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.
Try two board-style Granulomatosis with Polyangiitis (Wegener) and ANCA-Associated Vasculitides questions
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Question 1MusculoskeletalMedium
A 28-year-old female has had 5 episodes of hemoptysis over 3 months, each producing 5-10 mL of bright red blood. She has no cough, dyspnea, fever, or weight loss. She is a non-smoker. CXR is normal. Urinalysis shows 2+ blood with RBC casts. Serum creatinine has risen from 0.8 to 2.4 over 4 months. Proteinase 3 (PR3)-ANCA (c-ANCA) is positive at 1:256. CT chest shows bilateral ground-glass opacities. Which of the following is the most likely diagnosis?
ASystemic lupus erythematosus
BEGPA (Churg-Strauss syndrome)
CGoodpasture syndrome (anti-GBM disease)
DGranulomatosis with polyangiitis
EMicroscopic polyangiitis
Reveal answer & full explanation
Correct answer: D — Granulomatosis with polyangiitis
ASystemic lupus erythematosus
BEGPA (Churg-Strauss syndrome)
CGoodpasture syndrome (anti-GBM disease)
DGranulomatosis with polyangiitis✓
EMicroscopic polyangiitis
Why Granulomatosis with polyangiitis is correct
Granulomatosis with polyangiitis (GPA) is an ANCA-associated small-vessel vasculitis that classically produces a pulmonary-renal syndrome
ANCA patterns: c-ANCA/anti-proteinase 3 (PR3) is positive in 80–90% of GPA (as in this patient at 1:256); p-ANCA/anti-myeloperoxidase (MPO) predominates in microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA)
This patient's positive c-ANCA/PR3, RBC casts with rapidly rising creatinine, and diffuse ground-glass opacities (alveolar hemorrhage) fit GPA over the other pulmonary-renal syndromes
Why the others are wrong
Goodpasture syndrome (anti-GBM disease) — causes a pulmonary-renal syndrome but is driven by anti-GBM antibodies, not c-ANCA/PR3 (confused-with: right syndrome, wrong antibody)
Microscopic polyangiitis — an ANCA-associated vasculitis, but typically p-ANCA/anti-MPO rather than the c-ANCA/PR3 seen here (confused-with: wrong ANCA subtype)
Systemic lupus erythematosus — associated with ANA and anti-dsDNA and an immune-complex (not pauci-immune) glomerulonephritis, not c-ANCA/PR3 (anchoring on young female)
EGPA (Churg-Strauss syndrome) — an ANCA-associated vasculitis whose name overlaps with granulomatosis with polyangiitis, but it is characterized by adult-onset asthma and peripheral eosinophilia, often with nasal polyps and mononeuritis multiplex, and ANCA is present in only about 30 to 40% of patients, usually as p-ANCA/MPO rather than the c-ANCA/PR3 seen here (confused-with: similar name, wrong ANCA subtype)
Induction option 1: rituximab plus high-dose corticosteroids — RAVE trial showed non-inferiority to cyclophosphamide; preferred for fertility preservation, relapsing disease, or ANCA-associated GN
Induction option 2: cyclophosphamide plus high-dose corticosteroids — used for very severe disease (e.g., massive alveolar hemorrhage, rapidly progressive GN)
Plasma exchange: the PEXIVAS trial (2020) showed PLEX did not reduce the primary composite of death or end-stage kidney disease (ESKD), but it still lowers ESKD risk; per KDIGO, PLEX remains recommended for severe renal disease (e.g., creatinine >3.4 mg/dL or dialysis-dependence) or diffuse alveolar hemorrhage
Maintenance therapy: rituximab (e.g., every 6 months for 18–24 months) — the MAINRITSAN trial showed superiority over azathioprine
Question 2MusculoskeletalMedium
A 62-year-old man reports 8 weeks of fatigue, low-grade fevers, and a 12-lb weight loss. He has had persistent bloody nasal crusting, recurrent sinusitis, and a new "collapse" of the bridge of his nose. Over the past week he developed cough with streaky hemoptysis. Vitals: temperature 38.1°C, blood pressure 134/82 mm Hg. Labs show creatinine 2.9 mg/dL (was 1.0 mg/dL three months ago), and urinalysis reveals dysmorphic red blood cells with red blood cell casts. Chest CT shows bilateral cavitary pulmonary nodules. C3 and C4 are normal, and PR3-ANCA (c-ANCA) is positive. Which of the following is the most likely diagnosis?
