clonal hematopoiesis in giant cell arteritis

Conditions: Giant Cell Arteritis; Temporal Arteritis; Clonal Hematopoiesis of Indeterminate Potential; Horton Disease; Systemic Vasculitis Primary

Summary: the goal of this clinical trial is to verify whether chip is correlated with the clinical, instrumental, and histological characteristics of gca, and to characterize the pathogenetic effects of clonal hemopoiesis on vasculitis. the main objective of this study is to verify if clonal hematopoiesis of indeterminate potential (chip) affects gca manifestations, course/response to therapies, and pathogenesis. patients who are going to be diagnosed with gca and for which a fast track is available for a rapid diagnostic work-up including pre-treatment temporal artery biopsy. patients with chip will be identified and characterized by using whole exome sequencing from the peripheral blood samples. the presence and characteristics of chip will be correlated with baseline clinical, instrumental, and histologic gca features.

gca is the most frequent idiopathic vasculitis in the elderly, characterized by significant morbidity, with possible formation of aneurysms and arterial dissections and with possible evolution into ischemic tissue events, such as irreversible blindness or stroke. arterial inflammation is maintained by a leukocyte infiltrate infiltrating the vessel wall through vasa vasorum, composed primarily of macrophages (sometimes structured into granulomas with multinucleated giant cells) and cluster of differentiation (cd) 4+ t cells, but also from cluster of differentiation (cd) 8+ and dendritic cells. however, there are heterogeneous clinical pictures, in correlation to the spatial distribution of arterial lesions, to the finding of arterial ischemia, aneurysms or any relapses. even today, there is a need to understand the pathogenetic mechanisms underlying clinical and prognostic differences in gca and to identify patients with different clinical outcomes and response to therapies in advance. clonal hemopoiesis is instead characterized by the presence in the bloodstream of a hematopoietic clone with a selective advantage following somatic mutations, in the absence of other obvious hematological conditions: in fact, it cannot be detected by standard diagnostic tools, but requires a genetic assessment of blood mosaicism or the presence of known relevant mutations. mutated leukocytes have a more intense inflammatory and atherogenic response with inflammatory stimuli, both infectious and non-infectious, favoring a proinflammatory microenvironment in elderly patients, underlying the concept of "age-related inflammation". one study identified chip in 33% of patients with gca. the investigators hypothesize that specific mutations responsible for the hematopoietic clone could favor a proinflammatory dysregulation of leukocytes within vasculitic lesions, affecting the activity of arterial injury. the purpose of this study is to verify whether chip is correlated with the clinical, instrumental and histological characteristics of gca, and to characterize the pathophysiologic effects of clonal hemopoiesis on vasculitis.

Eligibility criteria:
inclusion criteria: * patients with suspected active gca entering into a fast-track work-up and healthy matched controls. * capability of providing valid consent to study enrollment. * possibility of performing temporal artery biopsy within three hours from enrollment. exclusion criteria: * active concurrent viral, fungal or bacterial infections (including active/latent tuberculosis treated for less than 4 weeks, hiv and hepatitis b/c virus (hbv/hcv) infections. * concurrent systemic inflammation not attributable to gca (inflammatory diseases in treatment-free remission are accepted). * use of other immunosuppressive agents in the last 3 months. * use of systemic steroids (any dose in the last week, \> 15 mg/die of prednisone equivalent in the last month). * solid or hematologic malignancies (active or with less than 6 months free of disease or antiblastic chemotherapy (hormone therapy is allowed). * previous solid or hematopoietic stem cell transplantation (corneal transplants are allowed). * any systemic immunosuppressive or steroidal therapy. * chronic renal failure with glomerular filtration rate (gfr) \< 45 ml/min \*1.73 m2. * moderate-severe liver failure (child-pugh b or c), hepatitis in stages of activity. * diabetes mellitus. * heart failure with new york heart association score (nyha) \>=2. * severe hypoproteinemia/malnutrition. * chronic respiratory failure requiring o2 therapy or ventilation therapy at home. * any other condition judged by the local investigator as a contra-indication to eligibility.

Keywords: temporal artery biopsy giant cell arteritis clonal hematopoiesis of indeterminate potential single cell transcriptomics large vessels vasculitis horton disease whole exome sequencing