INTRODUCTION — The relationship between antineutrophil cytoplasmic autoantibodies (ANCA) and granulomatosis polyangiitis (GPA), microscopic polyangiitis (MPA), and "renal-limited" vasculitis (pauci-immune glomerulonephritis without evidence of extrarenal disease) is well established [1-4]. ANCA are also present in a substantial subset (approximately 40 percent) of patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome, abbreviated as EGPA) . ANCA testing plays a critical role in the diagnosis and classification of vasculitides, even as debate about their ultimate importance in the pathogenesis and pathophysiology of these conditions continues.
Following a brief discussion of certain technical issues related to the performance of ANCA assays, a review of the disease associations of ANCA and clinical utility of ANCA testing will be presented here. The role of ANCA in the pathogenesis of GPA and related vasculitides is discussed separately. (See "Pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis".)
TECHNIQUES TO DETECT ANCA — Two types of antineutrophil cytoplasmic autoantibody (ANCA) assays are in wide use:
●Indirect immunofluorescence assay, using alcohol-fixed buffy coat leukocytes
●Enzyme-linked immunosorbent assay (ELISA), using purified specific antigens
Of these two techniques, the immunofluorescence assay is more sensitive, and the ELISA is more specific. The optimal approach to clinical testing for ANCA is therefore to perform both immunofluorescence, if available, and ELISA to detect antibodies against the vasculitis-specific target antigens [6,7]. However, in the United States, ANCA testing is not standardized, and therefore, the sensitivity and specificity will vary among laboratories; there are also no standardized reference values for normal ranges. Ultimately, standardized testing with a highly sensitive and specific ELISA may replace the strategy of immunofluorescence followed by ELISA . (See 'Pitfalls of interpreting immunofluorescence results' below.)
In vasculitis, the two relevant target antigens are proteinase 3 (PR3) and myeloperoxidase (MPO). Both PR3 and MPO are located in cytoplasmic azurophilic granules of neutrophils and the peroxidase-positive lysosomes of monocytes. Antibodies with target specificities for PR3 and MPO are called "PR3-ANCA" and "MPO-ANCA," respectively.
Indirect immunofluorescence test for ANCA
Immunofluorescence patterns in vasculitis — When the sera of patients with ANCA-associated vasculitis are incubated with ethanol-fixed human neutrophils, two major immunofluorescence patterns are observed (picture 1A-B):
●C-ANCA pattern – With the cytoplasmic ANCA (C-ANCA) pattern, the staining is diffuse throughout the cytoplasm. In most cases, antibodies directed against PR3 cause this pattern [9,10], but MPO-ANCA can occasionally be responsible.
●P-ANCA pattern – The perinuclear ANCA (P-ANCA) pattern results from a staining pattern around the nucleus, which represents an artifact of weak ethanol fixation. With ethanol fixation of the neutrophil substrate, positively charged granule constituents rearrange themselves around the negatively charged nuclear membrane, leading to perinuclear fluorescence . Among patients with vasculitis, the antibody responsible for this pattern is usually directed against MPO (and only occasionally PR3).
Immunofluorescence patterns in nonvasculitic conditions — Atypical ANCA patterns may be observed on immunofluorescence testing in patients with immune-mediated conditions other than systemic vasculitis (eg, connective tissue disorders, inflammatory bowel disease, and autoimmune hepatitis). These atypical ANCA patterns may be confused with P-ANCA patterns. However, ELISA testing for antibodies against MPO or PR3 is negative in such cases.
Pitfalls of interpreting immunofluorescence results — For several reasons, caution is required in the interpretation of both positive and negative C- and P-ANCA immunofluorescence patterns:
●There is a subjective component to the interpretation of immunofluorescence assays because the tests are based upon visual interpretation of the immunofluorescence pattern; this is sometimes not straightforward. Thus, the positive or negative predictive value of a given test result depends upon the experience of the individual who performs the assay. The positive and negative predictive values are likely to be better with results from a research laboratory than with a commercial assay, but variability exists in all laboratories .
●ANCA testing remains unstandardized in the United States, and there are no references for normal ranges. In evaluating the utility of ANCA testing in clinical practice, it must be borne in mind that most studies of ANCA serologies have been performed at tertiary care centers using research laboratories focused on ANCA testing. Translating the test characteristics from the environments of research laboratories to clinical practice must be done with caution.
