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Clonal haematopoiesis across the age spectrum of vasculitis patients with Takayasu’s arteritis, ANCA-associated vasculitis and giant cell arteritis
  1. Fernanda Gutierrez-Rodrigues1,
  2. Kristina V Wells2,
  3. Adrianna I Jones2,
  4. Dalton Hironaka1,
  5. Cameron Rankin2,
  6. Massimo Gadina2,
  7. Keith A Sikora2,
  8. Lemlem Alemu1,
  9. Rodrigo T Calado3,
  10. Kaitlin A Quinn2,
  11. Bhavisha Patel1,
  12. Neal S Young1,
  13. Peter C Grayson2
  1. 1 Hematology Branch, National Heart Lung and Blood Institute Division of Intramural Research, Bethesda, Maryland, USA
  2. 2 National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA
  3. 3 Medical Imaging, Hematology, and Oncology, University of São Paulo, Sao Paulo, Brazil
  1. Correspondence to Dr Peter C Grayson, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA; peter.grayson{at}nih.gov

Abstract

Objectives Ageing and inflammation are associated with clonal haematopoiesis (CH), the emergence of somatic mutations in haematopoietic cells. This study details CH in patients with systemic vasculitis in association with clinical, haematological and immunological parameters.

Methods Patients with three forms of vasculitis were screened for CH in peripheral blood by error-corrected sequencing. Relative contributions of age and vasculitis on CH prevalence were calculated using multivariable logistic regression. Clonal hierarchies were assessed by proteogenomic single-cell DNA sequencing, and functional experiments were performed in association with CH status.

Results Patients with Takayasu’s arteritis (TAK; n=70; mean age=33.2 years), antineutrophil cytoplasmic antibody-associated vasculitis (AAV; n=47; mean age=55.3 years) and giant cell arteritis (GCA; n=59; mean age=71.2 years) were studied. CH, most commonly in DNMT3A and TET2, was detected in 34% (60/176) of patients versus 18% (28/151) of age-matched controls (p<0.01). Prevalence of CH was independently associated with age (standardised B=0.96, p<0.01) and vasculitis (standardised B=0.46, p<0.01), occurring in 61%, 32% and 13% of patients with GCA, AAV and TAK, respectively. Both branched and linear clonal trajectories showed myeloid-lineage bias, and CH was associated with markers of cellular activation. In GCA, mutations were detected in temporal artery biopsies, and clinical relapse correlated with CH in a dose-dependent relationship with clone size.

Conclusions Age was more strongly associated with CH prevalence than inflammation in systemic vasculitis. Clonal profile was dominated by DNMT3A mutations which were associated with relapse in GCA. CH is not likely a primary causal factor in systemic vasculitis but may contribute to inflammation.

  • Vasculitis
  • Giant Cell Arteritis
  • Polymorphism, Genetic

Data availability statement

Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

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Footnotes

  • Handling editor Josef S Smolen

  • Twitter @MassimoGadina

  • Contributors FG-R, KVW, AIJ, MG, BP, NSY and PCG conceptualised and designed the study, and interpreted the results, wrote and edited the manuscript. FG-R, DH and LA performed and analysed error-corrected sequencing (ECS) experiments. FG-R interpreted the single-cell proteogenomic DNA results. AIJ, CR and KAS performed functional experiments. RTC provided healthy controls data for ECS analysis. KVW, AIJ, KAQ and PCG performed statistical analysis for clinical outcomes. KAQ and PCG provided clinical care. PCG accepts full responsibility for the work and conduct of the study, had access to the data, and controlled the decision to publish.

  • Funding This research was funded by the Intramural Research Program of the National Heart, Lung, and Blood Institute and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.