Antibody Associated Vasculitis Patients Research Articles

FC059: Cardiovascular Outcomes in Anti-Neutrophil Cytoplasmic Antibody Associated Vasculitis in Denmark 1996–2018

Abstract BACKGROUND AND AIMS Antineutrophil cytoplasmic antibody associated vasculitis (AAV) is a group of autoimmune systemic inflammatory diseases, with cardiovascular disease being the leading cause of death. However, large-scale real-world data on the risk of long-term cardiovascular outcomes associated with AAV are limited. Therefore, to understand, screen and optimize prevention of cardiovascular disease in AAV patients, we investigated the risk of long-term ischemic cardiovascular events, including ischemic heart disease, coronary angiogram (CAG), percutaneous coronary intervention (PCI) and ventricular arrhythmia/use of implantable cardioverter-defibrillator (ICD) devices. Secondary outcomes included heart failure (HF), atrial fibrillation (AF), stroke, venous thrombotic events and cardiac arrest. METHOD We included all incident patients with AAV diagnosed during 1996–2018. Patients were identified from the Danish nationwide healthcare registries by use of a recently validated method (positive predictive value of 97%) [1] comprising at least two consecutive hospital encounters registered as either polyangiitis with granulomatosis or microscopic polyangiitis (International Classification of Diseases, 10th Edition [ICD-10]: DM31.3 and DM31.7). Patients with AAV were matched 1:3 with controls from the general population on age and gender. We computed adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs) for each cardiovascular outcome, with all-cause mortality accounted for as a competing risk. G-computation of HRs was performed to estimate 5-year absolute risks standardized to the distribution of risk factors in the population. RESULTS A total of 2306 AAV patients [median age: 62.9 years (25th–75th percentile: 50.9–72.0 years), 52.6% male gender] were matched with 6918 controls. Median study follow-up was 9.5 years (25th–75th percentile: 5.3–15.8 years). Compared with controls, AAV patients had a higher rate of ischemic heart disease [HR 1.67 (95% CI 1.45–1.95)], myocardial infarction [HR 1.43 (95% CI 1.11–1.83)], CAG [HR 1.51 (95% CI 1.27–1.80)], PCI [HR 1.42 (95% CI 1.11–1.88)] and ventricular arrhythmia/ICD implantation [HR 2.03 (95% CI 1.17–3.55)]. Secondarily, AAV patients also had an increased rate of additional adverse cardiovascular events: HF [HR 1.77 (95% CI 1.48–2.11)], deep vein thrombosis [HR 2.89 (95% CI 2.24–3.72)], pulmonary embolism [HR 3.59 (95% CI 2.74–4.72)], AF [HR 1.73 (95% CI 1.51–1.98)], ischemic stroke [HR 1.34 (95% CI 1.12–1.61)] and in-hospital cardiac arrest [HR 1.97 (95% CI 1.29–2.99)]. AAV patients had a significantly increased standardized 5-year absolute risk of all outcomes except for MI, PCI and ventricular arrhythmia/ICD implantations compared with controls. CONCLUSION In this large nationwide registry-based follow-up study, AAV patients had a higher risk of ischemic cardiovascular events and were more likely to require revascularization therapy compared with matched control subjects. Moreover, AAV patients had a higher risk of HF, atrial- and ventricular arrhythmias as well as venous thrombotic events and ischemic stroke when compared with matched control subjects.

Identification of diagnostic markers and immune cell infiltration characteristics in antineutrophil cytoplasmic antibody-associated vasculitis by weighted gene co-expression network analysis

BackgroundAntineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a group of life-threatening systemic autoimmune diseases. The aim of this study was to determine the relationship between the AAV hub gene and immune cell infiltration, and its value for clinical disease treatment.MethodsWe downloaded the microarray information of 37 AAV patients and 27 controls from Gene Expression Omnibus (GEO). Genes were classified into totally different modules exploitation weighted gene co-expression network analysis (WGCNA). AAV diagnostic indicators were screened and then assessed immune cell infiltration by the least absolute shrinkage and selection operator (LASSO) and CIBERSORT. Finally, Connectivity Map analysis was applied to predict possible AAV glomerulus injury improvement therapies.ResultsWGCNA was developed and differentially expressed genes were classified into 6 modules, the black module was most tightly correlated to AAV. Among them, TIMP1 and FCER1G were most closely related to clinical features. Resting mast cells and monocytes emerged as having the foremost distinguished variations in AAV. C3AR1 and FCER1G were involved in AAV development by immune regulation. Connectivity Map analysis indicated the most significant compound was fisetin.ConclusionsThe present study is that the initial to spot immune cell infiltration with microarray data of glomeruli in AAV, which provides novel proof and clues for additional analysis of the molecular mechanisms.

