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Objectives Diagnosing patients with ANCA-associated vasculitis (AAV) can be challenging owing to its rarity and complexity. Diagnostic delay can have severe consequences, such as chronic organ damage or even death. Given that few studies have addressed diagnostic pathways to identify opportunities to improve, we performed a clinical audit to evaluate the diagnostic phase. Methods This retrospective, observational study of electronic medical records data in hospitals focused on diagnostic procedures during the first assessment until diagnosis. Results We included 230 AAV patients from nine hospitals. First assessments were mainly performed by a specialist in internal medicine (52%), pulmonology (14%), ENT (13%) or rheumatology (10%). The overall median time to diagnosis was 13 [interquartile range: 2–49] days, and in patients primarily examined by a specialist in internal medicine it was 6 [1–25] days, rheumatology 14 [4–45] days, pulmonology 15 [5–70] days and ENT 57 [16–176] days (P = 0.004). Twenty-two of 31 (71%) patients primarily assessed by a specialist in ENT had non-generalized disease, of whom 14 (64%) had ENT-limited activity. Two hundred and nineteen biopsies were performed in 187 patients (81%). Histopathological support for AAV was observed in 86% of kidney biopsies, 64% of lung biopsies and 34% of ENT biopsies. Conclusion In The Netherlands, AAV is diagnosed and managed predominantly by internal medicine specialists. Diagnostic delay was associated with non-generalized disease and ENT involvement at presentation. Additionally, ENT biopsies had a low diagnostic yield, in contrast to kidney and lung biopsies. Awareness of this should lead to more frequent consideration of AAV and early referral for a multidisciplinary approach when AAV is suspected.

The introduction of immunosuppressive therapy for ANCA-associated vasculitis (AAV) has greatly improved outcomes, though patients now accumulate damage from vasculitis activity and adverse effects of treatment. Prediction of treatment outcomes using gene variants might help reduce this damage by allowing for personalized treatment. Several studies have studied genetic polymorphisms in relation to treatment outcomes of AAV. This review gives an overview of these studies, discussing both gene polymorphisms associated with inflammatory pathways (potentially influencing disease outcomes such as activity, severity, and relapse risk) and pharmacogenetics (potentially influencing drug metabolism and/or drug response). Subsequently, potential benefits of testing genetic variants for AAV and the steps needed for its implementation in clinical practice are discussed. The conclusion of this review is that measurement of most polymorphisms is currently not indicated in clinical practice.

Introduction: Despite the availability of several guidelines on the diagnosis and treatment of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), clinical routine practice will only improve when an implementation strategy is in place to support clinical decision making and adequate implementation of guidelines. We describe here an initiative to establish national and multidisciplinary consensus on broad aspects of the diagnosis and treatment of AAV relevant to daily clinical practice in the Netherlands.Methods: A multidisciplinary working group of physicians in the Netherlands with expertise on AAV addressed the broad spectrum of diagnosis, terminology, and immunosuppressive and non-immunosuppressive treatment, including an algorithm for AAV patients. Based on recommendations from (inter)national guidelines, national consensus was established using a Delphi-based method during a conference in conjunction with a nationally distributed online consensus survey. Cut-off for consensus was 70% (dis)agreement.Results: Ninety-eight professionals were involved in the Delphi procedure to assess consensus on 5o statements regarding diagnosis, treatment, and organisation of care for AAV patients. Consensus was achieved for 37/50 statements (74%) in different domains of diagnosis and treatment of AAV including consensus on the treatment algorithm for AAV.Conclusion: We present a national, multidisciplinary consensus on a diagnostic strategy and treatment algorithm for AAV patients as part of the implementation of (inter)national guideline-derived recommendations in the Netherlands. Future studies will focus on evaluating local implementation of treatment protocols for AAV, and assessments of current and future clinical practice variation in the care for AAV patients in the Netherlands.

INTRODUCTION: Despite the availability of several guidelines on the diagnosis and treatment of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), clinical routine practice will only improve when an implementation strategy is in place to support clinical decision making and adequate implementation of guidelines. We describe here an initiative to establish national and multidisciplinary consensus on broad aspects of the diagnosis and treatment of AAV relevant to daily clinical practice in the Netherlands. METHODS: A multidisciplinary working group of physicians in the Netherlands with expertise on AAV addressed the broad spectrum of diagnosis, terminology, and immunosuppressive and non-immunosuppressive treatment, including an algorithm for AAV patients. Based on recommendations from (inter)national guidelines, national consensus was established using a Delphi-based method during a conference in conjunction with a nationally distributed online consensus survey. Cut-off for consensus was 70% (dis)agreement. RESULTS: Ninety-eight professionals were involved in the Delphi procedure to assess consensus on 50 statements regarding diagnosis, treatment, and organisation of care for AAV patients. Consensus was achieved for 37/50 statements (74%) in different domains of diagnosis and treatment of AAV including consensus on the treatment algorithm for AAV. CONCLUSION: We present a national, multidisciplinary consensus on a diagnostic strategy and treatment algorithm for AAV patients as part of the implementation of (inter)national guideline-derived recommendations in the Netherlands. Future studies will focus on evaluating local implementation of treatment protocols for AAV, and assessments of current and future clinical practice variation in the care for AAV patients in the Netherlands.

BACKGROUND Little is known about the autoreactive B cells in antineutrophil cytoplasmic antibody–associated (ANCA-associated) vasculitis (AAV). We aimed to investigate tolerance checkpoints of circulating antigen-specific proteinase 3–reactive (PR3+) B cells. METHODS Multicolor flow cytometry in combination with bioinformatics and functional in vitro studies were performed on baseline samples of PBMCs from 154 well-characterized participants of the RAVE trial (NCT00104299) with severely active PR3-AAV and myeloperoxidase-AAV (MPO-AAV) and 27 healthy controls (HCs). Clinical data and outcomes from the trial were correlated with PR3+ B cells (total and subsets). RESULTS The frequency of PR3+ B cells among circulating B cells was higher in participants with PR3-AAV (4.77% median [IQR, 3.98%–6.01%]) than in participants with MPO-AAV (3.16% median [IQR, 2.51%–5.22%]) and participants with AAV compared with HCs (1.67% median [IQR, 1.27%–2.16%], P < 0.001 for all comparisons), implying a defective central tolerance checkpoint in patients with AAV. Only PBMCs from participants with PR3-AAV contained PR3+ B cells capable of secreting PR3-ANCA IgG in vitro, proving they were functionally distinct from those of participants with MPO-AAV and HCs. Unsupervised clustering identified subtle subsets of atypical autoreactive PR3+ memory B cells accumulating through the maturation process in patients with PR3-AAV. PR3+ B cells were enriched in the memory B cell compartment of participants with PR3-AAV and were associated with higher serum CXCL13 levels, suggesting an increased germinal center activity. PR3+ B cells correlated with systemic inflammation (C-reactive protein and erythrocyte sedimentation rate, P < 0.05) and complete remission (P < 0.001). CONCLUSION This study suggests the presence of defective central antigen-independent and peripheral antigen-dependent checkpoints in patients with PR3-AAV, elucidating the selection process of autoreactive B cells. Trial registration ClinicalTrials.gov NCT00104299. Funding The Vasculitis Foundation, the National Institute of Allergy and Infectious Diseases of the NIH, and the Mayo Foundation for Education and Research.

