ANCA-negative Patients Research Articles

Myeloperoxidase-Antineutrophil Cytoplasmic Antibody (ANCA)-Positive and ANCA-Negative Patients With Granulomatosis With Polyangiitis (Wegener's): Distinct Patient Subsets.

To examine the relationship of antineutrophil cytoplasmic antibody (ANCA) type and ANCA-associated vasculitis (AAV) diagnosis with demographic features, disease manifestations, and clinical outcomes. We focused on patients who account for the differences between ANCA type and disease type classifications: anti-myeloperoxidase (MPO)-ANCA-positive and ANCA-negative patients with granulomatosis with polyangiitis (Wegener's) (GPA). We performed a pooled analysis of the Wegener's Granulomatosis Etanercept Trial and the Rituximab in ANCA-Associated Vasculitis trial comparing patients with MPO-ANCA-positive GPA and patients with ANCA-negative GPA to patients with proteinase 3 (PR3)-ANCA-positive GPA and patients with MPO-ANCA-positive microscopic polyangiitis (MPA). Of the 365 patients analyzed, 273 (75%) had PR3-ANCA-positive GPA, 33 (9%) had MPO-ANCA-positive GPA, 15 (4%) had ANCA-negative GPA, and 44 (12%) had MPO-ANCA-positive MPA. MPO-ANCA-positive GPA patients were younger at diagnosis compared to MPO-ANCA-positive MPA patients (53 versus 61 years; P = 0.02). Their disease manifestations and rates of relapse were similar to those of PR3-ANCA-positive GPA patients. Relapse was more frequent in MPO-ANCA-positive GPA patients than in patients with MPO-ANCA-positive MPA at trial entry as well as at 12 and 18 months. ANCA-negative patients with GPA had lower Birmingham Vasculitis Activity Score for Wegener's Granulomatosis scores at trial entry than PR3-ANCA-positive patients with GPA (4.5 versus 7.7; P < 0.01), primarily because of a lower prevalence of renal involvement. We were unable to demonstrate important clinical differences between MPO-ANCA-positive and PR3-ANCA-positive patients with GPA. The risk of relapse was associated more closely with disease type than with ANCA type in this patient cohort. These findings deserve consideration in the assessment of relapse risk in patients with AAV.

Clinical analysis of 43 patients with eosinophilic granulomatosis with polyangiitis

To describe the clinical features of eosinophilic granulomatosis with polyangiitis (EGPA). Patients who fulfilled the criteria for EGPA managed at the Beijing Chaoyang Hospital of Capital Medical University between May 2005 and Feb 2014 were retrospectively investigated. Patients' characteristics were compared according to antineutrophil cytoplasmic antibody (ANCA) status.Patients were followed up in outpatient service or by telephone to evaluate the treatment result. There were 43 patients included, 24 males and 19 females. Mean age at onset was (53.0±15.0) years old. The most common onset symptom of EGPA was asthma in 30 (69.8%) patients. Asthma was also the most common symptom in 42 (97.7%) patients, followed by sinusitis and rhinitis in 40(93.0%) patients and peripheral neuropathy in 26 (60.5%) patients. ANCA positive was found in 13 (30.2%) patients, mainly anti-myeloperoxidase antibodies. High resolution computed tomography scanning (HRCT) of the chest was performed in all the patients, and the main anomalies included ground-glass opacities in 34 (79.1%) patients and bronchial wall thickening and/or bronchial dilatation in 22 (51.2%) patients. Pulmonary function tests available at diagnosis in 33 patients mainly demonstrated an obstructive ventilatory defect. There were totally 33 patients who underwent biopsy, 21 (63.6%) patients had histologic findings supporting a diagnosis of EGPA, including eosinophil infiltration in 21 patients, vasculitis in 5 patients, but no granuloma. ANCA-positive patients were more likely to have fever and renal disease, more honeycombing pattern in the HRCT image and more significantly decreased pulmonary diffusion function, while ANCA-negative patients were more likely to have significant obstructive ventilatory defect. 41 patients received oral corticosteroids, among them, 19 patients additionally received immunosuppressants. 35 Patients were followed for a median of 30 (13, 46) months, 3 patients died (mortality 8.57%), among the other 32 patients, asthma was still the most common symptom in 16 (50%) patients at their last visit, and prednisone administration had to be continued for 23 (71.9%) patients. The clinical manifestations of EGPA may vary widely, and it involves different organs. Physicians should be alert to EGPA when seeing patients with refractory asthma and eosinophilia.

