Extrarenal disease in ANCA-associated vasculitis: challenges and evolving therapeutic strategies on behalf of the Immunonephrology Working Group (IWG) of the ERA

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are systemic small-vessel necrotizing vasculitides, including microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Genetic factors, particularly human leukocyte antigen (HLA) variants, contribute to disease susceptibility and define distinct myeloperoxidase (MPO) and proteinase-3 (PR3) associated phenotypes. This review summarizes current understanding of organ-specific manifestations, therapeutic advances, and prognostic determinants of AAV, with particular relevance for nephrologists. Kidney involvement is common, particularly in MPA, whereas GPA and EGPA more frequently present with extrarenal manifestations. Pulmonary involvement is also frequent, ranging from alveolar haemorrhage and interstitial lung disease (ILD) in MPA to granulomatous nodules and airway disease in GPA, while asthma dominates in EGPA. Other frequent manifestations include ear, nose and throat (ENT), peripheral nervous system, cutaneous, and constitutional manifestations, with ENT activity and non-haemorrhagic respiratory manifestations correlating with relapse risk. Current treatment emphasizes rituximab or cyclophosphamide with reduced-dose glucocorticoids for induction, avacopan for glucocorticoid-sparing strategies, and rituximab for maintenance. Avacopan has shown benefits beyond renal outcomes. Furthermore, anti-interleukin-5 therapies have recently been approved for the treatment of EGPA. Contrarily, ILD remains a therapeutic challenge, with limited evidence for antifibrotic agents. AAV patients are at high risk of infections, thromboembolism, and malignancy, influenced by both disease activity and treatment exposure. Mortality remains high, driven mainly by infections, with kidney and lung involvement serving as major prognostic determinants. For nephrologists, early recognition of extrarenal manifestations, vigilance for relapse beyond the kidney, and multidisciplinary collaboration are crucial for optimizing long-term outcomes.