Active Associated Vasculitis Research Articles

Detection of serum interleukin-18 level and neutrophil/lymphocyte ratio in patients with antineutrophil cytoplasmic antibody-associated vasculitis and its clinical significance.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune diseases. This study aimed to investigate the clinical significance of changes in interleukin-18 (IL-18) and neutrophil/lymphocyte ratio (NLR) in the pathogenesis of AAV and the impact of NLR on the prognosis of patients. The clinical data of 52 AAV patients (AAV group) who met the conditions of hospitalization, 30 patients with mild mesangial proliferative glomerulonephritis (disease controls), and 30 healthy volunteers (normal controls) in Nephrology Department of Liuzhou People's Hospital from May 2020 to August 2022 were selected. A total of 52 AAV patients were divided into active phase (>15 points) and remission phase (≤15 points) based on the Birmingham vasculitis activity score (BVAS). Serum IL-18 level was detected by enzyme-linked immunosorbent assay in three groups. Pearson product moment correlation analysis was performed to investigate the correlation between serum IL-18 levels and clinical laboratory indicators, and receiver operating characteristic (ROC) curve analysis was performed on serum IL-18, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) levels, and NLR in AAV patients. The levels of serum creatinine, parathyroid hormone, β2-microglobulin (β2-MG), ESR, CRP, and IL-18 in active stage of AAV were significantly higher than those in remission stage of AAV. Moreover, the serum IL-18 level of active AAV patients was significantly higher than that of disease control group (P < 0.05). The levels of eGFR, hemoglobin, and complement C3 were significantly lower than those during the remission (P < 0.05). Pearson product moment correlation analysis showed that serum IL-18 level in AAV patients was positively correlated with BVAS score and ESR level. The area under the curve of serum IL-18, NLR, CRP, ESR levels evaluated by ROC curve was 0.921, 0.899, 0.83, and 0.75, respectively. Kaplan-Meier survival curve showed that the cumulative survival rate of patients in low NLR group was significantly higher than that in high NLR group (68.36 vs 42.89%), with significant difference (Log-Rank = 6.745, P = 0.025 < 0.05). IL-18 may be adopted as one of the important biological markers to judge the disease of AAV, and the cumulative survival rate of patients with high NLR is low, which may be applied as an indicator to evaluate the poor prognosis of patients with AAV.

The intrinsic coagulation pathway plays a dominant role in driving hypercoagulability in ANCA-associated vasculitis

AbstractThe risk of a venous thrombotic event (VTE) is increased in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV); however, a detailed understanding of the underlying mechanisms of hypercoagulability is limited. We assessed prospectively different coagulation parameters in 71 patients with active AAV at baseline and after 6 months of follow-up. D-dimers and fibrinogen were increased in most patients at presentation and remained elevated in half of the patients. Particularly, thrombin-antithrombin (T:AT) complex and activated coagulation factors in complex with their natural inhibitors of the intrinsic coagulation pathway (ie, activated FXII:C1 esterase inhibitor [FXIIa:C1Inh], FXIa:AT, and FXIa:alpha1-antitrypsin [FXIa:α1AT]) were profoundly elevated in patients at baseline. Thrombin formation was dominantly correlated with coagulation factors of the intrinsic pathway (ie, FXIIa:AT, FXIa:AT, FXIa:α1AT, and FXIa:C1Inh) compared to the extrinsic pathway (ie, FVIIa:AT). Hypercoagulability correlated with higher disease activity, ANCA levels, C-reactive protein, serum creatinine, and proteinuria. VTEs were observed in 5 out of 71 (7%) patients within 1 month (interquartile range, 1-5) after inclusion. Baseline T:AT levels were significantly higher in patients with VTE than in those without VTE (P = .044), but other clinical or laboratory markers were comparable between both groups. Hypercoagulability is dominantly characterized by activation of the intrinsic coagulation pathway and elevated D-dimers in active AAV. The driving factors of hypercoagulability are yet to be studied but are most likely related to an interplay of increased disease activity, vascular inflammation, and endothelial damage. Future targets for intervention could include inhibitors of the intrinsic coagulation pathway and compounds specifically reducing the hyperinflammatory state.

