Granulomatosis with Polyangiitis

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Practice Essentials

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.

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:

Ophthalmic manifestations

Ear, nose, and throat manifestations

Chronic sinusitis is the most common initial complaint in GPA, occurring in 67% of cases; failure to respond to conventional treatment is suggestive. Other ENT manifestations are as follows:

Pulmonary

Pulmonary involvement in GPA can be asymptomatic, insidious in onset, or severe and fulminant. Pulmonary disease may cause any of the following:

Musculoskeletal manifestations

Renal manifestations

Nervous system manifestations

Peripheral nervous system (PNS) involvement may occur in as many as 67% of patients, typically later in the disease course, and includes the following:

CNS manifestations include vasculitis of small to medium–sized vessels of the brain or spinal cord and granulomatous masses that involve the orbit, optic nerve, meninges, or brain.[4]

Cutaneous manifestations

Additional findings

See Clinical Presentation for more detail.

Diagnosis

Routine laboratory tests are nonspecific in GPA. Results may include the following:

Antineutrophil cytoplasmic antibody (ANCA) testing

Chest radiography and CT scanning

Other studies

See Workup for more detail

Management

Induction of remission in GPA is approached as follows:

Maintenance of remission

See Treatment and Medication for more detail.

Image library


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Saddle nose deformity in a 26-year-old man with granulomatosis with polyangiitis. Image courtesy of P. Papadopoulos, MD.

Background

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 images below). (See Etiology.)


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Lung biopsy specimen from a patient with granulomatosis with polyangiitis showing evidence of vasculitis and inflammation (high-power view). Image cou....


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Lung biopsy specimen from a patient with granulomatosis with polyangiitis showing evidence of vasculitis and inflammation (high-power view). Image cou....

In 1897, Peter McBride likely gave the first written description of a patient with the condition. In 1931, Klinger described a 70-year-old physician with constitutional symptoms, joint symptoms, proptosis, widespread upper respiratory tract inflammation leading to saddle nose deformity, glomerulonephritis, and pulmonary lesions. (See Presentation.)

In 1936, Dr. Frederich Wegener reported three patients with similar clinical features and published his findings on their distinct clinical and histopathologic findings, leading to the eponymous designation of the disease.

In 1954, Goodman and Churg provided the definitive description of GPA upon their identification of a triad of pathological features that characterize the disease, including (1) systemic necrotizing angiitis, (2) necrotizing granulomatous inflammation of the respiratory tract, and (3) necrotizing glomerulonephritis. (See Etiology, Presentation, and Workup.)

The American College of Rheumatology, European League Against Rheumatism, and American Society of Nephrology have recommended a gradual shift from honorific eponyms to disease-descriptive or etiology-based nomenclature. In the case of GPA, the change was triggered by evidence that Wegener was a member of the Nazi party before and during World War II. The recommended alternative name was already being used in the medical literature.[8]

Before the institution of effective therapy, the mean survival of adults with untreated GPA was only 5 months, with 82% of patients dying within the first year and 90% of patients dying within the second year. Despite improvement with the use of corticosteroids, the mean survival time was increased only to 12.5 months.

With the advent of cytotoxic therapy for GPA, patient survival markedly improved. In 1983, Fauci et al reported a 93% complete remission rate in 85 patients (mean age 43.6 y, range 14-75 y) treated with prednisone and oral cyclophosphamide. (See Treatment and Medication.)[1]

1990 criteria for the classification of granulomatosis with polyangiitis

These criteria from the American College of Rheumatology are used for enrolling patients in studies and should not be considered as diagnostic criteria. These criteria were developed before antineutrophil cytoplasmic antibody (ANCA) testing was in widespread use as a diagnostic test for GPA. The criteria are as follows:

For the purposes of classification, a patient is said to have GPA if at least 2 of these 4 criteria are present. The presence of any 2 or more criteria yields a sensitivity of 88.2% and a specificity of 92%.[9]

Limited versus severe granulomatosis with polyangiitis

GPA is one of the ANCA-associated vasculitides (AAVs) and has a predilection for the upper and lower respiratory tracts and the kidneys. It has a spectrum of clinical presentations and may be divided broadly into limited or severe disease.

Individuals with limited GPA present with clinical findings largely isolated to the upper and lower respiratory tracts and are generally not considered to have organ- or life-threatening disease. Persons with severe disease present with significant multisystem manifestations that may involve the lungs, kidneys, and other organs, in addition to the respiratory tract. Severe disease can also be described as generalized disease.

Consensus does not exist as to whether limited GPA represents early severe disease or an altogether separate clinical entity. The terminology, limited versus severe, can sometimes be problematic because pulmonary and/or renal involvement may be absent at the onset of symptoms.

Longitudinal follow-up of the National Institutes of Health GPA cohort (158 patients who were observed for 6 mo to 24 y) demonstrated that 18% of patients initially had renal disease and that 77% had glomerulonephritis upon later analysis.[3] Thus, patients initially diagnosed with limited GPA may subsequently develop generalized disease with renal involvement.

Analysis of another GPA cohort, that of the Wegener Granulomatosis Etanercept Trial (WGET), suggested that limited disease may be a qualitatively different clinical entity. In the WGET cohort, patients classified as having limited disease had more severe upper respiratory tract damage, were more likely to have flares after remission, and tended to have identical manifestations when they relapsed.[10]

Below is an outline of the differences between limited and severe GPA based on the WGET trial manual of operations.

Limited granulomatosis with polyangiitis

This designation is reserved for cases that fulfill the modified American College of Rheumatology criteria for the classification of GPA in the absence of disease features that pose immediate threats to either a critical individual organ or to the patient's life. Specifically, this means the following:

Severe granulomatosis with polyangiitis

Any patient with GPA whose disease is not classifiable as limited has severe disease, by definition.[10]

Patient education

Patients with GPA and their families must be educated on the serious nature of this disease. Potential risks and adverse effects of immunosuppressive medications should be detailed.

Etiology

The 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.

ANCAs

The discovery of ANCAs within neutrophils in the majority of patients with GPA suggested the role of humoral autoimmunity. GPA is usually associated with the presence of diffuse staining cytoplasmic ANCA (C-ANCA) directed against serine proteinase 3 antigen (PR3-ANCA), the so-called Wegener autoantigen.

The other AAVs include microscopic polyangiitis, renal-limited vasculitis, and Churg-Strauss syndrome (allergic granulomatous angiitis), which are more commonly associated with perinuclear-staining ANCA (P-ANCA) directed against myeloperoxidase (MPO-ANCA).

A pathogenic role for PR3-ANCAs in GPA has been proposed, because PR3-ANCA is strongly associated with the disease; over 90% of GPA patients have been reported to have ANCA positivity during active disease.[11] Longitudinal observations have indicated that relapse is sometimes heralded by a rise in PR3-ANCA titers, although other studies could not confirm these results.[12, 13, 14]

Schlieben et al reported that a newborn developed a pulmonary-renal syndrome associated with transplacental passage of MPO-ANCA immunoglobulin G (IgG) from a mother with ANCA disease who developed a clinical and serologic flare of disease during pregnancy.[15]

Another argument for the pathogenic role of PR3-ANCA comes from observations that ANCA persistence after induction of remission in patients with GPA is associated with relapse.[16] Additionally, efficacy of treatment with rituximab, a B-cell depleting monoclonal antibody and, thus, an inhibitor of antibody production, supports a pathogenic role of ANCA in patients with AAV.[17, 18]

Evidence also comes from in vitro studies. The in vitro effects of PR3-ANCA described to date include activation of primed neutrophils, leading to production of reactive oxygen species, and release of lytic enzymes such as elastase and PR3, which act to promote tissue injury.[19, 20] In vitro data also demonstrate the role of complement in AAV and show that ANCAs are involved in neutrophil-endothelial cell activation. Both of these processes likely help to target the endothelium, resulting in necrotizing vasculitis.[21]

In vivo experimental studies have demonstrated a pathogenic role for MPO-ANCA in mice and rat models. MPO-ANCA induces a pauci-immune necrotizing glomerulonephritis and hemorrhagic capillaritis in these animal models.[22] Neutrophils, as well as the complement system, are necessary for lesion development.[21] Despite this in vivo evidence for a pathogenic role of MPO-ANCA in AAV-like syndromes in animal models, no definitive in vivo evidence has yet been found for PR3-ANCA. Further research is necessary to further elaborate its role in GPA.

