Approximately 90% of patients with GPA have nasal involvement. This is often the first disease manifestation. The typical symptoms are persistent rhinorrhea, unusually severe nasal obstruction, epistaxis, and bloody or brown nasal crusts (Table 32–1). Cartilaginous inflammation may lead to perforation of the nasal septum and collapse of the nasal bridge (a “saddle-nose” deformity) (Figure 32–1). Bony erosions of the sinus cavities are characteristic of GPA but only develop after long-standing disease (months).
Table 32–1. Major Clinical Manifestations of Granulomatosis with Polyangiitis (Formerly Wegener Granulomatosis). ||Download (.pdf)
Table 32–1. Major Clinical Manifestations of Granulomatosis with Polyangiitis (Formerly Wegener Granulomatosis).
|Nose||Persistent rhinorrhea; bloody, brown nasal crusts; nasal obstruction; nasal septal perforation; saddle-nose deformity|
|Sinuses||Sinusitis with radiologic evidence of bony erosions|
|Ears||Conductive hearing loss due to granulomatous inflammation in the middle ear; sensorineural hearing loss; mixed hearing loss common|
|Mouth||Strawberry gums; tongue or other oral ulcers; occasional purpuric lesions on palate|
|Eyes||Orbital pseudotumor; scleritis (often necrotizing); episcleritis; conjunctivitis; keratitis (risk of corneal melt); uveitis (anterior)|
|Lungs||Nodular, cavitary lesions; nonspecific pulmonary infiltrates; alveolar hemorrhage; bronchial lesions|
|Heart||Occasional valvular lesions, usually not evident during life; pericarditis|
|Gastrointestinal||Mesenteric vasculitis uncommon; splenic involvement quite common but usually subclinical (detected as splenic infarcts on cross-sectional imaging)|
Cartilaginous inflammation of the nose in granulomatosis with polyangiitis (Wegener granulomatosis) may lead to nasal septal perforation and ultimately to collapse of the nasal bridge (“saddle-nose” deformity).
Both conductive and sensorineural forms of hearing loss occur in GPA. The usual pattern of auditory dysfunction is a mixed one, with the simultaneous occurrence of both conductive and sensorineural hearing loss. Conductive hearing loss results from granulomatous involvement of the middle ear, most often leading to serous otitis media. Granulomatous inflammation in the middle ear may also compress the seventh cranial nerve as it courses through the middle ear cavity, leading to a peripheral facial nerve palsy. (This is often misdiagnosed as Bell palsy or Lyme disease.) Sensorineural hearing loss results from inner ear (cochlear) involvement and may also be associated with vestibular dysfunction (eg, nausea, vertigo, tinnitus). However, the sensorineural hearing loss associated with GPA is seldom profound. Additional information about sensorineural hearing loss is found in Chapter 68.
GPA may present with a variety of inflammatory lesions of the eye (Figure 32–2). Orbital pseudotumors in the retrobulbar space may lead to proptosis and visual loss through optic nerve ischemia (compression of the nerve’s blood supply by the space-occupying mass). Scleritis causes photophobia and painful, often nodular, scleral erythema. If unchecked, necrotizing scleritis may lead to scleral thinning, scleromalacia perforans, and visual loss. Peripheral keratitis may cause ulcerations on the margin of the cornea and lead to the syndrome of “corneal melt.”
A: CT scan of the orbit showing an orbital pseudotumor, leading to proptosis and visual loss. B: Scleritis with a marginal corneal ulceration. C: Painless erythema of the superficial surface of the eye—episcleritis—the most common ocular complication of granulomatosis with polyangiitis (formerly Wegener granulomatosis).
Episcleritis and conjunctivitis constitute less serious ocular complications of GPA but are very common. Their occurrence may be the presenting symptom of the disease or the first manifestation of a flare. Nasolacrimal duct obstruction leads to poor outflow of tears such that the eyes in a patient with GPA are characteristically wet. Anterior uveitis is rare in GPA in comparison to other rheumatologic conditions such as ankylosing spondylitis (see Chapter 17), Behçet disease (see Chapter 38), and sarcoidosis (see Chapter 54). Central retinal artery occlusions are a known complication of this disorder, but other retinal lesions and posterior uveitis are uncommon.