Complement alternative pathway determines disease susceptibility and severity in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis

Activation of the alternative pathway (AP) of complement is involved in the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV), although the underlying molecular mechanisms are unclear. To gain insight into the role of the AP, common gene variants in CFH/CFHR1-5, CFB, C3 and MCP, and longitudinal determinations of plasma C3, C4, FH, FHR-1, FHR-2, FHR-5, FB, properdin and sC5b-9 levels were analyzed in a Spanish AAV cohort consisting of 102 patients; 54 with active AAV (active cohort) and 48 in remission not receiving immunosuppressants or dialysis therapy (remission cohort). The validation cohort consisted of 100 patients with ANCA-associated glomerulonephritis. Here, we demonstrated that common genetic variants in complement components of the AP are associated with disease susceptibility (CFB32Q/W) or severity of kidney damage in AAV (CFH-H1, CFHH2 and ΔCFHR3/1). Plasma levels of complement components were significantly different between active and remission cohorts. In longitudinal observations, a high degree of AP activation at diagnosis was associated with worse disease outcome, while high basal FHR-1 levels and lower FH/FHR-1 ratios determined severe forms of kidney associated AAV. These genetic and plasmatic findings were confirmed in the validation cohort. Additionally, autoantibodies against FH and C3 convertase were identified in one and five active patients, respectively. Thus, our study identified key genetic and plasma components of the AP that determine disease susceptibility, prognosis, and severity in AAV. Our data also suggests that balance between FH and FHR-1 is critical and supports FHR-1 as a novel AP-specific therapeutic target in AAV.

Elevated plasma FXII is associated with disease activity in ANCA-associated vasculitis: A Retrospective Cross-Sectional Study in Western China

This study examined whether plasma FXII levels reflect disease activity in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Plasma FXII levels were detected by ELISA in 127 patients with AAV, and their associations with disease activity and plasma myeloperoxidase (MPO)-ANCA titre were examined. Immunofluorescent co-staining of FXII and neutrophils was performed on the renal tissues of patients with AAV. MPO expression in renal biopsy tissues was determined by immunohistochemical staining. The association between plasma FXII levels and histological activity was assessed in 82 patients who underwent kidney biopsy. Plasma FXII levels were considerably increased in patients with clinically active AAV compared to those in clinical remission and healthy individuals. Plasma FXII levels correlated positively with creatinine (r = 0.377), CRP (r = 0.222), urine red blood cell (r = 0.203), serum MPO-ANCA titer (r = 0.353), white blood cell (r = 0.194), percentage of glomeruli with crescents (P = 0.001), capillary breaks (P = 0.001), interstitial inflammation (P < 0.001) and fibrinoid necrosis (p < 0.001) on kidney biopsy. The plasma FXII optimal cut-off value for evaluating AAV activity was 24.5 μg/mL (sensitivity = 0.81, specificity = 0.82, P = 0.0001), which was superior to that achieved using conventional serologic biomarkers. Co-expression of FXII and neutrophils was higher, with increased MPO expression, in renal tissue with pathologically active AAV than that observed in pathologically inactive tissues. In conclusion, elevated plasma FXII levels reflect AAV clinical and histologic activity, and can serve as markers of active AAV.

Augmented thrombin formation is related to circulating levels of extracellular vesicles exposing tissue factor and citrullinated histone-3 in anti-neutrophil cytoplasmic antibody-associated vasculitides.

To study circulating myeloperoxidase (MPO)-positive extracellular vesicles (MPO+EVs) exposing citrullinated histone-3 (H3Cit), tissue factor (TF), and plasminogen (Plg) in association to thrombin generation in patients with anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). We have involved well-characterized patients with AAV together with population-based controls. Flow cytometry was used to assess the levels of MPO+EVs in citrated plasma. MPO+EVs were phenotyped by anti-MPO-antibodies together with anti-CD142 (anti-TF), anti-H3Cit, and anti-Plg antibodies. A modified Calibrated Automated Thrombogram (CAT) assay was utilized to measure thrombin generation in plasma initiated by EVs-enriched pellets. The activity of AAV was evaluated with the Birmingham Vasculitis Activity Score (BVAS). This study comprised 46 AAV patients, 23 in the active stage of the disease and 23 in remission, as well as 23 age- and sex matched population-based controls. Augmented levels of all investigated MPO+ EVs were found in active AAV patients in comparison to the subgroup of patients in remission and controls. Thrombin generation, measured by endogenous thrombin potential (ETP) and peak of thrombin formation, was higher in plasma when triggered by EVs-enriched pellet from AAV patients. ETP and peak were associated with the levels of MPO+TF+ and MPO+H3Cit+ EVs. Additionally, MPO+TF+ EVs correlated with the disease activity evaluated with BVAS. Augmented thrombin generation is found in AAV patients regardless of disease activity and is associated with higher exposure of TF and H3Cit on MPO+EVs. This may contribute to the increased risk of thrombosis seen in AAV patients.

