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Background: This study investigated poor prognostic factors for the relapse of interstitial lung disease (ILD) in patients with microscopic polyangiitis (MPA) after remission induction therapy., Methods: We enrolled patients diagnosed with MPA complicated by ILD according to the Chapel Hill Consensus definition from 2001 to 2023 in multiple institutions in the REVEAL cohort. All patients who were treated with immunosuppressive therapy were followed up, and those who relapsed with ILD were extracted in this study. We explored the risk factors for predicting ILD relapse in patients with MPA-ILD by comparing the demographic, clinical, laboratory, and radiological findings and treatments between the relapsed and non-relapsed groups on admission., Results: Of 243 patients with MPA, 134 (55.1%) with MPA-ILD were enrolled. Among them, 28 (20.9%) relapsed during a mean follow-up of 4.2 years. The initial serum Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) levels and the prevalence of usual interstitial pneumonia (UIP) pattern were significantly higher in the relapsed group. The biomarkers were also risk factors for relapse in multivariate Cox regression analysis. The best cut-off values of KL-6, SP-D for predicting ILD relapse were 430 U/mL and 89.5 ng/mL, respectively. We created prediction models based on the best cut-off values for KL-6, SP-D, and the presence of the UIP pattern (KSU model). The 10-year relapse rate was significantly different among patients with MPA-ILD stratified by the number of risk factors based on the KSU model. A higher relapse rate was associated with higher all-cause mortality., Conclusions: The initial serum high KL-6 and SP-D levels and the prevalence of the UIP pattern were associated with ILD relapse in patients with MPA-ILD. Our multicentre cohort study indicated that the KSU model, which consists of KL-6 ≥ 430 U/mL, SP-D ≥ 89.5 ng/mL, and the presence of the UIP pattern, is a useful predictor of ILD relapse in patients with MPA after immunosuppressive therapy., Competing Interests: Declarations. Ethics approval and consent to participate: The study was conducted in accordance with the Declaration of Helsinki and its amendments, and it was approved by the Osaka Medical College and the Faculties of Medicine Ethics Committee (approval no. 1529) and by the individual participating centres, including Kyoto University (approval no. R1540) and Osaka Metropolitan University (approval no. 2023-027). The Ethics Committee of Kyoto University waived the requirement for informed consent because of the anonymous nature of the data. Written informed consent was obtained from each patient at the other institutions. Consent for publication: Not applicable. Competing interests: SM has received research grant from Japan Intractable Diseases Research Foundation and Promotion and Mutual Aid Corporation for Private Schools of Japan. TK has received payments for lectures from Abbvie, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Pfizer, and Boehringer Ingelheim. RW receives research grant from AbbVie and speaker’s fee from Asahi Kasei, Chugai, Eli Lilly, GSK, and UCB Japan. RH received research grants from GSK, and speaker fee from Abbvie, Asahi Kasei, Brystol-Meyers Squibb, Eisai, Eli Lilly, GSK, Kissei, and Pfizer. MH received research grants and/or speaker fee from Abbvie, Asahi Kasei, Astellas, Brystol Meyers, Chugai, Eisai, Daiichi Sankyo, Eli Lilly, Novartis Pharma, Tanabe Mitsubishi. TT received research grants and/or speaker fee from Abbvie, Asahi Kasei, Astellas, Brystol-Meyers Squibb, Chugai, Eisai, Eli Lilly, Janssen pharma, Nihon Shinyaku, Mitsubishi-Tanabe, Takeda, and Pfizer. Other authors (AO, DN, YM, MS, TT, AM, KK, TY, WY) do not have any conflict of interest., (© 2024. The Author(s).)

Background and Hypothesis: Using a mouse model of MPA with microvascular lesion with a clone (VasSF) of recombinant single chain fragments of the variable region of human IgG, we previously showed that vasculitis-associated apolipoprotein A2 (VAP2) may be a therapeutic target for vasculitis. The present study estimated the target molecules for VasSF and the association between VAP2 and cytokine levels in patient sera in terms of microvascular lesion severity., Methods: Sera and clinical information were collected from patients with microscopic polyangiitis and granulomatosis with polyangiitis (MPA/GPA) and infectious disease. Neutrophil counts, levels of C-reactive protein (CRP), creatinine, total cholesterol associated with microvascular lesion, HDL cholesterol, low-density lipoprotein cholesterol, triglycerides, glomerular filtration rate (eGFR), and cytokines were estimated. Serum VAP2 signals were determined with Western blotting., Results: VasSF bound to a 24 kDa molecule in the serum of active MPA/GPA patients. Anti-AP2 antibody also bound with the same 24 kDa molecule, named VAP2, because of size difference from normal APOA2. The VAP2 signal was significantly stronger in the active-disease group but significantly weakened in remission. The signal correlated positively with eGFR but not with the Birmingham Vasculitis Activity Score, CRP, MPO-ANCA, or PR3-ANCA levels. It correlated negatively with MPO activity, IL-16, MIF, and IL-1Ra. Moreover, VasSF bound to a 17 kDa molecule in the remission phase., Conclusion: The 24 kDa VAP2 molecule may be associated with neutrophil functions because of its inverse correlation with MPO activity, IL-16, MIF, and IL-1Ra, suggesting that VAP2-APOA1 formation in HDL triggers microvascular injury. VasSF may reverse the injury by removing APOA1-VAP2 heterodimers from peripheral blood vessels., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: This study aimed to investigate whether the serum extracellular newly identified receptor for advanced glycation end products binding protein (EN-RAGE) and the soluble form of RAGE (sRAGE) measured at diagnosis are associated with all-cause mortality in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA)., Materials and Methods: Serum EN-RAGE and sRAGE were measured in 75 immunosuppressive drug-naïve MPA and GPA patients using an immunoassay, with their clinical and laboratory data reviewed. The optimal cut-off point of EN-RAGE and sRAGE was calculated by finding the threshold with the maximum sum of sensitivity and specificity. In addition, the least absolute shrinkage and selection operator regression was adopted to select variables included in the multivariable Cox proportional hazards (PH) regression model., Results: The median age of the patients was 67.0 years, and 34% were male. Neither serum EN-RAGE nor sRAGE at diagnosis was correlated with the Birmingham Vasculitis Activity Score. Furthermore, no correlation was observed between serum EN-RAGE and sRAGE. Deceased patients had significantly lower serum EN-RAGE and higher serum sRAGE at diagnosis compared to surviving patients. Patients with serum EN-RAGE at diagnosis ≤84.37 ng/mL and serum sRAGE at diagnosis ≥1.82 ng/mL showed significantly lower survival probabilities compared to those without. In multivariable Cox PH regression model, only serum sRAGE at diagnosis ≥1.82 ng/mL, rather than serum EN-RAGE at diagnosis ≤84.37 ng/mL, was independently associated with all-cause mortality (hazard ratio 7.094)., Conclusion: This study is the first to demonstrate that serum sRAGE at diagnosis may independently predict all-cause mortality during follow-up in patients with MPA and GPA., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2024.)

