Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis

INTRODUCTION — Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) are a group of disorders that include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), renal-limited vasculitis, and eosinophilic granulomatosis with polyangiitis (EGPA) [1,2]. All are associated with ANCA, affect predominantly small-sized arteries, and have similar features on kidney histology (eg, a focal necrotizing, often crescentic, pauci-immune glomerulonephritis).

The clinical manifestations and diagnosis of GPA, MPA, and renal-limited vasculitis are reviewed here. EGPA has a different presentation and prognosis compared with the other forms of AAV and is discussed separately:

●(See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)

●(See "Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): Treatment and prognosis".)

Issues related to ANCA, the pathogenesis of AAV, and the vasculitides in general are discussed separately:

●(See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)

●(See "Pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis".)

●(See "Overview of and approach to the vasculitides in adults".)

NOMENCLATURE — Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are both necrotizing vasculitides predominantly affecting small-sized arteries that present variably in terms of organ manifestations and disease severity. The most commonly and severely affected organs include the upper and lower respiratory tract and the kidneys. Because of their strong association with antineutrophil cytoplasmic autoantibody (ANCA), they also referred to as ANCA-associated vasculitis (AAV). (See "Overview of and approach to the vasculitides in adults", section on 'Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)' and "Overview of and approach to the vasculitides in adults", section on 'ANCA-associated vasculitis'.)

Eosinophilic granulomatosis with polyangiitis (EGPA) is also included in the spectrum of AAV, but given that it is clinically and pathologically different from GPA and MPA, and that more than one-half of patients with EGPA are negative for ANCA, patients with EGPA are not included in clinical trials of patients with AAV and are discussed separately. (See "Overview of and approach to the vasculitides in adults", section on 'Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)' and "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)

AAV can also occur in a single organ, particularly in a subset referred to as renal-limited AAV.

ANCA-negative AAV describes cases in which the patient otherwise clinically appears to have GPA, MPA, EGPA, or renal-limited AAV but has negative results on serologic testing for ANCA.

EPIDEMIOLOGY — The prevalence of granulomatosis with polyangiitis (GPA) ranges from 2.3 to 146.0 cases per million persons, with an incidence of 0.4 to 11.9 cases per million person-years [3]. By comparison, the prevalence of microscopic polyangiitis (MPA) ranges from 9.0 to 94.0 cases per million persons, with an incidence of 0.5 to 24.0 cases per million person-years [3].

The incidence of GPA and MPA varies widely depending upon geography. GPA mainly affects regions of the world in which the population is predominantly of European ancestry and is rarely observed in East Asia. By contrast, MPA is more predominantly observed in Asian countries such as China and Japan [4,5]. The incidence of GPA also appears to correlate with latitude and is lower toward the equator [6,7]. Studies of multiethnic populations in France and in the United States report at least a twofold higher incidence of GPA and MPA among White populations compared with other ethnicities [8,9].

GPA and MPA most commonly occur in older adults, although these diseases have been reported at all ages [3,10,11]. Males and females are equally affected. GPA and MPA are rare among children.

CLINICAL MANIFESTATIONS — The small blood vessels in almost any organ or tissue can be involved in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), but the upper and lower respiratory tracts and the kidneys are most commonly affected. Patients can present with severe organ-threatening or life-threatening disease; however, less severe presentations can also occur. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Assessment of disease severity'.)

Overview of clinical features — Patients with both GPA and MPA typically present with nonspecific symptoms including fever, malaise, anorexia, weight loss, myalgias, and arthralgias [3,10,12,13]. Prodromal symptoms may last for weeks to months without evidence of specific organ involvement [12,14]. As a result, GPA and MPA can be frequently misdiagnosed initially as infections, malignancies, or inflammatory joint disease. When lesions involve the ear, nose, and throat (ENT), other symptoms may include rhinosinusitis, cough, dyspnea, and hemoptysis. Other typical findings may include urinary abnormalities (hematuria, proteinuria, an active urine sediment) with or without kidney function impairment, purpuric lesions in the skin, or evidence of neurologic dysfunction (particularly foot or wrist drop). Occasionally, patients may present more explosively, over a period of days.

Approximately one-fourth of patients present with clinical features such as migratory polyarthropathy, nasal crusting, or other findings that do not include organ-threatening manifestations [15]. Compared with those who have severe organ-threatening involvement, such patients have the following characteristics:

●They are younger at disease onset and more likely to be women.

●They are more likely to have chronic, recurring disease and destructive upper respiratory tract disease (saddle nose deformity). (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Respiratory tract involvement".)

The terms "limited" and "nonsevere" have been used to describe patients who present without organ-threatening manifestations. However, up to 80 percent of patients with initially diagnosed nonsevere GPA eventually develop glomerulonephritis or another severe manifestation of disease. The absence of kidney involvement does not imply benign disease, since involvement of other organs such as the lungs, heart, gastrointestinal tract, and central nervous system may be serious and life threatening. Thus, the use of the terms "limited" and "nonsevere" may be too misleading to remain useful.

Specific organ involvement

Ear, nose, and throat involvement — ENT manifestations can occur in patients with either GPA or MPA. However, they are much more common in patients with GPA (estimated frequency is 90 percent versus 35 percent in MPA) [10,11,13].

