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MEDEN-NMOSD NMA

Comparative Evaluation of Rituximab Versus Approved Therapies in Aquaporin-4-IgG-Positive Neuromyelitis Optica Spectrum Disorder: A Systematic Review and Network Meta-analysis

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Year of Publication: 2026

Authors: Barzegar M, Samadzadeh S, Audoin B, et al. (MEDEN study group)

Journal: Neurology and Therapy

Citation: Neurol Ther. 2026 Jul 16 (online). doi:10.1007/s40120-026-00989-x

Link: https://doi.org/10.1007/s40120-026-00989-x

Bottom Line

This network meta-analysis of 8 trials suggests hazard-ratio point estimates numerically favoring eculizumab and ravulizumab over rituximab for time to first relapse, but all comparisons were statistically non-significant with extremely wide confidence intervals — the analysis is hypothesis-generating and does not establish superiority of any therapy over rituximab.

Major Points

  • PRISMA-guided systematic review across PubMed, Scopus, CINAHL, EMBASE, Web of Science, Cochrane Library, and gray literature through 31 October 2024, updated 1 November 2025; frequentist network meta-analysis with random-effects model using the R netmeta package.
  • From 6337 records screened, 8 trials were included: RIN-1 and Nikoo et al. (rituximab), SAkuraSky and SAkuraStar (satralizumab), PREVENT (eculizumab), N-MOmentum (inebilizumab), TANGO (tocilizumab), and CHAMPION-NMOSD (ravulizumab).
  • Combination ± monotherapy network (5 trials): rituximab HR 5.00 (95% CI 0.25–101.01) vs ravulizumab ± IST, HR 1.17 (0.12–10.89) vs eculizumab ± IST, HR 0.29 (0.04–2.23) vs satralizumab ± IST.
  • Monotherapy network (6 trials): rituximab HR 3.33 (0.13–83.16) vs ravulizumab, HR 1.59 (0.05–50.17) vs eculizumab, HR 0.31 (0.04–2.31) vs inebilizumab, HR 0.27 (0.03–2.21) vs satralizumab.
  • P-score rankings placed ravulizumab and eculizumab highest but with high uncertainty; authors emphasize these should not guide clinical decisions.
  • Substantial between-trial heterogeneity: variations in prior treatment, baseline ARR (1.9 in eculizumab/ravulizumab trials vs 1.4–1.5 in rituximab/satralizumab trials), relapse definitions and adjudication (investigator vs blinded committee), and ethnicity (RIN-1 was Japanese-only).
  • Rituximab is likely to remain a cornerstone of NMOSD therapy globally because of its substantially lower cost and wider accessibility, particularly in resource-limited settings.

Design

Study Type: Systematic Review and Network Meta-analysis (frequentist, random-effects)

Randomization:

Blinding: Not applicable (meta-analysis of RCTs and open-label trials)

Enrollment Period: Databases searched through 31 October 2024; updated 1 November 2025

Follow-up Duration: Varied across included trials (e.g., 72 weeks in RIN-1; event-driven in PREVENT; ~50 weeks in CHAMPION-NMOSD)

Countries: International (trials from Japan, USA, Europe, and multinational cohorts)

Sample Size: 8

Analysis: Frequentist network meta-analysis using R netmeta v4.5.1, random-effects model; continuity correction (0.5) applied for zero-event arms; P-scores used for treatment ranking; PRISMA reporting; JBI critical appraisal for quality; OSF registration UW5MQ.

Inclusion Criteria

  • Population: patients with AQP4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD).
  • Intervention: rituximab, eculizumab, inebilizumab, ravulizumab, satralizumab, or tocilizumab.
  • Comparator: placebo or any other active intervention.
  • Study type: randomized controlled trials or open-label trials.
  • Outcomes reported that could be pooled (primarily time to first relapse).
  • Peer-reviewed publications; abstracts from ACTRIMS, ECTRIMS, AAN, and EAN meetings (2021–2024) also screened.

Exclusion Criteria

  • Observational studies (cohort, case-control, cross-sectional, case series, case reports).
  • Studies not comparing a medication with placebo or another medication.
  • Reviews, animal studies, hypothesis papers, in vitro studies, and books.
  • Systematic reviews, meta-analyses, and other network meta-analyses.
  • Non-peer-reviewed articles.
  • Qualitative studies.
  • Patients who were AQP4-IgG-negative were excluded from the NMA.