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a heterogenous autoimmune disease. While traditionally stratified into two conditions, granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), the subclassification of ANCA-associated vasculitis is subject to continued debate. Here we aim to identify phenotypically distinct subgroups and develop a data-driven subclassification of ANCA-associated vasculitis, using a large real-world dataset., Methods: In the collaborative data reuse project FAIRVASC (Findable, Accessible, Interoperable, Reusable, Vasculitis), registry records of patients with ANCA-associated vasculitis were retrieved from six European vasculitis registries: the Czech Registry of ANCA-associated vasculitis (Czech Republic), the French Vasculitis Study Group Registry (FVSG; France), the Joint Vasculitis Registry in German-speaking Countries (GeVas; Germany), the Polish Vasculitis Registry (POLVAS; Poland), the Irish Rare Kidney Disease Registry (RKD; Ireland), and the Skåne Vasculitis Cohort (Sweden). We performed model-based clustering of 17 mixed-type clinical variables using a parsimonious mixture of two latent Gaussian variable models. Clinical validation of the optimal cluster solution was made through summary statistics of the clusters' demography, phenotypic and serological characteristics, and outcome. The predictive value of models featuring the cluster affiliations were compared with classifications based on clinical diagnosis and ANCA specificity. People with lived experience were involved throughout the FAIRVASVC project., Findings: A total of 3868 patients diagnosed with ANCA-associated vasculitis between Nov 1, 1966, and March 1, 2023, were included in the study across the six registries (Czech Registry n=371, FVSG n=1780, GeVas n=135, POLVAS n=792, RKD n=439, and Skåne Vasculitis Cohort n=351). There were 2434 (62·9%) patients with GPA and 1434 (37·1%) with MPA. Mean age at diagnosis was 57·2 years (SD 16·4); 2006 (51·9%) of 3867 patients were men and 1861 (48·1%) were women. We identified five clusters, with distinct phenotype, biochemical presentation, and disease outcome. Three clusters were characterised by kidney involvement: one severe kidney cluster (555 [14·3%] of 3868 patients) with high C-reactive protein (CRP) and serum creatinine concentrations, and variable ANCA specificity (SK cluster); one myeloperoxidase (MPO)-ANCA-positive kidney involvement cluster (782 [20·2%]) with limited extrarenal disease (MPO-K cluster); and one proteinase 3 (PR3)-ANCA-positive kidney involvement cluster (683 [17·7%]) with widespread extrarenal disease (PR3-K cluster). Two clusters were characterised by relative absence of kidney involvement: one was a predominantly PR3-ANCA-positive cluster (1202 [31·1%]) with inflammatory multisystem disease (IMS cluster), and one was a cluster (646 [16·7%]) with predominantly ear-nose-throat involvement and low CRP, with mainly younger patients (YR cluster). Compared with models fitted with clinical diagnosis or ANCA status, cluster-assigned models demonstrated improved predictive power with respect to both patient and kidney survival., Interpretation: Our study reinforces the view that ANCA-associated vasculitis is not merely a binary construct. Data-driven subclassification of ANCA-associated vasculitis exhibits higher predictive value than current approaches for key outcomes., Funding: European Union's Horizon 2020 research and innovation programme under the European Joint Programme on Rare Diseases., Competing Interests: Declaration of interests PL has received grants or contracts from the German Research Society, Federal Ministry of Education and Research, German Society for Rheumatology, John Grube Foundation, and Vifor Pharma; consulting fees from AbbVie, AstraZeneca, GSK, Novartis, UCB, and Vifor Pharma; payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events from AstraZeneca, Boehringer Ingelheim, GSK, Janssen, Novartis, Rheumaakademie, UCB, and Vifor Pharma; support for attending meetings or travel from Vifor Pharma; and has participated on Data Safety Monitoring Boards or Advisory Boards of AbbVie, AstraZeneca, GSK, and Vifor Pharma. XP has received grants as an investigator of academic studies of ANCA-associated vasculitis for which rituximab was provided by Roche Pharma. MS has received consulting fees from Vifor Pharma, Otsuka, and Hansa Biopharma. BT has received consulting fees from Novartis, AstraZeneca, CSL Vifor, GSK, and Boehringer Ingelheim; payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events from Novartis, AstraZeneca, CSL Vifor, GSK, and Boehringer Ingelheim; support for attending meetings or travel from GSK, AstraZeneca, and Novartis; and participates on the Advisory Board for Amgen. KW is a member of the Advisory Board at CSL Vifor. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objectives: Ceruloplasmin is an inhibitor of myeloperoxidase (MPO) activity that plays an important role in the pathophysiology of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). This study aimed to evaluate the prognostic impact of serum level of ceruloplasmin at diagnosis in patients with anti-MPO antibody-positive AAV., Methods: This retrospective monocentric study in Caen University Hospital involved all consecutive adult anti-MPO antibody-positive patients with microscopic polyangiitis or granulomatosis with polyangiitis, diagnosed between January 2010 and January 2022 with available serum sample at inclusion. Patients outcomes were analyzed from two subgroups constituted according to the median serum level of ceruloplasmin. The same analyses were then performed in anti-proteinase 3 (PR3) antibody-positive patients., Results: Within the 92 patients analyzed, 50 patients had anti-MPO antibodies with a median ceruloplasmin level of 0.44 [quartiles 1-3, 0.40-0.49] g/L and a median Birmingham Vasculitis Activity Score of 19 [14-22]. After a median follow-up period of 40 [22-86] months, 13 (26%) patients had died: 10 (40%) in the low ceruloplasmin group and 3 (12%) in the high ceruloplasmin group (p = 0.03), with a significantly worse survival rate in the low ceruloplasmin group (p = 0.021). No significant differences in relapse rate or renal failure was observed between the two groups. The same analyses performed in the group of AAV patients with anti-PR3 antibody did not show any differences., Conclusion: In anti-MPO AAV patients, serum level of ceruloplasmin at diagnosis seems to be associated with a significant impact on survival., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Camboulive et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shimojima, Kishida, Ichikawa, Takamatsu, Nomura and Sekijima.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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 (10 9 /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.

