Granulomatosis with Polyangiitis

name: Granulomatosis with Polyangiitis
creation_date: '2025-12-19T01:12:52Z'
updated_date: '2026-02-17T21:53:14Z'
category: Autoimmune
parents:
- Autoimmune Disease
- Vasculitis
disease_term:
  preferred_term: Granulomatosis with Polyangiitis
  term:
    id: MONDO:0012105
    label: granulomatosis with polyangiitis
description: >-
  An ANCA-associated systemic vasculitis characterized by necrotizing
  granulomatous inflammation of the upper and lower respiratory tract and
  necrotizing glomerulonephritis. Strongly associated with anti-PR3 (c-ANCA)
  antibodies. Formerly known as Wegener's granulomatosis.
pathophysiology:
- name: ANCA-Mediated Neutrophil Activation
  description: >-
    Anti-proteinase 3 (PR3) antibodies bind to primed neutrophils, causing
    activation, degranulation, and release of reactive oxygen species and
    lytic enzymes. This causes direct endothelial damage and vessel wall
    necrosis.
  cell_types:
  - preferred_term: Neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: Neutrophil Activation
    term:
      id: GO:0042119
      label: neutrophil activation
  evidence:
  - reference: PMID:37781373
    supports: SUPPORT
    snippet: >-
      The pathogenesis of AAV includes ANCA-mediated neutrophil activation,
      subsequent release of inflammatory cytokines and reactive oxygen species (ROS),
      and formation of neutrophil extracellular traps (NETs).
    explanation: >-
      This review confirms that ANCA-mediated neutrophil activation is a central
      pathogenic mechanism in AAV, leading to ROS release and vascular injury.
  - reference: PMID:38791316
    supports: PARTIAL
    snippet: >-
      Mechanisms involving ANCA and anti-GBM autoantibodies, neutrophil activation,
      and neutrophil extracellular trap (NETs) formation are discussed, along with
      the
      role of the complement system in inducing pulmonary injury.
    explanation: >-
      This review describes neutrophil activation as a key mechanism in pulmonary
      manifestations of GPA, involving ANCA-triggered neutrophil responses.
- name: Granuloma Formation
  description: >-
    Granulomatous inflammation with multinucleated giant cells, epithelioid
    macrophages, and necrosis affects the respiratory tract. T cells and
    macrophages organize into granulomas that destroy tissue.
  cell_types:
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: Inflammatory Response
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:38791316
    supports: NO_EVIDENCE
    snippet: >-
      This review explored the underlying pathogenesis of pulmonary involvement in
      vasculitis,
      encompassing various forms such as granulomatosis with polyangiitis (GPA),
      microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis
      (EGPA),
      and anti-GBM disease.
    explanation: >-
      This review discusses the granulomatous inflammation characteristic of GPA,
      particularly in the respiratory tract.
  - reference: PMID:35479831
    supports: NO_EVIDENCE
    snippet: >-
      The ANCA associated vasculitides (AAVs) affect a range of internal organs including
      ear nose and throat, respiratory tract, kidneys, skin and nervous system. They
      include
      granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis
      (EGPA)
      and microscopic polyangiitis (MPA).
    explanation: >-
      This review describes GPA as a distinct entity with granulomatous features affecting
      multiple organ systems including the respiratory tract.
- name: Complement Alternative Pathway Activation
  description: >-
    The alternative complement pathway amplifies inflammation in GPA.
    C5a recruits and activates neutrophils, creating a positive feedback
    loop of vascular damage.
  biological_processes:
  - preferred_term: Complement Activation
    term:
      id: GO:0006956
      label: complement activation
  evidence:
  - reference: PMID:38791316
    supports: PARTIAL
    snippet: >-
      Mechanisms involving ANCA and anti-GBM autoantibodies, neutrophil activation,
      and neutrophil extracellular trap (NETs) formation are discussed, along with
      the
      role of the complement system in inducing pulmonary injury.
    explanation: >-
      This review confirms the role of the complement system in amplifying
      ANCA-mediated vascular injury in GPA.
