← Back

MEDEN NMA

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

Year of Publication: 2026

Authors: Barzegar M, Samadzadeh S, Audoin B, ..., Asgari N; MEDEN study group

Journal: Neurology and Therapy

Citation: Barzegar M, et al. Comparative Evaluation of Rituximab Versus Approved Therapies in Aquaporin-4-IgG-Positive Neuromyelitis Optica Spectrum Disorder: A Systematic Review and Network Meta-analysis. Neurol Ther. 2026. doi:10.1007/s40120-026-00989-x

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

Clinical Question

How does rituximab compare with newer approved monoclonal antibodies (eculizumab, ravulizumab, inebilizumab, satralizumab) for preventing time to first relapse in AQP4-IgG-positive NMOSD?

Bottom Line

In this network meta-analysis, no statistically significant differences were found between rituximab and any approved monoclonal antibody for time to first relapse in AQP4-IgG-positive NMOSD. Point estimates favored eculizumab and ravulizumab over rituximab, but wide overlapping CIs and between-trial heterogeneity preclude definitive conclusions — head-to-head or registry-based comparative studies are needed.

        Major Points
        First NMA to systematically compare rituximab against all currently approved monoclonal antibodies for AQP4-IgG-positive NMOSD
Combination ± monotherapy analysis: rituximab had numerically higher HR for relapse vs ravulizumab (HR 5.00) and eculizumab (HR 1.17), but lower vs satralizumab (HR 0.29)
Monotherapy-only analysis: rituximab had higher HR vs ravulizumab (HR 3.33) and eculizumab (HR 1.59), but lower vs inebilizumab (HR 0.31) and satralizumab (HR 0.27)
All 95% CIs were extremely wide and crossed 1.0 — no statistically significant differences detected
Substantial between-trial heterogeneity in prior treatment, relapse history, and relapse adjudication definitions limits interpretation
Findings support the need for direct head-to-head trials or real-world comparative registry studies to guide therapy selection

      

Design

Study Type: Systematic review and frequentist network meta-analysis

Randomization:

Blinding: N/A (meta-analysis)

Allocation: N/A (meta-analysis)

Enrollment Period: Literature search through October 31, 2024; updated November 1, 2025

Follow-up Duration: Varied across included trials

Centers: 0

Countries:

Sample Size: 8

Analyzed: 8

Analysis: Frequentist NMA using netmeta package in R v4.5.1; pooled HRs with 95% CIs for time to first relapse; two analyses (combination ± monotherapy, and monotherapy-only); PRISMA guidelines followed

Power Calculation: Not applicable — formal heterogeneity assessment not performed due to sparse network

Registration: Open Science Framework (OSF) identifier UW5MQ

Inclusion Criteria

Patients who are AQP4-IgG-positive with NMOSD
Interventions: rituximab, eculizumab, inebilizumab, ravulizumab, satralizumab, or tocilizumab
Comparator: placebo or any other intervention
Study type: randomized clinical trials (RCTs) or open-label trials

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, books
Systematic reviews, meta-analyses, network meta-analyses
Non-peer-reviewed articles
Qualitative studies
AQP4-IgG-negative NMOSD patients excluded from NMA

Baseline Characteristics

Characteristic	RIN-1 (Rituximab vs Placebo)	Nikoo et al. (Rituximab vs Azathioprine)	PREVENT (Eculizumab vs Placebo)	CHAMPION (Ravulizumab vs Placebo)	N-MOmentum (Inebilizumab vs Placebo)
Year	2020	2017	2019	2023	2019
Type	Phase 3 RCT	Phase 3 open-label	Phase 3 RCT	Phase 3 open-label	Phase 2/3 RCT
Total N	38	86	143	105	230
AQP4+ N	38	42	143	105	213
Age	16-80	18-50	≥18	≥18	≥18
EDSS	≤7.0	≤7.0	≤7.0	≤7.0	≤7.5
Region	Japanese	Iranian
Baseline relapse			≥2 in previous 12mo or ≥3 in 24mo	≥1 in previous 12 months	≥1 in previous 12 months

Arms

Field	Rituximab	Eculizumab	Ravulizumab	Inebilizumab	Satralizumab
N	0	143	105	213	0
Intervention	Anti-CD20 monoclonal antibody (RIN-1, Nikoo trials)	Terminal complement C5 inhibitor (PREVENT trial)	Long-acting C5 complement inhibitor (CHAMPION trial)	Anti-CD19 monoclonal antibody (N-MOmentum trial)	Anti-IL-6 receptor monoclonal antibody
Duration	Trial-specific	Trial-specific	Trial-specific	Trial-specific	Trial-specific

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Time to first relapse comparing rituximab vs approved monoclonal antibody therapies in AQP4-IgG-positive NMOSD	Primary	Rituximab (reference)	Ravulizumab, eculizumab, inebilizumab, satralizumab	Rituximab vs ravulizumab ±IST: HR 5.00; vs eculizumab ±IST: HR 1.17; vs satralizumab ±IST: HR 0.29	Not statistically significant (all CIs cross 1.0)
	Secondary	Name: Time to first relapse (monotherapy only) — Rituximab vs Ravulizumab · HR 3.33 (95% CI 0.13-83.16)
	Secondary	Name: Time to first relapse (monotherapy only) — Rituximab vs Eculizumab · HR 1.59 (95% CI 0.05-50.17)
	Secondary	Name: Time to first relapse (monotherapy only) — Rituximab vs Inebilizumab · HR 0.31 (95% CI 0.04-2.31)
	Secondary	Name: Time to first relapse (monotherapy only) — Rituximab vs Satralizumab · HR 0.27 (95% CI 0.03-2.21)

Subgroup Analysis

Two prespecified analyses: (1) combination ± monotherapy (all AQP4+ patients regardless of concomitant IST); (2) monotherapy-only (patients receiving monoclonal antibody without concomitant IST). Separate combination-only analysis not performed because RIN-1 patients received monotherapy.