ENT manifestations include nasal crusting, sinusitis, otitis media, earache, otorrhea, persistent rhinorrhea, purulent/bloody nasal discharge, oral and/or nasal ulcers, and polychondritis. Patients frequently develop conductive and/or sensorineural hearing loss, either of which can lead to severe permanent hearing impairment [11].

Patients with GPA, compared with those with MPA, more frequently have evidence of bone and cartilage destruction resulting in a saddle nose deformity (picture 1), upper airway and retro-orbital masses (image 1) [16], and cranial nerve entrapment [14].

A more detailed discussion of upper and lower respiratory tract involvement in both GPA and MPA can be found elsewhere. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Respiratory tract involvement".)

Tracheal and pulmonary involvement — Patients with either GPA or MPA may present with involvement of airways or pulmonary parenchyma causing hoarseness, cough, dyspnea, stridor, wheezing, hemoptysis, or pleuritic pain [11,17-20]. These symptoms may be accompanied by signs of tracheal or subglottic stenosis, pulmonary consolidation, and/or pleural effusion. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Respiratory tract involvement".)

Patients may develop interstitial lung disease, complicated by pulmonary fibrosis and pulmonary arterial hypertension [17]. A detailed discussion of this issue can be found elsewhere. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Respiratory tract involvement".)

The chest radiograph findings are variable. Common manifestations include nodules, patchy or diffuse opacities and fleeting pulmonary infiltrates, and hilar adenopathy (image 2 and image 3) [21]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Respiratory tract involvement", section on 'Imaging'.)

Although parenchymal lung nodules are a well-recognized manifestation, antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) occasionally presents with tumor-like masses outside the lung. Among 20 such reported cases, the most common extrathoracic locations were the breast and kidney [22]. Failure to consider vasculitis in the differential diagnosis in such cases may lead to unnecessary surgery, including nephrectomy. Sometimes, a diagnosis of sarcoidosis or pulmonary tuberculosis will be made mistakenly.

Kidney involvement — Kidney involvement is common in GPA and MPA [11,13,23]. In studies from the National Institutes of Health (NIH) in the United States, evident glomerulonephritis was present in only 18 percent of patients at presentation [13], but glomerulonephritis subsequently developed in 77 to 85 percent of patients, usually within the first two years of disease onset [13,23].

The typical presentation of kidney involvement is that of a rapidly progressive glomerulonephritis. The manifestations of the glomerulonephritis in AAV are similar to those that occur in other causes of glomerulonephritis, including:

●Asymptomatic hematuria, which may remit and relapse, in association with normal kidney function. The diagnosis of ANCA-positive glomerulonephritis may be delayed in such patients in favor of a clinical diagnosis of thin basement membrane disease or immunoglobulin A (IgA) nephropathy. However, the risk of progression to end-stage kidney disease is considerably higher in ANCA-positive disease. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

●A rise in serum creatinine occurring over days or weeks with hematuria and cellular casts. Rapidly rising serum creatinine with hematuria, hypertension, and edema is a medical emergency that requires urgent therapy.

●A variable degree of proteinuria that is usually subnephrotic [13,19]. Proteinuria of 1 g per day or less in patients with AAV is most likely the consequence of fibrosed glomeruli or tubular fibrosis in an individual who may or may not be in remission. Higher amounts of proteinuria, and certainly proteinuria above 3 g/day, may be more common in patients who present later in the course of disease and who have had previous necrotizing glomerulonephritis (and therefore have more focal and segmental glomerulosclerosis/fibrosis at the time of presentation). Alternatively, patients with AAV who have high amounts of proteinuria may have a second concurrent glomerular disease (such as membranous nephropathy) or an atypical histologic pattern characterized by glomerular immune complex deposition [24,25]. (See 'Differential diagnosis' below.)

Cutaneous involvement — Approximately 30 to 50 percent of patients with GPA or MPA have manifestations of cutaneous vasculitis [26]. The most common skin lesion is purpura involving the lower extremities that may be accompanied by focal necrosis and ulceration [27]. Skin lesions may also include urticaria, livedo reticularis, and nodules. Occasional patients with erythema nodosum, pyoderma gangrenosum, and Sweet syndrome may also have ANCA-positive disease. (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis".)

Ophthalmic and orbital involvement — Patients with AAV may develop conjunctivitis, corneal ulceration, episcleritis/scleritis, optic neuropathy, retinal vasculitis, and uveitis [14,28,29]. In addition, retro-orbital pseudotumor and nasolacrimal duct obstruction may occur [30].

Affected patients can present with a variety of symptoms and signs including eye pain, foreign body sensation, visual disturbance, diplopia, and proptosis. (See "The red eye: Evaluation and management" and "Overview of diplopia".)

Neurologic involvement — Patients with AAV may develop clinical manifestations involving the nervous system, including multiple mononeuropathy (also called mononeuritis multiplex), sensory neuropathy, cranial nerve abnormalities, central nervous system mass lesions, external ophthalmoplegia, and sensorineural hearing loss [31,32]. Meningeal disease is most commonly associated with granulomatous inflammation of the central nervous system. (See "Clinical manifestations and diagnosis of vasculitic neuropathies".)

