First-year cumulative myeloperoxidase-ANCA titres are associated with all-cause mortality in patients with microscopic polyangiitis.

OBJECTIVES: We investigated whether first-year cumulative myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) and proteinase 3 (PR3)-ANCA titres were associated with all-cause mortality and relapse during follow-up in patients with microscopic polyangiitis (MPA) and granMETHODS: Altogether, 74 patients with MPA and 40 with GPA were included in this study. Their clinical data at diagnosis were collected. First-year cumulative ANCA titres were defined as the area under the curve (AUC) of ANCA titres during the first year after MPA or GPA diagnosis, which was obtained using the trapezoidal rule. All-cause mortality and relapse were considered poor outcomes of MPA and GPA. RESULTS: The median ages of patients with MPA and GPA were 65.5 and 60.5 years, respectively. No significant correlation was observed between ANCA titres at diagnosis and concurrent MPA and GPA activity or the inflammatory burden. First-year cumulative MPO-ANCA titres exhibited a significant AUC for all-cause mortality during follow-up in patients with MPA. The optimal cut-off of first-year cumulative MPO-ANCA titres for all-cause mortality was determined as 720.8 IU/mL using receiver operating characteristic curve analysis. MPA patients with first-year cumulative MPO-ANCA titres ≥720.8 IU/mL exhibited a significantly higher risk for all-cause mortality than those without (relative risk 13.250). Additionally, MPA patients with first-year cumulative MPO-ANCA titres ≥720.8 IU/mL exhibited a significantly lower cumulative patients' survival rate than those without. CONCLUSIONS: This is the first study to demonstrate the association between first-year cumulative MPO-ANCA titres and all-cause mortality during follow-up in patients with MPA.

Oxidative Stress Promotes Instability of Regulatory T Cells in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

We investigated the characteristics of regulatory T cells (Tregs), focusing on the relationship between their stability and reactive oxygen species (ROS), in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Intracellular expressions of effector cytokines, forkhead box protein 3 (FoxP3), ROS, phosphorylated mammalian target of rapamycin (mTOR), and sirtuin 1 (SIRT1) in Tregs from peripheral blood mononuclear cells (PBMCs) of patients with AAV and healthy controls (HC) were analyzed. The alterations in and functional ability of Tregs were compared before and after resveratrol (RVL) treatment of PBMCs in patients with AAV. Significantly higher expressions of interferon (IFN)-γ, interleukin (IL)-17, IL-4, ROS, and phosphorylated mTOR (pho-mTOR) and lower expression of SIRT1 in CD4+CD25+FoxP3+ cells were found in patients with AAV than in the HC. FoxP3 expression in CD4+CD25+ cells and suppressive function of Tregs were significantly lower in patients with AAV than in the HC. Tregs after RVL treatment demonstrated significant decreases in IFN-γ, ROS, and pho-mTOR levels and increases in FoxP3, SIRT1 levels, and functional activity. Conversely, the direct activation of SIRT1 by SRT1720 resulted in decreased FoxP3 expression, with no reduction in ROS levels. The pho-mTOR levels were significantly higher in Tregs after activation by SRT1720 than in those after RVL treatment. This study suggested that imbalanced changes in Tregs could be attributed to mTOR activation, in which ROS overproduction was predominantly implicated. Therefore, ROS is a key mediator for promoting Tregs instability in AAV.

Initial serum GM-CSF levels are associated with the severity of cerebral small vessel disease in microscopic polyangiitis patients.

Serum cytokine levels were comprehensively measured, and the association with cerebrovascular lesions on brain magnetic resonance imaging (MRI) in microscopic polyangiitis (MPA) patients was investigated. The initial serum granulocyte-macrophage colony-stimulating factor (GM-CSF) levels were significantly higher in the high-grade white matter hyperintensities (WMH) group than those in the low-grade WMH group. In multivariate analyses, high serum levels of GM-CSF were independently associated with high-grade WMH. The initial serum GM-CSF levels correlated positively with the Birmingham Vasculitis Activity Score and semi-quantitative scales of WMH. The initial serum GM-CSF levels were associated with the severity of WMH in MPA patients.

Clinical features and long-term outcomes of interstitial lung disease with anti-neutrophil cytoplasmic antibody.

