Granulomatosis with Polyangiitis (GPA)

  1. Overview and History
  2. Pathogenesis and ANCA Immunology
  3. Classic Triad: Upper Respiratory Tract
  4. Classic Triad: Lower Respiratory Tract and Kidneys
  5. Additional Organ Involvement
  6. Diagnosis
  7. Treatment: Induction and Remission
  8. Prognosis and Monitoring
  9. Featured Videos

Overview and History

Granulomatosis with Polyangiitis (GPA) was formerly called Wegener's granulomatosis. The eponym was officially retired in 2011 by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) following research into Friedrich Wegener's documented Nazi Party membership and activities during World War II. The current descriptive name better reflects the pathology of the disease.

GPA is one of the three major ANCA-associated vasculitides (AAV), alongside Microscopic Polyangiitis (MPA) and Eosinophilic Granulomatosis with Polyangiitis (EGPA). Its defining hallmarks are granulomatous inflammation and necrotizing vasculitis that primarily targets the upper respiratory tract, lower respiratory tract, and kidneys — the classic clinical triad.

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Pathogenesis and ANCA Immunology

The disease is driven by anti-neutrophil cytoplasmic antibodies targeting proteinase 3 (PR3), producing a characteristic c-ANCA pattern on indirect immunofluorescence (IIF). Anti-PR3 ANCA is detected in 80–90% of patients with active generalized GPA and is the dominant autoantibody; anti-MPO ANCA accounts for the remaining minority.

The two-hit model of ANCA-mediated vasculitis explains how these antibodies damage blood vessels:

  1. Priming (first hit): Pro-inflammatory cytokines (IL-8, TNF-α) — released during infections or other stimuli — cause neutrophils to translocate PR3 and MPO from intracellular granules to the cell surface, making them accessible to circulating ANCA.
  2. ANCA activation (second hit): ANCA binds surface-expressed PR3, activating primed neutrophils. Activated neutrophils adhere to vascular endothelium, degranulate, and release reactive oxygen species (ROS) and pro-inflammatory cytokines. This cascade produces vessel wall necrosis and tissue destruction characteristic of vasculitis.

The C5a–C5aR axis amplifies neutrophil priming through complement activation, providing the mechanistic rationale for avacopan, a selective C5a receptor (C5aR) antagonist approved for treatment.

Granuloma formation is mechanistically distinct from ANCA-mediated vasculitis. CD4+ Th1 and Th17 cells aggregate around areas of necrosis in the airways, forming the granulomas that give the disease its name. This T-cell-driven mechanism is particularly important in the upper respiratory tract and explains why B-cell depletion with rituximab does not fully prevent granulomatous relapse at these sites.

Nasal colonization with Staphylococcus aureus is an established trigger for disease relapse, likely through superantigen-driven polyclonal T-cell activation. Eradication with trimethoprim-sulfamethoxazole (TMP-SMX) reduces relapse risk and is part of standard maintenance management.

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Classic Triad: Upper Respiratory Tract

Upper respiratory tract involvement is the presenting feature in the majority of GPA patients and is often mistaken for recurrent sinusitis or chronic rhinitis before the diagnosis is established. The destructive, treatment-resistant nature of these symptoms distinguishes GPA from common infections.

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Classic Triad: Lower Respiratory Tract and Kidneys

Pulmonary and renal involvement define the severity spectrum of GPA. Together with upper respiratory disease, they form the classic triad and account for the bulk of early mortality when untreated.

Pulmonary Manifestations

Renal Manifestations: Rapidly Progressive Glomerulonephritis (RPGN)

Renal disease in GPA takes the form of pauci-immune crescentic glomerulonephritis — so named because immunofluorescence of kidney biopsy specimens shows few or no immune complex deposits (in contrast to the full-house immunofluorescence of lupus nephritis or the linear IgG of anti-GBM disease). Despite the absence of deposited immune complexes, ANCA-mediated neutrophil activation produces severe fibrinoid necrosis and crescent formation.

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Additional Organ Involvement

While the upper respiratory tract, lungs, and kidneys define the classic triad, GPA can involve virtually any organ system. Recognizing these additional manifestations is critical for diagnosis, particularly in atypical or limited presentations.

Eyes (15–50% of patients)

Nervous System

Skin

Joints

Arthralgia and non-erosive migratory arthritis occur in up to 50% of patients, often as an early or prodromal feature before the diagnosis is established.

Disease Severity Classification

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Diagnosis

Diagnosis requires integrating clinical features, ANCA serology, imaging, urinalysis, and — whenever possible — tissue biopsy. No single test is sufficient.

ANCA Serology

Biopsy (Gold Standard)

Urinalysis

Urinalysis with microscopy is mandatory at diagnosis and during follow-up. Hematuria with RBC casts indicates active glomerulonephritis and demands urgent evaluation regardless of creatinine level.

Imaging

Classification Criteria

The 2022 ACR/EULAR classification criteria for GPA use a points-based system incorporating nasal/sinus findings, pulmonary nodules/cavities, renal histology, ANCA pattern, and biopsy findings. These criteria are designed for classification in research contexts, not as diagnostic criteria for individual patients.

