31 [1.53-12.13], p = 0.006).

Interpretation

Blood GFAP may help identify pwPPMS at risk of progression. Combination of high GFAP and low NfL levels could distinguish non-active pwPMS with particularly high progression risk.

SUBMITTER: Abdelhak A

PROVIDER: S-EPMC10863922 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Publications

Serum glial fibrillary acidic protein and disability progression in progressive multiple sclerosis.

Abdelhak Ahmed A Antweiler Kai K Kowarik Markus C MC Senel Makbule M Havla Joachim J Zettl Uwe K UK Kleiter Ingo I Skripuletz Thomas T Haarmann Axel A Stahmann Alexander A Huss Andre A Gingele Stefan S Krumbholz Markus M Benkert Pascal P Kuhle Jens J Friede Tim T Ludolph Albert C AC Ziemann Ulf U Kümpfel Tania T Tumani Hayrettin H

Annals of clinical and translational neurology 20231219 2

<h4>Objective</h4>Progression prediction is a significant unmet need in people with progressive multiple sclerosis (pwPMS). Studies on glial fibrillary acidic protein (GFAP) have either been limited to single center with relapsing MS or were based solely on Expanded Disability Status Scale (EDSS), which limits its generalizability to state-of-the-art clinical settings and trials applying combined outcome parameters.<h4>Methods</h4>Serum GFAP and NfL (neurofilament light chain) were investigated ...[more]

PMID: 38111972

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Project description:ImportanceThere is a lack of validated biomarkers for disability progression independent of relapse activity (PIRA) in multiple sclerosis (MS).ObjectiveTo determine how serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) correlate with features of disease progression vs acute focal inflammation in MS and how they can prognosticate disease progression.Design, setting, and participantsData were acquired in the longitudinal Swiss MS cohort (SMSC; a consortium of tertiary referral hospitals) from January 1, 2012, to October 20, 2022. The SMSC is a prospective, multicenter study performed in 8 centers in Switzerland. For this nested study, participants had to meet the following inclusion criteria: cohort 1, patients with MS and either stable or worsening disability and similar baseline Expanded Disability Status Scale scores with no relapses during the entire follow-up; and cohort 2, all SMSC study patients who had initiated and continued B-cell-depleting treatment (ie, ocrelizumab or rituximab).ExposuresPatients received standard immunotherapies or were untreated.Main outcomes and measuresIn cohort 1, sGFAP and sNfL levels were measured longitudinally using Simoa assays. Healthy control samples served as the reference. In cohort 2, sGFAP and sNfL levels were determined cross-sectionally.ResultsThis study included a total of 355 patients (103 [29.0%] in cohort 1: median [IQR] age, 42.1 [33.2-47.6] years; 73 female patients [70.9%]; and 252 [71.0%] in cohort 2: median [IQR] age, 44.3 [33.3-54.7] years; 156 female patients [61.9%]) and 259 healthy controls with a median [IQR] age of 44.3 [36.3-52.3] years and 177 female individuals (68.3%). sGFAP levels in controls increased as a function of age (1.5% per year; P < .001), were inversely correlated with BMI (-1.1% per BMI unit; P = .01), and were 14.9% higher in women than in men (P = .004). In cohort 1, patients with worsening progressive MS showed 50.9% higher sGFAP levels compared with those with stable MS after additional sNfL adjustment, whereas the 25% increase of sNfL disappeared after additional sGFAP adjustment. Higher sGFAP at baseline was associated with accelerated gray matter brain volume loss (per doubling: 0.24% per year; P < .001) but not white matter loss. sGFAP levels remained unchanged during disease exacerbations vs remission phases. In cohort 2, median (IQR) sGFAP z scores were higher in patients developing future confirmed disability worsening compared with those with stable disability (1.94 [0.36-2.23] vs 0.71 [-0.13 to 1.73]; P = .002); this was not significant for sNfL. However, the combined elevation of z scores of both biomarkers resulted in a 4- to 5-fold increased risk of confirmed disability worsening (hazard ratio [HR], 4.09; 95% CI, 2.04-8.18; P < .001) and PIRA (HR, 4.71; 95% CI, 2.05-9.77; P < .001).Conclusions and relevanceResults of this cohort study suggest that sGFAP is a prognostic biomarker for future PIRA and revealed its complementary potential next to sNfL. sGFAP may serve as a useful biomarker for disease progression in MS in individual patient management and drug development.

Project description:Background and objectivesStable patients with multiple sclerosis (MS) may discontinue treatment, but the risk of disease activity is unknown. Serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) are biomarkers of subclinical disease activity and may help risk stratification. In this study, sNfL and sGFAP levels in stable patients were evaluated before and after treatment discontinuation to determine association with disease activity.MethodsThis observational study included patients enrolled in the Comprehensive Longitudinal Investigation in MS at the Brigham and Women's Hospital who discontinued treatment after >2 years disease activity-free. Two serum samples within 2 years, before and after treatment stop, were sent for sNfL and sGFAP measurements by single-molecule array. Biannual neurologic examinations and yearly MRI scans determined disease activity by 3 time-to-event outcomes: 6-month confirmed disability worsening (CDW), clinical attacks, and MRI activity (new T2 or contrast-enhancing lesions). Associations between each outcome and log-transformed sNfL and sGFAP levels pretreatment stop and posttreatment stop and the percent change were estimated using multivariable Cox regression analysis adjusting for age, disability, disease duration, and duration from attack before treatment stop.ResultsSeventy-eight patients (92% female) discontinued treatment at a median (interquartile range) age of 48.5 years (39.0-55.7) and disease duration of 12.3 years (7.5-18.8) and were followed up for 6.3 years (4.2-8.5). CDW occurred in 27 patients (35%), new attacks in 19 (24%), and new MRI activity in 26 (33%). Higher posttreatment stop sNfL level was associated with CDW (adjusted hazard ratio (aHR) 2.80, 95% CI 1.36-5.76, p = 0.005) and new MRI activity (aHR 3.09, 95% CI 1.42-6.70, p = 0.004). Patients who had >100% increase in sNfL level from pretreatment stop to posttreatment stop had greater risk of CDW (HR 3.87, 95% CI 1.4-10.7, p = 0.009) and developing new MRI activity (HR 4.02, 95% CI 1.51-10.7, p = 0.005). Patients who had >50% increase in sGFAP level also had greater risk of CDW (HR 5.34, 95% CI 1.4-19.9, p = 0.012) and developing new MRI activity (HR 5.16, 95% CI 1.71-15.6, p = 0.004).DiscussionStable patients who discontinue treatment may be risk stratified by sNfL and sGFAP levels measured before and after discontinuing treatment. Further studies are needed to validate findings and determine whether resuming treatment in patients with increasing biomarker levels reduces risk of subsequent disease activity.

Dataset Information

Serum glial fibrillary acidic protein and disability progression in progressive multiple sclerosis.

Objective

Methods

Results

Interpretation

Publications

Serum glial fibrillary acidic protein and disability progression in progressive multiple sclerosis.

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