Clinical Implication of Proteinase-3-antineutrophil Cytoplasmic Antibody in Patients with Idiopathic Interstitial Pneumonias.

The clinical significance of proteinase-3-antineutrophil cytoplasmic antibody (PR3-ANCA) positivity is not well established in idiopathic interstitial pneumonia (IIP) patients. We aimed to determine the clinical features of PR3-ANCA-positive IIP patients. We retrospectively reviewed 377 consecutive IIP patients; of these, 360 patients had PR3-ANCA and myeloperoxidase-antineutrophil cytoplasmic antibody test results available. The clinical features of PR3-ANCA-positive IIP patients and control ANCA-negative idiopathic pulmonary fibrosis patients (ANCA-negative IPF) were compared. Sixteen patients (4.4%) were PR3-ANCA-positive IIP and 94 (26%) were ANCA-negative IPF. The median age at diagnosis (72 vs. 70years, P=0.17) and proportion of males (75 vs. 89%, P=0.12) in PR3-ANCA-positive IIP and ANCA-negative IPF patients, respectively, were not significantly different. Radiologically, the HRCT patterns of PR3-ANCA-positive IIP patients varied (UIP, n=3, 18.8%; possible UIP, n=3, 18.8%; NSIP, n=5, 31.3%; unclassifiable CT pattern, n=5, 31.3%) more than those of ANCA-negative IPF patients (UIP, n=69, 73.4%; possible UIP, n=25, 26.6%; P<0.001). No PR3-ANCA-positive IIP patients developed ANCA-associated vasculitis. The 5-year survival rate was 50% in PR3-ANCA-positive IIP patients and 52% in ANCA-negative IPF patients with no significant difference (P=0.96 by log-rank test). The HRCT patterns of PR3-ANCA-positive IIP patients varied more than those of the IPF patients, but the clinical features of high IIP-onset age and male predominance were similar between the groups. Furthermore, PR3-ANCA-positive IIP patients had a poor prognosis similar to that of IPF patients.

Long-term Prognosis of Anti-Neutrophil Cytoplasmic Antibody-Negative Renal Vasculitis: Cohort Study in Korea.

Few studies have reported on the long-term prognosis of anti-neutrophil cytoplasmic antibody (ANCA)-negative renal vasculitis. Between April 2003 and December 2013, 48 patients were diagnosed with renal vasculitis. Their ANCA status was tested using indirect immunofluorescence and enzyme-linked immunosorbent assays. During a median (interquartile range) follow-up duration of 933.5 (257.5–2,079.0) days, 41.7% of patients progressed to end stage renal disease (ESRD) and 43.8% died from any cause. Of 48 patients, 6 and 42 were ANCA-negative and positive, respectively. The rate of ESRD within 3 months was higher in ANCA-negative patients than in ANCA-positive patients (P = 0.038). In Kaplan-Meier survival analysis, ANCA-negative patients showed shorter renal survival than did ANCA-positive patients (log-rank P = 0.033). In univariate Cox-proportional hazard regression analysis, ANCA-negative patients showed increased risk of ESRD, with a hazard ratio 3.190 (95% confidence interval, 1.028–9.895, P = 0.045). However, the effect of ANCA status on renal survival was not statistically significant in multivariate analysis. Finally, ANCA status did not significantly affect patient survival. In conclusion, long-term patient and renal survival of ANCA-negative renal vasculitis patients did not differ from those of ANCA-positive renal vasculitis patients. Therefore, different treatment strategy depending on ANCA status might be unnecessary.

