Granulomatosis with Polyangiitis

Essentials of Diagnosis

• Triad of

  • Upper respiratory tract disease

  • Lower respiratory disease

  • Glomerulonephritis

• Suspect if upper respiratory tract symptoms (eg, nasal congestion, sinusitis) are refractory to usual treatment

• Kidney disease often rapidly progressive

• Venous thromboembolism commonly occurs

• ANCAs (90% of patients), usually directed against proteinase-3 (but may be directed against myeloperoxidase)

• Tissue biopsy usually necessary for diagnosis

General Considerations

• Granulomatosis with polyangiitis is a disease of predominantly small arteries

• Characterized in its full expression by

  • Vasculitis of small arteries, arterioles, and capillaries

  • Necrotizing granulomatous lesions of both upper and lower respiratory tract

  • Glomerulonephritis

  • Other organ manifestations

Demographics

• Annual incidence of 12 per million

• Occurs most commonly in the fourth and fifth decades of life

• Affects men and women with equal frequency

Symptoms and Signs

• Usually develops over 4–12 months

• Fever, malaise, and weight loss

• Upper respiratory tract symptoms develop in 90% of patients

• Lower respiratory tract symptoms develop in 60% of patients

• Some patients develop both upper and lower respiratory tract symptoms

• Upper respiratory tract symptoms can include

  • Nasal congestion

  • Sinusitis

  • Otitis media, mastoiditis

  • Inflammation of the gums

  • Stridor due to subglottic stenosis

• Physical examination can be remarkable for congestion, crusting, ulceration, bleeding, and even perforation of the nasal septum

• The lung is affected initially in 40% and eventually in 80%, with symptoms including cough, dyspnea, and hemoptysis

• Renal involvement (75%) may be subclinical until renal insufficiency is advanced

• Other early symptoms can include

  • Unilateral proptosis (from orbital pseudotumor)

  • Red eye from scleritis

  • Arthritis

  • Purpura

  • Dysesthesia due to neuropathy

• Destruction of the nasal cartilage with "saddle nose" deformity occurs late

• Patients are at high risk for venous thrombotic events (deep venous thrombosis, pulmonary embolism)

Differential Diagnosis

• Polyarteritis nodosa

• Microscopic polyangiitis

• Eosinophilic granulomatosis with polyangiitis

• Chronic sinusitis

• Goodpasture disease

• Systemic lupus erythematosus

• Sarcoidosis

• Cocaine use

Laboratory Tests

• c-ANCA

  • Caused by antibodies to proteinase-3, a constituent of neutrophil granules

  • Has a high specificity (> 90%)

  • In the setting of active disease, the sensitivity of c-ANCA is also reasonably high (= 70%)

• p-ANCA

  • Caused by antibodies to myeloperoxidase and is much less specific than c-ANCA

  • Approximately 10–25% of patients with classic granulomatosis with polyangiitis have p-ANCA

• Most patients have anemia, mild leukocytosis, and elevated acute-phase reactants

• If kidney involvement is present

  • Proteinuria occurs

  • The urinary sediment contains red cells and red cell casts

Imaging Studies

• Chest CT is more sensitive than chest radiograph for infiltrates, nodules, masses, and cavities

• Pleural effusions are uncommon

Procedures

• ANCA testing does not eliminate the need in most cases for confirmation of the diagnosis by tissue biopsy

• The full range of pathologic changes is usually evident only on thoracoscopic lung biopsy

• Histologic features include

  • Vasculitis

  • Granulomatous inflammation

  • Geographic necrosis

  • Acute and chronic inflammation

• Renal biopsy discloses a segmental necrotizing glomerulonephritis with multiple crescents (characteristic but not diagnostic)

• Current practice divides treatment into two phases

  • Induction of remission

  • Maintenance of remission

• Choice of induction therapy is dictated by whether the patient has mild disease (ie, no significant kidney dysfunction) versus severe immediately life- or organ-threatening disease (eg, rapidly progressive glomerulonephritis or pulmonary hemorrhage)

Medications

• Inducing remission for patients with severe disease

  • Prednisone (1 mg/kg daily) plus cyclophosphamide (2 mg/kg/day orally with adjustments required for acute or chronic kidney disease and age >70 years old)

  • Cyclophosphamide is best given daily by mouth; intermittent high-dose intravenous cyclophosphamide is less effective

  • Whenever cyclophosphamide is used, Pneumocystis jirovecii prophylaxis with either single-strength oral trimethoprim-sulfamethoxazole daily or dapsone 100 mg/day (after checking G6PD level) is essential

    • To minimize toxicity, patients are treated with cyclophosphamide for only 3–6 months

    • Once remission is achieved, the patient is switched to a maintenance regimen

  • Rituximab, a B-cell depleting antibody

    • Rituximab in combination with corticosteroids (prednisone 1 mg/kg orally daily) is approved by the FDA for the treatment of both granulomatosis with polyangiitis and microscopic polyangiitis

    • Both rituximab and cyclophosphamide increase the risk of developing life-threatening opportunistic infections (including progressive multifocal leukoencephalopathy [PML])

• Maintaining remission in patients with normal or near normal kidney function after cyclophosphamide induction

  • Azathioprine (up to 2 mg/kg/day orally)

  • Methotrexate (20–25 mg/wk administered either orally or intramuscularly)

    • Should not be used in patients with kidney dysfunction

    • An appropriate substitute for cyclophosphamide or rituximab for initial and maintenance treatment in patients who have mild disease and normal kidney function because of superior side-effect profile

  • Rituximab (500 mg administered intravenously when remission is achieved, repeated in 14 days, then repeated as a single dose approximately every 6 months)

Follow-Up

• Complete blood count every 2 weeks for patients taking cyclophosphamide daily

Complications

Permanent disease-related complications

• Suffered by 85% of patients

• End-stage renal disease

• Decreased hearing

• Visual impairment

• Subglottic stenosis

• Saddle-nose deformity

• Deep venous thrombophlebitis or pulmonary embolism

Permanent treatment-related complications

• Suffered by 40% of patients

• Multitudinous side effects of corticosteroids

• Cyclophosphamide

  • Bone marrow hypoplasia

  • Secondary malignancy (bladder, leukemia)

  • Hemorrhagic cystitis

  • Infertility

Prognosis

• Without treatment, granulomatosis with angiitis is invariably fatal, most patients surviving < 1 year after diagnosis

• With cyclophosphamide and prednisone treatment, remissions have been induced in up to 75% of patients, though half of these patients eventually suffer disease recurrences

When to Refer

• All patients should be referred to a rheumatologist. Other subspecialty consultations may be appropriate

When to Admit

• Alveolar hemorrhage

• Rapidly progressive glomerulonephritis