Inborn errors of immunity and AAV: a complex picture

We read with great interest the manuscript by Gül et al. on monogenic systemic vasculitis (Gül, A. et al. The pathogenesis, clinical presentations and treatment of monogenic systemic vasculitis. Nat. Rev. Rheumatol. 21, 414–425 (2025))¹. We thank the authors for presenting a detailed synthesis of current knowledge on the clinical features of these genetic disorders and the putative mechanisms that link different genetic defects to vascular inflammation. Gül et al.¹ also discuss the potential relevance of these genes (and their associated pathways) for the sporadic forms of vasculitis that they clinically resemble. We would like to provide further comments on the genetic defects associated with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV).

First, although a robust link between AAV and specific genetic disorders (particularly among type I interferonopathies) is emerging, much progress is still needed to better understand the nature of this association². For instance, ANCA specificity and titres are lacking in many studies that describe these conditions, as is their association with specific small vessel vasculitis manifestations (such as alveolar vasculitis and pauci-immune glomerulonephritis). These aspects are indeed crucial to assess the pathogenic value of ANCA (that is, the presence of true AAV), as opposed to an unspecific biological sign of autoimmunity.