●Immunofluorescence results are not highly specific for the diagnosis of vasculitis. The C-ANCA pattern has a greater specificity than the P-ANCA pattern for vasculitis. (See 'Disease associations' below.)
●Antibodies to a host of azurophilic granule proteins can cause a P-ANCA staining pattern. These include antibodies directed against lactoferrin, elastase, cathepsin G, bactericidal/permeability-increasing protein (BPI), catalase, lysozyme, beta-glucuronidase, and others. A positive P-ANCA immunofluorescence staining pattern may also be detected in a wide variety of inflammatory illnesses and has a low specificity for vasculitis. A positive immunofluorescence assay should therefore always prompt testing by ELISA to determine the specific antibody (or antibodies) responsible for the pattern.
●Because of the frequent difficulty in distinguishing the P-ANCA pattern of immunofluorescence from that caused by antinuclear antibodies (ANA), individuals with ANA frequently have "false-positive" results on ANCA testing by immunofluorescence. Typically, in patients who have a positive ANA, a positive P-ANCA is a false positive. However, pauci-immune necrotizing glomerulonephritis has been reported in patients with systemic lupus erythematosus (SLE) with positive P-ANCA, and ELISA testing should be performed in all such patients .
●To avoid false-positive P-ANCA tests, immunofluorescence assays should be routinely performed on both formalin- and ethanol-fixed substrates. This is because formalin-fixed neutrophils prevent the rearrangement of charged cellular components around the nucleus. The use of both cell substrates permits the distinction between antibodies causing a "true" P-ANCA pattern and those directed against the nuclear antigens (ANA). (See "Measurement and clinical significance of antinuclear antibodies".)
Solid-phase immunoassays — Solid-phase immunoassays (eg, ELISAs) are used for detection of specific antibodies to PR3 and MPO are commercially available and should be part of any standardized approach to the testing for ANCA. ELISAs are the most commonly used solid-phase assay but alternative solid-phase assays are also available .
PR3-ANCA and MPO-ANCA are associated with substantially higher specificities and positive predictive values than the immunofluorescence patterns to which they usually correspond (C- and P-ANCA, respectively) . However, errors can be made if these tests are not performed in experienced laboratories. ELISAs for other antigens are also available, but the indications for their use are unclear.
ANCA-associated vasculitis — Antineutrophil cytoplasmic autoantibodies (ANCA) are associated with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss), "renal-limited" vasculitis, and certain drug-induced vasculitis syndromes . In these conditions, ANCA consistently have specificities for either proteinase 3 (PR3) or myeloperoxidase (MPO) but almost never for both.
Granulomatosis with polyangiitis — Approximately 90 percent of patients with active, generalized GPA are ANCA positive. However, a small subset of patients with active, generalized GPA or more limited forms of the disease do not have ANCA (such as a subset of patients with predominantly upper respiratory tract disease and no kidney involvement). Thus, the absence of ANCA does not exclude the diagnosis of GPA. In large measure, the sensitivity of PR3-ANCA for GPA is related to activity of disease at the time of sampling .
Among patients who have GPA with ANCA, 80 to 90 percent have PR3-ANCA. The remainder of ANCA-positive GPA patients have MPO-ANCA. Necrotizing granulomatous inflammation, the histopathologic hallmark of GPA, has been reported in both PR3- and MPO-ANCA-positive individuals. (See "Pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis", section on 'Testing for ANCA' and "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis", section on 'Histopathology'.)
Microscopic polyangiitis — Nearly 90 percent of patients with MPA are ANCA positive . In contrast to GPA, most ANCA-positive patients with MPA have MPO-ANCA, with a minority having PR3-ANCA. Because PR3-ANCA or MPO-ANCA may occur in both GPA and MPA, these diseases cannot be distinguished on the basis of ANCA specificity. Data pertaining to ANCA and MPA are also complicated by the lack of consensus concerning the definition of MPA. The distinction between GPA and MPA is important chiefly because of differential tendencies to flare. Although both diseases may flare after the achievement of remission, GPA is substantially more likely to relapse [17-19]. (See "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'.)
Renal-limited vasculitis — Pauci-immune vasculitis limited to the kidney is characterized by necrotizing glomerulonephritis with little or no deposition of immunoreactants (immunoglobulin G [IgG], immunoglobulin M [IgM], immunoglobulin A [IgA], and complement components). The majority of patients with renal-limited vasculitis are ANCA positive, with 75 to 80 percent having MPO-ANCA.