Objective Improved biomarkers of current disease activity and prediction of relapse are needed in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). For clinical relevance, biomarkers must perform well longitudinally in patients on treatment and in patients with nonsevere flares. Methods Twenty-two proteins were measured in 347 serum samples from 74 patients with AAV enrolled in a clinical trial. Samples were collected at Month 6 after remission induction, then every 3 months until Month 18, or at the time of flare. Associations of protein concentrations with concurrent disease activity and with future flare were analyzed using mixed-effects models, Cox proportional hazards models, and conditional logistic regression. Results Forty-two patients had flares during the 12-month follow-up period, and 32 remained in remission. Twenty-two patients had severe flares. Six experimental markers (CXCL13, IL-6, IL-8, IL-15, IL-18BP, and matrix metalloproteinase-3 [MMP-3]) and ESR were associated with disease activity using all three methods (P < 0.05, with P < 0.01 in at least one method). A rise in IL-8, IL-15, or IL-18BP was associated temporally with flare. Combining C-reactive protein (CRP), IL-18BP, neutrophil gelatinase-associated lipocalin (NGAL), and sIL-2R alpha improved association with active AAV. CXCL13 and MMP-3 were increased during treatment with prednisone, independent of disease activity. Marker concentrations during remission were not predictive of future flare. Conclusion Serum biomarkers of inflammation and tissue damage and repair have been previously shown to be strongly associated with severe active AAV were less strongly associated with active AAV in a longitudinal study that included mild flares and varying treatment. Markers rising contemporaneously with flare or with an improved association in combination merit further study.

Objective To assess the frequency of venous thromboembolism (VTE) events in the Rituximab in Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (RAVE) trial and identify novel potential risk factors. Methods VTE events in 197 patients enrolled in the RAVE trial were analyzed. Baseline demographic and clinical characteristics were recorded, and univariate and multivariate analyses were performed to identify factors associated with VTE in ANCA-associated vasculitis (AAV). Results VTE occurred in 16 patients (8.1%) with an overall average time to event of 1.5 months (range 1.0-2.75). In univariate analyses with calculation of hazard ratios (HRs) and 95% confidence intervals (95% CIs), heart involvement (HR 17.408 [95% CI 2.247-134.842]; P = 0.006), positive proteinase 3 (PR3)-ANCA (HR 7.731 [95% CI 1.021-58.545]; P = 0.048), pulmonary hemorrhage (HR 3.889 [95% CI 1.448-10.448]; P = 0.008), and the presence of red blood cell casts (HR 15.617 [95% CI 3.491-69.854]; P

Background. Early detection of renal involvement in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is of major clinical importance to allow prompt initiation of treatment and limit renal damage. Urinary soluble cluster of differentiation 163 (usCD163) has recently been identified as a potential biomarker for active renal vasculitis. However, a significant number of patients with active renal vasculitis test negative using usCD163. We therefore studied whether soluble CD25 (sCD25), a T cell activation marker, could improve the detection of renal flares in AAV.Methods. sCD25 and sCD163 levels in serum and urine were measured by enzyme-linked immunosorbent assay in 72 patients with active renal AAV, 20 with active extrarenal disease, 62 patients in remission and 18 healthy controls. Urinary and blood CD4(+) T and CD4(+) T effector memory (TEM) cell counts were measured in 22 patients with active renal vasculitis. Receiver operating characteristics (ROC) curves were generated and recursive partitioning was used to calculate whether usCD25 and serumsoluble CD25 (ssCD25) add utility to usCD163.Results. usCD25, ssCD25 and usCD163 levels were significantly higher during active renal disease and significantly decreased after induction of remission. A combination of usCD25, usCD163 and ssCD25 outperformed all individual markers (sensitivity 84.7%, specificity 95.1%). Patients positive for sCD25 but negative for usCD163 (n = 10) had significantly higher C-reactive protein levels and significantly lower serum creatinine and proteinuria levels compared with the usCD163positive patients. usCD25 correlated positively with urinary CD4(+) T and CD4(+) TEM cell numbers, whereas ssCD25 correlated negatively with circulating CD4(+) T and CD4+ TEMcells.Conclusion. Measurement of usCD25 and ssCD25 complements usCD163 in the detection of active renal vasculitis.

Anti-neutrophil cytoplasmic antibodies (ANCA) are a group of autoantibodies, predominantly IgG, involved in the pathogenesis of several autoimmune disorders, detected either through indirect immunofluorescence or enzyme-linked immunosorbent assay. By means of indirect immunofluorescence, the main patterns are C-ANCA (cytoplasmic) and P-ANCA (perinuclear), while proteinase 3 (PR3) and myeloperoxidase (MPO) represent the main autoantigens in granulomatosis with polyangiitis and microscopic polyangiitis, both belonging to the family of ANCA-associated vasculitis (AAV). While several experiments established the pathogenicity of MPO-ANCA, evidence remains elusive for PR3-ANCA and an additional target antigen, i.e. LAMP2, has been postulated with specific clinical relevance. The presence of a subset of AAV without ANCA may be explained by the presence of further target antigens or the presence of molecules in blood which make ANCA undetectable. A rise in ANCA titers is not necessarily predictive of a flare of disease in AAV if not accompanied by clinical manifestations. ANCA may develop through variable mechanisms, such as autoantigen complementarity, apoptosis impairment, neutrophil extracellular traps dysfunction and molecular mimicry. We will provide herein a comprehensive review of the available evidence on the biological mechanisms, pathogenetic role, and clinical implications of ANCA testing and disease management. Further, we will address the remaining open challenges in the field, including the role of ANCA in inflammatory bowel disease and in cocaine-induced vasculitis.

Anti-neutrophil cytoplasmic antibodies (ANCA) are a group of autoantibodies, predominantly IgG, involved in the pathogenesis of several autoimmune disorders, detected either through indirect immunofluorescence or enzyme-linked immunosorbent assay. By means of indirect immunofluorescence, the main patterns are C-ANCA (cytoplasmic) and P-ANCA (perinuclear), while proteinase 3 (PR3) and myeloperoxidase (MPO) represent the main autoantigens in granulomatosis with polyangiitis and microscopic polyangiitis, both belonging to the family of ANCA-associated vasculitis (AAV). While several experiments established the pathogenicity of MPO-ANCA, evidence remains elusive for PR3-ANCA and an additional target antigen, i.e. LAMP2, has been postulated with specific clinical relevance. The presence of a subset of AAV without ANCA may be explained by the presence of further target antigens or the presence of molecules in blood which make ANCA undetectable. A rise in ANCA titers is not necessarily predictive of a flare of disease in AAV if not accompanied by clinical manifestations. ANCA may develop through variable mechanisms, such as autoantigen complementarity, apoptosis impairment, neutrophil extracellular traps dysfunction and molecular mimicry. We will provide herein a comprehensive review of the available evidence on the biological mechanisms, pathogenetic role, and clinical implications of ANCA testing and disease management. Further, we will address the remaining open challenges in the field, including the role of ANCA in inflammatory bowel disease and in cocaine-induced vasculitis.

