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RIFUND-MS

Dimethyl Fumarate, But Not Rituximab, Reduces Serum GFAP Levels and PIRMA in Relapsing-Remitting MS

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Year of Publication: 2026

Authors: Shawket F, Lycke J, Salzer J, ..., Svenningsson A

Journal: Annals of Clinical and Translational Neurology

Citation: Ann Clin Transl Neurol 2026;0:1-11

Link: https://doi.org/10.1002/acn3.70395

Clinical Question

Does rituximab or dimethyl fumarate better reduce astrocytic injury biomarkers and progression independent of relapse/MRI activity in RRMS?

Bottom Line

In RRMS, DMF but not RTX significantly reduced serum GFAP over 2 years, and RTX was associated with 3-fold higher risk of PIRMA despite superior MRI suppression. These findings challenge the assumption that MRI efficacy equals neuroprotection, and implicate GFAP as a clinically meaningful biomarker of DMT neuroprotective effects.

Major Points

  • DMF significantly reduced sGFAP by ~18% over 2 years while RTX produced no significant reduction (3.6%), despite RTX achieving far superior MRI lesion suppression
  • Both agents reduced sNfL comparably (~46–51%) with no significant difference between arms (p=0.06)
  • RTX-treated patients had 3.3-fold higher risk of PIRMA compared to DMF (HR 3.3, 95% CI 1.1–10, p=0.04)
  • PIRA (HR 2.0, p=0.06) and CDW (HR 2.6, p=0.07) trended toward DMF benefit but did not reach significance
  • Higher serum GFAP was an independent predictor of PIRMA (HR 2.60 per doubling, 95% CI 1.28–5.30, p=0.008)
  • DMF's Nrf2-activating mechanism may confer astrocyte-protective effects beyond its anti-inflammatory action
  • MRI efficacy alone does not predict neuroprotective biomarker profile or disability-independent progression risk

Design

Study Type: Biomarker sub-study of a rater-blinded, randomized, open-label trial (RIFUND-MS RCT)

Randomization: 1

Blinding: Rater-blinded; treating physicians and patients not blinded

Allocation: 1:1

Enrollment Period: July 2016 – April 2021

Follow-up Duration: 24 months

Centers: 17

Countries: Sweden

Sample Size: 200

Analyzed: 197

Analysis: Intention-to-treat; per-protocol sensitivity analysis

Power Calculation: Main RIFUND-MS trial powered for PIRA; biomarker endpoints were secondary/exploratory

Registration: NCT02746744

Inclusion Criteria

  • Age 18–65 years
  • Diagnosis of RRMS or CIS
  • EDSS ≤5.5
  • No disease-modifying therapy in prior 6 months (natalizumab: 3 months)
  • Eligible for rituximab or dimethyl fumarate per treating neurologist

Exclusion Criteria

  • Prior treatment with immunosuppressants or B-cell depleting agents
  • Active serious infection
  • Pregnancy or planned pregnancy during the study
  • Contraindication to either study drug

Arms

FieldRituximabDimethyl Fumarate
N9998
InterventionRituximab 1000 mg IV at baseline, then 500 mg IV every 6 monthsDimethyl fumarate 240 mg twice daily orally
Duration24 months24 months

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Serum GFAP change over 24 months (area-under-the-curve longitudinal analysis)PrimaryRTX: 3.6% decrease (p=0.81, NS)DMF: ~18% decrease (p<0.001)0.02 (ITT); 0.004 (per protocol)
Serum NfL change over 24 monthsSecondaryRTX: ~50.7% reductionDMF: ~46.4% reduction0.06 (global treatment difference, NS)
PIRMA (Progression Independent of Relapse and MRI Activity)SecondaryRTX: higher risk (reference arm DMF)DMF: reference0.04
PIRA (Progression Independent of Relapse Activity)SecondaryRTX: higher riskDMF: reference0.06 (NS)
Confirmed Disability Worsening (CDW)SecondaryRTX: higher riskDMF: reference0.07 (NS)
sGFAP as predictor of PIRMA (per doubling of GFAP)Secondary0.008
T2 lesion activity (new/enlarging lesions)SecondaryRTX: superior suppressionDMF: more T2 activityFavored RTX (p not individually reported)
Annualized relapse rateSecondaryRTX: lower ARRDMF: higher ARRFavored RTX
Serious adverse eventsSafetyRTX: reported (details in supplement)DMF: reported (details in supplement)
Infusion reactionsSafetyRTX: common with first infusionDMF: not applicable
Gastrointestinal adverse effectsSafetyRTX: not primary concernDMF: common; main cause of discontinuation
Study discontinuation due to adverse effectsAdverseRTX: lower rateDMF: higher rate (primarily GI side effects)

Subgroup Analysis

Patients with higher baseline sGFAP showed more pronounced benefit from DMF on GFAP reduction. Per-protocol sensitivity analysis (excluding switchers and those receiving concomitant steroids) confirmed the sGFAP treatment difference (p=0.004) and preserved the PIRMA HR direction. No formal subgroup analyses by age, sex, or prior treatment reported.

Criticisms

  • Open-label design (rater-blinded only) — potential for bias in subjective assessments
  • Small sample size (n=197) limits statistical power for disability progression endpoints
  • Short 24-month follow-up may be insufficient to detect meaningful disability differences in RRMS
  • No placebo arm — head-to-head comparison does not allow inference vs untreated patients
  • PIRMA definition incorporates MRI activity; its framing as 'independent' of MRI is conceptually contested
  • Approximately 35% had prior DMT exposure, which may confound biomarker trajectories

Funding

Swedish Research Council (grant 2016-00398), Swedish Brain Fund, regional ALF funds

Based on: RIFUND-MS (Annals of Clinical and Translational Neurology, 2026)

Authors: Shawket F, Lycke J, Salzer J, ..., Svenningsson A

Citation: Ann Clin Transl Neurol 2026;0:1-11

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