Antineutrophil cytoplasmic antibody-associated vasculitis classification by cluster analysis based on clinical phenotypes: a single-center retrospective cohort study.

OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) refers to a group of small vessel inflammatory disorders. Overlapping clinical phenotypes of AAV subgroups continually provoke controversies over their diagnostic and classification criteria. METHODS: Using the agglomerative hierarchical clustering method, we classified 210 Korean patients diagnosed with AAV into mutually exclusive clusters according to Birmingham Vasculitis Activity Score items, ANCA specificity, sex, and age. We analyzed the resulting clusters' outcomes to investigate the clinical significance of the classification. We proposed a distance-based algorithm of patient assignment and explored its clinically relevant modification. RESULTS: In total, 116 patients (55%) had microscopic polyangiitis, 53 (25%) had granulomatosis with polyangiitis, and 42 (20%) had eosinophilic granulomatosis with polyangiitis. Our model grouped the patients into five clusters, namely, "limited proteinase 3 (PR3)-ANCA vasculitis," "generalized PR3-ANCA vasculitis," "ANCA-negative vasculitis," "renal-limited vasculitis," and "myeloperoxidase-ANCA vasculitis." Patients clustered under "generalized PR3-ANCA vasculitis" had a higher relapse rate (hazard ratio [HR] = 2.12, P = 0.067). The incidence of end-stage renal disease was higher in patients belonging to the "renal-limited vasculitis" cluster (HR=1.50, P=0.03), and those in the "ANCA-negative vasculitis" cluster experienced a relatively milder clinical course of AAV (mortality = 0). CONCLUSION: Because the clusters were naturally derived from their distinguished phenotypes and have different clinical courses, our clustering method may be a more clinically relevant classification system for AAV, revealing its phenotypic diversity. We also proposed a simple and intuitive distance-based assignment algorithm, which can be easily modified according to specific clinical needs. Key Points • In this study with a single-center AAV cohort, we showed that AAV can be divided into five distinct subclasses with different disease courses based on the clinical and laboratory features of the patients. • Our study revealed ethnic differences in AAV manifestation and suggests that physicians may need to analyze their own AAV patients to assess the disease status of AAV patients. • We proposed a distance-based cluster membership assignment method that can be clinically modified to fit the specific purpose of grouping patients.

Comparison of the 2022 ACR/EULAR Classification Criteria for Antineutrophil Cytoplasmic Antibody-Associated Vasculitis with Previous Criteria.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises group of small vessel vasculitides, including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). In 2022, the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) jointly proposed new classification criteria for AAV (the 2022 ACR/EULAR criteria). In this review, we briefly summarize the 2022 ACR/EULAR criteria for GPA, MPA, and EGPA, and introduce our clinical experience with applying them to patients who were previously diagnosed with AAV based on three criteria: firstly, the classification criteria for GPA and EGPA proposed by the ACR in 1990; secondly, the algorithm for the classification of AAV and polyarteritis nodosa proposed by the European Medicines Agency algorithm in 2007 (the 2007 EMA algorithm); and thirdly, the revised International Chapel Hill Consensus Conference nomenclature of vasculitides in 2012 (the 2012 CHCC definitions). We found that concordance rate was highest in patients with MPA (96.6%), followed by those with EGPA (86.3%) and GPA (73.8%). In addition, compared to previous criteria, we noted several issues of the undervalued or overvalued items in the 2022 ACR/EULAR criteria for classifying AAV and provided several suggestions. To increase the diagnostic accuracy and reduce the discordance rate among the new and previous criteria for AAV, we suggest that the previous criteria should be considered together with the 2022 ACR/EULAR criteria when applying the classification criteria for AAV to patients suspected of AAV.

The oxidative phosphorylation inhibitor IM156 suppresses B-cell activation by regulating mitochondrial membrane potential and contributes to the mitigation of systemic lupus erythematosus.

