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Dimethyl Fumarate, But Not Rituximab, Reduces Serum GFAP Levels and PIRMA in Relapsing-Remitting MS
F Shawket1, J Lycke2,3, J Salzer4
1Department of Clinical Sciences, Karolinska Institutet Danderyd Hospital and Department of Neurology, Danderyd Hospital, Stockholm, Sweden.
Objective:
Serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels are believed to reflect mainly acute and chronic disease processes in multiple sclerosis (MS), respectively. In this study, we investigated whether dimethyl fumarate (DMF) and rituximab (RTX) differentially affect these biomarkers.
Methods:
RIFUND-MS was a 2-year, rater-blinded, 1:1 randomized controlled multicenter trial comparing DMF and RTX in relapsing-remitting multiple sclerosis (RRMS). Serum samples for analysis of sNFL and sGFAP were collected at baseline and 0, 6, 12 and 24. Log-transformed biomarker data were analyzed with linear mixed models, based on intention to treat (ITT), per protocol (PP) and accounting for therapy switches. Cox proportional hazards models were performed to evaluate progression outcomes.
Results:
Of 200 participants, 197 were analyzed. Based on ITT, sNfL decreased significantly in both arms from baseline to month 24; by 50.7% (CI 43.7%-56.8%; p < 0.001) with RTX, and by 46.4% (CI 38.6%-53.2%; p < 0.001) with DMF, no differences between treatments (global p-value: ITT = 0.06; PP = 0.08; switch group = 0.15). In contrast, sGFAP remained stable in RTX (3.6% decrease; CI -7.8%-13.8%, p = 0.81) but decreased with DMF (18.4%; CI 8.5%-27.2%; p < 0.001). Global analyses favored DMF (ITT = 0.02; PP = 0.004; switch group = 0.74). The risk of progression independent of relapse and MRI activity (PIRMA) was higher with RTX (HR 3.3, CI 1.1-10, p = 0.04).
Interpretation:
Both RTX and DMF reduced sNfL levels, consistent with suppression of acute inflammatory disease activity. However, only DMF was associated with a sustained reduction in sGFAP and a lower risk of non-inflammatory disability progression. These findings suggest that DMF may exert additional effects on astrocyte-related or compartmentalized CNS pathology beyond peripheral immune modulation.
Insights
Dimethyl fumarate (DMF) and rituximab (RTX) both reduced serum neurofilament light chain (sNfL) in multiple sclerosis (MS) patients. However, only DMF significantly lowered glial fibrillary acidic protein (sGFAP) and reduced the risk of disability progression.
Area of Science:
- Neuroimmunology
- Biomarker Research
- Clinical Trials
Background:
- Serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are key biomarkers in multiple sclerosis (MS).
- sNfL is thought to reflect acute disease activity, while sGFAP is associated with chronic neurodegeneration.
- Investigating differential effects of disease-modifying therapies on these biomarkers is crucial for understanding treatment mechanisms.
Purpose of the Study:
- To compare the effects of dimethyl fumarate (DMF) and rituximab (RTX) on serum sNfL and sGFAP levels in patients with relapsing-remitting multiple sclerosis (RRMS).
- To assess whether these therapies differentially impact acute and chronic disease processes as indicated by biomarker changes.
- To evaluate the association of biomarker changes with clinical and MRI outcomes.
Main Methods:
- A 2-year, rater-blinded, randomized controlled trial (RIFUND-MS) comparing DMF and RTX in RRMS patients.
- Serum samples were collected at baseline and multiple time points (0, 6, 12, 24 months) for sNfL and sGFAP analysis.
- Linear mixed models and Cox proportional hazards models were used to analyze biomarker data and progression outcomes, respectively.
Main Results:
- Both DMF and RTX significantly reduced sNfL levels from baseline to 24 months, with no significant difference between treatments.
- sGFAP levels remained stable with RTX but showed a significant decrease with DMF.
- DMF treatment was associated with a lower risk of progression independent of relapse and MRI activity (PIRMA) compared to RTX.
Conclusions:
- Both DMF and RTX effectively suppress acute inflammatory activity in MS, as evidenced by sNfL reduction.
- DMF demonstrates an advantage over RTX in reducing sGFAP, suggesting a potential benefit in addressing chronic neurodegenerative processes.
- These findings indicate that DMF may offer additional benefits beyond peripheral immune modulation, potentially targeting astrocyte-related pathology and reducing non-inflammatory disability progression in MS.
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