The role of anti-HMGB1 antibody and anti-moesin antibody in ANCA-associated vasculitis

ObjectiveThe study aims to evaluate the role of anti-high mobility group box 1 (HMGB1) antibody and anti-moesin antibody in the diagnosis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and its possible relationship with the different clinical manifestations. MethodsThe study involved 60 AAV patients, 58 patients with autoimmune disease other than AAV and 50 healthy subjects. The serum levels of anti-HMGB1 and anti-moesin antibodies were determined by enzyme-linked immunosorbent assay (ELISA), and the second determination was made 3 months after treatment of AAV patients. ResultsSerum levels of anti-HMGB1 and anti-moesin antibodies in AAV group were significantly higher than those in non-AAV group and HC group. The area under the curve (AUC) of anti-HMGB1 and anti-moesin in diagnosing AAV were 0.977 and 0.670, respectively. Anti-HMGB1 levels were significantly elevated in AAV patients with pulmonary involvement, while the concentrations of anti-moesin were significantly increased in patients with renal damage. Anti-moesin were positively correlated with BVAS (r=0.261, P=0.044), creatinine (r=0.296, P=0.024) and negatively correlated with complement C3 (r=−0.363, P=0.013). Besides, anti-moesin levels of active AAV patients were significantly higher than those in inactive patients. The concentrations of serum anti-HMGB1 could be significantly decreased after induction remission treatment (P<0.05). ConclusionAnti-HMGB1 and anti-moesin antibodies play important roles in the diagnosis and prognosis of AAV, which may act as potential disease markers for AAV.

The role of anti-HMGB1 antibody and anti-moesin antibody in ANCA-associated vasculitis

ObjectiveThe study aims to evaluate the role of anti-high mobility group box 1 (HMGB1) antibody and anti-moesin antibody in the diagnosis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and its possible relationship with the different clinical manifestations. MethodsThe study involved 60 AAV patients, 58 patients with autoimmune disease other than AAV and 50 healthy subjects. The serum levels of anti-HMGB1 and anti-moesin antibodies were determined by enzyme-linked immunosorbent assay (ELISA), and the second determination was made 3 months after treatment of AAV patients. ResultsSerum levels of anti-HMGB1 and anti-moesin antibodies in AAV group were significantly higher than those in non-AAV group and HC group. The area under the curve (AUC) of anti-HMGB1 and anti-moesin in diagnosing AAV were 0.977 and 0.670, respectively. Anti-HMGB1 levels were significantly elevated in AAV patients with pulmonary involvement, while the concentrations of anti-moesin were significantly increased in patients with renal damage. Anti-moesin were positively correlated with BVAS (r=0.261, P=0.044), creatinine (r=0.296, P=0.024) and negatively correlated with complement C3 (r=−0.363, P=0.013). Besides, anti-moesin levels of active AAV patients were significantly higher than those in inactive patients. The concentrations of serum anti-HMGB1 could be significantly decreased after induction remission treatment (P<0.05). ConclusionAnti-HMGB1 and anti-moesin antibodies play important roles in the diagnosis and prognosis of AAV, which may act as potential disease markers for AAV.

Acute Brain Infarction in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Korean Single-Center Study.

This study investigated the clinical and radiological features of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients with acute brain infarction, using a cohort of Korean patients with AAV. This study included 263 patients with AAV. Acute brain infarction was defined as infarction that occurred within 7 days or less. The brain territories affected by acute brain infarction were investigated. Active AAV was arbitrarily defined as the highest tertile of Birmingham Vasculitis Activity Score (BVAS). The median age at diagnosis was 59.0 years, and 35.4% were male. Fourteen cases of acute brain infarction occurred in 12 patients (4.6%), which was calculated as 1332.2 per 100,000 patient-years and 10 times higher than the incidence rate in the Korean general population. Patients with AAV with acute brain infarction exhibited significantly older age, increased BVAS at diagnosis, and a more frequent history of prior brain infarction compared with those without. The brain territories affected in AAV patients were middle cerebral artery (50.0%), multiple territories (35.7%), and posterior cerebral artery (14.3%). Lacunar infarction and microhemorrhage were observed in 42.9% and 71.4% of cases, respectively. Prior brain infarction and BVAS at diagnosis were independently associated with acute brain infarction (hazard ratios, 7.037 and 1.089). Patients with AAV with prior brain infarction or BVAS for active AAV exhibited significantly lower cumulative acute brain infarction-free survival rates than those without. Acute brain infarction was observed in 4.6% of AAV patients, and both prior brain infarction and BVAS at diagnosis were independently associated with acute brain infarction.

