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Background
ANCA stands for anti-neutrophilic cytoplasmic antibodies. These are a class of antibodies identified by immunofluorescence. In general, serologic testing for ANCA is recommended for patients with:
Glomerulonephritis
Pulmonary hemorrhage, especially Pulmonary-Renal syndrome
Cutaneous vasculitis with systemic features
Mononeuritis multiplex or other peripheral neuropathy
Long standing sinusitis or otitis
Subglottic tracheal stenosis
Retro-orbital massIf a patient has 1 of these clinical features or other strong clinical evidence for small-vessel vasculitis, the positive ANCA test will provide over 90% confirmation of a vasculitis.
ANCA Microscopic Polyangiitis Wegener's Granulomatosis Churg-Strauss Syndrome PR3-ANCA 40% 75% 10% MPO-ANCA 50% 20% 60% Negative 10% 5% 30%
ANCA TYPE IF PATTERN ANTIGEN CHARACTERIZATION Coarsely granular cytoplasmic pattern with central and interlobular accentuation PR3 Wegener's granulomatosis
Microscopic polyarteritis
Churg-Strauss syndromeFlat, nongranular diffuse cytoplasmic pattern Mostly unknown, MPO and bactericidal/permeability increasing protein in some case ? Perinuclear cytoplasmic with nuclear extension
Caused by artifactual redistribution of the MPO antigen to the nucleus during substrate preparation
MPO Microscopic polyarteritis
Necrotizing and crescentic glomerulonephritis
Churg-Strauss syndrome
Classic polyarteritis nodosa
Wegener's granulomatosis
SLE
Rheumatoid arthritis
Chronic IBDWithout nuclear extension Elastase
Cathepsin G
Lactoferrin
Lysozyme
(x-ANCA)Snow-drift pattern, mixture of C- and P-ANCA pattern Nonspecific, or lactoferrin, lysozyme, beta-glucuronidase, cathepsin G, and so forth Primary sclerosing cholangitis
Primary biliary cirrhosis
Autoimmune hepatitis
SLE
RAOUTLINE
Reference Methods Clinical Utility Heart
Hemodialysis patients
Inflammatory bowel disease
Systemic lupus erythematosus
Vasculitis
Wegener's GranulomatosisInterfering Diseases or Substances that Alter Levels Commonly Used Terms Internet Links
CLINICAL UTILITY CHARACTERIZATION GENERAL Clinical significance of ANCA in 98 patients.
Geffriaud-Ricouard C, Noel LH, Chauveau D, Houhou S, Grunfeld JP, Lesavre P.
Departement de Nephrologie, Hopital Necker, Paris, France.
Adv Exp Med Biol 1993;336:273-9 Abstract quote
Clinical and histological data leading to precise diagnosis were retrospectively obtained in 98 patients with antineutrophil cytoplasmic antibodies (ANCA) detected by indirect immunofluorescence (IIF).
Specificity was determined by myeloperoxidase (MPO) and proteinase 3 (PR3) specific ELISA in all and a comparative study based on ANCA specificity was performed. Vasculitis was present in all cases. PR3-ANCA occurred predominantly in males (25/38) with WG (19/38). MPO-ANCA occurred predominantly in older women and were often associated with various autoimmune disorders. There was a high prevalence of lung hemorrhage (18/45) and mPA (26/45) in this group.
Patients with negative MPO and PR3 specific ELISA despite positive IIF (n = 15) were almost exclusively WG (13/15) and were characterized by a high prevalence of hepatic and digestive manifestations. Renal and patient survival at the 75th percentile was 15 months with MPO-ANCA and 16 months with PR3, and was similar for patients with WG and mPA.
With immunosuppressive treatment, ANCA disappeared in 66% of cases and this disappearance was always associated with absence of disease activity.
International Consensus Statement on Testing and Reporting of Antineutrophil Cytoplasmic Antibodies (ANCA)
Savige J, Gillis D, Benson E, Davies D, Esnault V, Falk RJ, Hagen EC, Jayne D, Jennette JC, Paspaliaris B, Pollock W, Pusey C, Savage CO, Silvestrini R, van der Woude F, Wieslander J, Wiik A
. University Department of Medicine, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia.
Am J Clin Pathol 1999 Apr;111(4):507-13 Abstract quote
Antineutrophil cytoplasmic antibody (ANCA) tests are used to diagnose and monitor inflammatory activity in the primary systemic small vessel vasculitides. ANCA is best demonstrated in these diseases by using a combination of indirect immunofluorescence (IIF) of normal peripheral blood neutrophils and enzyme-linked immunosorbent assays (ELISAs) that detect ANCA specific for proteinase 3 (PR3) or myeloperoxidase (MPO).
