Granulomatosis with Polyangiitis (GPA)Dz

Synonyms:  GPA, Wegener’s granulomatosus

ICD-9 Code: 446.4.

Definition: Granulomatosis with polyangiitis (GPA) is a vasculitic syndrome associated with upper respiratory, pulmonary, and renal involvement. It is characterized histologically by necrotizing granulomatous vasculitis of small arteries and veins.

Etiology: Although it has long been suspected that GPA relates to exposure to some environmental agent, none has been implicated.  There is no evidence of immune complex disease. There are no other associated risk factors nor any genetic predisposition. It is unknown whether ANCA are pathogenic or epiphenomenal.

Pathology: Characteristic changes include granulomatous and vasculitic involvement of the upper and lower respiratory tract, sinuses, orbit, kidney, CNS, or heart. Vascular lesions involve small vessels with granuloma and multinucleated giant cells. Kidney lesions may present as pauci-immune rapidly progressive glomerulonephritis, focal necrotizing glomerulonephritis, crescentic glomerulonephritis, and less commonly, diffuse proliferative glomerulonephritis, or interstitial nephritis. Arteritis is seen in <8% of renal lesions. Vasculitis of the vasa nervorum is seen with mononeuritis multiplex.

Demographics: The mean age at onset is approximately 40 years, ranging from 8 to 80 years. Males are affected slightly more commonly than females. GPA is uncommon, with a prevalence of approximately three cases per 100,000 population. Nearly 97% of patients are white and 2% are African American.

Cardinal Findings: Patients with GPA may present with a variety of manifestations. The most common symptoms reflect upper and lower respiratory tract involvement (see Table 49). Patients may also exhibit constitutional symptoms, such as fever, weight loss, and malaise. Others have no or minimal symptoms and have their disease discovered on a chest radiograph.

Although it can affect multiple organs, pulmonary, upper airway, and renal involvement are the most characteristic features. Approximately 25% of patients with GPA have the classic triad of involvement in these three organ systems. Others have more limited disease; ~20% have only upper and lower respiratory lesions, and ~17% each have renal involvement with either upper or lower respiratory tract involvement. The extent of lung and kidney disease usually determines therapy.

—Upper respiratory tract: Features include sinusitis, cough, rhinitis, nasal ulcers, serous otitis media, hearing loss, and, rarely, subglottic stenosis. Upper respiratory tract involvement in GPA is not typically life threatening. However, it can be a source of chronic and severe symptoms such as epistaxis, sinus tenderness, and purulent rhinorrhea. It can also destroy the nasal cartilage, leading to a “saddle nose” deformity. Many with GPA experience frequent bouts of infectious sinusitis, particularly with S. aureus. Sinus symptoms related to infection may be quite difficult to distinguish from those related to a flare of vasculitis. There also may be a causal relationship between infection and disease relapse.
—Pulmonary: Findings include dyspnea, cough, hemoptysis, and pleurisy. Bilateral pulmonary infiltrates (often nodular) are seen in half of patients and may eventually cavitate.
—Renal: Kidney involvement almost always follows upper and lower respiratory tract disease and may manifest as proteinuria, hematuria, red cell casts, or renal insufficiency. Hypertension is rarely seen. Glomerulonephritis is seen in a minority of patients at the onset but eventually develops in nearly 85% of cases. The typical renal lesion of GPA is a focal and segmental glomerulonephritis. This may progress to a diffuse necrotizing crescentic glomerulonephritis and may be associated with rapid onset of renal failure. However, end-stage renal disease is seen in <10% of patients.
—Ocular: Nearly half of patients have ocular findings, including proptosis (from retroorbital pseudotumor), conjunctivitis, dacryocystitis, scleritis, and cavernous sinus thrombosis.

Table 49

Uncommon Findings: Less frequent manifestations of GPA include arthralgia (less commonly arthritis), cutaneous nodules, palpable purpura, granulomatous prostatitis, and parotitis. Mononeuritis multiplex is seen in <15% of patients. Other CNS findings include cranial neuropathy (II, V, VII, IX, XII) and polyneuropathy.

