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.
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.
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).
The study will rely on the patients with GCA enrolled in referral centers for vasculitis, All centers have a fast-track for suspected GCA, mainly from their Emergency Departments. This allows clinical evaluation of patients with multi-dimensional disease characterization, comprising ultrasonography of the temporal, axillary and carotid arteries, temporal artery biopsies, and screening for large vessels involvement with a combination of ultrasonography and Position Emission Tomography/Computed Tomography within five days from clinical evaluation. Temporal artery biopsy will be performed in all patients with cranial symptoms for GCA or in the case of diagnostic uncertainty.
Cohort
Prospective
Temporal arterial biopsy
Diagnostic testCollection of 30 ml of peripheral blood in ethylenediaminetetraacetic acid (EDTA) tubes performed at baseline, 6 months, 12 months and in case of flare before month 12. In addition, the temporal artery specimen (at least 5 mm in length) exceeding that used for clinical activity (at least 10 mm in length in accordance with current clinical recommendations) will be digested to use for research purposes (about protocols for collecting, processing, storing and sending biopsy, refer to Standard Operating Procedures, SOP).
Whole exome sequencing
Diagnostic testPatients with CHIP will be identified and characterized by using whole exome sequencing from the peripheral blood samples. M-CHIP will be further characterized by: i) clone dimension as defined by Variant Allele Fraction (VAF); ii) mutations in specific genes such as DNMT3A, Tet methylcytosine dioxygenase 2 (TET2), Additional Sex combs (ASXL1), or Janus kinase 2 (JAK2); iii) multiple mutations. L-CHIP will be further characterized by: i) clone dimension as defined by the VAF; ii) mutations in specific genes such as Dual Specificity Phosphatase 22 (DUSP22), FAT atypical cadherin 1 (FAT1), (Histone-lysine N-methyltransferase 2D (KMT2D); iii) multiple mutations; iv) co-occurrence of mutations heralding M- and L-CHIP.
Single cell transcriptomics
Diagnostic testThe investigators will identify actively inflamed arterial biopsies from three treatment-naïve patients without CHIP, and three treatment-naïve patients with CHIP driven by the most relevant gene mutation. Arterial wall Cluster of Differentiation (CD) 45+ leukocytes will be isolated after digestion of arterial tissue and characterized by single cell transcriptomics, with a specific focus on wall infiltrating T cells and macrophages and their subsets (eg: Vascular dendritic cells, Th1, Th2, Th17, Treg, M1- and M2-like,…). Frequencies of these subsets and their genetic expression will be compared between wall-infiltrating leukocytes from GCA patients with or without CH, focusing on histological events supposed to be pathogenic in GCA, or known to be dysfunctional in CHIP.
Correlation of GCA with M-CHIP-driven by DNMT3A mutations
Patients with M-CHIP will be identified by whole exome sequencing from the peripheral blood. The prevalence of DNMT3A-driven M-CHIP will be compared in the GCA patients vs matched controls by Chi-squared test or Fisher test.
Correlation of GCA with M-CHIP-driven by TET2, ASXL1 and JAK2 mutations
Patients with M-CHIP will be identified by whole exome sequencing from the peripheral blood. The prevalence of TET2, ASXL1 or JAK2-driven M-CHIP will be compared in the GCA patients vs matched controls by Chi-squared test or Fisher test.
Correlation of GCA with L-CHIP-driven by DUSP22, FAT1 and KMT2D mutations
Patients with L-CHIP will be identified by whole exome sequencing from the peripheral blood. The prevalence of DUSP22, FAT1 or KMT2D-driven L-CHIP will be compared in the GCA patients vs matched controls by Chi-squared test or Fisher test.
Correlation of GCA with M-CHIP and L-CHIP clone dimension
Patients with M-CHIP or L-CHIP will be characterized for the dimension of the mutated clone in the peripheral blood by assessing the Variant Allele Fraction (VAF) at whole exome sequencing. The VAF will be compared between the GCA group and the matched controls by an unmatched non-parametric test (Mann-Whitney U test).
Correlation of GCA with M-CHIP and L-CHIP multiple mutations
The prevalence of M-CHIP and L-CHIP driven by multiple mutations as assessed by whole exome sequencing will be compared between the GCA group and the matched controls by Chi-squared test or Fisher test.
Demonstration of the impact of CHIP on single-cell transcriptomics of arterial wall-infiltrating leukocytes
Arterial wall Cluster of Differentiation (CD) 45+ leukocytes will be isolated after digestion of arterial tissue and characterized by single-cell transcriptomics, with a specific focus on wall infiltrating T cells and macrophages and their subsets (eg: Vascular dendritic cells, Th1, Th2, Th17, Treg, M1- and M2-like,…). Frequencies of these subsets and their genetic expression will be compared between wall-infiltrating leukocytes from GCA patients with or without CH, focusing on events supposed to be pathogenic in GCA, or known to be dysfunctional in CHIP: cytokine production, inflammasome activation and apoptosis, lymphocyte exhaustion, neoangiogenesis, tissue remodeling (fibrosis or matrix protease production), mitochondrial function and production of reactive oxygen species (ROS), neoangiogenesis, T-Cell receptor and B-cell receptor and costimulatory pathways.
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