Granulomatosis with polyangiitis

Granulomatosis with polyangiitis (GPA; previously referred to as Wegener granulomatosis) is a systemic vasculitis that affects both small and medium-sized vessels. Patients typically initially present with a limited form that consists of constitutional symptoms and localized manifestations, such as chronic sinusitis, rhinitis, otitis media, ocular involvement, and/or skin lesions. More serious manifestations may develop in later stages, including pulmonary complications and glomerulonephritis; the heart may also be involved. Testing modalities include laboratory studies, imaging, and biopsy. Diagnosis is confirmed by biopsy findings of necrotizing granulomatous inflammation. Pharmacotherapy consists of immunosuppressive drugs, typically glucocorticoids combined with methotrexate, cyclophosphamide, or rituximab. Relapses are common.

Granulomatosis with polyangiitis is a type of systemic ANCA-associated vasculitis of small and medium-sized vessels characterized by necrotizing granulomatous inflammation, and it typically affects the lungs, paranasal sinuses, and kidneys. ^[1]

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

Epidemiological data refers to the US, unless otherwise specified.

Idiopathic ^[4]

• 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 ^[5][6]
• 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.

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

General principles ^[7][8]

• Suspect GPA in patients with either:
  • Characteristic clinical features (i.e., glomerulonephritis, pulmonary nodules, and ENT inflammation)
  • Positive c-ANCA
• Consult rheumatology.
• Obtain laboratory and imaging studies to:
  • Determine the extent and severity of organ involvement
  • Rule out differential diagnoses (e.g., infection, neoplasm)
• Characteristic histopathological findings confirm the diagnosis.

Laboratory studies ^[7]

• Routine studies
  • Inflammatory markers: ↑ ESR or ↑ CRP
  • CBC: normocytic normochromic anemia
  • BMP: ↑ creatinine and ↑ BUN
  • Serum AAT level: ↓ ^[9][10]
  • Urinalysis: microscopic hematuria, proteinuria
  • Urine sediment: nephritic sediment (dysmorphic RBC and RBC casts)
• Serology: ANCA (positive in ∼ 90% of patients) ^[7][11]
  • PR3-ANCA in ∼ 75% of patients
  • MPO-ANCA in ∼ 20% of patients

While positive PR3-ANCAs have a high sensitivity for GPA (∼ 98%), their absence does not exclude the diagnosis. ^[8]

Imaging studies ^[7]

Chest imaging

• Obtain a chest X-ray or CT chest for all patients to assess for lung involvement.
• Supportive findings
  • Multiple bilateral cavitating nodular lesions
  • Pulmonary hemorrhage

Additional studies

Consider additional studies to assess for organ involvement as needed, e.g.:

• Kidney ultrasound
  • Consider as part of the workup of AKI or CKD.
  • May also be used to guide a percutaneous kidney biopsy
• CT paranasal sinuses
  • Consider in patients with upper respiratory symptoms.
  • May show sinusitis, bone erosions, and/or masses in the retroorbital space, paranasal sinuses, and/or mastoid
• Cardiac studies (e.g., ECG, TTE): Consider in patients with cardiac symptoms.

Biopsy ^[7][12]

• Indications
  • Consider in all patients to confirm the diagnosis.
  • In patients with renal disease, a kidney biopsy may be required to assess for relapse and/or irreversible damage.
• Samples: may be obtained from any affected tissue
• Findings ^[12]
  • Necrosis
  • Vasculitis of small and medium-sized vessels
  • Intravascular and extravascular granulomas (mainly in the lungs and upper airways)
  • Renal tissue: pauci-immune focal and segmental necrotizing glomerulonephritis

Biopsy may not be required in certain patients, e.g., those with characteristic clinical features and positive PR3-ANCA, because results will not affect management. ^[7]

For patients with severe kidney or lung disease, do not delay treatment for biopsy. Several days of treatment do not significantly reduce the biopsy yield of biopsy samples. ^[7]

The differential diagnoses listed here are not exhaustive.

General principles ^[1][12]

• Consult rheumatology and other specialties (e.g., nephrology, pulmonology, otorhinolaryngology) as required.
• The goal of pharmacotherapy is to achieve remission within 3 months. ^[7]
• Plasmapheresis may be considered in certain patients, e.g., patients with concomitant anti-GBM disease. ^[1]
• Manage hemoptysis and ARDS urgently, if present.
  • See “Acute management checklist for life-threatening hemoptysis.”
  • See “Acute management checklist for ARDS.”

GPA can rarely cause life-threatening hemoptysis and/or ARDS from diffuse alveolar hemorrhage that may require mechanical ventilation and/or ECMO. ^[13]

Pharmacotherapy ^[1]

Induction of remission

Indication: patients with active disease

• Nonsevere disease
  • Glucocorticoids
  • PLUS a glucocorticoid-sparing agent, e.g., methotrexate (preferred) or azathioprine
• Severe disease (i.e., organ- or life-threatening)
  • Glucocorticoids
  • PLUS a glucocorticoid-sparing agent, e.g., rituximab ; (preferred) or cyclophosphamide ^[1]

Maintenance of remission

Indication: patients who initially presented with severe disease

• Slowly taper glucocorticoids to the minimum effective dose. ^[1]
• Glucocorticoid-sparing agents: e.g., rituximab (preferred), methotrexate, or azathioprine
• Duration of treatment: typically ≥ 18 months

Assessment for concurrent immunosuppressive states (e.g., HIV, TB, diabetes mellitus) is required before starting immunosuppressive therapy. ^[7]

Management of associated symptoms ^[7]

• Assess ASCVD risk and manage as indicated.
• Patients with sinonasal disease
  • Consider topical nasal antibiotics, lubricants, and/or glucocorticoids.
  • Consider referral for nasal reconstructive surgery.
• Patients with end-stage renal disease: Consider referral for kidney transplantation.

Supportive care ^[1][7]

• Prevent complications of glucocorticoid therapy.
• Monitor for adverse effects of immunosuppressants.
• Consider pneumocystis pneumonia prophylaxis.

• Without adequate treatment, the 1-year survival rate is < 20%. ^[14]
• 5-year survival with adequate treatment is approx. 80%. ^[15]
• Diffuse alveolar hemorrhage is a common cause of death.