Peripheral nervous system involvement is noted in approximately 15 percent of patients with GPA and 70 percent of those with MPA [33,34]. (See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)

The presence of multiple mononeuropathy in patients with AAV has been associated with a worse prognosis compared with those without this feature [35].

Other manifestations — Other organ systems less commonly involved include the gastrointestinal tract, heart (pericarditis, myocarditis, conduction system abnormalities), lower genitourinary tract (including the ureters and prostate), parotid glands, gingiva (eg, hyperplastic strawberry gums), thyroid, liver, or breast [13,36-40].

Patients with AAV have a higher incidence of deep venous thrombosis (DVT) [41-45]. The etiology of the hypercoagulable state in such patients is not clear [46,47], although circulating anti-plasminogen antibodies have been demonstrated in patients with AAV and DVT [44].

A case report of a patient with AAV and the adult-onset inflammatory disorder referred to as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome has been described [48]. VEXAS should be considered in adult males with unexplained cytopenias and/or refractory or persistent symptoms of vasculitis; however, VEXAS is more clearly associated with other forms of vasculitis, including giant cell arteritis, polyarteritis nodosa, and relapsing polychondritis. (See "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity", section on 'Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome'.)

DIAGNOSIS

When to suspect GPA or MPA — The diagnosis of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) should be suspected in any patient who presents with constitutional symptoms along with clinical evidence of glomerulonephritis, upper or lower respiratory tract involvement, or multiple mononeuropathy. The suspicion should be greatly increased if there is laboratory detection of antineutrophil cytoplasmic autoantibody (ANCA). Some patients may present with manifestations limited to a single organ, such as the kidneys or the upper respiratory tract, and then may later evolve to include other organ involvement. In a subset of patients, the disease will be limited to a single organ (eg, renal-limited vasculitis).

Evaluation — The initial evaluation should include a thorough history, physical examination, and laboratory testing (algorithm 1). Exclusion of other potential disease mimics, particularly infection, is an important part of the initial work-up. Early referral to specialists, depending upon the organ involvement and severity of disease, is often appropriate, and multidisciplinary specialty involvement (eg, by rheumatology, nephrology, and pulmonology) may be required.

History and physical examination — A comprehensive history and physical examination should be performed in all patients, with an attention to the following:

●History – Patients should be questioned about the presence of any of the following:

•Constitutional symptoms, such as fever, fatigue, malaise, anorexia, or weight loss

•Arthralgias or myalgias

•Skin lesions

•Persistent nasal crusting, rhinorrhea, epistaxis, or sinusitis

•Ear pain or hearing loss

•Hoarseness, stridor, dyspnea, or wheezing

•Pleuritic chest pain

•Cough with or without hemoptysis

•Blood in the urine or dark (brown) colored urine

•Eye pain, visual disturbances, diplopia, or proptosis

•Numbness or paresthesias in the hands or feet

•Recent exposure (within the prior 6 to 12 months) to medications or drugs associated with drug-induced ANCA-associated vasculitis (see "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Drug-induced ANCA-associated vasculitis')

●Physical examination – Pertinent physical examination findings include the following:

•Elevated blood pressure

•Proptosis or bulging of one or both of the eyes

•Nasal or oral ulcers, nasal crusting, nasal membrane erythema, or purulent or bloody nasal discharge

•Hearing loss

•Skin lesions such as palpable purpura, livedo reticularis, skin necrosis, or skin ulcers

•Decreased or abnormal breath sounds

•Sensory loss

•Motor weakness, such as foot drop or wrist drop

•Lower-extremity edema

Laboratory testing

Testing for ANCA — Testing for antineutrophil cytoplasmic autoantibody (ANCA) should be performed in any adult patient who presents with symptoms suggestive of a vasculitis. In clinical practice, ANCA can be detected using an indirect immunofluorescence (IIF) assay or antigen-specific enzyme-linked immunosorbent assays (ELISAs) for proteinase 3 (PR3) and myeloperoxidase (MPO). These two techniques work well as a combined testing system. The IIF assay is more sensitive, but more subject to misinterpretation. ELISA for PR3-ANCA and MPO-ANCA is more specific, and is considered an essential component of testing for ANCA [49]. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Techniques to detect ANCA'.)

Approximately 82 to 94 percent of patients with either GPA or MPA have a positive ANCA, depending upon the severity of disease [50,51]. GPA is primarily associated with PR3-ANCA (65 to 75 percent of cases), while MPA is primarily associated with MPO-ANCA (55 to 65 percent of cases) [3]. However, 20 to 30 percent of patients with clinical GPA or MPA have the alternative ANCA, and at least 10 percent of patients are ANCA negative [52-54]. The majority of patients with renal-limited vasculitis are ANCA positive, with 75 to 80 percent having MPO-ANCA.

The predictive value of ANCA testing depends heavily upon the clinical presentation of the patient in whom the test is performed. As an example, the finding of an elevated ANCA titer in a patient presenting with acute or rapidly progressive glomerulonephritis predicts the presence of GPA, MPA, or idiopathic necrotizing glomerulonephritis with an accuracy that approaches 98 percent [53,55,56]. However, the diagnostic accuracy of ANCA is substantially lower in patients whose clinical features are less compelling, such as those with only chronic sinusitis as a complaint.

