Associated Vasculitis Disease Research Articles

Role of bronchoscopy for respiratory involvement in granulomatosis with polyangiitis and microscopic polyangiitis.

This study describes data from bronchoscopy performed at the diagnosis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We conducted a retrospective study between 2004 and 2019 in patients aged >18 years with a diagnosis of microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA) who underwent bronchoscopy at onset of the disease. We collected bronchoalveolar lavage (BAL) and histological findings obtained during bronchoscopy. 274 patients with AAV were identified. Among 92 bronchoscopies, 62 were performed at diagnosis, and 58 procedures were finally analysed. Cough was more frequent in patients with MPA than GPA (p=0.02). The presence of endobronchial lesions (24.1%) was found to be significantly associated with GPA (p<0.0001) and proteinase 3-ANCA (p=0.01). The most frequent endobronchial lesions were inflammation and hyperaemia of the bronchial mucosa (50%), followed by stenoses (28%), ulcerations (21%) and mass-like granulomatosis (7%). The diagnostic yield of bronchial biopsies was useful for visible lesions (66.6% versus 0%; p=0.006). On BAL, diffuse alveolar haemorrhage (DAH) was detected in 31 (53.4%) patients and was more frequent in MPA patients (70.4% versus 38.7%; p=0.016). In 16.1% of DAH cases, BAL confirmed the diagnosis despite the absence of clinical or biological arguments. The incidence of microbial infections on BAL (38%) was similar between MPA and GPA (p=0.54). Bronchoscopy is an informative procedure at the onset of AAV disease in patients with respiratory manifestations. Endobronchial lesions are more frequently found in GPA and should be biopsied. BAL can be used to confirm DAH or diagnose superadded infection.

Soluble immune checkpoint molecules in patients with antineutrophil cytoplasmic antibody-associated vasculitis

Immune checkpoint molecules balance immune effector responses with regulatory reactions. We speculated that soluble immune checkpoint molecules are involved in dysregulation of the immune response and autoimmunity. We evaluated the association between soluble immune checkpoint molecules and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).A total of 56 patients with AAV from a prospective observational cohort and 40 healthy controls (HCs) were analyzed. Soluble PD-1, PD-L1, PD-L2, CTLA-4, CD28, CD80, CD86, ICOS, TIM-3, BTLA, CD40, LAG-3, TLR-2, and CD27 were measured in stored sera using the Milliplex MAP assay. Paired analyses were performed before and after the treatment. AAV-specific indices, including Birmingham vasculitis activity score, five factor score , vasculitis damage index, and blood samples, were collected.Patients with AAV had higher levels of sPD-L1, sCD28, sCD80, sCD86, sICOS, sTIM-3, sLAG-3, sTLR-2, and sCD27 and lower level of sCTLA-4 than HCs (p < 0.05). Patients with AAV had higher serum sCD28, sCD80, sTIM-3, and sCD27 levels than HCs at baseline and decreased after treatment. Furthermore, the serum levels of sCD28 and sTIM-3 were significantly correlated with disease activity.This study demonstrated altered concentrations of serum soluble immune checkpoint molecules in patients with AAV. In particular, sCD28 and sTIM-3 may act as surrogate markers of AAV disease activity.

[High burden of disease in patients with ANCA-associated vasculitis : Aclaims data study in Germany].

