Antineutrophil Cytoplasm Research Articles

Maintenance with Rituximab in anti-neutrophil cytoplasm antibody vasculitis

Vessel Plus is an open acccess journal, which publishes articles related to vascular diseases, including acute respiratory distress syndrome, aneurysm, atherosclerosis, hypertension, stroke, peripheral vascular or pulmonary vascular diseases, etc.

P-ANCA POSITIVE GRANULOMATOSIS WITH POLYANGIITIS

SESSION TITLE: Medical Student/Resident Pulmonary Manifestations of Systemic Disease Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: It is challenging to diagnose ANCA associated vasculitis (AAV) and specify the subtype of AAV due to the overlap in symptoms and lab findings. Diagnosis can be supported by positive ANCA titer or a biopsy that confirms vasculitis present [2]. The typical ANCA pattern associated with GPA is c-ANCA. GPA is associated with P-ANCA (MPO positive) in less than 20% of the cases and approximately 10 % are ANCA negative [1] . Otorhinolaryngologic symptoms may be the initial clinical manifestation of GPA because the upper respiratory tract is involved in 70–100% of cases. Both patients of GPA and MPA can present with tracheal complications such as tracheal stenosis although it is more common in GPA. Glottic or supraglottic stenosis is a rare manifestation of AAV [1]. We present this rare case of p ANCA associated GPA presenting as stridor. CASE PRESENTATION: A 62-year-old female presented with cough, dyspnea, weight loss and tongue sores. She had significant stridor on physical exam. CT of the neck and soft tissues showed aryepiglottic edema, subglottic stenosis and pan sinus disease. Laryngoscopy in the ED and showed poor true vocal cord mobility. She then underwent tracheostomy, in addition to tongue biopsy. Direct laryngoscopy confirmed tight vocal cords, with no evidence of subglottic stenosis and normal arytenoids. Despite that the patient had increasing oxygen requirements. Her chest CT showed increased bilateral lung opacities. Bronchoscopy showed evidence of diffuse alveolar hemorrhage and granulomatous appearance of the trachea and the main stem bronchi. Work up for vasculitis was in process, while the tongue biopsy confirmed vascular inflammation and fibrinoid necrosis. later we had positive P-ANCA titer of >1:10240, MPO 25 AU/ML, negative PR3 and Anti GBM. she was started on pulse methylprednisolone and rituximab in addition to five sessions of plasmapheresis. DISCUSSION: GPA is distinguished from MPA by the absence of granulomas in the latter. Most involved organs are lungs, kidneys and ear, nose and throat. ENT involvement occurs in more than 50% of patients with AAV and can manifest as simple crusting, chronic sinusitis and rhinorrhea, to as severe as hearing loss or oral or nasal ulcers. Early diagnosis is crucial to prevent long term complications.[1] Tracheobronchial involvement is less common in GPA and would usually present as subglottic stenosis. [1], even rare is vocal cord paralysis. Our patient was diagnosed with AAV related vocal cord paralysis, which manifested as stridor. Severe active GPA can be treated with Glucocorticoids along with chemotherapeutic agents i.e cyclophosphamide or Rituximab infusion. Plasmapheresis is also helpful as it helps remove ANCA from the blood in addition to other inflammatory mediators [3]. CONCLUSIONS: Vocal cord paralysis is a rare presenting symptom for GPA, it is important to recognize it as early treatment affects the prognosis of the patient. Reference #1: 1.Greco A, Marinelli C, Fusconi M, et al. Clinic manifestations in granulomatosis with polyangiitis. Int J Immunopathol Pharmacol. 2016;29(2):151–159. doi:10.1177/0394632015617063 Reference #2: 2.Wojciechowska J, Krajewski W, Krajewski P, Kręcicki T. Granulomatosis With Polyangiitis in Otolaryngologist Practice: A Review of Current Knowledge. Clin Exp Otorhinolaryngol. 2016;9(1):8–13. doi:10.21053/ceo.2016.9.1.8 Reference #3: 3.Walsh M, Merkel PA, Peh CA, et al. Plasma exchange and glucocorticoid dosing in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis (PEXIVAS): protocol for a randomized controlled trial. Trials. 2013;14:73. Published 2013 Mar 14. doi:10.1186/1745-6215-14-73 DISCLOSURES: No relevant relationships by Reena Bansal, source=Web Response No relevant relationships by Lana Hasan, source=Web Response No relevant relationships by Rajani Jagana, source=Web Response No relevant relationships by Natalya Shlyakhova, source=Web Response

Environmental risk factors associated with ANCA associated vasculitis: A systematic mapping review.

Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a rare multi-system autoimmune disease, characterised by a pauci-immune necrotising small-vessel vasculitis, with a relapsing and remitting course. Like many autoimmune diseases, the exact aetiology of AAV, and the factors that influence relapse are unknown. Evidence suggests a complex interaction of polygenic genetic susceptibility, epigenetic influences and environmental triggers. This systematic mapping review focuses on the environmental risk factors associated with AAV. The aim was to identify gaps in the literature, thus informing further research. Articles that examined any environmental risk factor in AAV disease activity (new onset disease or relapse) were included. Studies had to make explicit reference to AAV, which includes the 3 clinico-pathological phenotypes (GPA, MPA and EGPA), rather than isolated ANCA-positivity. All articles identified were English-language, full manuscripts involving adult humans (>16 years). There was no restriction on publication date and all study designs, except single case reports, were included. The systematic search was performed on 9th December 2019, using the following databases: EMBASE, Medline (Ovid), Cochrane Library, CINAHL and Web of Science. The search yielded a total of 2375 articles. 307 duplicates were removed, resulting in the title and abstract of 2068 articles for screening. Of these, 1809 were excluded. Thus, 259 remained for full-text review, of which 181 were excluded. 78 articles were included in this review. The most notable findings support the role of various pollutants - primarily silica and other environmental antigens released during natural disasters and through farming. Assorted geoepidemiological triggers were also identified including seasonality and latitude-dependent factors such as UV radiation. Finally, infection was tightly associated, but the exact microorganism(s) is not clear - Staphylococcus aureus is the most presently convincing. The precise aetiology of AAV has yet to be elucidated. It is likely that different triggers, and the degree to which they influence disease activity, vary by subgroup (e.g. ANCA subtype, geographic region). There is a need for more interoperable disease registries to facilitate international collaboration and hence large-scale epidemiological studies, with novel analytical techniques.

CanVasc Consensus Recommendations for the Management of Antineutrophil Cytoplasm Antibody-associated Vasculitis: 2020 Update.

In 2015, the Canadian Vasculitis Research Network (CanVasc) created recommendations for the management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) in Canada. The current update aims to revise existing recommendations and create additional recommendations, as needed, based on a review of new available evidence. A needs assessment survey of CanVasc members informed questions for an updated systematic literature review (publications spanning May 2014 to September 2019) using Medline, Embase, and Cochrane. New and revised recommendations were developed and categorized according to the level of evidence and strength of each recommendation. The CanVasc working group used a 2-step modified Delphi procedure to reach > 80% consensus on the inclusion, wording, and grading of each new and revised recommendation. Eleven new and 16 revised recommendations were created and 12 original (2015) recommendations were retained. New and revised recommendations are discussed in detail within this document. Five original recommendations were removed, of which 4 were incorporated into the explanatory text. The supplementary material for practical use was revised to reflect the updated recommendations. The 2020 updated recommendations provide rheumatologists, nephrologists, and other specialists caring for patients with AAV in Canada with new management guidance, based on current evidence and consensus from Canadian experts.

2020 international consensus on ANCA testing beyond systemic vasculitis.