Current treatment strategies for autoimmune diseases may not sufficiently control aberrant metabolism in B-cells. To address this concern, we investigated a biguanide derivative, IM156, as a potential regulator for B-cell metabolism in vitro and in vivo on overactive B-cells stimulated by the pro-inflammatory receptor TLR-9 agonist CpG oligodeoxynucleotide, a mimic of viral/bacterial DNA. Using RNA sequencing, we analyzed the B-cell transcriptome expression, identifying the major molecular pathways affected by IM156 in vivo. We also evaluated the anti-inflammatory effects of IM156 in lupus-prone NZB/W F1 mice. CD19+B-cells exhibited higher mitochondrial mass and mitochondrial membrane potential compared to T-cells and were more susceptible to IM156-mediated oxidative phosphorylation inhibition. In vivo, IM156 inhibited mitochondrial oxidative phosphorylation, cell cycle progression, plasmablast differentiation, and activation marker levels in CpG oligodeoxynucleotide-stimulated mouse spleen B-cells. Interestingly, IM156 treatment significantly increased overall survival, reduced glomerulonephritis and inhibited B-cell activation in the NZB/W F1 mice. Thus, our data indicated that IM156 suppressed the mitochondrial membrane potentials of activated B-cells in mice, contributing to the mitigation of lupus activity. Hence, IM156 may represent a therapeutic alternative for autoimmune disease mediated by B-cell hyperactivity.

Extracellular histones aggravate autoimmune arthritis by lytic cell death.

Although recent studies have demonstrated a proinflammatory effect of extracellular histones in sepsis via endothelial cytotoxicity, little is known about their contribution to autoimmune arthritis. Therefore, we investigated the role of extracellular histones in autoimmune arthritis and their cytotoxic effect on synoviocytes and macrophages. We measured histones in the synovial fluid of patients with rheumatoid arthritis (RA) and evaluated arthritis severity in a serum-transfer arthritis (STA) mouse model with intraperitoneal histone injection. Histone-induced cytotoxicity was measured using SYTOX green staining in the synoviocyte cell line MH7A and macrophages differentiated from the monocytic cell line THP-1, and the production of damage-associated molecular patterns (DAMPs) was measured by HMGB1 and ATP. Furthermore, we performed RNA-seq analysis of THP-1 cells stimulated with H2B-α1 peptide or with its citrullinated form. The levels of histones were elevated in RA synovial fluid, and histones aggravated arthritis in the STA model. Histones induced cytotoxicity and DAMP production in synoviocytes and macrophages. Chondroitin sulfate reduced histone-induced cytotoxicity, while lipopolysaccharides aggravated cytotoxicity. Moreover, the cytotoxicity decreased when the arginines in H2B-α1 were replaced with citrullines, which demonstrated its electrostatic nature. In transcriptome analysis, H2B-α1 changed the gene expression pattern of THP-1 cells involving chemokines, interleukin-1, -4, -10, -13, and toll-like receptor (TLR) signaling pathways. Extracellular histones were increased in RA synovial fluid and aggravated synovitis in STA. They induced lytic cell death through electrostatic interaction with synoviocytes and macrophages, leading to the secretion of DAMPs. These findings suggest that histones play a central role in autoimmune arthritis.

Clinical Significance of Antineutrophil Cytoplasmic Antibody Positivity in Patients Infected with SARS-CoV-2.

OBJECTIVES: To investigate the rate of antineutrophil cytoplasmic antibody (ANCA) positivity and its clinical significance in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: This study included 178 patients infected with SARS-CoV-2 who were enrolled in a cohort at a single centre. Myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA levels in stored blood sera were measured using immunoassay kits. Mortality, mechanical ventilator care, and severe infection were assessed as three poor outcomes. The 2022 American College of Rheumatology and the European Alliance of Associations for Rheumatology (ACR/EULAR) classification criteria for the three subtypes of AAV were applied only to patients who had MPO-ANCA or PR3-ANCA among study subjects. RESULTS: The detection rate of ANCA positivity was 18.5%. MPO-ANCA and PR3-ANCA were found in 22 (12.4%) and 14 (7.9%) patients, respectively. However, neither MPO-ANCA nor PR3-ANCA affected the three poor outcomes. According to the new criteria, 12 (6.7%) and 21 (11.8%) patients were classified as having granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), respectively. CONCLUSIONS: SARS-CoV-2 infection may increase the rate of ANCA positivity. Although it might not affect poor outcomes, it might contribute to the classification of GPA and MPA despite uncertain clinical significance.

Association Between Idiopathic Cutaneous Leukocytoclastic Angiitis and ANCA-negative Microscopic Polyangiitis.