PROBLEMS IN THE DIAGNOSIS AND TREATMENT OF ANCA-ASSOCIATED SYSTEMIC VASCULITIS: IN THE FOCUS OF ANCA-NEGATIVE PAUCI-IMMUNE GLOMERULONEPHRITIS

One of the most common causes of rapidly progressive glomerulonephritis (GN) is the so-called pauci-immune crescentic GN that is characterized by no luminescence in kidney tissue samples during immunofluorescence microscopy and by the hyperproduction of antineutrophil cytoplasmic antibodies (ANCA). At the same time, serum ANCAs are absent in a number of cases of pauci-immune GN. Based on their own experience, the authors present the clinical and morphological characteristics of patients with ANCA-negative pauci-immune GN and analyze the data available in the literature. Subjects and methods. This retrospective study included 8 patients with ANCA-negative pauci-immune GN, who were followed up at two Russian centers (the Center of Nephrology and the Center of Rheumatology) in 2011 to 2015. Results and discussion. According to our data, ANCAs are not detectable in 6% of the patients with ANCA-associated systemic vasculitis (SV) with renal involvement and/or pauci-immune GN. The mean age at onset of the disease in the ANCA-negative patients was 50±18 years (range 19 to 74 years); the male/female ratio was 1:1. Four (50%) cases were diagnosed with microscopic polyangiitis; 2 cases had granulomatosis with polyangiitis; isolated renal injury was present in other 2 patients. The Birmingham SV activity index averaged 19.6±7.9. Hematuria was observed in all cases and it was massive in 4. The mean daily urinary protein level was 3.4±2.7 g; three (38%) patients were observed to have nephrotic syndrome. The blood creatinine level averaged 704±405 μmol/l; GN was characterized by a rapidly progressive course in 6 (75%) patients; hemodialysis was needed in 5. A morphological study of the kidney determined crescents (in on an average of 52 glomeruli) in the majority of cases and glomerulosclerosis in one patient. All the patients were observed to have varying degrees of interstitial fibrosis. Three (38%) treated patients achieved remission. The mortality rates were 38%. Interestingly, the data from our group as well those obtained by the study of European cohorts were slightly different from those of the studies conducted in Asia, according to which a renal biopsy more frequently revealed glomerular crescents; the levels of protein in the urine were higher and renal survival was worse. Thus, serum ANCAs are absent in 3–39% of cases of pauci-immune crescentic GN, but the clinical and morphological picture corresponds to ANCA-associated SV. A kidney biopsy helps establish the correct diagnosis, timely use induction treatment, and improve prognosis.

Clinicopathologic Characteristics and Outcomes of Lupus Nephritis With Antineutrophil Cytoplasmic Antibody: A Retrospective Study.

Few studies have analyzed the clinicopathologic characteristics and outcomes of lupus nephritis (LN) patients with antineutrophil cytoplasmic antibody (ANCA).The clinical and renal histopathologic data of 154 patients with biopsy-proven LN from 2011 to 2013 were analyzed retrospectively. The patients were followed up for a median period of 16.8 ± 9.4 months, and their outcomes were analyzed. Multivariate Cox analysis was used to evaluate the independent factors for poor outcomes.Among the 154 LN patients, 26 (16.88%) were seropositive for ANCA. The incidences of alopecia, oral ulcer, photosensitivity and skin lesion, and psychosomatic manifestations in the ANCA-positive group were significantly higher than in the ANCA-negative group (P = 0.007, 0.02, 0.02, and 0.03, respectively). Compared with the ANCA-negative group, the ANCA-positive group had significantly lower levels of complement C3 (P = 0.03). Additionally, the positive rate of antinucleosome antibodies, antihistone antibodies, antimitochondrial antibody M2, and anticardiolipin antibodies were higher significantly in the ANCA-positive patients than in the ANCA-negative patients (P = 0.001, 0.001, 0.03, 0.005, respectively). The ANCA-positive group had a notably higher chronic index than the ANCA-negative group (P = 0.01). During the follow-up, the complete remission rate in the ANCA-negative group was higher than that in the ANCA-positive group (P = 0.01). The cumulative renal survival rate in the ANCA-positive group was significantly lower than in the ANCA-negative group (log-rank = 6.59, P = 0.01). Multivariate Cox analysis revealed that the reduced estimated glomerular filtration rate (HR, 1.02; 95% confidence interval, 1.01 to 1.03; P = 0.005), NLR (HR, 1.20; 95% confidence interval, 1.02 to 1.40; P = 0.03), and ANCA (HR, 3.37; 95% confidence interval, 1.12 to 10.09; P = 0.03) were independent risk factors for patients’ renal survival after adjusting for age, sex, crescent formation, and glomerulosclerosis.The study found ANCA in LN patients is not rare, and patients with ANCA present with more severe clinicopathologic injuries. Thus, ANCA is an independent risk factor for poor renal outcomes in LN patients.

