Positive Antineutrophil Cytoplasmic Autoantibody Research Articles

Clinicopathological Features and Outcomes of IgA Nephropathy with Serum Antineutrophil Cytoplasmic Autoantibody Positivity

Introduction: IgA nephropathy (IgAN) with serum antineutrophil cytoplasmic autoantibody (ANCA) positivity is uncommon. This study analyzed the clinicopathologic features and prognosis of IgAN patients with serum ANCA positivity. Methods: 2,864 IgAN patients were tested for ANCA by the indirect immunofluorescence assay and chemiluminescence immunoassay. Patients with serum ANCA positivity (n = 85) were identified, and their clinical, pathological, and prognostic characteristics were analyzed. They were compared with ANCA-negative IgAN patients (n = 170) and ANCA-associated systemic vasculitis (AAV) with renal involvement patients (n = 85) selected randomly. Results: 2.97% (85/2,864) of IgAN were ANCA positive, and 4 patients were diagnosed as having crescentic IgAN with ANCA positivity. The clinicopathological characteristics of ANCA-positive IgAN patients were comparable to ANCA-negative IgAN patients, but they had higher antinuclear antibody (ANA)-positive rates, lower levels of renal interstitial inflammation, and fewer immune depositions than ANCA-negative IgAN patients. Compared with AAV patients, ANCA-positive IgAN patients were younger and had fewer extrarenal manifestations, milder renal damage, and more immune complex depositions. The renal outcomes were similar between IgAN patients with and without ANCA positivity. Multivariate Cox analysis revealed that in IgAN patients with ANCA positivity, male, ANA positivity, higher serum creatinine and proteinuria, and more severe renal tubular atrophy/interstitial fibrosis were risk factors for adverse renal outcomes. Conclusion: The clinical, pathological features and prognosis of ANCA-positive IgAN patients were similar to those of ANCA-negative IgAN patients except for higher ANA-positive rate, milder renal inflammation, and fewer immune depositions. ANA positivity was an independent risk factor for adverse renal outcomes in ANCA-positive IgAN patients.

FC064: Histopathological and Clinical Outcomes of Anca Negative Versus Anca Positive Pauci-Immune Glomerulonephritis

Abstract BACKGROUND It has been suggested that pauci-immune small vessel vasculitis exhibits a different spectrum of disease in the absence of detectable circulating anti-neutrophil cytoplasmic autoantibodies (ANCA). This study aims to investigate the differences in clinical presentation, renal histopathological and clinical outcomes amongst vasculitis patients with or without detectable circulating ANCA. METHOD A cohort study of biopsy proven pauci-immune glomerulonephritis was constructed from a single centre between 2006 and 2016 and followed up until June 2021. Patients were stratified by ANCA status at the time of diagnosis and primary outcomes compared the histopathological classification, clinical presentation and outcomes including mortality and end stage renal disease (ESRD) of those with ANCA negative and positive disease. Secondary outcomes looked at multivariate survival and logistic models comparing remission and relapse rates between the two groups. RESULTS From 146 patients, 21.9% (n = 32) had ANCA negative disease with a male predominance of 66% (n = 21) and a younger mean age at diagnosis compared to those with positive ANCA serology; 51.44 ± 19.57 years versus 65.6 ± 12.10 years, respectively (P ≤ 0.001). ANCA negative serology was associated with more renal limited disease (n = 20, 62.3% versus n = 44, 38.6% ANCA positive) and the presence of extra-renal disease with ENT and constitutional symptoms occurred more frequently in ANCA positive patients (27% versus 0%; P = 0.0013). There was a comparable spread across the Berden classification, with no significant difference seen between the positive and negative groups (Table 1). The predominant class across both cohorts was focal classification. At the time of diagnosis, ANCA-negative patients had lower eGFR than those with positive ANCA serology (14.0 versus 18.0 mL/min/1.73 m2; P = 0.09 922). At the end of follow-up, 53.1% (n = 17) of ANCA-negative patients had progressed to end stage renal disease (ESRD) which was higher than those with ANCA positivity (n = 13, 11.7%). When adjusting for age, sex and induction therapy, the hazard ratio (HR) for ESRD was five times higher in ANCA-negative patients compared to ANCA positive [HR 5.20 (2.02–13.39); P ≤ 0.001]. Mortality rates were higher in the ANCA-negative cohort (Figure 1). Following HR calculations and multivariate analysis, age was associated with a higher risk of death. In addition, despite the ANCA-negative cohort being younger, when adjusting for age, sex and induction therapy, the HR of death was three times higher in the ANCA-negative cohort [HR 3.0 (1.36–6.63); P = 0.007]. CONCLUSION Our single-centre experience suggests that ANCA negative disease tends to occur in younger patients, with a higher rate of renal limited disease. Seronegative disease is less likely to relapse but is associated with a high mortality rate. The reasons for these differences between ANCA-positive and ANCA-negative cohorts are complex and multifaceted. Some reports hypothesize that the cause for severe disease at presentation in the absence of circulating ANCA is due to a delay in diagnosis and treatment by clinicians [1,2]. This study provides the impetus for further trials looking at ANCA-negative and ANCA-positive disease.

