Clonal Hematopoiesis in Giant Cell Arteritis

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.

Conditions

• Giant Cell Arteritis
• Temporal Arteritis
• Clonal Hematopoiesis of Indeterminate Potential
• Horton Disease
• Systemic Vasculitis Primary

Interventions

DIAGNOSTIC_TEST

Temporal arterial biopsy

Collection 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).

DIAGNOSTIC_TEST

Whole exome sequencing

Patients 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.

DIAGNOSTIC_TEST

Single cell transcriptomics

The 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.

Sponsors & Collaborators

• ASST Fatebenefratelli Sacco

  lead OTHER

Principal Investigators

• Enrico Tombetti, Dr. · ASST Fatebenefratelli Sacco

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2024-03-31

Primary Completion

2028-03-31

Completion

2031-03-31