Monoclonal Antibodies Show Greater Relapse Reduction in AQP4-IgG Seropositive vs Seronegative NMOSD, Meta-Analysis Finds

A recent meta-analysis published in the Journal of Neuroimmunology may offer the most comprehensive head-to-head comparison to date of monoclonal antibody efficacy by aquaporin-4 immunoglobulin G (AQP4-IgG) serostatus in neuromyelitis optica spectrum disorder (NMOSD).¹ The findings suggested that although these agents remain effective tools across the spectrum, clinicians should calibrate treatment expectations for seronegative patients, who appear to derive meaningfully less benefit from currently available biologics.

Monoclonal antibodies, including complement inhibitors, interleukin-6 (IL-6) receptor antagonists, and B-cell depleting agents, have transformed relapse prevention in NMOSD since the pivotal phase 3 trials that secured regulatory approvals for eculizumab (Soliris; Alexion), inebilizumab (Uplizna; Amgen), satralizumab (Enspryng; Genentech), and ravulizumab (Ultomiris; Alexion), all in AQP4-IgG seropositive disease.^2-4 Yet 10–30% of patients meeting clinical NMOSD criteria are seronegative, and this population has historically been underrepresented in randomized controlled trials (RCTs), leaving clinicians with limited evidence to guide treatment decisions.¹

Study Overview

In this study, lead author Khaled Zammar, MD, MSc, chief resident in the Neurology Department at Hamad Medical Corporation in Qatar, and colleagues conducted a PRISMA-compliant systematic review and random-effects meta-analysis registered prospectively in PROSPERO. Searches of PubMed/MEDLINE, Embase, and Cochrane CENTRAL from inception through January 2025 identified 13 eligible studies, 4 RCTs and 9 observational cohorts, comprising of 1284 patients, with 1010 AQP4-IgG seropositive and 274 seronegative.

Included agents were rituximab, eculizumab, satralizumab, inebilizumab, tocilizumab, and ravulizumab. The primary outcomes were annualized relapse rate (ARR) and binary relapse events, while secondary outcomes included changes in Expanded Disability Status Scale (EDSS) scores and infectious adverse events.

Key Findings

The clearest signal emerged from relapse analyzed as a binary event. Pooling data from 9 studies, seropositive patients demonstrated a 34% lower risk of experiencing a relapse compared with seronegative patients (risk ratio [RR] = 0.66; 95% CI: 0.49–0.89; P = .007), with no heterogeneity across studies (I2 = 0%). A preplanned subgroup analysis restricted to 4 RCTs sharpened this estimate considerably: a 59% relative risk reduction favoring seropositive patients (RR = 0.41; 95% CI: 0.25–0.69; P = .0008; I2 = 0%), rated high certainty of evidence by GRADE.

By contrast, when ARR was examined as a continuous measure across 7 studies, no statistically significant difference emerged between groups (standardized mean difference [SMD] = 0.23; P = .61), though the analysis was substantially limited by high heterogeneity (I2 = 94%), likely reflecting variability in baseline disease severity, follow-up duration, and treatment protocols. Similarly, disability progression measured by EDSS (4 studies; SMD = 1.07; P = 0.32; I2 = 96%) and infectious adverse events (2 studies; RR = 1.13; P = 0.61; I2 = 0%) did not differ significantly between serostatus groups.

Clinical Context

NMOSD is a severe, relapse-driven autoimmune disorder of the central nervous system characterized by optic neuritis, transverse myelitis, and brainstem attacks that cumulatively drive neurological disability.⁵ AQP4-IgG seropositivity underlies approximately 70–90% of cases; the pathophysiology is mechanistically linked to complement activation and astrocyte injury at AQP4-expressing foot processes, the precise target of approved biologics. The seronegative population is heterogeneous, potentially encompassing patients with undetected AQP4-IgG because of assay insensitivity, those with myelin oligodendrocyte glycoprotein antibody disease (MOGAD), and true double-seronegative NMOSD of uncertain pathophysiology.¹

That distinction matters for interpreting treatment response. Prior RCT subgroup data had signaled this differential, the SAkuraStar trial (NCT02073279) showed robust efficacy in seropositive patients (hazard ratio [HR], 0.26) but no benefit in seronegative patients (HR, 1.19)³; this meta-analysis pools those signals for the first time with appropriate statistical rigor.

READ MORE: Real-World Registry Data Support Eculizumab, Ravulizumab as Effective Treatments for NMOSD

Interpretation

The authors interpreted the dichotomous relapse finding as the most reliable efficacy signal, given its low heterogeneity and high certainty rating from RCTs. The concordance between mechanistic logic, agents designed around AQP4-mediated complement and B-cell pathways, and observed superior efficacy in seropositive disease lends biological plausibility to the result. Importantly, the comparable safety profiles across serostatus groups suggest that continuing monoclonal antibody therapy in seronegative patients is not unreasonable, though treatment expectations and shared decision-making conversations should account for the reduced efficacy signal.

Limitations

Several methodological constraints tempered the conclusions. The seronegative cohort was small (n = 274) and heterogeneous, with anti-MOG antibody testing inconsistently performed across studies, meaning an unknown proportion of "seronegative" patients may have had MOGAD. AQP4-IgG assay methodology varied across studies, from less sensitive indirect immunofluorescence to live cell-based assays, raising the possibility of serostatus misclassification. The pooling of mechanistically distinct agents precluded agent-specific conclusions, and the safety analysis rested on only 2 studies. Publication bias was suggested by funnel plot asymmetry in 3 of 4 outcomes. Finally, follow-up ranged from 12 months to more than 8 years, contributing to outcome heterogeneity.

Future Research

The investigators call for prospective studies enrolling patients with seronegative NMOSD specifically, along with agent-specific subgroup analyses, standardized serological testing protocols incorporating both AQP4-IgG and MOG-IgG cell-based assays, and biomarker discovery efforts aimed at predicting treatment response in this population.

REFERENCES
1. Zammar K, Safan A, Abushalbak DJ, et al. Monoclonal antibody efficacy in seropositive vs seronegative NMOSD: systematic review and meta-analysis. J Neuroimmunol. 2026;417:578945. doi:10.1016/j.jneuroim.2026.578945
2. Pittock SJ, Berthele A, Fujihara K, et al. Eculizumab in Aquaporin-4-Positive Neuromyelitis Optica Spectrum Disorder. N Engl J Med. 2019;381(7):614-625. doi:10.1056/NEJMoa1900866
3. Traboulsee A, Greenberg BM, Bennett JL, et al. Safety and efficacy of satralizumab monotherapy in neuromyelitis optica spectrum disorder: a randomised, double-blind, multicentre, placebo-controlled phase 3 trial. Lancet Neurol. 2020;19(5):402-412. doi:10.1016/S1474-4422(20)30078-8
4. Yamamura T, Kleiter I, Fujihara K, et al. Trial of Satralizumab in Neuromyelitis Optica Spectrum Disorder. N Engl J Med. 2019;381(22):2114-2124. doi:10.1056/NEJMoa1901747
5. Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85(2):177-189. doi:10.1212/WNL.0000000000001729