Hintergrund und ZielsetzungUnter dem Begriff der mit antineutrophilen zytoplasmatischen Antikörpern (ANCA) assoziierten Vaskulitis (AAV) wird eine Gruppe seltener, chronischer, durch rezidivierende systemische Entzündungen gekennzeichneter Autoimmunerkrankungen mit vielfältigen Morbiditäten zusammengefasst. Patienten mit AAV leiden unter diversen Organmanifestationen und schweren Nebenwirkungen der Therapie. In dieser retrospektiven Studie wurde die konkrete Belastung der Patienten durch die AAV-Erkrankung in Deutschland untersucht.MethodikBasierend auf anonymisierten Längsschnittdaten der gesetzlichen Krankenversicherung (GKV) zur medizinischen Versorgung zwischen 2013 und 2016 wurden aus einer repräsentativen Kohorte von etwa 3 Mio. Versicherten Patienten mit Granulomatose mit Polyangiitis (GPA) und mikroskopischer Polyangiitis (MPA) identifiziert und ausgewählte klinische Aspekte systematisch analysiert.ErgebnisseDie häufigsten begleitenden Morbiditäten von GPA und MPA waren Nieren- und Atemwegserkrankungen. Eine schwere Nierenbeteiligung trat bei 11,6 % der GPA- und 24,3 % der MPA-Patienten innerhalb von 15 Quartalen nach der Diagnose auf. Bei einem Drittel der Patienten mit AAV entwickelten sich innerhalb der ersten 3 Quartale nach Diagnose schwere Infektionen. Die Rate der schweren Rezidive betrug jährlich 5–8 %. Patienten mit AAV und Nierenbeteiligung oder Infektionen zeigten zudem eine hohe jährliche Mortalitätsrate von 14,4 % bzw. 5,6 %.SchlussfolgerungAnhand dieser Analyse deutscher Versorgungsdaten wurden krankheitsspezifische Annahmen der Belastung von Patienten mit AAV bestätigt und für den deutschen Kontext konkretisiert. Patienten mit AAV leiden unter einer hohen Morbiditätsbelastung, einschließlich multipler Krankheitsmanifestationen, Rezidiven und schwerer Komplikationen aufgrund der AAV-Therapie.Zusatzmaterial onlineDie Online-Version dieses Beitrags (10.1007/s00108-021-01181-z) enthält eine zusätzliche Tabelle sowie zwei weitere Abbildungen.

Kidney biopsy chronicity grading in antineutrophil cytoplasmic antibody-associated vasculitis.

BackgroundKidney biopsy is valuable for prognostic assessment of renal outcomes in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with glomerulonephritis (AAV-GN) but the impact of chronic changes is not determined.MethodsWe conducted a retrospective cohort study of myeloperoxidase (MPO)- or proteinase 3 (PR3)-ANCA-positive patients with AAV and active renal disease. We applied the Mayo Clinic Chronicity Score (MCCS) and validated and evaluated its implications on outcome prediction in AAV-GN.ResultsWe analyzed 329 patients with kidney biopsies available to score. The extent of chronicity was graded by MCCS as minimal [102 (31.0%)], mild [106 (32.2%)], moderate [86 (26.1%)] and severe [35 (10.6%)]. The MCCS grades correlated with the degree of renal function impairment at presentation [mean estimated glomerular filtration rate (eGFR) 48.3 versus 29.2 versus 23.7 versus 18.5 mL/min/1.73 m2, respectively; P < 0.0001]. Higher degrees of the individual components of the MCCS (glomerulosclerosis, interstitial fibrosis, tubular atrophy and arteriosclerosis) were associated with lower median eGFR (P < 0.0001) and decreased event-free [kidney failure (KF) and death] survival (P = 0.002, P < 0.0001, P < 0.0001 and P = 0.017, respectively). Patients with lower MCCS grades recovered renal function more frequently (P < 0.0001). Increasing MCCS grades were associated with decreased renal recovery (P = 0.001), more frequent events and shorter time to KF (P < 0.0001), KF and death (P < 0.0001) and death (P = 0.042), independent of the remission induction treatment used (cyclophosphamide or rituximab). The MCCS stratified renal outcomes for each MCCS grade and can be used in clinical practice as a cutoff for KF prediction (MCCS ≥4).ConclusionsChronic changes on kidney histology independently predict renal function, outcomes and response to treatment in AAV-GN.

Systematic Scoring of Tubular Injury Patterns Reveals Interplay between Distinct Tubular and Glomerular Lesions in ANCA-Associated Glomerulonephritis.