Objectives: Previous studies have shown that adipokines may serve as potential biomarkers reflecting disease activity in various autoimmune diseases. Here, we investigated the relationship between four adipokines and clinical/laboratory findings in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA)., Methods: Sera from 63 patients with MPA and GPA who were registered in a prospective cohort were used to detect serum levels of adiponectin, chemerin, resistin, and vaspin using commercial enzyme-linked immunosorbent assay kits. Associations between adipokines and clinical and laboratory data was assessed using Pearson's correlation analysis., Results: The median age was 65.0 years, 24 patients were male, and 42 patients were diagnosed with MPA. The median levels of adiponectin, chemerin, resistin, and vaspin in patient sera were 13.9 ng/mL, 9.2 ng/mL, 23.7 ng/mL, and 0.1 ng/mL, respectively. A significant correlation between chemerin level and five-factor score (FFS) was found (r = 0.320, p = 0.011), and resistin was correlated with both Birmingham vasculitis activity score and FFS (r = 0.256, p = 0.043 and r = 0.320, p = 0.011). Regarding laboratory data, adiponectin level was associated with creatinine, and chemerin level was associated with creatinine, albumin, and erythrocyte sedimentation rate (ESR). On the other hand, resistin was found to be associated with white blood cell count, creatinine, ESR, and C-reactive protein. Age did not have a significant impact on the levels of adipokines., Conclusions: The expression of adipokines in the sera of patients with MPA and GPA differs depending on clinical and laboratory features, and serum resistin may be suggested as a potential biomarker reflecting disease activity., Competing Interests: The authors have declared that no competing interests exist.

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., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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.

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-A 165 b (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-A 165 b 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-A 165 b concentrations in patients with microscopic polyangiitis and EGPA, respectively. However, despite the comparable concentrations of sVEGF-A and sVEGF-A 165 b during the 6 months of treatment in granulomatosis with polyangiitis patients, correlation analysis revealed that the differences in log 2 -transformed concentrations of sVEGF-A and sVEGF-A 165 b were inversely correlated with time to remission in granulomatosis with polyangiitis patients., Conclusion: These results suggest that sVEGF-A and -A 165 b can serve as potential markers of time to remission in patients with granulomatosis with polyangiitis.

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.

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.

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.

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) ., (Copyright: © 2020 SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES.)

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.

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.

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., Competing Interests: The authors have declared that no competing interests exist.

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.

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.

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.

Objective: To evaluate circulating cytokine profiles in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV), classified by antineutrophil cytoplasmic antibody (ANCA) specificity (proteinase 3 ANCA [PR3-ANCA] versus myeloperoxidase ANCA [MPO-ANCA]) or by clinical diagnosis (granulomatosis with polyangiitis [GPA] versus microscopic polyangiitis [MPA])., Methods: A panel of 29 cytokines was tested in 186 patients with active AAV at inclusion into the Rituximab in AAV trial. Cytokine concentrations were compared between groups within each classification system. Multivariable analyses adjusted for age, sex, and renal insufficiency were performed, with each biomarker as a dependent variable and ANCA specificity and clinical diagnosis as explanatory variables of interest., Results: Levels of 9 circulating cytokines (interleukin-6 [IL-6], granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-15, IL-18, CXCL8/IL-8, CCL-17/thymus and activation-regulated chemokine [TARC], IL-18 binding protein [IL-18 BP], soluble IL-2 receptor α [sIL-2Rα], and nerve growth factor β [NGFβ]) were significantly higher in PR3-AAV than MPO-AAV, 4 cytokines (sIL6R, soluble tumor necrosis factor receptor type II [sTNFRII], neutrophil gelatinase-associated lipocalin [NGAL], and soluble intercellular adhesion molecule 1 [sICAM-1]) were higher in MPO-AAV than in PR3-AAV, 6 cytokines (IL-6, GM-CSF, IL-15, IL-18, sIL-2Rα, and NGFβ) were higher in GPA than in MPA, and 3 cytokines (osteopontin, sTNFRII, and NGAL) were higher in MPA than in GPA (all P < 0.05). For nearly all cytokines, the difference between PR3-AAV and MPO-AAV was larger than that between GPA and MPA. The multivariate analysis showed that 8 cytokines (IL-15, IL-8, IL-18 BP, NGF-β, sICAM-1, TARC, osteopontin, and kidney injury molecule 1 (P < 0.05) distinguished patients with AAV better (lower P values and larger effect sizes) when grouped by ANCA specificity than by clinical diagnosis., Conclusion: Distinct cytokine profiles were identified for PR3-AAV versus MPO-AAV and for GPA versus MPA. Differences in these circulating immune mediators are more strongly associated with ANCA specificity than with clinical diagnosis, suggesting that heterogeneity in the AAV subtypes extends beyond clinical phenotypes., (© 2018, American College of Rheumatology.)