Two classic mouth lesions of GPA are gum inflammation (“strawberry gums” [Figure 32-3]) and tongue ulcers. The gum inflammation of GPA, which derives its name from the resemblance of the dental papillae to strawberries, is quite distinctive among rheumatologic conditions. The oral ulcerations of GPA, caused by medium-vessel vasculitis, typically occur on the lateral sides of the posterior tongue. Strawberry gums and tongue ulcers, both quite painful, respond promptly to glucocorticoids.
Granulomatosis with polyangiitis (formerly Wegener granulomatosis) patient with intense inflammation of the gums, a physical finding known as “strawberry gums.”
Subglottic stenosis, the result of tracheal inflammation and scarring below the vocal cords, is a potentially disabling manifestation that is largely specific to GPA (relapsing polychondritis can also cause this lesion). Subglottic involvement is often asymptomatic and may manifest itself only as a subtle hoarseness. With time, however, airway scarring and profound tracheal narrowing may occur. Pulmonary function tests with flow volume loops can show a fixed extrathoracic obstructive defect, but this may not become apparent until the process is advanced. Supraglottic disease, although substantially less common than subglottic stenosis, may also occur in GPA.
Approximately 80% of patients with GPA have pulmonary lesions during the course of their disease. Pulmonary symptoms include cough, hemoptysis, dyspnea, and sometimes pleuritic chest pain. Lung lesions are often asymptomatic, however, and some are detectable only if chest imaging is performed. The most common radiologic findings are pulmonary infiltrates and nodules (Figure 32–4). The infiltrates, which may wax and wane, are often misdiagnosed initially as pneumonia. Single, large pulmonary nodules are often misdiagnosed as lung cancer. Nodules are usually multiple, bilateral, and often cavitary. Many nodules have peripheral locations and, if wedge-shaped, may be mistaken for pulmonary emboli.
Chest radiograph and computed tomography scan show multiple bilateral nodules. A: Posteroanterior view of the chest shows bilateral lung nodules. B: Computed tomography scan of the chest in the same patient shows additional lesions not evident of the radiograph.
Pulmonary capillaritis can lead to hemoptysis and rapidly changing alveolar infiltrates. Large airway disease leading to significant bronchial stenosis, similar to the findings found in subglottic stenosis, occurs in a minority of GPA patients. Large airway disease may be more common in pediatric than in adult GPA. Finally, venous thrombotic events (particularly deep venous thromboses) occur in a substantial proportion of patients, perhaps as a complication of the disease’s propensity to involve the venous circulation. These events tend to occur in close association with periods of active disease. Pulmonary emboli should be considered in the GPA patient in whom dyspnea, pleuritic chest pain, or other compatible symptoms develop.
Renal disease, among the most ominous clinical manifestations of GPA, is often a marker for swift disease progression. Renal involvement, present in approximately 20% of patients with GPA at the time of diagnosis, develops eventually in a substantially higher portion of patients (up to 80%) during the course of the disease. The clinical presentation of renal disease in GPA is rapidly progressive glomerulonephritis: hematuria, red blood cell casts, proteinuria (usually non-nephrotic), and rising serum creatinine. Without appropriate therapy, loss of renal function can ensue within days or weeks. More subacute courses of renal diseases also develop in some patients with GPA, particularly those with anti-myeloperoxidase antibodies (MPO-ANCA) as opposed to PR3-ANCA. GPA is also known to present with renal mass lesions that mimic malignancy.
Nonspecific arthralgias and frank arthritis often occur early in the course of GPA. The arthritis of GPA is migratory in nature and may assume a variety of joint patterns. The most common form of arthritis is a pauci- or monoarticular syndrome of lower or upper extremity joints that is often migratory in nature. Polyarthritis of the small joints of the hands can also occur. Digital ischemia and gangrene resulting from inflammation in medium-sized digital arteries are occasionally the presenting feature of GPA. The skin manifestations of GPA include the full array of findings associated with cutaneous vasculitis: palpable purpura, papules, ulcers, and vesiculobullous lesions.