A historical study of American patients with anti-neutrophil cytoplasmic antibody negative pauci-immune glomerulonephritis.

Anti-neutrophil cytoplasmic antibodies (ANCA) play an important role in the pathogenesis of ANCA-associated vasculitis. The lack of ANCA antibodies may indicate a variation in clinical presentation and outcomes of this disease. We identified 74 adult patients between 1995 and 2009 with the diagnosis of pauci-immune glomerulonephritis. Demographics, histological features, and treatment outcomes were compared between ANCA-positive and ANCA-negative patients. These factors were correlated with renal function at presentation and follow-up. Of the 74 patients, 57 were ANCA-positive, and 17 were ANCA-negative. Demographics and mean Birmingham Vasculitis Activity Score were similar between ANCA-negative and ANCA-positive patients at presentation. Renal function was significantly worse at presentation in the ANCA-negative patients (eGFR 16.59 vs. 31.89ml/min/1.73m(2), p = 0.03). Patients in the ANCA-negative group had a significantly higher interstitial fibrosis score compared to the ANCA-positive group (2.1 vs.1.6, p = 0.04). The median time to remission was shorter in the ANCA-negative patients (51 vs. 78days, p = 0.01). Long-term renal function and 1-year patient and renal survival were similar between ANCA-negative and ANCA-positive patients. Baseline eGFR, percentage of normal glomeruli, glomerular sclerosis, and tubulointerstitial scarring predicted eGFR at 1year in both groups similarly. This is the first historical review of American patients with pauci-immune glomerulonephritis, comparing patients with ANCA-negative and ANCA-positive serology. Although ANCA-negative patients present with lower eGFR and more interstitial fibrosis, 1-year and long-term outcomes in both groups are similar.

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.

Increased levels of neutrophil extracellular trap remnants in the circulation of patients with small vessel vasculitis, but an inverse correlation to anti-neutrophil cytoplasmic antibodies during remission.

Neutrophil extracellular traps (NETs) have been visualized at the site of ANCA-associated vasculitis (AAV) lesions. Increased levels of NET remnants in the circulation have been reported in some AAV patients with active disease. The aim of the present study was to analyse NET remnants in a larger cohort of AAV patients with varying degrees of disease activity and to elucidate possible factors responsible for remnant variation. Levels of NET remnants in the circulation of healthy controls (HCs; n = 31) and AAV patients (n = 93) were determined with ELISA. NET remnants were then correlated with ANCA levels, spontaneous and induced cell death (NETosis/necrosis) in vitro, neutrophil count and corticosteroid therapy. Patients with active disease showed higher levels of circulating NET remnants compared with patients in remission (P = 0.026) and HCs (P = 0.006). From patients sampled during both remission and active disease, we found increased levels during active disease (P = 0.0010). In remission, ANCA-negative patients had higher levels of NET remnants than ANCA-positive patients and a negative correlation was observed between NET remnants and PR3-ANCA (rs = -0.287, P = 0.048). NET remnants correlated with neutrophil count in HCs (rs = 0.503, P = 0.014) but not in patients during remission. Neutrophils from patients showed enhanced spontaneous cell death (P = 0.043). We found increased levels of circulating NET remnants in patients with active AAV. Furthermore, AAV patients exhibited an increased propensity for spontaneous cell death. NET remnant levels seem to be positively related to disease activity and neutrophil count, but inversely related to ANCA at least during remission.