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., Competing Interests: The authors have declared that no competing interests exist.

Mean platelet volume (MPV) was known to be associated with the inflammatory burdens in various diseases, but not microscopic polyangiitis (MPA) yet. In this study, we investigated the association between MPV and Birmingham vasculitis activity score (BVAS) in 88 patients with MPA. We retrospectively reviewed the medical records of 88 patients with MPA. Clinical and laboratory data at diagnosis and partially at follow-up were collected. Linear regression analyses were used to clarify the association between MPV and BVAS. We also stratified MPA patients into three groups according to tertile of BVAS and define the lower limit of the highest tertile as the cut-off of BVAS for severe MPA. The area under the receiver operator characteristic curve (AUROC) was used to identify the cut-off of MPV for severe MPA (8.85 fL). The mean age was 60.5 years and 25 patients were male (28.4%). In univariable linear regression analysis, MPV was negatively correlated with BVAS (r = - 0.326). In multivariable linear regression analysis, MPA was independently associated with BVAS (β = - 0.260). When we classified MPA patients into two groups based on the cutoff of MPV for severe MPA, patients having MPV ≤ 8.85 fL exhibited the higher frequency of severe MPA than those having MPV > 8.85 fL (RR 5.000). In addition, MPV increased along with improvement of vasculitis activity during the follow-up. In conclusion, MPV is significantly associated with BVAS and it can estimate the current BVAS in patients with MPA.

We herein describe a case of a 6-year-old girl diagnosed with microscopic polyangiitis (MPA) after a long diagnostic process demanding the cooperation of paediatric respiratory medicine specialists, rheumatologists, nephrologists and radiologist. First symptoms of MPA were observed after Mycoplasma pneumoniae infection and included persistent crepitations at the basis of both lungs and mild haematuria. CT imaging showed features of lung fibrosis, renal biopsy was indicative of mesangial proliferative glomerulonephritis, in the skin biopsy features of microscopic polyangiitis were described. In the laboratory tests pANCA antibodies specific for myeloperoxidase (MPO) were present in high titer. MPA with initial features of lung fibrosis is an unusual presentation of this rare disease, usually observed in adult population. This unique case illustrates the diagnostic and therapeutic challenges in paediatric vasculitis patients with an unusual initial presentation in the form of interstitial lung disease. In the manuscript we also discuss the possible aetiology of lung fibrosis in microscopic polyangiitis MPA and provide the review of the current literature on the topic of childhood-onset MPA.

Background: Microscopic polyangiitis (MPA), which is classified as an anti-neutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis, is one of the most frequent primary vasculitides in Japan. We earlier nominated 16 genes (IRF7, IFIT1, IFIT5, OASL, CLC, GBP-1, PSMB9, HERC5, CCR1, CD36, MS4A4A, BIRC4BP, PLSCR1, DEFA1/DEFA3, DEFA4, and COL9A2) as predictors of response to remission induction therapy against MPA. The aim of this study is to determine the accuracy of prediction using these 16 predictors., Methods: Thirty-nine MPA patients were selected randomly and retrospectively from the Japanese nationwide RemIT-JAV-RPGN cohort and enrolled in this study. Remission induction therapy was conducted according to the Guidelines of Treatment for ANCA-Associated Vasculitis published by the Ministry of Health, Labour, and Welfare of Japan. Response to remission induction therapy was predicted by profiling the altered expressions of the 16 predictors between the period before and 1 week after the beginning of treatment. Remission is defined as the absence of clinical manifestations of active vasculitis (Birmingham Vasculitis Activity Score 2003: 0 or 1 point). Persistent remission for 18 months is regarded as a "good response," whereas no remission or relapse after remission is regarded as a "poor response.", Results: "Poor" and "good" responses were predicted in 7 and 32 patients, respectively. Five out of 7 patients with "poor" prediction and 1 out of 32 patients with "good" prediction experienced relapse after remission. One out of 7 patients with "poor" prediction was not conducted to remission. Accordingly, the sensitivity and specificity to predict poor response was 85.7% (6/7) and 96.9% (31/32), respectively., Conclusions: Response to remission induction therapy can be predicted by monitoring the altered expressions of the 16 predictors in the peripheral blood at an early point of treatment in MPA patients.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is systemic vascular inflammation. Microscopic polyangiitis (MPA) is a major type of AAV in Japan. MPA often affects the kidneys and lungs, leading to death if untreated. Induction therapy (i.e., initial treatment) for MPA has not been optimized, although methylprednisolone and cyclophosphamide are commonly used. Recently, rituximab (RTX) (a monoclonal antibody against the protein CD20) has also been used to treat refractory AAV. RTX at 375 mg/m 2 /week for 4 weeks (i.e., the conventional lymphoma dosing schedule) is used, but the optimal dosing schedule is controversial. Indeed, a single-dose of RTX successfully controlled nephrotic syndrome. However, to date, the effectiveness of a single RTX dose in treating MPA has not been fully investigated in Japan. This was a retrospective observational study. Six newly diagnosed patients with MPA were initially treated with methylprednisolone and a single dose of RTX (375 mg/m 2 ). We investigated the patients' clinical features, as well as the efficacy and safety of RTX treatment. All patients attained remission on a tapered prednisolone dose of < 10 mg/day during the first 12 months. One patient relapsed after 12 months whereas another required hospitalization owing to infective spondyloarthritis. Adverse reactions to RTX infusion and late-onset neutropenia were not observed. Therefore, a single-dose treatment with RTX induced remission with few complications, and allowed tapering the prednisolone treatment. We conclude that a single dose of RTX is a promising induction therapy for MPA, reducing the cost associated with multiple doses.