Examination of the skin should include careful inspection for the nodular lesions of “Churg-Strauss granulomas” (cutaneous extravascular necrotizing granulomas). These nodules are located typically on the extensor surfaces of the elbows and other pressure points (Figure 32–5). Splinter hemorrhages may occur in GPA, raising diagnostic confusion with endocarditis. Lesions resembling pyoderma gangrenosum but caused by a medium-vessel vasculitis may also occur. Although involvement of the brain parenchyma with GPA has been reported, meningeal inflammation (presenting as excruciating headaches and cranial neuropathies) is a more typical central nervous system disease manifestation. Mononeuritis multiplex can complicate GPA but is less characteristic of this disease than other forms of systemic vasculitis (eg, polyarteritis nodosa, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis [the Churg-Strauss syndrome]).
The patient has granulomatosis with polyangiitis (formerly Wegener granulomatosis) and has a positive test result for rheumatoid factor. The nodule over the extensor surface of the elbow was initially misdiagnosed as a rheumatoid nodule instead of a “Churg-Strauss granuloma” (cutaneous extravascular necrotizing granuloma).
The results of routine laboratory tests and more specialized assays in GPA are shown in Table 32–2. All of these tests are appropriate at the initial evaluation of a patient with possible GPA. The exclusion of renal disease through the careful performance of a urinalysis is essential in the evaluation and follow-up of all patients with GPA. The erythrocyte sedimentation rate and serum C-reactive protein level are useful (albeit imperfect) biomarkers in the longitudinal evaluation of disease activity. The utility of ANCA testing is discussed below.
Table 32–2. The Laboratory Evaluation in Granulomatosis with Polyangiitis (Formerly Wegener Granulomatosis). ||Download (.pdf)
Table 32–2. The Laboratory Evaluation in Granulomatosis with Polyangiitis (Formerly Wegener Granulomatosis).
|Complete blood cell count|
- Normochromic, normocytic anemia; acute, severe anemias possible in alveolar hemorrhage
- Mild to moderate leukocytosis common, usually not exceeding 18 × 109/L
- Moderate to pronounced thrombocytosis typical, ranging from platelet counts of 400 × 109/L to occasionally >1000 × 109/L
|Electrolytes||Hyperkalemia in the setting of advanced renal dysfunction|
|Liver function test||Hepatic involvement is quite unusual in GPA; when present, there can be elevations of transaminases (AST/ALT) in excess of 1000 mg/dL|
|Urinalysis with microscopy|
- Hematuria (ranging from mild to so high that red blood cells are too numerous to count)
- Red blood cell casts
- Proteinuria (nephritic range proteinuria in a small minority)
|Erythrocyte sedimentation rate/ C-reactive protein||Dramatic elevations of acute phase reactants are typical, generally with good correlation to disease activity|
|Rheumatoid factor||Positive in 40–50% of patients, often leading to diagnostic confusion with rheumatoid arthritis|
|C3, C4||Complement levels are normal to elevated in GPA, in contrast to systemic lupus erythematosus, cryoglobulinemia, and other diseases in which immune complexes appear to play major roles|
|ANCA||Positive in 60–90% of patients with GPA|
|Anti-GBM||A minority of patients with GPA also have anti-GBM antibodies|
Up to one third of patients with GPA have asymptomatic pulmonary lesions on radiologic imaging. Computed tomography is superior to chest radiography in demonstrating the extent of pulmonary disease. Consequently, patients with confirmed or strongly suspected diagnoses of GPA should have CT scans of the chest as baseline studies. Virtually any finding (with the rare exception of hilar and mediastinal adenopathy) may be present on chest imaging in GPA, including pleural effusions and nonspecific infiltrates.
Because of the numerous potential mimickers of GPA and the frequent shortcomings of ANCA (see next section on ANCA testing), the diagnosis of GPA is most secure when established through biopsy of an involved organ. Among the organs commonly involved in GPA, those most likely to yield tissue that permits a diagnosis are (in descending order): lung, kidney, and upper respiratory tract (nose or sinuses). The tissue necrosis associated with GPA is frequently so extensive within diseased tissues that it is termed “geographic necrosis.”
Even when all three pathologic hallmarks (granulomatous inflammation, vasculitis, and necrosis) are present, the diagnosis of GPA requires the careful integration of pathologic findings with clinical, laboratory, and radiologic data. Acid-fast and fungal pathogens must be excluded by special stains and cultures.