Genetics

Typically, most autoimmune diseases are attributed to a genetic predisposition combined with exposure to an inciting factor. Genotypic associations in GPA include the following[19, 23, 24, 25, 26, 27, 28] :

Microbes

The role of microbes in the pathogenesis of AAV has also been explored, although the mechanism has not been fully explained. The first evidence for this was discovered by Stegeman et al, who noted that nasal carriage of Staphylococcus aureus is associated with relapses of GPA (relative risk, 9.0) and prophylactic treatment with trimethoprim-sulfamethoxazole (TMP-SMZ) can reduce the likelihood of relapse by 60%.[16]

Since then, there has been the discovery that complementary PR3, which shows homology with certain S aureus –derived peptides, may induce antibodies to PR3.[29] Additionally, at least in rat models, infection with gram-negative bacteria may lead to the development of AAV in susceptible individuals.[30]

Other factors

Living in northern latitudes, farming, drug and environmental allergies, and exposures to solvents or silica have all been linked to the development of GPA.[25, 31] Reports vary as to whether disease onset is associated with a seasonal peak.

Epidemiology

GPA is a rare disease with an as yet undetermined incidence. The prevalence of GPA in the United States is estimated to be 3 cases per 100,000 people.

The incidence and prevalence of GPA in the United Kingdom is estimated at 10.2 cases and 250 cases per million population, respectively.

Race-, sex-, and age-related demographics

GPA is more common in individuals of northern European descent (approximately 90%); it occurs less commonly in blacks.

In European populations, GPA is slightly more common in men, with a male-to-female ratio of 1.5:1.[32] Women are more likely to have limited disease.[10]

The onset of GPA may occur at any age, although patients typically present at age 35-55 years. GPA is rare in childhood.[33]

Prognosis

The remission rate in GPA ranges from 30-93%, depending on the definition of remission and the remission induction therapy used.[34] With aggressive therapy for active disease, more than 50% of patients with GPA recover renal function and are able to become dialysis independent.[35, 36]

Unfortunately, relapse is common in GPA. Typically, up to half of patients with GPA experience relapse within 5 years.[37] The rate (18-40% at 24 mo) and time to first relapse (15-29 mo) varies.[34] Factors associated with relapse include treatment (< 10 g of cyclophosphamide in the first 6 mo, maintaining a high dose of prednisone [>20 mg/day] for < 2.75 mo, and goal of 0 dose of glucocorticoids), ANCA status at diagnosis, and target organ involvement (lung involvement, cardiac involvement, renal involvement, chronic nasal carriage of S aureus).[34, 38]

Rising PR3-ANCA (C-ANCA) titers may correlate with disease activity in approximately two-thirds of patients. However, the relationship is unreliable; thus, negative PR3-ANCA results do not necessarily exclude the possibility of relapse.[37] As significant adverse effects are associated with immunosuppressive therapy, especially cyclophosphamide, ANCA persistence or reappearance should be used as a warning signal rather than an indication to escalate therapy.

Poorer survival is associated with older age, target organ involvement, and target organ damage. Renal involvement has been consistently shown to confer a poorer prognosis. An absence of renal involvement is associated with a 100% 5-year survival rate, compared with approximately 70% in individuals with renal disease.[39] An increased risk of cardiovascular events is also noted. Overall, the 10-year survival rate ranges from 75-88%.[39] Most morbidity in GPA is currently treatment related.

Complications

In a longitudinal cohort consisting of 158 patients with GPA, from the National Institutes of Health (NIH), 86% of patients experienced permanent damage from their disease.[40] Permanent damage includes the following:

Respiratory problems may result from upper-airway obstruction (eg, subglottic stenosis) or pulmonary involvement (eg, pleural effusion, dyspnea, diffuse alveolar hemorrhage [DAH]).

Many patients in the NIH cohort (42%) also experienced permanent treatment-associated morbidity, including hemorrhagic cystitis, osteoporotic fractures, urothelial (bladder) cancer, myelodysplasia, and avascular necrosis.[40] Urotoxic adverse events associated with cyclophosphamide use are related to cumulative dose and oral administration. Cyclophosphamide treatment of systemic vasculitis increases the risk of urothelial cancer 5-fold over that of the general population.[41]

Furthermore, the development of other cancers associated with immunosuppression in patients with AAV is a concern, as it is for patients with other inflammatory rheumatologic and nonrheumatologic diseases and for patients who have undergone organ transplantation. Increased rates of leukemia, lymphoma, and nonmelanoma skin cancers have been reported in a number of studies of treated patients with AAV. The observed overall incidence of cancers in this population is 1.6-2.4 times higher than in the general population.[42] Clinicians caring for these patients should keep this increased risk in mind and refer and/or screen appropriately.

Additionally, an increased rate of cardiovascular events is noted in patients with AAV. A European study that reviewed outcomes during long-term follow-up of patients with GPA and microscopic polyangiitis determined that within 5 years of diagnosis, 14% of patients experienced at least 1 cardiovascular event. This was 3.7 times higher than was expected in the background population. This study determined that older age, diastolic hypertension, negative PR3-ANCA status, and positive MPO-ANCA status are independent determinants of cardiovascular outcomes in patients without prior cardiovascular disease.[43]

Mortality

Severe, untreated GPA is associated with a very high (>90%) mortality rate. Historically, patients with untreated GPA had a mean survival of 5 months from diagnosis; the mortality rate was 82% at 1 year. The introduction of corticosteroids prolonged the median survival by only 7.5 months.

With the advent of cytotoxic therapy, patient survival in GPA markedly improved. According to a meta-analysis, with current treatments, the 5-year survival rate ranges from 74-79%.[39] The 1-year mortality rate is still high, around 11% (range, 2.2-25%), depending on disease severity and the intensity of treatment.[44]

The most common causes of death in GPA are as follows:

History

Clinician awareness is important to prevent delayed or missed diagnosis. Recurrent respiratory infection in an adult may be an indicator of granulomatosis with polyangiitis (GPA). However, the clinician must remain mindful that GPA has a spectrum of clinical presentations.

Patients may report the following chronic, nonspecific constitutional complaints:

Ophthalmic symptoms

Ocular involvement occurs in many patients, including the following:

Ear, nose, and throat symptoms

The symptoms causing pediatric patients to seek medical care are usually attributable to the upper and lower respiratory tract.

Chronic sinusitis is the most common initial complaint (67%); failure to respond to conventional treatment is suggestive. Rhinitis and epistaxis occur in 22% and 11% of patients with GPA, respectively.[1]

The development of a saddle nose deformity caused by collapse of nasal support is common. Serous otitis media and hearing loss are the presenting manifestations of GPA in some patients. Tracheal or subglottic granulomatous masses can cause stridor and lead to respiratory compromise.


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Granulomatosis with polyangiitis (formerly known as Wegener granulomatosis). Large ulceration of the pharynx covered with a dense necrotic membrane.

Pulmonary symptoms

Pulmonary involvement can be asymptomatic, insidious in onset, or severe and fulminant. Pulmonary disease may cause any of the following[1] :

Musculoskeletal symptoms

Musculoskeletal symptoms are common. Arthralgias are usually polyarticular and symmetric, affecting small and large joints. Arthritis can also occur, and typically affects large joints, but is rarely deforming.

Renal involvement

Renal disease is present in 17% of patients at initial diagnosis and is usually asymptomatic.[3] Renal failure occurs in 11% at presentation.[1] Renal disease manifests as crescentic necrotizing glomerulonephritis characterized by urinary sediment with more than 5 red blood cells per high-power field or erythrocyte casts.

Nervous system symptoms

The nervous system is affected in numerous patients. Peripheral nervous system (PNS) involvement may occur in as many as 67% of patients, typically later in the disease course. PNS manifestations include mononeuritis multiplex, sensorimotor polyneuropathy, and cranial nerve palsies. Central nervous system (CNS) manifestations include vasculitis of small to medium–sized vessels of the brain or spinal cord and granulomatous masses that involve the orbit, optic nerve, meninges or brain.[4]

Cutaneous symptoms

The skin is involved in 45% of patients with GPA due to vasculitis and can lead to palpable purpura or skin ulcers.[1]


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Necrotic, purpuric, and blistering plaque on the wrist in a patient with granulomatosis with polyangiitis.

Cardiac symptoms

Cardiac involvement is rarely detected antemortem but includes pericarditis and coronary arteritis in 10-20% of cases. Necrotizing vasculitis of the coronary vessels can result in a myocardial infarction or sudden death.

Physical Examination

Signs related to the head, ears, eyes, nose, and throat

Sinusitis and disease in the nasal mucosa are the most common findings. Ocular findings include scleritis, episcleritis, keratitis, uveitis, and conjunctivitis. Proptosis may signal a retrobulbar granulomatous mass. Xanthelasma has also been reported.

Otitis media and/or hearing loss may be present. Purulent or serosanguinous nasal discharge may be seen. Saddle nose deformity may be present. (See image below.)


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Saddle nose deformity in a 26-year-old man with granulomatosis with polyangiitis. Image courtesy of P. Papadopoulos, MD.

Oral involvement is rare; however, a classic presentation includes "strawberry gingival hyperplasia."