BACKGROUND: Patients with interstitial lung disease (ILD) are occasionally positive for anti-neutrophil cytoplasmic antibodies (ANCAs). Differences between ILDs secondary to microscopic polyangiitis (MPA) and isolated ANCA-positive idiopathic interstitial pneumonia (IIP) remain unclear. The aim of this study was to explore the differences in clinical features and outcomes between MPA-associated ILDs and isolated ANCA-positive IIPs. METHODS: We reviewed 1338 ILDs patients with available ANCA results and retrospectively analysed 80 patients who were ANCA-positive. MPA-associated ILDs (MPA-ILDs group) and isolated ANCA-positive IIPs (ANCA-IIPs group) were compared. RESULTS: Among 80 patients with ANCA-positive ILDs, 31 (38.75%) had MPA-ILDs, and 49 (61.25%) had isolated ANCA-positive IIPs. Compared with ANCA-IIPs group, patients in MPA-ILDs group had a higher proportion of fever (p = 0.006) and higher neutrophil count (p = 0.011), erythrocyte sedimentation rate (ESR) (p < 0.001) and C-reactive protein (CRP) (p = 0.005). Multivariable analysis showed that ESR level was an independent risk factor for mortality in all 80 ANCA-positive ILDs patients (HR 1.028, p = 0.001). Survival in MPA-ILDs group was lower than that in ANCA-IIPs group, and further stratified analysis revealed that ANCA-IIPs patients with elevated ESR or CRP had a worse prognosis than those with normal inflammation markers, with 5-year cumulative survival rates of 60.00%, 86.90% and 100.00% in MPA-ILDs and ANCA-IIPs with and without elevated inflammation markers, respectively. CONCLUSIONS: Among patients with ANCA-positive ILDs, the prognoses of ANCA-IIPs with normal inflammation markers, ANCA-IIPs with elevated inflammation markers and MPA-ILDs were sequentially poorer. Therefore, stratified treatment should be considered in the management of ILDs patients positive for ANCAs.

Fibrosis-5 predicts end-stage renal disease in patients with microscopic polyangiitis and granulomatosis with polyangiitis without substantial liver diseases.

We previously reported that fibrosis-4 (FIB-4) was associated with poor outcomes of microscopic polyangiitis (MPA) and granuloma with polyangiitis (GPA). We also investigated the potential of FIB-5, a novel index, in predicting all-cause mortality and end-stage renal disease (ESRD) during follow-up in patients with MPA and GPA without substantial liver diseases. Clinical and laboratory data at diagnosis were collected by reviewing the medical records of 180 patients with MPA and GPA. FIB-5 was obtained by a following equation: FIB-5 = (serum albumin (g/L) × 0.3 + platelet count (109/L) × 0.05) - (alkaline phosphatase (IU/L) × 0.014 + aspartate aminotransferase/alanine aminotransferase ratio × 6 + 14). The median age of the patients at diagnosis was 61.0 years. FIB-5 at diagnosis could not reflect the cross-sectional vasculitis activity. The cutoffs of FIB-5 for poor outcomes was set as 0.82 (the lowest tertile) and -0.42 (the lowest quartile) at diagnosis. In Kaplan-Meier survival analysis, patients with FIB-5 < 0.82 and those with FIB-5 < -0.42 exhibited lower ESRD-free survival rates than those without. However, it could not predict all-cause mortality. In multivariable Cox hazards analysis, both FFS (Hazard ratio (HR) 1.554) and FIB-5 < 0.82 (HR 2.096) as well as both FFS (HR 1.534) and FIB-5 < -0.42 (HR 2.073) at diagnosis independently predicted ESRD during follow-up. In conclusion, FIB-5 < 0.82 and FIB-5 < -0.42 at diagnosis could predict the occurrence of ESRD, but not all-cause mortality, during follow-up in patients with MPA and GPA without substantial liver diseases.

CCL2 produced by CD68+/CD163+ macrophages as a promising clinical biomarker of microscopic polyangiitis-interstitial lung disease.