A negative ANCA assay does not exclude the diagnosis of GPA or MPA. Some patients with a negative ANCA despite clinical and histologic features of ANCA-associated vasculitis may have an MPO-ANCA that cannot be detected by routine laboratory testing because it is masked by circulating fragments of enzymatically degraded ceruloplasmin, which may be elevated in patients with active disease [57]. Also, ANCA status may change over time; a patient who is ANCA negative upon presentation with constitutional symptoms and pulmonary infiltrates may become PR3-ANCA positive upon the development of more generalized disease (eg, the occurrence of glomerulonephritis). A negative test for ANCA may therefore create a false sense of security.

A false-positive perinuclear ANCA (P-ANCA) test can occur in patients who are antinuclear antibody (ANA) positive. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Pitfalls of interpreting immunofluorescence results'.)

A detailed discussion of ANCA testing, including its accuracy in GPA, MPA, renal-limited vasculitis, and other disorders in which ANCA can occur (eg, infective endocarditis and other infections, drug-induced vasculitis), is presented separately. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)

Additional laboratory testing — In addition to testing for ANCA, we obtain the following laboratory tests in all patients suspected of having GPA or MPA to exclude other processes or determine the extent of disease involvement:

●Serum creatinine level and urinalysis with urine sediment – A serum creatinine and urinalysis with urine sediment may help identify the presence of kidney involvement and the degree of injury if present. Patients with evidence of abnormal kidney function, microscopic hematuria, proteinuria, or an active urinary sediment (eg, with dysmorphic red cells [acanthocytes] and/or red cell casts) may need further evaluation with a kidney biopsy.

●Complete blood count – Common abnormalities include leukocytosis, thrombocytosis (>400,000/microL), and a normochromic, normocytic anemia [13].

●Erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) levels – A marked elevation in ESR and CRP may be present; however, levels of acute phase reactants have poor specificity for vasculitis.

●Other – Other laboratory tests that should be performed to help exclude alternative diagnoses, include the following:

•ANA

•Anti-glomerular basement membrane (anti-GBM) antibodies

•Serum C3 and C4 complement levels

•Cryoglobulins

•Tests for hepatitis B and C viruses and HIV

•Liver function tests

•Tuberculosis screen

•Blood cultures

Imaging studies — A chest radiograph and computed tomography (CT) scan should be done in all patients who have pulmonary symptoms and are suspected of having GPA or MPA. CT scanning often discloses lesions that are not seen on plain radiographs and demonstrates previously undetected nodules (particularly behind the diaphragm), unsuspected cavitation in nodules, alveolar opacities, large-airway inflammation or stenotic lesions, and pleural-based lesions (image 3) [21]. Most clinicians obtain baseline radiographic studies, including chest radiography, and frequently a chest CT scan in all patients who are newly diagnosed with GPA or MPA, prior to initiating immunosuppressive therapy. (See 'Tracheal and pulmonary involvement' above.)

Selective use of additional imaging is useful in evaluating patients who are suspected or known to have GPA or MPA, including a CT scan of the head (sinuses, orbits, mastoids) in patients with visual or upper respiratory tract symptoms or signs and a CT scan of the neck (subglottic region) in patients with symptoms or signs of subglottic stenosis. In most situations, CT scans in patients with GPA or MPA (particularly those with suspected or diagnosed kidney involvement) should be performed without an iodinated contrast agent administered.

Tissue biopsy

Indications — Whenever possible, the diagnosis of GPA or MPA (or renal-limited vasculitis) should be confirmed by biopsy of a site of suspected active disease.

In patients with positive ANCA testing, the issue of whether treatment can be undertaken without tissue biopsy is controversial. Some clinicians undertake treatment without tissue biopsy in selected cases in which the clinical presentation is highly consistent with pauci-immune vasculitis and in which the results of ANCA testing are unequivocal (eg, both cytoplasmic ANCA [C-ANCA] and PR3-ANCA positive). However, we believe that, unless the clinical setting indicates an extremely high probability of vasculitis, then all reasonable attempts to confirm clinical suspicions with histopathological proof should be undertaken before committing patients to long-term treatment with potentially toxic medications, particularly since the ability to make the clinical diagnosis will vary widely with the experience of the clinician. If a biopsy cannot be immediately obtained, therapy should not be delayed, but a biopsy should be obtained as soon as possible after initiation of therapy.

The initiation of therapy without a confirmatory biopsy may be appropriate in selected circumstances, such as the severely ill ventilator-dependent patient without extrapulmonary involvement in whom the performance of a lung biopsy to obtain adequate tissue may result in significant morbidity or mortality. Even in this setting, an attempt should be made to confirm the diagnosis by tissue biopsy once the patient is stable, especially if there remains clinical uncertainty about the diagnosis.

Choice of biopsy site — Tissue for diagnosis and/or prognosis is usually obtained from a skin or kidney biopsy. Less commonly, a lung biopsy can be performed (usually thoracoscopic) in place of a kidney or skin biopsy. We rarely perform transbronchial lung biopsies or nasal biopsies since these tests are often unhelpful. Kidney biopsies are commonly done in patients with overt manifestations of kidney disease (such as reduced estimated glomerular filtration rate or active urine sediment). Many experts, however, feel that a kidney biopsy is not required for the initiation of therapy among patients who have been diagnosed with GPA or MPA (or renal-limited vasculitis) using clinical and serologic features and histologic analysis of tissue of another affected organ such as the skin or lung. Biopsy of other organs has given variable results [58].