Assessment of longitudinal serum neutrophil extracellular trap–inducing activity in anti-neutrophil cytoplasmic antibody–associated vasculitis and glomerulonephritis in a prospective cohort using a novel bio-impedance technique

Neutrophil extracellular traps (NET) have been implicated in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Here, we developed a novel, label-free, high-throughput bio-impedance technique to effectively measure serum NET-inducing activity. Using this technique, NET-inducing activity of serum derived from patients with AAV was assessed in a prospective cohort of 62 patients presenting with active AAV with major organ involvement. Thirty-five patients presented with new and 27 patients presented with relapsing AAV, of whom 38 had kidney and/or 31 had lung involvement. NET-inducing activity was assessed at diagnosis of active AAV (time zero), during the first 6 weeks of treatment, and after 6 months of treatment. Forty-seven patients revealed elevated NET-inducing activity at time zero. After initiation of immunosuppressive treatment, NET-inducing activity was reduced at six weeks. A subsequent increase at six months could potentially identify patients with relapsing disease (hazard ratio, 11.45 [interquartile range 1.36-96.74]). NET-inducing activity at time zero correlated with kidney function and proteinuria. Importantly, in kidney tissue, NETs co-localized with lesions typical of ANCA-associated glomerulonephritis and even correlated with systemic serum NET-inducing activity. Thus, our prospective data corroborate the importance of NET formation in AAV and ANCA-associated glomerulonephritis and the potential of longitudinal evaluation, as monitored by our novel bio-impedance assay and detailed histological evaluation.

Urinary T Cells Identify Renal Antineutrophil Cytoplasmic Antibody-Associated Vasculitis and Predict Prognosis: A Proof of Concept Study

Necrotizing crescentic glomerulonephritis is a major contributor to morbidity and mortality in Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). Because therapy relies on immunosuppressive agents with potentially severe adverse effects, a reliable noninvasive biomarker of disease activity is needed to guide treatment. We used flow cytometry to quantify T cell subsets in blood and urine samples from 95 patients with AAV and 8 controls to evaluate their biomarker characteristics. These were compared to soluble markers, monocyte chemoattractant protein-1 (MCP-1), soluble CD163 (sCD163), soluble CD25 (sCD25), and complement C5a (C5a), measured using multiplex analysis. Available kidney biopsies (n= 21) were classified according to Berden. Patients with active renal AAV (rAAV) showed significantly higher urinary cell counts than those in remission, or those with extrarenal manifestation, or healthy controls. Urinary T cells showed robust discrimination of disease activity with superior performance compared to MCP-1 and sCD163. Patients whose kidney biopsies had been classified as "crescentic" according to Berden classification showed higher urinary T cell counts. Discordant regulatory T cells (Treg) proportions and CD4+/CD8+ ratio in blood and urine suggested that urinary cells reflect tissue migration rather than mere micro-bleeding. Furthermore, urinary Treg and T helper cells (TH17) patterns were associated with clinical response and risk of renal relapse. Urinary T cells reflect the renal inflammatory milieu in AAV and provide further insights into the pathogenesis of this chronic condition. Their promising potential as noninvasive diagnostic and prognostic biomarkers deserves further exploitation.

Renal Expression of Annexin A1 Is Associated With the Severity of Renal Injury in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.