Characteristics and prognosis of ANCA-positive retroperitoneal fibrosis: A systematic literature review.

Anti-neutrophil cytoplasmic autoantibody (ANCA)-positive retroperitoneal fibrosis (RPF) is extremely rare. This study aimed to clarify the clinical characteristics and prognosis of patients with ANCA-positive RPF. We conducted a systematic literature review of articles reporting on ANCA-positive RPF from the database inception dates until March 8, 2020. We identified 19 patients with ANCA-positive RPF with a mean age of 62 years; a male dominance (68.4%) was noted. Most patients presented with systemic symptoms and/or lower back or abdominal pain. Proteinase 3 (PR3) -ANCA positivity was predominant compared with myeloperoxidase (MPO)-ANCA (63.2% vs. 36.8%, respectively), and all patients showed elevated serum C-reactive protein levels. Of note, 26.7% of patients had isolated RPF without any other ANCA-associated systemic organ involvement. Regarding typical manifestations of ANCA- associated vasculitis, ear, nose, and throat involvement occurred in 26.3%, lung involvement in 36.8%, and kidney involvement (rapidly progressive glomerulonephritis) in 31.6% of patients. Necrosis and granulomatous inflammation, vasculitis, and multinucleated giant cells were pathologically observed in tissue sections of RPF, whereas tertiary lymphoid organ formation was not identified. Glucocorticoids with or without other immunosuppressive treatments were effective in most patients, but 4 patients experienced disease relapse during the clinical course. All relapsed patients were positive for PR3-ANCA. Clinical features of ANCA-positive RPF are associated with systemic inflammatory components such as fever and elevated serum C-reactive protein levels. ANCA-. positive RPF presents as an "isolated" involved organ in one-third of patients. Immunosuppressive treatments are effective, but the disease can recur, particularly in PR3-ANCA-positive patients.

Antineutrophil cytoplasmic autoantibody (ANCA) positive immunoglobulin A (IgA) nephropathy: Case reports and review of literature

BackgroundThere are reports of circulating antineutrophil cytoplasmic autoantibodies (ANCA) in patients with immunoglobulin A (IgA) nephropathy with an uncertain pathogenic role. Aim of the workTo present the findings of myeloperoxidase (MPO) ANCA-positive patients amid a different course of IgA nephropathy with crescents and to discuss the efficacy of immunosuppressive therapy. Case presentationTwo cases of IgA nephropathy associated with positive ANCA are reported and a review of the literature data is presented. The first patient presented with a progressive nephropathy and significantly impaired renal function at baseline, whereas in the second patient renal function remained stable over 10 years, despite the recurrent exacerbations of the disease. Both patients had extrarenal manifestations (joint pain and/or anemia) and elevated markers of inflammation (erythrocyte sedimentation rate, C-reactive protein) that are not typical features for IgA nephropathy. In the first case, immunosuppressive therapy with corticosteroids and cyclophosphamide resulted in improvement of kidney function. The second case showed the potential efficacy of rituximab as an induction remission and maintenance therapy for ANCA-positive IgA nephropathy. ConclusionWhether the association of IgA nephropathy with ANCA positivity is coincidental or constitutes a novel entity remains debated. Circulating ANCA can be found in patients with IgA nephropathy. They can be truly pathogenic and contribute to kidney damage and may induce overt systemic vasculitis or at least extrarenal signs and symptoms. ANCA-positive IgA nephropathy can respond to immunosuppressive regimens, including rituximab, similar to patients with ANCA-associated vasculitis (AAV).

