Giant-Cell Arteritis (GCA) is the most frequent idiopathic vasculitis of the elderly, characterised by patchy inflammatory lesions of the medium and large arteries and a robust systemic acute-phase response (1). Arterial inflammation may result in end-organ ischemia (such as optic nerve or retinal ischemia, which can cause blindness and represent the most important medical emergency in ophthalmology (2)), and arterial aneurysms/dissection. The aetiopathogenesis of GCA is poorly understood, although it is believed
that a feed-forward self-sustaining mechanism, involving lymphocytes and macrophages, maintains inflammation in the arterial wall, causing persisting tissue injury and arterial remodelling (3–5). Immunosuppression with glucocorticoids and biologic agents is used to target the inflammatory process. There is substantial heterogeneity regarding development of vascular complications, immunosuppression-related infections, or disease relapses, and full understanding of the underlying mechanisms is an unmet need.
Clonal hematopoiesis of indeterminate potential (CHIP) is a preleukemic condition highly prevalent in the elderly, in which somatic mosaicism occurs in the hematopoietic lineage as results of specific cancer-associated mutations (6). Despite being undetectable with traditional diagnostic tools, CHIP has clinical relevance far beyond the small risk of development of hematologic cancers, as the CHIP-driving mutation might result in dysregulated innate and adaptive immunity with a pro-inflammatory imbalance(7). Thus, CHIP
is one of the variables affecting “inflammaging” and has a direct proatherogenic effect (8,9). Given a preliminary observation of a 33% prevalence of CHIP in GCA, we will test the hypothesis that specific CHIP-driving mutations might represent relevant genetic modifiers of GCA, helping to dissect the clinical heterogeneity of GCA. With a case-control design,
we will verify the association of GCA with specific CHIP-driving mutations evaluated with whole exome sequencing. Next, we will verify the association of individual genotype with disease manifestations, including ischemia and relapses. Lastly, we will use single-cell transcriptomic to verify the impact of the most relevant CHIP-driving mutation on polarisation, gene expression and pathway enrichment of the arterial wall-infiltrating leukocytes, which are considered key pathogenic populations in GCA (10). The relevant events identified will be validated on arterial biopsies. Should our hypothesis be proven, clinicians will have a peripheral-blood biomarker to predict disease complications and relapses,
researchers will improve pathogenic insight in GCA and in CHIP effects within the landscape of tissue-resident leucocytes in the setting of inflammatory disease of the elderly. Additionally, this biomarker would be the ideal candidate to be tested for predicting the response to specific therapies, favouring precision medicine.