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small vessel vasculitis, most frequently presenting as microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA). Acute tubular injury with the presence of tubulitis was previously reported to be of prognostic value in ANCA glomerulonephritis (GN). In particular, distinct tubular injury lesions were associated with the deterioration of kidney function at AAV disease onset, as well as renal resistance to treatment, and higher risk of progression to composite outcome in patients with AAV. To expand our knowledge regarding distinct tubular lesions in AAV, we aimed to describe acute tubular injury patterns in association with glomerular lesions in ANCA GN by systematic histological scoring. Methods: A total number of 48 renal biopsies with confirmed renal involvement of AAV admitted to the University Medical Center Göttingen from 2015 to 2020 were retrospectively examined. By systematic scoring of tubular injury lesions, the association between clinical parameters, laboratory markers, and histopathological findings was explored. Results: We have shown that cellular casts in renal biopsies were frequently observed in the majority of cases with ANCA GN. Furthermore, we showed that tubular epithelial simplification with dilatation correlated with MPA and MPO subtypes, C3c hypocomplementemia, severe renal involvement, and uACR. Red blood cell (RBC) casts were associated with increased levels of C-reactive protein (CRP), leukocyturia, and hematuria. Finally, we found that hyaline casts were associated with an increased fraction of glomeruli with global glomerular sclerosis. Conclusions: Acute tubular injury patterns were correlated with active ANCA GN, whereas tubular injury lesions reflecting the later stages of kidney disease correlated with chronic glomerular lesions. These results suggest an interplay between different renal compartments.

MO303URINARY ALBUMIN-TO-CREATININE RATIO INDICATES NECROTIZING AND CRESCENTIC GLOMERULONEPHRITIS IN ANCA-ASSOCIATED VASCULITIS

Abstract Background and Aims Renal involvement is a common and severe complication of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) as it can cause acute kidney injury (AKI), end-stage renal disease (ESRD) or death. We have previously reported that elevated urinary albumin-to-creatinine ratio (uACR) correlates with rapid deterioration of kidney function in ANCA GN. Therefore, we here aimed to describe the association between proteinuric findings and histopathological diagnosis of necrotizing and crescentic ANCA GN in 50 urinary samples at admission and corresponding renal biopsies of patients with AAV. Method A total number of 50 urinary samples at admission and corresponding renal biopsies with confirmed renal involvement of AAV were retrospectively included between 2015 till 2020 in a single-center observational study. Results Renal involvement of AAV revealed variable proteinuria ranging from low-range to nephrotic syndromes, however most patients presented with subnephrotic proteinuria predominated by albumin (uACR). Severely increased uACR levels &amp;gt;300 mg/g correlated with reduction of normal glomeruli (P&amp;lt;0.001), attributed to increased glomerular crescents (P&amp;lt;0.001) and necrosis (P=0.008). By contrast, no such association was observed for global sclerotic glomeruli (P=0.58), revealing that uACR reflects necrotizing and crescentic ANCA GN rather than adaptive glomerular hyperfilitration in chronic sclerosing stage. These findings were additionnaly bolstered by histopathological subgrouping and ARRS: patients with uACR levels &amp;gt;300 mg/g were classified either into Berden’s crescentic class (P=0.002) or ANCA renal risk score (ARRS) high/intermediate risk (P=0.003). No association between uACR levels and extrarenal manifestation of AAV disease could be observered, suggesting that uACR levels reflected specific renal involvement with ANCA GN and further confirmed by survival analysis for cumulative incidence of RRT during the short-term course of disease. In summary, uACR measurements at admission were associated with renal biopsy findings thereafter. Levels of uACR &amp;gt;300 mg/g were more frequently observed in necrotizing and crescentic ANCA GN with classification either into Berden’s crescentic class or ARRS high/intermediate risk and specific for renal involvement in AAV. Conclusion Early identification of patients who mostly benefit from aggressive immunosuppressive therapy is of clinical importance. Our observation that uACR levels at disease onset predict necrotizing and crescentic ANCA GN requires further investigation for therapeutic decision especially in patients with severe deterioration of kidney function.