Pauci-immune crescentic glomerulonephritis: A series of 21 cases

Background: Pauci-immune crescentic glomerulonephritis is the most common cause of crescentic glomerulonephritis (CrGN). Patients usually present with rapidly progressive glomerulonephritis (RPGN) with hematuria, proteinuria, and elevated serum creatinine levels. The characteristic feature of pauci-immune CrGN is focal necrotizing CrGN associated with little or no glomerular staining for immunoglobulin (Ig) by immunofluorescence microscopic examination. Most patients (80-85%) with pauci-immune CrGN, including the patients with and without systemic vasculitis, have antineutrophil cytoplasmic autoantibodies (ANCAs). Aims and Objectives: To study and compare the histological and laboratory features of ANCA-positive and ANCA-negative pauci-immune CrGN. Materials and Methods: Patients who were diagnosed with pauci-immune CrGN from January 2012 to May 2015, at BABINA Diagnostics, were included in this retrospective study. The terms pauci-immune and crescentic glomerulonephritis were defined according to standard guidelines. The demographic and laboratory data were extracted from the Laboratory Information System (LIS) for analysis. ANCA tests were performed by both indirect immunofluorescence (IIF) assay (EUROIMMUN, Lubeck, Germany) and antigen-specific enzyme-linked immunosorbent assay (ELISA) (ORGENTEC Diagnostika GmbH, Germany). Renal specimens were evaluated using direct immunofluorescence (for Ig and complement components) and light microscopy using routine and special stains. Results: Four (19%) out of the 21 cases of pauci-immune CrGN were ANCA negative. Acute features on histology were seen more than chronic features than ANCA-negative cases. Conclusion: Among the patients with pauci-immune CrGN, ANCA-negative patients were not rare. Compared with ANCA-positive patients, ANCA-negative patients had a lower percentage of normal glomeruli, more of chronic features, and a higher level of proteinuria.

Ear, nose, and throat involvement in eosinophilic granulomatosis with polyangiitis

Eosinophilic granulomatosis with polyangiitis (EGPA) is the rarest of the anti-neutrophil cytoplasm antibody (ANCA)-associated small-vessel vasculitides. In Europe, its prevalence ranges from 10 to 15/million and annual incidence from 0.9 to 1.2/million. EGPA affects men and woman equally, with a mean age of 50 years at diagnosis. The most characteristic features include late-onset asthma, pulmonary infiltrates, mono- or polyneuropathy, and peripheral and extravascular eosinophils. Ear, nose, and throat (ENT) manifestations are particularly frequent, occurring in 30–80% of patients and most often early in the disease process. ENT features include allergic rhinitis, chronic sinusitis and polyposis, lacrimal and salivary gland involvement, otitis media and, rarely, cranial nerve involvement. The diagnosis of EGPA may be relatively straightforward in the 30–40% of ANCA-positive patients and in those with biopsies demonstrating vasculitis, but it can be more challenging, or even debatable, in ANCA-negative patients who do not present clear evidence of vasculitis. Because EGPA is a multisystem disease, it requires a multidisciplinary approach for diagnosis and management, including by an otolaryngologist. Keywords: vasculitis; eosinophilic granulomatosis with polyangiitis; Churg-Strauss syndrome; hypereosinophilia; ANCA (Published: 1 April 2015) Citation: Advances in Cellular and Molecular Otolaryngology 2015, 3: 27181 - http://dx.doi.org/10.3402/acmo.v3.27181

Heart transplantation in a patient with eosinophilic granulomatosis with polyangiitis known as Churg-Strauss syndrome

Eosinophilic granulomatosis with polyangiitis (EGPA), also known as Churg-Strauss syndrome, is a rare systemic necrotizing vasculitis affecting smallto medium-sized vessels. EGPA is associated with severe asthma and eosinophilia. The most frequently involved organs are skin and peripheral nerves; however, EGPA may involve other organs, such as the gastrointestinal tract, kidney, and heart. Antineutrophil cytoplasm antibodies (ANCAs)-related abnormal immune reactions are known to be associated with EGPA, but only 30%–40% of patients have a positive marker of ANCA. ANCA-negative patients are at higher risk of cardiac involvement than ANCApositive patients. Cardiac involvement is one of the leading causes of mortality and could be resistant to conventional treatment. Early treatment with steroid plus cyclophosphamide is important because it could give chances of restoration of cardiac function. For patients undergoing heart transplantation, we should consider the severity of cardiac disease and the presence of systemic diseases, including vasculitis. Here, we report a case of a 25-year-old EGPA patient with cardiac involvement who eventually received heart transplantation for progressive heart failure, although treated with systemic corticosteroid with cyclophosphamide. EGPA patients undergoing heart transplantion are rarely reported worldwide, and this is the first case report in Korea. (Allergy Asthma Respir Dis 2015;3:159-163)