BackgroundIncreasing studies demonstrated the importance of activation of neutrophils in the pathogenesis of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). Previous studies showed that annexin A1 (ANXA1) inhibited the recruitment, transendothelial migration and respiratory burst of neutrophils and induced apoptosis of neutrophils. The current study aimed to investigate the plasma and renal levels of ANXA1 as well as their association with the disease severity in AAV patients.MethodsThirty-one AAV patients in active stage and 35 AAV patients in remission stage were recruited. The expression of ANXA1 in renal specimens was assessed by immunohistochemistry. The co-localization of ANXA1 with renal intrinsic and infiltrating cells was detected by double immunofluorescence. The plasma levels of ANXA1 were determined by ELISA. The association of plasma and renal levels of ANXA1 with clinicopathological parameters was further analyzed.ResultsPlasma levels of ANXA1 were significantly higher in active AAV patients than those in AAV patients in remission as well as healthy controls. The renal expression of ANXA1 was significantly higher in active AAV patients than in healthy controls and disease controls. Double immunofluorescence assay showed that ANXA1 was expressed in glomerular endothelial cells, mesangial cells, podocytes, proximal tubular epithelial cells, neutrophils, monocytes/macrophages and T cells in AAV patients. The mean optical density of ANXA1 in glomeruli was correlated with serum creatinine levels (r = −0.491, P = 0.005) and eGFR (r = 0.492, P = 0.005) at renal biopsy and the proportion of crescents (r = −0.423, P = 0.018) in renal specimens of AAV patients. The expression of ANXA1 in glomeruli of AAV patients achieving complete renal recovery was significantly higher than those achieving partial renal recovery.ConclusionIn AAV patients, the renal expression of ANXA1 was associated with the severity of renal injury.

Increased Circulating PD-1 hi CXCR5 - Peripheral T Helper Cells are Associated with Disease Activity of ANCA-Associated Vasculitis.

Newly identified PD-1 hiCXCR5 -CD4 + T cells, termed as peripheral helper T cells (Tph), have been found elevated and playing pathogenic role in some autoimmune diseases like systemic lupus erythematosus (SLE) and rheumatic arthritis (RA). However, the potential role of Tph cells in Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) remains unclear. Here, we explored the potential clinical significance of circulating Tph cells in the pathogenesis of AAV. Comparing 32 active AAV patients and 18 age- and sex-matched healthy controls (HCs), we found that the frequency of circulating Tph cells was significantly expanded in active AAV patients. Besides, programmed death 1 (PD-1) expression on the surface of Tph cells was significantly up-regulated in active AAV patients. Importantly, the frequency of circulating Tph cells was greatly decreased in AAV patients after receiving treatment. Tph cells frequency was positively correlated with the Birmingham Vasculitis Activity Score (BVAS), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), neutrophil lymphocyte ratio (NLR) and cellular crescent in active AAV patients, but negatively correlated with fibrosus crescent. Tph cells frequency was also positively correlated with naïve B cells, serum concentration of MPO-ANCAs, serum tumor necrosis factor-α (TNF-α), IL-4, IL-21 and IL-12. However, serum IL-10 exhibited negative correlation with circulating Tph cells in active AAV patients. These results demonstrated that circulating Tph cells are greatly expanded in active AAV patients and are positively associated with serum MPO-ANCAs and disease activity, thus contributing to the pathogenesis of AAV.

Anti-ETAR and suPAR as markers of disease activity in renal ANCA-associated vasculitis

PurposeIn anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), there is a lack of reliable biomarkers of disease activity. The aim of the study was to evaluate soluble urokinase plasminogen activator receptor (suPAR) and anti-endothelin-1 type A receptor (anti-ETAR) antibodies levels in active phase and remission of AAV. Patients and methodsWe enrolled 60 patients (median age 63.0 years) with renal AAV into this study. Plasma suPAR, urine suPAR (expressed as urine suPAR/creatinine ratio) and serum anti-ETAR antibodies were assayed by ELISA. Disease activity was assessed using Birmingham Vasculitis Activity Score (BVAS) and patients were divided into 2 subgroups based on their BVAS scores, namely: active AAV subgroup (BVAS≥1) and remission subgroup (BVAS ​= ​0). Median follow-up was 12 months. ResultsPatients with active AAV had higher levels of all candidate biomarkers in comparison to those in remission (p ​< ​0.05). C-statistics for plasma suPAR, urine suPAR/creatinine ratio and serum anti-ETAR were 0.807, 0.713 and 0.783, respectively. In multivariable analysis, no clear associations were found between serum anti-ETAR and BVAS, while both plasma suPAR and serum anti-ETAR were independently influenced by estimated glomerular filtration rate (eGFR). ConclusionsPlasma suPAR better discriminated between active AAV and remission in comparison to urine suPAR/creatinine ratio and serum anti-ETAR antibodies.

Mechanisms of thrombosis in ANCA-associated vasculitis.

Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have a two- to threefold greater risk of developing venous as well as arterial thrombotic events. Although such thrombotic events are more commonly seen during phases of active AAV, they are also recognized to occur during AAV in remission. Endothelial injury is a key pathogenic event in AAV. Endothelial injury can be caused by neutrophil activation and release of thrombogenic tissue factor into the circulation. Neutrophil activation further results in the formation of neutrophil extracellular traps (NETs). NETs contribute to thrombosis by expressing tissue factor. NETs have also been detected in cutaneous thrombi from patients with AAV induced by hydralazine. Activated neutrophils in AAV patients release thrombogenic microparticles loaded with tissue factor which further enhances clotting of blood. Antiphospholipid antibodies (APLs) have been detected in up to a third of AAV and might also be induced by drugs such as cocaine adulterated with levamisole and propylthiouracil, which are known to trigger AAV. Such APLs further drive the thrombosis in AAV. Once thrombogenesis occurs, the homeostatic mechanisms resulting in clot dissolution are further impaired in AAV due to anti-plasminogen antibodies. The ongoing pandemic of coronavirus disease 2019 (COVID-19) is associated with endothelial injury and NETosis, mechanisms which are in common with AAV. Reports of new-onset AAV following COVID-19 have been described in the literature, and there could be shared mechanisms driving these processes that require further evaluation.

POS1230 OUTCOME FOLLOWING COVID-19 INFECTION IN ANTI-NEUTROPHIL CYTOPLASMIC ANTIBODY (ANCA)-ASSOCIATED VASCULITIS

Background:Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) require immunosuppressive therapy for disease control and reduction of disease relapse and may be at risk for complications during Sars-CoV-2 (COVID-19) infection.Objectives:To analyze the consequences of COVID-19 in a large cohort of AAV patients regarding occurrence, need of hospitalization, treatment at the intensive care units (ICU), or death.Methods:Data were retrieved from March 2020 to mid-January 2021 from medical records from the AAV cohort (n=233). Patients diagnosed with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) or eosinophilic granulomatosis with polyangiitis (EGPA) were included. Data included age, gender, diagnosis, ongoing immunosuppressive medication at onset of COVID-19 or at last follow-up in non-COVID individuals. Renal involvement (ever) and estimated glomerular filtration rate (eGFR) were included. COVID-19 was confirmed either by a positive PCR test in the upper airways or by serology. Severe COVID-19 was defined as need of non-invasive ventilation, ICU care, and/or death.Results:The cohort comprised of 172 patients with GPA, 50 with MPA and 11 with EGPA. There were 121 females (52%). During the study period, 20 patients (8.6%) were diagnosed with COVID-19. The median age at data retrieval in all patients was 68 years (21-93), in the COVID-19 group 63 (29-93) and 68.5 (21-90) years in the non-COVID patients.Fourty-three patients in all (18%) were hospitalized during the study period of which 11 (4.7%) due to COVID-19 infection. In all, 8 deaths occurred of which 3 were related to COVID-19.At data retrieval, 110 (47%) patients were on prednisolone treatment, 10/20 (50%) in the COVID-19 group and 100 (47%) in the non-COVID-19 group (p=0.5), with significantly higher doses in COVID-19 patients (p&lt;0.001). In patients hospitalized with COVID-19, 6/11 (54.5%) were on prednisolone, median dose 5 mg/day (0-50). In the total group 112 (48%) were on disease modifying anti-rheumatic drugs (DMARD) and 64 (27.5%) on rituximab as maintenance therapy. Eight patients were on induction treatment with either cyclophosphamide or rituximab.Of the 20 COVID-19 cases, 8 had severe COVID-19. Of these, 2 were inactive without immunosuppressive treatment, 4 had stable disease with prednisolone (5-7.5 mg/day) in combination with DMARDs, and 2 were active treated with high dose prednisolone (25-50 mg/day) in combination with cyclophosphamide and rituximab (n=1) or rituximab (n=1).A higher proportion of patients had active AAV (p=0.03) in the severe COVID-19 then in the non-COVID group (10/213 patients).In the group with the severe COVID-19, 1/8 (12%) patient had rituximab as maintenance therapy, compared to 61/213 (28.6%) in the group of non-COVID-19 patients (p=0.5).Renal involvement (ever) was present in 144 patients (62%), in 6 patients (30%) with COVID- 19, from which 5 (62%) were in the group of severe COVID-19 patients. Median eGFR did not differ between severe COVID-19 and remaining patients with renal involvement independently of COVID-19 infection.Conclusion:We found a high rate of severe COVID-19 infection in our cohort of AAV patients which indicates risk for serious complications, especially in patients with active disease and intense immunosuppressive therapy. Maintenance therapy with rituximab did not seem to increase the risk for severe COVID-19. The findings stress the need for continued shielding and early vaccination in AAV patients.Disclosure of Interests:None declared

The therapeutic effect of plasma exchange on ANCA-associated vasculitis: A meta-analysis.