OBJECTIVES: Microscopic polyangiitis (MPA) is often complicated by interstitial lung disease (ILD); however, biomarkers that can be used to diagnose and predict the progression of MPA-ILD have not been identified. In this study, we evaluated various serum biomarkers in MPA-ILD to assess their diagnostic and predictive performance. METHODS: We enrolled 49 patients with anti-neutrophil cytoplasmic antibody (ANCA)+ MPA and 10 healthy controls, with 32 of the MPA patients also presenting ILD. The presence of ILD was assessed by high-resolution CT and evaluated by ground-glass opacity and fibrosis score. We compared 16 biomarker profiles among MPA-ILD patients, those without ILD, and healthy controls and extracted biomarkers with higher levels in MPA-ILD groups to determine correlations with disease activity and other biomarkers. Three lung biopsies were examined by haematoxylin-eosin staining and immunostaining. RESULTS: Initial serum C-C motif chemokine ligand 2 (CCL2) levels were significantly higher in the MPA-ILD group than those of the MPA group, and were significantly higher in MPA-ILD patients 1 year after immunosuppressive therapy than those before treatment. Initial serum CCL2 levels positively correlated with an increased fibrosis score during the year after treatment and with initial serum platelet-derived growth factor levels. Immunohistochemical staining showed intense CCL2 signals in CD68+/CD163+ macrophages and metaplastic epithelial cells in MPA-ILD lungs. CONCLUSION: CCL2 is associated with MPA-ILD pathogenesis and suggested its potential efficacy as a useful marker for diagnosing and predicting MPA-ILD progression. Therefore, targeting CCL2 in alveolar CD68+/CD163+ macrophages might represent a therapeutic intervention in ANCA+ MPA-ILD.

Vascular endothelial growth factor (VEGF)-A and VEGF-A165b are associated with time to remission of granulomatosis with polyangiitis in a nationwide Japanese prospective cohort study.

BACKGROUND: Effective prognostic markers are needed for antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study evaluated the clinical associations of serum vascular endothelial growth factor-A (sVEGF-A) and sVEGF-A165b (an antiangiogenic isoform of VEGF-A) concentrations with time to remission of AAV in a nationwide Japanese prospective follow-up cohort. METHODS: We collected samples from patients with AAV who were enrolled in the nationwide Japanese cohort study (RemIT-JAV-RPGN). We measured sVEGF-A and sVEGF-A165b concentrations using enzyme-linked immunosorbent assays in 57 serum samples collected 6 months before and after initiation of AAV treatment. Patients were classified based on AAV disease subtypes: microscopic polyangiitis, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis (EGPA). RESULTS: Results revealed significant reductions in sVEGF-A and sVEGF-A165b concentrations in patients with microscopic polyangiitis and EGPA, respectively. However, despite the comparable concentrations of sVEGF-A and sVEGF-A165b during the 6 months of treatment in granulomatosis with polyangiitis patients, correlation analysis revealed that the differences in log2-transformed concentrations of sVEGF-A and sVEGF-A165b were inversely correlated with time to remission in granulomatosis with polyangiitis patients. CONCLUSION: These results suggest that sVEGF-A and -A165b can serve as potential markers of time to remission in patients with granulomatosis with polyangiitis.

Skewed peripheral B- and T-cell compartments in patients with ANCA-associated vasculitis.

OBJECTIVES: To characterize lymphocytes dysregulation in patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). METHODS: Using flow cytometry, we analysed B- and T-cell subsets in peripheral blood from 37 untreated patients with active disease (29 GPA and 8 MPA) and 22 healthy controls (HCs). RESULTS: GPA patients had increased Th2 (1.8 vs 1.0%, P = 0.02), Th9 (1.1 vs 0.2%, P = 0.0007) and Th17 (1.4 vs 0.9%, P = 0.03) cells compared with HC. Patients with MPO-ANCAs had significantly more CD21- B cells than HC or PR3-ANCA patients (6.9 vs 3.3% and 4.4%, P = 0.01). CD69 expressing B cells were significantly higher in GPA and MPA (3.0 and 5.9 vs 1.4%, P = 0.02 and P = 0.03, respectively) compared with HC, whereas B-cell activating factor-receptor expression was decreased in GPA and MPA (median fluorescence intensity ratio 11.8 and 13.7 vs 45.1 in HC, P < 0.0001 and P = 0.003, respectively). Finally, IL-6-producing B cells were increased in GPA vs HC (25.8 vs 14.9%, P < 0.0001) and decreased in MPA vs HC (4.6 vs 14.9%, P = 0.005), whereas TNF-α-producing B cells were lower in both GPA and MPA patients compared with controls (15 and 8.4 vs 30%, P = 0.01 and P = 0.006, respectively). CONCLUSION: Skewed T-cell polarization towards Th2, Th9 and Th17 responses characterizes GPA, whereas B-cell populations are dysregulated in both GPA and MPA with an activated phenotype and a decreased B-cell activating factor-receptor expression. Finally, inflammatory B cells producing IL-6 are dramatically increased in GPA, providing an additional mechanism by which rituximab could be effective.

