RIFUND-MS
(2026)Objective
To compare the effects of rituximab vs dimethyl fumarate on serum GFAP, serum NfL, and PIRMA over 2 years in RRMS.
Study Summary
• Both arms significantly reduced sNfL (~46% DMF vs ~51% RTX at month 24) with no significant between-arm difference (global p=0.06)
• PIRMA risk was 3.3-fold higher with RTX vs DMF (HR 3.3, 95% CI 1.1–10, p=0.04); higher sGFAP independently predicted PIRMA risk (HR 2.60 per doubling, 95% CI 1.28–5.30, p=0.008)
Intervention
Rituximab 1000 mg IV then 500 mg q6mo vs dimethyl fumarate 240 mg BID for 2 years in RRMS/CIS
Inclusion Criteria
RRMS or CIS, age 18–65, EDSS ≤5.5, no prior DMT in 6 months
Study Design
Arms: Rituximab (n=99) vs Dimethyl Fumarate (n=98)
Patients per Arm: 99 rituximab, 98 dimethyl fumarate (197 total analyzed)
Outcome
• sNfL: both reduced similarly (~46–51%); no significant between-arm difference (p=0.06)
• PIRMA: HR 3.3 (95% CI 1.1–10, p=0.04) higher with RTX; PIRA HR 2.0 (p=0.06) and CDW HR 2.6 (p=0.07) trended toward DMF but did not reach significance
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 2.6, 95% CI 0.9–7.3, p=0.06) and CDW (HR 2.6, 95% CI 0.9–7.3, 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
Study Design
- Study Type
- Biomarker sub-study of a rater-blinded, randomized, open-label trial (RIFUND-MS RCT)
- Randomization
- Yes
- Blinding
- Rater-blinded; treating physicians and patients not blinded
- Sample Size
- 200
- Follow-up
- 24 months
- Centers
- 17
- Countries
- Sweden
Primary Outcome
Definition: Reduction of serum NfL and serum GFAP in each treatment arm over 24 months (linear mixed model, log2-transformed concentrations). sNfL was a predetermined secondary endpoint of the RIFUND-MS trial; sGFAP was analyzed post hoc.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| RTX: sGFAP −3.6% (NS); sNfL −50.7% (p<0.001) | DMF: sGFAP −18.4% (p<0.001); sNfL −46.4% (p<0.001) | - (sGFAP: DMF −18.4 (−27.2, −8.5), RTX −3.6 (−13.8, 7.8); sNfL: DMF −46.4 (−53.2, −38.6), RTX −50.7 (−56.8, −43.7)) | sGFAP DMF p<0.001, RTX p=0.81; global sGFAP treatment difference ITT p=0.02, PP p=0.004. sNfL both arms p<0.001; global sNfL treatment difference p=0.06 |
Limitations & 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
- Wide confidence intervals for HRs reflect limited number of progression events (n=18)
- Majority of patients (>90%) had prior DMT exposure, which may confound biomarker trajectories
- sGFAP analyses were post hoc, not pre-specified — findings should be interpreted as hypothesis-generating
- Safety outcomes and adverse event denominators are not reported in this biomarker sub-study
Citation
Ann Clin Transl Neurol 2026;0:1-11