This document follows up on a 2017 revised international consensus on anti-neutrophil cytoplasm antibodies (ANCA) testing in granulomatosis with polyangiitis and microscopic polyangiitis and focuses on the clinical and diagnostic value of ANCA detection in patients with connective tissue diseases, idiopathic interstitial pneumonia, autoimmune liver diseases, inflammatory bowel diseases, anti-glomerular basement membrane (GBM) disease, infections, malignancy, and during drug treatment. Current evidence suggests that in certain settings beyond systemic vasculitis, ANCA may have clinical, pathogenic and/or diagnostic relevance. Antigen-specific ANCA targeting proteinase-3 and myeloperoxidase should be tested by solid phase immunoassays in any patient with clinical features suggesting ANCA-associated vasculitis and in all patients with anti-GBM disease, idiopathic interstitial pneumonia, and infective endocarditis associated with nephritis, whereas in patients with other aforementioned disorders routine ANCA testing is not recommended. Among patients with autoimmune liver diseases or inflammatory bowel diseases, ANCA testing may be justified in patients with suspected autoimmune hepatitis type 1 who do not have conventional autoantibodies or in case of diagnostic uncertainty to discriminate ulcerative colitis from Crohn's disease. In these cases, ANCA should be tested by indirect immunofluorescence as the target antigens are not yet well characterized. Many questions concerning the optimal use of ANCA testing in patients without ANCA-associated vasculitis remain to be answered.

Updates for the treatment of EGPA

Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg–Strauss syndrome) is the least frequent antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). Major advances of our knowledge on its pathophysiology have revealed features of both AAV and eosinophilic disorders. The development of targeted biotherapies for both diseases opened new possibilities for EGPA management. In this review, we highlight the rationale underlying the routine treatment strategy, which relies mainly on corticosteroids, with immunosuppressant adjunction for severe disease. However, novel therapies are still needed for refractory/relapsing disease and to alleviate the corticosteroid-dependence of asthma and chronic rhinosinusitis. At present, the most promising biotherapies target either eosinophil biology, like mepolizumab, an anti-interleukin-5, or the B-cell compartment, with rituximab. Recent clinical data on new treatment options are discussed and therapeutic strategies are proposed.

ANCA-associated vasculitides: Recommendations of the French Vasculitis Study Group on the use of immunosuppressants and biotherapies for remission induction and maintenance

Treatment of vasculitides associated with anti-neutrophil cytoplasm antibodies (ANCA) (AAVs) has evolved dramatically in recent years, particularly since the demonstration of rituximab efficacy as remission induction and maintenance therapy for granulomatosis with polyangiitis and microscopic polyangiitis. In 2013, the French Vasculitis Study Group (FVSG) published recommendations for its use by clinicians. Since then, new data have made it possible to better specify and codify prescription of rituximab to treat AAVs. Herein, the FVSG Recommendations Committee, an expert panel comprised of physicians with extensive experience in the treatment and management of vasculitides, presents its consensus guidelines based on literature analysis, the results of prospective therapeutic trials and personal experience.

International Consensus on ANCA Testing in Eosinophilic Granulomatosis with Polyangiitis.

An international consensus on anti-neutrophil cytoplasm antibodies (ANCA) testing in eosinophilic granulomatosis with polyangiitis (EGPA) is presented. ANCA, specific for myeloperoxidase (MPO), can be detected in 30-35% of EGPA patients. MPO-ANCA should be tested with antigen-specific immunoassays in any patient with eosinophilic asthma and clinical features suggesting EGPA, including constitutional symptoms, purpura, polyneuropathy, unexplained heart, gastrointestinal or kidney disease, and/or pulmonary infiltrates or hemorrhage. A positive MPO-ANCA result contributes to the diagnostic work‑up for EGPA. Patients with MPO-ANCA associated EGPA have more frequently vasculitis features, such as glomerulonephritis, neuropathy, and skin manifestations than patients with ANCA negative EGPA. However, the presence of MPO-ANCA is neither sensitive nor specific enough to identify whether a patient should be subclassified as having "vasculitic" or "eosinophilic" EGPA. At present, ANCA status cannot guide treatment decisions, that is, whether cyclophosphamide, rituximab or mepolizumab should be added to conventional glucocorticoid treatment. In EGPA, monitoring of ANCA is only useful when MPO-ANCA was tested positive at disease onset.