The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a group of disorders involving severe, systemic, small-vessel vasculitis and are characterized by the development of autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). The three AAV subgroups, namely granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophilic GPA (EGPA), are defined according to clinical features. However, genetic and other clinical findings suggest that these clinical syndromes may be better classified as PR3-positive AAV (PR3-AAV), MPO-positive AAV (MPO-AAV) and, for EGPA, by the presence or absence of ANCA (ANCA+ or ANCA–, respectively). Although any tissue can be involved in AAV, the upper and lower respiratory tract and kidneys are most commonly and severely affected. AAVs have a complex and unique pathogenesis, with evidence for a loss of tolerance to neutrophil proteins, which leads to ANCA-mediated neutrophil activation, recruitment and injury, with effector T cells also involved. Without therapy, prognosis is poor but treatments, typically immunosuppressants, have improved survival, albeit with considerable morbidity from glucocorticoids and other immunosuppressive medications. Current challenges include improving the measures of disease activity and risk of relapse, uncertainty about optimal therapy duration and a need for targeted therapies with fewer adverse effects. Meeting these challenges requires a more detailed knowledge of the fundamental biology of AAV as well as cooperative international research and clinical trials with meaningful input from patients.

Introduction: Despite the availability of several guidelines on the diagnosis and treatment of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), clinical routine practice will only improve when an implementation strategy is in place to support clinical decision making and adequate implementation of guidelines. We describe here an initiative to establish national and multidis-ciplinary consensus on broad aspects of the diagnosis and treatment of AAV relevant to daily clinical practice in the Netherlands. Methods: A multidisciplinary working group of physicians in the Netherlands with expertise on AAV addressed the broad spectrum of diagnosis, terminology, and immunosuppressive and non-immunosuppressive treatment, including an algorithm for AAV patients. Based on recommendations from (inter)national guidelines, national consensus was established using a Delphi-based method during a conference in conjunction with a nationally distributed online consensus survey. Cut-off for consensus was 70% (dis)agreement. Results: Ninety-eight professionals were involved in the Delphi procedure to assess consensus on 50 statements regarding diagnosis, treatment, and organisation of care for AAV patients. Consensus was achieved for 37/50 statements (74%) in different domains of diagnosis and treatment of AAV including consensus on the treatment algorithm for AAV. Conclusion: We present a national, multidisciplinary consensus on a diagnostic strategy and treatment algorithm for AAV patients as part of the implementation of (inter)national guideline-derived recommendations in the Netherlands. Future studies will focus on evaluating local implementation of treatment protocols for AAV, and assessments of current and future clinical practice variation in the care for AAV patients in the Netherlands.

Correction: Volume: 10 Issue: 1 Article Number: 38 DOI: 10.1186/s13601-020-00343-w Published: SEP 28 2020 Because of the inflammatory mechanisms of most chronic upper airway diseases such as rhinitis and chronic rhinosinusitis, systemic steroids have been used for their treatment for decades. However, it has been very well documented that-potentially severe-side-effects can occur with the accumulation of systemic steroid courses over the years. A consensus document summarizing the benefits of systemic steroids for each upper airway disease type, as well as highlighting the potential harms of this treatment is currently lacking. Therefore, a panel of international experts in the field of Rhinology reviewed the available literature with the aim of providing recommendations for the use of systemic steroids in treating upper airway disease.

Objectives: The activation and inhibition of T-cells has been well-studied under physiological conditions. Co-inhibition is an important mechanism to keep effector T-cells in check. Co-inhibitors mediate peripheral self-tolerance and limit the immune response. Dysfunctional co-inhibition is associated with loss of T-cell regulation and induction of autoimmunity. Therefore, we investigated the co-inhibitor B- and T-Lymphocyte attenuator (BTLA) in ANCA-associated vasculitis (AAV). Methods: Fifty-six AAV patients and 32 healthy controls (HC) were recruited. Flow cytometry was performed to investigate the expression of BTLA on T-cells. Double negative T-cells were defined as CD3(+)CD4(-)CD8(-). To assess the functionality of BTLA, CFSE-labeled T-cells were stimulated in presence or absence of an agonistic anti-BTLA antibody. In addition, impact of BTLA-mediated co-inhibition on Th17 cells was studied. Results: AAV patients in remission had a decreased expression of BTLA on double negative T-cells (CD3(+)CD4(-)CD8(-)). On all other subtypes of T-cells, expression of BTLA was comparable to healthy controls. TCR-independent stimulation of T-cells resulted in down-regulation of BTLA on Th cells in AAV and HC, being significantly lower in HC. Co-inhibition via BTLA led to suppression of T-cell proliferation in AAV as well as in HC. As a result of BTLA mediated co-inhibition, Th17 cells were suppressed to the same extent in AAV and HC. Conclusion: BTLA expression is altered on double negative T-cells but not on other T-cell subsets in quiescent AAV. BTLA-induced co-inhibition has the capacity to suppress Th17 cells and is functional in AAV. Thus, BTLA-mediated co-inhibition might be exploited for future targeted therapies in AAV.

ANCA-associated vasculitis (AAV) is characterized by inflammation and destruction of small and medium-sized vessels. Current management strategies for AAV have been validated in large groups of patients. However, recent insights indicate that distinct patient subsets may actually exist within AAV, thereby justifying the development of more personalized treatment strategies. In this review, we discuss current evidence for a better classification of AAV based on ANCA type. We describe how thus defined categories of AAV patients may differ in genetic background, clinical presentation, immune pathology, response to treatment and disease outcome. We also explore how these insights may provide a rationale for targeted treatments in different categories of AAV patients. Finally, we provide recommendations on how to further establish precision medicine in AAV.

Purpose of review In antineutrophil cytoplasmic antibodies-associated vasculitis (AAV), the treatment of choice is either Rituximab or cyclophosphamide in combination with steroids. In less extended forms of AAV, however, less toxic regimens are being used.In the current review, we will focus on the role of one of these less toxic regimens, that is trimethoprim-sulfamethoxazole monotherapy as induction treatment or as maintenance therapy in AAV. Recent findings A substantial portion of patients with active granulomatosis with polyangiitis (GPA) limited to the upper airways can be initially controlled with trimethoprim-sulfamethoxazole (2 x 960 mg/day) monotherapy. In patients with initially a complete response, long-term control of the disease seems possible. In addition, trimethoprim-sulfamethoxazole (2 x 960 mg/day) maintenance therapy is an option for patients with GPA that have been proven to be frequent relapsers. The mechanism by which trimethoprim-sulfamethoxazole works in GPA is at present unknown. Suppression of Staphylococcus aureus carriage and/or anti-inflammatory mechanisms has been postulated. Summary Trimethoprim-sulfamethoxazole may be considered as a safe initial treatment in GPA patients with disease localized to the ear, nose, and throat region. Furthermore, trimethoprim-sulfamethoxazole in a dose of 2x960mg/day may be used to prevent relapses in GPA.

Background: Cardiovascular diseases (CVD) are the major causes of death in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) during long-term follow-up. This study investigated risk factors for cardiovascular events (CVE) and CVD-related mortality in Chinese AAV patients.Methods: Five hundred and four AAV patients in our center were retrospectively included. The predictive value of variables associated with CVE- and CVD-related mortality were analyzed.Results: During follow-up of a median duration of 38 (range 1-228) months, 117 out of 504 patients had CVE. Independent predictors of CVE were age [increase by 10 years, hazard ratio (HR) 1.436, 95% confidence interval (CI) 1.187-1.736, p = 0.000], systolic blood pressure (increase by 10 mmHg, HR = 1.171, 95% CI: 1.038-1.321, p = 0.010), estimated glomerular filtration rate (eGFR) (increase by 1 mL/min/1.73 m(2), HR = 0.992, 95% CI: 0.984-0.999, p = 0.020), high-density lipoprotein level (HR = 0.530, 95% CI: 0.303-0.926, p = 0.026) and the Birmingham Vasculitis Activity Score (BVAS) (HR = 1.039, 95% CI: 1.011-1.067, p = 0.006). Forty-one patients died from CVD. Independent predictors of CVD-related mortality were age (increase by 10 years; HR = 1.732, 95% CI: 1.237-2.426, p = 0.001), eGFR (increase by 1 mL/min/1.73 m(2), HR = 0.984, 95% CI: 0.970-0.997, p = 0.016), pre-existing CV disease (HR = 2.872, 95% CI: 1.503-5.487, p = 0.001) and BVAS (HR = 1.064, 95% CI: 1.018-1.113, p = 0.006). We further analyzed CVE- and CVD-related mortality after 2 years since diagnosis, and found BVAS were still an independent predictor of CVE- and CVD-related mortality.Conclusion: Besides the traditional risk factors, BVAS at presentation was an independent predictor of CVE- and CVD-related mortality in patients with AAV. (C) 2018 Published by Elsevier Inc.