MO083SYSTEMATIC HISTOLOGICAL SCORING OF TUBULOINTERSTITIAL LESIONS CORRELATE WITH CLINICAL PARAMETERS IN ANCA-ASSOCIATED GLOMERULONEPHRITIS

Abstract Background and Aims Renal involvement is a common and severe complication of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We have previously reported that severe deterioration of kidney function is associated with necrotizing and crescentic ANCA glomerulonephritis (GN), classified into Berden’s crescentic class or ANCA renal risk score (ARRS) high risk. However, tubulointerstitial inflammation associated with either histopathological subgrouping or ARRS remains elusive. Furthermore, clinical and laboratory markers of AAV disease severity or deterioration of kidney function in association with inflammatory findings in the kidney have not been described yet. Since aggressive immunosuppressive therapy is recommended for remission induction especially in severe cases of AAV, we here aimed to expand our current knowledge with regard to histopathological classification of tubulointerstitial injury and inflammatory findings analogous to the Banff classification. Method A total number of 50 renal biopsies with confirmed renal involvement of AAV were retrospectively included between 2015 till 2020 in a single-center observational study. Renal biopsies were evaluated for either focal, crescentic, mixed or sclerotic class (according to Berden et al.) and ARRS low, intermediate or high risk (according to Brix et al.). Inflammatory and fibrotic tubulointerstital alterations were evaluated analogous to Banff scoring system for allograft pathology. Results We here show that distinct inflammatory lesions are associated with glomerular findings classified into either histopathological subgrouping or ARRS. Furthermore, interstitial inflammation and tubulitis correlate with disease severity and decline of kidney function in AAV. Finally, we provide data that tubulointerstitial injury and inflammatory findings correlate with short-term outcome in response to aggressive immunosuppression and remission induction therapy. Conclusion In summary, we here provide evidence that a systematic scoring of inflammatory and degenerative tubulointerstitial lesions correlate with severe renal impairment and short-term response to remission induction therapy. Since aggressive immunosuppressive therapy is recommended for remission induction especially in severe cases of AAV, systematic histopathological scoring of tubuloinsterstital lesions could further improve our current knowledge of ANCA GN progression.

Investigation of type I interferon responses in ANCA-associated vasculitis

Type I interferon (IFN) dysregulation is a major contributory factor in the development of several autoimmune diseases, termed type I interferonopathies, and is thought to be the pathogenic link with chronic inflammation in these conditions. Anti-neutrophil cytoplasmic antibody (ANCA)-Associated Vasculitis (AAV) is an autoimmune disease characterised by necrotising inflammation of small blood vessels. The underlying biology of AAV is not well understood, however several studies have noted abnormalities in type I IFN responses. We hypothesised that type I IFN responses are systemically dysregulated in AAV, consistent with features of a type I interferonopathy. To investigate this, we measured the expression of seven interferon regulated genes (IRGs) (ISG15, SIGLEC1, STAT1, RSAD2, IFI27, IFI44L and IFIT1) in peripheral blood samples, as well as three type I IFN regulated proteins (CXCL10, MCP-1 and CCL19) in serum samples from AAV patients, healthy controls and disease controls. We found no difference in type I IFN regulated gene or protein expression between AAV patients and healthy controls. Furthermore, IRG and IFN regulated protein expression did not correlate with clinical measurements of disease activity in AAV patients. Thus, we conclude that systemic type I IFN responses are not key drivers of AAV pathogenesis and AAV should not be considered a type I interferonopathy.

Systematic Histological Scoring Reveals More Prominent Interstitial Inflammation in Myeloperoxidase-ANCA Compared to Proteinase 3-ANCA Glomerulonephritis.