Urinary soluble CD163 as a biomarker of disease activity and relapse in antineutrophil cytoplasm antibody-associated glomerulonephritis.

BackgroundAntineutrophil cytoplasm antibody (ANCA)-associated vasculitis is a chronic relapsing and remitting autoimmune disease. Urinary soluble CD163 (usCD163) has been proposed as a biomarker of active renal vasculitis. We aimed to assess the potential usefulness of usCD163 for diagnosing renal relapse in patients with ANCA-associated glomerulonephritis.MethodsOne hundred and fifty-six samples from 47 patients with ANCA-associated glomerulonephritis belonging to two different cohorts (incident and prevalent) and 20 healthy controls were studied. Patients from the incident cohort were prospectively followed up, and usCD163 concentrations were measured every 3 months. Renal relapses were identified and changes in usCD163 concentrations were analysed.ResultsNormalized usCD163 concentrations were elevated at disease onset in all patients with active renal vasculitis, with a median concentration of 601 ng/mmol (interquartile range 221–1404 ng/mmol). On the other hand, usCD163 concentrations were undetectable among control patients with renal vasculitis in remission. Except for non-responders, usCD163 concentrations progressively decreased in all patients after treatment. In the presence of vasculitis relapse, there was a consistent increase in usCD163 concentrations, compared with previous values. The area under the receiver-operating characteristic curve of absolute and relative changes in usCD163 concentrations to identify relapse of ANCA-associated glomerulonephritis was 0.96 [95% confidence interval (CI) 0.91–1.00; P = 0.001] and 0.95 (95% CI 0.90–1.00; P = 0.001), respectively. Sensitivity and specificity for a relative increase of 20%, or an absolute increase of 20 ng/mmol, in usCD163 concentrations were 100% for both, and 89.3% and 87.5%, respectively. Urinary sCD163 concentrations significantly correlated with Birmingham Vasculitis Activity Score scores at Month 6 (r = 0.737; P = 0.006) and Month 12 (r = 0.804; P = 0.005).ConclusionsusCD163 represents an accurate biomarker for the detection of active renal vasculitis and relapse. Its close association with disease activity provides additional information for monitoring treatment response.

P0383A LONG-TERM RETROSPECTIVE OUTCOME ANALYSIS OF ANCA-NEGATIVE PAUCI-IMMUNE GLOMERULONEPHRITIS

Abstract Background and Aims Pauci-immune glomerulonephritis (GN), usually associated with circulating antineutrophil cytoplasm antibodies (ANCA), is one of the most common causes of rapidly progressive glomerulonephritis that results in high incidence of end-stage kidney disease (ESKD). Most of the existing large trials looking at treatment efficacies exclude ANCA-negative patients, and relatively few studies have reported their long-term outcomes. Therefore, we conducted a single-centre retrospective study to examine the long-term overall survival and renal outcome in this cohort of patients. Method All cases of newly diagnosed biopsy-proven pauci-immune GN from 2006 - 2019 were identified through a local histopathology database. Patients with negative anti-myeloperoxidase (MPO) and anti-proteinase-3 (PR3) serology were identified (ANCA-negative group) and comparisons made with the cohort of patients with positive serology (MPO/PR3 positive group). Patients with relapsing ANCA-GN, eosinophilic granulomatosis with polyangitis, other co-existing glomerulonephritis or missing data on induction therapy or outcome were excluded. Baseline demographics, initial serum creatinine (sCr), estimated glomerular filtration rate (eGFR), systemic involvement and histopathology features including percentage normal glomeruli, and interstitial fibrosis/tubular atrophy score of >25% were collected and compared. Kaplan Meier survival analysis was used to compare overall survival and end-stage kidney disease (ESKD) progression rate between the two groups. Results 178 patients were identified with a median follow-up of 44 months. 83 were female (47%) and median age was 62 years. 15 (8%) were ANCA-negative. 163 (92%) were MPO- and/or PR3-ANCA positive. There were no differences in baseline characteristics such as age, gender and proportion of patients with normal glomeruli <25% on initial histology. However, we observed a significantly higher proportion of patients with renal-limited vasculitis in the ANCA-negative group (67% vs 24% p=0.01) and more severe renal dysfunction at presentation (median sCr 309umol/L vs 204umol/L, p= 0.01). We also demonstrated a higher proportion of patients with an IFTA score of >25% on renal biopsy (53% with >25% IFTA in ANCA-negative cohort vs 27%, p =0.03). The ANCA-negative group were more likely to receive combination immunosuppressive therapy that included plasma exchange (47% vs 23%, p value 0.04). When considering overall survival there was significantly higher mortality (40% vs 16%, p value 0.009) and rate of progression to ESKD (53% vs 18%, p value 0.001) in the ANCA-negative group as a whole. When we compared patients with renal-limited vasculitis only however, there was no significant difference in either overall survival or rate of progression to ESKD (p=0.85 and 0.84 respectively). We found that ANCA-negative patients with systemic disease did still have significantly higher rates of both progression to ESKD and overall mortality (p=0.002 and p=0.02 respectively). Conclusion In our cohort, patients with ANCA-negative pauci-immune GN have poorer renal function and higher IFTA scores on biopsy at presentation perhaps reflecting delayed diagnosis due to a lack of diagnostic serology and the higher proportion of renal-limited disease in this subgroup. Despite intensive immunosuppressive therapy, this study observed overall higher treatment failure rates in ANCA-negative patients, largely in those with systemic disease. This possibly relates to a different underlying disease process. Larger, prospective studies are required to enhance understanding of the disease pathogenesis to allow optimal tailored treatment for these patients.