Pulmonary/respiratory signs/symptoms

Pulmonary/respiratory symptoms can include the following:

Cutaneous findings

Cutaneous findings are variable and nonspecific and usually affect the lower extremities. Palpable purpura, papules, subcutaneous nodules, and ulcerations are the most common findings. Ulcerations may resemble pyoderma gangrenosum.

Petechiae, vesicles, pustules, hemorrhagic bullae, livedo reticularis, digital necrosis, subungual splinter hemorrhages, and genital ulcers resembling squamous cell carcinoma have been reported.


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Several necrotic, purpuric, and blistering papules and plaques on the hands in a patient with granulomatosis with polyangiitis.

Additional findings

Other symptoms may include the following:

Approach Considerations

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.[46]

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 glomerulonephritis.

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 is available, provided that the patient understands the risks of the procedure.

ANCA Detection

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.)


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C-ANCA immunofluorescence pattern. Staining for antineutrophil cytoplasmic antibody by indirect immunofluorescence shows heavy cytoplasmic staining, w....


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P-ANCA immunofluorescence pattern. Perinuclear antineutrophil cytoplasmic antibody staining pattern by indirect immunofluorescence shows perinuclear s....

IF represents a qualitative ANCA assay, and significant inter-reader variability exists. Enzyme-linked immunosorbent assay (ELISA) provides target antigen-specific characterization of ANCA (ie, anti-PR3 and anti-myeloperoxidase [MPO]) and should be used to confirm IF findings. Combining IF and ELISA enhances the sensitivity and specificity of a diagnosis of AAV to 96% and 98.5%, respectively.[24] Only ANCAs directed against PR3 or MPO have been associated with primary vasculitic syndromes.

C-ANCA directed against PR3 is most specific for GPA. According to the WGET trial, IF shows positive C-ANCA results in 88% of all patients with GPA. IF shows positive C-ANCA results in 87% of patients with severe disease and in 90% of those with limited disease.[10] Using both IF and ELISA, ANCA is detectable in nearly 100% of patients with active generalized GPA.[24]

Some patients with GPA express P-ANCA specific for MPO. Analysis of the WGET cohort demonstrated that IF showed positive P-ANCA results in 13% of patients with severe disease; 10%of patients with limited disease were P-ANCA–positive.[10] A few patients with GPA are ANCA-negative, although this fraction appears to be exceedingly small.[11, 19]

Rising C-ANCA titers may herald a relapse in some patients with GPA, but this relationship is unreliable. Thus, patients with rising ANCA titers should not be treated with cytotoxic medications in the absence of signs, symptoms, or other objective evidence of disease relapse.[23, 37]

Further considerations in P-ANCA testing

In contrast to GPA, the indirect IF staining pattern in microscopic polyangiitis and allergic granulomatous angiitis is often perinuclear (P-ANCA). This is an artifactual phenomenon that occurs during the ethanol fixation process of neutrophils, resulting in the displacement of the basic positively charged proteins (eg, MPO, lactoferrin, lysozyme, elastase, cathepsin G) from the cytoplasm to the nuclear region. MPO is the antigen at which these autoantibodies are most often directed in the setting of small-vessel vasculitis. This antibody can be observed in microscopic polyangiitis, allergic granulomatous angiitis, idiopathic crescentic glomerulonephritis, and, occasionally, GPA.

A positive finding on a P-ANCA test alone can be observed in a number of other diseases that would not qualify as small-vessel vasculitis. These include inflammatory bowel disease, Kawasaki disease, polyarteritis nodosa, Felty syndrome, and infections such as human immunodeficiency virus (HIV) infection and endocarditis. Because of the variability of the P-ANCA target antigen, more specific antibody testing is recommended strongly. A positive P-ANCA test result should be used to diagnose small vessel vasculitis only when it is used in conjunction with a positive antimyeloperoxidase titer in the setting of high clinical suspicion.

Cautions

In summary, be cautious not to equate a positive ANCA test result with disease. When used appropriately, the ANCA test is a very powerful test with high degrees of sensitivity and specificity; however, when used in the wrong setting, it can lead to misdiagnosis with resultant inappropriate treatment using potentially toxic therapy. Indeed, a positive C-ANCA test result in patients with only sinusitis has a posttest probability of 7-16% of correctly diagnosing GPA. In patients with sinusitis, pulmonary infiltrates or nodules, and active urinary sediment with RBC casts, a positive C-ANCA test finding has a posttest probability of GPA of 98%. Moreover, ANCA tests should not be used to correlate with clinical disease in patients with established diagnoses of vasculitis.

Radiography and CT Scanning

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. (See the images below.)


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Granulomatosis with polyangiitis. Bilateral nodules observed on a plain chest radiograph in a patient with hemoptysis and hematuria. Image courtesy of....


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This 42-year-old man presented with hemoptysis, weight loss, and night sweats. He was diagnosed with the limited form of granulomatosis with polyangii....


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Granulomatosis with polyangiitis. This patient presented with massive hemoptysis. No nodules are identified on the chest radiograph, although a subseq....


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Shown is a chest radiograph of an 11-year-old girl who presented with an upper respiratory tract infection, myalgias, and arthralgias for 1 month, fol....


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An 11-year-old girl presented with an upper respiratory tract infection, myalgias, and arthralgias for 1 month followed by an abrupt presentation with....


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Bilateral cavitating nodules in a patient with granulomatosis with polyangiitis.

Diffuse alveolar opacities due to diffuse alveolar hemorrhage (DAH), atelectasis, and obstructive pneumonia caused by bronchial stenosis may also be seen. Findings on computed tomography (CT) scans and high-resolution CT (HRCT) scans include consolidation, patchy or diffuse ground-glass opacities, or both. (See the images below.)


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Diffuse alveolar hemorrhage in a 21-year-old man with granulomatosis with polyangiitis. Image courtesy of the US Government.


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Diffuse alveolar hemorrhage in a 21-year-old man with granulomatosis with polyangiitis. Image courtesy of the US Government.

Additional CT scan findings include stenoses of the larynx or tracheobronchial tree, bronchial wall thickening, bronchiectasis, pleural thickening or effusion, and lymphadenopathy.

Sinus radiography

Opacification, bony destruction, and mucosal thickening are reported, but these signs are not specific to GPA. (See the image below.)


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Extensive thickening of the maxillary sinuses in a patient with granulomatosis with polyangiitis. The patient also had intermittent epistaxis.

Sinus CT scanning

This is the radiographic test of choice to evaluate sinus disease. Findings on thin-section sinus CT scans are abnormal in more than 90% of adults with GPA. A similar number would be expected in the pediatric population, based on an 83% incidence of sinusitis reported by Rottem et al.[47]

Pulmonary Testing

In patients old enough to cooperate, spirometry, plethysmography, and diffusing capacity should be performed as soon as possible to identify abnormalities and provide a baseline.

Good inspiratory and expiratory loops should be obtained. If these are flattened, subglottic stenosis or other causes for central airway obstruction should be suspected.

Because most pediatric subglottic stenosis is not found initially, spirometry, particularly with a good baseline flow volume loop, can be used to screen noninvasively for this development.

Spirometry may show either restrictive or obstructive patterns, and the diffusing capacity of lung for carbon monoxide (DLCO) may be decreased or increased, as in the case of DAH.[2]

Although a decreased diffusing capacity is a common finding in GPA, it may still fall within the reference range. In alveolar hemorrhage, the single-breath diffusing capacity is increased.

In adults, limitation to flow and decrease of the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) are the most common pulmonary function test abnormalities. Focal and interstitial infiltrates and peripheral mass lesions produce decreased lung volumes.

Bronchoscopy

This study is helpful in the evaluation of alveolar hemorrhage, infection, airway disease, and endobronchial lesions.

Transbronchial biopsy in diffuse lung disease has a low yield of diagnostic findings, presumably because of the geographic nature of the granulomatous inflammation. Bronchoscopy may also be used as needed for palliative measures for narrowed airways (ie, stents).[48]

Biopsy

The diagnosis of GPA is generally confirmed with tissue biopsy from a site of active disease, and renal and lung biopsies are most specific for GPA. However, sampling error may occur, and histopathologic findings can be nonspecific. Tissue diagnosis may not be required if the clinical gestalt is convincing and a site for biopsy is not apparent or would be too invasive to obtain. For example, the finding of leukocytoclastic vasculitis in the setting of pulmonary nodules and PR3-ANCA may be sufficient for the diagnosis.

Renal biopsy may be easier to perform than lung biopsy and has a greater diagnostic yield. The typical renal lesion of GPA is segmental crescentic necrotizing glomerulonephritis with little or no immunoglobulin or complement deposition (pauci-immune). Generally, vasculitis is not observed, but this histology helps in establishing the diagnosis. Renal biopsy findings cannot be used to distinguish between GPA and microscopic polyarteritis. (See the image below.)