Analyses of registry data of patients with anti-GBM and antineutrophil cytoplasmatic antibody-associated (ANCA) vasculitis treated with or without therapeutic apheresis

Therapeutic apheresis (TA) as a treatment for antibody-associated vasculitis (AAV) was questioned by the PEXIVAS although the MEPEX study favored TA.The aim of this study was to evaluate the efficacy of TA to improve renal function in patients consecutively included in the WAA-apheresis registry versus patients not treated with TA. Materials and methodsIncluded were 192 patients that suffered from anti-glomerular basement membrane disease (anti-GBM, n = 28) and antineutrophil cytoplasmic antibody-associated vasculitis of MPO or PR3 origin. Of these 119 had performed TA and the other 73 had not performed TA for theses diagnoses (CTRL). ResultsElderly had an increased risk to die within 12 months (p = 0.002). All 28 anti-GBM had renal involvement, 21 dialysis dependent. At 3 month nine (36 %) did not need dialysis. Baseline data regarding renal function of AAV patients, subtype MPO and PR3, were worse in the TA groups than in CTRL. Recovery out of dialysis was better for the PR3-TA group compared with 1) the controls of MEPEX (RR 0.59, CI 0.43−0.80) and 2) the MPO-TA patients (RR 0.28, CI 0.12−0.68). The MPO-TA recovered similarly as the MEPEX-CTRL. Renal function improved most for TA-patients from baseline during the first 3 months (MPO-TA and PR3-TA) and stabilized thereafter and less for MPO-CTRL and PR3-CTRL. ConclusionPR3-TA patients seem to have best chances to get out of dialysis. PR3-TA and MPO-TA improved residual renal function better than CTRL. The present study recommends reconsiderations to use TA for AAV especially those with PR3-vasculitis with severe renal vasculitis.

The neutrophil-to-lymphocyte ratio as a marker of vasculitis activity, severe infection and mortality in anca-associated vasculitis: A retrospective study

IntroductionAnti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a multisystemic disease. Despite the improvement in mortality rate since the introduction of immunosuppression, long-term prognosis is still uncertain not only because of the disease activity but also due to treatment associated adverse effects. The neutrophil-to-lymphocyte ratio (NLR) has been demonstrated as an inflammatory marker in multiple settings. In this study, we aimed to investigate the prognostic ability of the NLR in AAV patients. MethodsWe conducted a retrospective analysis of the clinical records of all adult patients with AVV admitted to the Nephrology and Renal Transplantation Department of Centro Hospitalar Universitário Lisboa Norte from January 2006 to December 2019. NLR was calculated at admission. The outcomes measured were severe infection at 3 months and one-year mortality. The prognostic ability of the NLR was determined using the receiver operating characteristic (ROC) curve. A cut-off value was defined as that with the highest validity. All variables underwent univariate analysis to determine statistically significant factors that may have outcomes. Only variables which significantly differed were used in the multivariate analysis using the logistic regression method. ResultsWe registered 45 cases of AVV. The mean age at diagnosis was 67.5±12.1 years and 23 patients were male. The mean Birmingham Vasculitis Activity Score (BVAS) at presentation was 26.0±10.4. Twenty-nine patients were ANCA-MPO positive, 7 ANCA-PR3 positive and 9 were considered negative ANCA vasculitis. At admission, mean serum creatinine (SCr) was 4.9±2.5mg/dL, erythrocyte sedimentation rate (ESR) was 76.9±33.8mm/h, hemoglobin was 9.5±1.7g/dL, C-reactive protein was 13.2±5.8mg/dL and NLR was 8.5±6.8. Thirty-five patients were treated with cyclophosphamide, eight patients with rituximab for induction therapy. Twenty patients developed severe infection within the first three months after starting induction immunosuppression. In a multivariate analysis, older age (73.6±10.5 vs. 62.6±11.3, p=0.002, adjusted OR 1.08 [95% CI 1.01–1.16], p=0.035) and higher NLR (11.9±7.4 vs. 5.9±5.0, p=0.002, adjusted OR 1.14 [95% CI 1.01–1.29], p=0.035) were predictors of severe infection at 3 months. NLR ≥4.04 predicted severe infection at 3 months with a sensitivity of 95% and specificity of 52% and the AUROC curve was 0.0794 (95% CI 0.647–0.900). Nine patients died within the first year. Severe infection at 3 months was independently associated with mortality within the first year (OR 6.19 [95% CI 1.12–34.32], p=0.037). ConclusionsNLR at diagnosis was an independent predictor of severe infection within the first 3 months after immunosuppression start, and severe infection within the first three months was consequently correlated with one-year mortality. NLR is an easily calculated and low-cost laboratory inflammation biomarker and can prove useful in identifying AAV patients at risk of infection and poorer prognosis.