Complications: Complications may include saddle nose deformity, hearing loss, labyrinthitis, tracheal obstruction, pulmonary cavitation, end-stage renal disease (<10%), visual loss, amenorrhea, and therapy-related infection. Cyclophosphamide therapy may result in hemorrhagic cystitis and an increased risk of bladder cancer.

Diagnostic Tests: Most patients exhibit a normochromic, normocytic anemia, leukocytosis without eosinophilia, elevated ESR, hypergammaglobulinemia, and normal complement levels.
—ANCA: A major advance in the treatment of patients with GPA was the description of antineutrophil cytoplasmic antibodies (ANCA). These antibodies bind to proteinase-3, a cytoplasmic en- zyme. Depending on disease activity, 50% to 90% of patients with GPA have positive C-ANCA tests. This test is relatively specific because C-ANCA are uncommonly seen in other diseases. In the context of characteristic clinical findings, many physicians use the presence of C-ANCA as a diagnostic aid. The titer of C-ANCA may also vary with disease activity. Some patients have a decreased C-ANCA titer or even disappearance of C-ANCA with successful therapy, and an increased titer with a flare of disease activity; however, the activity of GPA cannot be determined solely by following C-ANCA titers.

Differential Diagnosis: Other pulmonary/renal syndromes, such as Goodpasture syndrome, subacute bacterial endocarditis and SLE, are in the differential diagnosis. The upper respiratory tract involvement may resemble relapsing polychondritis or midline granuloma. Pulmonary manifestations of GPA mimic sarcoidosis or vasculitides (e.g., Churg-Strauss syndrome), granulomatous infectious processes (e.g., tuberculosis, histoplasmosis, blastomycosis), and neoplastic diseases (e.g., lymphomatoid granulomatosis, lymphoma).

Diagnosis: GPA may be diagnosed by several means. Histopathologic definition of granulomatous vasculitis on respiratory tract biopsy specimen establishes the diagnosis in the correct clinical setting. Pulmonary biopsy specimens should be obtained by open lung biopsy rather than transbronchially because the latter has a lower diagnostic yield and may be as- sociated with uncontrolled bleeding. Renal biopsy is seldom diagnostic or specific for GPA but may support the diagnosis depending on the other organ involvement. The ACR has formulated classification criteria that may help differentiate patients with GPA from those with other types of vasculitis (Table 50).
A patient may be classified as having GPA if two or more criteria are present (sensitivity, 88.2%; specificity, 92%).

(table 50)

Therapy: Before the use of immunomodulatory drugs, GPA was usually a fatal disease with a mean survival of approximately 6 months and >80% 1-year mortality. Addition of prednisone prolonged the mean survival to approximately 1 year. Currently, the standard of care includes the use of cytotoxic drugs, particularly cyclophosphamide, and the long-term remission rate exceeds 90%. Therapy typically includes high-dose corticosteroids (e.g., 1 mg/kg/day prednisone) in conjunction with cyclophosphamide at doses of 1 to 2 mg/kg/day. Intermittent pulse intravenous cyclophosphamide does not appear as efficacious as daily oral dosing. When the manifestations of disease are under control, the dose of prednisone may be tapered. In general, cyclophosphamide is continued for at least a year after the disease is quiescent. For patients not responding to, or intolerant of, therapy with cyclophosphamide, MTX has been used with some success. In anecdotal reports, trimethoprim/sulfamethoxazole was reported to have possible value in treating GPA, especially when limited to the upper respiratory tract. Long-term treatment with this antibiotic decreases relapse of disease activity slightly. However, this therapy should not be considered a substitute for immunomodulatory therapy in patients with active GPA. The use of TNF inhibitors is under investigation.

Prognosis: Relapse is common in GPA; >45% of success- fully treated patients experience a relapse; median time to relapse is 42 months. The chance of cure is uncertain. Thus, all patients should be followed for relapse. The frequency of relapse and treatment exposure increases the risk of morbidity and mortality. Treatment-related morbidity may be significant and may include features related to corticosteroids (e.g., diabetes, fracture, osteonecrosis, cataracts) or cyclophosphamide (e.g., hair loss, hemorrhagic cystitis, bladder cancer, myelodysplasia). Death is usually related to renal disease, pulmonary disease, infection, or malignancy.

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