Objective: This study retrospectively reviewed the process of classifying antineutrophil cytoplasmic antibody (ANCA)-negative granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) in a cohort of patients with ANCA-associated vasculitis (AAV), and investigated the association between recurrent idiopathic cutaneous leukocytoclastic angiitis and ANCA-negative MPA. Methods: The medical records of 242 patients with AAV were retrospectively reviewed Of 49 patients with ANCA-negative AAV, 24 patients with ANCA-negative eosinophilic GPA (EGPA) were excluded, because ANCA positivity or negativity is not critical in classifying EGPA Ultimately, 25 patients with ANCA-negative GPA and MPA were analysed in this study The classification of GPA and MPA were based on the 2007 European Medicines Agency algorithm for AAV. Results: The median age of patients with ANCA-negative GPA and MPA was 540 years and 24% were male Of the 25 patients without ANCA, 8 patients were classified as GPA and 17 as MPA Eight patients with ANCA-negative GPA were easily confirmed as definitive GPA Fourteen of the 17 patients ANCA-negative MPA were classified as MPA based on histological features suggestive of AAV without granuloma formation and the absence of surrogate markers for GPA Meanwhile, three of the patients that were ANCA-negative exhibited only recurrent idiopathic cutaneous leukocytoclastic angiitis without other major organs affected and thus were classified as possible MPA Within one year, they were classified as definitive MPA based on ANCA positivity and/or renal histology. Conclusion: Recurrent idiopathic cutaneous leukocytoclastic angiitis may be associated with ANCA-negative MPA in patients who exhibit cutaneous necrotising vasculitis.

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

OBJECTIVES: 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). METHODS: 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. RESULTS: 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 (ß=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. CONCLUSIONS: These results suggest the potential possibility of serum Gal-9 levels in assessing AAV disease activity.

Serum progranulin as a predictive marker for high activity of antineutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: This study investigated whether serum progranulin could act as a predictive marker for high disease activity of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Fifty-eight AAV patients were included in this study. Clinical and laboratory data were obtained at blood collection. The Short-Form 36-Item Health Survey Physical and Mental Component Summaries (SF-36 PCS and SF-36 MCS), Birmingham Vasculitis activity score (BVAS), Five-Factor Score (FFS), and Vasculitis Damage Index (VDI) were assessed as AAV-specific indices. Whole blood was collected and serum samples were isolated and stored at -80°C. Serum progranulin concentration was quantified by ELISA kits. RESULTS: The median age of patients was 63.0 years (19 men). The median BVAS was 11.0, and the median serum progranulin level was 49.0 ng/ml. Serum progranulin was significantly correlated with BVAS, FFS, erythrocyte sedimentation rate, C-reactive protein level, SF-36 PCS, haemoglobin, and serum albumin. Severe AAV was arbitrarily defined as the highest tertile of BVAS (BVAS ≥16). When the cut-offs of serum progranulin were set as 55.16 ng/ml and 43.01 ng/ml for severe AAV, AAV patients with serum progranulin ≥55.16 and 43.01 ng/ml had significantly higher risks of severe AAV than those without (relative risk (RR) 4.167 and 4.524, respectively). CONCLUSIONS: Progranulin might play an anti-inflammatory role in AAV pathogenesis and serum progranulin could be used as a predictive marker for high activity of AAV.

Predictive Ability of Serum IL-27 Level for Assessing Activity of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Serum interleukin- (IL-) 27 level has been reported to increase in patients with several autoimmune diseases; however, its significance in patients with antineutrophil cytoplasmic antibody- (ANCA-) associated vasculitis (AAV) is unknown. In this study, we investigated the associations between serum IL-27, laboratory features, and activity of AAV and evaluate the predictive ability of serum IL-27 level for disease activity. This study included 77 AAV patients, and we collected clinical and laboratory data at blood sampling. Inflammation-related variables included white blood cell, neutrophil, lymphocyte and platelet counts, serum albumin, erythrocyte sedimentation rate, and C-reactive protein levels. Serum IL-27 and IL-18 levels were measured from stored sera using Human Magnetic Luminex® assay. High disease activity of AAV was defined as the highest tertile of Birmingham vasculitis activity score (BVAS) (≥11). The mean age of the enrolled patients was 59.9 years, and 38 (49.4%) were diagnosed as microscopic polyangiitis. In the multivariable analysis, serum albumin (ß = -0.419) and serum IL-27 level (ß = 0.221) were significantly associated with BVAS. Furthermore, patients with renal manifestation exhibited higher serum IL-27 (mean 308.7 pg/mL vs. 105.8 pg/mL) and IL-18 levels (mean 376.7 pg/mL vs. 270.4 pg/mL) than those without. On applying the optimal cut-off of serum IL-27 level for predicting high activity, AAV patients with serum IL - 27 level ≥ 300.8 pg/mL had a significantly higher risk for having high disease activity than those with serum IL - 27 level < 300.8 pg/mL (relative risk 3.380, 95% confidence interval 1.223, 9.345, P = 0.016). These results suggest that serum IL-27 level is associated with the cross-sectional activity and the presence of renal manifestation and could be used to predict high disease activity in patients with AAV.