Biopsies of the upper respiratory tract (nose, sinuses, and subglottic region) are frequently nondiagnostic, yielding only nonspecific acute and chronic inflammation. Upper respiratory tract biopsies demonstrate the complete diagnostic triad in only about 15% of cases. However, these biopsies are generally safer than lung or kidney biopsies, and the finding of even parts of this triad in a nose or sinus biopsy may serve as compelling evidence for the diagnosis of GPA, provided that other manifestations of the disease are present elsewhere. Compelling if not diagnostic histopathologic findings may clinch the diagnosis if the patient’s ANCA serologies are also consistent with GPA.
GPA finds its fullest pathologic expression in the lung, where the large amounts of tissue obtained at open or thoracoscopic lung biopsy may capture the entire spectrum of disease. Transbronchial and radiologically-guided needle biopsies usually fail to yield diagnostic tissue specimens. The leukocytoclastic vasculitis of GPA may involve arteries, veins, and capillaries, with or without granulomatous features. Vascular necrosis begins as clusters of neutrophils within the blood vessel wall (microabscesses) that degenerate and become surrounded by palisading histiocytes. Coalescence of such neutrophilic microabscesses leads to geographic necrosis.
Renal biopsy findings are not specific for GPA because other pauci-immune forms of glomerulonephritis can have identical histopathologic features. However, renal biopsy results are sufficiently characteristic to establish the diagnosis in appropriate clinical settings. The typical renal lesion of GPA is segmental necrotizing glomerulonephritis, with or without crescent formation. Thrombotic changes in the glomerular capillary loops are among the earliest histologic lesions. Immunofluorescence studies of renal biopsies in GPA confirm the “pauci-immune” nature of the renal involvement (ie, the relatively sparse immunoglobulin and complement deposition found in this disorder compared with such diseases as systemic lupus erythematosus, Henoch-Schönlein purpura, and Goodpasture syndrome).
Serologic Testing for ANCA
ANCAs are directed against antigens that reside within the primary granules of neutrophils and monocytes. Positive ANCA assays are often instrumental in suggesting the diagnosis. In patients with multiple classic organ system features of GPA, a positive ANCA assay that has been confirmed by both immunofluorescence and enzyme immunoassay testing can preclude the need for biopsy. However, a small percentage of patients with disseminated GPA are ANCA-negative, so a negative ANCA assay does not exclude the diagnosis. Among patients with “limited” disease (see Treatment section), 30% or more may lack ANCA. Rises and falls in ANCA titers often demonstrate poor correlation with the timing of disease flares and should never be used as the sole guide to the use of immunosuppression.
The two types of ANCA tests now in common use are immunofluorescence assays and enzyme immunoassays. These two tests are complementary in the diagnosis of GPA. Both should be used in evaluating patients in whom this disease is suspected.
With immunofluorescence, three principal patterns are recognized: cytoplasmic (C-ANCA), perinuclear (P-ANCA), and atypical. Immunofluorescence testing alone has low specificity and a low positive predictive value for GPA. Hence, the diagnosis of GPA should never rest primarily on a positive immunofluorescence assay, regardless of whether the pattern is C-ANCA or P-ANCA. In patients with vasculitis, the C-ANCA pattern usually corresponds to the presence of antiproteinase-3 antibodies (PR3-ANCA), detected by enzyme immunoassay. The combination of a C-ANCA pattern by immunofluorescence and a positive PR3-ANCA by enzyme immunoassay has a high positive predictive value for GPA.
The P-ANCA pattern usually corresponds to the presence of MPO-ANCA in patients with vasculitis. MPO-ANCA occur in approximately 10% of patients with GPA but are more typical of microscopic polyangiitis (see Chapter 33), eosinophilic granulomatosis with polyangiitis (the Churg-Strauss syndrome; see Chapter 34), and necrotizing crescentic glomerulonephritis (ie, renal-limited, ANCA-associated vasculitis).
Atypical immunofluorescence ANCA patterns, which may occur in association with a wide variety of diseases such as inflammatory bowel disease and connective tissue disorders, are not directed against either PR3 or MPO and do not imply the presence of a primary vasculitis. Atypical ANCA patterns of immunofluorescence are often misread by inexperienced laboratories as showing perinuclear immunofluorescence.