Differential Diagnosis

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Treatment: Induction and Remission

Treatment is divided into two phases: induction (achieving remission rapidly to prevent organ damage) and maintenance (sustaining remission while minimizing cumulative drug toxicity). The approach depends on disease severity.

Induction of Remission — Severe/Organ-Threatening Disease

Avacopan (Adjunct to Induction)

Avacopan (30 mg orally twice daily), a selective C5aR antagonist, received FDA approval in October 2021 for GPA and MPA. The ADVOCATE trial (Jayne et al., NEJM 2021) demonstrated non-inferiority to prednisone at week 26 and superiority at week 52, with a significantly reduced cumulative glucocorticoid burden. Avacopan is used as an adjunct to rituximab or cyclophosphamide, not as monotherapy.

Maintenance of Remission

Plasma Exchange — No Longer Routinely Recommended

The PEXIVAS trial (Walsh et al., NEJM 2020) found that adding plasma exchange to standard immunosuppression provided no benefit in reducing the composite endpoint of ESRD or death in severe ANCA-associated vasculitis with RPGN. Plasma exchange is no longer recommended as routine adjunctive therapy, though individual clinical judgment applies in extreme presentations.

TMP-SMX

Trimethoprim-sulfamethoxazole (TMP-SMX) serves dual roles: (1) eradicating nasal S. aureus carriage to reduce relapse risk, and (2) prophylaxis against Pneumocystis jirovecii pneumonia (PCP) during immunosuppression. It is appropriate for limited disease/maintenance and mandatory as PCP prophylaxis during induction-phase immunosuppression.

Subglottic Stenosis

Subglottic stenosis often requires ENT-directed intervention independent of systemic immunosuppression, because the stenosis reflects fibrotic scarring rather than active vasculitis. Intralesional triamcinolone injection with sequential balloon dilation is the standard approach; tracheostomy may be required for critical airway narrowing.

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Prognosis and Monitoring

Modern immunosuppression achieves complete remission in 75–90% of patients, transforming what was once a rapidly fatal disease into a manageable — though relapsing — chronic illness.

Relapse

Relapse rates remain high: 50–70% of patients experience at least one relapse over 5 years. Anti-PR3 ANCA positivity is a stronger predictor of relapse than anti-MPO positivity, reflecting the granuloma-forming tendency of GPA that persists even with B-cell depletion. ANCA titers correlate with disease activity and should be monitored every 3 months in the first year; a rising titer warrants clinical reassessment for subclinical relapse.

Damage Accrual

Even with effective treatment, GPA causes cumulative organ damage: chronic sinusitis and nasal deformity, conductive or sensorineural hearing loss, renal insufficiency from prior RPGN, peripheral neuropathy, and subglottic scarring. The VDI (Vasculitis Damage Index) is used in clinical research to quantify this accrued damage.

Infection

Infection is the leading cause of early mortality in GPA patients. Heavy immunosuppression during induction creates vulnerability to PCP, invasive fungal infections, and bacterial sepsis. PCP prophylaxis with TMP-SMX (or atovaquone/dapsone if sulfa-allergic) is mandatory during cyclophosphamide- or rituximab-based induction.

Malignancy

Long-term cyclophosphamide use carries significant risks: hemorrhagic cystitis and bladder cancer (from acrolein metabolite accumulation), myelodysplasia, and lymphoma. Mesna co-administration and adequate hydration reduce bladder toxicity. Regular urinalysis is recommended for all patients with prior cyclophosphamide exposure. Rituximab-based regimens have largely reduced the need for prolonged cyclophosphamide and mitigate this risk.

Laboratory Monitoring

Key Research Papers

  1. Stone JH et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221-232. (RAVE trial) — PMID 20647199
  2. Guillevin L et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014;371(19):1771-1780. (MAINRITSAN trial) — PMID 24824563
  3. Jayne DRW et al. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med. 2021;384(7):599-609. (ADVOCATE trial) — PMID 32937116
  4. Walsh M et al. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis. N Engl J Med. 2020;382(7):622-631. (PEXIVAS trial) — PMID 32537958
  5. Jayne D et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003;349(1):36-44. (CYCAZAREM) — PMID 14500795
  6. Guilpain P et al. Granulomatosis with polyangiitis. Presse Med. 2013;42(4 Pt 2):651-659. — PMID 25398785
  7. Seo P, Stone JH. The antineutrophil cytoplasmic antibody-associated vasculitides. Am J Med. 2004;117(1):39-50. — PMID 17579222
  8. Lutalo PM, D'Cruz DP. Diagnosis and classification of granulomatosis with polyangiitis (aka Wegener's granulomatosis). J Autoimmun. 2014;48-49:94-98. — PMID 23953308
  9. Robson JC et al. 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for granulomatosis with polyangiitis. Arthritis Rheumatol. 2022;74(3):393-399. — PMID 35549081
  10. Hoffman GS et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116(6):488-498. — PMID 9514515
  11. Kronbichler A et al. Rituximab for granulomatosis with polyangiitis: clinical evidence and mechanisms of action. Ther Adv Musculoskel Dis. 2015;7(3):79-90. — PMID 32057046
  12. McAdoo SP, Pusey CD. Anti-glomerular basement membrane disease. Clin J Am Soc Nephrol. 2017;12(7):1162-1172. — PMID 26040706

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