Systemic vasculitides (SVs) is a group of diseases characterised by inflammation/necrosis of the blood vessel wall in various organs. Simultaneous brain and heart involvement is a cause of increased morbidity/mortality in SV. We aimed to present evidence of concurrent brain/heart involvement in SV and the role of a combined brain/heart magnetic resonance imaging (MRI) in their risk stratification. Cerebral vasculitis (CV) can be presented as focal deficits, seizures, headache, neuropsychiatric manifestations or cognitive dysfunction and cardiovascular disease (CVD) as myocardial/vascular inflammation, perfusion/function defects and fibrosis. MRI is a non-invasive, non-radiating technique that allows the reliable identification of intraparenchymal brain lesions and the detection of myocardial/vascular inflammation and fibrosis. However, its use in SV is currently hampered by high cost, lack of availability/expertise and lack of awareness among the clinicians. Although there are no clinical data supporting the combined use of brain/heart MRI in asymptomatic SV, it would be called for in cases with clinical suspicion of brain/heart involvement, especially in those at high risk for CVD/stroke such as SLE/APS. Furthermore, it may be of value in SV with multi-organ involvement, cognitive dysfunction or other neuropsychiatric symptoms with concurrent cardiac involvement, presenting as typical or atypical symptoms with normal routine cardiac evaluation, new onset of arrhythmia and/or HF.

Systemic vasculitides (SVs) is a group of diseases characterised by inflammation/necrosis of the blood vessel wall in various organs. Simultaneous brain and heart involvement is a cause of increased morbidity/mortality in SV. We aimed to present evidence of concurrent brain/heart involvement in SV and the role of a combined brain/heart magnetic resonance imaging (MRI) in their risk stratification. Cerebral vasculitis (CV) can be presented as focal deficits, seizures, headache, neuropsychiatric manifestations or cognitive dysfunction and cardiovascular disease (CVD) as myocardial/vascular inflammation, perfusion/function defects and fibrosis. MRI is a non-invasive, non-radiating technique that allows the reliable identification of intraparenchymal brain lesions and the detection of myocardial/vascular inflammation and fibrosis. However, its use in SV is currently hampered by high cost, lack of availability/expertise and lack of awareness among the clinicians. Although there are no clinical data supporting the combined use of brain/heart MRI in asymptomatic SV, it would be called for in cases with clinical suspicion of brain/heart involvement, especially in those at high risk for CVD/stroke such as SLE/APS. Furthermore, it may be of value in SV with multi-organ involvement, cognitive dysfunction or other neuropsychiatric symptoms with concurrent cardiac involvement, presenting as typical or atypical symptoms with normal routine cardiac evaluation, new onset of arrhythmia and/or HF.

Previous studies have suggested an increased risk for cardiovascular events in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). We analyzed the presence of atherosclerotic damage in patients with AAV in relation to the presence of CD4(+)CD28(null) T cells and antibodies against cytomegalovirus (CMV) and human Heat-Shock Protein 60 (hHSP60). In this cross-sectional study, patients with inactive AAV were compared with healthy controls (HC). Carotid intima-media thickness (IMT) and aortic pulse-wave velocity (PWV) were measured. In addition, CD4(+)CD28(null) T cells, anti-CMV, and anti-hHSP60 levels were determined. Forty patients with AAV were included. Patients' spouses were recruited as HC (N = 38). CD4(+)CD28(null) T cells are present in patients with AAV in a higher percentage (median 3.1, range 0.01-85) than in HC (0.28, 0-36, P

Summary Anti-neutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). However, ANCA alone are not sufficient to generate disease, and some evidence suggests that infectious triggers may serve as inciting events for AAV disease activity. Antibodies of the immunoglobulin (Ig)M isotype often serve as markers of recent infection, and IgM ANCA have been identified previously in patients with AAV, although the frequency and clinical relevance of IgM ANCA is not well established. We sought to characterize IgM ANCA more clearly by creating a novel enzyme-linked immunosorbent assay (ELISA) for IgM antibodies to proteinase 3 [IgM proteinase 3 (PR3)–ANCA], which we applied to two large, clinically well-characterized trial cohorts of patients with granulomatosis with polyangiitis and microscopic polyangiitis. In the first cohort, IgM PR3–ANCA occurred with a frequency of 15·0%, and were associated with a higher degree of disease severity and a trend towards a higher rate of alveolar haemorrhage (29·6 versus 15·7%, P = 0·10). Analysis of follow-up samples in this cohort showed that the presence of IgM PR3–ANCA was transient, but could recur. In the second cohort, IgM PR3–ANCA occurred with a frequency of 41·1%, and were also associated with a higher degree of disease severity. A higher rate of alveolar haemorrhage was observed among those with IgM PR3–ANCA (45·3 versus 15·8%; P

ObjectiveThis multicentre study was performed to evaluate the diagnostic accuracy of a wide spectrum of novel technologies nowadays available for detection of myeloperoxidase (MPO) and proteinase 3 (PR3)-antineutrophil cytoplasmic antibodies (ANCAs).MethodsSera (obtained at the time of diagnosis) from 251 patients with ANCA-associated vasculitis (AAV), including granulomatosis with polyangiitis and microscopic polyangiitis, and from 924 disease controls were tested for the presence of cytoplasmic pattern/perinuclear pattern and atypical ANCA (A-ANCA) by indirect immunofluorescence (IIF) (at two sites) and for the presence of PR3-ANCA and MPO-ANCA by eight different immunoassays.ResultsThe area under the curve (AUC) of the receiver operating characteristic curve to discriminate AAV from controls was 0.923 (95% CI 0.902 to 0.944) and 0.843 (95% CI 0.814 to 0.871) for the two IIF methods. For the antigen-specific immunoassays, the AUC varied between 0.936 (95% CI 0.912 to 0.960) and 0.959 (95% CI 0.941 to 0.976), except for one immunoassay for which the AUC was 0.919 (95% CI 0.892 to 0.945).ConclusionsOur comparison of various ANCA detection methods showed (i) large variability between the two IIF methods tested and (ii) a high diagnostic performance of PR3-ANCA and MPO-ANCA by immunoassay to discriminate AAV from disease controls. Consequently, dual IIF/antigen-specific immunoassay testing of each sample is not necessary for maximal diagnostic accuracy. These results indicate that the current international consensus on ANCA testing for AAV needs revision.

