You are on page 1of 5

Granulomatosis with polyangiitis (GPA), formerly known as Wegener granulomatosis, is a rare multisystem

autoimmune disease of unknown etiology. Its hallmark features include necrotizing granulomatous inflammation
and pauci-immune vasculitis in small- and medium-sized blood vessels. See the image below.
Necrotic, purpuric, and blistering plaque on the wrist in a patient with granulomatosis with polyangiitis.

See Vasculitis: Case Presentations, a Critical Images slideshow, for more information on clinical, histologic, and
radiographic imaging findings in various forms of vasculitis.
he pathologic hallmarks of GPA are vasculitis of the small- to medium-sized vessels, "geographic" necrosis,
and granulomatous inflammation, particularly in the airways. The initial pathologic lesion is that of the
granuloma believed to be caused by cellular immune processes.
Environmental exposures, including respiratory tract infections, have been implicated as inciting factors for
granuloma formation. A better understanding of the progression from granuloma to vasculitis may shed light on
the possible etiology and pathogenesis of GPA. It is probable that a complex interaction exists between the
environment and host factors, many of which are genetically determined. Cellular immune processes are also
involved in tissue injury owing to the inflammatory cascade.
Routine laboratory tests are nonspecific in granulomatosis with polyangiitis (GPA). Elevated blood urea
nitrogen (BUN) and creatinine levels may signal renal involvement. Hypoalbuminemia may be present. Serum
complement levels are within the reference range or increased. [49]
Mild normochromic normocytic anemia is present in 50% of patients. A peripheral blood smear may show
schistocytes and burr cells. Leukocytosis is also common, with a neutrophil predominance. Eosinophilia is not a
feature of GPA but rather of allergic granulomatous angiitis (Churg-Strauss syndrome).
Westergren erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels are elevated in 90% of
patients with active and generalized disease. They may decrease in response to treatment.
In patients with renal involvement, urinalysis may show non-nephrotic–range to nephrotic-range proteinuria,
microscopic hematuria, and the presence of red blood cell (RBC) casts consistent with underlying
Rheumatoid factor is positive in a low titer in two thirds of patients, whereas antinuclear antibody is present in
10-20% of patients. Hypergammaglobulinemia may be present.
Whether tissue diagnosis is always required for GPA remains controversial. As the therapy for severe GPA is
not benign, tissue diagnosis is recommended if a biopsy site isavailable , provided that the patient
understands the risks of the procedure.
Antineutrophil cytoplasmic antibodies (ANCAs) can be detected with serologic assays. The 2 types of assays
in common use are immunofluorescence (IF) and enzyme immunoassay. Three types of IF patterns are
recognized: C-ANCA (cytoplasmic antibody), P-ANCA (perinuclear antibody), and atypical ANCA. (See the
images below.) Findings on chest radiography are abnormal in two thirds of adults with GPA. The most
common radiologic findings are single or multiple nodules and masses. Nodules are typically diffuse, and
approximately 50% are cavitated.

Signs and symptoms
GPA has a spectrum of clinical presentations that includes recurrent respiratory infection in adults and upper
and lower respiratory tract problems in children. In addition, patients may report the following chronic,
nonspecific constitutional complaints:

Fevers, night sweats
Fatigue, lethargy
Loss of appetite
Weight loss
Ophthalmic manifestations

affecting small and medium joints Arthritis. or brain. resulting in saddle nose deformity (common) Serous otitis media and hearing loss So-called strawberry gingival hyperplasia Stridor. myocardial infarction. or sudden death Gastrointestinal: Abdominal pain may be present with splanchnic vasculitis See Clinical Presentation for more detail. nose. typically affecting large joints. and includes the following:    Mononeuritis multiplex Sensorimotor polyneuropathy Cranial nerve palsies CNS manifestations include vasculitis of small to medium–sized vessels of the brain or spinal cord and granulomatous masses that involve the orbit. ulcerations may resemble pyoderma gangrenosum Petechiae. [4] Cutaneous manifestations    Cutaneous findings are variable and nonspecific and usually affect the lower extremities Palpable purpura or skin ulcers (45%) [1] . subungual splinter hemorrhages. and genital ulcers resembling squamous cell carcinoma have been reported Additional findings   Cardiac: Pericardial rub. but rarely deforming Renal manifestations  Crescentic necrotizing glomerulonephritis characterized by urinary sediment with more than 5 RBCs per HPF or erythrocyte casts  Renal disease is present in 17% of patients at initial diagnosis and is usually asymptomatic [3]  Renal failure occurs in 11% at presentation [1] Nervous system manifestations Peripheral nervous system (PNS) involvement may occur in as many as 67% of patients. with dullness on percussion. from tracheal or subglottic granulomatous masses Pulmonary Pulmonary involvement in GPA can be asymptomatic. meninges. digital necrosis. Other ENT manifestations are as follows:       Rhinitis (22%) [1] Epistaxis (11%) [1] Collapse of nasal support. decreased breath sounds. vesicles. failure to respond to conventional treatment is suggestive. . insidious in onset. and throat manifestations Chronic sinusitis is the most common initial complaint in GPA. livedo reticularis. usually polyarticular and symmetrical. or severe and fulminant. typically later in the disease course. pustules. and crackles on auscultation Musculoskeletal manifestations    Myalgias Arthralgias. Pulmonary disease may cause any of the following:        Pulmonary infiltrates (71%) Cough (34%) Hemoptysis (18%) Chest discomfort (8%) [1] Dyspnea (7%) [1] Diffuse alveolar hemorrhage due to alveolar capillaritis (5%-45%) [2] Atelectasis. occurring in 67% of cases.       Conjunctivitis Episcleritis Uveitis Optic nerve vasculitis Retinal artery occlusion Nasolacrimal duct occlusion Proptosis Ear. hemorrhagic bullae. possibly leading to respiratory compromise. optic nerve.