Immunopathogenesis of ANCA-Associated Vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disorder which affects small- and, to a lesser degree, medium-sized vessels. ANCA-associated vasculitis encompasses three disease phenotypes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). This classification is largely based on clinical presentations and has several limitations. Recent research provided evidence that genetic background, risk of relapse, prognosis, and co-morbidities are more closely related to the ANCA serotype, proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA, compared to the disease phenotypes GPA or MPA. This finding has been extended to the investigation of biomarkers predicting disease activity, which again more closely relate to the ANCA serotype. Discoveries related to the immunopathogenesis translated into clinical practice as targeted therapies are on the rise. This review will summarize the current understanding of the immunopathogenesis of ANCA-associated vasculitis and the interplay between ANCA serotype and proposed disease biomarkers and illustrate how the extending knowledge of the immunopathogenesis will likely translate into development of a personalized medicine approach in the management of ANCA-associated vasculitis.

Interstitial lung disease and microscopic polyangiitis in chilean patients.

OBJECTIVE: To describe the clinical and serological patients characteristics with Microscopic Polyangiitis (MPA) and Interstitial lung disease (ILD). METHODS: Of all the patients with AAV diagnosed between 2007-2017 at the Hospital Clinico Universidad de Chile, those with MPA and ILD were selected and studied retrospectively. RESULTS: All patients were Hispanic; median age at diagnosis 65 years (32-84). 59% were female. All were positive for p-ANCA, 16 patients for MPO. Most common manifestations were constitutional symptoms, weight loss and fever. CT-Scans patterns were Usual Interstitial Pneumonia (UIP) in 10 patients, Nonspecific Interstitial Pneumonia (NSIP) in 6 and fibrosis not UIP or NSIP pattern in 1. In 6 cases, ILD was diagnosed 0.5-14 years before MPA and concomitantly in 11. CONCLUSIONS: Although infrequent, Microscopic Polyangiitis should be suspected in patients with ILD particularly if extra-pulmonary manifestations that rise the possibility of a systemic illness are present, regardless of the time elapsed between the latter and the diagnosis of this type of lung involvement. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (1): 37-42).

Serum Mannose-Binding Lectin Levels Are Correlated with the Disease Activity of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Single-Center Study.

Mannose-binding lectin (MBL) is a soluble pattern-recognition molecule, which plays a crucial role in the innate immune system and the activation of lectin complement pathway. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease affecting the small vasculatures and is characterized by the alteration of innate and adaptive immunity and complement activation. In this study, we investigated whether serum MBL is associated with disease activity of AAV, which was measured by ELISA. Associations between serum MBL and AAV-specific indices, as well as clinical and laboratory data were assessed using Kendall's tau. Among the 80 patients, 42 (52.5%), 21 (26.3), and 17 (21.3%) patients were classified as microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA), respectively. The median values of erythrocyte sedimentation rate, C-reactive protein, and serum MBL were 36.5 (normal range < 20) mm/h, 2.4 (normal range < 8) mg/dL, and 8.6 ng/mL, respectively. The median serum levels of MBL in MPA, GPA, and EGPA patients were 8.4, 9.3, and 8.2 ng/mL. Correlation analysis showed that serum MBL was associated with Birmingham Vasculitis Activity Score (BVAS) (R = 0.169, p = 0.027), but not with other AAV-specific indices and clinical and laboratory data. In addition, serum MBL was significantly associated with the pulmonary manifestation score based on BVAS (R = 0.247, p = 0.001). In summary, among the AAV-specific indices and clinical and laboratory variables analyzed, serum MBL is correlated with BVAS and pulmonary manifestation score based on the BVAS.

Complement profile in microscopic polyangiitis and granulomatosis with polyangiitis: analysis using sera from a nationwide prospective cohort study.