In the absence of kidney involvement, the diagnosis of GPA or MPA may be made by lung biopsy. Lung biopsy most often requires open or thoracoscopic lung biopsy. In a small number of cases (<10 percent), sufficient tissue for diagnosis can be obtained by transbronchial biopsy of the lung; however, the absence of granulomatous vasculitis on transbronchial specimens should not be considered adequate evidence to exclude the diagnosis of GPA [59]. Thus, we rarely perform transbronchial biopsy in the diagnostic evaluation of GPA or MPA. If a lung biopsy is performed, special stains and cultures should be routinely sent to exclude the presence of infections that can produce granulomas (eg, tuberculosis), vasculitis, or necrosis.

A positive lung biopsy precludes the need for a kidney biopsy in many cases. However, a kidney biopsy is indicated when there is suspicion of an alternative or concomitant disease process occurring in the kidney or if the treatment selected (eg, the use of plasma exchange in addition to immunosuppressive therapy for associated anti-GBM disease) depends upon the presence of confirmed vasculitis in the kidney. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Role of plasma exchange'.)

Nasal biopsy, although relatively noninvasive, is limited by the high rate of falsely negative or nonspecific results due to the small amount of tissue that can be removed, and therefore, we rarely perform nasal biopsies in the diagnostic evaluation of GPA or MPA. Occasionally, the nasal biopsy may be useful in identifying other causes of upper respiratory tract symptoms, such as infection, malignancy, and noninflammatory disease (trauma).

Histopathology — The histopathologic findings on biopsies of affected organs are described below:

●Kidney – The severity of the kidney biopsy findings in GPA and MPA generally parallel the severity of the clinical presentation, ranging from mild focal and segmental glomerulonephritis in patients with asymptomatic hematuria and normal or near-normal kidney function to a diffuse necrotizing and crescentic glomerulonephritis in patients with acute kidney injury (picture 2) [23,24,60,61]. Patients with GPA, but not MPA, may have granulomatous changes [2,19], although granulomas are rarely found in kidney biopsy specimens, even among patients with well-documented GPA. Arteritis is occasionally seen.

In most patients, the glomerulonephritis is associated with few or no immune deposits in the glomeruli (pauci-immune glomerulonephritis) on immunofluorescence and electron microscopy [2]. Almost all patients with pauci-immune crescentic glomerulonephritis test positive for ANCA (96 percent in two series) [62,63]. The glomerular involvement is often accompanied by mononuclear tubulointerstitial infiltrates.

Although most patients have pauci-immune glomerulonephritis, some patients with ANCA-positive vasculitis have atypical pathology:

•Some individuals present with interstitial nephritis associated with vasculitis in the vasa recta, without glomerulonephritis [64]. Such patients may subsequently develop the classic pauci-immune necrotizing glomerulonephritis [65,66]. Other patients present with necrotizing glomerulonephritis and subsequently develop interstitial nephritis that may be drug induced [67].

•Patients with ANCA-positive glomerulonephritis occasionally have glomerular immune complex deposition on immunofluorescence and/or electron microscopy, which has been associated with more severe disease [24,25].

•Some patients with ANCA-positive disease will also have anti-GBM antibodies and linear immunofluorescence for immunoglobulin G (IgG) and C3 complement along the glomerular basement membrane. Such patients experience a disease course between that of patients with pure ANCA disease and that of patients with anti-GBM disease [68-70].

Histologic analysis of biopsy tissue by light microscopy contributes to the ability to predict kidney outcomes [71-73]. A classification system of kidney lesions has been developed that identifies four categories of glomerular lesions:

•Focal ‒ At least 50 percent of glomeruli are normal (ie, without vasculitic lesions or global sclerosis), although there may be subtle ischemic changes or a minimum number of inflammatory cells (fewer than four neutrophils, lymphocytes, or monocytes).

•Crescentic ‒ At least 50 percent of glomeruli have cellular crescents that are either cellular or fibrotic.

•Sclerotic ‒ At least 50 percent of glomeruli are globally sclerotic (defined as more than 80 percent sclerosis of the glomerulus).

•Mixed ‒ Less than 50 percent of glomeruli are normal, less than 50 percent are crescentic, and less than 50 percent are globally sclerotic.

The prognostic value of this classification was assessed in a validation study performed on biopsies from 100 European patients with at least one year of follow-up [73]. Of these, 35 patients reached end-stage kidney disease in just over one year. The sequence of categories listed above corresponded to the severity of kidney function impairment at one and five years, with the best and worst kidney function associated with focal and sclerotic lesions, respectively. Assessment of tubulointerstitial lesions did not independently alter the prognosis. By contrast, this histopathologic classification system performed less well in a Chinese population [74].

●Skin – Biopsy of the skin reveals a "nonspecific" leukocytoclastic vasculitis with little or no complement and immunoglobulin on immunofluorescence. Importantly, there are also other, non-vasculitic skin lesions that can be seen in patients with GPA and MPA [26]. (See "Overview of cutaneous small vessel vasculitis", section on 'Biopsy'.)