Efficacy of tacrolimus as maintenance therapy after cyclophosphamide for treating antineutrophil cytoplasmic antibody-associated vasculitis.

ABSTRACT: Azathioprine (AZA), methotrexate, or rituximab is used for the maintenance therapy of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Although the efficacy of tacrolimus (TAC) in various autoimmune diseases has been demonstrated, there have been few reports on the efficacy of TAC in AAV. We investigated the efficacy of TAC as maintenance therapy for AAV and compared its efficacy with that of AZA.We retrospectively analyzed the medical records of 81 patients with AAV who received cyclophosphamide as induction therapy and AZA or TAC as maintenance therapy. All-cause death, relapse, and progression to end-stage renal disease (ESRD) were analyzed.Among 81 patients with AAV, 69 patients received AZA alone, 6 patients received TAC alone, and 6 patients received TAC after AZA for maintenance therapy. Overall, 11 patients (13.6%) died, 30 patients (37.0%) experienced relapse, and 16 patients (19.8%) progressed to ESRD during a median of 33.8 months. No significant differences were observed in cumulative patients', relapse-free, and ESRD-free survival rates between patients administered AZA alone and TAC alone. There were no significant differences in the cumulative patients' and relapse-free survival rate between patients who received AZA alone and TAC after AZA. However, the cumulative ESRD-free survival rate was lower in patients who received TAC after AZA than in those who received AZA alone (P = .027).Patients who received TAC as maintenance therapy showed a higher incidence of ESRD than those who received AZA; however, this might be attributed to the lack of efficacy of AZA rather than the low ESRD prevention effect of TAC.

Clinical significance of large unstained cell count in estimating the current activity of antineutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: We investigated whether large unstained cell (LUC) count could estimate the current high activity according to Birmingham vasculitis activity score (BVAS) in patients with antineutrophil cytoplasmic antibody (ANCA) positive ANCA-associated vasculitis (AAV). METHODS: We retrospectively reviewed the medical records of 176 immunosuppressive drug-naïve patients with ANCA positive AAV. Clinical and laboratory data at diagnosis, including LUC count, were collected. High BVAS was defined as the highest tertile of BVAS (BVAS ≥ 15) in this study. RESULTS: The median age was 61.0 years, and 64.8% were female. The median LUC count was 60.0 mm3 , and LUC was detected in 106 patients. LUC count was significantly correlated with BVAS, age, white blood cell count, haemoglobin, platelet count, serum albumin, erythrocyte sedimentation rate and C-reactive protein. Overall, the median BVAS in AAV patients with LUC positivity was significantly higher than that in those without (14.0 vs 10.0). When the cut-off of LUC count for the current high BVAS was set as BVAS ≥ 15 mm3 , AAV patients with LUC count ≥ 15 mm3 had a significantly higher risk for the current high BVAS than those with LUC count < 15 mm3 (relative risk 2.596). However, in the multivariable linear and logistic regression analyses, LUC did not seem to estimate the current BVAS independently among clinical and laboratory variables. CONCLUSION: LUC count was significantly correlated with the current BVAS and LUC count ≥ 15 mm3 could estimate the current high BVAS in patients with ANCA positive AAV.

The Efficacy of Mycophenolate Mofetil in Remission Maintenance Therapy for Microscopic Polyangiitis and Granulomatosis with Polyangiitis.