Objective.The objective of this study was to identify risk factors for a relapse at the time of an increase in antineutrophil cytoplasmic antibodies (ANCA) in patients with renal ANCA-associated vasculitis (AAV).Methods.All patients between January 2000 and November 2011 with renal AAV having an ANCA rise during remission were included. Differences in time to relapse since the ANCA rise were assessed using a Cox regression model. The level of 25-hydroxy Vitamin D (25(OH)D) was assessed at the ANCA rise and at a subsequent relapse or time-matched during remission.Results.Sixty patients had an ANCA rise, of whom 36 patients relapsed. Three risk factors were associated with a relapse at the time of the ANCA increase: previous disease activity not treated with cyclophosphamide or rituximab (HR 3.48, 95% CI 1.60–7.59), an ANCA rise during the fall season (HR 4.37, 95% CI 1.60–11.90), and an extended ANCA rise (HR 3.57, 95% CI 1.50–8.48). Levels of 25(OH)D significantly decreased during followup in relapsing patients, but not in patients who remained in remission (difference −6.3 ± 14.4, p = 0.017 vs 2.7 ± 16.3, p = 0.430).Conclusion.ANCA rises occurring during the fall season are more frequently followed by a relapse than ANCA rises occurring during other seasons. Although it is tempting to speculate that decreasing Vitamin D levels following the ANCA rise can be held responsible for the subsequent relapse, this remains to be determined.

BACKGROUND: Anti-neutrophil cytoplasmic antibody associated vasculitis (AAV) is a typical disease of the elderly. In AAV, there is an age-specific increase in disease incidence with age being a predictor of disease outcome. In this study, we aimed to determine the contribution of age to the development of AAV employing a mouse model of anti-myeloperoxidase (MPO) antibody-mediated glomerulonephritis.METHODS: Anti-MPO IgG and lipopolysaccharide (LPS)-mediated glomerulonephritis was induced in 3- and 18-month-old C57Bl6 mice. Clinical and pathological parameters of disease severity, alterations in the immune system and kidney specific changes in these mice were evaluated.RESULTS: Eighteen-month-old mice developed increased disease severity upon injection of anti-MPO IgG/LPS compared with 3-month-old mice. This was evidenced by increased albuminuria, more extensive glomerular capillary necrosis and increased glomerular neutrophil accumulation. Glomerular crescent formation was mild in both young and old mice. Old mice displayed higher plasma interleukin-6 levels as well as higher proportions of circulating neutrophils and activated monocytes compared with young mice. In addition, renal mRNA levels of inflammatory genes and endothelial adhesion molecules were higher in 18-month-old mice compared with 3-month-old mice.CONCLUSION: In conclusion, our results indicate that aged mice develop more severe clinical and pathological disease upon induction of anti-MPO IgG/LPS-mediated glomerulonephritis. These findings may be attributed to age-related changes in the immune system as well as in the kidney itself.

Introduction: Granulomatosis with Polyangiitis (GPA; formerly Wegener's) and Microscopic Polyangiitis (MPA) are inflammatory disease entities affecting small to medium vessels. They are characterized by the presence of anti-neutrophil cytoplasmic antibodies (ANCA) and are frequently grouped together with Eosinophilic Granulomatosis with Polyangiitis (EGPA; formerly Churg Strauss Syndrome) under the term ANCA-associated Vasculitis (AAV). Due to effective immunosuppressive therapy that was introduced more than 45 years ago, AAV has become a chronic disease in which relapses occur frequently during maintenance treatment or later on after all immunosuppressive therapy is stopped. Since relapses are associated with morbidity and mortality, early detection and prevention of relapses is of great importance. Areas covered: This review focuses on the potential strategies to guide maintenance therapy in patients with GPA or MPA, with an emphasis on patient classifications and the role of serial ANCA measurements. Expert opinion: Risk factors for relapses, e.g., genetic background of the patient, have been studied during the last three decades. Only few of these risk factors directly influence the management of patients. One potentially important factor that may influence therapeutic decisions in AAV patients is serial measurement of ANCA. Recently, it became clear that serial ANCA measurement is an attractive approach in AAV patients with (a history of) capillaritis, e.g., renal involvement or alveolar haemorrhage, but not in patients with more limited disease. Whether ANCA rises can be used to guide therapy and - hence- to prevent relapses has been a great debate during the last three decades. At present, we conclude that small studies do support such an approach but that these findings require further validation in larger randomized clinical trials.

Background: Immunopathologic features predict renal function at baseline and follow-up in antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN). The interstitial infiltrate consists predominantly of T lymphocytes, but their pathophysiologic significance is unclear, especially in light of the success of B-cell-directed therapy. Methods: Renal biopsies from 33 patients treated with cyclophosphamide (CYC; n = 17) or rituximab (RTX; n = 16) in the RTX in ANCA-associated vasculitis (RAVE) trial were classified according to the new ANCA GN classification. T- and B-cell infiltration in the interstitium was assessed by immunostaining for CD3 and CD20. Correlations of clinical and histologic parameters with renal function at set time points were examined. Results: The mean (SD) baseline estimated glomerular filtration rate was 36 (20) mL/min/1.73 m2. ANCA GN class distribution was 46% focal, 33% mixed, 12% sclerotic and 9% crescentic. The interstitial infiltrate consisted of >50% CD3 positive cells in 69% of biopsies, but >50% CD20 positive cells only in 8% of biopsies. In a multiple linear regression model, only baseline glomerular filtration rate (GFR) correlated with GFR at 6, 12, and 18 months. Interstitial B- and T-cell infiltrates had no significant impact on long-term prognosis, independent of the treatment limb. A differential effect was noted only at 6 months, where a dense CD3 positive infiltrate predicted lower GFR in the RTX group and a CD20 positive infiltrate predicted higher GFR in the CYC group. Conclusions: In ANCA-associated GN, the interstitial infiltrate contains mainly T lymphocytes. However, it is neither reflecting baseline renal function nor predictive of response to treatment, regardless of the immunosuppression regimen employed.

Introduction: Granulomatosis with Polyangiitis (GPA; formerly Wegener's) and Microscopic Polyangiitis (MPA) are inflammatory disease entities affecting small to medium vessels. They are characterized by the presence of anti-neutrophil cytoplasmic antibodies (ANCA) and are frequently grouped together with Eosinophilic Granulomatosis with Polyangiitis (EGPA; formerly Churg Strauss Syndrome) under the term ANCA-associated Vasculitis (AAV). Due to effective immunosuppressive therapy that was introduced more than 45 years ago, AAV has become a chronic disease in which relapses occur frequently during maintenance treatment or later on after all immunosuppressive therapy is stopped. Since relapses are associated with morbidity and mortality, early detection and prevention of relapses is of great importance.Areas covered: This review focuses on the potential strategies to guide maintenance therapy in patients with GPA or MPA, with an emphasis on patient classifications and the role of serial ANCA measurements.Expert opinion: Risk factors for relapses, e.g., genetic background of the patient, have been studied during the last three decades. Only few of these risk factors directly influence the management of patients. One potentially important factor that may influence therapeutic decisions in AAV patients is serial measurement of ANCA. Recently, it became clear that serial ANCA measurement is an attractive approach in AAV patients with (a history of) capillaritis, e.g., renal involvement or alveolar haemorrhage, but not in patients with more limited disease. Whether ANCA rises can be used to guide therapy and - hence- to prevent relapses has been a great debate during the last three decades. At present, we conclude that small studies do support such an approach but that these findings require further validation in larger randomized clinical trials.