OBJECTIVE: The complement cascade, especially the alternative pathway of complement, has been shown in basic research to be associated with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). We aimed to elucidate relationships between serum complement components and clinical characteristics in AAV. METHOD: In a nationwide prospective cohort study (RemIT-JAV-RPGN), we measured the serum levels of C1q, C2, C3, C3b/iC3b, C4, C4b, C5, C5a, C9, factor B, factor D, factor H, factor I, mannose-binding lectin, and properdin in 52 patients with microscopic polyangiitis (MPA) and 39 patients with granulomatosis with polyangiitis (GPA). RESULTS: The properdin level of MPA and GPA was significantly lower than that of healthy donors. The properdin level was negatively correlated with the Birmingham Vasculitis Activity Score (BVAS) (ρ = -0.2148, p = 0.0409). The factor D level at 6 months was significantly positively correlated with the Vasculitis Damage Index (VDI) at 6, 12, and 24 months (ρ = 0.4207, 0.4132, and 0.3115, respectively). Patients with a higher ratio of C5a to C5 had higher neutrophil percentage and serum immunoglobulin G levels, and significantly lower creatinine levels. Cluster analysis divided the MPA and GPA patients into three subgroups. A principal component (PC) analysis aggregated 15 types of complements into alternative pathway-related PC 1 and complement classical pathway and common pathway-related PC 2. CONCLUSIONS: The serum levels of properdin and factor D were correlated with the BVAS and the VDI in MPA and GPA, respectively. Our analyses suggested the pathological heterogeneity of MPA and GPA from the aspect of complement components.

Evaluation of 12 different assays for detecting ANCA in Chinese patients with GPA and MPA: a multicenter study in China.

OBJECTIVE: Due to lack of comprehensive evaluation for various detection methods for antineutrophil cytoplasmic antibody (ANCA) in Chinese population, we evaluate the diagnostic performance of 12 established analysis methods in Chinese patients having granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). METHODS: Sera were collected from 209 patients with GPA or MPA and 243 diseases controls from 15 centers. Twelve different reagents were employed for C-ANCA, P-ANCA, myeloperoxidase (MPO)-ANCA, and proteinase 3(PR3)-ANCA detection. The accuracy, sensitivity, and specificity of each method were analyzed. RESULTS: The accuracy of the two indirect immunofluorescence (IIF) and two line immunoassay (LIA) was 0.838 and 0.874, 0.869, and 0.862, respectively. The accuracy of the eight quantitative antigen-specific immunoassays was varied from 0.867 to 0.967. The sensitivity of ANCA-associated vasculitis (AAV) was 0.770 and 0.761 for the two IIF, 0.727 and 0.718 for the two LIAs, respectively. For the eight quantitative antigen-specific immunoassays, the sensitivity varied from 0.79 to 0.967. The specificity was 0.897 and 0.971 for the two IIF, 0.992 and 0.988 for the two LIAs, respectively. For the eight quantitative antigen-specific immunoassays, the specificity of AAV varied from 0.963 to 0.983. CONCLUSION: For Chinese patients suspected of having GPA and MPA, both the first-generation enzyme-linked immunosorbent assay (ELISA) and high-quality antigen-specific immunoassay can be used to detect MPO-ANCA and PR3-ANCA alone, without the combined detection with IIF to have good diagnostic performance. The chemiluminescent immunoassay (CLIA) seems to be a method worth recommending.Key points• Quantitative antigen-specific immunoassays can be used to detect MPO-ANCA and PR3-ANCA without IIF in Chinese.• CLIA has the maximum AUC value and the minimum LR (-) value, which seems to be a method worth recommending.

Neutrophils from ANCA-associated vasculitis patients show an increased capacity to activate the complement system via the alternative pathway after ANCA stimulation.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), are autoimmune conditions associated with small vessel inflammation. Earlier studies indicate that complement activation via the alternative pathway plays a major role in the pathogenesis. In this study we have investigated if ANCA-activation of neutrophils from AAV patients leads to activation of the alternative complement pathway. C5a-primed neutrophils (PMN) from 10 AAV patients and 10 healthy controls (HC) were stimulated with PMA or IgG purified from PR3-ANCA positive patients (ANCA IgG). The supernatants were analyzed for release of complement proteins and markers of different granules by ELISA, and release of microparticles (MP) by flow cytometry. The ability of the supernatants to activate the alternative complement pathway was determined by incubation with normal serum and C3bBbP and C5a were measured by ELISA. MP were analyzed by flow cytometry and removed by centrifugation. The supernatants from the AAV patients' neutrophils produced significantly more C3bBbP compared with HCs (p = 0.0001). C3bBbP levels correlated with the number of MP. After removal of MP from the supernatants, alternative pathway activation was significantly lower. This study shows that primed and ANCA-stimulated neutrophils from AAV patients have a greater ability to activate the alternative complement pathway compared to primed neutrophils from healthy controls. This finding emphasizes the role of complement in the pathogenesis of AAV - underlining the therapeutic potential of C5a and other complement blockade.