P040 Vasculitis in a patient with refractory Crohn's disease

BACKGROUND: Crohn's disease (CD) is associated with a variety of cutaneous manifestations, many of which parallel disease activity. Leukocytoclastic vasculitis (LV) is a rare and underdiagnosed cutaneous manifestation of CD. CASE: A twenty-year old woman presented to our unit with a rash affecting her lower extremities eleven days after ileocolic resection and ileostomy for refractory CD. Her past medical history included the diagnosis of penetrating CD for 3-years (anti-TNF refractory). Investigations revealed: normal full blood count and electrolytes, negative serologies (HIV, HBV, syphilis, HCV), normal C-reactive protein (CRP), negative rheumatoid factor, negative anti-nuclear antibodies (ANA), positive antineutrophil cytoplasmic autoantibody (ANCA). Skin biopsy diagnosed LV, characterized by angiocentric neutrophilic infiltrate with normal epidermis and no granulomata or fibrinoid necrosis. DISCUSSION: LV is an immune-complex syndrome characterized by palpable purpura commonly located in the lower limbs and ankles. It is a rare skin manifestation of CD. Lesions range from 1mm to several centimeters. The condition may also present as urticarial papules, nodules, vesicles, plaques, hemorrhagic bullae and necrotic ulcers. Fever, arthralgia, myalgia and ankle swelling may be present. It is often associated with active intestinal disease. It is believed that direct exposure of immune cells of inflamed intestinal mucosa to fecal antigens may lead to formation of immune complexes, deposited in vessel walls causing vasculitis. LV may also be triggered by medications, infections, surgery, chemicals and other autoimmune diseases. Our patient improved spontaneously after few weeks of surgery. During follow-up, she had no signs of skin lesions or intestinal flares. CONCLUSION: LV is rare a small-vessel vasculitis that may be observed in inflammatory bowel disease patients. Treatment of the predisposing condition is essential in patients with skin-limited disease.

ANCA-positive IgA nephropathy without necrotising or crescentic glomerulonephritis: a clinical conundrum

IgA nephropathy, the most prevalent form of primary glomerular disease, usually portends a favourable outcome. Antineutrophil cytoplasmic autoantibodies (ANCAs) have been reported in association with IgA nephropathy in a small...

Genetic loci of Staphylococcus aureus associated with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides

The proteinase 3 (PR3)-positive anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) granulomatosis with polyangiitis (GPA) has been associated with chronic nasal S. aureus carriage, which is a risk factor for disease relapse. The present study was aimed at comparing the genetic make-up of S. aureus isolates from PR3-ANCA-positive GPA patients with that of isolates from patients suffering from myeloperoxidase (MPO)-ANCA-positive AAV, and isolates from healthy controls. Based on a DNA microarray-based approach, we show that not only PR3-ANCA-positive GPA patients, but also MPO-ANCA-positive AAV patients mainly carried S. aureus types that are prevalent in the general population. Nonetheless, our data suggests that MPO-ANCA-associated S. aureus isolates may be distinct from healthy control- and PR3-ANCA-associated isolates. Furthermore, several genetic loci of S. aureus are associated with either PR3-ANCA- or MPO-ANCA-positive AAV, indicating a possible role for pore-forming toxins, such as leukocidins, in PR3-ANCA-positive GPA. Contrary to previous studies, no association between AAV and superantigens was detected. Our findings also show that a lowered humoral immune response to S. aureus is common for PR3-ANCA- and MPO-ANCA-positive AAV. Altogether, our observations imply that the presence or absence of particular virulence genes of S. aureus isolates from AAV patients contributes to disease progression and/or relapse.

Long-term outcomes in antineutrophil cytoplasmic autoantibody-positive eosinophilic granulomatosis with polyangiitis patients with renal involvement: a retrospective study of 14 Chinese patients.