ANCA-positive pauci-immune necrotizing glomerulonephritis is considered to be part of the GPA/MPA spectrum because the histopathologic findings in the kidney are indistinguishable from those of the glomerulonephritis in GPA or MPA and because some patients who present with disease limited to the kidney eventually exhibit extrarenal manifestations of either GPA or MPA . (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis", section on 'Establishing the diagnosis'.)
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) — ANCA, both PR3 and MPO, have been detected with variable frequencies in patients with EGPA [21-26]. Although variable from study to study, approximately 30 to 50 percent of patients with EGPA are ANCA positive, with the percentage being somewhat higher in those with active, untreated disease [5,24]. Among patients with ANCA-positive EGPA, MPO-ANCA is substantially more frequent than PR3-ANCA. As an example, in one series, 40 of 102 patients with EGPA were ANCA positive, and 29 (73 percent) had specificity for MPO-ANCA . In a second study, 38 of 43 ANCA-positive patients with EGPA were tested for MPO and PR3; MPO was identified in 34 patients (79 percent), and PR3 was identified in none .
Some studies suggest the possibility of clinical differences among patients with EGPA who are ANCA positive compared with those who are ANCA negative [5,25,27]. ANCA-positive patients are more likely to have glomerulonephritis, alveolar hemorrhage, and neurologic disease, whereas ANCA-negative patients are more likely to have cardiac and other pulmonary involvement. However, there is certainly overlap in clinical presentations among patients with and without ANCA (as is true in GPA and MPA). (See "Epidemiology, pathogenesis, and pathology of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)
Anti-GBM autoantibody disease — Between 10 and 50 percent of patients with anti-glomerular basement membrane (GBM) autoantibody disease are ANCA positive at the time of diagnosis, and ANCA is usually directed against MPO rather than PR3 [28-33]. In general, patients who are positive for both anti-GBM autoantibodies and ANCA have a higher risk of relapse than patients positive only for anti-GBM autoantibodies. In such "double-positive" patients, the initial clinical presentation is often similar to patients with isolated anti-GBM disease, whereas relapses are usually characteristic of patients with isolated ANCA-associated vasculitis. A detailed discussion of double-positive anti-GBM and ANCA-associated disease can be found elsewhere. (See "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Double-positive anti-GBM and ANCA-associated disease'.)
In patients with both ANCA and anti-GBM autoantibodies, the relationship between the two antibodies is unknown. The antigen specificity for the anti-GBM autoantibodies is the same as in patients with anti-GBM autoantibody disease alone, suggesting that the inciting antigen is the same .
Drug-induced ANCA-associated vasculitis — Certain medications may induce forms of vasculitis associated with ANCA. Most patients reported with drug-induced ANCA-associated vasculitis have MPO-ANCA, frequently in very high titers . A small number have PR3-ANCA.
Many cases of drug-induced ANCA-associated vasculitis are associated with constitutional symptoms, arthralgias/arthritis, and cutaneous vasculitis. However, the full range of clinical features associated with ANCA, including crescentic glomerulonephritis and alveolar hemorrhage, can also occur.
The strongest links between medications and ANCA-associated vasculitis are with drugs employed in the treatment of hyperthyroidism (propylthiouracil, methimazole [thiamazole], and carbimazole), hydralazine, and minocycline. Of these, hydralazine is the most common cause of drug-induced ANCA-associated vasculitis . As discussed below, many cases of "drug-induced lupus" are actually drug-induced ANCA-associated vasculitis. Other implicated drugs in clinical use include sofosbuvir, allopurinol, penicillamine, procainamide, clozapine, phenytoin, rifampicin, cefotaxime, isoniazid, and indomethacin [36-42]. However, causal associations between these drugs and ANCA-associated vasculitis are not well established.
Drug-induced ANCA-associated vasculitis is sufficiently uncommon that the possibility of this complication should not preclude the use of medications associated with this condition. Clinicians frequently utilizing these medications should be aware of the potential for the development of ANCA-associated vasculitis. The detection of ANCA among patients taking these medications should prompt an evaluation to determine if vasculitis is present; the clinical differentiation between drug-induced "seropositivity" and drug-induced disease can be difficult to ascertain.