Clinical role of albumin to globulin ratio in microscopic polyangiitis: a retrospective monocentric study.

We investigated whether albumin to globulin ratio (AGR) at diagnosis may be associated with all-cause mortality in immunosuppressive drug-naïve patients with microscopic polyangiitis (MPA). We retrospectively reviewed the medical records of 88 MPA patients, who were first classified and in whom medications was first initiated in our tertiary Hospital. We collected clinical and laboratory data as well as the rate of all-cause mortality. AGR at diagnosis was calculated as a ratio of serum albumin over globulin fraction (protein-albumin). We compared variables between survived and deceased patients. The multivariable Cox hazard model was conducted to appropriately obtain the hazard ratios (HRs). The mean age at diagnosis was 56.3 years and 24 patients (27.3%) were men. Seven patients died for the mean follow-up period of 49.7 months. Deceased patients were elder than survived patients (P = 0.048). Five factor score (FFS) (2009) (P = 0.001), creatinine (P = 0.026) and AGR (P = 0.007) at diagnosis in deceased patients were higher than those in the survived. In the multivariable Cox hazard model analysis, only AGR at diagnosis (HR 0.004) was inversely associated with all-cause mortality during the follow-up. Furthermore, when the cutoff of AGR for death was set as 0.88, patients with AGR ≤ 0.88 exhibited the lower cumulative patients survival rate than those with AGR > 0.88 (P = 0.006). Among the conventional and MPA-related risk factors for mortality, AGR at diagnosis is inversely associated with all-cause mortality during follow-up in MPA patients.

No overlap between IgG4-related disease and microscopic polyangiitis and granulomatosis with polyangiitis despite elevated serum IgG4 at diagnosis: a retrospective monocentric study.

OBJECTIVES: We investigated whether elevated serum IgG4 at the time of diagnosis of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) may be associated with concurrent IgG4-related disease (IgG4-RD) in immunosuppressive drug-naïve patients. METHODS: We retrospectively reviewed the medical records of 46 MPA and GPA patients with results on serum IgG4 and histology at diagnosis. Elevated serum IgG4 was defined as IgG4 > 135 mg/dL. We collected clinical and laboratory data at diagnosis including ANCA, white blood cell (WBC) count, haemoglobin, platelet, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum IgG4, and calculated Birmingham vasculitis activity score (BVAS) at diagnosis. We compared variables between patients with MPA and GPA and assessed the correlation of serum IgG4 and other continuous variables. RESULTS: Twenty-eight patients (60.9%) were classified as MPA and 18 patients (39.1%) as GPA. The mean age at diagnosis was 61.0 years and 17 patients (37.0%) were men. The serum IgG4 at diagnosis was 1202.7 mg/dL and 37 patients (80.4%) had elevated serum IgG4 at diagnosis. We found no patients, who could be classified as IgG4-RD according to comprehensive diagnostic criteria for IgG4-RD among 46 patients. The mean serum IgG at diagnosis was not different between the two groups. Serum IgG4 was significantly correlated with inflammation-related variables at diagnosis including BVAS (r = 0.367), platelet (r = 0.398), ESR (r = 0.327), and CRP (r = 0.373). CONCLUSIONS: Elevated serum IgG4 is not associated with concurrent IgG4-RD, and it may reflect activity and inflammatory burden of vasculitis in patients with MPA and GPA at diagnosis.