BackgroundThe clinic-pathological features and outcomes of Chinese patients with antineutrophil cytoplasmic autoantibody (ANCA)-positive eosinophilic granulomatosis with polyangiitis (EGPA) and renal involvement have not been studied.MethodsFourteen EGPA patients with renal involvement were included. All patients underwent renal biopsy. Clinic-pathological features and outcomes were retrospectively analyzed.ResultsThe most common initial symptom of EGPA was asthma (57.1 %), followed by hemoptysis (21.4 %), gross hematuria (14.3 %), and arthritis (7.1 %). All patients had positive serum ANCA (anti-MPO in 12, anti-PR3 in 2). Elevated eosinophils (median 15 %, range 10–45 %) were found in all patients. The median serum IgE level was 463 g/L (range 200–1000 g/L). All patients presented with renal dysfunction, with a median SCr of 5.4 mg/dL (range 1.47–11 mg/dL), seven patients (50 %) required initial renal replacement therapy. Thirteen patients showed hematuria and proteinuria (median 1.1 g/24 h, range 0.5–7.8 g/24 h). Renal biopsy showed pauci-immune segmental necrotizing glomerulonephritis with crescents in 13 patients and acute interstitial nephritis in one patient. Twelve patients (85.7 %) showed renal interstitial eosinophil infiltration, among whom three had eosinophilic granuloma. Among seven patients (71.4 %) who required initial dialysis, 5 discontinued dialysis, one died, one received maintenance dialysis after glucocorticoids plus immunosuppressive for induction treatment. Twelve patients were followed up for a median of 43.5 months (range 6–83 months), during follow-up, two patients progressed to end-stage renal disease, nine had chronic kidney disease with eGFR < 60 mL/min, and two patients had normal eGFR.ConclusionsRenal involvement in ANCA-positive EGPA could be severe and showed varied renal histology. Although intensive immunosuppressive therapy effectively improved the renal function, the long-term renal survival was poor. Early diagnosis and treatment are essential to improve long-term renal survival.

Clinical features of IgA nephropathy with serum ANCA positivity: a retrospective case–control study

BackgroundThe coexistence of IgA nephropathy (IgAN) and antineutrophil cytoplasmic autoantibodies (ANCAs) is relatively rare. Only a few studies have reported the features of these patients.MethodsWe studied the clinical and histological features of 20 ANCA-positive IgAN patients. They were compared with ANCA-negative IgAN patients (n = 40) and ANCA-associated systemic vasculitis (AASV) patients (n = 40) with a randomly selected and matched proportion of crescentic glomeruli. Furthermore, 9 ANCA-positive crescentic IgAN patients out of the 20 cases were compared with two control groups with crescentic nephritis.ResultsANCA-positive IgAN patients showed older age, lower haemoglobin and higher inflammatory indicator levels at baseline, and a higher percentage of general symptoms and pulmonary involvement, compared with ANCA-negative IgAN patients, and were comparable to AASV patients. Histologically, there was a significantly higher percentage of fibrinoid necrosis in glomeruli in ANCA-positive IgAN patients and in AASV patients compared with ANCA-negative IgAN patients (35, 25 and 0%, respectively, P = 0.003). After immunosuppressive therapy, ANCA-positive crescentic IgAN patients were more likely to withdraw from dialysis (75 versus 9.1%, P = 0.03) and not to reach end-stage renal disease within 6 months (11.1 versus 66.7%, P = 0.01) compared with ANCA-negative crescentic IgAN patients.ConclusionsIgAN patients with ANCA positivity showed more severe clinical and histological features when compared with ANCA-negative IgAN patients and were comparable to AASV patients. However, renal prognosis was relatively better in ANCA-positive crescentic IgAN patients after aggressive immunosuppressive therapy in the short term, compared with ANCA-negative patients.

THU0313 Antineutrophil Cytoplasmic Autoantibodies (ANCA) Positivity as a Red Flag of Severe Disease in Lupus Nephritis.

BackgroundThe presence of vasculitis is a well-documented finding in patients with systemic lupus erythematosus (SLE) but it is not yet clear if antineutrophil cytoplasmic autoantibodies (ANCA) play a pathogenetic role...