Because of the inflammatory mechanisms of most chronic upper airway diseases such as rhinitis and chronic rhinosinusitis, systemic steroids have been used for their treatment for decades. However, it has been very well documented that-potentially severe-side-effects can occur with the accumulation of systemic steroid courses over the years. A consensus document summarizing the benefits of systemic steroids for each upper airway disease type, as well as highlighting the potential harms of this treatment is currently lacking. Therefore, a panel of international experts in the field of Rhinology reviewed the available literature with the aim of providing recommendations for the use of systemic steroids in treating upper airway disease. ispartof: CLINICAL AND TRANSLATIONAL ALLERGY vol:10 issue:1 ispartof: location:England status: published

Objectives: Regulatory T cells (Tregs) are frequently functionally impaired in patients with granulomatosis with polyangiitis (GPA). However, the mechanism underlying their impaired function is unknown. Here, we hypothesized that Treg dysfunction in GPA is due to altered microRNA (miRNA) expression.Methods: RNA isolated from FACS-sorted memory ((M)) Tregs (CD4(+)CD45RO(+)CD25(+)CD127(-)) of 8 healthy controls (HCs) and 8 GPA patients without treatment was subjected to miRNA microarray analysis. Five differentially expressed miRNAs were validated in a larger cohort by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). An miRNA target gene database search revealed targets that were tested with RT-qPCR in (M)Tregs from patients and HCs. cAMP levels were measured using flow cytometry.Results: Microarray analysis revealed 19 differentially expressed miRNAs, of which miR-142-3p was confirmed to be significantly upregulated in (M)Tregs from GPA patients compared to those from HCs (1.9-fold, p = 0.03). In vitro overexpression of miR-142-3p lowered the suppressive capacity of (M)Tregs (2.1-fold, p = 0.03), and miR-142-3p expression correlated negatively with the suppressive capacity (rho = -0.446, p = 0.04). Overexpression of miR-142-3p significantly decreased cAMP levels (p = 0.02) and tended to decrease the mRNA levels of a predicted target gene, adenylate cyclase 9 (ADCY9; p = 0.06). In comparison to those from HCs, (M)Tregs from GPA patients had lower ADCY9 mRNA levels (2-fold, p = 0.008) and produced significantly less cAMP after stimulation. Importantly, induction of cAMP production in miR-142-3p overexpressed (M)Tregs by forskolin restored their suppressive function in vitro.Conclusion: Overexpression of miR-142-3p in (M)Tregs from GPA patients might cause functional impairment by targeting ADCY9, which leads to the suppression of cAMP production.

Objectives: The activation and inhibition of T-cells has been well-studied under physiological conditions. Co-inhibition is an important mechanism to keep effector T-cells in check. Co-inhibitors mediate peripheral self-tolerance and limit the immune response. Dysfunctional co-inhibition is associated with loss of T-cell regulation and induction of autoimmunity. Therefore, we investigated the co-inhibitor B- and T-Lymphocyte attenuator (BTLA) in ANCA-associated vasculitis (AAV). Methods: Fifty-six AAV patients and 32 healthy controls (HC) were recruited. Flow cytometry was performed to investigate the expression of BTLA on T-cells. Double negative T-cells were defined as CD3⁺CD4−CD8−. To assess the functionality of BTLA, CFSE-labeled T-cells were stimulated in presence or absence of an agonistic anti-BTLA antibody. In addition, impact of BTLA-mediated co-inhibition on Th17 cells was studied. Results: AAV patients in remission had a decreased expression of BTLA on double negative T-cells (CD3⁺CD4−CD8−). On all other subtypes of T-cells, expression of BTLA was comparable to healthy controls. TCR-independent stimulation of T-cells resulted in down-regulation of BTLA on Th cells in AAV and HC, being significantly lower in HC. Co-inhibition via BTLA led to suppression of T-cell proliferation in AAV as well as in HC. As a result of BTLA mediated co-inhibition, Th17 cells were suppressed to the same extent in AAV and HC. Conclusion: BTLA expression is altered on double negative T-cells but not on other T-cell subsets in quiescent AAV. BTLA-induced co-inhibition has the capacity to suppress Th17 cells and is functional in AAV. Thus, BTLA-mediated co-inhibition might be exploited for future targeted therapies in AAV. OA Förderung 2019

Background: Granulomatosis with polyangiitis (GPA) patients are prone to disease relapses. We aimed to determine whether GPA patients at risk for relapse can be identified by differences in B cell subset frequencies. Methods: Eighty-five GPA patients were monitored for a median period of 3.1 years (range: 0.1-6.3). Circulating B cell subset frequencies were analyzed by flow cytometry determining the expression of CD19, CD38, and CD27. B cell subset frequencies at the time of inclusion of future-relapsing (F-R) and non-relapsing (N-R) patients were compared and related to relapse-free survival. Additionally, CD27+CD38hi B cells were assessed in urine and kidney biopsies from active anti-neutrophil cytoplasmic autoantibody-associated vasculitides (AAV) patients with renal involvement. Results: Within 1.6 years, 30% of patients experienced a relapse. The CD27+CD38hi B cell frequency at the time of inclusion was increased in F-R (median: 2.39%) compared to N-R patients (median: 1.03%; p = 0.0025) and a trend was found compared with the HCs (median: 1.33%; p = 0.08). This increased CD27+CD38hi B cell frequency at inclusion was correlated to decreased relapse-free survival in GPA patients. In addition, 74.7% of patients with an increased CD27+CD38hi B cell frequency (≥2.39%) relapsed during follow-up compared to 19.7% of patients with a CD27+CD38hi B cell frequency of

Human CD4+FoxP3+T-cells are heterogeneous in function and include not only suppressive cells (Tregs), but also effector cells that transiently express FoxP3 upon activation. Previous studies in Granulomatosis with Polyangiitis (GPA-)patients have demonstrated an increase in FoxP3+T-cells with impaired suppressive capacity and an increase in Th17 cells. We hypothesized that the increase in FoxP3+T-cells results from an increase in non-suppressive effector-like cells. The frequency of circulating CD4+FoxP3+T-cell subsets were determined by flow cytometry in 46 GPA-patients in remission and 22 matched healthy controls (HCs). Expression levels of FoxP3 and CD45RO were used to distinguish between CD45RO−FoxP3low resting Tregs (rTreg), CD45RO+FoxP3high activated Tregs (aTreg) and CD45RO+FoxP3low proinflammatory non-suppressive T-cells (nonTreg). Intracellular expression of IFNγ, IL-17, and IL-21 was compared within these subsets. We found a significant increase in the frequency of nonTreg cells in GPA-patients as compared with HCs. Importantly, within the nonTreg subset, antineutrophil cytoplasmic autoantibody (ANCA-)positive patients demonstrated a significantly higher percentage of IL-17+ and IL-21+ cells when compared with ANCA-negative patients and HCs. Moreover, expanded nonTregs from ANCA-positive patients induced excessive proliferation of responder cells in vitro and exhibited higher IL-21 production. Production of IL-17 and IL-21 in non-suppressive FoxP3+T-cells may point toward a pathogenic role in ANCA formation.

