The emerging concept of ANCA-associated vasculitis related to inborn errors of immunity

ANCA-associated vasculitis (AAV) is a group of rare small vessels vasculitis that preferentially affect the kidneys, lungs and upper airways. Although the detailed pathophysiology remains unclear, genetic background has been shown to play a role in sporadic forms of AAV. The discovery of these susceptibility genes (and associated biological pathways) involved in AAV have shaped the current understanding of AAV pathophysiology. In addition to common genetic polymorphisms, specific rare inborn errors of immunity (IEI) have been described with a high frequency of ANCA (antineutrophil cytoplasmic antibodies) positivity and vasculitis features in young individuals (in addition to other manifestations). A systematic literature search revealed that patients with pathogenic variants in COPA, STING1, DNASE1L3, and PIK3CD are at increased risk of developing ANCA and AAV features, including alveolar hemorrhage, interstitial lung disease, pauciimmune glomerulonephritis, and upper airways involvement (septum perforation, saddle-nose deformity, chronic nasal/sinuses ulceration). Some of these IEI may also present with a mixed phenotype and/or auto-antibodies profile associating features of AAV and other autoimmune diseases (in particular systemic lupus erythematosus). Notably, a proportion of reports and series lack serological (ANCA specificity and titers) and/or histopathological data, making challenging to assess the likelihood for ANCA pathogenicity in some patients with IEI (as opposed to unspecific signs of biologic autoimmunity). This point is nonetheless essential to make appropriate therapeutic decisions. In addition, since most of the genes mentioned above are involved in the type 1 interferon signaling, the role of this pathway in AAV etiopathogenesis deserves further investigation. In this review, we will describe these IEI, their overlap with sporadic AAV, and their evocative features. Next, we will discuss how these monogenic conditions might inform our general understanding of AAV pathophysiology. We also propose some directions for future research in order to better define the link between ANCA and IEI. Finally, we will consider how making the diagnosis of an IEI in a patient with AAV features might impact individual management. Schematic clinical approach to the diagnosis and management of inborn errors of immunity with a presentation of ANCA-associated vasculitis (created with biorender.com ). Abbreviations: AAV: ANCA-associated vasculitis; ANCA: Antineutrophil cytoplasmic antibodies; COPA: Coatomer protein complex subunit α; DNASE1l3: Deoxyribonuclease 1 L3; IAH: Intra-alveolar hemorrhage; IFN: Interferon; ILD: Interstitial lung disease; JIA: Juvenile idiopathic arthritis; MPO: Myeloperoxidase; PIK3CD: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic Subunit Delta; PR3: Proteinase 3; SAVI: STING-associated vasculopathy with onset in infancy; SLE: Systemic lupus erythematosus • Increased risk of AAV has been identified in specific rare inborn errors of immunity (IEI). • The identification of monogenic forms of AAV has opened new research avenues to study AAV. • Sporadic and monogenic forms of AAV display both similarities and differences; some clues should prompt testing for IEI. • Diagnosing an IEI in a patient with AAV-like phenotype will impact the individual management.