Objectives: We reclassified Korean patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) into 3 categories of AAV including MPO-ANCA, PR3-ANCA and ANCA-negative vasculitis, and investigated clinical and prognostic features., Methods: We reviewed the medical records of 133 patients with microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic GPA (EGPA), who had either myeloperoxidase (MPO)-ANCA, proteinase 3 (PR3)-ANCA or no ANCA, and who had ever achieved the first remission. We compared clinical manifestations, initial Birmingham vasculitis activity score (BVAS) and five factor score (FFS), and relapse rates., Results: Patients with ANCA-negative vasculitis had the youngest mean age at diagnosis (50.0 years old) among AAV categories. General, cutaneous and renal manifestations were commonly observed in MPO-ANCA vasculitis, while mucous membrane, eye, ear nose throat (ENT) and renal manifestations were often documented in PR3-ANCA vasculitis. ENT manifestation was also frequently observed in ANCA-negative vasculitis. However, there were no significant differences in pulmonary and nervous system manifestations among 3 AAV categories. There were no significant differences in cumulative relapse free survival according to the presence of MPO-ANCA or PR3-ANCA or no ANCA. Meanwhile, initial BVAS or BVAS for GPA ≥13.5 in MPO-ANCA vasculitis and initial FFS (1996) ≥1 in MPO-ANCA and ANCA-negative vasculitis were significant predictors of relapse of each AAV category., Conclusions: Clinical manifestations varied AAV categories, and neither MPO-ANCA nor PR3-ANCA significantly affected relapse of AAV. Initial BVAS or BVAS for GPA and FFS (1996) helped to predict relapse of specified AAV categories.

Objectives: We investigated whether specified organ involvements, antineutrophil cytoplasmic antibody (ANCA) positivity, Birmingham vasculitis activity score (BVAS) and five factor scores (FFS) at diagnosis could predict relapse of microscopic polyangiitis (MPA)., Methods: We reviewed the medical records of 90 patients with MPA. We collected clinical and prognostic data, (MPO)-ANCA and proteinase 3 (PR3)-ANCA, BVAS and FFS at diagnosis, and we compared them between the two groups. The optimal cut-off values of BVAS and FFS (1996) for predicting relapse were extrapolated., Results: The mean age of patients (63 women) was 62.3 years and the mean follow-up duration was 41.7 months. At diagnosis, the mean BVAS, FFS (1996) and FFS (2009) of patients in no remission group were higher than those of patients in remission group (p<0.005 for all). Patients in relapse group exhibited chest and renal manifestations more frequently than those in no relapse group and the mean BVAS and FFS (1996) of patients in relapse group were significantly higher than those of patients in remission group (p<0.005 for all). There were no differences in MPO-ANCA and PR3-ANCA between the two groups. On multivariate logistic regression analysis, chest and renal manifestations were all independent predictors of relapse (OR 2.013 and OR 3.517). Patients who had BVAS ≥13.5 and FFS ≥ 1 exhibited a significantly increased risk of relapse than those who did not (RR 4.408 and RR 3.030)., Conclusions: Chest and renal involvements, BVAS ≥13.5 and FFS ≥1 at diagnosis were independent predictors of relapse of MPA.

A 20-year-old woman, who was suffering from appetite loss, weight loss and livedo reticularis for one and half months, was referred to our hospital. On admission, laboratory studies demonstrated proteinuria (1.0 g/g Cr), hematuria (erythrocytes': 50 - 99/HPF), ,.enal dysfunction (Cr : 2.09 mg/dL), elevated C reactive protein (CRP: 10.82 mg/dL), elevated MPO-ANCA titer (11.6 U/mL) and elevated pentraxin3 (PTX3: 24.05 ng/mL). Her kidney and skin biopsy revealed massive crescentic necrotizing glomerulonephritis and leukocytoclastic vasculitis, respectively. She was diagnosed with microscopic polyangiitis (MPA), and treated with 500 mg/day of intravenous methyl-prednisolone (mPSL) for 3 days followed by 40 mg/day of oral PSL, rituximab (375 mg/m² once a week for a month) and plasma exchange. When PSL tapered to 30 mg/day in 4 weeks, her renal function was only partially recovered, while the CRP level had been normalized and the MPO-ANCA titer was almost negative (3.6 IU/mL). To evaluate histological activity, a second renal biopsy was conducted, which showed fibrocellular crescents in 32% of her glomeruli. The PTX3 level remained high (14.82 ng/mL) at that point. Taken together, the vasculitis was considered to be active still. Steroid pulse therapy for 3 days was administered again, followed by oral PSL 30 mg/day. Her renal function completely recovered in 70 days. The PTX3 level also normalized in 161 days. PTX3 is one of the short pentraxins, produced by a variety of cell types in response to pro-inflammatory signals such as IL-1 and TNF-α. It was reported that PTX3 reflects activity of vasculitis independently from CRP. In the presenting case, when the second renal biopsy revealed a histologically active lesion of the vasculitis, PTX3 was elevated independently from CRP and MPO-ANCA, suggesting that PTX3 may be a more sensitive marker of the disease activity than other tests.