Objective. Relapse following remission is common in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), particularly with ANCAs directed at proteinase 3 (PR3). This study was undertaken to evaluate the association of an increase in PR3-ANCA level with subsequent relapse. Methods. Data from the Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial were used. Starting from the time of achieving complete remission, serialmeasurements by direct and capture enzyme-linked immunosorbent assays (ELISAs) were analyzed in 93 patients with PR3-ANCA, using Cox proportional hazards regression. Results. An increase in PR3-ANCA level was identified in 58 of 93 subjects (62.4%) by direct ELISA and in 59 of 93 (63.4%) by capture ELISA. Relapses occurred in 55 of 93 subjects (59.1%), with 25 and 21 occurring within 1 year after an increase by direct ELISA and capture ELISA, respectively. An increase by direct ELISA was associated with subsequent severe relapses (hazard ratio [HR] 4.57; P

Heleen Ameye, Sabine Fransis, Evelyne Lerut, Christoph Metalidis and Ben Sprangers Department of Nephrology, University Hospitals Leuven, Leuven, Belgium; Department of Pathology, Ziekenhuis OostLimburg Hospital, Genk, Belgium; Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium; Department of Nephrology, Ziekenhuis Oost-Limburg Hospital, Genk, Belgium; and Department of Microbiology and Immunology, University of Leuven, Leuven, Belgium

Purpose of reviewAntineutrophil cytoplasmic autoantibodies (ANCAs) are considered important diagnostic tests in the work-up of patients suspected of vasculitis. Here we discuss new developments in the methodology of testing, the pitfalls in using these tests as diagnostic tools, and the value of serial ANCA testing for the follow-up of patients with ANCA-associated vasculitis including treatment decisions.Recent findingsBoth the indirect immunofluorescence (IIF) test and antigen-specific assays should be performed. New methodologies include automated reading in the IIF test and third-generation assays (anchor ELISA and bead-based multiplex assay) for the antigenic-specific assays. ANCA testing should be done in the right clinical context as positive results for PR3-ANCA and MPO-ANCA do occur in other conditions than vasculitis as well. These ANCAs develop in about 10% of patients with infective endocarditis. The occurrence of drug-induced ANCA and ANCA, also directed against elastase, following use of levamisole-adulterated cocaine should be recognized. In the right clinical context, ANCA are highly sensitive and specific for their associated disease. The value of serial ANCA testing for the follow-up of patients with ANCA-associated vasculitis is still under discussion but may be relevant in patients with renal involvement and in patients treated with rituximab.SummaryThe techniques for ANCA testing improve further but new tests should be standardized and validated. Their diagnostic value in the right clinical context is undisputed. Their value for the follow-up of patients is still under discussion.

Purpose of reviewAntineutrophil cytoplasmic autoantibodies (ANCAs) are considered important diagnostic tests in the work-up of patients suspected of vasculitis. Here we discuss new developments in the methodology of testing, the pitfalls in using these tests as diagnostic tools, and the value of serial ANCA testing for the follow-up of patients with ANCA-associated vasculitis including treatment decisions.Recent findingsBoth the indirect immunofluorescence (IIF) test and antigen-specific assays should be performed. New methodologies include automated reading in the IIF test and third-generation assays (anchor ELISA and bead-based multiplex assay) for the antigenic-specific assays. ANCA testing should be done in the right clinical context as positive results for PR3-ANCA and MPO-ANCA do occur in other conditions than vasculitis as well. These ANCAs develop in about 10% of patients with infective endocarditis. The occurrence of drug-induced ANCA and ANCA, also directed against elastase, following use of levamisole-adulterated cocaine should be recognized. In the right clinical context, ANCA are highly sensitive and specific for their associated disease. The value of serial ANCA testing for the follow-up of patients with ANCA-associated vasculitis is still under discussion but may be relevant in patients with renal involvement and in patients treated with rituximab.SummaryThe techniques for ANCA testing improve further but new tests should be standardized and validated. Their diagnostic value in the right clinical context is undisputed. Their value for the follow-up of patients is still under discussion.

Objective: We studied whether in ANCA-associated vasculitis patients, duration of AZA maintenance influenced relapse rate during long-term follow-up.Methods: Three hundred and eighty newly diagnosed ANCA-associated vasculitis patients from six European multicentre studies treated with AZA maintenance were included; 58% were male, median age at diagnosis 59.4 years (interquartile range: 48.3-68.2 years); granulomatosis with polyangiitis, n = 236; microscopic polyangiitis, n = 132; or renal limited vasculitis, n = 12. Patients were grouped according to the duration of AZA maintenance after remission induction: ⩽18 months, ⩽24 months, ⩽36 months, ⩽48 months or > 48 months. Primary outcome was relapse-free survival at 60 months.Results: During follow-up, 84 first relapses occurred during AZA-maintenance therapy (1 relapse per 117 patient months) and 71 after withdrawal of AZA (1 relapse/113 months). During the first 12 months after withdrawal, 20 relapses occurred (1 relapse/119 months) and 29 relapses >12 months after withdrawal (1 relapse/186 months). Relapse-free survival at 60 months was 65.3% for patients receiving AZA maintenance >18 months after diagnosis vs 55% for those who discontinued maintenance ⩽18 months (P = 0.11). Relapse-free survival was associated with induction therapy (i.v. vs oral) and ANCA specificity (PR3-ANCA vs MPO-ANCA/negative).Conclusion: Post hoc analysis of combined trial data suggest that stopping AZA maintenance therapy does not lead to a significant increase in relapse rate and AZA maintenance for more than 18 months after diagnosis does not significantly influence relapse-free survival. ANCA specificity has more effect on relapse-free survival than duration of maintenance therapy and should be used to tailor therapy individually.

Age-associated changes in the immune system including alterations in surface protein expression are thought to contribute to an increased susceptibility for autoimmune diseases. The balance between the expression of coinhibitory and costimulatory surface protein molecules, also known as immune checkpoint molecules, is crucial in fine-tuning the immune response and preventing autoimmunity. The activation of specific inhibitory signaling pathways allows cancer cells to evade recognition and destruction by the host immune system. The use of immune checkpoint inhibitors (ICIs) to treat cancer has proven to be effective producing durable antitumor responses in multiple cancer types. However, one of the disadvantages derived from the use of these agents is the appearance of inflammatory manifestations termed immune-related adverse events (irAEs). These irAEs are often relatively mild, but more severe irAEs have been reported as well including several forms of vasculitis. In this article, we argue that age-related changes in expression and function of immune checkpoint molecules lead to an unstable immune system, which is prone to tolerance failure and autoimmune vasculitis development. The topic is introduced by a case report from our hospital describing a melanoma patient treated with ICIs and who subsequently developed biopsy-proven giant cell arteritis. Following this case report, we present an in-depth review on the role of immune checkpoint pathways in the development and progression of autoimmune vasculitis and its relation with an aging immune system.

Aim. We describe the clinical pattern of ANCA-associated vasculitis (AAV) and assess long-term prognostic factors of patients and renal survival and relapse. Methods. Data from 85 patients with renal biopsy-proven AAV at a single center with up to 20-year [median 16.2 years (95% CI 14.9-17.7)] follow-up were retrospectively collected. Results. Overall, 55% of the patients had microscopic polyangiitis (MPA) and 45% had granulomatosis with polyangiitis (GPA). The histopathological classes were focal in 35%, crescentic in 26%, mixed in 20%, and sclerotic glomerulonephritis in 19% of the patients. As induction treatment, a combination of cyclophosphamide and corticosteroids was given to 82%, while a combination of azathioprine and corticosteroids was maintenance therapy in 79%. The twenty-year patient survival was 45%. In a multivariable analysis, age ≥58 years [hazard ratio (HR) 7.64, 95% CI 3.44-16.95] and myeloperoxidase (MPO) ANCA (HR 2.12, 95% CI 1.08-4.17) were associated with shorter patient survival time. Renal survival was 68% overall: 88% in focal, 71% in crescentic, 56% in mixed, and 37% in sclerotic class (p=0.01). Female sex (HR 0.26, 95% CI 0.10-0.73) was a predictor of improved renal survival, whereas GFR Conclusion. We confirmed the improved patient and renal survival in AAV patients with glomerulonephritis, while relapse remained the primary challenge. Histopathological classification may be relevant for survival.