Anti-myeloperoxidase and proteinase 3 antibodies for nephritis flare prediction in anti-neutrophil cytoplasmic antibody-associated vasculitis.

The value of myeloperoxidase (MPO) and proteinase 3 (PR3) antibody titres in the assessment of renal disease activity and flare prediction in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is not well known. We performed a retrospective study including 113 AVV patients with renal biopsy-proven pauci-immune necrotizing glomerulonephritis from seven Spanish hospitals. The main inclusion criteria were assessment of MPO antibodies using multiplex flow immunoassay and PR3 antibody measurements using immunoassay chemiluminescence with an identical range of values for all participating centres. Serum MPO antibodies 3 ± 1.2 months before relapse were higher in patients who relapsed [19.2 ± 12.2 versus 3.2 ± 5.1 antibody index (AI); P < 0.001]. The discrimination value of MPO antibodies 3 months before renal relapse had an area under the receiver operating characteristics curve (AUC) of 0.82 [95% confidence interval (CI) 0.73-0.92; P < 0.001]. ΔMPO antibodies (change in antibodies titration 6 months before relapse) were higher in patients who relapsed (8.3 ± 12 versus 0.9 ± 3.1 AI; P = 0.001). The discrimination value of ΔMPO had an AUC of 0.76 (95% CI 0.63-0.88; P < 0.001). The positive predictive value of renal relapse in PR3 patients is 100% and the negative predictive value of renal relapse in patients with PR3-positive titres is 57.1%. Serum PR3 antibodies were higher in patients who relapsed 2.8 ± 1.4 months before relapse (58.6 ± 24.6 versus 2.0 ± 0.6 AI; P < 0.001). MPO level monitoring using multiplex flow immunoassay and PR3 measurements using immunoassay chemiluminescence are useful and sensitive tools for the prediction of renal relapse in the follow-up of AAV patients with renal disease and relevant surrogate markers of renal disease activity.

The novel fibrosis index at diagnosis may predict all-cause mortality in patients with antineutrophil cytoplasmic antibody-associated vasculitis without substantial liver diseases

OBJECTIVES:Antineutrophil cyto plasmic antibody-associated vasculitis (AAV) is a fatal disease. Currently, predictors of mortality due to AAV are based on the distribution of organ involvement. The novel fibrosis index (NFI) is an index composed of laboratory results that reflect the degree of liver fibrosis. This study aimed to evaluate whether NFI can predict poor outcomes in patients with AAV without substantial liver disease.METHODS:A total of 210 patients with immunosuppressive drug-naïve AAV were retrospectively reviewed. NFI was calculated as follows: NFI=(serum bilirubin × (alkaline phosphatase)2)/(platelet count×(serum albumin)2). NFI cut-off was set at 1.24 (the highest quartile). Poor outcomes were defined as all-cause mortality, relapse, and end-stage renal disease (ESRD).RESULTS:During the median 34.5 months of follow-up, 21 patients (10%) died, 72 patients (34.3%) relapsed, and 38 patients (18.1%) had ESRD due to AAV progression. The median calculated NFI was 0.61, and it was higher in AAV patients with all-cause mortality than in those without mortality, but the difference was not statistically significant (1.26 vs. 0.59). AAV patients with NFI at diagnosis ≥1.24 exhibited a significantly lower cumulative patient survival rate than those with NFI at diagnosis <1.24 (p=0.002). Multivariate Cox hazard model analysis showed that NFI at diagnosis ≥1.24 was an independent predictor of all-cause mortality in AAV (hazard ratios [HR] 2.850, 95% confidence interval [CI] 1.026, 7.910).CONCLUSIONS:NFI ≥1.24, which may be an independent predictive marker for all-cause mortality in AAV patients without substantial liver disease.