Hydralazine — Hydralazine has been associated with two drug-induced systemic rheumatic syndromes:
●Drug-induced lupus (see "Drug-induced lupus")
●Drug-induced ANCA-associated vasculitis, which is a potentially more serious condition
Unlike drug-induced lupus caused by hydralazine, hydralazine-induced ANCA-associated vasculitis is frequently associated with kidney involvement (usually a pauci-immune glomerulonephritis), antibodies to double-stranded DNA, and high titers of MPO-ANCA, as well as anti-histone antibodies and hypocomplementemia; patients generally require immunosuppressive therapy in addition to withdrawal of hydralazine [34,43,44]. In the largest series including 80 cases of hydralazine-induced ANCA-associated glomerulonephritis, extrarenal involvement was uncommon (18 percent with pulmonary involvement, 4 percent with purpura, 3 percent with upper airway involvement) . On kidney biopsy, the predominant pattern on light microscopy was necrotizing and crescentic glomerulonephritis; however, compared with primary ANCA glomerulonephritis, the biopsies were less frequently pauci-immune on immunofluorescence and had more frequent mesangial hypercellularity, detectable electron dense deposits, and endothelial tubuloreticular inclusions. More than three-fourths of patients were on hydralazine for over 12 months. Among the 51 patients who had clinical follow-up, 42 patients received immunosuppressive therapy (including glucocorticoids, cyclophosphamide, rituximab, and/or mycophenolate) with or without plasmapheresis; all discontinued hydralazine. Fourteen patients (27 percent) progressed to end-stage kidney disease (ESKD), and 11 (21 percent) died; these outcomes are similar to those of patients with primary ANCA-associated glomerulonephritis treated with standard therapy [46,47]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Drug-induced ANCA-associated vasculitis'.)
Propylthiouracil — Propylthiouracil may be the most common offending agent in drug-induced ANCA seropositivity. In general, patients with this complication have taken the medication for months or even years. A relatively high percentage of patients administered propylthiouracil develop ANCA. In a cross-sectional study, for example, 27 percent of patients receiving long-term treatment with propylthiouracil developed MPO-ANCA seropositivity . However, only a small proportion of such patients develop clinical vasculitis. In another study of 209 patients with hyperthyroidism, 13 (6 percent) were positive for either MPO- or PR3-ANCA or for ANCA directed against human leukocyte elastase . The presence of ANCA was highly associated with treatment with propylthiouracil and related antithyroid drugs (odds ratio [OR] 11.8, 95% CI 1.5-93.3). ANCA positivity with glomerulonephritis developed in approximately one-third (4 of 13).
Although the mechanism of ANCA seropositivity and vasculitis caused by propylthiouracil has not been well defined, it is known that propylthiouracil accumulates in neutrophils and that it binds to and alters the MPO antigen [50,51]. This alteration could potentially lead to the formation of autoantibodies in susceptible individuals.
In patients who develop a vasculitis, the syndrome often resolves with discontinuation of propylthiouracil, but severe cases may require treatment with glucocorticoids and other immunosuppressive medications. ANCA titers do not usually persist after active vasculitis has abated. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Drug-induced ANCA-associated vasculitis'.)
Minocycline — Minocycline has been associated with arthritis, fever, livedo reticularis, and the induction of ANCA in a report of seven patients . The perinuclear ANCA (P-ANCA) immunofluorescence pattern typically associated with this disorder is usually directed against minor antigens such as cathepsin G, elastase, and bactericidal/permeability-increasing protein (BPI) rather than against MPO [52,53]. Symptoms typically resolve with the cessation of minocycline therapy and recur with drug rechallenge. Some patients require treatment with glucocorticoids.
More serious manifestations of an ANCA-positive vasculitis have been described in association with minocycline therapy, including crescentic glomerulonephritis, a lupus-like syndrome, and cutaneous polyarteritis nodosa (PAN) [54-57].
Cocaine and levamisole — Approximately 70 percent of cocaine bought illicitly in the United States is contaminated or "cut" with levamisole, an anti-helminthic agent with immunomodulatory properties. The use of levamisole-contaminated cocaine is associated with ANCA vasculitis, which can cause a unique vasculopathy associated with gangrenous skin lesions [58-63]. Levamisole exposure is associated with "dual positivity" for PR3- and MPO-ANCA. One of the largest series described 30 patients who presented between 2009 and 2010 . The most common clinical manifestations included arthralgias (83 percent) and skin lesions (61 percent). Seventy-two percent of patients reported fever, night sweats, weight loss, myalgias, or other constitutional symptoms. All patients had a positive MPO-ANCA, and 50 percent also had a positive PR3-ANCA. Twenty-eight percent of patients had leukopenia. An abnormal urinalysis (including proteinuria, hematuria, or cellular casts) was present in eight patients, and two patients developed pulmonary hemorrhage.
