Distinct molecular signature in relapsed patients with ANCA-associated vasculitis.

OBJECTIVES: The pathogenesis of relapses in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) remains ill defined. We aimed to identify whether there are any differences in the molecular profile between patients with relapsing versus new-onset disease. METHODS: Whole blood RNA sequencing in 21 patients with MPA or GPA and 12 age-matched/sex-matched healthy controls was performed; 11 patients had active disease, either newly diagnosed (treatment-naïve, n=6) or relapsed (off-therapy, n=5) and 10 were in remission, either on (n=4) or off (n=6) maintenance therapy. Differential gene expression and functional enrichment analysis were conducted. RESULTS: Relapsing patients with MPA/GPA exhibited a distinct molecular profile compared with healthy controls, newly diagnosed patients or those in remission. Specifically, patients with a major relapse displayed a unique pattern of 41 neutrophil degranulation-associated genes, encoding neutrophil granular proteins, proteins mediating neutrophil adhesion and chemotaxis and proteins involved in myelopoiesis. CONCLUSIONS: In this well-defined MPA/GPA cohort, we report for the first time a distinct relapse-associated transcriptional signature consistent with enhanced neutrophil activity. Therapies targeting neutrophil activation could represent a novel approach for preventing or treating relapses in MPA/GPA.