Proteomic profiling of the large-vessel vasculitis spectrum identifies shared signatures of innate immune activation and stromal remodelling

Takayasu arteritis (TAK) and giant cell arteritis (GCA), the most common forms of large-vessel vasculitis (LVV), can result in serious morbidity. Understanding the molecular basis of LVV should aid in developing better biomarkers and treatments. Plasma proteomic profiling of 184 proteins was performed in two cohorts. Cohort 1 included patients with established TAK (n=96) and large-vessel GCA (LV-GCA, n=35) in addition to healthy control participants (HCs, n=35). Cohort 2 comprised patients presenting acutely with possible cranial-GCA in whom the diagnosis was subsequently confirmed (C-GCA, n=150) or excluded (Not C-GCA, n=89). Proteomic findings were compared to published transcriptomic data from LVV-affected arteries. In Cohort 1, comparison to HCs revealed 52 differentially abundant proteins (DAPs) in TAK and 72 in LV-GCA. Within-case analyses identified 16 and 18 disease activity-associated proteins in TAK and LV-GCA, respectively. In Cohort 2, comparing C-GCA versus Not C-GCA revealed 31 DAPs. Analysis within C-GCA cases suggested the presence of distinct endotypes, with more pronounced proteomic changes in the biopsy-proven subgroup. Cross-comparison of TAK, LV-GCA and biopsy-proven C-GCA revealed highly similar plasma proteomic profiles, with 26 shared DAPs including IL6, monocyte/macrophage related proteins (CCL7, CSF1), tissue remodelling proteins (TIMP1, TNC) and novel associations (TNFSF14, IL7R). Plasma proteomic findings reflected LVV arterial phenotype; for 42% of DAPs, the corresponding gene was differentially expressed in tissue. These findings suggest shared pathobiology across the LVV spectrum involving innate immunity, lymphocyte homeostasis and tissue remodelling. Network-based analyses highlighted immune-stromal crosstalk and identified novel therapeutic targets (e.g. TNFSF14).