Granulomatosis with polyangiitis

The aetiology of granulomatosis with polyangiitis (GPA) (formerly known as Wegener's granulomatosis) is poorly understood.[13] A non-infectious immune aetiology has been proposed based on a number of factors:

the presence of anti-neutrophil cytoplasmic antibodies (ANCA) in most cases
supportive in vitro findings
a lack of evidence to suggest a causative infectious agent
association with other autoimmune diseases (especially autoimmune thyroid disease)
response to immunosuppressive therapy.

Although the risk of GPA in first-degree relatives is low overall, genetic factors are nonetheless likely to be important.[14] A genome-wide association study demonstrated an association between antiproteinase 3 ANCA and HLA-DP, alpha-1-antitrypsin, and proteinase 3.[15] Silica, heavy metals, and other chemicals have been proposed as potential environmental triggers, but no links have been definitively proven.[16] Annual fluctuation and seasonal variations in disease incidence suggest a potential role for infection in triggering onset, but these observations have not been consistent across studies and specific infectious triggers have not yet been identified.[16] Although nasal carriage of Staphylococcus aureus may be a risk factor for disease relapse in patients with established GPA, eradication of S aureus has not been clearly shown to reduce the risk of relapse.[17]

GPA typically targets small to medium-size arteries and arterioles. Granulomatous inflammation and vasculitis are the histopathological hallmarks of the disease. Frank granuloma formation may be seen. Necrotising inflammation is typical; when necrosis is present over a large confluent area (typically seen on open lung biopsy), it may be described as geographic necrosis. Immunofluorescence and electron microscopy of affected tissues typically reveal few or no immune deposits; in the kidney this is referred to as pauci-immune glomerulonephritis. This feature helps distinguish GPA from other systemic inflammatory disorders such as systemic lupus erythematosus (SLE) and infective endocarditis, where immune complex deposition is expected.

The association of anti-neutrophil cytoplasmic antibodies (ANCA) with GPA has been noted for more than 20 years.[18] There is some evidence to suggest that ANCA may be involved in disease pathogenesis, although this has not been clearly established.[13] The specific immune system has also been implicated: T cells are involved in granuloma formation and maintenance, and autoreactive PR3-specific T cells have been described.[19] The reported efficacy of B-cell depletion therapy with rituximab suggests that B cells may play a key role in disease pathogenesis. Relevant effects of B cells in this context include cytokine production, antigen presentation, and ANCA production.[20]

Clinical classification

There is no accepted formal classification of disease subtypes validated in clinical practice. Differentiation of patients with systemic and limited disease based on the presence or absence of renal involvement can be misleading, as a majority of patients who initially appear to have limited GPA subsequently develop renal disease during the course of their disease. Consequently, these terms are best avoided.

Pathophysiology

Classification

Clinical classification