The neutrophil-to-lymphocyte ratio as a marker of vasculitis activity, severe infection and mortality in anca-associated vasculitis: A retrospective study

IntroductionAnti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a multisystemic disease. Despite the improvement in mortality rate since the introduction of immunosuppression, long-term prognosis is still uncertain not only because of the disease activity but also due to treatment associated adverse effects. The neutrophil-to-lymphocyte ratio (NLR) has been demonstrated as an inflammatory marker in multiple settings. In this study, we aimed to investigate the prognostic ability of the NLR in AAV patients. MethodsWe conducted a retrospective analysis of the clinical records of all adult patients with AVV admitted to the Nephrology and Renal Transplantation Department of Centro Hospitalar Universitário Lisboa Norte from January 2006 to December 2019. NLR was calculated at admission. The outcomes measured were severe infection at 3 months and one-year mortality. The prognostic ability of the NLR was determined using the receiver operating characteristic (ROC) curve. A cut-off value was defined as that with the highest validity. All variables underwent univariate analysis to determine statistically significant factors that may have outcomes. Only variables which significantly differed were used in the multivariate analysis using the logistic regression method. ResultsWe registered 45 cases of AVV. The mean age at diagnosis was 67.5±12.1 years and 23 patients were male. The mean Birmingham Vasculitis Activity Score (BVAS) at presentation was 26.0±10.4. Twenty-nine patients were ANCA-MPO positive, 7 ANCA-PR3 positive and 9 were considered negative ANCA vasculitis. At admission, mean serum creatinine (SCr) was 4.9±2.5mg/dL, erythrocyte sedimentation rate (ESR) was 76.9±33.8mm/h, hemoglobin was 9.5±1.7g/dL, C-reactive protein was 13.2±5.8mg/dL and NLR was 8.5±6.8. Thirty-five patients were treated with cyclophosphamide, eight patients with rituximab for induction therapy. Twenty patients developed severe infection within the first three months after starting induction immunosuppression. In a multivariate analysis, older age (73.6±10.5 vs. 62.6±11.3, p=0.002, adjusted OR 1.08 [95% CI 1.01–1.16], p=0.035) and higher NLR (11.9±7.4 vs. 5.9±5.0, p=0.002, adjusted OR 1.14 [95% CI 1.01–1.29], p=0.035) were predictors of severe infection at 3 months. NLR ≥4.04 predicted severe infection at 3 months with a sensitivity of 95% and specificity of 52% and the AUROC curve was 0.0794 (95% CI 0.647–0.900). Nine patients died within the first year. Severe infection at 3 months was independently associated with mortality within the first year (OR 6.19 [95% CI 1.12–34.32], p=0.037). ConclusionsNLR at diagnosis was an independent predictor of severe infection within the first 3 months after immunosuppression start, and severe infection within the first three months was consequently correlated with one-year mortality. NLR is an easily calculated and low-cost laboratory inflammation biomarker and can prove useful in identifying AAV patients at risk of infection and poorer prognosis.

High Incidence of Arterial and Venous Thrombosis in Antineutrophil Cytoplasmic Antibody-associated Vasculitis.

To determine the incidence of arterial thrombotic events (ATE) and venous thromboembolism (VTE) in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This is a retrospective cohort study presenting the incidence of ATE (coronary events or ischemic stroke) and VTE [pulmonary embolism (PE) or deep venous thrombosis (DVT)] in patients diagnosed with AAV between 2005 and 2014. There were 204 patients with AAV who were identified. Median followup for surviving patients was 5.8 (range 1-10) years, accounting for 1088 person-years (PY). The incidence of ATE was 2.67/100 PY (1.56 for coronary events and 1.10 for ischemic stroke) and for VTE was 1.47/100 PY (0.83 for DVT only and 0.64 for PE with/without DVT). On multivariate analysis, prior ischemic heart disease (IHD) and advancing age were the only independent predictors of ATE. Among patients without prior IHD or stroke, the incidence of ATE remained elevated at 2.32/100 PY (1.26 for coronary events and 1.06 for ischemic stroke). ATE, but not VTE, was an independent predictor of all-cause mortality. Event rates for both ATE and VTE were highest in the first year after diagnosis of AAV but remained above the population incidence during the 10-year followup period. In comparison to reported rates for the UK population, the event rates in our AAV patients were 15-times higher for coronary events, 11-times higher for incident stroke, and 20-times higher for VTE. Patients with AAV have a high incidence of arterial and venous thrombosis, particularly in the first year after diagnosis.