For ANCA testing in "new" patients, IIF must be performed on all serum samples. Serum samples containing ANCA, any other cytoplasmic fluorescence, or an antinuclear antibody (ANA) that results in homogeneous or peripheral nuclear fluorescence then should be tested in ELISAs for PR3-ANCA and MPO-ANCA. Optimally, ELISAs for PR3-ANCA and MPO-ANCA should be performed on all serum samples. Inclusion of the most recent positive sample in the IIF or ELISA may help demonstrate a change in antibody level. Reports should use recommended terms.
Any report of positive neutrophil fluorescence issued before the ELISA results are available should indicate that positive fluorescence alone is not specific for the diagnosis of Wegener granulomatosis or microscopic polyangiitis and that decisions about treatment should not be based solely on the ANCA results.
Antineutrophil cytoplasmic autoantibody in the absence of Wegener's granulomatosis or microscopic polyangiitis: implications for the surgical pathologist.Gal AA, Velasquez A.
Departments of Pathology and Laboratory Medicine (AAG) and Division of Critical Care and Respiratory Medicine (AV), Emory University School of Medicine, Atlanta, Georgia.
Mod Pathol 2002 Mar;15(3):197-204 Abstract quote Antineutrophil cytoplasmic antibodies (ANCA) are useful serologic markers for the diagnosis and management of patients with Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA). However, problems in diagnosis and classification may occur when patients with other disorders develop ANCA.
A 7-year review (1993-1999) disclosed 247 patients whose sera tested positively for ANCA by an indirect immunofluorescence method: 166 patients for cytoplasmic-ANCA (C-ANCA) and 81 patients for perinuclear-ANCA (P-ANCA) Twenty-seven patients had active pulmonary disease and underwent open-lung biopsy or transbronchial biopsy. Eight patients (30%) had a disease other than WG or MPA, and their clinical, pathological, and serological findings were reviewed. The patients, all women, ranged in age from 28 to 77 years (median, 37 y). Dyspnea (n = 6), cough (n = 6), chest pain (n = 2), and/or hemoptysis (n = 2) were present. The duration of symptoms lasted from 3 weeks to 6 years (median, 6 mo). ANCA titers were C-ANCA (n = 4; range, 1:40-1280) or P-ANCA (n = 4; range, 1:40-640). The lung biopsies disclosed nonspecific interstitial pneumonia (n = 4), bronchiolitis obliterans organizing pneumonia (n = 1), diffuse alveolar damage (n = 1), organizing diffuse alveolar hemorrhage without capillaritis (n = 1), and necrotic granuloma (n = 1). No cases showed characteristic histology for WG or MPA. The final diagnoses were various connective tissue disorders (n = 5), chronic hypersensitivity pneumonia (n = 1), postinfectious bronchitis/bronchiectasis (n = 1), and ulcerative colitis-related lung disease (n = 1).
Surgical pathologists should be aware that significantly elevated ANCA titers may be associated with diverse forms of pulmonary disease. ANCA positivity alone, in the absence of appropriate clinical or pathologic findings, should not be used to substantiate a diagnosis of WG or MPA.
DISEASE ASSOCIATIONS HEART
Atypical manifestation of a cytoplasmic antineutrophil cytoplasmic antibody (PR3-ANCA)-associated vasculitis with involvement of aortic intima and parietal endocardium.Schildhaus HU, Von Netzer B, Dombrowski F, Pfeifer U.
Institute of Pathology, University of Bonn, Germany.
Hum Pathol 2002 Apr;33(4):441-5 Abstract quote The traditional classification of vasculitis, based on the size of affected vessels, has meanwhile been extended by using antineutrophil cytoplasmic antibodies (ANCAs) as seromarkers in the differential diagnosis of different types of vasculitis.
We report an autopsy case of fulminant generalized vasculitis positive for C-ANCA (1:320) and anti-proteinase 3 (PR3) antibodies (>100 U/mL) in a 63-year-old man. The unusually broad histologic spectrum included periarteritis nodosa-like lesions in medium-sized vessels and leucocytoclastic vasculitis in small vessels, as well as capillaritis. In addition, the left atrial and ventricular endocardium and the intima of the aorta thoracalis were patchily involved in the inflammatory process. Glomerulonephritis and/or immune complexes were not detectable by electron microscopy or immunohistochemistry.
To the best of our knowledge, involvement of the aortic intima ("intimitis") and the parietal endocardium has not been described in PR3-ANCA-positive vasculitis to date.