PURPOSE: The present study compared the efficacy of mycophenolate mofetil (MMF) with that of azathioprine (AZA) in Korean patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). MATERIALS AND METHODS: The medical records of 69 patients with MPA and GPA who received cyclophosphamide and subsequently received AZA or MMF for remission maintenance therapy were reviewed. All-cause mortality, relapse, end-stage renal disease (ESRD), cerebrovascular accident, and cardiovascular disease were evaluated as poor outcomes. Having a lower Birmingham Vasculitis Activity Score (BVAS) was defined as the lowest tertile of BVAS (BVAS ≤11 in this study). RESULTS: In comparative analysis of the occurrence of poor outcomes among patients taking AZA only, MMF only, and MMF after AZA, patients taking MMF only exhibited a significantly lower cumulative ESRD-free survival rate than patients taking AZA only (p=0.028). In terms of ESRD occurrence between the groups based on BVAS at diagnosis, among patients with MPA and GPA with higher BVAS at diagnosis, patients taking MMF only exhibited a significantly lower cumulative ESRD-free survival rate than those taking AZA only (p=0.047). Among patients with MPA and GPA with the lowest tertile of BVAS at diagnosis, cumulative ESRD-free survival rates did not differ. CONCLUSION: With regard to ESRD occurrence, the efficacy of MMF in remission maintenance therapy was less effective than AZA in patients with MPA and GPA. However, among patients with lower BVAS, there was no difference in the occurrence of poor outcomes between patients taking MMF and those taking AZA.

Detection of intracellular monosodium urate crystals in gout synovial fluid using optical diffraction tomography.

Optical diffraction tomography (ODT) enables imaging of unlabeled intracellular components by measuring the three-dimensional (3D) refractive index (RI). We aimed to detect intracellular monosodium urate (MSU) crystals in synovial leukocytes derived from gout patients using ODT. The 3D RI values of the synthetic MSU crystals, measured by ODT, ranged between 1.383 and 1.440. After adding synthetic MSU crystals to a macrophage, RI tomograms were reconstructed using ODT, and the reconstructed RI tomograms discerned intracellular and extracellular MSU crystals. We observed unlabeled synthetic MSU crystal entry into the cytoplasm of a macrophage through time-lapse imaging. Furthermore, using gout patient-derived synovial leukocytes, we successfully obtained RI tomogram images of intracellular MSU crystals. The 3D RI identification of MSU crystals was verified with birefringence through polarization-sensitive ODT measurements. Together, our results provide evidence that this novel ODT can identify birefringent MSU crystals in synovial leukocytes of patients with gout.

Male Sex Is a Significant Predictor of All-cause Mortality in Patients with Antineutrophil Cytoplasmic Antibody-associated Vasculitis.

BACKGROUND: We investigated and compared the initial clinical features at diagnosis and the poor outcomes during follow-up in Korean patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) based on sex. METHODS: The medical records of 223 immunosuppressive drug-naïve patients with AAV were reviewed. Age, body mass index (BMI), smoking history, AAV subtypes, ANCA positivity, clinical manifestations, Birmingham vasculitis activity score (BVAS), five-factor score (FFS), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) at diagnosis were collected. All-cause mortality, end-stage renal disease (ESRD), cerebrovascular accident (CVA) and cardiovascular disease (CVD) were assessed as the poor outcomes of AAV during follow-up. RESULTS: The median age was 59.0 years and 74 of 223 AAV patients (33.2%) were men. Among variables at diagnosis, male patients exhibited higher BMI than female. However, there were no differences in other demographic data, AAV subtypes, ANCA positivity, BVAS, FFS, ESR and CRP between the two groups. Male patients received cyclophosphamide more frequently, but there were no significant differences in the frequencies of the poor outcomes of AAV between the two groups. Male patients exhibited a significantly lower cumulative patients' survival rate than female patients during the follow-up period based on all-cause mortality (P = 0.037). In the multivariable analysis, both male sex (hazard ratio [HR], 2.378) and FFS (HR, 1.693) at diagnosis were significantly and independently associated with all-cause mortality during follow-up. CONCLUSION: Male sex is a significant and independent predictor of all-cause mortality in AAV patients.

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.