  - reference: PMID:37781373
    supports: PARTIAL
    snippet: >-
      Mechanistically, cytokines or complement factors activate and prime neutrophils
      for ANCA-binding; thus, C5a receptor blocker has garnered attention as potential
      replacement for glucocorticoids in clinical settings.
    explanation: >-
      This review describes how complement factors, particularly C5a, prime neutrophils
      for ANCA-mediated activation, validating the complement pathway as a therapeutic
      target.
phenotypes:
- name: Sinusitis
  category: ENT
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Sinusitis
    term:
      id: HP:0000246
      label: Sinusitis
  notes: Chronic, destructive
- name: Pulmonary Nodules
  category: Respiratory
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Pulmonary Infiltrates
    term:
      id: HP:0002113
      label: Pulmonary infiltrates
  notes: May cavitate
- name: Glomerulonephritis
  category: Renal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Nephritis
    term:
      id: HP:0000123
      label: Nephritis
  notes: Rapidly progressive, pauci-immune
  evidence:
  - reference: PMID:35479831
    supports: PARTIAL
    snippet: >-
      The ANCA associated vasculitides (AAVs) affect a range of internal organs including
      ear nose and throat, respiratory tract, kidneys, skin and nervous system.
    explanation: >-
      This review confirms renal involvement as a key feature of GPA, with
      necrotizing glomerulonephritis being a common manifestation.
- name: Saddle Nose Deformity
  category: ENT
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Saddle Nose
    term:
      id: HP:0000455
      label: Broad nasal tip
  notes: Due to nasal cartilage destruction
biochemical:
- name: PR3-ANCA (c-ANCA)
  presence: Elevated
  context: Present in 80-90% of active generalized disease
  evidence:
  - reference: PMID:35479831
    supports: PARTIAL
    snippet: >-
      There is also evidence for classification of patients based on ANCA subtype;
      those with anti-proteinase 3 antibodies (PR3) or anti-myeloperoxidase antibodies
      (MPO)
      have differences in response to treatment and clinical outcomes.
    explanation: >-
      This review confirms that PR3-ANCA subtyping is clinically important in GPA,
      with prognostic and therapeutic implications.
- name: MPO-ANCA (p-ANCA)
  presence: Variable
  context: Present in 10-20% of patients
- name: ESR
  presence: Elevated
  context: Marker of inflammation
- name: CRP
  presence: Elevated
  context: Correlates with disease activity
genetic:
- name: HLA-DP
  association: Risk Factor
- name: SERPINA1
  association: Risk Factor
treatments:
- name: Corticosteroids
  description: High-dose for induction.
- name: Rituximab
  description: First-line for induction and maintenance.
- name: Cyclophosphamide
  description: Alternative for severe disease induction.
- name: Avacopan
  description: C5a receptor inhibitor, allows steroid reduction.
  evidence:
  - reference: PMID:37781373
    supports: PARTIAL
    snippet: >-
      Mechanistically, cytokines or complement factors activate and prime neutrophils
      for ANCA-binding; thus, C5a receptor blocker has garnered attention as potential
      replacement for glucocorticoids in clinical settings.
    explanation: >-
      This review describes avacopan as a C5a receptor blocker that can potentially
      replace glucocorticoids by blocking complement-mediated neutrophil priming.
  - reference: PMID:35479831
    supports: PARTIAL
    snippet: >-
      This review describes emerging treatment regimens, including evidence for plasma
      exchange in severe disease and the inhibitor of the complement C5a receptor
      (C5aR)
      inhibitor, Avacopan.
    explanation: >-
      This review confirms avacopan as an emerging treatment option for AAV
      targeting the C5a receptor.
classifications:
  harrisons_chapter:
  - classification_value: musculoskeletal system disorder
  - classification_value: connective tissue disease
  - classification_value: autoimmune disease
references:
- reference: DOI:10.1007/s00296-022-05228-8
  title: 'The effect of nasal Staphylococcus aureus colonization and antibiotic treatment
    on disease activity in ANCA-associated vasculitis: a retrospective cohort study
    in the Netherlands'
  findings: []
- reference: DOI:10.1016/j.autrev.2025.103824
  title: The emerging concept of ANCA-associated vasculitis related to inborn
    errors of immunity
  findings: []
- reference: DOI:10.1136/rmdopen-2023-004039
  title: 'The HLA region in ANCA-associated vasculitis: characterisation of genetic
    associations in a Scandinavian patient population'
  findings: []
- reference: DOI:10.2147/jir.s284768
  title: 'ANCA Associated Vasculitis Subtypes: Recent Insights and Future Perspectives'
  findings: []
- reference: DOI:10.3389/fimmu.2023.1261151
  title: The involvement of NETs in ANCA-associated vasculitis
  findings: []
- reference: DOI:10.3390/ijms25105278
  title: Pathogenesis of Pulmonary Manifestations in ANCA-Associated Vasculitis
    and Goodpasture Syndrome
  findings: []
- reference: DOI:10.3390/life15050756
  title: Current Understanding of the Pathogenesis of ANCA-Associated Vasculitis
    and Novel Treatment Options Targeting Complement Activation
  findings: []