Isolated pancreatic involvement is a rare initial presentation in patients with ANCA-associated vasculitis. We report a patient with a suspected malignant pancreatic mass, referred to our hospital for pancreaticoduodenectomy. However, the pancreatic mass proved to be the initial manifestation of ANCA-associated vasculitis.

ObjectiveTo discover biomarkers involved in the pathophysiology of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and to determine whether low-density granulocytes (LDGs) contribute to gene expression signatures in AAV.MethodsThe source of clinical data and linked biologic specimens was a randomized controlled treatment trial in AAV. RNA sequencing of whole blood from patients with AAV was performed during active disease at the baseline visit and during remission 6 months later. Gene expression was compared between patients who met versus those who did not meet the primary trial outcome of clinical remission at 6 months (responders versus nonresponders). Measurement of neutrophil-related gene expression was confirmed in peripheral blood mononuclear cells (PBMCs) to validate the findings in whole blood. A negative-selection strategy isolated LDGs from PBMC fractions.ResultsDifferential expression between responders (n=77) and nonresponders (n=35) was detected in 2,346 transcripts at the baseline visit (PConclusionIn AAV, increased expression of a granulocyte gene signature is associated with disease activity and decreased response to treatment. The source of this signature is likely LDGs, a potentially pathogenic cell type in AAV.

Until recently, standard of care for patients with generalized or severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has consisted of an induction regimen with cyclophosphamide (CYC) and corticosteroids followed by maintenance treatment with azathioprine. This regimen is associated with significant toxicity resulting in considerable morbidity and mortality whereas relapses are still not infrequent. In two controlled trials, the Rituximab in ANCA-associated Vasculitis study (RAVE) and the RITUXVAS trial of the European Vasculitis Study Group (EUVAS), rituximab (RTX) proved non-inferior to CYC for induction of remission. In addition, outcome at 18 months for the RAVE trial and 12 months for the RITUXVAS trial showed that RTX without maintenance treatment was as efficacious as CYC followed by azathioprine maintenance. To prevent relapses, which occur particularly in patients positive for PR3-ANCA, 500 mg RTX given every 6 months was shown to be superior to azathioprine in a French study. Thus, RTX is a new and promising therapeutic armamentarium for AAV although long-term safety has still to be established.

Rituximab (RTX) is non-inferior to cyclophosphamide (CYC) followed by azathioprine (AZA) for remission-induction in severe ANCA-associated vasculitis (AAV), but renal outcomes are unknown. This is a post hoc analysis of patients enrolled in the Rituximab for ANCA-Associated Vasculitis (RAVE) Trial who had renal involvement (biopsy proven pauci-immune GN, red blood cell casts in the urine, and/or a rise in serum creatinine concentration attributed to vasculitis). Remission-induction regimens were RTX at 375 mg/m(2) x 4 or CYC at 2 mg/kg/d. CYC was replaced by AZA (2 mg/kg/d) after 3-6 months. Both groups received glucocorticoids. Complete remission (CR) was defined as Birmingham Vasculitis Activity Score/Wegener's Granulomatosis (BVAS/WG)=0 off prednisone. Fifty-two percent (102 of 197) of the patients had renal involvement at entry. Of these patients, 51 were randomized to RTX, and 51 to CYC/AZA. Mean eGFR was lower in the RTX group (41 versus 50 ml/min per 1.73 m(2); P=0.05); 61% and 75% of patients treated with RTX and 63% and 76% of patients treated with CYC/AZA achieved CR by 6 and 18 months, respectively. No differences in remission rates or increases in eGFR at 18 months were evident when analysis was stratified by ANCA type, AAV diagnosis (granulomatosis with polyangiitis versus microscopic polyangiitis), or new diagnosis (versus relapsing disease) at entry. There were no differences between treatment groups in relapses at 6, 12, or 18 months. No differences in adverse events were observed. In conclusion, patients with AAV and renal involvement respond similarly to remission induction with RTX plus glucocorticoids or CYC plus glucocorticoids.

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) are severe chronic auto-immune diseases in which the small vessels are inflamed. Nowadays, in the majority of patients disease can be brought into remission with cyclophosphamide and corticosteroids. However, depending upon disease characteristics patients with AAV have a risk of 29-60% to experience relapses of disease within 5 years despite maintenance therapy after induction of remission with less toxic agents, such as azathioprine, methotrexate or mycophenolate mofetil. More recently, rituximab has been found effective in both induction and maintenance of remission in AAV. This review discusses the different aspects of maintenance therapy in AAV based on reported cohorts and studies, including the different agents, therapy duration, efficacy or lack thereof and future directions. Finally, recommendations are made who to treat and for how long.

Until recently, standard of care for patients with generalized or severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has consisted of an induction regimen with cyclophosphamide (CYC) and corticosteroids followed by maintenance treatment with azathioprine. This regimen is associated with significant toxicity resulting in considerable morbidity and mortality whereas relapses are still not infrequent. In two controlled trials, the Rituximab in ANCA-associated Vasculitis study (RAVE) and the RITUXVAS trial of the European Vasculitis Study Group (EUVAS), rituximab (RTX) proved non-inferior to CYC for induction of remission. In addition, outcome at 18 months for the RAVE trial and 12 months for the RITUXVAS trial showed that RTX without maintenance treatment was as efficacious as CYC followed by azathioprine maintenance. To prevent relapses, which occur particularly in patients positive for PR3-ANCA, 500 mg RTX given every 6 months was shown to be superior to azathioprine in a French study. Thus, RTX is a new and promising therapeutic armamentarium for AAV although long-term safety has still to be established.

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) are severe chronic auto-immune diseases in which the small vessels are inflamed. Nowadays, in the majority of patients disease can be brought into remission with cyclophosphamide and corticosteroids. However, depending upon disease characteristics patients with AAV have a risk of 29-60% to experience relapses of disease within 5 years despite maintenance therapy after induction of remission with less toxic agents, such as azathioprine, methotrexate or mycophenolate mofetil. More recently, rituximab has been found effective in both induction and maintenance of remission in AAV. This review discusses the different aspects of maintenance therapy in AAV based on reported cohorts and studies, including the different agents, therapy duration, efficacy or lack thereof and future directions. Finally, recommendations are made who to treat and for how long.

Granulomatosis with polyangiitis and microscopic polyangiitis are anti-neutrophil cytoplasmic antibody-associated vasculitides (AAVs) that are prone to cycles of remission and relapse. The introduction of cytotoxic therapy has changed the prognosis for these diseases from typically fatal to manageable chronic illnesses with a relapsing course. Despite improvements in outcomes, recurrence of disease and drug-related toxicity continue to produce significant morbidity and mortality. Better understanding of the pathogenesis of AAV and the mechanism of action of cyclophosphamide has led to investigation of therapies that target B cells. Two randomized controlled trials have shown that rituximab is not inferior to cyclophosphamide for induction of remission in severe AAV, with no significant difference in the incidence of overall adverse events in rituximab- versus cyclophosphamide-treated patients. Data from ongoing clinical trials will determine the role of rituximab in the maintenance of remission.