Criticisms

Very wide confidence intervals for all HR estimates limit clinical inference
Substantial heterogeneity in prior treatment, baseline relapse history, and relapse adjudication definitions across included trials
Sparse network precluded formal statistical heterogeneity assessment
PREVENT monotherapy HR had to be estimated from time-to-first-relapse data (not reported directly)
RIN-1 group difference required conversion to HR for consistency with other studies
No head-to-head trials of rituximab vs approved monoclonal antibodies exist

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

Authors: Barzegar M, Samadzadeh S, Audoin B, ..., Asgari N; MEDEN study group

Content summarized and formatted by NeuroTrials.ai.

MEDEN NMA

(2026)

Objective

To compare the effect of rituximab on time to first relapse with ravulizumab, eculizumab, inebilizumab, and satralizumab in patients with AQP4-IgG-positive NMOSD via network meta-analysis.

Study Summary

• Rituximab vs ravulizumab ±IST: HR 5.00 (95% CI 0.25-101.01); vs eculizumab ±IST: HR 1.17 (95% CI 0.12-10.89); none statistically significant
• Monotherapy subgroup: rituximab vs ravulizumab HR 3.33 (95% CI 0.13-83.16); vs satralizumab HR 0.27 (95% CI 0.03-2.21); CIs wide
• Safety outcomes not assessed in this network meta-analysis; only time to first relapse was evaluated

Intervention

Systematic review and frequentist network meta-analysis of 8 RCTs/open-label trials comparing rituximab, eculizumab, ravulizumab, inebilizumab, and satralizumab in AQP4-IgG-positive NMOSD

Inclusion Criteria

AQP4-IgG-positive NMOSD patients enrolled in RCTs or open-label trials evaluating rituximab, eculizumab, inebilizumab, ravulizumab, satralizumab, or tocilizumab vs placebo or active comparator

Study Design

Arms: Rituximab vs Eculizumab vs Ravulizumab vs Inebilizumab vs Satralizumab (8 trials pooled via NMA)

Patients per Arm: 8 trials included from 6337 records screened (RIN-1 n=38, Nikoo n=86, PREVENT n=143, CHAMPION n=105, N-MOmentum n=230, plus others)

Outcome

• No statistically significant differences between rituximab and any approved monoclonal antibody for time to first relapse
• Point estimates favored eculizumab and ravulizumab over rituximab
• Point estimates favored rituximab over satralizumab and inebilizumab
• Wide overlapping CIs and between-study heterogeneity preclude definitive conclusions
• Head-to-head trials or registry-based studies needed

Bottom Line

Major Points

First NMA to systematically compare rituximab against all currently approved monoclonal antibodies for AQP4-IgG-positive NMOSD
Combination ± monotherapy analysis: rituximab had numerically higher HR for relapse vs ravulizumab (HR 5.00) and eculizumab (HR 1.17), but lower vs satralizumab (HR 0.29)
Monotherapy-only analysis: rituximab had higher HR vs ravulizumab (HR 3.33) and eculizumab (HR 1.59), but lower vs inebilizumab (HR 0.31) and satralizumab (HR 0.27)
All 95% CIs were extremely wide and crossed 1.0 — no statistically significant differences detected
Substantial between-trial heterogeneity in prior treatment, relapse history, and relapse adjudication definitions limits interpretation
Findings support the need for direct head-to-head trials or real-world comparative registry studies to guide therapy selection

Study Design

Study Type: Systematic review and frequentist network meta-analysis
Randomization: No
Blinding: N/A (meta-analysis)
Sample Size: 8
Follow-up: Varied across included trials

Primary Outcome

Definition: Time to first relapse comparing rituximab vs approved monoclonal antibody therapies in AQP4-IgG-positive NMOSD

Control	Intervention	HR/OR	P-value
Rituximab (reference)	Ravulizumab, eculizumab, inebilizumab, satralizumab	- (Ravulizumab ±IST: 0.25-101.01; Eculizumab ±IST: 0.12-10.89; Satralizumab ±IST: 0.04-2.23)	Not statistically significant (all CIs cross 1.0)

Limitations & Criticisms

Very wide confidence intervals for all HR estimates limit clinical inference
Substantial heterogeneity in prior treatment, baseline relapse history, and relapse adjudication definitions across included trials
Sparse network precluded formal statistical heterogeneity assessment
PREVENT monotherapy HR had to be estimated from time-to-first-relapse data (not reported directly)
RIN-1 group difference required conversion to HR for consistency with other studies
No head-to-head trials of rituximab vs approved monoclonal antibodies exist

Citation

Barzegar M, et al. Comparative Evaluation of Rituximab Versus Approved Therapies in Aquaporin-4-IgG-Positive Neuromyelitis Optica Spectrum Disorder: A Systematic Review and Network Meta-analysis. Neurol Ther. 2026. doi:10.1007/s40120-026-00989-x

View Original Publication →

MEDEN NMA

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

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Ask about MEDEN NMA