Patients with neuromyelitis optica spectrum disorder (NMOSD) that have an onset of the condition at a younger age, polysystem involvement in the first attack, and increased or unchanged titer of aquaporin-4 (AQP4-IgG) are most likely to experience relapse under treatment with immunosuppressants, a study found.

The study suggested a higher efficacy treatment than immunosuppressants might be necessary to prevent relapse in younger patients with NMOSD with seropositive AQP4-IgG. Moreover, the time for AQP4-IgG to become seronegative and the change of AQP4-IgG titer might become the surrogate efficacy biomarkers in clinical trials.

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The study was published online in Annals of Neurology.

The cohort-based study prospectively collected data from 400 patients with NMOSD seropositive for AQP4-IgG and treated with immunosuppressants. Moreover, a fixed cell-based assay was used to detect serum AQP4-IgG every 6 months.

Study results indicated that 128 patients became AQP4-IgG seronegative after undergoing immunosuppressant treatment with a significant decrease in mean annualized relapse rate. Moreover, a positive correlation was found between the time to become seronegative and the relapse rate. Additionally, older age at disease onset, immunosuppressant initiation at onset, and shorter disease duration before the maintenance therapy were the independent risk factors for AQP4-IgG becoming seronegative.

Similarly, the independent risk factors for relapse were the younger age (less than 46.4 years) at onset, the poly-system involvement in the first attack, and unchanged or increased AQP4-IgG titer. Furthermore, the relapse risk was not found to be associated with gender, seropositivity for systemic autoimmune antibodies, combination with connective tissue disease, or with incomplete recovery from the first attack.

“Our study finds that age at disease onset, AQP4-IgG dynamics, poly-system involved in the first attack, and maintenance therapy before relapse may influence the clinical outcomes of AQP4-IgG seropositive NMOSD patients treated with immunosuppressants”, the authors highlighted.

Protein aquaporin-4 (AQP4-IgG) is an essential diagnostic marker and plays a key role in NMOSD pathogenesis, the researchers noted. However, approx. 20% to 30% of patients meeting NMOSD clinical criteria are AQP4-IgG seronegative1, with no female predominance, they added.

Prior studies have reported that some seronegative patients have been found to have other autoantibodies, such as the antibody against myelin oligodendrocyte glycoprotein (MOG-IgG), the study authors noted. Previous studies have investigated the relationship between AQP4-IgG and disease activity but have yet to reach consistent conclusions due to differences in antibody detection methods, statistical analysis, and the heterogeneity of seronegative patients, they added.

Although traditional immunosuppressive medications like mycophenolate mofetil and azathioprine are widely used in the treatment of NMOSD due to their convenience and lower cost, a significant percentage of patients receiving these medications still experience relapses, the researchers noted.

AQP4-IgG has been proposed as a potential biomarker for clinical relapse in NMOSD due to its role in pathogenesis. However, the clinical significance of monitoring serum AQP4-IgG levels in predicting relapse remains uncertain, they concluded.


Yin HX, Wang YJ, Liu MG. et al. Aquaporin‐4 antibody dynamics and relapse risk in seropositive Neuromyelitis Optica Spectrum Disorder treated with immunosuppressants. Annals of Neurology. Published online February 25, 2023. doi: 10.1002/ana.26623