How COVID-19 Has Changed the Management of Glomerular Diseases.

A 26-year-old woman contacted our office asking for an urgent call back. She had a history of steroid-dependent and frequently relapsing minimal change disease, and calls like this usually meant her home dipsticks had turned positive. Instead, she reported that she had just tested positive for the

Microscopic polyangiitis: Clinical characteristics and long-term outcomes of 378 patients from the French Vasculitis Study Group Registry

ObjectiveTo describe characteristics and long-term outcomes of patients with microscopic polyangiitis (MPA), an antineutrophil cytoplasm antibody (ANCA)-associated small-vessel necrotizing vasculitis. MethodsMPA patients from the French Vasculitis Study Group Registry satisfying the European Medicines Agency algorithm were analyzed retrospectively. Characteristics at diagnosis, treatments, relapses and deaths were analyzed to identify factors predictive of death or relapse. ResultsBetween 1966 and 2017, 378 MPA patients (median age 63.7 years) were diagnosed and followed for a mean of 5.5 years. At diagnosis, the main clinical manifestations included renal involvement (74%), arthralgias (45%), skin (41%), lung (40%) and mononeuritis multiplex (32%), with less frequent alveolar hemorrhage (16%), cardiomyopathy (5%) and severe gastrointestinal signs (4%); mean serum creatinine was 217 μmol/L. ANCA were detected in 298/347 (86%) patients by immunofluorescence and/or enzyme-linked immunosorbent assay (ELISA). Among the 293 patients with available ELISA specificities, 272 (92.8%) recognized myeloperoxidase and 13 (4.4%) proteinase-3. During follow-up, 131 (34.7%) patients relapsed and 78 (20.6%) died, mainly from infections. Respective 5-year overall and relapse-free survival rates were 84.2% and 60.4%. Multivariable analyses retained age >65 years, creatinine >130 μmol/L, severe gastrointestinal involvement and mononeuritis multiplex as independent risk factors for death. Renal impairment was associated with a lower risk of relapse. ConclusionNon-renal manifestations and several risk factors for death or relapse were frequent in this nationwide cohort. While mortality was low, and mainly due to treatment-related complications, relapses remained frequent, suggesting that MPA management can be further improved.

Rituximab for maintenance of remission in ANCA-associated vasculitis: expert consensus guidelines-Executive summary.

