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The pathogenesis, clinical presentations and treatment of monogenic systemic vasculitis

Nature Reviews Rheumatology volume 21, pages 414–425 (2025)Cite this article

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Abstract

Many monogenic autoinflammatory diseases, including DADA2 (deficiency of adenosine deaminase 2), HA20 (haploinsufficiency of A20), SAVI (STING-associated vasculopathy with onset in infancy), COPA syndrome, LAVLI (LYN kinase-associated vasculopathy and liver fibrosis) and VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, present predominantly with vasculitis and constitute a substantial subgroup of vasculitic conditions associated with a ‘probable aetiology’. The spectrum of monogenic vasculitis encompasses all sizes and types of blood vessel, ranging from large vessels to medium-size and small vessels, and from the arterial side to the venous side of the vasculature. Monogenic vasculitis typically starts early in life during infancy or childhood; VEXAS syndrome, which presents in late adulthood, is an exception. The activation of myeloid cells via inflammasome and nuclear factor-κB pathways, type I interferon-enhanced autoimmune mechanisms and/or dysregulated adaptive immune responses have an important role in the development of immune-mediated endothelial dysfunction and vascular damage. Genetic testing is essential for the diagnosis of underlying monogenic autoinflammatory diseases; however, the penetrance of genetic variants can vary. Increased awareness and recognition of distinctive clinical findings could facilitate earlier diagnosis and allow for more-targeted treatments.

Key points

  • Monogenic vasculitis usually starts during early childhood, whereas VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome typically develops in late adulthood.

  • Early recognition of distinctive clinical findings (such as early strokes) might aid diagnosis.

  • Genetic diagnosis is crucial, but variable penetrance of variants should be kept in mind when interpreting findings and during genetic counselling.

  • Activation of myeloid cells, type I interferon-enhanced autoimmune responses and endothelial dysfunction contribute to vascular damage.

  • Increased awareness of these rare diseases could aid earlier diagnosis and initiation of targeted treatments.

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Fig. 1: Spectrum of vascular involvement in monogenic vasculitis.

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Authors and Affiliations

  1. Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

    Ahmet Gül

  2. Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD, USA

    Ivona Aksentijevich

  3. Infection, Immunity and Inflammation, University College London Great Ormond Street Institute of Child Health, London, UK

    Paul Brogan

  4. UOC Reumatologia e Malattie Autoinfiammatorie, IRCCS Istituto Giannina Gaslini, Genova, Italy

    Marco Gattorno

  5. National Institutes of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA

    Peter C. Grayson

  6. Department of Paediatric Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey

    Seza Ozen

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  2. Ivona Aksentijevich
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Gül, A., Aksentijevich, I., Brogan, P. et al. The pathogenesis, clinical presentations and treatment of monogenic systemic vasculitis. Nat Rev Rheumatol 21, 414–425 (2025). https://doi.org/10.1038/s41584-025-01250-9

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