PR3-ANCA Positivity Research Articles

Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis in Mexican Population: Clinical Phenotype, Autoantibody Profile and Renal Characteristics

Objective: To describe the clinical, serological characteristics, and renal histology in Mexican patients with antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV). Methods: Forty patients with diagnosis of AAV and renal biopsy, followed at a tertiary care center in Mexico City from 2002-2012 were retrospectively studied. Demographics, comorbidities, clinical, laboratory variables, disease activity, mortality, renal variables and histological classes were analyzed. Additionally, 50 patients with AAV, and a control group (other systemic vasculitis, systemic lupus erythematosus, infections, healthy subjects) were studied transversally to assess the prevalence of specific antibodies (ANCA, MPO, PR3, cathepsin G, lysozyme, lactoferrin, BPI and elastase), and their association with clinical manifestations. Results: Granulomatosis with polyangiitis (GPA) was the predominant phenotype, and median age at diagnosis was 53 years. High disease activity (BVAS/GPA=24), general symptoms (98%), renal (80%), pulmonary (63%), and ear, nose and throat (ENT) (58%) involvement were frequent at diagnosis. Renal damage was present at diagnosis (serum creatinine 3.9 mg/dl, estimated glomerular filtration rate 16 ml/min, 24 hr proteinuria 2.5 g, 15% on dialysis). The most prevalent renal histological class was sclerotic (58%), followed by mixed (32%), focal (8%), and crescentic (2%). No significant differences were found between histological classes in comorbidities, clinical, renal and laboratory variables, or survival. The main ANCA immunofluorescence pattern was C-ANCA (68%), followed by XANCA (22%), and P-ANCA (18%). PR3-ANCA (high sensitive) was the most frequent antibody, positive in 86%, while positivity for MPO-ANCA was observed in 18%. ANCA positivity was more frequent in patients with AAV than the control group (p<0.001). Antibodies directed to minor targets were infrequent in patients with AAV (2%). No significant correlations were identified between autoantibodies and clinical manifestations. Conclusion: GPA phenotype, C-ANCA and PR3-ANCA positivity, high disease activity, chronic renal damage, general symptoms, ENT and lung involvement at diagnosis distinguish our population with AAV.

Genetic aspects of anti-neutrophil cytoplasmic antibody-associated vasculitis.

The genetics of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a complex area of investigation because of the low frequency of AAVs, the rarity of familial cases and the complexity of disease phenotypes. However, recent studies have been able to gather significant numbers of patients, and multicentre collaborative efforts have allowed the performance of two genome-wide association studies (GWASs). Genetic association studies based on candidate gene approaches and the two GWASs have greatly contributed to our current understanding of the genetic basis of AAV. The central role of autoimmunity has been confirmed by the significant association with HLA polymorphisms; interestingly, the three main AAV subtypes are associated with distinct HLA variants, i.e. granulomatosis with polyangiitis (Wegener's GPA) with HLA-DP1, microscopic polyangiitis with HLA-DQ and eosinophilic GPA (Churg-Strauss) with HLA-DRB4. GWASs also revealed that polymorphic variants of genes encoding proteinase 3 (PR3), the predominant antigenic target of ANCA in GPA, and its main inhibitor, alpha-1 antitrypsin, are highly associated with GPA and, even more significantly, with PR3-ANCA positivity (regardless of the clinical diagnosis); this emphasizes the central pathogenic role of PR3 and humoral autoimmunity in PR3-ANCA positive vasculitis. Finally, candidate gene approach studies have shown associations with other variants involved in autoimmunity, such as those belonging to the CTLA-4 and PTPN22 genes, although these findings warrant replication in larger studies. Additional studies are underway to better characterize disease associations within the AAV spectrum, which could provide new pathogenetic clues and possibly new treatment targets.

Treatment of ANCA-associated vasculitis

Antineutrophil cytoplasmic autoantibody (ANCA)-associated diseases are small-vessel vasculitides, encompassing granulomatosis with polyangiitis (formerly Wegener's granulomatosis), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis. Once considered life-threatening diseases, the introduction of stage-adapted immunosuppressive therapy and medications with decreased toxicity has improved patients' survival. Treatment is biphasic, consisting of induction of remission (3-6 months) for rapid control of disease activity and maintenance of remission (at least 18 months) to prevent disease relapse using therapeutic alternatives that have reduced toxicity. This Review summarizes current treatment strategies for these diseases, with a special focus on long-term follow-up data from key randomized controlled trials and new developments in remission induction and maintenance therapy. Current treatment strategies have substantial short-term and long-term adverse effects, and relapses are frequent; thus, less-toxic and more-effective approaches are needed. Moreover, the optimal intensity and duration of maintenance therapy remains under debate. Clinical trials have traditionally considered ANCA-associated vasculitides as a single disease entity. However, future studies must stratify participants according to their specific disease, clinical features (different types of organ manifestation, PR3-ANCA or MPO-ANCA positivity) and disease severity.

