The pathogenesis, clinical presentations and treatment of monogenic systemic vasculitis.

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.