Influence of variable domain glycosylation on anti-neutrophil cytoplasmic autoantibodies and anti-glomerular basement membrane autoantibodies

BackgroundThe pathophysiological significance of variable region glycosylation of autoantibodies is still unclear. In the current study, the influence of the variable region N-linked oligosaccharides on the reactivity of three autoantibody specificities was investigated with Sambucus nigra agglutinin (SNA), which mainly binds to oligosaccharides with terminal α2, 6-linked sialic acid on the variable region of IgG.MethodsTwenty-seven patients with serum positive anti-neutrophil cytoplasmic autoantibodies (ANCA) against myeploperoxidase (MPO) or proteinase 3 (PR3), or autoantibodies against glomerular basement membrane (GBM) were included. Total IgG was isolated and separated into non-SNA-binding and SNA-binding fractions with SNA affinity chromatography. Antigen-specific IgG was purified by immunoaffinity chromatography.ResultsAt the same concentration of IgG, the antigen binding level of non-SNA-binding IgG was significantly lower than that of SNA-binding IgG for MPO-ANCA (absorbance value at 405 nm, 0.572 ± 0.590 vs. 0.962 ± 0.670, P < 0.001) and for PR3-ANCA (0.362 ± 0.530 vs. 0.560 ± 0.531, P = 0.003). The antigen binding level of non-SNA-binding IgG was significantly higher than that of SNA-binding IgG for anti-GBM antibodies (1.301 ± 0.594 vs. 1.172 ± 0.583, P = 0.044). The level of variable region glycosylation of total IgG was significantly lower than that of affinity-purified MPO-ANCA (1.021 ± 0.201 vs. 1.434 ± 0.134, P = 0.004). The level of variable region glycosylation of total IgG was significantly higher than that of affinity-purified anti-GBM antibodies (1.034 ± 0.340 vs. 0.734 ± 0.333, P = 0.007). The SNA-binding fraction of MPO-ANCA-containing IgG and PR3-ANCA-containing IgG induced higher levels of neutrophil oxygen radical production than the corresponding non-SNA-binding fractions (P < 0.001 and P = 0.043, respectively). The level of variable region glycosylation of affinity-purified MPO-ANCA was higher in active AAV than the same patients in remission (P = 0.001).ConclusionCharacteristics of variable region glycosylation of ANCA and anti-GBM antibodies were different from that of total IgG, which might influence the antigen-binding ability of these antibodies. Variable region glycosylation of ANCA might influence the effect of ANCA-induced neutrophils respiratory burst.

Diffuse Bilateral Orbital Inflammation in Churg- Strauss Syndrome

A 33-year-old man was diagnosed with asthma and within 5 weeks developed bilateral periocular swelling. Examination revealed bilateral axial proptosis with conjunctival nodules. His blood tests revealed a positive p-antineutrophil cytoplasmic autoantibody with significant eosinophilia. MRI of the orbit showed enlarged extraocular muscles, lacrimal glands, and infiltrative changes in the orbital fat. Biopsy demonstrated granulomatous inflammation with eosinophil predominance. A diagnosis of diffuse bilateral inflammation in Churg-Strauss syndrome was made and the patient responded dramatically to prednisolone with resolution of systemic and orbital findings. The second case was a 72-year-old woman with a prolonged prodromal phase of asthma, paranasal sinus disease, and bilateral orbital involvement by a process consistent with reactive lymphoid hyperplasia on initial biopsy. Three years later she developed rapidly worsening orbital disease, marked peripheral eosinophilia, and orbital biopsy showed evidence of granulomatous inflammation with marked eosinophil infiltration and vasculitic changes, and a weakly positive antineutrophil cytoplasmic autoantibody. Hence, diffuse bilateral orbital inflammation occurring in the setting of asthma and peripheral eosinophilia should raise the possibility of Churg-Strauss syndrome and warrants biopsy as early institution of therapy can reduce both systemic and ophthalmic complications.