The therapeutic effect of plasma exchange (PLEX) combined with conventional treatment in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) remains controversial. We searched PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure for randomized controlled trials (RCTs) and cohort studies that compared PLEX added to conventional therapy with conventional therapy only in active AAV. 19 studies were included for the meta-analysis. Compared with the conventional therapy group, the PLEX group had a significantly reduced risk of end-stage renal disease (ESRD) at 3months (odds ratio (OR) = 0.32, 95% confidence interval (CI) = 0.16 - 0.66, p=0.002, I2 = 0%), and the ANCA titerwas also decreased (OR = 40.99, 95% Cl = 23.56 - 58.43, p<0.00001, I2 = 42%). The plasma and non-plasma exchange groups had no substantial differences in terms of short- and long-term outcomes, including all-cause mortality, ESRD risk at 12 months and 5 years, remission rate, serum creatine levels, or serious adverse events. PLEX therapy was not associated with favorable long-term outcomes, although the results showed benefits in the incidence of ESRD rate at 3 months and ANCA titers in patients with AAV. No advantage of PLEX added to conventional therapy on mortality and complete remission was observed in patients with diffuse alveolar hemorrhage. Further high-quality multicenter RCTs with a high number of participants are required to assess the potential efficacy of PLEX in active AAV.

Usefulness of tissue inhibitor of metalloproteinase 1 as a predictor of sustained remission in patients with antineutrophil cytoplasmic antibody-associated vasculitis

BackgroundWe previously identified tissue inhibitor of metalloproteinase 1 (TIMP-1) as a biomarker of disease activity that distinguished mildly or highly active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) from remission 6 months after the initiation of remission-induction therapy. In the present study, we investigated whether TIMP-1 is clinically useful as a predictor of relapse and sustained remission in AAV patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) during maintenance therapy.MethodsThe relationship between serum TIMP-1 levels and clinical outcomes in AAV patients receiving maintenance therapy was assessed using the follow-up data of a Japanese large-cohort study (the RemIT-JAV-RPGN study) and data collected from AAV patients on maintenance therapy in our hospital (the MAAV-EU study).ResultsIn the RemIT-JAV RPGN study, serum levels of TIMP-1 were significantly higher in mildly active AAV patients with MPA and GPA 6 months after the initiation of remission-induction therapy than in patients in remission. Regarding maintenance therapy, elevated levels of TIMP-1 in patients in remission were associated with relapse and/or difficulty reducing the glucocorticoid dosage after 6 to 12 months. In the MAAV-EU study, serum levels of TIMP-1 were elevated in relapsed patients 6 months before relapse, earlier than the increase in serum levels of CRP. Analyses of both studies revealed that approximately 30% of patients in remission with a serum TIMP-1 level ≥ 150 ng/mL relapsed after 6 to 12 months, while the majority of patients with a TIMP-1 level < 150 ng/mL sustained remission for at least 12 months.ConclusionWe herein demonstrated that TIMP-1 is more useful as a predictive biomarker of sustained remission than as a predictor of relapse in maintenance therapy for AAV. TIMP-1 levels < 150 ng/mL are important for the long-term maintenance of remission and may be an indicator for the tapering or cessation of treatment.

Double-negative T cells are absolutely elevated in patients with antineutrophil cytoplasmic autoantibody-associated vasculitis

CD3+CD4−CD8− [double-negative (DN)] T cells play vital roles in the pathogenesis of autoimmune disorders. In this study, we investigated the exact level of DN T cells in patients with antineutrophil cytoplasmic autoantibody (ANCA)–associated vasculitis (AAV). Forty patients with active AAV and 19 healthy controls (HCs) were enrolled in this study. Peripheral mononuclear cells were characterised phenotypically via flow cytometry. The potential clinical value of DN T cells was then assessed by the receiver operating characteristic (ROC) curves. The percentage (p < 0.001) and absolute number (p = 0.028) of DN T cells were found to be significantly higher in patients with AAV than in HCs. Relative to HCs, a lower percentage of DN T cells from patients with AAV was of the CD62L+CD45RO+ phenotype (p = 0.024), a higher percentage of these cells was of the CD62L–CD45RO– phenotype (p = 0.043). Patients with AAV had increased percentages of DN T cells expressing interferon (IFN)-γ (p = 0.032), interleukin (IL)-4 (p = 0.039) and IL-17 (p = 0.042). Furthermore, the percentages of IL-17–producing CD4+ T cells and IFN-γ–producing CD8+ T cells were significantly higher in patients with AAV than in HCs (p = 0.014, p = 0.008). Compared with the CD4+ and CD8+ T-cell subsets, DN T cells had the highest fractions of intracellular IL-17 in HCs and patients with AAV (both p < 0.001). In patients with AAV and renal damage, the percentage of DN T cells was expanded relative to that in patients without renal damage (p = 0.016). In addition, conventional methylprednisolone effectively reduced the percentage and overall number of DN T cells in patients with AAV (p = 0.028, p = 0.007). DN T cells represent a T-lymphocyte subset that produces inflammatory cytokines (IFN-γ, IL-4 and IL-17) and is absolutely elevated in patients with AAV. Additional investigations are required to determine their precise role in patients with AAV.

