Background: ANCA-associated small vessel vasculitis (AAV) and large vessel vasculitis (LVV) are two clinically distinct forms of vasculitides with a high risk of relapse. The potential role of the innate immune system in disease flares has so far not been assessed in detail.

Objectives: We aimed to evaluate and compare the role of immune cells in flaring patients of both vasculitis subtypes.

Methods: Patients were included in the Bern Vasculitis Study (BEVAS) at the Bern University Hospital or sampled at the University Hospital Kiev between October 2023 and October 2025. Cell counts and other clinical data were collected. Whole blood was collected from 12 untreated flaring AAV patients (8 female patients, mean age 51.4 years), 10 untreated flaring LVV patients (7 female patients, mean age 71.5 years), and 11 healthy controls (HC, 7 female HC, mean age 62.9 years) in PAX-gene tubes. AAV diagnoses included 2 patients with eosinophilic granulomatosis with polyangiitis (EGPA), 5 patients with granulomatosis with polyangiitis (GPA) and 5 patients with microscopic polyangiitis (MPA). RNA was extracted according to the manufacturer’s protocol (Quiagen PAXgene Blood RNA Kit). Transcriptomes were analysed by RNA sequencing (Lexogen QuantSeq 3’ mRNA-Seq, Illumina NovaSeq 6000). Differentially expressed genes across disease groups were calcualted using DESeq2 (DEG; ± fold change > 1.5, p adj < 0.05). Pathway enrichment was assessed using the clusterProfiler R package, applying both over-representation analysis (ORA) and gene set enrichment analysis (GSEA).

Results: We identified 97 DEG in AAV compared to HC, and 473 DEG between LVV and HC in whole blood samples. Strikingly, only 19 genes were differentially expressed between AAV and LVV, out of which only one was involved in B cell activation (CD24). ORA of DEG, distinguishing both vasculitis subtypes from HC, identified pathways exclusively involved in innate immunity. GSEA of both AAV and LVV versus HC pointed to a striking overlap in upregulated pathways comprising seven out of ten top signaling pathways, including “IL6 JAK Stat3 signaling”, “TNF signaling” and “complement activation”. The top enriched gene sets differentiating AAV from LVV indicated an increased expression of interferon gamma and alpha response in AAV. Interestingly, genes involved in platelet activation were higher expressed in LVV compared to AAV, including von Willebrand Factor receptor gene platelet glycoprotein IX (GP9). Accordingly, platelet numbers were significantly increased in LVV compared to AAV.

Conclusions: Our results suggest that the rather homogeneous transcriptome of circulating immune cells does not sufficiently explain the clinically distinct phenotypes of AAV and LVV. However, flares of LVV patients were characterized by increased platelet activity and numbers.

Figure 1.

Heatmap of differentially expressed genes involved in platelet activation in the blood of patients with AAV, LVV and HC. The genes (rows) are hierarchically clustered using Pearson correlation and average linkage on z -score quantification intensities.

Figure 2.

Platelet counts of untreated LVV and AAV patients in the peripheral blood.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: Jennifer Amsler Consultant of Novartis, Research grant from Vontobel Foundation, Marco Kreuzer: None declared, Liubov Petelytska: None declared, Oleg Iaremenko: None declared, Lisa Christ research/non-financial support, advisory fees, and stock ownership from AbbVie, AstraZeneca, BMS, Gilead, Novartis, Pfizer, Roche, Sanofi, and Vifor., Matthias Gasser: None declared, Fabio Ryser: None declared, Adela-Cristina Sarbu: None declared, Luca Seitz: None declared, Pascal Marco Seitz: None declared, Britta Maurer on an advisory board for Janssen and Boehringer., lecturing fees from Boehringer Ingelheim, GaxoSmithKline, Novartis, Otsuka, and Merck Sharpe & Dohme, consulting fees from Novartis, Boehringer Ingelheim, Janssen-Cilag, and GaxoSmithKline, research grants from AbbVie, Protagen, and Novartis Biomedical Research, Kerstin Klein: None declared.