Objectives: The contribution of infections to the mortality of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is important, and early and careful infection control is necessary. We investigated the usefulness of the serum-soluble haemoglobin scavenger receptor CD163 for detecting the presence of infectious complications regardless of disease activity., Method: Soluble CD163 in serum obtained from 45 Japanese patients with myeloperoxidase (MPO)-AAV was measured by an enzyme-linked immunosorbent assay (ELISA). We evaluated 36 samples from active-vasculitis patients, 36 samples from inactive-vasculitis patients without infection, and 19 samples from inactive-vasculitis patients with infectious complications. Serum-soluble CD163 was also measured in 15 infectious patients without vasculitis and in 30 normal controls., Results: The mean serum-soluble CD163 level was higher in the patients with infectious complications than in the active-vasculitis patients, inactive-vasculitis patients, and normal controls. There were significant positive correlations between serum-soluble CD163 levels and white blood cell (WBC) count, serum C-reactive protein (CRP) levels, and serum albumin levels, but only serum CRP levels were correlated with serum-soluble CD163 levels in a multiple regression analysis. On the receiver-operating characteristic (ROC) curve, serum-soluble CD163 levels had 80.6% sensitivity and 86.7% specificity for differentiating patients with infection from those without infection. Among the active-vasculitis patients, the mean serum-soluble CD163 level of the patients with alveolar haemorrhage was significantly lower than that of the patients with interstitial lung diseases and that of the patients without pulmonary lesions., Conclusions: The serum-soluble CD163 level may be a useful marker for the detection of infectious complications in MPO-AAV patients.

Among antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), granulomatosis with polyangiitis (GPA) and proteinase 3-ANCA-positive AAV (PR3-AAV) are prevalent in European populations, while microscopic polyangiitis (MPA) and myeloperoxidase-ANCA-positive AAV (MPO-AAV) are predominant in the Japanese. We previously demonstrated association of DRB1*09:01-DQB1*03:03 haplotype, a haplotype common in East Asians but rare in the European populations, with MPA/MPO-AAV, suggesting that a population difference in HLA-class II plays a role in the epidemiology of this disease. To gain further insights, we increased the sample size and performed an extended association study of DRB1 and DPB1 with AAV subsets in 468 Japanese patients with AAV classified according to the European Medicines Agency algorithm (MPA: 285, GPA: 92, eosinophilic GPA [EGPA]: 56, unclassifiable: 35) and 596 healthy controls. Among these patients, 377 were positive for MPO-ANCA and 62 for PR3-ANCA. The significance level was set at α = 3.3x10-4 by applying Bonferroni correction. The association of DRB1*09:01 with MPO-AAV was confirmed (allele model, P = 2.1x10-4, odds ratio [OR] = 1.57). Protective association of DRB1*13:02 was detected against MPO-AAV (allele model, P = 2.3x10-5, OR = 0.42) and MPA (dominant model, P = 2.7x10-4, OR = 0.43). A trend toward increased frequency of DPB1*04:01, the risk allele for GPA in European populations, was observed among Japanese patients with PR3-AAV when conditioned on DRB1*13:02 (Padjusted = 0.0021, ORadjusted = 3.48). In contrast, the frequency of DPB1*04:01 was decreased among Japanese patients with MPO-AAV, and this effect lost significance when conditioned on DRB1*13:02 (Padjusted = 0.16), suggesting that DRB1*13:02 or other allele(s) in linkage disequilibrium may be responsible for the protection. The differential association of DPB1*04:01 with PR3-AAV and MPO-AAV and difference in DPB1*04:01 allele frequencies between populations supported the hypothesis that the HLA-class II population difference may account in part for these epidemiologic characteristics. Furthermore, taken together with our previous observations, the haplotype carrying DRB1*13:02 was suggested to be a shared protective factor against multiple autoimmune diseases.

A pancreatic tumor was suspected on the abdominal ultrasound of a 72-year-old man. Abdominal computed tomography showed pancreatic enlargement as well as a diffuse, poorly enhanced area in the pancreas; endoscopic ultrasound-guided fine needle aspiration biopsy and endoscopic retrograde cholangiopancreatography failed to provide a definitive diagnosis. Based on the trend of improvement of the pancreatic enlargement, the treatment plan involved follow-up examinations. Later, he was hospitalized with an alveolar hemorrhage and rapidly progressive glomerulonephritis; he tested positive for myeloperoxidase-anti-neutrophil cytoplasmic antibody (ANCA) and was diagnosed with ANCA-related vasculitis, specifically microscopic polyangiitis. It appears that factors such as thrombus formation caused by the vasculitis in the early stages of ANCA-related vasculitis cause abnormal distribution of the pancreatic blood flow, resulting in non-uniform pancreatitis. Pancreatic lesions in ANCA-related vasculitis are very rare. Only a few cases have been reported previously. Therefore, we report our case and a review of the literature.