© 2019 The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) encompasses three disease phenotypes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). Considerable improvements in therapy mean induction of remission occurs in most patients with AAV [1-4]. However, disease relapse continues to pose a burden to patients. Morbidity accrues with relapses through disease-related damage and adverse effects of therapies to manage these relapses, negatively impacting on quality of life [5]. Rituximab (RTX), a monoclonal antibody targeting CD20, leads to peripheral B cell depletion. This has been successfully trialled, and is licensed, for the induction and maintenance of remission in AAV [2, 3]. RTX is increasingly being used for the maintenance of remission in patients with AAV, to reduce the risk of relapse and its consequences [6]. Other commonly used agents that have been trialled for the maintenance of remission in AAV include azathioprine, methotrexate and mycophenolate [7-9]. The decision to select RTX for the maintenance of remission is multifactorial, including but not limited to, patient-related factors and preferences, previous treatment and response, consideration of the overall risk of relapse, and access to therapy. These guidelines have been developed by a group of physicians practising in the UK.

Clinical associations of renal involvement in ANCA-associated vasculitis.

Renal involvement in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis is associated with significant morbidity and higher mortality rates. This study examined clinical manifestations associated with renal involvement in ANCA-associated vasculitis within a large, international cross-sectional cohort. Univariate and multivariate analyses were performed to identify clinical factors associated with renal disease, which was defined as i) a serum-creatinine >30% above normal and a fall in creatinine-clearance >25%; or ii) haematuria attributable to active vasculitis. The study cohort include 1230 patients from 31 countries; 723 (58.8%) presented with renal involvement: microscopic polyangiitis (82.2%), granulomatosis with polyangiitis (58.6%), and eosinophilic granulomatosis with polyangiitis (26.4%). The following clinical and laboratory factors were more common among patients with renal disease: age (OR 1.01, 95% CI 1.01-1.02), fever (OR 1.97, 95% CI 1.35-2.88), fatigue (OR 1.55, 95% CI 1.14-2.10), weight loss (OR 1.62, 95% CI 1.23-2.12), polyarthritis (OR 1.39, 95% CI 1.02-1.89), petechiae/purpura (OR 1.47, 95% CI 1.06-2.05), pulmonary haemorrhage (OR 5.23, 95% CI 1.39-19.63), gastrointestinal symptoms (OR 2.19, 95% CI 1.34-3.58), seizures (OR 3.42, 95% CI 1.26-9.30), lower serum albumin (OR 2.42, 95% CI 1.64-3.57), higher CRP (OR 2.06, 95% CI 1.04-4.06), low serum C3 at baseline (OR 3.86, 95% CI 1.30-11.53), myeloperoxidase- (OR 7.97, 95% CI 2.74-23.20) and proteinase 3-ANCA (OR 3.40, 95% CI 1.22-9.50). The following clinical factors were less common among patients with renal disease: mononeuritis multiplex (OR 0.63, 95% CI 0.41-0.98), proptosis/exophthalmos (OR 0.19, 95% CI 0.06-0.59), nasal polyps (OR 0.32, 95% CI 0.19-0.55), septal defect/perforation (OR 0.29, 95% CI 0.14-0.60), respiratory distress/pulmonary fibrosis/asthma (OR 0.08, 95% CI 0.04-0.19), and wheeze/obstructive airway disease (OR 0.29, 95% CI 0.16-0.52). In this large international study, several clinical and laboratory factors were identified as associated with renal involvement in ANCA-associated vasculitis.

Associations and Outcomes Between Chronic Traumatic Encephalopathy and Vasculitis in Adult Patients.

Chronic traumatic encephalopathy (CTE) results from brain injuries and traumas due to accelerated impacts on the head. In severe cases, the diseases cause brain damage, given the head trauma. On the other hand, vasculitis occurs through antibodies that mistake protein vessels as foreign, hence fighting them and resulting in their damage. Examination is usually conducted through blood tests, with antibodies being identified in the antineutrophil cytoplasm. It is unfortunate that its devastating effects also affect the brain of a human, hence leading to dis-functioning. When vasculitis is left untreated, it results in multiple adverse effects on the human body and health both in the short term and in the long term. This study aims to bring to the awareness of neurosurgeons the associations between CTE and vasculitis. This study has proved that there is a close correlation between the progression of CTE and vasculitis. The inflammatory of the blood vessels, as witnessed in vasculitis, increases the risk factors for CTE. The scaling of the vessels and manifestation of different vasculitis conditions in active central nervous system cells results in the worsening of neurodegeneration of the CTE disease.