Severe Pulmonary Hemorrhage in Patients With End-Stage Renal Disease in Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

BackgroundIt has been reported that after patients with antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV) progress to end-stage renal disease (ESRD), they are less likely to experience relapse of vasculitis. However, we encountered a few patients with ESRD suffering severe pulmonary hemorrhage caused by relapse of AAV. The current study presents our observation on these patients. MethodsOf 198 consecutive patients with AAV with follow-up data in our center, 66 progressed to ESRD during follow-up. Clinical and laboratory data were collected and retrospectively analyzed. ResultsAmong the 66 patients with ESRD, 5 experienced severe pulmonary hemorrhage. They had positive serum perinuclear ANCA and myeloperoxidase ANCA and were diagnosed as microscopic polyangiitis. All 5 patients achieved remission after initial induction therapy. The average duration of follow-up was 47.0 (range 8.0–98.0) months. After progressing to ESRD and starting hemodialysis, these patients experienced severe pulmonary hemorrhage within 9.0 (range 2.0–23.0) months. After immunosuppressive therapy, pulmonary hemorrhage ceased in 4 patients, and the other died of respiratory failure. ConclusionsSevere pulmonary hemorrhage can occur in ESRD patients with AAV. Disease activity and relapses of AAV should be monitored even after patients progress to ESRD.

Wegener’s granulomatosis in the thyroid mimicking a tumour

Wegener's granulomatosis (WG) is a systemic vasculitis characterised by the presence of necrotizing granulomas and classically manifests as a triad of upper and lower respiratory tract involvement along with glomerulonephritis. Other rather unusual presentations of WG include ocular, salivary gland, cutaneous, gastrointestinal and cardiac involvement. We report a case in a 51-year-old woman suffering from WG with positive antineutrophil cytoplasmic autoantibodies and antibodies directed against proteinase 3. Under maintenance therapy, the patient developed two thyroid nodules suspicious for malignancy which led to thyroidectomy. Postoperative histological examination revealed a tumour-forming WG mimicking a malignant thyroid tumour. We conclude that, although extremely rare, Wegener's. granulomatosis should be added to the list of differential diagnoses of tumours of the thyroid gland.

Clinical and histopathologic features of 8 patients with microscopic polyangiitis including two with a slowly progressive clinical course

Microscopic polyangiitis (MPA) is a systemic antineutrophil cytoplasmic autoantibody-associated vasculitis associated with necrotizing and crescentic glomerulonephritis and pulmonary capillaritis. MPA generally has a rapidly progressive clinical course, but there have been recent reports of slowly progressive cases. To evaluate the typical cutaneous findings of MPA, we recorded the clinical and histopathologic features of the cutaneous manifestations. Eight patients with MPA, who had presented with cutaneous manifestations between 2001 and 2005 in our department, were retrospectively reviewed. They had necrotizing vasculitis in their cutaneous lesions as confirmed by skin biopsy specimens. Patients with other known connective tissue diseases were not included in the study. All 8 patients with MPA presented cutaneously with erythematous macules on their extremities. Livedo reticularis (5/8, 68%) was also observed. Six of the 8 patients with MPA were given the diagnosis within 3 months of their initial manifestation. In skin biopsy specimens, necrotizing vasculitis was noted in the reticular dermis to the subcutaneous fat. In contrast, the other two patients with MPA were given the diagnosis about 10 years after their initial manifestation. Histopathologic findings demonstrated necrotizing vasculitis with moderate neutrophilic infiltrations in the papillary to middle dermis in the latter two patients. Serum myeloperoxidase-antineutrophil cytoplasmic autoantibody levels were only moderlately elevated in the latter two patients and they were given the diagnosis of slowly progressive MPA. Histopathologically, palisading granulomas were present on the elbow of one of them. The study was based on histopathological analysis in a limited number of patients due to the rareness of the investigated disease. There appears to be a correlation between a slowly progressive clinical course of MPA and the depth of dermal involvement and the severity of neutrophilic infiltration in biopsy specimens. Based on these results, we believe that these characteristic patterns may help clinicians establish an earlier diagnosis of possible MPA with positive antineutrophil cytoplasmic autoantibody titers.

Azurocidin is a novel antigen for anti-neutrophil cytoplasmic autoantibodies (ANCA) in systemic vasculitis.