Levamisole is occasionally used as a glucocorticoid-sparing agent for the management of nephrotic syndrome in children; its availability is limited worldwide, and it is only approved by the US Food and Drug Administration (FDA) as an anti-helminthic agent. A cohort study including 71 children taking levamisole for nephrotic syndrome found that 12 out of 33 patients tested were positive for ANCA . Only 2 of these 12 patients developed clinical findings suggestive of ANCA-associated vasculitis resulting in discontinuation of levamisole. (See "Treatment of idiopathic nephrotic syndrome in children", section on 'Levamisole'.)
Interstitial nephritis — Interstitial nephritis may be seen with ANCA-associated vasculitis when the vasculitis involves the renal medulla [39,40]. In addition, acute drug-induced interstitial nephritis has occasionally been associated with ANCA formation, with the ANCA reacting against MPO, elastase, and lactoferrin . (See "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'Establishing the cause'.)
Nonvasculitic systemic rheumatic diseases — ANCA have been reported in virtually all systemic rheumatic diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's disease, inflammatory myopathies, juvenile chronic arthritis, reactive arthritis, relapsing polychondritis, systemic sclerosis, and the antiphospholipid syndrome. In most cases, the immunofluorescence pattern is P-ANCA. Atypical fluorescence patterns also occur in these settings, while cytoplasmic ANCA (C-ANCA) patterns are rare. The clinical significance of the presence of ANCA in these disorders is unclear. Many reports of ANCA in these diseases preceded the availability of reliable enzyme-linked immunosorbent assays (ELISAs) for PR3- and MPO-ANCA, and ANCA were detected with only immunofluorescence assays. When tested for ANCA using both immunofluorescence and ELISA methods, many of these patients with a positive test for ANCA by immunofluorescence had a negative test for ANCA by ELISA . A multitude of target antigens has been described in patients with these disorders, including lactoferrin, elastase, lysozyme, cathepsin G, and others. In some cases, the specific target antigen remains to be identified.
Autoimmune gastrointestinal disorders — ANCA positivity is seen in 60 to 80 percent of patients with ulcerative colitis and the related disorder primary sclerosing cholangitis. It is observed in only 10 to 27 percent of patients with Crohn disease, in whom only low titers are present.
The P-ANCA in these conditions appears to be predominantly directed against a myeloid cell-specific 50 kilodalton nuclear envelope protein . Other reported antigen targets include BPI, lactoferrin, cathepsin G, elastase, lysozyme, and PR3 .
The pathogenetic significance of these antibodies is unclear. The titers of ANCA do not vary with the activity or severity of the disease and, in ulcerative colitis, do not fall after colectomy.
Cystic fibrosis — Non-MPO P-ANCA are common in patients with cystic fibrosis, particularly among those with bacterial airway infections [68,69]. The ANCA is directed against BPI , with a strong association with Pseudomonas aeruginosa infection and colonization . BPI is a potent antimicrobial factor of the innate defense, which is present in the azurophilic granules of neutrophils . In one series of 66 patients with cystic fibrosis, BPI-IgG- and BPI-IgA-ANCA were found in 91 and 83 percent, respectively . Anti-BPI titers were directly related to the severity of airway destruction. It is unclear whether this relationship represents an epiphenomenon or a response (adaptive or maladaptive) to gram-negative infection with release of endotoxin.
Infections — Positive tests for ANCA, especially C-ANCA and PR3-ANCA, have been reported in patients with subacute bacterial endocarditis and other forms of bacteremia [72-75]. In a large series from France in which stored serum specimens from patients with bacteremia were later tested for ANCA, 18 percent of patients had positive tests for ANCA by immunofluorescence, and 8 percent were positive for PR3- or MPO-ANCA by ELISA . These data should prompt clinicians to have a low threshold to obtain blood cultures in patients with possible ANCA-associated vasculitis and in patients testing positive for ANCA.
De novo ANCA-associated vasculitis has been reported in the setting of coronavirus disease 2019 (COVID-19)  as well as following administration of COVID-19 mRNA vaccines [77,78]. However, the degree, if any, that SARS-CoV2 infection or vaccines targeting the virus are causal for vasculitis is not known. (See "COVID-19: Issues related to acute kidney injury, glomerular disease, and hypertension", section on 'Glomerular disease' and "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'COVID-19 as a risk factor for rheumatologic disease'.)
