Importance
Capturing individual multiple sclerosis (MS) progression is difficult; few studies have evaluated glial fibrillary acidic protein (GFAP) in large longitudinal cohorts with independent validation.
Objective
To investigate whether serum GFAP levels and treatment-related changes are associated with future progression independent of relapse activity (PIRA).
Design, Setting, and Participants
This was a prospective observational study using 2 large MS cohorts: the Swiss MS Cohort (SMSC; initiated in June 2012; data extraction September 22, 2025) and the Expression, Proteomics, Imaging, Clinical study (EPIC; initiated in July 2004; data extraction February 21, 2024). The study took place at tertiary MS centers (8 for SMSC and 1 for EPIC). A total of 2329 persons with MS from both cohorts with at least 1 available time point with neurofilament light chain (NfL) and GFAP measurements were included (overall 18 629 measurements).
Exposures
Clinical data and NfL and GFAP z scores, collected and calculated every 6 or 12 months.
Main Outcomes and Measures
Risk of future PIRA, defined as Expanded Disability Status Scale score worsening confirmed after 6 or more months without relapses (in SMSC), or a composite additionally including greater than 20% worsening in the 9-hole peg test or timed 25-ft walk test (in EPIC).
Results
The SMSC and EPIC cohorts consisted of 1709 (13 375 samples; median [IQR] follow-up, 6.9 [2.5-10.7] years and age, 40.6 [32.1-50.1] years; 1128 [66.0%] female) and 620 (5254 samples; median [IQR] follow-up, 13.1 [9.4-14.0] years and age, 42.0 [35.0-50.0] years; 432 [69.7%] female) persons with MS, respectively. Consistent with prior work, high NfL was associated with relapse risk within the next year, whereas high GFAP was associated with long-term PIRA risk. In addition, elevated GFAP (z score >1.0 [84th percentile]) was associated with an average 40% higher hazard of short-term PIRA in the subsequent visit interval (SMSC: median [IQR] 346 [190-375] days; hazard ratio [HR], 1.45, 95% CI, 1.21-1.75; P < .001; EPIC: 385 [355-518] days; HR, 1.36; 95% CI, 1.07-1.71; P = .01). GFAP-based cohort enrichment in clinical trials targeting PIRA as an end point could reduce sample size by approximately 20%. Further, in SMSC, every yearly GFAP z score unit reduction during the first 2 years receiving fingolimod or B-cell-depleting therapy was associated with a lower risk of subsequent PIRA (54% risk reduction; HR, 0.46; 95% CI, 0.26-0.84; P = .01 and 67% risk reduction; HR, 0.33; 95% CI, 0.18-0.61; P < .001), respectively.
Conclusions and Relevance
In this cohort study, elevated GFAP was associated with a higher risk of PIRA, while treatment-associated reductions were associated with a lower PIRA risk. Together, these results suggest that serum GFAP may serve as a biomarker for personalized risk stratification and treatment monitoring and as a screening tool to reduce cohort size in clinical trials targeting MS progression.
M. Einsiedler, S. Sandgren, S. Schaedelin et al.· JAMA Neurology· 0 citations
BACKGROUND AND OBJECTIVES
Serum neurofilament light chain (sNfL) reflects inflammatory axonal damage in relapsing multiple sclerosis (RMS). Longitudinal sNfL dynamics may aid treatment response assessment, although data on expected changes under disease-modifying treatments remain limited, particularly in real-world practice. This study evaluated whether on-treatment changes in sNfL were associated with subsequent evidence of disease activity (EDA) and whether they provided complementary information to established treatment response scoring systems (TRSS).
METHODS
This prospective, real-world cohort study was conducted at the Multiple Sclerosis Center of Catalonia (Cemcat). Adult RMS patients initiating disease-modifying treatments (DMTs) with serum samples at treatment initiation (baseline) and after 1 year (Y1) were included. The primary exposure was change in sNfL z-scores (ΔzNfL = zNfLY1 - zNfL-baseline) analyzed using data-derived thresholds (ΔzNfL ≥0 and <0.5-point reduction). At Y1, Expanded Disability Status Scale progression, clinical/radiologic activity, and TRSS (Rio [RS], modified Rio [mRS], and MAGNIMS) were assessed. The primary outcome was EDA between years 1 and 2 (EDA-Y2). Multivariable logistic regression models evaluated associations between ΔzNfL and EDA-Y2, as well as the added value of ΔzNfL across TRSS strata.