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A renal biopsy specimen from a 13-year-old girl with antineutrophil cytoplasmic antibody (C-ANCA)–positive pulmonary renal syndrome. Seven weeks after....

Although findings on a renal biopsy are often negative for the presence of granulomas in GPA, renal biopsy is nonetheless a very useful diagnostic tool, especially in the setting of pulmonary-renal syndrome.

Importantly, renal biopsy with indirect immunofluorescent staining allows exclusion of anti–glomerular basement membrane (GBM) antibody disease in the setting of a pulmonary renal syndrome. Because of the importance of treating anti-GBM with plasma exchange, this therapy is often started empirically and continued until this disease can be ruled out.

Lung biopsy is performed in the absence of renal involvement by either open or thoracoscopic lung biopsy. Biopsy may reveal the entire histologic spectrum of GPA to include vasculitis and granulomatous inflammation. Chronic infections should be excluded.

In the setting of pulmonary hemorrhage, pulmonary biopsy is much more risky. If the cause of a new infiltrate is unclear, bronchoscopy can be used to confirm the presence of blood. Lavage fluid is bloody and contains hemosiderin-laden macrophages. Stains and cultures should be obtained to rule out infection.

Upper respiratory tract tissue biopsies (nose, sinuses, subglottic region) are frequently nondiagnostic, yielding only nonspecific acute and chronic inflammation in up to 50% of biopsy samples. Upper respiratory tract biopsies demonstrate the full pathologic triad of granulomatous inflammation, vasculitis, and necrosis in only about 15% of cases. However, in the correct clinical context, finding only parts of this triad in an upper respiratory tract biopsy may support the diagnosis of GPA.

Peripheral nerve biopsy can be considered if signs or symptoms such as paresthesias or mononeuritis multiplex are present.

A retrospective study suggested that even in the absence of myalgias or creatine kinase elevation, a muscle biopsy can aid in the diagnosis of systemic vasculitides because biopsy findings can reveal necrotizing or nonnecrotizing vasculitis.[49] Prospective studies are needed.

Histologic Findings

Lung

Histologic examination of lung samples may reveal the classic triad of parenchymal necrosis, vasculitis, and granulomatous inflammation characterized by an inflammatory infiltrate composed of neutrophils, lymphocytes, plasma cells, histiocytes, and eosinophils. (See the images below.)


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Lung biopsy specimen from a patient with granulomatosis with polyangiitis showing evidence of vasculitis and inflammation (high-power view). Image cou....


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Lung biopsy specimen from a patient with granulomatosis with polyangiitis showing evidence of vasculitis and inflammation (high-power view). Image cou....

Pulmonary vasculitis may affect arteries, veins, and capillaries, is pauci-immune, and can be granulomatous or nongranulomatous. Vasculitis causes vessel wall necrosis with infiltration by neutrophils, which degenerate and become surrounded by palisading histiocytes and multinucleated giant cells. The neutrophilic debris coalesces into irregularly bordered microabscesses, which can become extensive areas of "geographic" necrosis.

Kidney

Segmental pauci-immune crescentic necrotizing glomerulonephritis is typically seen. The earliest histologic abnormalities include thrombotic changes in the glomerular capillary loops. The finding of granulomatous inflammation in renal biopsy samples is unusual. Generally, vasculitis is not observed in renal biopsy specimens. (See the image below.)


View Image

Focal glomerulonephritis with crescent formation on renal biopsy specimen, characteristic of granulomatosis with polyangiitis.

Skin

Leukocytoclastic vasculitis is most commonly reported.

Approach Considerations

The mainstay of treatment for granulomatosis with polyangiitis (GPA) is a combination of corticosteroids and cytotoxic agents. Treatment should be tailored to appropriately treat GPA manifestations while minimizing long-term toxicities to the patient. Untreated generalized or severe GPA typically carries a dismal prognosis, with up to 90% of patients dying within 2 years, usually of respiratory or renal failure. Even non-renal GPA carries a mortality rate of up to 40%.[39]

Outcomes for this previously fatal disease improved dramatically with the introduction in the 1970s of cyclophosphamide, which is administered in combination with corticosteroids.[3] Approximately 90% of patients with GPA respond to cyclophosphamide, with approximately 75% experiencing complete remission. However, 30%-50% of those who initially respond experience at least one relapse, requiring another course of therapy.

In general, limited disease does not require as aggressive therapy as does severe disease. Additionally, treatment recommendations are different for induction of remission and maintenance of remission.

Grading

Current treatment recommendations in GPA depend on the severity and activity of disease. The European Vasculitis Study Group recommends grading disease severity of antineutrophil cytoplasmic antibody (ANCA) – associated vasculitis (AAV) into the following 5 categories[5] :

Activity

Contact sports are to be avoided for 1 month following a kidney biopsy. Otherwise, activities are as tolerated. Because patients are immunosuppressed, they should attempt to minimize exposure to ill contacts.

Consultations

GPA is a multisystem disease that requires a multidisciplinary approach to management, involving rheumatologists, pulmonologists, nephrologists, and otolaryngologists (ear, nose, and throat specialists). In addition, a baseline ophthalmologic examination should be considered.

Deterrence/prevention

No known deterrents prevent the development of GPA.

Remission Induction

Cyclophosphamide

Generalized or severe disease generally requires aggressive therapy. Since introduced by Fauci et al in the 1970s, oral cyclophosphamide in combination with high-dose glucocorticoids (ie, prednisone 1mg/kg/day) has been the criterion standard for induction of remission in AAV.

Eventually, intravenous cyclophosphamide was investigated as an alternative to oral cyclophosphamide in an effort to decrease treatment-associated toxicities, and, while the emphasis has been placed on optimizing treatment by minimizing exposure to cyclophosphamide and seeking alternative comparable therapies, the combination of cyclophosphamide (intravenous or oral) and glucocorticoids remained the recommended therapy for induction of remission in generalized/severe GPA for years.[5]

In 2011, however, the US Food and Drug Administration (FDA) approved the use of rituximab (a monoclonal antibody that targets B cells), in combination with glucocorticoids, as an alternative to cyclophosphamide for induction of remission in AAV (GPA and microscopic polyangiitis).

Cyclophosphamide can be given either by a daily oral route or intermittent intravenous route in combination with high-dose glucocorticoids. The recommended daily oral dose of cyclophosphamide is 2 mg/kg/day (not to exceed 200 mg/day). Pulsed (intravenous) cyclophosphamide (15 mg/kg every 2 weeks for the first 3 pulses, then every 3 weeks for the next 3-6 pulses) is an alternative to daily oral cyclophosphamide; it results in less cumulative exposure to cyclophosphamide and, therefore, theoretically causes fewer adverse effects.

Pulsed cyclophosphamide has been shown to be as effective as daily oral cyclophosphamide in inducing remission.[50] A study found, however, that there was a trend toward higher relapse rates with pulsed cyclophosphamide later in the maintenance phase of treatment. Nonetheless, this study was not intended to detect a difference between the 2 groups; more studies are needed.[5, 50]

Cyclophosphamide doses are reduced as needed for renal function and age. Cyclophosphamide therapy is usually continued until significant disease improvement or remission occurs, typically 3-6 months. The patient is then transitioned to a less toxic medication for maintenance of remission. Cyclophosphamide toxicity manifests as hemorrhagic cystitis (in 15-43% of cases after oral treatment), bladder cancer (30-fold increased incidence as compared with controls), increased risk of other malignancies, cytopenias, infertility, and opportunistic infections, typically occurring during cyclophosphamide-induced leukopenia.

Patients receiving pulse cyclophosphamide should also be given oral or intravenous 2-mercaptoethanesulfonate sodium (Mesna), which binds to acrolein, the toxic metabolite of cyclophosphamide responsible for hemorrhagic cystitis. Once bound to acrolein, the toxic metabolite can no longer bind to cell-surface proteins in the bladder, limiting the risk of local cyclophosphamide-associated toxicity. Mesna may also be beneficial in patients receiving continuous oral cyclophosphamide.

The recommended IV dosing of mesna is equal to 20% (weight/weight) of the IV cyclophosphamide dose, divided into 3 equal doses. The first dose of IV mesna is administered 15-30 minutes prior to IV cyclophosphamide. The 2 remaining doses are then given 4 hours and 8 hours following IV cyclophosphamide. Peak urinary concentrations with IV mesna dosing occur in 1 hour.[51]

The dose of oral mesna should be equal to 40% of the cyclophosphamide doses (oral or IV), based on a 50% oral bioavailability, and divided into 3 equal doses. The first dose of oral mesna should be given 2 hours before cyclophosphamide (oral or IV). The second and third oral doses can still be given 4 hours and 8 hours after cyclophosphamide, as with IV mesna dosing. The bioavailability is not affected by food intake, and peak urinary concentrations occur in 3 hours.[51]

Frequent urinalyses should be performed while the patient is receiving either intravenous or oral cyclophosphamide, and should also be performed throughout the patient’s life to screen for the development of bladder cancer. Urine cytology can also be considered. Additionally, complete blood count (CBC) monitoring should be performed every 1-2 weeks throughout the course of daily oral cyclophosphamide to detect and prevent leukopenia. CBC counts should be performed on day 10 and 14 after each intravenous pulse and immediately before the next intravenous dose as well.