●Upper respiratory tract and lungs – The typical finding on upper respiratory tract biopsies in patients with GPA and MPA is acute and chronic inflammation either with a capillaritis or, less commonly, granulomatous features. Granulomatous inflammation is diagnostic for GPA. Among patients with MPA who undergo lung biopsy, the typical histologic lesion is pulmonary capillaritis. Among patients with GPA, granulomatous inflammation may be seen.

Other diagnostic procedures — In patients with suspected GPA or MPA, bronchoalveolar lavage (BAL), performed during flexible bronchoscopy, can be helpful in the diagnosis of alveolar hemorrhage, but its use in identifying a specific etiology is limited. Sequential lavages (usually three instillations in 20 to 60 mL aliquots) are performed at the same site in the lung in patients with suspected alveolar hemorrhage. The recovered samples are visually inspected for any increase in hemorrhagic appearance from the first syringe to the third and are microscopically examined for red cells and leukocytes. (See "Basic principles and technique of bronchoalveolar lavage".)

Establishing the diagnosis — The diagnosis of GPA and MPA is based upon the combination of characteristic clinical findings, laboratory tests, and imaging studies (algorithm 1). A positive ANCA test strongly supports but does not confirm the diagnosis, since both diagnostically false-positive and false-negative results may be seen. Histologic examination of tissue obtained by biopsy of an affected organ (generally, kidney, skin, or lung) remains the most definitive method to establish a diagnosis and is still often required.

While there are no universally accepted diagnostic criteria, we describe diagnostic scenarios and considerations for the main clinical diagnoses below:

●GPA – Patients with GPA typically present with symptoms and signs of small-vessel vasculitis involving the ear, nose, and throat (ENT); airways and lungs; kidneys; skin; eyes; and/or peripheral nervous system. Most patients (65 to 75 percent) are positive for PR3-ANCA. Tissue biopsy typically shows evidence of necrotizing granulomatous inflammation, usually involving the upper and lower respiratory tract, and necrotizing vasculitis affecting small-to-medium vessels; pauci-immune necrotizing glomerulonephritis is common.

●MPA – Patients with MPA may present with similar symptoms and signs of small-vessel vasculitis as those with GPA. Most patients (55 to 65 percent) are positive for MPO-ANCA. While the kidneys and skin are very commonly affected, ENT involvement is less frequent in MPA than in GPA. Tissue biopsy typically shows necrotizing vasculitis primarily affecting small-to-medium vessels; pauci-immune necrotizing glomerulonephritis is common. In contrast with GPA, granulomatous inflammation is generally absent.

●Renal-limited vasculitis – Although pauci-immune necrotizing glomerulonephritis typically occurs in association with involvement of other organs in both GPA and MPA, some patients present with a renal-limited, ANCA-positive (75 to 80 percent MPO-ANCA) vasculitis [61,62,75,76].

Renal-limited vasculitis is considered to be part of the GPA/MPA spectrum because the histopathologic findings in the kidney are often indistinguishable from those in GPA and MPA [61]. Some patients who are considered to have renal-limited vasculitis may subsequently develop extrarenal manifestations of GPA or MPA, occasionally during a relapse that may occur years after the initial onset of disease [11,77]. Patients with renal-limited vasculitis tend to have more glomerulosclerosis on kidney biopsy than those with GPA, probably because patients with renal-limited vasculitis present to a clinician later in the course of the disease due to the absence of extrarenal manifestations [61].

●ANCA-negative pauci-immune crescentic glomerulonephritis – Patients with ANCA-negative pauci-immune crescentic glomerulonephritis may be part of the spectrum of GPA and MPA, and they have similar kidney biopsy findings and prognosis [60]. Limited data from case series suggest that a subset of cases of ANCA-negative pauci-immune glomerulonephritis are associated with bacterial infections and malignancy [78].

Classification criteria, which were developed for use in clinical and epidemiological research, have sometimes been used historically for the purpose of diagnosis but have limitations when used for this purpose. (See 'Classification criteria' below.)

DIFFERENTIAL DIAGNOSIS — The distinction of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) from other systemic rheumatic diseases is a frequent clinical challenge. This includes diseases with similar general clinical features, similar lung and/or kidney signs, and/or positive ANCA serologies. While it is beyond the scope of this review to provide a comprehensive list of all possible alternative diagnoses, we present several important mimics of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) below:

●Eosinophilic granulomatosis with polyangiitis (EGPA) – The vasculitis in patients with GPA, MPA, and EGPA is pathologically indistinguishable. Asthma and eosinophilia may distinguish EGPA from GPA and MPA. (See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)

●Polyarteritis nodosa – The cardinal features of classic polyarteritis nodosa, a vasculitis of the medium-sized muscular arteries, include renal infarcts, renal artery stenosis, and visceral microaneurysms, all of which are infrequently observed in GPA or MPA. Glomerulonephritis, other manifestations of small-vessel vasculitis, and a positive ANCA are observed in GPA and MPA but not classic polyarteritis nodosa [2]. In addition, unlike polyarteritis nodosa, the majority of patients with GPA and MPA are positive for antibodies to either proteinase 3 (PR3) or myeloperoxidase (MPO), respectively. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults".)