Correlation between serum cysteine-rich protein 61 and disease activity of antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVES: Cysteine-rich protein 61 (CYR61) stimulates protein kinase B (Akt)-mediated nuclear factor-kappa B (NF-κB) signalling leading to an increase in pro-inflammatory cytokines, which play important roles in the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Hence, we investigated whether serum CYR61 was correlated with disease activity of AAV in a single-centre prospective cohort. METHODS: Seventy-two patients with AAV were randomly selected and included. Serum CYR61, interleukin (IL)-6 and IL-8 levels were quantified with the patients' stored sera, and clinical and laboratory data at the time of blood sampling were collected. Spearman's correlation and linear regression analysis was conducted to analyse the correlation between continuous variables. The optimal cut-off of serum CYR61 for predicting high disease activity was identified using the receiver operator characteristic curve. Birmingham vasculitis activity score (BVAS) was used as a measure to assess disease activity, and high disease activity was defined as BVAS ≥ 12. RESULTS: Serum CYR61 significantly correlated with BVAS (r = 0.249), erythrocyte sedimentation rate (r = 0.283), C-reactive protein (r = 0.298) and serum IL-6 (r = 0.319). However, a linear association was not found between CYR61 and BVAS (ß = 0.102, P = 0.304). The relative risk (RR) for high disease activity in AAV patients with serum CYR61 ≥ 236.2 pg/mL was higher than those with serum CYR61 < 236.2 pg/mL (RR 3.316, P = 0.018). CONCLUSION: Even though serum CYR61 was not directly proportional to the increase of BVAS, it could be predictive of high disease activity in AAV. Key Points • Serum CYR61 was significantly correlated with BVAS along with ESR, CRP and serum IL-6. • The cut-off of serum CYR61 for high disease activity of AAV was obtained as 236.2 pg/mL. • AAV patients with serum CYR61 ≥ 236.2 pg/mL had increased risk of having higher disease activity than those with serum CYR61 < 236.2 pg/mL (RR 3.316, P = 0.018).

Fibrinogen to albumin ratio reflects the activity of antineutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: We investigated whether fibrinogen to albumin ratio (FAR) at diagnosis could reflect the cross-sectional activity and predict poor outcomes in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: This cross-sectional study included 54 immunosuppressant drug-naïve patients with AAV who had the results of plasma fibrinogen and serum albumin at diagnosis. Clinical and laboratory data at diagnosis were collected, and all-cause mortality, cerebrovascular accident, cardiovascular disease, end-stage renal disease occurrences were assessed as poor outcomes. FAR was calculated by the following equation: FAR = plasma fibrinogen (g/dl)/serum albumin (g/dl). RESULTS: The median age was 65.5 years, and 59.3% of patients were men (33 MPA, 13 GPA and 8 EGPA). FAR was significantly correlated with Birmingham vasculitis activity score (BVAS; r = 0.271), erythrocyte sedimentation rate (ESR; r = 0.668) and C-reactive protein (CRP; r = 0.638). High BVAS was defined as BVAS ≥16, and the cut-off of FAR at diagnosis was set as 0.118. AAV patients with FAR at diagnosis ≥0.118 had a significantly higher risk for the cross-sectional high BVAS than those without (RR 3.361). In the univariable linear regression analysis, CRP (ß = 0.383) and FAR (ß = 0.297) were significantly correlated with BVAS at diagnosis. However, in the multivariable analysis, none of them was correlated with the cross-sectional BVAS. FAR at diagnosis could not predict poor outcomes during follow-up in AAV patients. CONCLUSIONS: Fibrinogen to albumin ratio at diagnosis could reflect the cross-sectional BVAS but could not predict poor outcomes in patients with AAV.