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic vasculitis, most frequently presenting as microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA). Kidney involvement is a common and severe complication of ANCA AAV which is observed in a considerable subset of patients, mainly affecting glomeruli. However, tubulointerstitial lesions have also been described in ANCA glomerulonephritis (GN). Therefore, we aim to describe active and chronic tubulointerstitial lesions in ANCA GN subtypes by systematic scoring analogous to the Banff scoring system while also utilizing clinical and laboratory findings. Methods: A total of 49 kidney biopsies with ANCA GN were retrospectively included in a single-center cohort study between 2015–2020. Results: We report that MPO-ANCA GN is associated with more severe deterioration of kidney function independent of systemic markers of AAV disease activity, and is also associated with increased proteinuria in MPO-ANCA GN and a decreased fraction of normal glomeruli. Finally, MPO-ANCA GN showed distinct, active, and chronic tubulointerstitial lesions. Conclusion: New insights into the pathophysiology of both entities, as well as differences in the clinical presentation of MPO- versus PR3-ANCA GN, could potentially pave the way for more precise treatment regimens. Therefore, it is important to understand the differences in histopathological presentation, especially in yet underestimated active tubulointerstitial lesions of ANCA GN subtypes. This research could further improve our understanding of distinct pathophysiological mechanisms.

Serum chitinase-3-like 1 protein is a useful biomarker to assess disease activity in ANCA-associated vasculitis: an observational study

BackgroundTo investigate whether serum chitinase-3-like 1 protein (YKL-40) is associated with disease activity in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).MethodsELISA was performed in serum samples from AAV patients who were enrolled in our prospective observational cohort to estimate levels of YKL-40. Birmingham vasculitis activity score (BVAS) (version 3), five factor score (FFS), and short form-36 (SF-36), as well as clinical and laboratory data were collected. Kidney expression of YKL-40 was assessed by immunohistochemical staining using renal biopsy tissues from ANCA-associated glomerulonephritis patients (AAGN). Severe AAV and FFS were defined as BVAS ≥ 12 and FFS ≥ 2, and the correlations between laboratory variables, BVAS, FFS, and SF-36 score were assessed using linear regression analysis. The optimal cut-off of serum YKL-40 for severe AAV and high FFS was calculated using the receiver operator characteristic curve analysis.ResultsOf the included 60 patients, 32 (53.3%), 17 (28.3%), and 11 (18.3%) were classified as microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis. The median BVAS and FFS were 7.0 and 1.0, whereas the mean SF-36 physical and mental component scores were 50.5 and 58.3. Serum YKL-40 level was higher in patients with severe AAV and high FFS compared to those without (p = 0.007 and p < 0.001); multivariable linear regression analysis revealed that serum YKL-40 was independently associated with BVAS, FFS, and SF-36 scores. On kidney tissues obtained from AAGN patients, strong cytoplasmic staining of YKL-40 was found in cells present in inflammatory lesions. In addition, AAV patients had higher levels of serum YKL-40 compared to those with systemic lupus erythematosus, rheumatoid arthritis, osteoarthritis, and healthy control. The proportion of patients having severe AAV and high FFS was significantly higher in those with serum YKL-40 > 221.3 ng/mL and > 227.1 ng/mL than those without (relative risk 2.852 and 7.000). In 12 patients with serial YKL-40 testing, 11 patients (91.7%) exhibited a reduction in serum YKL-40 levels following a decrease in disease activity (p < 0.001).ConclusionOur findings suggest that serum YKL-40 may be a clinically useful biomarker to assess AAV disease activity.Trial registrationRetrospectively registered.

Serum galectin-9 could be a potential biomarker in assessing the disease activity of antineutrophil cytoplasmic antibody-associated vasculitis.

Serum galectin levels have been reported to be associated with the activity in autoimmune diseases. This study investigated whether serum levels of galectin (Gal)-1, Gal-3, and Gal-9 could be used as biomarkers in assessing the disease activity of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Eighty AAV patients were selected for inclusion in our AAV cohort. AAV-specific indices and clinical and laboratory data were assessed on the same day when blood samples were obtained from the patient and serum levels of Gal-1, Gal-3, and Gal-9 were measured by ELISA from obtained sera. High disease activity was defined as Birmingham vasculitis activity score (BVAS) ≥ 12. The optimal cut-off value of galectins was extrapolated by receiver operator characteristic analysis and linear and logistic regression analyses were performed to evaluate the association between Gal-3, Gal-9, and BVAS. The median values of BVAS, Gal-1, Gal-3, and Gal-9 were 8.0, 38.1 ng/mL, 12.4 ng/mL, and 1017.7 ng/mL, respectively. Serum Gal-3 and Gal-9 levels were correlated with BVAS (r=0.375 and r=0.462), while only serum Gal-9 levels were independently associated with BVAS (β=0.250) in linear regression analyses. Serum Gal-9 ≥10.28 ng/mL was also associated with high activity of AAV (odds ratio 5.303) in multivariable logistic regression analysis. In addition, serum Gal-1, Gal-3, and Gal-9 levels were found to differ according to ANCA positivity status and the presence of renal manifestations. These results suggest the potential possibility of serum Gal-9 levels in assessing AAV disease activity.