C‐ANCA/Proteinase 3–Positive Colitis in Children

Anti-neutrophil cytoplasmic antibodies (ANCAs) detected by indirect immunofluorescence have been found in patients with inflammatory bowel disease (IBD). Nevertheless, specific antibodies against proteinase-3 (PR3) are rare in this context. Sera from 30 consecutive pediatric patients with IBD were evaluated for ANCA-indirect immunofluorescence and its specific antibodies to investigate whether PR3-ANCA positivity (PR3-ANCA+) identifies a distinct IBD subtype. The 5 PR3-ANCA+ patients (17%) showed significantly more concomitant biliary disease and severe anal blood loss (P < 0.05). None had vasculitis features at diagnosis nor during follow-up. This pilot study demonstrates significant clinical differences between the PR3-ANCA-positive and -negative IBD subset.

Clinical Outcomes of Remission Induction Therapy for Severe Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other). Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3-ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.

AB0479 Cocaine-induced vasculitis: a series of five cases

BackgroundCocaine-induced vasculitis is an increasingly recognized syndrome that can present with a number of manifestations. This mimic of idiopathic vasculitis has become more common secondary to an increase in the...

Chromogranin A — A comparison of serum and plasma results from different ELISA kits

Antineutrophil cytoplasmic antibodies (ANCA) are used as diagnostic markers for systemic vasculitis. However,the specificity and sensitivity of ANCA detection differs from centre to centre due in large part to variations in methodology. We compared 8 commercial ELISA kits and an in-house method (HM) for their specificity and sensitivity in detecting ANCA against proteinase 3 (PR3-ANCA, 7 kits) and meyloperoxidse (MPO-ANCA, 8 kits). Sera from 5 patients with systemic lupus erythematosus (SLE), 28 with Wegener's granulomatosis (WG), 22 with microscopic polyangiitis (MPA), 5 with idiopathic rapidly progressive glomerulonephritis (RPGN), and 5 healthy controls were examined by both the indirect immunofluorescence technique (IFT) and the ELISA kits. Sera from healthy controls and patients with SLE or cANCA-negative WG were shown to be PR3-ANCA negative by all 7 PR3-ANCA kits. In 25 cANCA-positive sera from WG patients, PR3-ANCA positivity ranged from 44% to 84%. An absolute concordance among the 7 kits was noted in 56% of the cANCA-positive samples. The PR3-ANCA levels in 5 of the 7 kits correlated with the cANCA titers in IFT. Sera from the healthy controls and 4 out of the 5 SLE and pANCA-negative patients were found to be MPO-ANCA negative in all 8 MPO-ANCA kits. In 20 pANCA-positive sera, MPO-ANCA positivity ranged from 25% to 75%. Thirty-five percent of MPO-ANCA-positive sera were confirmed by capture ELISA, immunoblot and inhibition assay. The concordance rate was only 30% among pANCA-positive sera in the 8 MPO-ANCA kits. No significant correlation was observed between pANCA titers and MPO-ANCA levels. The HM showed that 65% of cANCA-positive sera were PR3-ANCA positive, and 45% of pANCA-positive sera were MPO-ANCA positive. Our results indicate that the sensitivities and specificities for ANCA detection differ significantly among the commercial kits tested and underline the necessity of establishing uniform international standards for ANCA ELISA procedures in order to permit more reliable interpretation and comparison of data.

Spectrum of Wegener Granulomatosis in a Mexican Population

Wegener granulomatosis (WG) is a disease considered infrequent among non-Caucasians. Few data exist on its characteristics in Latin America, except for isolated case reports and a paper on clinical features from a Chilean group. In this article we present the clinical characteristics of our cohort plus a preliminary evaluation of the risk factors for death. In comparison to large series from countries with a high WG prevalence, we observed similar age and gender distribution, disease category (localized or generalized), PR3-ANCA positivity, remission, relapse frequency, mortality, and death causes. These last ones are equally distributed, but infections account for an important proportion. Factors related with mortality were mainly those associated with side effects of treatment. We are currently expanding the data on this item as in other series, death is mainly related to the disease itself. The pending agenda includes knowing the prevalence and incidence of WG in Mexico, as well as other characteristics, such as genetic factors, that may influence its behavior in our country.

