Takayasu arteritis (TAK) and giant cell arteritis (GCA) are the primary forms of large vessel vasculitis (LVV) and can result in serious cardiovascular morbidity. Improved understanding of the molecular basis of these diseases is required to develop novel biomarkers and targeted treatments. Moreover, it is unclear whether shared or distinct pathogenic processes underpin the LVV spectrum. To address this, we performed plasma proteomic profiling, quantifying 184 plasma proteins using Olink immunoassays in two independent cohorts totalling 405 individuals. In Cohort 1, comparison of patients with TAK (N=96) and large vessel-GCA (LV-GCA) (N=35) versus healthy controls (HCs) (N=35) revealed 52 and 72 significant differentially abundant proteins, respectively. Correlation with disease activity status identified novel TAK and LV-GCA disease activity markers. Cohort 2 consisted of patients presenting acutely with possible cranial GCA (C-GCA); C-GCA was subsequently confirmed (n=150) or excluded (n=89). 31 proteins were associated with C-GCA. Analyses stratified by temporal artery biopsy results revealed enrichment of the proteomic signal in biopsy-proven GCA, suggesting the presence of distinct endotypes within C-GCA. Cross-disease comparison revealed that active TAK, LV-GCA and biopsy-proven C-GCA had highly similar plasma proteomic profiles. Twenty-six proteomic associations were shared across all three groups including IL6, monocyte/macrophage related proteins (CCL5, CCL7, CSF1), tissue remodelling proteins (VEGFA, TIMP1, TNC) and proteins not previously linked to LVV (TNFSF14, IL7R). We also observed disease-specific associations including increased CXCL9 in LV-GCA and C-GCA but not in TAK and decreases in the extracellular matrix protein COMP in TAK but not in LV-GCA or C-GCA. Evaluation of publicly available transcriptomic data from LV-GCA aortic tissue revealed that 47 of the 112 proteins significantly altered in ≥1 LVV type had significantly altered mRNA expression in LVV aortic tissue. Similarities in LVV proteomic profiles suggest shared pathobiology involving innate immunity, particularly monocyte/macrophages, lymphocyte homeostasis and tissue remodelling processes. Our results highlight a signature of immune-stromal cross talk in LVV and identify potential novel therapeutic targets in this axis (e.g. TNFSF14). The correspondence of plasma signatures to tissue phenotype highlights the potential for non-invasive monitoring of arterial inflammation and injury.

J.E.P. has received travel and accommodation expenses to speak at Olink-sponsored academic meetings (none in the last 5 years). C.P. is a recipient of a research grant from Galapagos BV; unrelated this study. A.W.M. previously received a research grant from Roche PLC, for unrelated work, and has undertaken consultancy or received honoraria for speaking at educational events on behalf of her institution from AstraZeneca, Roche and Vifor in the last 5 years. R.A.L has served on advisory boards for GSK and Roche; has received assistance to attend meetings from CSL Vifor; has received grants from Roche, Celgene/BMS and CSL Vifor, and has participated in clinical trials for Roche, GSK, Novartis, and InflaRx.

This study was funded in part by the Medical Research Council (MRC) ?Treatment According to Response in Giant cEll arTeritis? (TARGET) Partnership award, Medical Research Foundation (MRF-042-0001-RG-PETE-C0839), Vasculitis UK (V2105), MRC Confidence in Concept (Leeds), the NIHR Imperial Biomedical Research Centre (BRC), and the NIHR Leeds BRC. The TABUL study was funded via an NIHR Heath Technology Assessment grant. N.C. was supported by an MRC DiMen award. CP was supported by Versus Arthritis (Career Development Fellowship, 21223) and Imperial College - Wellcome Trust Institutional Strategic Support Fund (ISSF). J.E.P. is supported by a Medical Research Foundation Fellowship (MRF-057-0003-RG-PETE-C0799). A.W.M. is an NIHR Senior Investigator and supported by the NIHR Leeds BRC and was previously supported by the NIHR Leeds MedTech and Invitro Diagnostics Co-operative and MRC TARGET Partnership grant. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Cohort 1: Patients and healthy controls provided written informed consent, and samples were collected as a sub-collection registered with the Imperial College Healthcare Tissue Bank (licence: 12275; National Research Ethics Service approval 17/WA/0161). Cohort 2: Overall study approval was granted by the Berkshire Research Ethics Committee (09/H0505/132) and approved was also granted at local participating clinical sites.

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