HEMODIALYSIS PATIENTS ANCA in haemodialysis patients.
Weidemann S, Andrassy K, Ritz E.
Department Internal Medicine, Ruperto Carola University, Heidelberg, Germany.
Nephrol Dial Transplant 1993;8(9):839-45 Abstract quote
The prevalence of positive ANCA as well as the prevalence of PR-3 and MPO antibodies were examined in a cross-sectional sample of 1277 haemodialysis patients from 16 German haemodialysis centres.
We found 32 patients positive for c-ANCA (median titre 1:40; range 1:20-1:320) and 65 for p-ANCA (1:80; 1:20-1:1280). Twenty-two percent of the c-ANCA-positive and 31% of the p-ANCA-positive patients had PR-3 and MPO antibodies by ELISA respectively. Clinical evidence of vasculitis was found in 11 of 32 c-ANCA-positive and 19 of 65 p-ANCA-positive patients. Of the 11 c-ANCA-positive, four had a known diagnosis of Wegener's granulomatosis (WG); WG was recognized after the test in a further five patients and two had renal limited RPGN. Of the 19 p-ANCA-positive patients, three had a clinical diagnosis of microscopic polyarteritis (MP), MP was newly diagnosed in a further 12, WG in one and renal limited RPGN in three. The patients had not received cyclophosphamide (the diagnosis had been non-specified 'systemic disease'). Thus false-positive ANCA, as defined by absence of vasculitis, was found in 5% of dialysis patients versus 0% in patients with preterminal renal failure (n = 152) or blood donors (n = 150).
Patients with vasculitis tended to have higher c-ANCA and p-ANCA titres respectively, but there was a considerable overlap. Titres were not higher in patients symptomatic at the time of examination (6 of 11 c-ANCA and 10 of 19 p-ANCA), but PR-3 and MPO ELISA were positive in all but two.(
INFLAMMATORY BOWEL DISEASE
Neutrophil-specific autoantibodies in chronic inflammatory bowel diseases.
Wiik A.
Department of Autoimmunology, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S, Denmark.
Autoimmun Rev. 2002 Feb;1(1-2):67-72 Abstract quote
This review intends to highlight important differences between neutrophil-specific autoantibodies (NSA) typically found in chronic inflammatory bowel diseases (CIBD) and anti-neutrophil cytoplasm antibodies (ANCA) associated with primary systemic small vessel vasculitides (SSVV).
Indirect immunofluorescence (IF) techniques alone cannot distinguish NSA from ANCA and special measures must be taken to separate these two autoantibody populations. Many autoantigens originating in all cell compartments may be targeted by NSA in CIBD, several of these being constituents of neutrophil nuclei. Apart from the use of NSA in the differential diagnosis between Crohn's disease (CD) and ulcerative colitis (UC), very limited clinical significance is ascribed to these antibodies in CIBD.
Laboratory reports on NSA-positivity must be clearly distinguishable from reports on ANCA to help avoid clinical misinterpretation.Anti-neutrophil cytoplasmic auto-antibodies (ANCA) in ulcerative colitis (UC): no relationship with disease activity.
Reumaux D, Colombel JF, Masy E, Duclos B, Heresbach D, Belaiche J, Cortot A, Duthilleul P;
GETAID. Groupe d'Etude des Affections Inflammatoires du Tube Digestif. Departement d'Hematologie-Immunologie-Cytogenetique, Centre Hospitalier de Valenciennes, France.
Inflamm Bowel Dis 2000 Nov;6(4):270-4 Abstract quote
The relationship between anti-neutrophil cytoplasmic auto-antibodies (ANCA) and disease activity in inflammatory bowel diseases remains controversial.
The aim of this study was to highlight the relationship between ANCA presence or titers and disease activity in ulcerative colitis (UC). Three groups of patients with UC were studied: 1) group A included 39 patients who had not undergone colectomy, 2) group B, 43 patients with subtotal colectomy and ileo-rectal anastomosis, 3) group C, 98 patients with proctocolectomy and ileo-anal anastomosis, including 88% with pouchitis and 12% without pouchitis at the time of the study. Determination of ANCA was performed using the standardized indirect immunofluorescence assay. ANCA were positive in 59%, 65%, and 54% of patients from groups A, B, and C, respectively (NS). No relationship between ANCA presence or titers and UC activity could be detected within groups A and B. In group C, 45 of 86 patients (52%) without pouchitis and 8 of 12 patients (67%) with pouchitis, were ANCA positive (NS).
These results do not support a relationship between ANCA and UC activity in this cohort of 180 patients.
