Granulomatosis with polyangiitis

Granulomatosis with polyangiitis (GPA, previously known as Wegener granulomatosis) is a systemic vasculitis that affects both small and medium-sized vessels. Patients typically initially suffer from a limited form that may consist of constitutional symptoms and localized manifestations, such as chronic sinusitis, rhinitis, otitis media, ocular conditions, and/or skin lesions. In later stages, more serious manifestations may arise, including pulmonary complications and glomerulonephritis, although the skin, eyes, and heart may also be involved. Diagnosis is based on laboratory testing (positive for PR3-ANCA/c-ANCA), imaging, and biopsy of affected organs, which demonstrate necrotizing granulomatous inflammation. GPA is treated with immunosuppressive drugs, typically consisting of glucocorticoids combined with methotrexate, cyclophosphamide, or rituximab. Relapses are common.

• Sex: ♂ = ♀
• Peak incidence: 40–60 years ^[1]
• Prevalence: ∼ 3 per 100,000 ^[2]

Epidemiological data refers to the US, unless otherwise specified.

• Idiopathic ^[3]

• GPA is a type of ANCA-associated vasculitis. ^{[4][5][6][7][8]}
• The following processes play a key role in the pathophysiology of GPA:
  • Aberrant epigenetic expression of proteinase-3 on the cell membrane of neutrophils
  • Formation of antibodies against proteinase-3 (PR3-ANCA)
• Binding of PR3-ANCA to PR3 activates neutrophils → release of neutrophilic inflammatory mediators, formation of neutrophil extracellular traps, complement activation → damage to endothelial cells of small blood vessels

• Constitutional symptoms: fever, night sweats, weight loss, arthralgias
• ENT involvement: often the first clinical manifestation
  • Chronic rhinitis/sinusitis: nasopharyngeal ulcerations → nasal septum perforation → saddle nose deformity (depression of the nasal dorsum)
  • Chronic otitis and/or mastoiditis
  • In some cases, thick, purulent discharge, sometimes containing blood
  • Oral ulcers
  • Strawberry gingivitis: a characteristic feature of granulomatosis with polyangiitis characterized by painful, erythematous, gingival inflammation with petechiae that results in the appearance of the surface of a strawberry ^[9][10]
• Lower respiratory tract: potentially life-threatening
  • Treatment-resistant, pneumonia-like symptoms with cough, dyspnea, hemoptysis, wheezing, hoarseness, and/or pleuritic pain
  • Clinical features of pulmonary fibrosis, pulmonary hypertension, and/or pulmonary hemorrhage may occur.
• Renal involvement: potentially life-threatening
  • Pauci-immune glomerulonephritis (Pauci‑immune indicates that there is little evidence of immune complex/antibody deposits.) → rapidly progressive (crescentic) glomerulonephritis (RPGN) with possible pulmonary-renal syndrome
  • Typically causes hematuria and red cell casts
• Skin lesions
  • Papules, vesicles, ulcers
  • Purpura of the lower extremities
  • May lead to necrotizing vasculitis of small vessels → dry gangrene of digits
• Ocular involvement
  • Conjunctivitis, episcleritis, retinal vasculitis
  • Corneal ulcerations
• Cardiac involvement: potentially life-threatening
  • Pericarditis, myocarditis
  • Vasculitis of the coronary arteries; may lead to myocardial infarction and death
  • Rarely: cardiomyopathy

Upper respiratory manifestations (i.e., purulent, sometimes bloody discharge, chronic nasopharyngeal infections, saddle nose deformity) are the most common chief complaints.

GPA triad: necrotizing vasculitis of small arteries, upper/lower respiratory tract manifestations, and glomerulonephritis.

• Laboratory analysis
  • Blood
    • ↑ Creatinine and ↑ BUN
    • ↑ ESR and ↑ CRP
    • Evidence of PR3-ANCA/c-ANCA (anti-proteinase 3): highly sensitive and positive in ∼ 90% of patients ^[11]
    • Normocytic normochromic anemia
  • Urine
    • Urinalysis: microscopic hematuria, proteinuria
    • Urine sediment: dysmorphic RBC and RBC casts → nephritic sediment
• Imaging: chest x-ray/CT show multiple bilateral cavitating nodular lesions
• Pathology
  • Diagnosis should be confirmed by biopsy of affected tissue.
  • Typically shows classic triad of:
    • Necrotic, partially granulomatous vasculitis of small and medium-sized vessels
    • Necrotizing granulomas; (intravascular and extravascular) mainly in lung and upper airways
    • Necrotizing glomerulonephritis

A biopsy is necessary to confirm the diagnosis.

The differential diagnoses listed here are not exhaustive.

• Remission induction
  • If mild disease
    • Glucocorticoids PLUS methotrexate (MTX)
    • Patients who do not benefit from MTX may be switched to either cyclophosphamide or rituximab.
  • If moderate to severe disease
    • Glucocorticoids PLUS either cyclophosphamide OR rituximab
    • PCP prophylaxis in patients receiving cyclophosphamide and corticosteroids: trimethoprim/sulfamethoxazole (TMP/SMX)
  • Glucocorticoids should be tapered gradually as soon as the patient begins responding to the immunosuppressant agent. ^[12][13]
  • In the case of concurrent Goodpasture syndrome: plasmapheresis
• Remission maintenance: immunosuppressive drugs (e.g., azathioprine, rituximab or methotrexate) ^[14][15]

• Without adequate treatment, the 1-year survival rate is < 20%. ^[16]
• 5-year survival with adequate treatment is approx. 80%. ^[17]
• Diffuse alveolar hemorrhage is a common cause of death.