NMOSD mAb Meta-analysis
(2026)Objective
To compare monoclonal antibody efficacy between AQP4-IgG seropositive and seronegative NMOSD patients through systematic review and meta-analysis.
Study Summary
• RCT-only subgroup showed 59% relative risk reduction favoring seropositive (RR 0.41; 95% CI 0.25-0.69; p=0.0008)
• No significant differences in continuous ARR (SMD 0.23; p=0.61), disability progression (SMD 1.07; p=0.32), or infectious adverse events (RR 1.13; p=0.61)
• Comparable safety profiles support continued mAb use in seronegative patients
Intervention
Monoclonal antibodies (rituximab, eculizumab, satralizumab, inebilizumab, tocilizumab, or ravulizumab) compared by AQP4-IgG serostatus
Inclusion Criteria
Adult NMOSD patients meeting 2006 Wingerchuk or 2015 IPND criteria, both AQP4-IgG seropositive and seronegative, treated with monoclonal antibodies
Study Design
Arms: AQP4-IgG Seropositive (n=1010) vs AQP4-IgG Seronegative (n=274)
Patients per Arm: Seropositive n=1010; Seronegative n=274
Outcome
• RCT subgroup: RR 0.41 (95% CI 0.25-0.69; p=0.0008), 59% RRR
• ARR (continuous): no difference (SMD 0.23; p=0.61; I²=94%)
• EDSS disability: no difference (SMD 1.07; p=0.32; I²=96%)
• Infectious AEs: no difference (RR 1.13; 95% CI 0.70-1.84; p=0.61)
Bottom Line
Monoclonal antibodies are significantly more effective at preventing relapses in AQP4-IgG seropositive than seronegative NMOSD patients (34% lower relapse risk overall; 59% RRR in RCT subgroup). Safety profiles are comparable, supporting continued use in seronegative patients, but serostatus should inform treatment selection and expectations.
Major Points
- Seropositive NMOSD patients had 34% lower relapse risk than seronegative patients on monoclonal antibodies (RR 0.66; 95% CI 0.49-0.89; p=0.007; I²=0%; 9 studies)
- RCT-only subgroup analysis demonstrated 59% relative risk reduction favoring seropositive (RR 0.41; 95% CI 0.25-0.69; p=0.0008; I²=0%; 4 RCTs)
- No significant difference in continuous ARR (SMD 0.23; 95% CI -0.66 to 1.13; p=0.61; I²=94%)
- No significant difference in disability progression by EDSS (SMD 1.07; 95% CI -1.04 to 3.17; p=0.32; I²=96%)
- Infectious adverse event rates comparable between groups (RR 1.13; 95% CI 0.70-1.84; p=0.61; I²=0%)
- GRADE certainty: high for relapse events (RCTs only), moderate for relapse events (all studies), very low for continuous ARR and EDSS, low for infectious AEs
- Serostatus should inform treatment selection and patient counseling regarding expected efficacy
Study Design
- Study Type
- Systematic review and meta-analysis
- Randomization
- No
- Blinding
- Not applicable (meta-analysis)
- Sample Size
- 1284
- Follow-up
- Varied across included studies: 12 months to median >8 years
- Countries
- Germany, Austria, Australia, India, Iran, Sweden, Egypt, Argentina, Turkey, China, Multinational
Primary Outcome
Definition: Relapse risk (dichotomous event) on monoclonal antibody therapy, comparing AQP4-IgG seropositive vs seronegative NMOSD patients
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Seronegative: higher relapse risk (reference) | Seropositive: 34% lower relapse risk | - (0.49-0.89) | 0.007 |
Limitations & Criticisms
- Substantial heterogeneity for continuous ARR (I²=94%) and EDSS (I²=96%) limits interpretation
- Seronegative subgroup considerably smaller (n=274 vs 1010 seropositive), limiting power
- Seronegative population is heterogeneous - may include undetected AQP4-IgG, MOGAD, and true double-seronegative patients
- Only 2 studies contributed to safety analysis
- Funnel plot asymmetry for ARR suggesting potential publication bias
- Observational studies of variable quality included alongside RCTs
- Different monoclonal antibodies pooled together despite different mechanisms
Citation
Zammar K, et al. Monoclonal antibody efficacy in seropositive vs seronegative NMOSD: systematic review and meta-analysis. J Neuroimmunol. 2026;417:578945.