Spleen tyrosine kinase inhibition is an effective treatment for established vasculitis in a pre-clinical model

The anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) are a group of life-threatening multi-system diseases characterized by necrotising inflammation of small blood vessels and crescentic glomerulonephritis. ANCA are thought to play a direct pathogenic role. Previous studies have shown that spleen tyrosine kinase (SYK) is phosphorylated during ANCA-induced neutrophil activation in vitro. However, the role of SYK in vivo is unknown. Here, we studied its role in the pathogenesis of experimental autoimmune vasculitis, a pre-clinical model of myeloperoxidase-ANCA-induced pauci-immune systemic vasculitis in the Wistar Kyoto rat. Up-regulation of SYK expression in inflamed renal and pulmonary tissue during early autoimmune vasculitis was confirmed by immunohistochemical and transcript analysis. R406, the active metabolite of fostamatinib, a small molecule kinase inhibitor with high selectivity for SYK, inhibited ANCA-induced pro-inflammatory responses in rat leucocytes in vitro. In an in vivo study, treatment with fostamatinib for 14 days after disease onset resulted in rapid resolution of urinary abnormalities, significantly improved renal and pulmonary pathology, and preserved renal function. Short-term exposure to fostamatinib did not significantly affect circulating myeloperoxidase-ANCA levels, suggesting inhibition of ANCA-induced inflammatory mechanisms in vivo. Finally, SYK expression was demonstrated within inflammatory glomerular lesions in ANCA-associated glomerulonephritis in patients, particularly within CD68+ve monocytes/macrophages. Thus, our data indicate that SYK inhibition warrants clinical investigation in the treatment of AAV.

Relapses in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis: a retrospective study.

To investigate the activity of relapsing events (RE) and their mode of presentation in patients with anti-neutrophil cytoplasmic (ANCA)-associated vasculitis (AAV). Patients diagnosed with AAV between 1990 and 2015 experiencing at least one RE were investigated. The different organ involvements were registered during each RE. Presentation at initial onset (IO) and RE were compared. The Birmingham Vasculitis Activity Score was used to assess the activity. Ninety-nine patients were followed: 54 patients with 96 RE and 45 patients with none. The rate of RE was 53% with a median time of follow-up of 6.8 years. The mean time to first RE was 2.8 years. Thirty patients experienced one single RE, 15 had 2, 5 had 3, 2 had 4, and 2 had, respectively, 7 and 8. Fifty-five percent of RE had the same features as IO. Compared to IO, some clinical manifestations were less present: constitutional symptoms (29% vs 69%), ear-nose-throat (50% vs 76%), lung involvement (59% vs 76%), peripheral neuropathies (14% vs 24%), arthritis (7% vs 27%), kidney (25% vs 41%), and heart (4% vs 20%) (p < 0.001). Skin, eye, and bowel manifestations were not significantly less involved during RE. The mean Birmingham Vasculitis Activity Score at IO was 9.02 and 5.11 at relapse (p < 0.0001). Among the 96 RE, 46% had a new organ involvement compared to IO: none were life-threatening. Global activity of RE in AAV patients is lower than that of IO. Fewer organs are involved in relapses. RE turned out to begin with the same manifestations as IO in most cases.Key Points•First study looking into clinical characteristics of relapses including mostly granulomatosis with polyangiitis.•Around half of patients with AAV seemed to relapse in a similar way compared to the initial diagnosis.•The activity score during relapsing events is less important.