Comparative efficacy and safety of mycophenolate mofetil versus cyclophosphamide in patients with active antineutrophil cytoplasmic antibody-associated vasculitis: ameta-analysis of randomized trials.

This study aimed to assess the efficacy and safety of mycophenolate mofetil (MMF) versus cyclophosphamide (CYC) in patients with active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We performed ameta-analysis of four randomized clinical trials (RCTs; 300 patients) to examine the relative efficacy and safety of MMF compared to CYC in patients with active AAV. There was no significant difference in remission at 6months between MMF and CYC (odds ratio [OR] 1.311, 95% confidence interval [CI] 0.570-3.017, P = 0.524). Additionally, the relapse rate did not differ between the MMF and CYC groups (OR 1.331, 95% CI 0.497-3.568, P = 0.570). There was no significant difference in serious adverse event (SAE; OR 1.232, 95% CI 0.754-2.014, P = 0.404) and infection rates (OR 0.958, 95% CI 0.561-1.634, P = 0.873) between the MMF and CYC groups. Some heterogeneity was found in the meta-analysis of remission and relapse rates (I2 = 57.4%, 63.4%), but no between-study heterogeneity was found during the meta-analysis of SAE and infection rate. Egger's regression test showed no evidence of publication bias (Egger's regression test P-values >0.1). MMF was an equally effective alternative treatment to CYC and MMF was comparable to CYC in patients with active AAV in terms of safety, suggesting that MMF can be used as an alternative to CYC for remission induction in AAV.

Measuring Circulating Complement Activation Products in Myeloperoxidase- and Proteinase 3-Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

There is accumulating evidence that complement activation is important in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) pathogenesis. This study was undertaken to investigate complement activation in AAV with myeloperoxidase (MPO) positivity and AAV with proteinase 3 (PR3) positivity after determining optimal methods for measuring activated complement factors in circulation. Participants included 98 patients with AAV (45 MPO-ANCA positive, 53 PR3-ANCA positive) and 35 healthy controls. Plasma was obtained from blood collected using EDTA tubes, with or without 100 μg/ml Futhan. Levels of Bb, C3a, C5a, soluble C5b-9 (sC5b-9), properdin, and C4d were measured by enzyme-linked immunosorbent assay. Group comparisons were made using Wilcoxon's 2-sample test. Paired data were analyzed using a matched pairs signed rank test. Compared to healthy controls, certain complement analyte levels were high in patients with active AAV with MPO positivity, including C3a (P < 0.0001), C5a (P = 0.0004), and sC5b-9 (P = 0.0007). During remission, levels of Bb (P = 0.001), C3a (P < 0.0001), and sC5b-9 (P = 0.003) were higher. Compared to healthy controls, C3a (P < 0.0001), C5a (P = 0.002), sC5b-9 (P = 0.0001), and C4d (P = 0.005) levels were higher in patients with active AAV with PR3 positivity; levels of C3a (P < 0.0001) and C4d (P = 0.007) were also higher duriing remission. There were no significant differences in any complement analyte for either ANCA serotype between patients with active disease and those with disease in remission. Among patients with paired samples, sC5-9 levels were significantly lower during disease remission compared to active disease. C5a was significantly lower among patients with disease in long-term remission who were not receiving therapy. For Bb, C5a, and sC5b-9, median levels and individual values were considerably higher in control and patient samples processed without Futhan compared to those processed with Futhan. Complement activation occurs in both MPO-positive AAV and PR3-positive AAV. The complement activation profile differs according to disease activity and possibly ANCA serotype. Futhan reduces in vitro complement activation and provides a more accurate measurement.