Granulomatosis with Polyangiitis

Granulomatosis with polyangiitis (formerly Wegener granulomatosis), which has an estimated incidence of approximately 12 cases per million individuals per year, is one of three vasculitides associated with ANCA.

The other “ANCA-associated vasculitides” include microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis.

Granulomatosis with polyangiitis is characterized by vasculitis of small arteries, arterioles, and capillaries, necrotizing granulomatous lesions of both upper and lower respiratory tract, glomerulonephritis, and other vasculitic organ manifestations.

Without treatment, generalized disease is invariably fatal, with most patients surviving less than 1 year after diagnosis.

It occurs most commonly in the fourth and fifth decades of life and affects men and women with equal frequency.

Diagnostic Essentials

• Classic triad of upper and lower respiratory tract disease and glomerulonephritis.
• Suspect if upper respiratory tract symptoms (eg, nasal congestion, sinusitis) are refractory to usual treatment.
• Kidney disease is 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.

Clinical Findings

Symptoms and Signs

The disorder usually develops over 4–12 months.

Upper respiratory tract symptoms develop in 90% of patients and lower respiratory tract symptoms develop in 60% of patients; some patients may have both upper and lower respiratory tract symptoms.

Upper respiratory tract symptoms can include nasal congestion, sinusitis, otitis media, mastoiditis, inflammation of the gums, or stridor due to subglottic stenosis. Since many of these symptoms are common, the underlying disease is not often suspected until the patient develops systemic symptoms, or the original problem is refractory to treatment.

The lungs are affected initially in 40% and eventually in 80%, with symptoms including cough, dyspnea, and hemoptysis.

Other early symptoms can include a migratory oligoarthritis with a predilection for large joints; a variety of symptoms related to ocular disease (unilateral proptosis from orbital pseudotumor; red eye from scleritis [Figure 1–8ck], episcleritis, anterior uveitis, or peripheral ulcerative keratitis); purpura or other skin lesions; and dysesthesia due to neuropathy.

Renal involvement, which develops in three-fourths of the cases, may be subclinical until kidney disease is advanced.

Fever, malaise, and weight loss are common.

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

Destruction of the nasal cartilage with “saddle nose” deformity occurs late.

Otitis media, proptosis, scleritis, episcleritis, and conjunctivitis are other common findings.

Newly acquired hypertension, a frequent feature of polyarteritis nodosa, is rarely a symptom of granulomatosis with polyangiitis.

Venous thrombotic events (eg, DVT and PE) are a common occurrence in granulomatosis with polyangiitis.

Although limited forms of granulomatosis with polyangiitis have been described in which the kidney is spared initially, kidney disease will develop in most untreated patients.

Laboratory Findings

Serum Tests and UA

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

If there is kidney involvement, proteinuria occurs and the urinary sediment contains red cells, often with red cell casts.

Serum tests for ANCA help in the diagnosis of granulomatosis with polyangiitis (Table 1–7ck).

The two key ANCA subtypes relevant to systemic vasculitis are those directed against proteinase-3 (PR3) and myeloperoxidase (MPO). Antibodies to these two antigens are termed “PR3-ANCA” and “MPO-ANCA,” respectively.

The cytoplasmic pattern of immunofluorescence (c-ANCA) caused by PR3-ANCA has a high specificity (> 90%) for granulomatosis with polyangiitis but may less commonly be seen in the other forms of ANCA-associated vasculitis.

A substantial percentage of patients with “limited” granulomatosis with polyangiitis, disease that does not pose an immediate threat to life and is often confined to the sinus and upper respiratory tract, are ANCA-negative.

ANCA levels correlate erratically with disease activity, and changes in titer should not dictate changes in therapy in the absence of supporting clinical data.

The perinuclear pattern (p-ANCA) caused by MPO-ANCA, is more likely to occur in microscopic polyangiitis or eosinophilic granulomatosis with polyangiitis but may be found in granulomatosis with polyangiitis.

Approximately 10–25% of patients with classic granulomatosis with polyangiitis have MPO-ANCA.

All positive immunofluorescence assays for ANCA should be confirmed by enzyme immunoassays for the specific autoantibodies directed against PR3 or MPO.

Histologic Findings

Although ANCA testing is helpful, there remains the need in most cases for diagnostic confirmation by tissue biopsy.

Histologic features of granulomatosis with polyangiitis include vasculitis, granulomatous inflammation, geographic necrosis, and acute and chronic inflammation.

The full range of pathologic changes is usually evident only on thoracoscopic lung biopsy; granulomas, observed only rarely in kidney biopsy specimens, are found much more commonly on lung biopsy specimens.

Nasal biopsies often do not show vasculitis but may show chronic inflammation and other changes that rule out nasopharyngeal cancer or infection.

Kidney biopsy discloses a segmental necrotizing glomerulonephritis with multiple crescents; this is characteristic but not diagnostic.