ANCA subclasses in IgG4-related disease and ANCA-associated vasculitis

Introduction IgG4-related disease (IgG4-RD) is a fibro-inflammatory condition characterized by fibrotic lesions with lymphoplasmacytic infiltration in one or more organs. Differential diagnosis from ANCA-associated vasculitis (AAV) can be difficult and AAV-IgG4-RD overlap has been reported. Anti-neutrophil cytoplasm antibodies (ANCA) are a hallmark of AAV and ANCA of IgG4 subclass have been detected in AAV-IgG4-RD overlap, but the role of IgG4 ANCA in differentiating AAV and IgG4-RD is presently unclear. Material and methods Anti-myeloperoxidase antibodies of each IgG subclass were detected by ELISA in 20 IgG4-RD ANCA-negative patients, in 35 ANCA-MPO+ AAV and in one AAV-IgG4-RD overlap patient. Results In the IgG4-RD cohort, 7 patients are positive for at least one ANCA-MPO subclass, but antibody amounts are very low compared to AAV. In the AAV-IgG4-RD overlap patient, only IgG2-ANCA and IgG3-ANCA are detected. AAV patients in the active phase of the disease present higher amounts of IgG4 ANCA-MPO; on the contrary, ANCA-MPO subclass-positive IgG4-RD patients do not display a higher disease activity. In AAV patients, co-expression of more than one ANCA-MPO subclass is associated with higher disease activity, while no such relation can be established in IgG4-RD. Conclusions Evaluation of ANCA subclasses does not help in phenotyping IgG4-RD patients. The lack of correlation with disease activity in IgG4-RD and the distribution of ANCA subclasses in the overlap patient suggest that ANCA-MPO do not play a major role in IgG4-RD.

Rituximab use in adult glomerulopathies and its rationale

Glomerulopathies are one of the leading causes of end-stage renal disease. In the last years, clinical research has made significant contributions to the understanding of such conditions. Recently, rituximab (RTX) has appeared as a reasonably safe treatment. The Kidney Disease: Improving Global Outcomes guidelines (KDIGO) recommended RTX only as initial treatment in antineutrophil cytoplasm antibody associated vasculitis (AAV) and in non-responders patients with lupus nephritis (LN), but these guidelines have not been updated since 2012. Nowadays, RTX seems to be at least as effective as other immunosuppressive regimens in idiopathic membranous nephropathy (IMN). In minimal-change disease, (MCD) this drug might allow a long-lasting remission period in steroid-dependent or frequently relapsing patients. Preliminary results support the use of RTX in patients with pure membranous LN and immunoglobulin-mediated membranoproliferative glomerulonephritis (MPGN), but not in patients with class III/IV LN or complement-mediated MPGN. No conclusion can be drawn in idiopathic focal segmental glomerulosclerosis (FSGS) and anti-glomerular basement membrane antibody glomerulonephritis (anti-GBM GN) because studies are small, heterogeneous, and scarce. Lastly, immunosuppression including RTX is not particularly useful in IgA nephropathy. This review presents the general background, outcomes, and safety for RTX treatment in different glomerulopathies. In this regard, we describe randomized controlled trials (RCTs) performed in adults, whenever possible. A literature search was performed using clinicaltrials.gov and PubMed.

Childhood GPA, EGPA, and MPA

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a term used to describe rare primary systemic vasculitides affecting small and medium-sized blood vessels. AAV diseases which include Granulomatosis with Polyangiitis (GPA), Eosinophilic Granulomatosis with Polyangiitis (EGPA), Microscopic Polyangiitis (MPA) and renal limited ANCA vasculitis. These multisystemic disorders involve upper and lower respiratory tract and kidneys associated with organ damage and long term sequelae. Newer understanding of pathogenesis in AAV have paved the way for clinical research with different biologic therapies. In spite of the paucity of clinical trials in pediatric AAV, the long-term survival of patients with AAV has improved dramatically. International collaborations will help to conduct clinical trials in pediatric AAV and help in better understanding of remission rates, relapse rates, and other outcomes. This article aims to provide a comprehensive review of pediatric AAV with a focus on epidemiology, disease pathogenesis, treatment trials, and prognosis.