We isolated a 27-kD protein using cation exchange chromatography from an acid extract of neutrophil granules. N-terminal amino acid sequence analysis of the first 10 residues showed that this protein is azurocidin, a member of the family of neutral serine proteinase found in the neutrophil, which shares amino acid sequence homology with the three other neutral serine proteinases, elastase, proteinase 3 (PR3) and cathepsin G, but unlike them is without proteolytic activity. To test whether, in addition to these proteases, azurocidin might be a target for the humoral autoimmune responses associated with human vasculitis, 185 indirect immunofluorescence (IIF)-positive ANCA sera, made up of four groups of sera with specificities for PR3 (n=37), myeloperoxidase (MPO; n=50), bactericidal/permeability-increasing protein (BPI; n=41) and sera that recognized none of them (triple negative, n=57), and 46 normal sera were screened for IgG anti-azurocidin antibodies using an ELISA incorporating purified azurocidin. Twenty of the 185 IIF-positive sera and 2/46 normal sera displayed reactivity with azurocidin. Positive sera could blot the 27-kD band by Western blot analysis. Further study of the 20 positive sera revealed that: (i) 10 also had autoreactivity for MPO, of which six additionally recognized lactoferrin; (ii) two had reactivity with BPI; (iii) the remaining eight sera were positive only for azurocidin. All 20 sera were from patients with systemic vasculitis, and four of the six sera with triple reactivity (for azurocidin, MPO and lactoferrin) were from patients with hydralazine-induced vasculitis. We concluded that: (i) azurocidin is a novel ANCA antigen; (ii) anti-azurocidin antibodies from a subgroup of patients might represent the consequence of a drug-induced multi-clone activation.

Immune complex deposits in ANCA-associated crescentic glomerulonephritis: A study of 126 cases

Necrotizing and crescentic glomerulonephritis related to antineutrophil cytoplasmic autoantibodies (ANCA) is typically referred to as "pauci-immune"; however, it is not unusual for renal biopsies in such cases to exhibit some immune complex deposition within glomeruli on immunofluorescence and/or electron microscopic study. The composition and intraglomerular localization of such deposits in ANCA-glomerulonephritis has not been widely studied, and their potential pathologic and clinical significance is not clear, although a possible synergistic effect between immune complexes and ANCA in producing more severe glomerulonephritis is suggested by some human and animal studies. Electron micrographs from 126 renal biopsies showing necrotizing/crescentic glomerulonephritis characterized by positive ANCA serology [C-ANCA, anti-proteinase 3 (anti-PR3), or anti-myeloperoxidase (MPO)] or necrotizing arteritis in the absence of known ANCA results were examined for the presence, quantity, and location of electron-dense deposits. The presence or absence of such deposits was correlated with histologic findings (fraction of glomeruli with crescents and segmental necrotizing lesions, mesangial and endocapillary hypercellularity), immunofluorescence findings, and clinical data, including serum creatinine and 24-hour urine protein levels at the time of biopsy. Sixty-eight (54%) of these biopsies showed glomerular immune complex deposits on electron microscopy; 87% of the latter also showed positive immunofluorescence findings for at least one immunoglobulin or complement component, although staining was relatively mild in most instances (< or =2+ on a 0 to 4+ scale in all but eight cases). Nearly half of biopsies negative for deposits by electron microscopy also showed positive immunofluorescence findings, though even more so than in cases with deposits on electron microscopy the intensity of immunofluorescence staining in these biopsies was typically very weak (trace or trace to 1+ in most cases, none >2+). Hypercellularity within the glomerular tuft was seen in 50% of biopsies with deposits on electron microscopy but only 14% of those without deposits; in each group this was usually mild and mesangial. Notably, the presence of deposits on electron microscopy was associated with a higher median level of proteinuria (3.2 versus 1.3 g/24 hours, P < 0.0001) and a higher median percentage of glomeruli with crescents (62.5% versus 44.0%, P= 0.06). Immune complex deposits were found on electron microscopy in just over half of renal biopsies with crescentic glomerulonephritis associated with positive ANCA serology and/or necrotizing arteritis. Clinical correlations suggest that these immune complex deposits may somehow potentiate the effect of ANCA in producing glomerulonephritis.