Pathologists characterize the kidney lesion of granulomatosis with polyangiitis (and other forms of “ANCA-associated vasculitis”) as a pauci-immune glomerulonephritis because of the relative absence (compared with immune complex–mediated disorders) of IgG, IgM, IgA, and complement proteins within glomeruli.

Imaging

Chest CT is more sensitive than chest radiography; lesions include infiltrates, nodules, masses, and cavities.

Pleural effusions are uncommon.

Often the radiographs prompt concern about lung cancer.

Hilar adenopathy large enough to be evident on chest film is unusual in granulomatosis with polyangiitis; if present, sarcoidosis, tumor, or infection is more likely.

Other common radiographic abnormalities include extensive sinusitis and even bony sinus erosions.

Differential Diagnosis

Due to refractory and severe sinusitis, granulomatosis with polyangiitis may be misdiagnosed as chronic infectious sinonasal disease and treated with antibiotics alone.

Initial complaints of joint pain can lead to a misdiagnosis of rheumatoid arthritis.

Lung cancer may be the first diagnostic consideration for some middle-aged patients with cough, hemoptysis, and lung masses.

Granulomatosis with polyangiitis shares with SLE, anti–glomerular basement membrane disease, and microscopic polyangiitis the ability to cause an acute pulmonary-renal syndrome.

Although both granulomatosis with polyangiitis and microscopic polyangiitis may have MPO-ANCA positivity, microscopic polyangiitis does not involve the sinuses or upper respiratory tract and does not have granulomatous inflammation on histopathology.

Cocaine use can destroy midline tissues—the nose and palate—that mimics granulomatosis with polyangiitis.

Patients using cocaine may have a drug-induced positive result for PR-3-ANCA, and lesional biopsies may demonstrate vasculitis from exposure to the toxin.

COPA syndrome, a rare genetic autoinflammatory interferonopathy condition, has many features of a systemic vasculitis such as diffuse alveolar hemorrhage, glomerulonephritis, and inflammatory arthritis.

Multiple autoantibodies may be simultaneously present in COPA syndrome including ANA, PR3-ANCA, MPO-ANCA, and rheumatoid factor, which is a clue that their presence lacks specificity.

COPA syndrome should be considered when children (< 20 years of age) present with multiorgan inflammatory symptoms (especially lung) that mimic granulomatosis with polyangiitis.

Treatment

Early treatment is crucial to preventing the devastating end-organ and catastrophic complications of this disease.

Current practice divides treatment into two phases: induction of remission and maintenance of remission.

Plasma exchange does not reduce the incidence of ESKD or death in severe ANCA-associated vasculitis.

Induction of Remission

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

American College of Rheumatology/Vasculitis Foundation recommendations for the treatment of granulomatosis with polyangiitis favor rituximab as first-line induction therapy.

Cyclophosphamide may also be used for induction therapy.

Avacopan, an oral C5a receptor inhibitor, is FDA-approved as add-on treatment for severe ANCA-associated vasculitis induction therapy in combination with rituximab or cyclophosphamide plus corticosteroids.

Although the standard induction regimen of corticosteroids in ANCA-associated vasculitis is 1 mg/kg orally daily, faster corticosteroid dose reductions have demonstrated equal efficacy with fewer corticosteroid-related complications, such as infections.

Rituximab plus Prednisone (plus Avacopan)

Rituximab, a B-cell–depleting antibody, is FDA-approved in combination with corticosteroids (prednisone 1 mg/kg orally daily) for the treatment of granulomatosis with polyangiitis and microscopic polyangiitis.

Studies demonstrate that rituximab is as effective as cyclophosphamide for remission induction in these conditions.

Cyclophosphamide plus Prednisone (plus Avacopan)

Remissions can be induced in > 90% of patients treated with prednisone (1 mg/kg od) plus cyclophosphamide (2 mg/kg/day PO or 15 mg/kg IV every 2 weeks for 3 doses, then every 3 weeks for at least 3 doses with adjustments required for acute or CKD and patients over age 70).

To minimize toxicity, patients are treated with cyclophosphamide for only 3–6 months; once remission is achieved, the patient is switched to a non-cyclophosphamide maintenance regimen.

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

Whenever cyclophosphamide or rituximab is used, Pneumocystis jirovecii prophylaxis with one single-strength oral trimethoprim-sulfamethoxazole daily is essential.

Methotrexate plus Prednisone

For nonsevere disease without life- or organ-threatening manifestations, methotrexate up to 25 mg oral or subcutaneous weekly, plus corticosteroids may be effective induction therapy.

Maintenance of Remission

Options for maintaining remission in patients with normal or near normal kidney function after rituximab or cyclophosphamide induction include azathioprine (up to 2 mg/kg/day orally), methotrexate (20–25 mg/week either orally or subcutaneously), mycophenolate mofetil, or rituximab.

Per treatment guidelines, rituximab, dosed at a fixed interval of 1 g every 6 months or 500 mg every 4 months, is favored as first-line maintenance treatment.