Serum levels of interleukin-32 and interleukin-6 in granulomatosis with polyangiitis and microscopic polyangiitis: association with clinical and biochemical findings.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disorder of unknown etiology with dysregulated cytokines levels. OBJECTIVES: The main aim of this study was to assess the clinical correlation between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, granulomatosis with polyangiitis (GPA) serum levels of the microscopic polyangiitis (MPA), serum levels of the proinflammatory cytokines, interleukin (IL)-32 and interleukin-6. METHODS: Study included 71 patients, 47 with GPA and 24 with MPA. Serum IL-32 and IL-6 concentrations were analyzed in all patients, and compared with levels observed in 10 controls. IL-32 and IL-6 were evaluated using DuoSet and Quantikine HS ELISA, respectively. IL-32 and IL-6 concentrations were correlated with disease-related clinical and laboratory findings. RESULTS: IL-32 and IL-6 levels were significantly higher in GPA and MPA than in controls, especially IL-32 levels in GPA were elevated. IL-32 concentrations correlated positively with anti-proteinase 3 - ANCA (PR3-ANCA) levels in GPA (P < 0.0001), and with anti-myeloperoxidase ANCA (MPO-ANCA) in MPA (P = 0.049). IL-32 levels correlated positively with disease activity in GPA and MPA (P < 0.0001). GPA patients with pulmonary, cutaneous, and musculoskeletal involvement presented the highest IL-6 serum levels. Cutaneous manifestations correlated positively with IL-6 levels in MPA patients (P = 0.05). ANCA-positive patients with GPA expressed significantly high IL-6 levels (P = 0.036). No significant difference in IL-32 values was observed between ANCA-positive and ANCA-negative patients. CONCLUSIONS: Patients with GPA and MPA present higher serum IL-32 and IL-6 levels than controls. IL-32 levels correlate positively with disease activity.

Microscopic polyangiitis necrotizing glomerulonephritis associated with pregnancy: case with a 20-year clinical course and review of the literature.

A 29-year-old woman with past medical history of hypertension was referred to our hospital for the evaluation of kidney dysfunction (serum creatinine 1.0 mg/dL), proteinuria (0.54 g/gCre), and microscopic hematuria. Renal biopsy before the first pregnancy was supportive for benign nephrosclerosis with no evidence of vasculitis. After her second pregnancy and delivery when she was 32 years old, she developed proteinuria of 3.2 g/gCre, hematuria, and elevated serum creatinine level of 2.6 mg/dL. Second renal biopsy revealed necrotizing glomerulonephritis and her serum MPO-ANCA was positive, leading to the diagnosis of MPA/renal-limited vasculitis (RLV). Interestingly, frozen preserved serum from 4 years earlier also tested positive for MPO-ANCA. Despite intensive treatment, hemodialysis was required 10 years later due to progressive deterioration of renal function. At that time, she developed pericarditis, bloody cardiac tamponade, and pulmonary alveolar hemorrhage, resulting in a diagnosis of systemic vasculitis MPA. She received living donor kidney transplantation at the age of 44 years, after which serum creatinine has been stable around 1.1 mg/dL without proteinuria or hematuria and MPO-ANCA has remained negative. The association of vasculitis with pregnancy and delivery is not well documented, especially in patients with MPA. Here, we report this MPO-ANCA positive woman developing MPA necrotizing glomerulonephritis after her second pregnancy and a 20-year clinical course.

Clinical significance of myeloperoxidase-anti-neutrophil cytoplasmic antibody in idiopathic interstitial pneumonias.

OBJECTIVE: Although a possible association among myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA), microscopic polyangiitis (MPA), and idiopathic pulmonary fibrosis (IPF) has been suggested, the clinical significance of MPO-ANCA in idiopathic interstitial pneumonias (IIPs), including IPF and non-IPF, remains unclear. We aimed to investigate the frequency of MPO-ANCA positivity, as well as MPA incidence and risk factors for development in patients initially diagnosed with IIP. METHODS: We retrospectively analysed 305 consecutive patients who were initially diagnosed as IIP and had MPO-ANCA results available. RESULTS: Of the 305 patients, 26 (8.5%) were MPO-ANCA-positive. Baseline characteristics were similar between the MPO-ANCA-positive and -negative patients. The cumulative 5-year MPA incidence was 24.3% in the MPO-ANCA-positive patients and 0% in the -negative patients (P < 0.0001). MPO-ANCA was positive in 15 of 133 (11.3%) patients initially diagnosed with IPF and in 11 of 172 (6.3%) patients initially diagnosed with non-IPF (P = 0.56), with cumulative 5-year MPA incidence of 6.2% and 1.0%, respectively (P = 0.10). Multivariate analysis revealed that UIP pattern on HRCT (HR = 3.20, P < 0.01) and no treatment for IIP (HR = 3.52, P < 0.01) were independently associated with MPA development in MPO-ANCA-positive patients. CONCLUSION: MPO-ANCA positivity was uncommon, but was associated with subsequent MPA development in patients initially diagnosed with IIP, including both IPF and non-IPF cases. The study suggested that attention should be paid to MPA development in MPO-ANCA-positive IIP patients with UIP pattern on HRCT and those without treatment for IIP.