Are anti-neutrophil cytoplasmic antibodies (ANCA) clinically useful in inflammatory bowel disease (IBD)?
Roozendaal C, Kallenberg CG.
Department of Clinical Immunology, University Hospital Groningen, Groningen, The Netherlands.
Clin Exp Immunol. 1999 May;116(2):206-13. Abstract quote
Since the first detection of ANCA in IBD, numerous studies have dealt with their prevalence, antigenic specificities, clinical significance, pathophysiological role, and their induction. This review summarizes the information obtained from those studies and shows that ANCA are not directly useful as diagnostic and prognostic factors in IBD.
ANCA were detected in 50-85% of patients with ulcerative colitis (UC) and 10-20% of patients with Crohn's disease (CD). Multiple target antigens are recognized by these autoantibodies, including both cytoplasmic and nuclear proteins. A pathophysiological role for ANCA in IBD is far from clear. On the one hand, it is suggested that ANCA are genetic markers of susceptibility for IBD, and on the other hand, the induction of ANCA in those diseases may just be an epiphenomenon of chronic inflammation.
We discuss recent evidence that ANCA may be induced by a break-through of tolerance towards bacterial antigens.
Anti-neutrophil cytoplasmic antibodies in inflammatory bowel disease with special attention for IgA-class antibodies.
Gigase P, De Clerck LS, Van Cotthem KA, Bridts CH, Stevens WJ, Van Outryve M, Pelckmans PA.
University of Antwerp, Belgium.
Dig Dis Sci. 1997 Oct;42(10):2171-4. Abstract quote
Perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) of the IgG class have been reported in inflammatory bowel disease, mainly in ulcerative colitis. Since this disease affects the gastrointestinal tract, we determined whether IgA class ANCA were present in inflammatory bowel disease.
We used an indirect immunofluorescence assay for IgG and IgA ANCA testing. Sera from 34 patients with Crohn's disease and 29 patients with ulcerative colitis were collected together with clinical and laboratory data. We found IgA class ANCA of a perinuclear type in 52% of patients with ulcerative colitis and in 9% of Crohn's disease patients. There was a significant association between the presence of IgA ANCA and the occurrence of blood in the feces in the ulcerative colitis group (P = 0.03). IgG ANCA was found in 56% of patients with ulcerative colitis and in 7% of patients with Crohn's disease. Because of partial overlap between IgG and IgA ANCA positivity, the sensitivity of ANCA testing in ulcerative colitis increased from 56% up to 78% by combining IgG and IgA assays.
In conclusion, IgA ANCA occurs with a high prevalence in ulcerative colitis. Moreover there is a possible relationship between IgA ANCA and disease activity in ulcerative colitis.
Anti-neutrophil cytoplasmic antibodies in chronic inflammatory bowel disease. Prevalence and diagnostic role.
Hertervig E, Wieslander J, Johansson C, Wiik A, Nilsson A.
Dept. of Medicine, University Hospital, Lund, Sweden.
Scand J Gastroenterol. 1995 Jul;30(7):693-8. Abstract quote
BACKGROUND: Anti-neutrophil cytoplasmic antibodies (ANCA), originally found to be associated with vasculitis, have been reported to be present in chronic inflammatory bowel disease. Most often the ANCA staining pattern is of the perinuclear type (p-ANCA), although nuclear and cytoplasmic stainings are seen. Single studies have shown some of the antibodies to react with lactoferrin or cathepsin G; however, most studies have not been able to determine a main antigenic specificity. We studied the prevalence of ANCA in sera from 155 patients with ulcerative colitis, 128 patients with Crohn's disease, and 51 patients with coeliac disease. The presence of ANCA was correlated to disease activity, extent, and age of onset of the diseases. Furthermore, we tried to characterize the antigen specificity by enzyme-linked immunosorbent assay (ELISA), using elastase, lactoferrin, myeloperoxidase, proteinase 3, and cathepsin G as antigens.
METHODS: The sera were screened for ANCA by indirect immunofluorescence. Anti-nuclear antibodies (ANA) were analysed on HEp2 cells, and ELISA for specific ANCA was performed using the antigens mentioned.
RESULTS: Most of the sera with positive immunofluorescence had the p-ANCA type of pattern. Seventy-eight of 155 (50.3%) of the patients with ulcerative colitis were ANCA-positive, compared with 31 of 128 (24.2%) of patients with Crohn's disease (p < 0.001). However, in the subgroup with Crohn's colitis, 16 of 44 (36.4%) were ANCA-positive. Only 4 of 51 patients (7.7%) with coeliac disease showed positive immunofluorescence (p < 0.001 compared with ulcerative colitis). Less than 10% of the samples were positive in the specific ELISA assays; thus other than the most well known granule proteins can be the target for ANCA in ulcerative colitis.