Caveolin-1 Single Nucleotide Polymorphism in Antineutrophil Cytoplasmic Antibody Associated Vasculitis

ObjectiveImmunosuppression is cornerstone treatment of antineutrophil cytoplasmic antibody associated vasculitis (AAV) but is later complicated by infection, cancer, cardiovascular and chronic kidney disease. Caveolin-1 is an essential structural protein for small cell membrane invaginations known as caveolae. Its functional role has been associated with these complications. For the first time, caveolin-1 (CAV1) gene variation is studied in AAV.Methods CAV1 single nucleotide polymorphism rs4730751 was analysed in genomic DNA from 187 white patients with AAV from Birmingham, United Kingdom. The primary outcome measure was the composite endpoint of time to all-cause mortality or renal replacement therapy. Secondary endpoints included time to all-cause mortality, death from sepsis or vascular disease, cancer and renal replacement therapy. Validation of results was sought from 589 white AAV patients, from two European cohorts.ResultsThe primary outcome occurred in 41.7% of Birmingham patients. In a multivariate model, non-CC genotype variation at the studied single nucleotide polymorphism was associated with increased risk from: the primary outcome measure [HR 1.86; 95% CI: 1.14-3.04; p=0.013], all-cause mortality [HR:1.83; 95% CI: 1.02-3.27; p=0.042], death from infection [HR:3.71; 95% CI: 1.28-10.77; p=0.016], death from vascular disease [HR:3.13; 95% CI: 1.07-9.10; p=0.037], and cancer [HR:5.55; 95% CI: 1.59-19.31; p=0.007]. In the validation cohort, the primary outcome rate was far lower (10.4%); no association between genotype and the studied endpoints was evident.ConclusionsThe presence of a CC genotype in Birmingham is associated with protection from adverse outcomes of immunosuppression treated AAV. Lack of replication in the European cohort may have resulted from low clinical event rates. These findings are worthy of further study in larger cohorts.

Invasive Pulmonary Aspergillosis in Patients With Antineutrophil Cytoplasmic Antibody Associated Vasculitis

Invasive pulmonary aspergillosis (IPA) has been reported as a severe opportunistic infection in immunocompromised patients without neutropenia or cancer. Patients with antineutrophil cytoplasmic antibody associated vasculitis (AAV) with immunosuppressive treatment are susceptible to IPA, but only few cases were reported in the literature. We retrospectively analyze the clinical characteristics of our patients with IPA in AAV. Hospitalized patients with AAV who developed IPA were selected. Their clinical data were retrospectively reviewed and possible risk factors for development of IPA were investigated. Seven of 157 patients with AAV were identified to have IPA. Two patients were classified as Wegener granulomatosis and 5 as microscopic polyangiitis with a mean age at 68.6 +/- 10.9 years. After immunosuppressive therapy, 7 patients developed IPA within 2 approximately 13 weeks. They had 1 or more risk factors increasing susceptibility to Aspergillus. Pre-existing chronic respiratory diseases were found in 5 patients. Despite intensive antifungal therapy, only 3 patients survived. The patients who died were older, with more severe lung injury and lower hemoglobin level. AAV patients with immunosuppressive therapy are susceptible to Aspergillus infection. Monitoring and prophylactic antifungal therapy should be recommended for patients at high risk.

Retinoid X receptor beta polymorphisms do not explain functional differences in vitamins D and A response in Antineutrophil cytoplasmic antibody associated vasculitis patients

It has been suggested that the retinoid X receptor beta (RXRB) gene is a risk factor for Wegener's granulomatosis. We addressed if there is a functional difference in the response to retinoic acid (RA) and vitamin D in Antineutrophil cytoplasmic antibody (ANCA) associated systemic vasculitis (AASV) patients and if this was associated with RXRB genotypes. TNFα and IL-10 production were measured in whole blood assay from AASV patients (n = 51) and healthy controls (HC, n = 67). One micromolar of 1,25-(OH)2 D3, 9-cis RA (9c-RA) or all-trans RA (ATRA) was added to the assay. Genotyping was performed for exons 7 and 2 of the RXRB gene and for a microsatellite in vicinity of the RXRB gene. Lipopolysaccharide (LPS) mediated TNFα production and IL-10 were significantly lower in patients. Addition of 1,25-(OH)2 D3, ATRA or 9c-RA, blunted TNFα production, more pronounced in patients. Although all three compounds inhibited IL-10 production significantly in HC, only 1,25-(OH)2 D3 was found to be effective in patients. Allele distribution of the RXRB microsatellite differed significantly between patients and HC. This was not found for the SNP in exons 2 and 7. Genotype of the latter correlated with the ability of 1,25-(OH)2 D3 and ATRA to inhibit IL-10 production. We provide immunological evidence for a functional difference in vitamins D and A responsiveness in AASV patients. Since the inhibition of TNFα was more effective in patients, vitamin D supplementation might be an additional therapeutical approach.