Lipid Profiles in Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis: A Cross-sectional Analysis

Objective. Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease (AID) characterised by necrotising intravascular inflammation. Growing evidence suggests that immune system triggers altered lipid metabolism in AIDs. We investigated whether changes in lipid profile correlate with severity of disease in AAV. Methods. Seven lipid profiles were evaluated utilizing frozen serum samples from 67 patients registered in the Severance Hospital ANCA-associated VasculitidEs cohort by a chemistry autoanalyzer. The Birmingham Vasculitis Activity Score (BVAS) version 3 was used to measure patient’s assessment of global disease activity. The relationship between the BVAS with continuous variables was calculated by Pearson’s correlation analysis. Results. Thirty-five (52.2%), 19 (28.4%), and 13 (19.4%) patients were diagnosed with microscopic polyangiitis, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis, respectively. Patients’ mean age was 60.0 years, and 22 (32.8%) were male. Among the lipid profiles investigated, total cholesterol, high-density lipoprotein, and low-density lipoprotein, and apolipoprotein A1 and B were significantly associated with BVAS; apolipoprotein A1 showed the highest correlation with BVAS (r=-0.521, p＜0.001), remaining consistent even in patients with new-onset disease (r=-0.430, p=0.012). Apolipoprotein A1 had the highest association with the renal manifestation score among the clinical scores comprising BVAS (r=-0.457, p＜0.001). Conclusion. Decreased lipid levels, especially apolipoprotein A1, are relevant to increased AAV disease activity, and differ according to organ involvement. Measuring lipid profiles could have clinical implications regarding the assessment of global disease activity and organ involvement patterns. (J Rheum Dis 2020;27:261 -269)

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.

Comparing outcomes of biopsy-proven anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis patients treated with cyclophosphamide in the 20th and 21st centuries: a 23-year study.

BackgroundAnti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a multisystem autoimmune disorder associated with significant morbidity and mortality. Approximately 80–90% of patients have circulating ANCAs. Long-term outcomes appear to be improving. This retrospective study analyses the incidence and patient outcomes over a period of 23 years at a single tertiary centre.MethodsOutcomes of patients diagnosed with AAV between 1 January 1988 and 31 December 2010 were collected retrospectively. Data including patient demographics, age of diagnosis, dates of starting renal replacement therapy, death and biochemistry results were collected. Patients were divided into two cohorts (1988–99 and 2000–10) and analysed using Stata software (StataCorp, College Station, TX, USA).ResultsA complete dataset was obtained for 273 patients. Of these patients, 101 were diagnosed between 1988 and 1999 while 172 were diagnosed between 2000 and 2010. The number of patients diagnosed with AAV increased from 2.2/million in 1988 to 10.3/million in 2010. A higher proportion of patients (56.4%) in the earlier cohort presented with creatinine >500 μmol/L compared with the later cohort (30.2%; P < 0.001). Overall patient survival improved significantly between the two cohorts. Cohort 1 had a median survival of 59 months compared with 125 months for Cohort 2 (P = 0.003).ConclusionsThis study shows that AAV is being diagnosed at an earlier stage, resulting in improved outcomes. This may be because of improvements in the management of AAV and chronic kidney disease.