CONCLUSION: ANCA occur significantly more often in ulcerative colitis than in Crohn's disease. However, the prevalence of ANCA is rather high in Crohn's colitis. ANCA are thus of limited value in differentiating Crohn's colitis from ulcerative colitis. ANCA found in inflammatory bowel disease are different from those associated with vasculitis. The antigen(s) responsible remain to be determined.
Autoantibodies to neutrophil cytoplasmic (ANCA) and endothelial cell surface antigens (AECA) in chronic inflammatory bowel disease.
Romas E, Paspaliaris B, d'Apice AJ, Elliott PR.
Department of Clinical Immunology, St Vincent's Hospital, Melbourne, Vic., Australia.
Aust N Z J Med. 1992 Dec;22(6):652-9 Abstract quote
Sera from 103 patients with chronic inflammatory bowel disease (IBD) were tested prospectively for antibodies against neutrophil cytoplasmic antigens (anti-neutrophil cytoplasm antibodies, ANCA) and endothelial cell surface antigens (anti-endothelial cell antibodies, AECA) by indirect immunofluorescence (IIF) and assays based on whole fixed neutrophils, purified neutrophil enzyme substrates and human umbilical vein endothelial cells.
Using IIF, ANCA were found in 26 IBD sera (25%) and in none of 51 controls. Twenty-two positive sera (85%) were from patients with ulcerative colitis (UC). The pattern of distribution of immunofluorescence was always perinuclear (P-ANCA). A majority of UC patients positive for these autoantibodies (68%) had active colitis, but none had evidence of vasculitis. Using a whole neutrophil ELISA, binding was demonstrable in 73% of UC sera compared to 27% of Crohn's (CD) sera and only 4% of controls. Unlike vasculitis sera, UC sera with P-ANCA did not bind strongly to myeloperoxidase (MPO). Forty-five per cent of IBD sera tested positive for IgG AECA in an endothelial cell ELISA, compared to seven of 51 (14%) controls. Binding correlated with both active and extensive colitis.
A type of P-ANCA, in most cases distinct from MPO-specific P-ANCA observed in vasculitis, is detected in a significant proportion of patients with UC, but rarely Crohn's colitis and therefore may be of differential diagnostic value. IgG AECA are also frequent in CIBD sera but are less disease specific than ANCA.SYSTEMIC LUPUS ERYTHEMATOSUS Anti-neutrophil cytoplasmic antibodies in 566 European patients with systemic lupus erythematosus: prevalence, clinical associations and correlation with other autoantibodies.
European Concerted Action on the Immunogenetics of SLE.
Galeazzi M, Morozzi G, Sebastiani GD, Bellisai F, Marcolongo R, Cervera R, De Ramon Garrido E, Fernandez-Nebro A, Houssiau F, Jedryka-Goral A, Mathieu A, Papasteriades C, Piette JC, Scorza R, Smolen J.
Istituto di Reumatologia, Universita di Siena, Italy
Clin Exp Rheumatol 1998 Sep-Oct;16(5):541-6 Abstract quote
OBJECTIVES: To evaluate, in a cohort of 566 patients with systemic lupus erythematosus (SLE) drawn from 11 European centres: (i) the prevalence of ANCAs and their subspecificities in a large series of European SLE patients; (ii) the possible associations of ANCA with the most common clinical manifestations of the disease; and (iii) whether ANCAs correlate with some of the autoantibodies commonly found in SLE.
METHODS: ANCA detection was performed by indirect immunofluorescence (IIF), and by ELISA for lactoferrin (LF), myeloperoxydase (MPO), proteinase3 (PR3) and lysozyme (LZ) subspecificities.
RESULTS: The prevalence of ANCA was 16.4% (IIF). The prevalence of LF was 14.3%, LZ 4.6%, MPO 9.3%, and PR3 1.7%. Our results show that ANCA is associated with certain clinical manifestations of SLE. In particular, positive correlations were found between IIF ANCA and serositis (p = 0.026), livedo reticularis (p = 0.01), venous thrombosis (p = 0.03) and arthritis (p = 0.04), while anti-LF antibodies were associated with serositis (p = 0.05) and livedo reticularis (p < 10(-3). Nevertheless, multivariate analysis demonstrated that other autoantibodies, such as aCL and SSA/Ro, are more closely correlated than ANCA with some of the aforementioned clinical features.