Systemic inflammation response index predicts all-cause mortality in patients with antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVES: A systemic inflammation response index (SIRI) has been recently introduced as a tool for the assessment of the prognosis of several critical medical conditions. In this study, we investigated whether SIRI at diagnosis could estimate the cross-sectional disease activity and predict poor prognosis during follow-up in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: We reviewed the medical records of 224 immunosuppressive drug-naïve AAV patients and obtained clinical and laboratory data both at diagnosis and during follow-up. SIRI was calculated using the following equation: SIRI = peripheral blood neutrophil count × monocyte count/lymphocyte count. RESULTS: The median age of AAV patients at diagnosis was 59.0 years and 33% were male. In the univariable linear regression analysis, SIRI value at diagnosis was not significantly correlated with the cross-sectional Birmingham vasculitis activity score (BVAS) (r = 0.125, P = 0.062). When the SIRI cut-off value at diagnosis was set at 2847.9 mm-3 using the receiver operator characteristic curve, the sensitivity was 56.0% and the specificity was 68.3% for all-cause mortality [area 0.618, 95% confidence interval (CI) 0.502, 0.734]. AAV patients with SIRI ≥ 2847.9 mm-3 had a significantly higher risk for all-cause mortality than those with SIRI < 2847.9 mm-3 [relative risk (RR) 2.747, 95% CI 1.181, 6.392]. During follow-up, AAV patients with SIRI ≥ 2847.9 mm-3 exhibited a significantly lower patients' survival rate than those with SIRI < 2847.9 mm-3 (P = 0.003). CONCLUSIONS: SIRI at diagnosis could predict all-cause mortality during follow-up but it could not estimate the cross-sectional BVAS in AAV patients.

The significance of cytoplasmic antinuclear antibody patterns in autoimmune liver disease.

We aimed to determine the significance of cytoplasmic antinuclear antibody (ANA) patterns using computer-aided immunofluorescence microscopy in patients with autoimmune liver diseases (AILD). ANA staining pattern was identified by treating cultured human epithelial type 2 (HEp-2) cells with the sera of the patients. Medical records of patients with suspected AILD who had positive cytoplasmic ANA patterns between February 2017 and November 2019 were retrospectively reviewed for clinical, laboratory, and immunological data. Cytoplasmic ANA patterns of AILD and non-AILD groups were compared. Further subgroup analysis of patients with AILD who had reticular or speckled cytoplasmic ANA patterns was conducted. We found that among the 196 patients with positive cytoplasmic ANA patterns, 113 (57.6%) were diagnosed with AILD. The percentage of reticular cytoplasmic pattern was higher in the AILD group than that in the non-AILD group (64.0% vs. 21.9%, p < 0.001). Furthermore, patients with AILD who exhibited a reticular ANA pattern demonstrated a higher positive rate for anti-mitochondrial antibodies (66.7% vs. 2.6%, p < 0.001) than those who exhibited the speckled ANA pattern. Moreover, AILD patients with the reticular ANA pattern displayed a lower positive rate for anti-smooth muscle antibodies (0% vs. 45%, p < 0.001) and nuclear ANA pattern (73.2% vs. 97.5%, p = 0.003) than those with the speckled ANA pattern. Therefore, cytoplasmic ANA patterns could be used to guide AILD characterization in suspected AILD cases, especially as the reticular ANA pattern is strongly associated with AILD. Thus, it is important to check cytoplasmic ANA patterns for AILD evaluation, even when nuclear ANA patterns are negative.

Total Haemolytic Complement Activity at Diagnosis as an Indicator of the Baseline Activity of Antineutrophil Cytoplasmic Antibody-associated Vasculitis.

Objective: The total haemolytic complement activity (CH50) assay evaluates the functioning of the complement system Accumulating evidence indicates that the activation of the complement system plays a critical role in the pathogenesis of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) Therefore, this study aimed to investigate whether CH50 levels at diagnosis could reflect the baseline activity of AAV. Methods: This retrospective study included 101 immunosuppressive drug-naïve patients with AAV At diagnosis, all patients underwent clinical assessments for disease activity, including measurement of the Birmingham Vasculitis Activity Score (BVAS) and Five Factor Score (FFS), and laboratory evaluations, such as tests for CH50, C3, and C4 levels The association between CH50 levels and disease activity was determined. Results: The median BVAS and FFS at diagnosis were 120 and 10, respectively, whereas the median CH50 level was 604 U/mL There was a negative correlation between the CH50 level and BVAS (r=-0241; p=0015) A CH50 cut-off value of 621 U/mL was used to classify the patients into two groups: patients with CH50 levels <621 U/mL (low-CH50 group) and those with CH50 levels ≥621 U/mL (high-CH50 group) The low-CH50 group had a higher proportion of patients with high disease activity, based on the BVAS, than the high-CH50 group (525% vs 238%, p=0004) Additionally, the low-CH50 group exhibited a lower relapse-free survival rate than the high-CH50 group; however, this difference was not statistically significant (p=0082). Conclusion: Low CH50 levels at diagnosis may reflect high baseline activity of AAV.