各種細菌による菌血症を繰り返しPR3-ANCA陽性を呈したM&amp;uuml;nchausen症候群の1例

A 29-year-old woman chiropractor with repeated episodes of bacteremia and positive for cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) and antiproteinase-3 (PR3) antibody had an 11-year history of asthma and repeated hospitalization. While hospitalized she developed a spiking nocturnal fever with chills and erythema of the lower leg. Her fever resolved spontaneously, but corticosteroid therapy and antibiotics did not effectively reduce her symptoms. Plain X-ray film and CT showed pulmonary changes, and lung biopsy granulomas without vasculitis. Immunological studies showed a positive PR3-ANCA (c-ANCA) test, and skin biopsy of the crural erythema showed foreign body granuloma. Multiple blood cultures were positive for several strains of bacteria, including Fusobacterium necrophurum, Mycobacterium fortuitum, and Clostridium species. When placed in a single room and monitored, she did not develop new fever or erythema. Because self-injury was assumed, she was diagnosed as having Münchausen syndrome. This is, to our knowledge, the first report of Münchausen syndrome with PR3-ANCA positivity. In patients with repeated infections, the possibility of self-injury, the development of PR3-ANCA positivity, and pulmonary granuloma with a disease profile similar to vasculitis syndrome should be considered in the definitive diagnosis.

Wegener's granulomatosis.

Wegener's granulomatosis is an organ- and/or life-threatening autoimmune disease of as yet unknown etiology. The classic clinical triad consists of necrotizing granulomatous inflammation of the upper and/or lower respiratory tract, necrotizing glomerulonephritis, and an autoimmune necrotizing systemic vasculitis affecting predominantly small vessels. The detection of antineutrophil cytoplasmic antibodies directed against proteinase 3 (PR3-ANCA) is highly specific for Wegener's granulomatosis. ANCA positivity is found only in about 50% of the patients with localized Wegener's granulomatosis (which is restricted to the respiratory tract and affects < or = 5% of the patients), whereas PR3-ANCA positivity is seen in 95% of the patients with generalized Wegener's granulomatosis. Studies showing an expansion of circulating tumor necrosis factor-(TNF-)alpha-producing Th1-type CD4(+)CD28(-) T-cell effector memory T-cells and their presence as Th1-type cytokine profile- driving cell population within granulomatous lesions provide the rationale for using TNF-alpha-blocking agents in Wegener's granulomatosis refractory to standard induction therapy with cyclophosphamide and corticosteroids ("Fauci's scheme"). Vasculitis is an independent risk factor for diffuse endothelial dysfunction and may be a consequence of TNF-alpha action on endothelial cells. Recently, another study has shown intima-media thickening of the wall of the common carotid artery and bulb, as well as a significantly increased incidence of stroke, myocardial infarction and occlusive artery disease in Wegener's granulomatosis. This study suggests that systemic inflammation and vasculitis contribute to accelerated arteriosclerosis in Wegener's granulomatosis.

Diagnostic value of classical and atypical antineutrophil cytoplasmic antibody (ANCA) immunofluorescence patterns.

BACKGROUND: The "classical" antineutrophil cytoplasmic antibody (C-ANCA) pattern seen on indirect immunofluorescence (IIF) is characterised by granular cytoplasmic staining showing central or interlobular accentuation, and is strongly associated with antiproteinase-3...

Comparison of eight commercial kits for quantitation of antineutrophil cytoplasmic antibodies (ANCA)

Antineutrophil cytoplasmic antibodies (ANCA) are used as diagnostic markers for systemic vasculitis. However,the specificity and sensitivity of ANCA detection differs from centre to centre due in large part to variations in methodology. We compared 8 commercial ELISA kits and an in-house method (HM) for their specificity and sensitivity in detecting ANCA against proteinase 3 (PR3-ANCA, 7 kits) and meyloperoxidse (MPO-ANCA, 8 kits). Sera from 5 patients with systemic lupus erythematosus (SLE), 28 with Wegener's granulomatosis (WG), 22 with microscopic polyangiitis (MPA), 5 with idiopathic rapidly progressive glomerulonephritis (RPGN), and 5 healthy controls were examined by both the indirect immunofluorescence technique (IFT) and the ELISA kits. Sera from healthy controls and patients with SLE or cANCA-negative WG were shown to be PR3-ANCA negative by all 7 PR3-ANCA kits. In 25 cANCA-positive sera from WG patients, PR3-ANCA positivity ranged from 44% to 84%. An absolute concordance among the 7 kits was noted in 56% of the cANCA-positive samples. The PR3-ANCA levels in 5 of the 7 kits correlated with the cANCA titers in IFT. Sera from the healthy controls and 4 out of the 5 SLE and pANCA-negative patients were found to be MPO-ANCA negative in all 8 MPO-ANCA kits. In 20 pANCA-positive sera, MPO-ANCA positivity ranged from 25% to 75%. Thirty-five percent of MPO-ANCA-positive sera were confirmed by capture ELISA, immunoblot and inhibition assay. The concordance rate was only 30% among pANCA-positive sera in the 8 MPO-ANCA kits. No significant correlation was observed between pANCA titers and MPO-ANCA levels. The HM showed that 65% of cANCA-positive sera were PR3-ANCA positive, and 45% of pANCA-positive sera were MPO-ANCA positive. Our results indicate that the sensitivities and specificities for ANCA detection differ significantly among the commercial kits tested and underline the necessity of establishing uniform international standards for ANCA ELISA procedures in order to permit more reliable interpretation and comparison of data.