CONCLUSION: Our results demonstrate that ANCA are detectable in SLE sera and that some of them are associated with particular clinical manifestations. Whether ANCA plays a direct pathogenetic role in the vascular damage of SLE or only represents an epiphenomenon or a marker of disease activity remains to be elucidated.
VASCULITIS Relationship between ANCA and disease activity in small vessel vasculitis patients with anti-MPO ANCA.
Ara J, Mirapeix E, Rodriguez R, Saurina A, Darnell A.
Servei de Nefrologia, Hospital Clinic, Barcelona, Spain.
Nephrol Dial Transplant 1999 Jul;14(7):1667-72 Abstract quote
BACKGROUND: We analysed the usefulness of antineutrophil cytoplasmic antibodies (ANCA) as a marker of clinical activity in patients with small vessel vasculitis associated with anti-myeloperoxidase (MPO) ANCA.
METHODS: We studied a group of 25 patients, 15 with microscopic polyangitis and 10 with renal limited vasculitis, so-called rapidly progressive glomerulonephritis type III. The clinical and serological follow-up was accomplished quarterly over an average of 2.79 +/- 2.08 years (range 0.25-6 years). ANCA was analysed by indirect immunofluorescence and enzyme-linked immunosorbent assays (ELISAs).
RESULTS: At the time of diagnosis, all patients were ANCA positive (P-ANCA and anti-MPO). Following a standardized treatment, all patients except one achieved complete remission of vasculitis in <3 months. One patient suddenly died during the active phase (1 month of follow-up) and with positive ANCA. Seroconversion from positive to negative occurred in 24/25 patients (96%). Eighteen of these 24 patients (75%) achieved the seroconversion within the first 6 months. During the follow-up, two patients had four major relapses, all of them associated with positive ANCA. ANCA seroconversion from negative to positive was observed in one patient with microscopic polyangitis without clinical relapse of vasculitis.
CONCLUSION: ANCA should be used in conjunction with other markers of disease activity in the management of microscopic polyangitis and renal limited vasculitis patients with anti-MPO ANCA.
Outcome analysis of patients with vasculitis associated with antineutrophil cytoplasmic antibodies.
Brijker F, Magee CC, Tervaert JW, O'Neill S, Walshe JJ.
Department of Clinical Immunology, University Hospital of Groningen, The Netherlands.
Clin Nephrol 1999 Dec;52(6):344-51 Abstract quote
BACKGROUND: Objective scoring systems of disease activity and disease-associated damage have proven useful in the management of patients with systemic vasculitis.
PATIENTS AND METHODS: We used the recently designed Birmingham vasculitis activity score (BVAS; maximum score 63) and vasculitis damage index (VDI; maximum score 59) to assess initial activity and long-term damage, respectively, in ANCA positive patients from one center over a 3-year period. Thirty-two patients with ANCA vasculitis were identified and analyzed as an historic cohort. The median BVAS for all vasculitis patients at first presentation was 19 (range 6 - 36). Patients with Wegener's granulomatosis had a significantly higher total score and respiratory BVAS score compared to the 15 with microscopic polyangiitis. The majority of patients received standard cyclophosphamide/steroid treatment.
RESULTS: At the end of follow-up (mean 24.9 months), 4 patients had died; all patients had evidence of permanent organ damage. The median total VDI score at last follow-up was 4.0 (range 0-11), with no differences between patients with Wegener's granulomatosis and microscopic polyangiitis. The VDI was not associated with the number of relapses. A high initial BVAS was found to correlate with a later high vasculitis damage index (r = 0.56). Initial renal or respiratory involvement was also associated with longterm damage in the same organ system.
CONCLUSION: Although mortality from ANCA-associated vasculitis has decreased, morbidity remains a common problem. High early-disease activity may identify patients at high risk of long-term organ damage, allowing more effective individualized therapy. This hypothesis requires validation in a prospective, controlled study.
Serial measurements of antineutrophil cytoplasmic autoantibodies in patients with systemic vasculitis.
Kyndt X, Reumaux D, Bridoux F, Tribout B, Bataille P, Hachulla E, Hatron PY, Duthilleul P, Vanhille P.
Department of Nephrology, Internal Medicine, Centre Hospitalier de Valenciennes, France.
Am J Med 1999 May;106(5):527-33 Abstract quote
PURPOSE: To assess the value of serial determinations of antineutrophil cytoplasmic autoantibodies (ANCA) for monitoring disease activity in patients with systemic vasculitis.
