Renal/Urology · PANCE / PANRE

Granulomatosis with Polyangiitis (Wegener) and ANCA-Associated Vasculitides

Pauci-immune small-vessel vasculitis (GPA, MPA, EGPA) presenting with RPGN and multisystem disease.

Also known as: GPA, Wegener granulomatosis, MPA, microscopic polyangiitis, EGPA, Churg-Strauss, ANCA-associated vasculitis, AAV, pauci-immune GN

Overview

A group of small-vessel vasculitides characterized by necrotizing inflammation of small to medium vessels with few or no immune deposits on biopsy (pauci-immune). Three syndromes per the 2012 Chapel Hill nomenclature: granulomatosis with polyangiitis (GPA, formerly Wegener), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss). Most patients have ANCA against either proteinase 3 (PR3-ANCA, c-ANCA) or myeloperoxidase (MPO-ANCA, p-ANCA).

Epidemiology

Incidence ~20 per million per year combined. GPA more common in Northern Europe and North America; MPA more common in Southern Europe and Asia. Peak age 65-75; slight male predominance. EGPA is rarer (~1-3 per million) and associated with asthma and eosinophilia.

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Risk factors

Age >50
Genetic: HLA-DPB1*0401 (GPA), HLA-DQ (MPA)
Silica exposure, farming dust
Drugs: hydralazine, propylthiouracil, minocycline, levamisole-adulterated cocaine
Chronic nasal carriage of Staphylococcus aureus (GPA)
Pre-existing asthma and eosinophilia (EGPA)

Pathophysiology

Loss of tolerance to neutrophil cytoplasmic antigens (PR3 or MPO) generates pathogenic ANCA. ANCA binds primed neutrophils, causing degranulation, reactive oxygen species, and release of neutrophil extracellular traps (NETs) that damage endothelium. The end result is necrotizing inflammation of arterioles, capillaries, and venules. GPA additionally features granulomatous inflammation of the upper and lower respiratory tract; EGPA features eosinophilic tissue infiltration and asthma.

Clinical presentation

Symptoms

Constitutional: weeks-to-months of fever, weight loss, fatigue, arthralgia, myalgia
GPA upper airway: sinusitis, epistaxis, nasal crusting, saddle-nose deformity, subglottic stenosis, otitis media, hearing loss
GPA/MPA lower airway: cough, hemoptysis, pulmonary infiltrates or cavitary nodules, alveolar hemorrhage
EGPA: asthma (often poorly controlled), allergic rhinitis, eosinophilic pneumonia
Renal: hematuria, proteinuria, rapidly rising creatinine — features of RPGN
Skin: palpable purpura, ulcers, livedo
Nervous system: mononeuritis multiplex (especially EGPA), CNS involvement (rare)
Eye: scleritis, episcleritis, retro-orbital pseudotumor (GPA)

Signs / physical exam

Saddle-nose deformity, septal perforation (GPA)
Purpura, nailfold infarcts
Diffuse pulmonary crackles, sometimes hemoptysis
Foot drop or wrist drop (mononeuritis multiplex)
Hypertension less common than in other GN syndromes

Classic findings

Triad of upper airway disease + pulmonary cavitary nodules + necrotizing crescentic GN suggests GPA. Asthma + peripheral eosinophilia + pulmonary infiltrates + mononeuritis multiplex suggests EGPA.

Differential diagnosis

Anti-GBM disease — Linear IgG on IF, anti-GBM antibody, often pulmonary hemorrhage; may coexist with ANCA
Lupus nephritis — Full-house IF, positive ANA/anti-dsDNA, low complement
IgA vasculitis (Henoch-Schönlein) — Palpable purpura, abdominal pain, mesangial IgA on biopsy
Polyarteritis nodosa — Medium-vessel vasculitis without GN; aneurysms on angiography; associated with HBV
Cryoglobulinemic vasculitis — Palpable purpura, low C4, positive cryoglobulins; often HCV-associated
Endocarditis with immune-complex GN — Fever, murmur, low complement, positive blood cultures; echocardiogram diagnostic
Drug-induced AAV — Hydralazine, propylthiouracil, minocycline, levamisole-cocaine — high-titer MPO-ANCA and often anti-elastase

Diagnostic workup

Diagnostic criteria

ACR/EULAR 2022 classification criteria distinguish GPA, MPA, and EGPA using weighted clinical, laboratory, and biopsy features. Histologic confirmation: kidney biopsy showing pauci-immune necrotizing crescentic GN; lung or upper airway biopsy showing necrotizing granulomas with vasculitis (GPA) or eosinophilic vasculitis with granulomas (EGPA).