Finally, infertility may be of great concern to both male and female patients who desire future childbearing. A study of 42 women in the WGET trial, aged 14 to 46 years (mean age 35 years), found that daily oral cyclophosphamide, even when administered for less than 6 months, was associated with diminished ovarian reserve, as evidenced by decreased anti-Müllerian hormone (AMH).[52] If there is time prior to the initiation of cyclophosphamide therapy, men may wish to pursue sperm banking and women of childbearing age should consider oral contraceptives and gonadotropin-releasing hormone analogues (ie, leuprolide) to help preserve fertility.[53]

Rituximab

Rituximab combined with high-dose glucocorticoids represents an alternative to cyclophosphamide for induction of remission in GPA; it is the first treatment ever approved by the FDA for AAV.

The evidence for this approval came from the Stone et al's RAVE (Rituximab in Antineutrophil Cytoplasmic Antibody ̶ Associated Vasculitis) trial.[17] Rituximab is a chimeric monoclonal anti-CD20 IgG1 antibody that induces apoptosis of B cells, with the exception of plasma cells and pre-B cells. Infusion of rituximab typically causes a 6-month depletion of circulating B cells and therefore may decrease the production of autoantibodies such as ANCAs.

The RAVE trial, which showed the noninferiority of rituximab compared with the cyclophosphamide control group, suggested that rituximab may be better for induction of relapsing disease. There were no significant differences between the treatment groups in the number or severity of adverse events.

The RITUXVAS trial, by The European Vasculitis Study Group (EUVAS), examined the use of rituximab in severe GPA with renal involvement in older patients and found rituximab was not superior to cyclophosphamide and was associated with a similar number of adverse events, although the rituximab group also received cyclophosphamide.[18] Both studies confirmed the efficacy and superiority of rituximab over cyclophosphamide in reducing ANCA positivity.[54]

Following the FDA approval, questions surfaced regarding the potential for rituximab as maintenance therapy for AAV, its optimal dosing frequency, and whether other immunosuppressive medications should be continued while patients are also receiving rituximab.

A retrospective review evaluated the relapse rate and tolerance of rituximab maintenance therapy in 28 AAV patients (4 with microscopic polyangiitis, 24 with GPA). The patients received a median of 4 rituximab infusions of differing dose and frequency over 38 months. Combined treatment included corticosteroids and other immunosuppressives (azathioprine, mycophenolate mofetil, methotrexate, leflunomide) at the time of the first rituximab maintenance infusion, although most had their immunosuppressive medication held for an average of 8 months after their first infusion. Results suggest that rituximab effectively maintained remission with a good safety profile, confirming previous reports.[55, 56]

A prospective trial (MAINRITSAN) has been started for patients with AAV who have achieved remission with conventional cyclophosphamide-based therapy to better determine if the low relapse rate was due to rituximab maintenance therapy or if concomitant immunosuppressive therapy played a role. Patients in the MAINRITSAN trial will be enrolled at remission and randomized to receive maintenance therapy with either rituximab (1 systematic infusion every 6 mo for 18 mo) or azathioprine (for 21 mo).[57]

Further studies may address whether rituximab is effective for limited disease, which is typically associated with more granulomatous features than vasculitic ones. Rituximab is typically thought to be more effective in the vasculitic phase rather than the granulomatous phase, but small studies have shown good results even in limited disease.[58, 59]

Adverse effects associated with rituximab include infusion reactions, mucocutaneous reactions, increased risk of infections (to include opportunistic infections such as progressive multifocal leukoencephalopathy), cytopenias, and malignancy. In rheumatoid arthritis patients, hypogammaglobulinemia before rituximab seemed to be more closely associated with risk of infection than during or after rituximab.[60] Whether rituximab-associated hypogammaglobulinemia is associated with risk of infection in AAV remains to be determined, although a retrospective study did not show an association.[55] Late-onset neutropenia has also been associated with rituximab in GPA; appropriate laboratory monitoring should be considered.[61]

Corticosteroids

Historically, glucocorticoid monotherapy prolonged median survival in GPA by only 7.5 months. There have been no clinical trials evaluating the role or dosing of glucocorticoids in AAV, but every clinical trial has used glucocorticoids in combination with other immunosuppressants. Thus, corticosteroids remain the cornerstone of treatment for AAV, especially for the induction of remission.[5]

One meta-analysis sought to answer the question of comparing glucocorticoid regimens in AAV. The authors found that studies with a longer course of glucocorticoids (ie, nonzero target dose) were associated with fewer relapses. Another retrospective study by McGregor et al found that once remission is reached for at least 1 month, glucocorticoid therapy beyond 6 months was associated with a greater risk of infection without a significantly reduced risk of relapse.[62] Further studies are still needed to define the best regimen with respect to glucocorticoid dose and duration of therapy.[38]

Glucocorticoids are usually given orally. If a rapid response is needed, however, such as in the case of rapidly progressive glomerulonephritis and/or alveolar hemorrhage, intravenous pulse methylprednisolone (0.5-1 g/day for 3 consecutive days) can be used and then followed by oral prednisone.

Initial high-dose glucocorticoids (1 mg/kg/day) should be continued for at least 1 month. Doses should not be reduced to less than 15 mg/day within the first 3 months. The dose should then be slowly tapered to a maintenance dose of 10 mg/day or less during remission.[5] Methods to prevent glucocorticoid-induced osteoporosis should be followed.

Trimethoprim-sulfamethoxazole

Pneumocystis pneumonia has an annual incidence of 1% but is a potentially deadly complication of immunosuppressive therapy in patients with GPA, especially with prolonged lymphocytopenia.

Prophylaxis against Pneumocystisjiroveci pneumonia should be instituted while patients are taking cyclophosphamide and corticosteroids (particularly high-dose corticosteroids). Typically, trimethopim-sulfamethoxazole (TMP-SMZ) at 160/800 mg 3 times weekly is used. If the patient has a sulfa allergy, dapsone 100 mg daily can be substituted. Pneumocystis prophylaxis has also been recommended during rituximab treatment and for at least 6 months following the last rituximab infusion.

Reports have examined TMP-SMZ use in isolation without other immunosuppressive medications in the induction phase of treatment in patients with very limited disease; however, prospective trials of TMP-SMZ as monotherapy have been disappointing.

In adults, TMP-SMZ has been shown to prevent relapses of GPA in remission.[16] This action of TMP-SMZ may be due to anti-inflammatory action or decrease in infections, particularly respiratory tract infections.

Plasma exchange

Plasma exchange may be considered in patients with rapidly progressive renal disease (serum creatinine level >5.65mg/dL) in order to preserve renal function.[5] Additionally, plasma exchange, along with aggressive immunotherapy, may be helpful in DAH.[63] Plasma exchange is used with daily oral cyclophosphamide and glucocorticoids, usually pulse methylprednisolone. Plasma exchange has not been shown to improve overall survival rates or relapse rates but has been associated with improved long-term survival, free of hemodialysis.[64, 65]

Jayne et al reported improved renal outcomes in adults with GPA or microscopic polyangiitis with severe renal failure (creatinine >5.8 mg/dL) who were treated with plasma exchange, when compared with intravenous methylprednisolone.[65] The patients in this multicenter European trial were also treated with oral prednisone and oral cyclophosphamide at the time of enrollment.

The proposed mechanism of action of plasma exchange in AAV includes removal of pathologic circulating factors (eg, ANCA, activated lymphocytes), removal of excess physiologic factors (eg, complement, coagulation factors, cytokines/chemokines), replacement of deficient plasma factors, and other, less well-defined mechanisms. Potential adverse events associated with plasma exchange include electrolyte disturbances, anaphylaxis, hemorrhage, and transfusion-related lung injury.[66]

Methotrexate

Localized, milder disease generally requires less aggressive therapy. A combination of methotrexate (oral or subcutaneous) and glucocorticoids can be considered as a less-toxic alternative to cyclophosphamide for the induction of remission of non–organ-threatening or non–life-threatening GPA.[5]

Methotrexate (20-25 mg/wk, oral or subcutaneous) can be used in patients with normal renal function. It may take longer to reach remission with methotrexate than with cyclophosphamide, but methotrexate has been shown to be equal to cyclophosphamide in terms of its capacity to induce remission in early AAV.[67] Daily folic acid 1 mg/day is recommended to lessen some of the adverse effects of methotrexate.

