Granuloma in ANCA-associated vasculitides: another reason to distinguish between syndromes?

The 2012 renewed Chapel Hill Consensus Conference (CHCC) officially named three clinicopathological entities, i.e. granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis (MPA), as major variants of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). Recent genetic and cohort studies revealed the need for further differentiation between the entities, for example regarding differences in outcome. As well as ANCA reactivity, upper and lower airway disease were found to be differentiating factors for AAV variants, improving prognostic ability regarding relapse prediction and associated clinical features. Extravascular granulomatosis, or "granuloma", which describes both clinically relevant granulomatous manifestations and histopathologically documented granulomatous inflammation, is characteristic of localized and systemic GPA, but not MPA. This review summarizes new knowledge regarding granuloma in the head and neck region of AAV, its histomorphological equivalents in the upper and lower respiratory tract, and evidence for a granulomatous phenotype of a persistent localized GPA variant. This comprises the development of disease activity and damage scores for extravascular lesions in the ear, nose, and throat (ENT) regions, and imaging techniques. In addition, findings linking extravascular manifestations to granulomatous inflammation are described. We hypothesize that, as for ANCA, necrotizing granulomatous inflammation and its clinical manifestations are discriminators, assisting subclassification of AAV and/or GPA subphenotypes which will be useful both for designing clinical trials and for treating patients successfully.