●Anti-glomerular basement membrane (anti-GBM) antibody disease – Anti-GBM antibody disease, substantially rarer than GPA and MPA, is another disorder that can present with features of a pulmonary-renal syndrome. Furthermore, these diseases can occur together; 10 to 40 percent of patients with anti-GBM antibody disease also form ANCA (mostly MPO rather than PR3), a minority of whom have manifestations compatible with extrarenal and extrapulmonary vasculitis [68-70,79,80]. (See "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis" and "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Anti-GBM autoantibody disease'.)

●Drug-induced ANCA-associated vasculitis – Certain medications (such as propylthiouracil, hydralazine, and minocycline) can induce forms of vasculitis associated with ANCA. Most patients have MPO-ANCA, usually in very high titers, although a small number have PR3-ANCA. Occasionally, serologies are positive for both anti-MPO and anti-PR3; levamisole (often a contaminant in cocaine) should be suspected in this setting. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Drug-induced ANCA-associated vasculitis'.)

●Infection – Certain infections may be associated with positive ANCA serologies, especially subacute bacterial endocarditis and other forms of bacteremia (positive anti-PR3 antibodies). (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies", section on 'Infections'.)

●Malignancy – Some malignancies, such as lymphoma, leukemia, and myeloproliferative and myelodysplastic disorders, have been associated with vasculitis and may mimic GPA or MPA [81].

●Concurrent glomerular disease – Some patients have two different types of glomerular disease at the same time. Thus, in selected cases it may be useful to consider the presence of another glomerular disease, particularly those that have been associated with concurrent ANCA-associated glomerulonephritis (see "Glomerular disease: Evaluation and differential diagnosis in adults"):

•Membranous nephropathy, which may represent a chance occurrence of two unrelated disease processes (see "Membranous nephropathy: Pathogenesis and etiology", section on 'Crescentic glomerulonephritis')

•Lupus nephritis (see "Lupus nephritis: Diagnosis and classification")

•Anti-GBM antibody disease (see "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis")

•IgA nephropathy (see "IgA nephropathy: Clinical features and diagnosis", section on 'Associated conditions')

•Bacterial infection-related glomerulonephritis (mostly poststreptococcal or Staphylococcus associated) in adults (see "Staphylococcus-associated glomerulonephritis in adults")

CLASSIFICATION CRITERIA — There have been several efforts to standardize the nomenclature, classification, and diagnostic criteria for small-vessel vasculitis [2,82-87]:

●In 1990, the American College of Rheumatology (ACR) proposed criteria for the vasculitides to facilitate standardization of research in patients with granulomatosis with polyangiitis (GPA) and help distinguish these patients from those with other forms of vasculitis [82]. However, these criteria were launched before the widespread recognition of microscopic polyangiitis (MPA) as a separate entity and prior to recognition of the significance of antineutrophil cytoplasmic autoantibody (ANCA) testing as a diagnostic tool. While the ACR classification criteria have been helpful and widely used in clinical research in GPA and other vasculitides, they lack sufficient sensitivity and specificity to be used as diagnostic criteria.

●The European Medicines Agency (EMA) developed an algorithm that was designed to help classify the ANCA-associated vasculitides (AAV) for epidemiological studies; however, this algorithm also had its limitations [83].

●The International Chapel Hill Consensus Conference (CHCC) nomenclature, which were revised in 2012, are the mostly commonly cited (table 1). The CHCC provided definitions of disease but not classification criteria [1,2]. These definitions have gained wide acceptance in defining vasculitides by pathology, including the size of affected vessels and the organ systems involved. However, the classification algorithms have important limitations.

●The ACR and European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) have developed and validated classification criteria for GPA and MPA using weighted parameters that are combined to derive a risk score [84-87].

Although the ACR criteria, the EMA algorithm, and the CHCC nomenclature system have been widely used by clinical researchers to help standardize the process of enrolling patients into clinical studies and differentiating among the ANCA-associated vasculitides, clinicians should not rely on these nomenclature systems to diagnose patients, as they were not designed for this purpose and generally do not perform well for this purpose. Accurate diagnostic criteria for GPA and MPA have yet to be developed.

An alternative approach to classification is based upon ANCA serology. The rationale for an ANCA-based classification is based upon the dual premises that patients who have proteinase 3 (PR3)- or myeloperoxidase (MPO)-ANCA have more closely associated disease findings and that respective ANCA subtypes have better predictive value with respect to long-term outcome and relapse propensity than do either the terms "GPA" or "eosinophilic granulomatosis with polyangiitis (EGPA)." Patients who are ANCA negative can have a GPA, MPA, or renal-limited vasculitis phenotype. However, immunosuppressive therapy is the same for patients with GPA, MPA, or renal-limited vasculitis [88,89]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of relapsing disease", section on 'Risk factors for relapse' and "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of disease resistant to initial therapy", section on 'Incidence and risk factors'.)