oral or subcutaneous) has been used for the maintenance of remission if the serum creatinine level is less than 1. CRP) Antineutrophil cytoplasmic antibody (ANCA) testing  Cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) directed against PR3 is most specific for GPA  Some patients with GPA express perinuclear-staining ANCA (p-ANCA) specific for myeloperoxidase (MPO)  Combining immunofluorescence and ELISAenhances the sensitivity and specificity of a diagnosis of an ANCA-associated vasculitis (AAV) to 96% and 98. atelectasis. cyclophosphamide in maintaining remission [6] Methotrexate (20-25 mg weekly. renal and lung biopsies are most specific for GPA See Workup for more detail Management Induction of remission in GPA is approached as follows:    Cyclophosphamide with high-dose glucocorticoids (criterion standard) Rituximab with high-dose glucocorticoids Methotrexate (oral or subcutaneous) with high-dose glucocorticoids. often longer Azathioprine (2 mg/kg/day) is safer than. pleural thickening or effusion. leukocytosis is common. treatment for maintenance of remission should be continued for at least 18 months. in non–organ-threatening or non– life-threatening GPA [5]  Plasma exchange may be considered in patients with rapidly progressive renal disease (serum creatinine level >5. bronchiectasis. airway disease. and diffusing capacity should be performed as soon as possible to identify abnormalities and provide a baseline  Bronchoscopy: Helpful in the evaluation of alveolar hemorrhage. and endobronchial lesions  Biopsy: The diagnosis of GPA is generally confirmed with tissue biopsy from a site of active disease.Diagnosis Routine laboratory tests are nonspecific in GPA. plethysmography. and obstructive pneumonia caused by bronchial stenosis may also be seen  Findings on CT scans include consolidation. but it is associated with more adverse effects [7]   . bronchial wall thickening.65mg/dL) inorder to preserve renal function [5] Maintenance of remission     Once induction of remission has occurred. respectively Chest radiography and CT scanning    The most common radiologic findings are single or multiple nodules and masses Nodules are typically diffuse. Results may include the following:    Abnormal kidney function tests and urinalysis in patients with renal involvement Rheumatoid factor is positive in a low titer in two thirds of patients CBC: Mild normochromic normocytic anemia is present in 50% of patients. and as effective as. and lymphadenopathy Other studies   Sinus CT scanning: The radiographic test of choice to evaluate sinus disease Pulmonary testing: Spirometry. patchy or diffuse ground-glass opacities. with a neutrophil predominance  Elevated inflammatory markers (ESR. or both  Additional CT scan findings include stenoses of the larynx or tracheobronchial tree. infection. and approximately 50% are cavitated Diffuse alveolar opacities.5%.5 mg/dL Leflunomide (20-30 mg/day) is as effective as methotrexate.