APolyarteritis nodosa
BChurg-Strauss syndrome
CMicroscopic polyangiitis
DGranulomatosis with polyangiitis
EAnti-glomerular basement membrane disease
Reveal answer & full explanation
Correct answer: D — Granulomatosis with polyangiitis
APolyarteritis nodosa
BChurg-Strauss syndrome
CMicroscopic polyangiitis
DGranulomatosis with polyangiitis✓
EAnti-glomerular basement membrane disease
Why Granulomatosis with polyangiitis is correct
The triad of upper-airway granulomatous disease (chronic sinusitis, bloody nasal crusting, saddle-nose deformity), lower-airway cavitary nodules with hemoptysis, and rapidly progressive glomerulonephritis (rising creatinine, dysmorphic RBCs, RBC casts) is the hallmark of GPA.
GPA is a pauci-immune small-vessel vasculitis, so complement (C3/C4) is characteristically normal, helping exclude immune-complex disease.
PR3-ANCA (c-ANCA) is the typical serology for GPA and strongly supports the diagnosis in this clinical context.
Why the others are wrong
Microscopic polyangiitis is also a pauci-immune RPGN with possible alveolar hemorrhage, but it is MPO-ANCA (p-ANCA) predominant and lacks the granulomatous upper-airway features (saddle-nose, destructive sinusitis) and cavitary nodules seen here.
Anti-glomerular basement membrane disease causes a pulmonary-renal syndrome but is defined by linear IgG on immunofluorescence and circulating anti-GBM antibody; it does not produce chronic destructive sinonasal disease or PR3-ANCA-driven cavitary nodules.
Polyarteritis nodosa is a medium-vessel vasculitis that spares glomeruli (no glomerulonephritis, RBC casts, or lung cavities) and is ANCA-negative, classically showing renal microaneurysms and a hepatitis B association.
Churg-Strauss syndrome — now called eosinophilic granulomatosis with polyangiitis, it is also a granulomatous ANCA-associated vasculitis that can involve the sinuses, lungs, and kidneys, but it is defined by asthma and peripheral eosinophilia, is ANCA-positive in only a minority of patients (usually MPO-ANCA), and causes nasal polyps and transient infiltrates rather than destructive saddle-nose disease and cavitary nodules.
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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
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 at weeks 0, 2, and 4, then every 3 weeks (usually 6-10 pulses; reduce dose for age and GFR <30) (alternative to rituximab)
Plasmapheresis — selective use after PEXIVAS trial (KDIGO 2024: consider for creatinine >3.4 mg/dL, dialysis requirement or rapidly rising creatinine, or alveolar hemorrhage with hypoxemia; routine use not recommended)
Pneumocystis prophylaxis with trimethoprim-sulfamethoxazole during immunosuppression
Non-severe disease (sinus, joint, skin involvement; no active glomerulonephritis or other organ-threatening disease)
Corticosteroids + methotrexate (ACR 2021; avoid with reduced GFR) or rituximab (EULAR 2022) for induction; mycophenolate mofetil is an alternative
Maintenance with the same agent or rituximab
Any active glomerulonephritis is organ-threatening — treat as severe disease with rituximab or cyclophosphamide induction
Severe disease — maintenance after induction remission
Rituximab is the preferred maintenance agent (e.g., 500 mg every 6 months per MAINRITSAN, or 1 g every 4 months per RITAZAREM in relapsing disease)
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 18 months to 4 years after remission (longer with higher relapse risk, e.g., PR3-ANCA or prior relapse)
EGPA
IL-5-targeted biologics — mepolizumab (anti-IL-5) or benralizumab (anti-IL-5 receptor alpha; FDA-approved for EGPA 2024) — particularly effective for asthma and eosinophilic features and steroid sparing
Cyclophosphamide or rituximab for severe organ involvement (cardiac, renal, neuro)
High-dose corticosteroids for induction
Second-line / adjunct
Intravenous immunoglobulin (IVIG) for refractory disease
Kidney transplantation for ESKD — delay until complete clinical remission for ≥6 months; persistent ANCA positivity alone should not delay transplant
Complications
ESKD (~25% within 5 years of severe renal involvement)
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 2024 — KDIGO 2024 Clinical Practice Guideline for the Management of Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (Kidney Int 2024;105(3S):S71-S116)
ACR/EULAR 2022 — Robson JC et al. 2022 ACR/EULAR Classification Criteria for Granulomatosis With Polyangiitis (Arthritis Rheumatol 2022;74:393-399); companion criteria for MPA (Suppiah R et al. 2022;74:400-406) and EGPA (Grayson PC et al. 2022;74:386-392)
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)
ACR/VF 2021 — Chung SA et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis (Arthritis Rheumatol 2021;73:1366-1383)
EULAR 2022 — Hellmich B et al. EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update (Ann Rheum Dis 2024;83:30-47)
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