Microscopic polyangiitis and granulomatosis with polyangiitis are rare anti-neutrophilic cytoplasmic antibody-associated systemic vasculitides that predominantly affect small to medium sized vessels of the lungs and kidneys. These syndromes are largely confined to older adults and often present sub-acutely following weeks to months of nonspecific prodromal symptoms. While both diseases often manifest within multiple organ systems concurrently, the disease spectrum of microscopic polyangiitis almost always includes the kidneys, while granulomatosis with polyangiitis is most commonly associated with pulmonary disease. We present two cases of rapid onset respiratory failure secondary to diffuse alveolar hemorrhage in young active duty military personnel. After serological testing and surgical lung biopsy, both patients were diagnosed with microscopic polyangiitis with isolated pulmonary involvement.

Objective: To investigate the association of farm exposure and the development of ANCA-associated vasculitis (AAV)., Methods: One hundred eighty-nine well defined patients with AAV (n = 119 with granulomatosis with polyangiitis [GPA], n = 48 with microscopic polyangiitis [MPA], n = 22 patients with eosinophilic granulomatosis with polyangiitis [EGPA]) and 190 controls (n = 119 patients with rheumatoid arthritis, n = 71 with large vessel vasculitis) were interrogated using a structured questionnaire. Factors investigated were occupation, farm exposure, contact to different livestock, participation in harvesting, residence next to a farm, MRSA status, and contact to domestic pets at disease onset or ever before. The odds ratio (OR) and 95% confidence interval [95%CI] were calculated for each item., Results: Univariate analysis revealed a strong association of AAV with regular farm exposure; OR 3.44 [95%CI 1.43-8.27]. AAV was also associated with regular contact to cattle 4.30 (1.43-8.27), pigs 2.75 (1.12-6.75) and MRSA carriage 3.38 (1.11-10.3). This association was stronger in the subgroup of GPA patients. OR in this group for farm exposure was 4.97; [2.02-12.2], for cattle 6.71 [95% CI 2.19-20.7], for pigs 4.34 [1.75-10.9], and MRSA carriage 5.06 [1.62-15.8]). There was no significant association of MPA or EGPA with these parameters., Conclusion: A significant association between farm exposure or farm animal exposure and AAV especially in the subgroup of patients with GPA has been identified. This suggests that these entities are distinct and have different triggers for the immune process.

Kidneys and lungs are the most common organs involved in microscopic polyangiitis (MPA). A retrospective analysis of pediatric MPA patients with pulmonary lesions over the past 10 years was performed to investigate clinical features of MPA in children with pulmonary lesions. There were 9 patients enrolled in our study, including 2 boys and 7 girls, with a median age of 6.6 years at the time of disease onset and a median disease course of 2 months. All of the patients exhibited tachypnea, and 7 exhibited cough and hemoptysis. The most common presentation on pulmonary imaging was ground glass or patchy shadows, which were observed in 6 cases. Seven patients manifested with hematuria and proteinuria, with renal histopathology of fibrinoid necrosis/exudation of the glomerular capillaries. All of the patients presented with normocytic normochromic anemia. Of the 9 patients, 7 were positive for perinuclear antineutrophil cytoplasmic antibody (p-ANCA) and/or myeloperoxidase (MPO), and 2 were positive for p-ANCA/MPO and cytoplasmic ANCA/proteinase 3. Eight patients had normal complement 3 (C3) levels, and one had an elevated C3 level. Five of the 9 patients were positive for antinuclear antibody ANA, and 4 were positive for double strand DNA (ds-DNA) antibody (3 were positive for both). The 7 patients who exhibited renal involvement received steroid plus cyclophosphamide (CTX) treatment. Of these patients, 4 achieved various degrees of remission, 2 were at the beginning of induction therapy, and one was lost to follow-up. Two patients with isolated pulmonary involvement received steroid plus leflunomide treatment and achieved complete remission. Diffuse alveolar hemorrhage was the most frequent presentation of lung involvement in children with MPA, and tachypnea, cough, hemoptysis and anemia were the common clinical symptoms. The majority of these patients exhibited hematuria, proteinuria and renal insufficiency. The efficacy of steroid plus CTX or leflunomide was evident in these patients.

The association between microscopic polyangiitis (MPA) and primary biliary cirrhosis (PBC) has seldom been reported. We describe here a patient who presented with sensorimotor neuropathy along with hypothyroidism, renal failure and liver dysfunction. Detection of antinuclear antibodies at a titer of 1/800, anti-SSA, anti-SSB, anti-GP210, anti-microsomial and p-ANCA anti-myeloperoxydase antibodies along with renal, salivary and liver biopsy led to a diagnosis of MPA associated with PBC, Sjogren's syndrome and Hashimoto's thyroiditis.