Some but not all studies have identified ANCA positivity in patients with mycobacterium tuberculosis [79-81], leprosy, acute parvovirus B19 infection, acute infectious mononucleosis, malaria, and aspergillosis [82,83].
Other concurrent glomerular diseases — In addition to anti-GBM autoantibody disease, ANCA-associated glomerular disease has also been described to coexist with a variety of other glomerular diseases including membranous nephropathy, lupus nephritis, IgA nephropathy, and bacterial infection-related glomerulonephritis (mostly poststreptococcal and Staphylococcus associated). This issue is reviewed elsewhere. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis", section on 'Differential diagnosis'.)
Other possible associations — In addition to the above disease associations, ANCA has also been observed in isolated patients with autoimmune hepatitis, thromboangiitis obliterans (Buerger's disease), preeclampsia and eclampsia, diffuse alveolar hemorrhage, chronic graft-versus-host disease, and cocaine-induced osteochondral destruction (cocaine-induced midline destructive lesions) [84-89].
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".)
●Techniques to detect ANCA – Two types of antineutrophil cytoplasmic autoantibody (ANCA) assays are in wide use: indirect immunofluorescence assay and enzyme-linked immunosorbent assay (ELISA). In vasculitis, the two relevant target antigens detected by ELISA are proteinase 3 (PR3) and myeloperoxidase (MPO). Specific ELISAs for antibodies to PR3 and MPO are commercially available and should be part of any standardized approach to the testing for ANCA. PR3-ANCA and MPO-ANCA are associated with substantially higher specificities and positive predictive values than the immunofluorescence patterns to which they usually correspond (cytoplasmic ANCA [C-ANCA] and perinuclear ANCA [P-ANCA], respectively). (See 'Techniques to detect ANCA' above.)
●Disease associations – ANCA are associated with a variety of disorders (see 'Disease associations' above):
•Granulomatosis with polyangiitis (GPA) – Approximately 90 percent of patients with active, generalized GPA are ANCA positive. Among patients who have GPA with ANCA, 80 to 90 percent have PR3-ANCA. (See 'Granulomatosis with polyangiitis' above.)
•Microscopic polyangiitis (MPA) – Nearly 90 percent of patients with MPA are ANCA positive, and most ANCA-positive patients with MPA have MPO-ANCA. (See 'Microscopic polyangiitis' above.)
•Renal-limited vasculitis – The majority of patients with renal-limited vasculitis are ANCA positive, with 75 to 80 percent having MPO-ANCA. (See 'Renal-limited vasculitis' above.)
•Eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss) – ANCA, both PR3 and MPO, have been detected with variable frequencies in patients with EGPA. Among such patients, the vast majority have MPO-ANCA. (See 'Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)' above.)
•Anti-glomerular basement membrane (GBM) autoantibody disease – Between 10 and 50 percent of patients with anti-GBM autoantibody disease are ANCA positive at the time of diagnosis, and ANCA is usually directed against MPO rather than PR3. In addition to anti-GBM autoantibody disease, ANCA-associated glomerular disease has also been described to coexist with a variety of other disorders including membranous nephropathy, lupus nephritis, IgA nephropathy, and bacterial infection-related glomerulonephritis (mostly poststreptococcal and Staphylococcus associated). (See 'Anti-GBM autoantibody disease' above and 'Other concurrent glomerular diseases' above.)
•Drug-induced ANCA-associated vasculitis – Certain medications may induce forms of vasculitis associated with ANCA (mostly MPO-ANCA), including hydralazine, propylthiouracil, methimazole, carbimazole, and minocycline. Other drugs, such as allopurinol, penicillamine, procainamide, thiamazole, clozapine, phenytoin, rifampicin, cefotaxime, isoniazid, and indomethacin, have less certain causal associations with ANCA-associated vasculitis. Levamisole-contaminated cocaine is also associated with drug-induced ANCA-associated vasculitis. (See 'Drug-induced ANCA-associated vasculitis' above.)
•Other – ANCA may also be seen with interstitial nephritis, nonvasculitic systemic rheumatic diseases, autoimmune gastrointestinal disorders (such as ulcerative colitis), cystic fibrosis, and various infections. (See 'Nonvasculitic systemic rheumatic diseases' above and 'Autoimmune gastrointestinal disorders' above and 'Cystic fibrosis' above and 'Infections' above.)
ACKNOWLEDGMENT — UpToDate thanks Dr. John H. Stone, who contributed to earlier versions of this topic review.
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