Research Article: Distinct remission immune architectures under rituximab and azathioprine in AQP4-IgG-positive neuromyelitis optica spectrum disorder
Abstract:
Maintenance immunotherapy is effective in AQP4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD), but how mechanistically distinct maintenance therapies organize the remission immune landscape and its relationship to neurological disability remains poorly defined.
We performed integrated multiparameter flow cytometry and plasma cytokine profiling in serial remission samples (up to three per patient) from 28 patients receiving rituximab (RTX, n = 14) or azathioprine (AZA, n = 14). Between-treatment comparisons, within-treatment coupling analyses, and disability-associated immune analyses were conducted using age-adjusted patient-clustered regression models with prespecified false discovery rate control.
RTX showed clear target engagement, characterized by profound B-cell depletion, gradual post-infusion reconstitution, and sustained reduction of natural killer T (NKT)-like cells. Beyond lineage depletion, RTX was associated with regulatory remodeling, including a memory-skewed regulatory T (Treg) phenotype and a lower effector-to-regulatory balance. In B-detectable RTX samples, the reconstituting B-cell compartment was transitional/naive-skewed with marked suppression of memory B cells. Although remission-phase cytokines were broadly low, interferon gamma-induced protein 10/CXC motif chemokine ligand 10 (IP-10/CXCL10) remained selectively elevated under RTX. Importantly, remission immune architecture differed by therapy: AZA showed a T cell immunoreceptor with Ig and ITIM domains (TIGIT)-linked regulatory disability axis, whereas RTX showed disability coupling to soluble inflammatory mediators, particularly interleukin-6 (IL-6) and IP-10.
Mechanistically distinct maintenance therapies impose divergent remission immune architectures in NMOSD. These findings support a treatment-aware framework for biomarker interpretation and suggest that remission monitoring should consider therapy-specific immune networks rather than isolated immune markers.
Introduction:
Maintenance immunotherapy is effective in AQP4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD), but how mechanistically distinct maintenance therapies organize the remission immune landscape and its relationship to neurological disability remains poorly defined.
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