Antineutrophil Cytoplasmic Antibodies in Patients with Idiopathic Inflammatory-Demyelinating Diseases

Objective: We assessed the clinical significance of antineutrophil cytoplasm antibodies (ANCA) in patients with idiopathic inflammatory-demyelinating disease (IIDD). Methods: A consecutive cohort of 269 subjects with IIDD and 595 controls was analyzed retrospectively. Results: Among all subjects, ANCA positivity rates were low [9.5% in a perinuclear pattern (pANCA) and 2.3% in a cytoplasmic pattern (cANCA)]. One of the 117 patients with multiple sclerosis (MS) had cANCA and 2 had pANCA. Ten patients with neuromyelitis optica (NMO; 13.9%) had pANCA and 3 (4.2%) had cANCA. Four patients with recurrent longitudinal extensive transverse myelitis (RLETM; 19.0%) had pANCA and 1 (4.8%) had cANCA. In monophasic TM, 22.9% were pANCA seropositive. Among patients with brainstem syndromes, 14.3% were pANCA seropositive. Patients with NMO, RLETM or monophasic TM had higher pANCA levels than patients with MS. There was a positive association between spinal cord (SC) lesions and ANCA, and especially between longitudinal extensive transverse myelitis and ANCA. Among anti-aquaporin 4 antibody-positive patients, ANCA-positive patients (n = 16) were older and had higher Expanded Disability Status Scale scores, more antinuclear antibodies, longer SC lesions and fewer brain abnormalities than the ANCA-negative patients (n = 68). In the NMO subgroup, ANCA-positive patients were older and had more antinuclear antibodies and longer SC lesions than ANCA-negative patients. Conclusion: Among the IIDDs, we found a higher occurrence of ANCA in patients with NMO spectrum disorders than in patients with MS. Therefore, ANCA is another interesting marker of autoimmunity in IIDD patients, especially those with anti-aquaporin 4 antibody.

Infective Endocarditis with Antineutrophil Cytoplasmic Antibody: Report of 13 Cases and Literature Review

ObjectiveChronic infections tend to induce the production of antineutrophil cytoplasmic antibody (ANCA). Infective endocarditis (IE) has been reported to exhibit positive ANCA tests and to mimic ANCA-associated vasculitis, which may lead to a misdiagnosis and inappropriate treatment. The aim of this study was to clarify whether there is any difference in the clinical features between ANCA-positive IE and ANCA-negative IE.MethodsA retrospective study was carried out on 39 IE patients whose proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA levels were measured. After dividing the patients into ANCA-positive and ANCA-negative IE, we compared their clinical features.Resultswe compared 13 ANCA-positive IE patients with 26 ANCA-negative IE patients. All 13 ANCA-positive IE patients were proteinase-3-ANCA positive. Compared with the ANCA-negative IE group, the prevalence of edema of the lower extremities, the serum lactate dehydrogenase (LDH) level and positive blood cultures rate were higher in ANCA-positive IE group, but there was no significant difference in other clinical features.ConclusionTherefore, if a patient presents with fever, arthralgia, skin rash and is ANCA-positive, appropriate steps should be taken to exclude infection (especially IE) before confirming the diagnosis of ANCA-associated vasculitis and embarking on long-term immunosuppressive therapy.

