In this episode of Hospital Medicine Unplugged, we break down ANCA-associated vasculitis (AAV)—granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA)—focusing on modern epidemiology, complement-driven pathophysiology, ANCA serotypes, and the rapidly evolving treatment landscape.

We start with epidemiology clinicians should recognize. The global incidence of AAV is ~17 per million person-years, with a prevalence near 198 per million. In the United States, incidence is roughly 3.3 per 100,000, with a prevalence of ~42 per 100,000. Subtype incidence varies: GPA (~9–15/million), MPA (~6/million), and EGPA (~2/million). The mean age at diagnosis is about 61, and rates have increased over the past decades due to greater recognition and widespread ANCA testing.

Next we unpack the pathophysiology that changed therapy. Complement activation—particularly the alternative pathway—plays a central role. C5a drives neutrophil activation and recruitment, creating an inflammatory amplification loop. Low C3 levels correlate with more aggressive disease and worse renal outcomes. This mechanistic insight led to avacopan, an oral C5a receptor antagonist that provides a glucocorticoid-sparing approach to treatment.

We then highlight the importance of ANCA serotype classification. Patients are increasingly categorized by PR3-ANCA vs MPO-ANCA, not just clinical phenotype. • PR3-ANCA disease is more often GPA, with ENT involvement, pulmonary nodules, and higher relapse risk. • MPO-ANCA disease more often presents as MPA, with renal-limited disease, interstitial lung disease, and higher mortality.

We also review EGPA as a distinct entity. Only ~40% of patients are ANCA-positive. Two clinical subsets exist: • ANCA-positive EGPA → vasculitic manifestations such as glomerulonephritis and neuropathy • ANCA-negative EGPA → eosinophilic disease with pulmonary infiltrates and cardiomyopathy Asthma is a defining feature, and cardiac involvement is a major driver of mortality.

Diagnosis relies on modern ANCA testing and organ evaluation. PR3- and MPO-specific immunoassays are now the preferred screening tests, with ~90–95% sensitivity for active GPA/MPA and >95% specificity. Renal disease occurs in 70–80% of GPA/MPA, typically as pauci-immune necrotizing crescentic glomerulonephritis, while pulmonary disease ranges from nodules and cavitation (PR3) to interstitial lung disease (MPO) and diffuse alveolar hemorrhage.

Management has evolved dramatically. First-line induction therapy combines glucocorticoids with rituximab or cyclophosphamide, with rituximab preferred for most patients—especially PR3-ANCA or relapsing disease. Reduced-dose steroid regimens are now recommended after trials like PEXIVAS, which showed lower infection risk without worse renal outcomes.

We also cover key modern therapies. • Avacopan, a C5a receptor antagonist, improves sustained remission and kidney recovery while reducing steroid exposure. • Plasma exchange remains controversial after the PEXIVAS trial, but may still be considered in severe kidney failure, dialysis-dependent disease, or diffuse alveolar hemorrhage.

For maintenance therapy, rituximab is now the preferred agent, outperforming azathioprine in major trials such as MAINRITSAN and RITAZAREM. Maintenance typically continues 2–4 years, especially in PR3-ANCA patients with high relapse risk.

We finish with EGPA-specific treatment advances. IL-5 pathway inhibitors have transformed care, including mepolizumab and the newer benralizumab, which improve remission rates and allow significant glucocorticoid reduction.

The bottom line: AAV management has shifted toward precision medicine—ANCA serotype classification, complement-targeted therapy, steroid-sparing strategies, and biologic maintenance treatments—dramatically improving survival and long-term outcomes.