ANCA-Associated Vasculitides: Granulomatosis with Polyangiitis and Microscopic Polyangiitis
Andre C. Teixeira, M.D.
Fabio R. Tavora, M.D., Ph.D.
Marie-Christine Aubry, M.D.
Introduction and Terminology
ANCA-associated vasculitides (AAV) are considered necrotizing vasculitides, with few or no immune deposits, predominantly affecting small vessels (capillaries, venules, arterioles, and small arteries), characterized by circulating antibodies, the antineutrophil cytoplasmic antibodies (ANCAs). They are further classified as granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis [WG]), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome) (Chapter 49).
Since the first descriptions by Godman and Churg,1,2 vasculitides have been classified by the caliber of the vessel involved. In 1990, the American College of Rheumatology (ACR) criteria assigned a new classification to most patients, but there was an unacceptable degree of overlap between the entities.3,4 These criteria were amended in 1994 by the Chapel Hill Consensus Conference, which restricted WG to those with granulomatous inflammation, included ANCAs, and introduced MPA as a novel category.5 A further change to the nomenclature of AAV occurred in 2012, following a second Chapel Hill Consensus Conference.6 Eponyms were replaced where possible with terms consistent with the known pathophysiology of each condition; hence, WG was renamed GPA.7
GPA is defined as a necrotizing granulomatous inflammation of the upper and lower respiratory tract, with necrotizing vasculitis of smalland medium-sized vessels. Necrotizing glomerulonephritis is common, but it is not essential for the diagnosis. According to the current criteria of the ACR, GPA is defined by the presence of at least two of the following four criteria: sinus involvement, lung x-ray showing nodules, a fixed pulmonary infiltrate or cavities, urinary sediment with hematuria or red cell casts, and histologic granulomas within an artery or in the perivascular area of an artery or arteriole. MPA is a necrotizing vasculitis, with few or no immune deposits, predominantly affecting small vessels. Necrotizing arteritis involving small and medium arteries may be present.8 Necrotizing glomerulonephritis is very common, and pulmonary capillaritis often occurs, but granulomatous inflammation is usually absent.
Etiology and Pathogenesis
The causes of AAV are unknown, and multiple factors play a role in its pathogenesis. AAV have a higher prevalence among the Chinese and Japanese populations.9 Familial AAV has been described and, while a putative hereditary factor has never been demonstrated, studies have indicated some genes related to disease susceptibility such as SERPINA-1 and PRTN-3.9,10 Single nucleotide polymorphisms in the major histocompatibility complex have also been reported. Several environmental factors probably related to AAV are deficiency of vitamin D, infections, silica exposure, and cocaine use.11,12,13
AAV is characterized by pauci-immune vascular inflammation, in which immunoglobulin deposition cannot be detected, and circulation of ANCAs is present. The proposed role for ANCA is of indirect recruitment of an autoinflammatory response.10 There is increasing evidence of other factors involved in AAV pathogenesis, like complement factors and T cells. By indirect immunofluorescence, two wellrecognized staining patterns of ANCA tend to show associations with specific diseases. In active GPA, the majority of ANCA demonstrates a cytoplasmic pattern (c-ANCA), although 5% to 20% of ANCA may exhibit a perinuclear pattern (p-ANCA). In MPA, the staining pattern tends to be perinuclear. The target antigen of c-ANCA is antiproteinase 3 (PR3-ANCA), a constituent of the azurophilic granules, and of p-ANCA, antimyeloperoxidase (MPO-ANCA).
Granulomatosis with Polyangiitis
Incidence, Clinical and Radiologic Findings
GPA is approximately twice as common as MPA. The age at diagnosis is between 45 and 60 years, and men and women are affected with similar frequency. The incidence of GPA has been evaluated between 7 and 12 new cases per million inhabitants per year.14 Constitutional signs (fever, asthenia, weight loss) are frequent (50%) but nonspecific. Sinonasal involvement is the most common manifestation of GPA. Ear, nose, and throat symptoms and signs are present in 70% to 100% of cases at diagnosis. Lung involvement affects 50% to 90% of patients, sometimes associated with tracheal and subglottic stenosis (16%).15 The most typical form of renal involvement is focal segmental necrotizing glomerulonephritis without deposition of immune complexes. The peripheral nervous system is affected in about one-third of patients, characterized by sensorimotor neuropathy. Other common sites of involvement are skin (10% to 50%), eyes (14% to 60%), heart (<10%), and gastrointestinal tract (5% to 11%). GPA may also be limited to the lungs with no other organ involvement and usually associated with a negative ANCA.16
The most common radiologic patterns of GPA include multiple angiocentric nodules or masses, frequently cavitated and associated with signs of hemorrhage as random alveolar opacities and pneumonic condensations. Pulmonary fibrosis and pleural involvement occur less commonly but can be present.
Histopathology
The classic histologic picture of GPA consists of necrotizing granulomatous inflammation accompanied by necrotizing vasculitis. The necrotic areas are usually irregular in contour, so-called geographic, with a basophilic “dirty” appearance due to the nuclear debris of the necrotic neutrophils (Fig. 48.1). The necrotic areas are surrounded by palisading epithelioid histiocytes and typically include multinucleated giant cells (Fig. 48.1). The multinucleated giant cells are often scattered in the inflammatory background. They have a distinctive appearance due to their hyperchromatic nuclei and thus easily recognizable even at low power. Background interstitial fibrosis and nonspecific chronic inflammation are typically present.
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