PATIENTS AND METHODS: Forty-three patients with histologically proven vasculitis (21 with Wegener's granulomatosis, 17 with microscopic polyangiitis, and 5 with renal-limited vasculitis) were studied for a median follow-up of 22 months. Disease activity was prospectively assessed and quantified by the Birmingham Vasculitis Activity Score. A total of 347 sera were analyzed for ANCA determination.
RESULTS: Relapses occurred in 23 (54%) of 43 patients. Diagnostic category (Wegener's granulomatosis vs micropolyangiitis and renal-limited vasculitis), severity of initial symptoms (mean vasculitis activity score, mean number of organs involved), and ANCA pattern [cytoplasmic-ANCA (c-ANCA) vs perinuclear-ANCA (p-ANCA)] did not significantly differ between relapsers and nonrelapsers. Lung involvement was more frequent at onset among relapsers [16 of 23 (70%) vs 6 of 20 (30%); P = 0.02]. Relapses were slightly, but not significantly, more frequent in patients with Wegener's granulomatosis or a c-ANCA pattern. The percentage of relapsers was greater in patients with persistently positive ANCA than in patients with negative or decreasing ANCA titers (86% vs 20%, P = 0.0001). However, the predictive value of an increase in ANCA titers for the occurrence of a subsequent relapse was only 28% (4 of 14) for c-ANCA, 12% (2 of 17) for anti-proteinase 3-ANCA, and 43% (6 of 14) for anti-myeloperoxidase-ANCA. An increase in ANCA occurred before or during relapse in 33% (10 of 30) of cases for c-ANCA/anti-proteinase 3 antibodies, and 73% (11 of 15) of cases for anti-myeloperoxidase antibodies.
CONCLUSION: The persistence of ANCA positivity is strongly associated with relapses. However, an increase in ANCA titers has a poor value for the early prediction of a subsequent relapse and should not be used as a sole parameter for therapeutic intervention. In addition, our results suggest that serial anti-myeloperoxidase determination may be useful as a prognostic marker in patients who are p-ANCA positive.
Antineutrophil cytoplasmic antibodies (ANCA) and systemic vasculitis: update of assays, immunopathogenesis, controversies, and report of a novel de novo ANCA-associated vasculitis after kidney transplantation.
Schultz DR, Diego JM.
Department of Medicine, University of Miami, School of Medicine, FL 33101, USA.
Semin Arthritis Rheum 2000 Apr;29(5):267-85 Abstract quote
OBJECTIVES: To characterize antineutrophil cytoplasmic antibodies (ANCA), their major autoantigens, disease associations, and pathophysiology in systemic vasculitides. To describe a patient with a novel de novo ANCA-associated vasculitis after kidney transplantation.
METHODS: We reviewed and compiled the literature on ANCA-related topics and systemic vasculitis. Laboratory and clinical data from a cadaveric kidney transplant patient who developed necrotizing vasculitis involving glomerular capillaries, with crescent formation associated with P-ANCA and myeloperoxidase, were analyzed.
RESULTS: Large-scale multi-center testing of patient and normal sera by the European ANCA Assay Standardization Project using immunofluorescence assays and enzyme immunoassays indicate the assays have good sensitivity and specificity, and diagnostic utility for ANCA-associated vasculitis. A few investigations covering basic and clinical research with ANCA remain controversial: whether endothelial cells do or do not express a 29-kd neutral serine protease termed proteinase-3 (PR-3), the target of ANCA in most individuals with Wegener's granulomatosis, and whether anti-myeloperoxidase (MPO) ANCAs recognize a restricted number of epitopes on MPO. This issue has relevance for using monoclonal antibodies to treat patients with vasculitis who have adverse effects from immunosuppressive drugs. The two allelic forms of FcgammaRIIa (H131/R131) and the two of FcgammaRIIlb (NA1/NA2) are discussed as possible inheritable genetic elements for vasculitic disorders and for signaling responses. Stimulatory and costimulatory molecules, and cytokine profiles of T lymphocytes are characterized to show that these cells are actively involved in the ANCA-associated vasculitides. The patient described had a de novo ANCA associated small vessel vasculitis which developed after renal transplantation.
CONCLUSIONS: There have been significant advances in the development of sensitive and specific ANCA assays. The immunopathogenetic mechanism of ANCA involves the constitutive FcgammaRs, ligands, and signaling responses to activate cytokine-primed neutrophils. This may lead to the generation of reactive oxygen intermediates, degranulation, and secretion of intracellular granule contents, and ultimately inflammation and vasculitis.
ANCA titres, even of IgG subclasses, and soluble CD14 fail to predict relapses in patients with ANCA-associated vasculitis.
Nowack R, Grab I, Flores-Suarez LF, Schnulle P, Yard B, van der Woude FJ.