A proposal has been made to address the problems with the ACR criteria, the CHCC definitions, and the EMA algorithm by using the terms "PR3-ANCA disease," "MPO-ANCA disease," and "seronegative ANCA disease." With this approach, no diagnostic criteria are needed other than serological findings. The fact that PR3-ANCA and MPO-ANCA have more prognostic significance than the terms "MPA" and "GPA" with respect to response to therapy, propensity for relapse, and patient outcome supports this proposed change in classification [88,90]. In addition, genetic variants that are associated with ANCA disease are more specifically linked with the antigen (PR3 versus MPO) rather than with the clinical phenotype [91,92].

In the absence of clearly accepted criteria for allocation of patients into specific disease categories, the use of the terms "GPA" and "MPA" will remain somewhat imprecise and may differ on the basis of geography and specialty [74].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults" and "Society guideline links: Vasculitis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Granulomatosis with polyangiitis (The Basics)")

SUMMARY

●Nomenclature – Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) are a group of disorders that include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), renal-limited vasculitis, and eosinophilic granulomatosis with polyangiitis (EGPA). All are associated with ANCA, affect predominantly small-sized arteries, and have similar features on kidney histology (eg, a focal necrotizing, often crescentic, pauci-immune glomerulonephritis). (See 'Introduction' above and 'Nomenclature' above.)

●Epidemiology – GPA and MPA most commonly occur in older adults, although these diseases have been reported at all ages. Males and females are equally affected. GPA and MPA are rare among children. The incidence of GPA and MPA varies widely depending upon geography. (See 'Epidemiology' above.)

●Clinical manifestations – Patients with both GPA and MPA typically present with nonspecific symptoms including fever, malaise, anorexia, weight loss, myalgias, and arthralgias. Prodromal symptoms may last for weeks to months without evidence of specific organ involvement.

Specific organ manifestations include the following:

•Ear, nose, and throat (ENT) – ENT manifestations include nasal crusting, sinusitis, otitis media, earache, otorrhea, persistent rhinorrhea, purulent/bloody nasal discharge, oral and/or nasal ulcers, and polychondritis. Patients frequently develop conductive and/or sensorineural hearing loss, either of which can lead to severe permanent hearing impairment. (See 'Ear, nose, and throat involvement' above.)

•Tracheal and pulmonary involvement – Involvement of airways or pulmonary parenchyma can cause hoarseness, cough, dyspnea, stridor, wheezing, hemoptysis, or pleuritic pain. A chest radiograph may reveal nodules, patchy or diffuse opacities and fleeting pulmonary infiltrates, and hilar adenopathy (image 2 and image 3). (See 'Tracheal and pulmonary involvement' above.)

•Kidney involvement – The typical presentation of kidney involvement is that of a rapidly progressive glomerulonephritis. Glomerulonephritis may present with asymptomatic hematuria with or without a rise in serum creatinine, as well as a variable degree of proteinuria that is usually subnephrotic. (See 'Kidney involvement' above.)

•Cutaneous involvement – A variety of cutaneous manifestations may occur, the most common being purpura involving the lower extremities that may be accompanied by focal necrosis and ulceration. Skin lesions may also include urticaria, livedo reticularis, and nodules. (See 'Cutaneous involvement' above.)

•Ophthalmic or orbital involvement – Ophthalmic or orbital involvement may include conjunctivitis, corneal ulceration, episcleritis/scleritis, optic neuropathy, retinal vasculitis, and uveitis. In addition, retro-orbital pseudotumor and nasolacrimal duct obstruction may also occur. (See 'Ophthalmic and orbital involvement' above.)

•Neurologic involvement – Neurologic involvement can include multiple mononeuropathy (also called mononeuritis multiplex), sensory neuropathy, cranial nerve abnormalities, central nervous system mass lesions, external ophthalmoplegia, and sensorineural hearing loss. (See 'Neurologic involvement' above.)

●When to suspect GPA or MPA – The diagnosis of GPA or MPA should be suspected in any patient who presents with constitutional symptoms and other clinical evidence of glomerulonephritis or upper or lower respiratory tract involvement. The suspicion should be further increased if there is laboratory detection of ANCA. Some patients may present with manifestations limited to a single organ such as the kidneys or the upper respiratory tract and then may later evolve to include other organ involvement. In a subset of patients, the disease will be limited to a single organ (eg, renal-limited vasculitis). (See 'When to suspect GPA or MPA' above.)

●Evaluation and diagnosis – The diagnosis of GPA and MPA is based upon the combination of characteristic clinical findings, laboratory tests, and imaging studies (algorithm 1). A positive ANCA test strongly supports but does not confirm the diagnosis, since both diagnostically false-positive and false-negative results may be seen. Histologic examination of tissue obtained by biopsy of an affected organ (generally, kidney, skin, or lung) remains the most definitive method to establish a diagnosis and is still often required. (See 'Evaluation' above and 'Establishing the diagnosis' above.)

●Differential diagnosis – The distinction of GPA and MPA from other systemic rheumatic diseases is a frequent clinical challenge. This includes diseases with similar general clinical features, similar lung and/or kidney signs, and/or positive ANCA serologies. Several important mimics of GPA and MPA include EGPA, polyarteritis nodosa, anti-glomerular basement membrane (anti-GBM) antibody disease, drug-induced ANCA-associated vasculitis, infection, and malignancy. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — UpToDate thanks Dr. John Stone, who contributed to earlier versions of this topic review.