Necroptosis controls NET generation and mediates complement activation, endothelial damage, and autoimmune vasculitis

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitutes life-threatening autoimmune diseases affecting every organ, including the kidneys, where they cause necrotizing crescentic glomerulonephritis. ANCA activates neutrophils and activated neutrophils damage the endothelium, leading to vascular inflammation and necrosis. Better understanding of neutrophil-mediated AAV disease mechanisms may reveal novel treatment strategies. Here we report that ANCA induces neutrophil extracellular traps (NETs) via receptor-interacting protein kinase (RIPK) 1/3- and mixed-lineage kinase domain-like (MLKL)-dependent necroptosis. NETs from ANCA-stimulated neutrophils caused endothelial cell (EC) damage in vitro. This effect was prevented by (i) pharmacologic inhibition of RIPK1 or (ii) enzymatic NET degradation. The alternative complement pathway (AP) was recently implicated in AAV, and C5a inhibition is currently being tested in clinical studies. We observed that NETs provided a scaffold for AP activation that in turn contributed to EC damage. We further established the in vivo relevance of NETs and the requirement of RIPK1/3/MLKL-dependent necroptosis, specifically in the bone marrow-derived compartment, for disease induction using murine AAV models and in human kidney biopsies. In summary, we identified a mechanistic link between ANCA-induced neutrophil activation, necroptosis, NETs, the AP, and endothelial damage. RIPK1 inhibitors are currently being evaluated in clinical trials and exhibit a novel therapeutic strategy in AAV.

18F-fluoro-deoxy-glucose positron emission tomography combined with computed tomography can reliably rule-out infection and cancer in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis suspected of disease relapse.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune diseases characterized by systemic inflammation in small- to medium-sized blood vessels. Although immunosuppressive therapy has greatly improved the prognosis for these patients, there are still significant comorbidities, such as cancer and infection, associated with AAV. These comorbidities are often indistinguishable from an underlying AAV disease relapse, and create a clinical conundrum, as these conditions are normally contraindications for immunosuppressive treatment. Thus, it is important to be able to rule out these comorbidities before initiation of immunosuppressive treatment. We examined 18F-fluoro-deoxy-glucose positron emission tomography combined with computed tomography (FDG-PET/CT)'s value in ruling out cancer or infection in patients with AAV.Data were obtained retrospectively for a clinically based cohort of AAV patients who underwent FDG-PET/CT during 2009 to 2014 owing to a suspicion of cancer, infection, or both cancer and infection indistinguishable from disease relapse. FDG-PET/CT conclusions were compared to the final diagnoses after follow-up analysis (mean 43 months).A total of 19 patients were included who underwent a total of 26 scans. The results of FDG-PET/CT outcome compared to final diagnosis were: 9 true positives, 3 false positives, 13 true negatives, and 1 false negative. The diagnostic probabilities for FDG-PET/CT with respect to overall comorbidity (i.e., cancer or infection) were: sensitivity 90% ( 95% confidence interval [CI] 60%–98%), specificity 81% ( 95% CI 57%–93%), positive predictive value 75% (95% CI 47%–91%), negative predictive value 93% (95% CI 68%–99%), and accuracy 84% (95% CI 66%–94%).FDG-PET/CT had a high negative predictive value and ruled out the comorbidities correctly in all but one case of urinary tract infection, a well-known limitation. Our study showed FGD-PET/CT's promise as an effective tool for ruling out cancer or infection in patients with AAV albeit in a limited population.

CD14 expression is increased on monocytes in patients with anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis and correlates with the expression of ANCA autoantigens.