RESULTS
A total of 329 patients (66.3% female; median age 39 years) initiated 352 DMTs; 342 remained on treatment for ≥1 year and 182 had complete EDA-Y2 data. Mean (SD) ΔzNfL at Y1 was -0.62 (1.2), with greater reductions in monoclonal antibody-treated and treatment-naïve patients. Lack of zNfL reduction over the first year (ΔzNfL ≥0) was associated with higher odds of EDA-Y2 in the overall cohort (OR [95% CI], p: 3.07 [1.47-6.39], 0.003), in treatment-naïve cases (14.04 [2.47-79.93], 0.003), and in those achieving No Evidence of Disease Activity (NEDA-3) at Y1 (4.54 [1.26-16.30], 0.02). Similar associations were observed for <0.5-point reductions. Adding ΔzNfL to TRSS showed persistent associations with EDA-Y2 despite otherwise favorable scores [e.g., RS: 2.26 (1.12-4.59), 0.024].
DISCUSSION
Failure to reduce zNfL levels after 1 year of treatment was associated with subsequent disease activity, even in patients otherwise considered stable, providing complementary information to clinical and MRI-based monitoring. Limitations include incomplete follow-up and the modest discriminative performance of ΔzNfL, supporting a complementary rather than stand-alone role for zNfL dynamics.
Victoria Fernández, Agustín Pappolla, Pere Carbonell-Mirabent et al.· Neurology· 0 citations
Antibody-mediated inflammatory diseases of the CNS, including aquaporin-4 antibody neuromyelitis optica spectrum disorder (AQP4-Ab NMOSD) and myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD), have undergone major therapeutic transformation with the advent of sensitive antibody assays and targeted immunotherapies. These advances have markedly reduced relapse rates and improved long-term outcomes. With improved disease control, questions regarding optimal treatment duration and the possibility of de-escalation or discontinuation are increasingly relevant. In AQP4-Ab NMOSD, relapses are typically severe and disabling, and most observational studies show a high risk of reactivation after tapering or withdrawal. Thus, discontinuation is never recommended. Successful de-escalation has been reported in selected patients with prolonged remission, although relapse risk persists, underscoring the need for individualized decisions and close monitoring. In contrast, MOGAD is clinically heterogeneous. Many patients, particularly children, experience a monophasic illness with good recovery, whereas relapse risk in adults appears to decline after several years. De-escalation strategies can thus be applied for anti-CD20 and IVIG. Recent cohort studies suggest that even discontinuation may be feasible after 2 to 5 years of remission in children and adults, especially in those who become seronegative for myelin oligodendrocyte glycoprotein immunoglobulin G. In seronegative NMOSD, the evidence base is limited and prognosis uncertain; attacks can be severe, no therapies are specifically approved, and although some experts suggest that discontinuation may be considered after 5 years of stability, this remains guided by expert opinion alone. Treatment de-escalation is sometimes necessary because of adverse effects, comorbidities, infections, treatment fatigue, or life circumstances such as pregnancy. In pregnancy, management requires balancing maternal disease control with fetal safety, with strategies ranging from continuation of selected therapies to temporary tapering or deferral. Monitoring with MRI, OCT, and emerging fluid biomarkers offers potential to detect early recurrence of disease activity, although none are validated for routine use. Prospective studies, real-world registry data, and dedicated trials are urgently needed to inform safe and patient-centered de-escalation/discontinuation strategies.
Y. Hacohen, G. Androdias, G. Arrambide et al.· Neurology· 0 citations
A review of current evidence on established and emerging fluid biomarkers in NMOSD and MOGAD, with emphasis on analytical performance, biological relevance, and clinical utility, and outlines priorities for future research.
S. Mariotto, Á. Cobo-Calvo, Michael Khalil et al.· Neurology(R) neuroimmunology...· 0 citations