Azathioprine for induction of remission has not been shown to be effective.[1]

Remission Maintenance

Once induction of remission has occurred, maintenance of remission should be continued for at least 18 months, often longer. Agents that can be used in remission maintenance include azathioprine, methotrexate, and leflunomide.[5] Long-term oral cyclophosphamide has been used for remission maintenance but results in significant toxicity, making it unattractive.

Azathioprine

Azathioprine has been proven inferior to cyclophosphamide during the induction phase of treatment. However, as shown by the CYCAZAREM (Cyclophosphamide Versus Azathioprine During Remission in ANCA-Associated Vasculitis) trial, azathioprine (2 mg/kg/day) is safer and as effective as cyclophosphamide in maintaining remission.[6] Azathioprine impairs leukocyte proliferation by inhibiting purine synthesis. It results in somewhat higher relapse rates than cyclophosphamide, especially if the patient is still PR3-ANCA–positive at the time of the switch from cyclophosphamide to azathioprine.[6, 68, 69]

Study data have raised the question as to whether the induction treatment phase can be shortened to 3 months with transition from cyclophosphamide to azathioprine. The European Vasculitis Study Group analyzed a group of 144 patients with ANCA-associated vasculitis (GPA and microscopic polyangiitis) who achieved remission with induction therapy of prednisolone and cyclophosphamide (2 mg/kg/day) for 3 months.

After a 3-month induction phase, patients were randomized to cyclophosphamide (1.5 mg/kg/day) or azathioprine (2 mg/kg/day). Remission rates and adverse effects were similar in both groups. The authors concluded that once remission is achieved with a 3-month course of prednisolone and cyclophosphamide, patients can be safely switched from cyclophosphamide to azathioprine to reduce the exposure to cyclophosphamide.

Methotrexate

Methotrexate (20-25 mg weekly, oral or subcutaneous) has been used for the maintenance of remission if the serum creatinine level is less than 1.5 mg/dL. Methotrexate has been shown to be similar to azathioprine in terms of adverse effects, efficacy in maintaining remission, and rates of relapse.[70] The rate of relapse with methotrexate ranges from 37-58%.[71, 72, 73, 74]

Leflunomide

Leflunomide (20-30 mg/day) is as effective as methotrexate, but it is associated with more adverse effects.[7] Leflunomide targets T cells by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase and thus limits pyrimidine synthesis. It is used in the treatment of rheumatoid arthritis. Leflunomide is metabolized by the liver and thus may be used in patients with renal insufficiency.

Because leflunomide has been reported to be associated with increased peripheral neuropathy symptoms, physicians should be aware that the development of neurologic symptoms could represent either a disease flare or an adverse medication effect.[4]

Other considerations

The glucocorticoid dose should be tapered to prednisone 10 mg/day (or less) during remission. The dose can be tapered gradually after 6-18 months, depending on the patient’s response.

The addition of TMP-SMZ (800/160 mg twice daily) to standard maintenance therapy may reduce the rate of relapse in GPA.[75]

Alternative or Promising Therapies

Intravenous immunoglobulin

Intravenous immunoglobulin (IVIG) may be effective by interfering with ANCAs and thus inhibiting ANCA-mediated neutrophil activation.[76] Good results were reported in a study of 22 patients with AAV given IVIG as an adjunct to immunosuppressants and/or glucocorticoids.[77]

Mycophenolate mofetil

Mycophenolate mofetil (MMF) (2 g/day) is a derivative of the fungus Penicillium stoloniferum that, similar to azathioprine, limits purine synthesis. MMF is primarily used for immunosuppression in transplant patients and suppresses B and T cells. Because of its favorable side-effect profile and clinical potency, MMF is being increasingly used in the management of systemic connective-tissue disorders and is typically used in combination with prednisone.

A study of microscopic polyangiitis, a myeloperoxidase (MPO)-ANCA ̶ associated vasculitis, suggested that MMF may be an alternative to cyclophosphamide in mild-to-moderate microscopic polyangiitis.[78] MMF has been used in small series of refractory GPA cases, for both induction and maintenance, with varying responses.[79, 80]

Nowack et al reported a good outcome in a study using MMF during the maintenance phase of treatment in 11 adult patients with ANCA-associated systemic vasculitis (9 patients with GPA, 2 patients with microscopic polyangiitis).[81] Patients were started on a regimen of MMF and low-dose oral corticosteroids after a 14-week induction period with steroids and oral cyclophosphamide. Outcome was assessed only to 15 months but was very good. Only 1 patient relapsed 14 months into the maintenance treatment phase. MMF was well tolerated at a dose of 2 g/day, with minimal adverse effects.

Joy et al evaluated MMF in patients with non–life-threatening recurrent or cyclophosphamide-resistant ANCA (+) small-vessel vasculitis.[79] A 24-week treatment period in conjunction with corticosteroids resulted in a marked reduction in disease activity as assessed by the Birmingham Vasculitis Activity Scoring system. Thus, MMF may be useful in this setting to avoid recurrent treatment with alkylating agents.

However, a European Vasculitis Study Group trial (IMPROVE, International Mycophenolate Mofetil to Reduce Outbreaks of Vasculitides) reported that MMF was less effective than azathioprine in the maintenance of remission of AAV.[82] Further studies are needed.

Etanercept

Etanercept is a dimeric, recombinant human fusion protein with 2 soluble p75 tumor necrosis factor ̶ alpha (TNF-α) receptors linked to the Fc region of human IgG1. The initial pilot study showed good response when etanercept was added to standard therapy.[83]

The larger Wegener Granulomatosis Etanercept Trial (WGET), which subsequently assessed the efficacy of etanercept in the treatment of GPA, suggested that etanercept does not improve AAV relapses and likely contributes to increased risk of infection and malignancy. Etanercept or placebo was added to standard therapy (corticosteroids plus cyclophosphamide or methotrexate). No improvement was found in the primary endpoint of sustained remission; moreover, more solid cancers were found in the etanercept group.[14] Additionally, the combination of anti-TNF therapy with an alkylating agent (ie, cyclophosphamide) may increase risk of solid tumors.

Infliximab

Infliximab is a chimeric monoclonal antibody to tumor necrosis factor–α (TNF-α) that consists of murine antigen recognition sites bound to human Fc regions. The results in various studies and/or case reports have been mixed, so it is not currently possible to comment on the efficacy of infliximab.[84, 85] The safety of infliximab therapy in patients with GPA, similar to the results in trials with etanercept, seems to be the limiting factor, as there were increased serious infections in the infliximab group.[86] Further studies are needed.

15-Deoxyspergualin

The drug 15-deoxyspergualin (0.5 mg/kg/day subcutaneous or intravenous) is a synthetic derivative of spergualin, a protein from Bacillus laterosporus that is capable of preventing T-cell and B-cell maturation. The medication is licensed in Japan for recurrent kidney transplant rejection. In addition, 15-desoxyspergualin has been used with some success in refractory GPA cases and in patients with contraindications to cytotoxic therapy.[87, 88, 89] It may offer a safer alternative to cyclophosphamide for induction therapy but is not yet supported for routine clinical use.[85]

Antithymocyte globulins

Antithymocyte globulins are polyclonal antibodies targeted against T-lymphocyte antigens. Infusion of antithymocyte globulin causes a deep, rapid depletion of T lymphocytes. It has been investigated for use in severe refractory GPA.[90] However, severe adverse effects, including death, may occur. Thus, antithymocyte globulin’s use is not clinically supported.[76, 85]

Alemtuzumab

Anti-CD52 therapy (alemtuzumab) is a humanized monoclonal antibody to CD52 that selectively depletes lymphocyte and macrophage populations. Its use in GPA is considered experimental.[91]

Abatacept

Abatacept is a soluble, cytotoxic T-lymphocyte Ag-4 immunoglobulin that binds CD28, in that way inhibiting T-cell activation. Abatacept has been used with some success to prevent disease progression in an animal model of crescentic glomerulonephritis.[92]

Stem cell transplantation

Hematopoietic stem cell transplant evidence is limited.[85]

Summary of Treatments

Induction of remission in severe or generalized GPA

Cyclophosphamide (EITHER oral OR intravenous dosing):

Rituximab:

Glucocorticoids:

Induction of remission in localized or milder GPA (ie, non-organ- or non-life-threatening disease)

Methotrexate:

Glucocorticoids:

Maintenance of remission

Immunosuppressive medications (azathioprine, methotrexate or leflunomide) that replace cyclophosphamide or rituximab and should be continued for at least 18mo. Glucocorticoids should also be continued in remission.

Azathioprine:

Methotrexate:

Leflunomide:

Glucocorticoids:

Adjunctive therapies

Surgical Indications

The natural history of GPA is such that inflammation may lead to tissue necrosis and damage to the nose, subglottic areas, trachea, and bronchi caused by fibrosis. Surgical intervention can be considered in these situations.

