Gene Expression Signatures Associated with Prior Rituximab Treatment in Patients with Anti-aquaporin-4 Antibody-positive (AQP4-Ab+) Neuromyelitis Optica Spectrum Disorder (NMOSD) in the CHAMPION-NMOSD Trial
Sean Pittock1, Irem Celen2, Kerstin Allen2, Dan Case2, Ruba Bou-Chahine2
1Mayo Clinic, 2Alexion, AstraZeneca Rare Disease
Objective:
Evaluate gene expression signatures at baseline and during treatment with ravulizumab, a complement component 5 (C5) inhibitor, among patients with AQP4-Ab+ NMOSD in CHAMPION-NMOSD.
Background:
AQP4-Ab+ NMOSD is an autoimmune disorder characterized by prominent inflammatory responses and complement dysregulation resulting in astrocyte and neuronal injury. Comparison of gene expression profiles of patients with AQP4-Ab+ NMOSD receiving ravulizumab and healthy adults may further inform this immune dysregulation.
Design/Methods:
Gene expression was analyzed using whole blood samples collected predose at baseline, week 26, and week 50 from 32/58 patients in CHAMPION-NMOSD and from 10 external demographically matched healthy individuals. RNA samples were used for RNA-seq and bioinformatics analyses.
Results:
Baseline gene expression profiles of patients with AQP4-Ab+ NMOSD differed from healthy individuals in an unsupervised clustering. Patients were further separated into 2 subgroups, with prior rituximab exposure identified as a predictor distinguishing one patient population from the other (univariate P=0.0187, multivariate P=0.0439). Significant differences in expression of genes involved in cytokine-receptor-mediated signaling and the complement pathway were observed between patients and healthy individuals. Patients with prior rituximab exposure experienced further dysregulation in these pathways compared with rituximab-naive patients. At baseline, significant gene expression-level differences were observed for C5, C3, and associated receptors as well as extracellular matrix regulating metalloenzymes. Neither patient group exhibited significant differences in these markers’ expression between baseline and week 50 of ravulizumab treatment. Despite decreased B-cell–associated gene expression in individuals with prior rituximab exposure, baseline cytotoxic-T-cell–, macrophage-, and neutrophil-associated gene expression levels tended to be higher than those in rituximab-naive patients.
Conclusions:
Patients with AQP4-Ab+ NMOSD had a distinct gene expression profile characterized by complement dysregulation, immune activation, and inflammation. This profile was more pronounced with prior rituximab exposure. The expression levels remained elevated following ravulizumab treatment. This enduring impact of rituximab use warrants further evaluation in this patient population.
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