Streptococcal viridans subacute bacterial endocarditis associated with antineutrophil cytoplasmic autoantibodies (ANCA)

We report an illustrative case of a 60-year-old man with Streptococcus viridans subacute bacterial endocarditis (SBE) and positive antineutrophil cytoplasmic autoantibodies (c-ANCA). C-ANCA positivity has been associated with a variety of rheumatic and infectious disease areas, but has been rarely associated with SBE. The patient had mitral valve prolapse with mitral regurgitation, and S viridans SBE developed after a dental procedure. Laboratory abnormalities included anemia, elevated erythrocyte sedimentation rate, positive rheumatoid factor, positive anticardiolipin antibody, positive lupus anticoagulant, and highly elevated c-ANCA level. We believe this is only the ninth reported case of S viridans SBE with a positive c-ANCA, and the third with mitral valve prolapse and vegetations. (Heart Lung® 2003;32:140-3.)

Prevalence of antineutrophil cytoplasmic autoantibodies in patients with tuberculosis

To determine the prevalence of antineutrophil cytoplasmic autoantibodies (ANCA) in sera of patients with tuberculosis compared with healthy control subjects and a group of patients with atopic asthma. The presence of ANCA was examined in patients with tuberculosis, and in asthmatic patients and healthy subjects as control groups, by means of indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) to detect anti-proteinase 3 (PR3-ANCA) and antimyeloperoxidase (MPO-ANCA) antibodies. ANCA were present in 20 (44.4%) of 45 tuberculosis patients by IIF (16 c-ANCA, four p-ANCA) and in 18 (40%) patients by ELISA (15 PR3-ANCA, three MPO-ANCA). High odds ratios for ANCA positivity were observed for tuberculosis patients when compared with both control groups. ANCA results were not related to the category of tuberculosis, stage of disease, presence of concomitant diseases or pharmacotherapy. As many clinical similarities between tuberculosis and Wegener's granulomatosis exist, we propose that a positive ANCA test in patients living in countries with a high prevalence of tuberculosis must be carefully interpreted as indicative of systemic vasculitis, especially when no signs of extrapulmonary involvement occur.

ANCA-associated crescentic glomerulonephritis with mesangial IgA deposits

Antineutrophil cytoplasmic autoantibodies (ANCA) are commonly associated with a necrotizing and crescentic glomerulonephritis (GN) that is pauci-immune, with few or no glomerular immune complex deposits detectable by immunofluorescence (IF) or electron microscopy (EM). Immunoglobulin A (IgA) nephropathy may also be manifest as a crescentic GN, but it is characterized by mesangial immune complex deposits containing IgA and is rarely associated with myeloperoxidase (MPO)- or proteinase 3 (PR3)-specific ANCA when an enzyme immunoassay is used to detect these antibodies. This report describes six patients with severe crescentic GN with mesangial IgA deposits by IF and mesangial electron-dense deposits by EM in patients with positive ANCA serological test results (four patients, anti-PR3; one patient, anti-MPO; one patient, anti-PR3 and anti-MPO). Patients presented with acute or progressive renal insufficiency, hematuria, proteinuria (nephrotic range in two patients), and hypertension. Three patients had evidence of systemic vasculitis: two patients at initial presentation and one patient later in the clinical course. Renal biopsy specimens showed crescents in greater than 50% of glomeruli in all cases, but only mild, focal and segmental mesangial and endocapillary hypercellularity, more typical of ANCA-associated crescentic GN than of crescentic IgA nephropathy without associated ANCA. Semiquantitative analysis of mesangial and endocapillary cellularity performed on renal biopsy slides from these six patients and from eight ANCA-negative patients with IgA nephropathy and crescents in greater than 50% of glomeruli showed significantly greater hypercellularity in the ANCA-negative cases. Three of five ANCA-positive patients for whom follow-up clinical data were available showed improved renal function after treatment with cyclophosphamide and corticosteroids and have not developed end-stage renal disease 17, 20, and 25 months postbiopsy. The remaining two patients were dialysis dependent at the time of biopsy and have remained so despite treatment with cyclophosphamide and corticosteroids. The findings suggest an overlap syndrome of ANCA-associated crescentic GN and IgA nephropathy that resembles the former both histologically and in its potential to respond to aggressive therapy if detected relatively early in its course.