Diagnosis and classification of eosinophilic granulomatosis with polyangiitis (formerly named Churg–Strauss syndrome)

Recently, a group of experts in the field suggested to rename Churg–Strauss syndrome as eosinophilic granulomatosis with polyangiitis (EGPA). This condition, first described in 1951, is a rare small- and medium-sized–vessel vasculitis characterized by an almost constant association with asthma and eosinophilia, and, by the presence of anti-myeloperoxidase (MPO) antineutrophil cytoplasm antibodies (ANCA) in 30–38% of the patients. Vasculitis typically develops in a previously asthmatic and eosinophilic middle-aged patient. Asthma is severe, associated with eosinophilia and extrapulmonary symptoms. Most frequently EGPA involves the peripheral nerves and skin. Other organs, however, may be affected and must be screened for vasculitis, especially those associated with a poorer prognosis, such as the heart, kidney and gastrointestinal tract, as assessed by the recently revised Five-Factor Score (FFS). Recent insights, particularly concerning clinical differences associated with ANCA status, showed that EGPA patients might constitute a heterogeneous group. Thus, EGPA patients with anti-MPO ANCA suffered more, albeit not exclusively, from vasculitis symptoms, such as glomerulonephritis, mononeuritis multiplex and alveolar hemorrhage, whereas ANCA-negative patients more frequently develop heart involvement. This observation led to the hypothesis that EGPA might be divided into different clinical and pathophysiological subtypes, which could be managed better with more specifically adapted therapies.For now, EGPA treatment still relies mainly on corticosteroids and, when necessary for patients with poorer prognoses, combined immunosuppressant drugs, especially cyclophosphamide. Overall survival of EGPA patients is good, despite not uncommon relapses.

Anti-neutrophil cytoplasmic autoantibody pathogenicity revisited: pathogenic versus non-pathogenic anti-neutrophil cytoplasmic autoantibody

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is strongly associated with autoantibodies against myeloperoxidase (MPO) and proteinase 3 (PR3). No clear consensus has been reached on the pathogenicity of these autoantibodies. Animal models for MPO-ANCA, in vitro data suggesting pathogenicity of ANCA, and one case of a neonate showing symptoms of vasculitis after transplacental transfer of MPO, argue in favour of a pathogenic role for ANCA. On the other hand, the presence of natural MPO and PR3 autoantibodies in healthy individuals, lack of a strong correlation between ANCA titres and disease activity, and the occurrence of ANCA-negative AAV patients argue against pathogenicity of ANCA. Recent papers have drawn attention to the possibility of epitope specificity defining ANCA pathogenicity. Certain MPO epitopes were found to be specific for active disease, and others remained present during remission or were also present in healthy individuals. One linear epitope, aa447-459, was not only exclusive for active disease, but also detected in the total Ig fraction of ANCA-negative patients, reactivity being masked in serum by ceruloplasmin. So, not all ANCA seems to be equal, some could be pathogenic while others are not. For development of an autoimmune response, a specific ANCA repertoire is required, which may occur through intra-molecular epitope spreading in patients.

Cardiac involvement in eosinophilic granulomatosis with polyangitis (Churg Strauss) (RCD code: I-3A.7a)

Eosinophilic granulomatosis with polyangitis – EGPA (previously known as Churg‑Strauss syndrome) is a rare, systemic, necrotizing small‑vessel vasculitis with accompanying bronchial asthma, eosinophilia and eosinophilic tissue infiltration of various tissues with granuloma formation. The pathognomonic laboratory feature of EGPA is prominent peripheral eosinophilia that commonly exceed 1,500 cells/μl, and the presence in approximately 40% of patients of the antineutrophil autoantibodies (ANCA). EGPA is one of the most common of the systemic vasculitides to affect the heart and if present it deteriorates the prognosis of the disease and increases mortality. Cardiac involvement varies widely ranging from 16–92% and is more common in ANCA negative patients. The cardiac manifestations varies in its clinical presentation. It may present as myocarditis with cardiomyopathy, pericarditis with pericardial effusion (up to 25% of patients), heart failure (18%),varies ventricular and supraventricular arrhythmias, valve involvement and sudden cardiac death. Epicardial coronary arteries involvement is rare, however, coronary angiography should be considered in patients presenting with angina symptoms to rule out important coronary vessels stenosis. Imaging techniques as transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR) may help in establishing the diagnosis of EGPA. The significance of often detected cardiac damage in CMR without clinical manifestation remains uncertain, however, some preliminary studies suggest that, these patients should be treated more intensively to prevent further cardiac involvement. The main treatment of EGPA consist of corticosteroids and additional immunosuppression in patients with worse prognosis. In differential diagnosis other forms of vasculitides and hypereosinophilic syndromes (HES) that may also affect the heart should be excluded.

