Background/Purpose: Clonal hematopoiesis (CH) is a pre-malignant state characterized by somatic mutations in hematologic precursor cells in genes associated with myeloid malignancies. Incidence of CH increases exponentially with age in healthy people and is associated with an increased risk for all-cause mortality and cardiovascular disease. Small studies report increased prevalence of CH in various inflammatory diseases. To what extent age versus inflammation underlies these associations is unclear. In this study, vasculitis patients with giant cell arteritis (GCA), ANCA-associated vasculitis (AAV), or Takayasu’s arteritis (TAK) were screened for CH to determine the relationship between CH and vasculitis in a cohort of patients with inflammatory disease across a wide age spectrum.

Methods: An error-correcting targeted sequencing panel was used to screen 137 vasculitis patients (GCA, AAV, TAK) and 30 healthy controls (HC) for somatic variants in peripheral blood in 40 genes related to CH. Variants were called if the variant allele fraction (VAF) > 0.5% and if the variants were predicted to impair protein function. Prevalence of CH in vasculitis was compared to controls using chi square test. Logistic regression was used to assess associations of age and vasculitis with CH. Relative contribution of predictor variables was assessed using standardized beta coefficients. Clinical features were compared using Fisher’s exact test, Wilcoxon rank sum test, or logistic regression as appropriate. Correlation between clone size and clinical features was assessed by linear regression.

Results: The prevalence of CH in GCA, AAV and TAK was 54.1% (26/48), 36.1% (13/36), and 11.3% (6/53) respectively, compared to 6.7% (2/30) in HC (p= 0.0007). Median age for GCA, AAV, TAK, and HC was 71.5 (range: 50-88), 60 (range: 19-77), 32 (range: 3-57), and 47 (range: 14-71) years, respectively. In a logistic regression model, age and vasculitis were independently associated with CH (Age: B=0.05, standardized b=0.99, p< 0.0001; Vasculitis: B=0.77, standardized b=0.53, p=0.04). Median VAF was 1.3% (0.51-51.3%) and did not differ by diagnosis. Clones at VAF >10% were found in 7.3% (10/137) of patients. Of the somatic mutations identified, DNMT3A (48/71=67.6%) and TET2(12/71=16.9%) were the most frequently mutated genes. Patients with CHIP had lower percent lymphocytes (17.4% vs 25.5%, p=0.02) and higher absolute neutrophil count (6.1 vs 5.2 K/uL, p=0.04) than those without CH. Adjusting for daily prednisone dose, neutrophil to lymphocyte ratio was significantly associated with presence of CH (B=0.06, p=0.04). The VAF of somatic mutations was positively associated with age (B=0.01, p=0.01) and monocyte count (B=0.83, p=0.01).

Conclusion: There is a complex relationship between age, inflammation and CH. Age is 1.9x more strongly associated with CH than vasculitis, but each are independent contributors. CH is associated with skewing of peripheral blood counts towards myeloid lineages in patients with vasculitis. Still unanswered is to what extent CH directly contributes to inflammation in vasculitis, or conversely what role systemic inflammation plays in generation of mutations and clonal selection.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/clonal-hematopoiesis-across-the-age-spectrum-in-patients-with-systemic-vasculitis/