For subglottic stenosis, which occurs in approximately 20% of patients with GPA, treatment is typically unresponsive to systemic immunosuppressive therapy. Surgical interventions are usually required in these patients, including laser treatment, mechanical dilation with injection of long-acting corticosteroids, or resection of the stenotic area with reanastomosis. Dilation-injection therapy is performed most commonly, with good effects.[93, 94]

Other surgical considerations in GPA are as follows:

Renal transplant is an option in patients with renal failure. Glomerulonephritis usually does not affect the transplanted kidney.

Outpatient Care

Patients with GPA should have regularly scheduled follow-up visits with the physician primarily responsible for managing his or her disease. Since recurrences occur frequently, patients should be monitored closely clinically, with radiologic studies and laboratory examinations that include renal function, erythrocyte sedimentatoin rate (ESR), ANCA levels, and urinalysis. Visits should also focus on untoward effects of therapeutic agents.

Infection is a major contributor to morbidity and mortality in GPA and often mimics a disease flare or manifests as atypical features caused by treatment-related immunosuppression. Providers should have a low threshold for treating suspicious symptoms with antibiotics.

Prophylaxis against Pneumocystis pneumonia is essential while patients are receiving conventional therapy for GPA. This can be achieved with TMP-SMZ single-strength once daily or double-strength formulation three times per week. Dapsone 100mg daily can be used in sulfa-allergic patients.

All patients who require long-term glucocorticoid treatment are at risk for glucocorticoid-induced osteoporosis. Baseline bone mineral density should be evaluated. If the density is normal, patients should take daily calcium and vitamin D supplementation. If the density is diminished at baseline or if long-term glucocorticoid use is anticipated, bisphosphonate therapy should be added. Risk versus benefit of bisphosphonate therapy should be discussed with women of childbearing age.

Medication Summary

The combination of cyclophosphamide (intravenous or oral) and corticosteroids remained the recommended therapy for induction of remission in generalized granulomatosis with polyangiitis (GPA) for years. In 2011, however, the FDA approved the use of rituximab, a monoclonal antibody that targets B cells, as an alternative to cyclophosphamide for the treatment of AAV (GPA and microscopic polyangiitis).

Prophylaxis against Pneumocystisjiroveci pneumonia should be instituted while patients are taking cyclophosphamide or rituximab and corticosteroids (particularly high-dose corticosteroids) and for at least 6 months following these medications. Typically, trimethoprim-sulfamethoxazole (TMP-SMZ) at 160/800 mg 3 times weekly is used. If the patient has a sulfa allergy, dapsone 100 mg daily can be substituted.

Prednisone

Clinical Context:  Prednisone is used as an immunosuppressant in the treatment of autoimmune disorders and vasculitis. By reversing increased capillary permeability and suppressing polymorphonuclear neutrophil (PMN) activity, it may decrease inflammation.

Methylprednisolone (Medrol, Solu-Medrol, Depo-Medrol)

Clinical Context:  Methylprednisolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Class Summary

Corticosteroids have immunosuppressant and anti-inflammatory action used to reduce activity of systemic vasculitis. High-dose methylprednisolone is used to halt pulmonary hemorrhage and reverse crescentic glomerulonephritis.

Cyclophosphamide

Clinical Context:  Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, cyclophosphamide's mechanism of action of active metabolites may involve cross-linking of deoxyribonucleic acid (DNA), which may interfere with the growth of normal and neoplastic cells. Complete blood cell (CBC) counts should be checked every 1-2 weeks while taking daily oral cyclophosphamide and at days 10 and 14 of each intravenous cyclophosphamide pulse to monitor for bone marrow suppression.

Class Summary

These agents have improved the prognosis of GPA. Cyclophosphamide is initiated with high-dose corticosteroids but is continued for at least 3-6 months (until there is significant disease improvement and/or remission).

Azathioprine (Imuran, Azasan)

Clinical Context:  Azathioprine inhibits mitosis and cellular metabolism by antagonizing purine metabolism and inhibiting the synthesis of DNA, ribonucleic acid (RNA), and proteins. Its effects may decrease the proliferation of immune cells and result in lower autoimmune activity.

Methotrexate (Rheumatrex, Trexall)

Clinical Context:  Methotrexate has an unknown mechanism of action in the treatment of inflammatory reactions; it may affect immune function. This agent ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). Adjust the dose gradually to attain a satisfactory response.

Class Summary

These agents are useful in patients who experience significant adverse effects with cyclophosphamide induction therapy, as induction therapy in mild to moderate disease, and, most commonly, for maintenance of remission. The immunosuppressive drug is generally started at a lower dose and gradually increased over time. The onset of effect generally takes several weeks; therefore, the use of these drugs in induction therapy for severe disease is not advised.

Rituximab (Rituxan)

Clinical Context:  Rituximab is a genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. The antibody is an IgG1 kappa immunoglobulin containing murine light- and heavy-chain variable region sequences and human constant region sequences.

Class Summary

In 2011, rituximab gained FDA approval for GPA; it is a promising alternative therapy to cyclophosphamide for induction of remission.

Trimethoprim-sulfamethoxazole (Septra DS, Bactrim, Bactrim DS)

Clinical Context:  TMP-SMZ inhibits the bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid, inhibiting folic acid synthesis. This results in the inhibition of bacterial growth. The antibacterial activity of TMP-SMZ includes common urinary tract pathogens, except Pseudomonas aeruginosa.

Class Summary

Trimethoprim-sulfamethoxazole (TMP-SMZ) is recommended for prophylaxis against Pjiroveci pneumonia, typically as a daily dose, with single-strength dosing, or a dose of 3 times weekly with double-strength dosing. It is continued for as long as the patient is on immunosuppressive therapy. Data show that TMP-SMZ may be beneficial in decreasing relapses during maintenance therapy of GPA. Twice-daily dosing should not be combined with methotrexate, if possible, due to the risk of pancytopenia.

Additionally, in adults, TMP-SMZ has been shown to prevent relapses of GPA in remission.[16] This action of TMP-SMZ may be due to anti-inflammatory action or decrease in infections, particularly respiratory tract infections.

Author

Christopher L Tracy, MD, Staff Rheumatologist, Fort Belvoir Community Hospital

Disclosure: Nothing to disclose.

Coauthor(s)

Patricia J Papadopoulos, MD, Staff Rheumatologist, MultiCare Rheumatology Specialists

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD, Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Disclosure: Nothing to disclose.

Additional Contributors

Michael R Bye, MD Professor of Clinical Pediatrics, Division of Pulmonary Medicine, Columbia University College of Physicians and Surgeons; Attending Physician, Pediatric Pulmonary Medicine, Morgan Stanley Children's Hospital of New York Presbyterian, Columbia University Medical Center

Michael R Bye, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

Heidi Connolly, MD Associate Professor of Pediatrics and Psychiatry, University of Rochester; Director, Pediatric Sleep Medicine Services, Strong Sleep Disorders Center

Heidi Connolly, MD is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society, and Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Elliot Goldberg, MD Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine

Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American College of Rheumatology

Disclosure: Nothing to disclose.

Robert John O'Brian, MD Staff Rheumatologist, National Naval Medical Center

Robert John O'Brian, MD is a member of the following medical societies: American College of Rheumatology

Disclosure: Nothing to disclose.

Girish D Sharma, MD Associate Professor of Pediatrics, Rush Medical College; Director, Section of Pediatric Pulmonology and Rush Cystic Fibrosis Center, Rush University Medical Center

Girish D Sharma, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Thoracic Society, and Royal College of Physicians of Ireland

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Debbie S Toder, MD Director of Cystic Fibrosis Center, Department of Pediatrics, Division of Pulmonary Medicine, Assistant Professor, Wayne State University and Children's Hospital of Michigan

Debbie S Toder, MD is a member of the following medical societies: American Academy of Pediatrics and American Thoracic Society

Disclosure: Nothing to disclose.

Rudolph P Valentini, MD Director of Dialysis Services, Associate Professor, Department of Pediatrics, Division of Pediatric Nephrology, Wayne State University; Vice Chief of Staff, Children's Hospital of Michigan

Rudolph P Valentini, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, and American Society of Pediatric Nephrology

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Robert E Wolf, MD, PhD Professor Emeritus, Department of Medicine, Louisiana State University Health Sciences Center at Shreveport; Chief, Rheumatology Section, Medical Service, Overton Brooks Veterans Administration Medical Center of Shreveport

Robert E Wolf, MD, PhD is a member of the following medical societies: American College of Rheumatology, Arthritis Foundation, and Society for Leukocyte Biology

Disclosure: Nothing to disclose.

Acknowledgments

The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army, Department of Defense, or the US Government. Additionally, this publication does not imply the Federal or Department of Defense endorsement of any product.

References

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Saddle nose deformity in a 26-year-old man with granulomatosis with polyangiitis. Image courtesy of P. Papadopoulos, MD.

