Clonal Hematopoiesis in Giant Cell Arteritis

NCT ID: NCT06244069

Last Updated: 2024-02-06

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Total Enrollment: 326 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2024-03-31
• Study Completion Date: 2031-03-31

Brief 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.

Detailed Description

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.

Conditions

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

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

GCA patients

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. The main biopsy specimen will be sent for histopathology for clinical diagnosis or final validation, while the remaining specimen (at least 5 mm in length) will be digested to use for research purposes. In the fast-track, patients should rapidly receive a multi-dimensional diagnostic assessment including ultrasonography of the temporal and axillary arteries. Screening for large vessels involvement should be performed according to the local practice by a combination of ultrasonography, Position Emission Tomography (PET) and Magnetic Resonance (MR). Ideally, this assessment should be performed within five days from clinical evaluation.

Temporal arterial biopsy

Intervention Type: DIAGNOSTIC_TEST

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).

Whole exome sequencing

Intervention Type: DIAGNOSTIC_TEST

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.

Single cell transcriptomics

Intervention Type: DIAGNOSTIC_TEST

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.

Healthy subjects

Healthy controls matched with GCA patients for age, sex, smoking status, previous cardiovascular events, BMI, history of cancer and cytotoxic chemo/radiotherapy.

No interventions assigned to this group

Interventions

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).

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DIAGNOSTIC_TEST

Other Intervention Names

Genetic analysis for CHIP

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

ASST Fatebenefratelli Sacco

OTHER

Sponsor Role: lead

Responsible Party

Enrico Tombetti

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Enrico Tombetti, Dr.

Role: PRINCIPAL_INVESTIGATOR

ASST Fatebenefratelli Sacco

Central Contacts

Enrico Tombetti, Dr.

Role: CONTACT

enrico.tombetti@asst-fbf-sacco.it

+393289098793

Other Identifiers

The CH-GCA Trial

Identifier Type: -

Identifier Source: org_study_id