We conducted a systematic review and meta-analysis to compare monoclonal antibody efficacy between AQP4-IgG seropositive and seronegative NMOSD patients.

Monoclonal antibodies have transformed the treatment of neuromyelitis optica spectrum disorder (NMOSD), yet their efficacy in seronegative patients remains uncertain. Subgroup analyses from pivotal trials and real-world studies have yielded conflicting results regarding treatment response by aquaporin-4 immunoglobulin G (AQP4-IgG) serostatus

We searched PubMed/MEDLINE, Embase, Cochrane CENTRAL, and clinical trial registries from inception through January 2025. Studies comparing efficacy outcomes of monoclonal antibodies (rituximab, eculizumab, satralizumab, inebilizumab, tocilizumab, or ravulizumab) between seropositive and seronegative NMOSD patients were eligible. Primary outcomes included annualized relapse rate (ARR) and relapse events. Secondary outcomes included disability progression (EDSS) and infectious adverse events. Random-effects meta-analysis was performed using Review Manager. The study was registered in PROSPERO.

Thirteen studies (4 RCTs, 9 observational) comprising 1,595 patients (1,051 seropositive; 346 seronegative) were included. Seropositive patients had significantly lower relapse risk compared to seronegative patients (RR = 0.64; 95% CI: 0.47–0.87; p = 0.005; I² = 0%; 7 studies), indicating 36% greater efficacy in preventing relapses. No significant differences were observed for continuous ARR (SMD = 0.25; 95% CI: −0.65 to 1.14; p = 0.59; I² = 95%; 7 studies), disability progression (SMD = 1.07; 95% CI: −1.04 to 3.17; p = 0.32; I² = 96%; 4 studies), or infectious adverse events (RR = 1.13; 95% CI: 0.70–1.84; p = 0.61; I² = 0%; 2 studies). High heterogeneity limited interpretation of ARR and disability outcomes.

Monoclonal antibodies demonstrate significantly greater efficacy in preventing relapses in AQP4-IgG seropositive compared to seronegative NMOSD patients. Serostatus should be considered when selecting treatments and setting therapeutic expectations. While monoclonal antibodies remain a treatment option for seronegative patients given comparable safety profiles, further research is needed to optimize therapeutic strategies for this population