Monocyte subsets with differing functional properties have been defined by their expression of CD14 and CD16. We investigated these subsets in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) and determined their surface expression of ANCA autoantigens. Flow cytometry was performed on blood from 14 patients with active AAV, 46 patients with AAV in remission and 21 controls. The proportion of classical (CD14(high) CD16(neg/low)), intermediate (CD14(high) CD16(high)) and non-classical (CD14(low) CD16(high)) monocytes and surface expression levels of CD14 and CD16 were determined, as well as surface expression of proteinase 3 (PR3) and myeloperoxidase (MPO) on monocyte subsets. There was no change in the proportion of monocytes in each subset in patients with AAV compared with healthy controls. The expression of CD14 on monocytes from patients with active AAV was increased, compared with patients in remission and healthy controls (P < 0.01). Patients with PR3-ANCA disease in remission also had increased monocyte expression of CD14 compared with controls (P < 0.01); however, levels in patients with MPO-ANCA disease in remission were lower than active MPO-ANCA patients, and not significantly different from controls. There was a correlation between CD14 and both PR3 and MPO expression on classical monocytes in AAV patients (r = 0.79, P < 0.0001 and r = 0.42, P < 0.005, respectively). In conclusion, there was an increase in monocyte CD14 expression in active AAV and PR3-ANCA disease in remission. The correlation of CD14 expression with ANCA autoantigen expression in AAV may reflect cell activation, and warrants further investigation into the potential for increased CD14 expression to trigger disease induction or relapse.

Serum IL-17 and IL-23 levels and autoantigen-specific Th17 cells are elevated in patients with ANCA-associated vasculitis

The Th17 subset has been implicated in the pathogenesis of a number of autoimmune diseases. However, little is known about its role in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). We measured serum levels of IL-17A and associated upstream cytokines and the frequency of IL-17-producing autoantigen-specific T cells in patients with AAV. ELISA on sera from acute (n = 28) and convalescent (n = 65) patients with AAV from Hammersmith Hospital was performed for IL-17A and the associated upstream cytokines IL-23, IL-6 and IL-1beta, as well as the Th1 cytokine IFN-gamma. ELISPOT was performed to measure autoantigen-specific recall T cell responses in convalescent patients and the frequency of IL-17- and IFN-gamma-producing cells. Serum IL-17A and IL-23 levels were significantly elevated in acute AAV patients compared to healthy controls (P < 0.01 and P < 0.001, respectively), but importantly, remained elevated in a proportion of convalescent patients. By contrast, no significant differences in IFN-gamma levels were detected between patient groups and controls. Patients with elevated levels of IL-23 compared to those with low IL-23 had more active disease as measured by Birmingham Vasculitis Activity Score (P < 0.05) and had higher ANCA titres (P < 0.05). Critically, immunosuppressive therapy did not always effectively suppress IL-23 or IL-17 production. Additionally, autoantigen-specific IL-17-producing, but not IFN-gamma-producing, cells were significantly elevated in patients during disease convalescence compared to healthy controls. These data implicate the Th17 axis and specifically IL-23 as mediators of more severe disease in AAV. Their persistence despite conventional treatment may contribute to high relapse rates.

CD45RC Isoform Expression Identifies Functionally Distinct T Cell Subsets Differentially Distributed between Healthy Individuals and AAV Patients

In animal models of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), the proportion of CD45RC T cell subsets is important for disease susceptibility. Their human counterparts are, however, functionally ill defined. In this report, we studied their distribution in healthy controls (HC), AAV patients and in Systemic lupus erythematous (SLE) patients as disease controls. We showed that CD45RC expression level on human CD4 and CD8 T cells identifies subsets that are highly variable among individuals. Interestingly, AAV patients exhibit an increased proportion of CD45RClow CD4 T cells as compared to HC and SLE patients. This increase is stable over time and independent of AAV subtype, ANCA specificity, disease duration, or number of relapses. We also analyzed the cytokine profile of purified CD4 and CD8 CD45RC T cell subsets from HC, after stimulation with anti-CD3 and anti-CD28 mAbs. The CD45RC subsets exhibit different cytokine profiles. Type-1 cytokines (IL-2, IFN-γ and TNF-α) were produced by all CD45RC T cell subsets, while the production of IL-17, type-2 (IL-4, IL-5) and regulatory (IL-10) cytokines was restricted to the CD45RClow subset. In conclusion, we have shown that CD45RC expression divides human T cells in functionally distinct subsets that are imbalanced in AAV. Since this imbalance is stable over time and independent of several disease parameters, we hypothesize that this is a pre-existing immune abnormality involved in the etiology of AAV.