Clonal Hematopoiesis in Giant Cell Arteritis

NCT06244069 | Not Yet Recruiting

• 1 other identifier: The CH-GCA Trial
• Study Type: observational
• Target: 326
• Locations: 0 countries
• Sites: N/A

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.

Conditions

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

Keywords

Temporal artery biopsy; Giant cell arteritis; Clonal Hematopoiesis of Indeterminate Potential; Single cell transcriptomics; Large vessels vasculitis; Horton disease; Whole Exome Sequencing

Outcome Measures

Primary Outcomes (1)

• 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.

  From beginning of study for 11 months

Secondary Outcomes (12)

• Correlation of GCA with M-CHIP-driven by TET2, ASXL1 and JAK2 mutations

  From beginning of study for 11 months

• Correlation of GCA with L-CHIP-driven by DUSP22, FAT1 and KMT2D mutations

  From beginning of study for 11 months

• Correlation of GCA with M-CHIP and L-CHIP clone dimension

  From beginning of study for 11 months

• Correlation of GCA with M-CHIP and L-CHIP multiple mutations

  From beginning of study for 11 months

• Correlation of ischemic features in GCA with specific CHIP mutations

  From beginning of study for 11 months

Other Outcomes (1)

• Demonstration of the impact of CHIP on single-cell transcriptomics of arterial wall-infiltrating leukocytes

  From 11th month of study to 18th month

Study Arms (2)

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.

Diagnostic Test: Temporal arterial biopsy; Diagnostic Test: Whole exome sequencing; Diagnostic Test: Single cell transcriptomics

Healthy subjects

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

Interventions

Temporal arterial biopsy 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).

GCA patients

Whole exome sequencing 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.

Also known as: Genetic analysis for CHIP

GCA patients

Single cell transcriptomics 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.

GCA patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

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.

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• ASST Fatebenefratelli Sacco: lead

MeSH Terms

Conditions

Giant Cell Arteritis

Interventions

Exome; Genetic Testing

Condition Hierarchy (Ancestors)

Vasculitis, Central Nervous System; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Arteritis; Vasculitis; Skin Diseases, Vascular; Skin Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Genome; Genetic Structures; Genetic Phenomena; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Genetic Techniques; Genetic Services; Health Services; Health Care Facilities Workforce and Services; Diagnostic Services; Preventive Health Services

Study Officials

• Enrico Tombetti, Dr.

  ASST Fatebenefratelli Sacco

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Enrico Tombetti, Dr.

CONTACT

+393289098793; enrico.tombetti@asst-fbf-sacco.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: January 23, 2024
• First Posted: February 6, 2024
• Study Start: March 1, 2024
• Primary Completion (Estimated): March 1, 2028
• Study Completion (Estimated): March 1, 2031
• Last Updated: February 6, 2024

Record last verified: 2024-02