Baseline Characteristics

CharacteristicIncluded Trials (8)Population Notes
RIN-1 (rituximab, Tahara 2020)Japan-only, n=38 (rituximab 19, placebo 19); AQP4-IgG+ 100%; 72-week follow-up; no prior-relapse requirement; baseline ARR ~1.5; low-dose prednisolone 2–5 mg/day permitted.
Nikoo et al. 2017 (rituximab vs azathioprine)Iran, primary outcome ARR (not time to first relapse); excluded from NMA time-to-relapse analysis.
PREVENT (eculizumab, Pittock 2019)n=143; AQP4-IgG+ 100%; ≥2 relapses in prior 12 months or ≥3 in prior 24 months required; baseline ARR ~1.9; IST allowed; event-driven follow-up.
CHAMPION-NMOSD (ravulizumab, Pittock 2023)n=105; open-label; AQP4-IgG+ 100%; ≥1 relapse in prior 12 months required; PREVENT placebo as external control; monotherapy; baseline ARR ~1.9.
N-MOmentum (inebilizumab, Cree 2019)AQP4-IgG+ subset analyzed; ≥1 relapse in prior 12 months; monotherapy; prednisone taper days 1–21.
SAkuraSky (satralizumab combination, Yamamura 2019)≥2 relapses required; concomitant IST permitted.
SAkuraStar (satralizumab monotherapy, Traboulsee 2020)≥1 relapse in prior 12 months; monotherapy; baseline ARR ~1.4–1.5.
TANGO (tocilizumab vs azathioprine, Zhang 2020)Open-label, comparator was azathioprine; excluded from primary network.
EthnicityJapanese-only in RIN-1; mixed/international in other trials.
Baseline ARR1.9 in PREVENT/CHAMPION (eculizumab, ravulizumab); 1.4–1.5 in RIN-1 (rituximab) and SAkuraSky (satralizumab).
Prior relapse requiredNone in RIN-1; ≥1 in most others; ≥2–3 in PREVENT and SAkuraSky.
Concomitant ISTNot allowed in RIN-1, SAkuraStar, N-MOmentum, CHAMPION; allowed in PREVENT, SAkuraSky; permitted ≤12 weeks in TANGO.

Arms

FieldRituximab (index therapy)Ravulizumab ± ISTEculizumab ± ISTInebilizumabSatralizumab ± ISTTocilizumab (TANGO)
InterventionAnti-CD20 monoclonal antibody; RIN-1 dosing per Tahara 2020 (n=19); Nikoo et al. dosing per Nikoo 2017.Long-acting terminal complement C5 inhibitor (CHAMPION-NMOSD).Terminal complement C5 inhibitor (PREVENT).Anti-CD19 monoclonal antibody (N-MOmentum, monotherapy).Anti-IL-6 receptor monoclonal antibody (SAkuraSky combination, SAkuraStar monotherapy).Anti-IL-6 receptor monoclonal antibody vs azathioprine; excluded from primary network because comparator was azathioprine.
DurationTrial-specific (RIN-1: 72 weeks)Median ~50 weeksEvent-driven197 days randomized periodTrial-specificTrial-specific

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Time to first relapse (hazard ratio, rituximab vs each comparator) — combination ± monotherapy network (5 trials: RIN-1, PREVENT, CHAMPION-NMOSD, SAkuraSky, SAkuraStar).PrimaryP-score Ranking (combination ± monotherapy): Ravulizumab ± IST 0.927 > Eculizumab ± IST 0.667 > Rituximab 0.618 > Satralizumab ± IST 0.287 · Interpretation: Point estimates favor ravulizumab and eculizumab over rituximab; wide CIs cross HR=1.0; no statistically significant difference.
Time to first relapse — monotherapy network (6 trials)Secondary
Rituximab vs Ravulizumab (monotherapy)Secondary3.33NS
Rituximab vs Eculizumab (monotherapy)Secondary1.59NS
Rituximab vs Inebilizumab (monotherapy)Secondary0.31NS
Rituximab vs Satralizumab (monotherapy)Secondary0.27NS
P-score ranking (monotherapy)Secondary
Zero-event armsSecondary
ARR, EDSS, steroid reduction, AQP4 titers, HACA, JCV, CD19/CD20 lymphocyte subsetsSecondary
NoteAdverseSafety comparisons were not performed. Authors state meaningful safety comparisons would require observational and real-world data, which were beyond the scope of this NMA.

Subgroup Analysis

Two pre-specified networks: (1) combination ± monotherapy including all seropositive patients (RIN-1, PREVENT, CHAMPION-NMOSD, SAkuraSky, SAkuraStar); (2) monotherapy only (adds N-MOmentum). AQP4-IgG-negative patients were excluded from the NMA.

Criticisms

  • Small rituximab evidence base: the only eligible rituximab trial for time-to-relapse (RIN-1) enrolled just 38 patients (19 per arm), limiting precision.
  • Zero-event arms in RIN-1, PREVENT (monotherapy), and CHAMPION required a 0.5 continuity correction, which may bias HR estimates.
  • Extremely wide confidence intervals (some crossing 100) make all pairwise comparisons statistically non-significant — point estimates and P-score rankings are hypothesis-generating only.
  • Substantial between-trial heterogeneity in relapse definitions and adjudication (investigator vs blinded committee; imaging-supported in RIN-1 and N-MOmentum only) violates NMA transitivity assumptions.
  • Baseline population differences: RIN-1 was Japanese-only (a population with better outcomes) and had no prior-relapse requirement, whereas PREVENT/CHAMPION required 1–3 relapses in the prior 12–24 months, with baseline ARR 1.9 vs 1.4–1.5.
  • CHAMPION-NMOSD used the PREVENT placebo group as an external comparator and was open-label, whereas most included trials were double-blind and placebo-controlled.
  • Time to first relapse ignores relapse severity, long-term ARR, cumulative disability, and quality of life — endpoints that may distinguish therapies clinically.
  • Extension phases were excluded (no placebo arm), limiting long-term inference.
  • No safety analysis, no direct head-to-head comparisons available, and only one trial per therapy (except satralizumab).

Funding

No funding or sponsorship was received for the publication of this article.

Based on: MEDEN-NMOSD NMA (Neurology and Therapy, 2026)

Authors: Barzegar M, Samadzadeh S, Audoin B, et al. (MEDEN study group)

Citation: Neurol Ther. 2026 Jul 16 (online). doi:10.1007/s40120-026-00989-x

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