Labs

ANCA — PR3-ANCA (c-ANCA, GPA predominant) and MPO-ANCA (p-ANCA, MPA and EGPA predominant); ELISA preferred over IF
CBC (anemia of inflammation; marked eosinophilia in EGPA), CMP, ESR/CRP (markedly elevated)
UA with microscopy (dysmorphic RBCs, RBC casts), UPCR or 24-hour protein
Complement C3/C4 (typically normal — distinguishes from immune-complex GN)
Anti-GBM antibody (always check — ~30% of anti-GBM patients are dual-positive)
Hepatitis B, hepatitis C, HIV, blood cultures (exclude endocarditis), cryoglobulins
IgG, IgA, IgE (elevated IgE in EGPA), tryptase
TB screening before immunosuppression

Imaging

Chest CT — cavitary nodules (GPA), ground-glass opacities (alveolar hemorrhage in MPA), migratory infiltrates (EGPA)
Sinus CT for GPA upper airway disease
Echocardiogram if cardiac involvement (EGPA myocarditis, endocarditis exclusion)

Diagnostic algorithm

Feature	GPA (Wegener)	MPA	EGPA (Churg-Strauss)
Predominant ANCA	PR3 (c-ANCA) ~75%	MPO (p-ANCA) ~60%	MPO (p-ANCA) ~40%
Upper airway	Yes — sinusitis, saddle nose, subglottic stenosis	Rare	Allergic rhinitis, nasal polyps
Asthma / eosinophilia	No	No	Yes (defining)
Granulomas on biopsy	Yes	No	Yes (eosinophilic)
Renal involvement	Common (RPGN)	Most common (RPGN)	Less common
Cardiac	Uncommon	Uncommon	Common — leading cause of death
Treatment cornerstone	Steroids + rituximab or CYC; avacopan	Same as GPA	Steroids + mepolizumab; CYC/RTX for severe

Comparative features of the three ANCA-associated vasculitides.

Treatment

First-line

Severe organ-threatening disease (RPGN, alveolar hemorrhage, mononeuritis multiplex) — induction with corticosteroids + cyclophosphamide OR rituximab
IV methylprednisolone pulse (500-1000 mg × 3 days) followed by oral prednisone 1 mg/kg/day taper
Rituximab 375 mg/m² weekly × 4 OR 1000 mg × 2 (preferred for relapsing disease, PR3-ANCA, and younger patients)
Cyclophosphamide IV pulse 15 mg/kg q2-3 weeks × 3-6 doses (alternative to rituximab)
Plasmapheresis — selective use after PEXIVAS trial (consider in severe pulmonary hemorrhage or creatinine >5.7 mg/dL; routine use not recommended)
Avacopan (C5a receptor antagonist) — adjunct that reduces steroid exposure (ADVOCATE trial)
Pneumocystis prophylaxis with trimethoprim-sulfamethoxazole during immunosuppression

Non-severe disease (mild renal, sinus, joint, skin involvement)

Methotrexate or mycophenolate mofetil + corticosteroids for induction
Maintenance with the same agent or rituximab

Severe disease — maintenance after induction remission

Rituximab every 6 months for ≥4 years (preferred per MAINRITSAN, RITAZAREM trials)
Azathioprine 2 mg/kg/day or methotrexate 20-25 mg weekly are alternatives
Taper prednisone to ≤5 mg/day by 6 months; consider full discontinuation with avacopan
Continue maintenance for at least 24-48 months

EGPA

Mepolizumab (anti-IL-5) is approved for EGPA — particularly effective for asthma and eosinophilic features
Cyclophosphamide or rituximab for severe organ involvement (cardiac, renal, neuro)
High-dose corticosteroids for induction

Second-line / adjunct

Intravenous immunoglobulin (IVIG) for refractory disease
Belimumab as adjunct (limited data)
Kidney transplantation for ESKD — generally safe once disease quiescent for >12 months

Complications

ESKD (~25% within 5 years of severe renal involvement)
Subglottic stenosis (GPA) requiring tracheal dilation
Pulmonary fibrosis, recurrent infections
Cardiac (EGPA): cardiomyopathy, pericarditis — leading cause of EGPA mortality
Mononeuritis multiplex with persistent neurologic deficits
Cyclophosphamide-related: gonadal toxicity, hemorrhagic cystitis, bladder cancer, secondary malignancies
Opportunistic infections from chronic immunosuppression

PANCE pearls

PR3-ANCA → think GPA (Wegener); MPO-ANCA → think MPA or EGPA; both can overlap.
Saddle-nose deformity, subglottic stenosis, and cavitary lung nodules are GPA hallmarks.
Asthma + eosinophilia + mononeuritis multiplex = think EGPA.
Rituximab is non-inferior to cyclophosphamide for induction (RAVE, RITUXVAS) and preferred for relapsing, PR3-ANCA, or fertility-concern patients.
Avacopan permits dramatic steroid reduction without losing efficacy (ADVOCATE trial).
Drug-induced AAV (hydralazine, PTU, levamisole-cocaine) usually resolves with drug withdrawal — search for it.

References

Chapel Hill 2012 — Jennette JC et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (Arthritis Rheum 2013;65:1-11)
KDIGO 2021 — KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases (Kidney Int 2021;100:S1-S276)
ACR/EULAR 2022 — ACR/EULAR 2022 Classification Criteria for ANCA-Associated Vasculitis (Arthritis Rheumatol 2022)
PEXIVAS — Walsh M et al. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis (NEJM 2020;382:622-631)
ADVOCATE — Jayne DRW et al. Avacopan for the treatment of ANCA-associated vasculitis (NEJM 2021;384:599-609)
RAVE — Stone JH et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis (NEJM 2010;363:221-232)

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