Autoantibodies to hLAMP-2 in ANCA-Negative Pauci-Immune Focal Necrotizing GN

Pauci-immune focal necrotizing GN (piFNGN) is usually associated with ANCAs that are thought to be pathogenic. However, 10%-15% of patients are ANCA negative and the cause of their injury is unknown. We previously reported a high frequency of autoantibodies to human lysosome-associated membrane protein-2 (hLAMP-2) in ANCA-associated piFNGN, and have now investigated whether the same is true in ANCA-negative patients. Of 11 patients, 8 (73%) had anti-hLAMP-2 antibodies detected by ELISA and confirmed by immunoblotting and indirect immunofluorescence. The autoantibodies from all 8 patients bound to native LAMP-2 purified from human glomeruli and recombinant hLAMP-2 expressed in ldlD cells, both with molecular masses of 110 kD. However, in contrast to anti-LAMP-2 antibodies from ANCA-positive patients, these antibodies from ANCA-negative patients failed to bind the more complexly glycosylated native neutrophil hLAMP-2 (190 kD). Treatment with the deglycosylating enzyme, endo-β-galactosidase, reduced the mass of neutrophil hLAMP-2 to 110 kD and enabled autoantibody binding. Similarly, pretreating neutrophils with endo-β-galactosidase or neuraminidase converted ANCA assay results from negative to positive. Finally, IgG from LAMP-2-positive ANCA-negative patients bound specifically to normal human kidney sections and to human glomerular endothelial cells in culture. In conclusion, in patients with ANCA-negative piFNGN, we have identified autoantibodies to hLAMP-2 that bind native glomerular but not neutrophil hLAMP-2, suggesting a role in pathogenesis.

The clinicopathologic characteristics of granulomatosis with polyangiitis (Wegener’s): a retrospective study of 45 patients in Korea

Objectives The aim of this study was to determine the clinicopathologic characteristics of granulomatosis with polyangiitis (Wegener’s) (GPA) in Korean patients.Methods The medical records of 45 patients with GPA treated in a single tertiary referral hospital were retrospectively analyzed with respect to clinical manifestations, including histology, ANCA positivity, disease stage, and disease activity. Patients were categorized into granulomatous, vasculitic, or mixed form based on an immunopathologic scoring system of granulomatous–vasculitic activity.Results Thirty-one patients (68.9 %) showed ANCA positivity (C-ANCA/P-ANCA, 42.2 %/20.0 %, proteinase-3 (PR3) ANCA/myeloperoxidase (MPO) ANCA, 44.1 %/16.1 %), and these patients (female 48.4 %) were found to be associated with a higher frequency of renal involvement (51.6 vs. 7.1 %, p = 0.004), elevated serum creatinine (29.0 vs. 0 %, p = 0.018), and higher mortality (29 vs. 7.1 %, p = 0.041) than ANCA-negative patients. Thirty-three patients (73.3 %, female 60.6 %) had the granulomatous form, whereas 8.9 and 17.8 % had the vasculitic and mixed forms, respectively. Patients with the granulomatous form were diagnosed earlier in their lives (mean age 51.2 vs. 62.3, p = 0.002) and had a lower frequency of renal involvement (21.2 vs. 100 %, p = 0.005) compared with those with the vasculitic form. Initial remission (69.7 vs. 25.0 %) and relapse (60.8 vs. 0 %) rates were higher for the granulomatous than for the vasculitic form.Conclusions Taken together, in Korean patients with GPA, the granulomatous form was predominant and associated with a younger age at diagnosis and a lower frequency of renal involvement than the vasculitic form. ANCA positivity was found in 68.9 % and associated with renal involvement and higher mortality.

FRI0250 Anca positivity in scleroderma patients identifies a poor prognosis: Myocarditis and survival

BackgroundPrevious studies have shown that about 7% of unselected systemic sclerosis (SSc) patients are positive for ANCA1. Some case reports have also described an ANCA–associated vasculitis in SSc patients with...