Antineutrophil cytoplasmic antibody (ANCA)‐associated vasculitis (AAV) encompasses a group of rare, multisystem diseases that are characterised by necrotising inflammation of small blood vessels, typically accompanied by an ANCA in the serum directed against the autoantigens myeloperoxidase (MPO) or proteinase‐3 (PR3). The aetiology of AAV remains incompletely understood, but evidence suggests a complex interplay between genetic predisposition and environmental factors. Genetic associations are strongest according to the antigen‐ANCA specificity (i.e., MPO‐ANCA or PR3‐ANCA) and the clinical syndrome (i.e., granulomatosis with polyangiitis GPA or microscopic polyangiitis MPA). Familial occurrences of AAV are exceedingly rare and typically involve concordant ANCA specificities and clinical syndromes. We report an unusual case of two biological sisters presenting with distinct AAV syndromes and differing ANCA specificities. The elder sister, in her fifties, was diagnosed with PR3‐ANCA‐positive GPA manifesting with pulmonary fibrosis, sinusitis, and renal involvement. The younger sister, presenting in her forties, was diagnosed with MPO‐ANCA‐positive MPA, predominantly affecting the kidneys. The elder sister declined to receive guideline‐directed immunosuppressive therapies and died 30 months postdiagnosis, whilst the younger sister responded well to cyclophosphamide‐based induction therapy and remains in remission over 5 years later. This familial discordance in ANCA specificity and clinical phenotype is highly unexpected and underscores the complexity of AAV pathogenesis. Despite thorough evaluation, no shared predisposition was identified, highlighting the potential for other, as yet undiscovered triggers. Our report highlights the need for timely, guideline‐directed immunosuppressive treatment in cases of AAV to improve outcomes. Furthermore, it emphasises gaps in current aetiological understanding, and advocates for continued research into the mechanisms underpinning these diseases as a way to identify potential future therapeutic targets.
Letts et al. (Thu,) studied this question.