Lung biopsy specimen from a patient with granulomatosis with polyangiitis showing evidence of vasculitis and inflammation (high-power view). Image courtesy of Z. Xu, MD.

Lung biopsy specimen from a patient with granulomatosis with polyangiitis showing evidence of vasculitis and inflammation (high-power view). Image courtesy of Z. Xu, MD.

Granulomatosis with polyangiitis (formerly known as Wegener granulomatosis). Large ulceration of the pharynx covered with a dense necrotic membrane.

Necrotic, purpuric, and blistering plaque on the wrist in a patient with granulomatosis with polyangiitis.

Saddle nose deformity in a 26-year-old man with granulomatosis with polyangiitis. Image courtesy of P. Papadopoulos, MD.

Several necrotic, purpuric, and blistering papules and plaques on the hands in a patient with granulomatosis with polyangiitis.

Goodpasture syndrome: Linear deposition of immunoglobulin G and C3 are observed on a renal biopsy specimen from a patient with Goodpasture syndrome. Immunofluorescence staining. Image courtesy of K. Orr, MD.

C-ANCA immunofluorescence pattern. Staining for antineutrophil cytoplasmic antibody by indirect immunofluorescence shows heavy cytoplasmic staining, whereas nuclei are nonreactive. Image courtesy of K. Orr, MD.

P-ANCA immunofluorescence pattern. Perinuclear antineutrophil cytoplasmic antibody staining pattern by indirect immunofluorescence shows perinuclear staining, whereas cytoplasm is nonreactive. Image courtesy of K. Orr, MD.

Granulomatosis with polyangiitis. Bilateral nodules observed on a plain chest radiograph in a patient with hemoptysis and hematuria. Image courtesy of G. Eschun, MD.

This 42-year-old man presented with hemoptysis, weight loss, and night sweats. He was diagnosed with the limited form of granulomatosis with polyangiitis.

Granulomatosis with polyangiitis. This patient presented with massive hemoptysis. No nodules are identified on the chest radiograph, although a subsequent CT scan showed several noncavitating nodules.

Shown is a chest radiograph of an 11-year-old girl who presented with an upper respiratory tract infection, myalgias, and arthralgias for 1 month, followed by an abrupt presentation with pallor, hemoptysis, and hypertension. Her bilateral fluffy infiltrates are suggestive of a pulmonary hemorrhage. She had an antineutrophil cytoplasmic autoantibody (ANCA)–positive pauci-immune necrotizing and crescentic glomerulonephritis associated with her pulmonary hemorrhage. Supportive therapy consisted of mechanical ventilation and hemodialysis along with immunosuppressive therapy. Her anti–glomerular basement membrane antibody test result was negative. Nearly 2 years later, she had a serum creatinine of 0.7mg/dL and no residual pulmonary disease.

An 11-year-old girl presented with an upper respiratory tract infection, myalgias, and arthralgias for 1 month followed by an abrupt presentation with pallor, hemoptysis, and hypertension. She had an antineutrophil cytoplasmic autoantibody (ANCA)–positive pauci-immune necrotizing and crescentic glomerulonephritis associated with her pulmonary hemorrhage. A follow-up chest radiograph obtained several days later shows a complete resolution of her pulmonary infiltrates. This rapid resolution is more consistent with hemorrhage than with pneumonia.

Bilateral cavitating nodules in a patient with granulomatosis with polyangiitis.

Diffuse alveolar hemorrhage in a 21-year-old man with granulomatosis with polyangiitis. Image courtesy of the US Government.

Diffuse alveolar hemorrhage in a 21-year-old man with granulomatosis with polyangiitis. Image courtesy of the US Government.

Extensive thickening of the maxillary sinuses in a patient with granulomatosis with polyangiitis. The patient also had intermittent epistaxis.

A renal biopsy specimen from a 13-year-old girl with antineutrophil cytoplasmic antibody (C-ANCA)–positive pulmonary renal syndrome. Seven weeks after presenting with sinusitis, she presented with an acute abdomen, pulmonary hemorrhage, and acute renal failure (creatinine 4.9mg/dL). This biopsy specimen shows a necrotizing and crescentic glomerulonephritis (Silver stain).

Lung biopsy specimen from a patient with granulomatosis with polyangiitis showing evidence of vasculitis and inflammation (high-power view). Image courtesy of Z. Xu, MD.

Lung biopsy specimen from a patient with granulomatosis with polyangiitis showing evidence of vasculitis and inflammation (high-power view). Image courtesy of Z. Xu, MD.

Focal glomerulonephritis with crescent formation on renal biopsy specimen, characteristic of granulomatosis with polyangiitis.

Saddle nose deformity in a 26-year-old man with granulomatosis with polyangiitis. Image courtesy of P. Papadopoulos, MD.

Necrotic, purpuric, and blistering plaque on the wrist in a patient with granulomatosis with polyangiitis.

Several necrotic, purpuric, and blistering papules and plaques on the hands in a patient with granulomatosis with polyangiitis.

Granulomatosis with polyangiitis (formerly known as Wegener granulomatosis). Large ulceration of the pharynx covered with a dense necrotic membrane.

Extensive thickening of the maxillary sinuses in a patient with granulomatosis with polyangiitis. The patient also had intermittent epistaxis.

Granulomatosis with polyangiitis. Bilateral nodules observed on a plain chest radiograph in a patient with hemoptysis and hematuria. Image courtesy of G. Eschun, MD.

This 42-year-old man presented with hemoptysis, weight loss, and night sweats. He was diagnosed with the limited form of granulomatosis with polyangiitis.

Bilateral cavitating nodules in a patient with granulomatosis with polyangiitis.

Granulomatosis with polyangiitis. This patient presented with massive hemoptysis. No nodules are identified on the chest radiograph, although a subsequent CT scan showed several noncavitating nodules.

Diffuse alveolar hemorrhage in a 21-year-old man with granulomatosis with polyangiitis. Image courtesy of the US Government.

Diffuse alveolar hemorrhage in a 21-year-old man with granulomatosis with polyangiitis. Image courtesy of the US Government.

Shown is a chest radiograph of an 11-year-old girl who presented with an upper respiratory tract infection, myalgias, and arthralgias for 1 month, followed by an abrupt presentation with pallor, hemoptysis, and hypertension. Her bilateral fluffy infiltrates are suggestive of a pulmonary hemorrhage. She had an antineutrophil cytoplasmic autoantibody (ANCA)–positive pauci-immune necrotizing and crescentic glomerulonephritis associated with her pulmonary hemorrhage. Supportive therapy consisted of mechanical ventilation and hemodialysis along with immunosuppressive therapy. Her anti–glomerular basement membrane antibody test result was negative. Nearly 2 years later, she had a serum creatinine of 0.7mg/dL and no residual pulmonary disease.

An 11-year-old girl presented with an upper respiratory tract infection, myalgias, and arthralgias for 1 month followed by an abrupt presentation with pallor, hemoptysis, and hypertension. She had an antineutrophil cytoplasmic autoantibody (ANCA)–positive pauci-immune necrotizing and crescentic glomerulonephritis associated with her pulmonary hemorrhage. A follow-up chest radiograph obtained several days later shows a complete resolution of her pulmonary infiltrates. This rapid resolution is more consistent with hemorrhage than with pneumonia.

A renal biopsy specimen from a 13-year-old girl with antineutrophil cytoplasmic antibody (C-ANCA)–positive pulmonary renal syndrome. Seven weeks after presenting with sinusitis, she presented with an acute abdomen, pulmonary hemorrhage, and acute renal failure (creatinine 4.9mg/dL). This biopsy specimen shows a necrotizing and crescentic glomerulonephritis (Silver stain).

Lung biopsy specimen from a patient with granulomatosis with polyangiitis showing evidence of vasculitis and inflammation (high-power view). Image courtesy of Z. Xu, MD.

Lung biopsy specimen from a patient with granulomatosis with polyangiitis showing evidence of vasculitis and inflammation (high-power view). Image courtesy of Z. Xu, MD.

Focal glomerulonephritis with crescent formation on renal biopsy specimen, characteristic of granulomatosis with polyangiitis.

C-ANCA immunofluorescence pattern. Staining for antineutrophil cytoplasmic antibody by indirect immunofluorescence shows heavy cytoplasmic staining, whereas nuclei are nonreactive. Image courtesy of K. Orr, MD.

P-ANCA immunofluorescence pattern. Perinuclear antineutrophil cytoplasmic antibody staining pattern by indirect immunofluorescence shows perinuclear staining, whereas cytoplasm is nonreactive. Image courtesy of K. Orr, MD.

Goodpasture syndrome: Linear deposition of immunoglobulin G and C3 are observed on a renal biopsy specimen from a patient with Goodpasture syndrome. Immunofluorescence staining. Image courtesy of K. Orr, MD.