Fifth Medical Clinic (Nephrology, Endocrinology), University-Clinic Mannheim, Faculty of Clinical Medicine of the University of Heidelberg, Mannheim, Germany.
Nephrol Dial Transplant 2001 Aug;16(8):1631-7 Abstract quote
BACKGROUND: Antineutrophil cytoplasmic autoantibodies (ANCA) are presumed to reflect disease-activity and to be useful for guidance of immunosuppressive therapy of ANCA-associated systemic vasculitis (AASV), but with respect to conventional ANCA assays this is controversial. ANCA titres, measured in the IgG3 subclass and modern capture ELISAs, have been said to be superior predictors of relapses of AASV.
METHODS: In this retrospective study serial measurements of ANCA parameters and soluble CD14 (sCD14) were performed in 169 consecutive sera over a median of 21 months in 18 patients with AASV and related to disease activity, assessed by Birmingham Vasculitis Activity Score (BVAS) for new or deteriorated (BVAS1), and for chronic disease activity (BVAS2). Fourteen patients had Wegener's granulomatosis (WG) and were C-ANCA positive with Pr 3-antibodies and four patients had microscopic polyangiitis (MPA) with P-ANCA and MPO-antibodies. In WG patients ANCA by IIF, Pr 3-ELISA for IgG, IgG1, IgG3, IgG4 and sCD14 were measured, as well as capture ELISA for Pr 3, and in MPA patients ANCA by IIF, MPO-ELISA for IgG and IgG1, IgG3, IgG4, and sCD14 respectively. In eight patients, data collection started at diagnosis, in 10 patients at remission.
RESULTS: The parameters predicted neither the nine major relapses (increase of immunosuppression necessary), nor the 26 minor relapses (increase of BVAS1>2) with sufficient sensitivity (>80%) or specificity (> 90%90%), and they also failed to predict relapses within the following 2 months. ANCA-IgG3 and capture ELISA for Pr 3 were not advantageous for prediction of relapses (sensitivity 0.45 and 0.19 respectively), and sCD14 remained elevated in all samples irrespective of disease activity.
CONCLUSIONS: There is no rationale for serial measurements of ANCA in AASV. For changes of therapy, the ANCA parameters should only be used in conjunction with clinical information.
WEGENER'S GRANULOMATOSIS Clinical spectrum associated with positive ANCA titres in 94 consecutive patients: is there a relation with PR-3 negative c-ANCA and hypergammaglobulinaemia?
Blockmans D, Stevens E, Marien G, Bobbaers H.
Department of Internal Medicine, University Hospital, Leuven, Belgium.
Ann Rheum Dis 1998 Mar;57(3):141-5 Abstract quote
OBJECTIVE: To calculate the positive predictive value (ppv) of cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCAs) and anti-proteinase 3 (PR 3) antibodies for Wegener's granulomatosis (WG) and to evaluate their association with other diseases.
METHODS: The clinical files of all 94 patients who had a positive c- or perinuclear (p)-ANCA test, or both, in the laboratory of the University Hospital, Leuven between April 1995 and March 1996 and who attended the Internal Medicine Department of the hospital were retrospectively studied.
RESULTS: Of the 94 patients with ANCAs (fluorescence titre > or = 1/40), 57 were c-ANCA positive and 45 p-ANCA positive (eight were simultaneously c- and p-ANCA positive). Of the 57 c-ANCA positive patients, 23 had WG. The ppv for WG thus was 40%. This value did not increase by defining a higher threshold for a positive ANCA. There was not a good relation between ANCA titres and disease activity in the WG patients, nor was there a relation between anti-PR 3 antibody levels and WG disease activity. The ppv of anti-PR 3 antibodies for WG however was very high (85%). There was a positive correlation between the level of (hyper) gammaglobulinaemia and c-ANCA titres in those patients with final diagnoses not known to be associated with c-ANCA. Forty five patients had positive p-ANCAs. The largest group were those with inflammatory bowel disease (n = 20, of whom the majority had colitis ulcerosa or primary sclerosing cholangitis, or both); the great majority of these patients had no anti-myeloperoxidase antibodies. Vasculitis was present in eight patients, of whom two had WG (both were also c-ANCA positive).
CONCLUSION: There is a low ppv of c-ANCAs for WG, caused by a high percentage of PR 3 negative, positive c-ANCA determinations, possibly related to hypergammaglobulinaemia. Anti-PR 3 antibodies have a high ppv for WG. However, neither c-ANCA titre, nor the level of anti-PR 3 antibodies correlated with the activity of the disease.
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