the smallest vessels (capillaries and small arterioles). As lesions progress. and the venous system. Mononeuritis multiplex is the most common form of PAN neuropathy. thrombosis. resulting in microaneurysm formation. resulting in fibrinoid necrosis. it certainly can occur early. organ ischemia or infarction. persistent headaches. Inflammation may start in the vessel intima and progress to include the entire arterial wall.[2] The lungs are usually spared with PAN. abdominal pain.[1]  PAN. and polyneuropathy revealed areas of focal inflammatory exudations that gave rise to palpable nodules along the course of medium-sized arteries. warrant complete neurologic evaluation. [5] The pathogenesis of polyarteritis nodosa (PAN) is unknown.These markers may be useful in evaluating some patients for active disease but do not correlate with activity in all patients [5] Leukocytosis. [9] Evidence of peripheral neuropathy should be sought carefully with history and electromyography (EMG). A typical PAN patient might present with fever. including brain-imaging studies. The autopsy of a patient with fever. night sweats. destroying the internal and external elastic lamina. being found in as many as 60% of patients. Electroencephalography (EEG) may show nonspecific findings of generalized slow wave activity during periods of encephalopathy or toxic delirium. although it typically occurs within 6 months of infection. Pathologic headaches are often difficult to differentiate from benign headaches solely on clinical grounds. and. Findings include the following:       Elevated erythrocyte sedimentation rate (ESR) and/or C-reactive protein . Classic polyarteritis nodosa (PAN or c-PAN) is a systemic vasculitis characterized by necrotizing inflammatory lesions that affect medium-sized and small muscular arteries.[8]Polyarteritis nodosa (PAN) spares large vessels (the aorta and its major branches). Vascular lesions in medium-sized muscular arteries occur mainly at bifurcations and branch points. Severe. Thrombi may develop at the site of the lesions. like other vasculitides. with or without neurologic deficit. [5] Aneurysms develop in the weakened vessel. skin ulcerations or tender nodules. virus replication may directly injure the vessel wall. and the kidney. weight loss. and no animal model is available for study. in HBV-PAN. weight loss. the role of immune complexes in non-HBV-related PAN remains unclear. but other forms can be present.[8] HBV-associated vasculitis almost always takes the form of PAN. the gut. aneurysmal rupture with hemorrhage. or thrombocytosis Hepatitis B surface antigen and hepatitic C serologies Elevated creatinine level Mild proteinuria Elevated levels of liver enzymes . since it is a common complication of polyarteritis nodosa (PAN). and severe muscle and joint pains developing over weeks or months. Evidence for immune complex–induced disease is confined to HBV-related PAN. affects multiple systems and has protean manifestations. although it most commonly affects skin (see the image below). H epatitis B virus (HBV) infection is strongly linked with PAN. HBV-PAN may occur at any time during the course of acute or chronic hepatitis B infection. carrying a subsequent risk for rupture and hemorrhage. proliferation of the intima or media may result in obstruction and subsequent tissue ischemia or infarction. PAN and other vasculitic diseases should be considered in many patients with stroke with multiple foci or a combination of hemorrhage and infarction. joints.  Kussmaul and Maier first described PAN in 1866. Many neurologic and systemic disorders can present with headache. peripheral nerves. Even though stroke is a late complication in many cases of PAN.[9] Endothelial dysfunction can perpetuate the inflammation through cytokine and adhesion molecule production. Laboratory studies Laboratory findings in PAN are nonspecific but can help to establish the systemic nature of the disease. preferentially at vessel bifurcations. normochromic anemia. [5] Impaired function of endothelial cells may be part of idiopathic PAN or a consequence of it. consequently.

 Hypergammaglobulinemia . This combination can provide prolonged survival for these patients. Cyclophosphamide is not routinely recommended in hepatitis B–related PAN as the use of steroids with cyclophosphamide in these patients has been demonstrated to enhance viral replication. circulating immune complexes. early diagnosis and treatment are critical in PAN. with mortality often associated with kidney failure. cardiac complications. corticosteroids are the cornerstone of treatment. Microcoil embolization of cerebral aneurysm may be indicated. Therefore. In contrast. The addition of cyclophosphamide is the standard of care for patients with idiopathic PAN whose disease issteroid refractory or includes major organ involvement. C4) may be observed in patients with HBV-related PAN but are otherwise uncharacteristic of idiopathic PAN. for hepatitis B–related PAN. Previously. but polymorphonuclear pleocytosis can be seen when meningeal signs are present. and decreased levels of serum complement (ie. Case reports have described successful use of rituximab[52] and infliximab.Found in 30% of patients with PAN Cryoglobulins.[54] Surgical care Surgery may be necessary for GI manifestations of PAN. treatment consists of schemes that include corticosteroids with antiviral agents and plasmapheresis. Postsurgical care may be needed for patients with PAN who develop bowel infarction. The treatment of polyarteritis nodosa (PAN) has improved dramatically. and appendicitis. untreated PAN was usually fatal within weeks to months. C3.[53] Plasma exchange has been used in a few patients with severe PAN. including bowel ischemia. Cerebrospinal fluid findings often are usually normal in PAN. . Biologic agents have been investigated in patients with steroid-refractory and recurrent PAN. cholecystitis. Currently. Antiviral drugs used include vidarabine or interferon alpha-2b. or GI complications.