Aim: To study the clinical features of early- and extended-stage microscopic polyangiitis (MPA) and its outcomes on the basis of a long-term follow-up in a rheumatologist's practice., Subjects and Methods: The clinical features of early- and extended-stage MPA were studied in detail and the premorbid background and possible precipitating factors were analyzed in 70 patients with MPA and the proven hyperproduction of antineutrophil cytoplasmic antibodies (anti-proteinase-3 (anti-PR3) antibodies in 55% and anti-myeloperoxidase (anti-MPO) antibodies in 45%) who had been followed up for more than a year., Results: There is evidence for the nosological unity of the two immunological types of MPA associated with anti-PR-3 or anti-MPO antibodies. MPA has been demonstrated to be an aggressive, polysyndromic disease prone to recurrences (52%), the typical manifestation of which is glomerulonephritis (94%) that is rapidly progressive in every four cases and accompanied by hemorrhagic alveolitis (69%) and involvement of other organs. ENT organs and lungs have been noted to be commonly involved in early-stage MPA, which was observed in 61% of the patients in the premorbid period, and to become the first manifestation of MPA (63%) concurrent with body temperature rises (64%), arthralgia or arthritis (41%). Respiratory tract involvement in MPA may be asymptomatic. Anti-PR-3-associated MPA may manifest itself more aggressively and in the first 2 years it is characterized by a poorer prognosis than of anti-MPO-associated MPA (survival rates, 82 and 94%, respectively; p = 0.04). With time, the differences were levelled off; recurrences in the patients with anti-PR-3 and anti-MPO develop equally frequently and proceed showing the similar clinical picture; the survival curves converge by age 3. Anti-MPO-associated MPA is characterized by the highest rate of lung involvement in the clinical phase of the disease (61%) and by a propensity to develop hemorrhagic alveolitis, diffuse interstitial (22%) or circumscribed pulmonary fibrosis in the outcome. CONCLUSION. The findings emphasize how important to diagnose MPA early and to prescribe long-term active treatment using the entire current arsenal of medications as soon as possible until severe injury to organs and systems develops. To specify regularities in the development of MPA may be of value for the better diagnosis of the disease and the further elaboration of optimal treatment policy.

Background: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare lung disease caused by the autoantibody against granulocyte-macrophage colony stimulating factor (GM-CSF). The clinical course of aPAP is variable; in severe cases, patients develop lethal respiratory failure due to pulmonary fibrosis. However, the pathogenesis of pulmonary fibrosis in aPAP has never been delineated., Case Presentation: Here, we describe a rare case of aPAP that was subsequently complicated by microscopic polyangiitis-related pulmonary fibrosis. The patient was a 75-year-old Japanese man diagnosed with aPAP based on the crazy-paving appearance on high-resolution computed tomography (HRCT), "milky" appearance of broncho-alveolar lavage fluid (BALF), and elevated serum levels of the anti-GM-CSF antibody. The patient was followed-up without aPAP-specific treatment for 3 years. During this period, both hematuria and proteinuria appeared; in addition, serum myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA) turned positive and increased markedly. The second BAL performed one year after the diagnosis, showed that the "milky" appearance had resolved. The HRCT showed that fibrotic changes had developed and that the crazy-paving appearance had disappeared. These data suggest an association between pulmonary fibrosis that developed during the natural course of aPAP and ANCA-related systemic vasculitis., Conclusion: This is the first case report that suggests the existence of a pathogenetic relationship between ANCA-associated systemic vasculitis and aPAP-related pulmonary fibrosis. The link between ANCA-associated systemic vasculitis and aPAP-related pulmonary fibrosis requires further investigation.

Objective: There are differences between Europe and Japan in the incidence and antineutrophil cytoplasmic antibody (ANCA) serotype of patients with microscopic polyangiitis (MPA). However, differences in phenotype or outcome have not been explored. We aimed to identify differences in phenotype and outcome of MPA between Europe and Japan., Methods: Sequential cohorts of patients with MPA and renal limited vasculitis were collected from European and Japanese centers (n = 147 and n = 312, respectively). Trial databases from the European Vasculitis Society and the Japanese patients with Myeloperoxidase (MPO)-ANCA-Associated Vasculitis (JMAAV) trial were studied (n = 254 and n = 48, respectively). We evaluated baseline characteristics including ANCA status and organ involvement, treatment, survival, and renal survival. Differences in survival and renal survival were studied using multivariate analysis., Results: The non-trial cohorts showed patients with MPA in Japan had a higher age at onset, more frequent MPO-ANCA positivity, lower serum creatinine, and more frequent interstitial pneumonitis than those in Europe (all p < 0.01). Comparisons between the trial databases demonstrated similar results. Cumulative patient survival and renal survival rates were not different between Europe and Japan (p = 0.71 and p = 0.38, respectively). Multivariate analysis identified age at onset, serum creatinine, gastrointestinal, and respiratory involvement as factors with higher risk of death. For endstage renal failure, serum creatinine and use of plasma exchange were identified as factors with higher risk, and immunosuppressant use as lower risk factors., Conclusion: Phenotypes in patients with MPA were different between Europe and Japan. However, the outcomes of patient survival and renal survival were similar.

Both microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) belong to ANCA-associated vasculitis (AAV), in which neutrophils play a key role in their pathology. In this study, in order to discriminate between MPA and GPA, protein profiles of peripheral blood polymorphonuclear cells (PMNs) of 11 MPA patients and 9 GPA patients and 10 healthy controls (HC) were analyzed by 2D-DIGE. In all the 864 spots detected, intensity of 55 spots was significantly different (p<0.05) among the three groups by ANOVA. 31 out of the 55 spots were identified by mass spectrometry. Orthogonal partial-least-squares-discriminate analysis revealed that the abundance profile of the protein spots discriminated the AAV group from the HC group, and the MPA group from the GPA group completely. 13 protein spots were considered as biomarker candidates to distinguish between MPA and GPA. In those, spots whose intensity was higher in MPA than in GPA included actin with various pI values, while a considerable part of spots whose intensity was higher in GPA were proteins related with the activity of neutrophils. Among the candidate proteins, ROC analysis showed that a combination of neutrophil gelatinase-associated lipocalin and a-kinase anchor protein 7 isoforms beta had a high diagnostic potential., Biological Significance: In this study, protein profiles of polymorphonuclear cells (PMNs) of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) patients and healthy controls (HC) were investigated by 2D-DIGE, and MS analysis. As a result, we found that the protein profiles of PMNs were useful for distinguishing between patients (MPA and GPA) and HC, and between patients with MPA and patients with GPA. Especially, we found that the 13 protein spots that consisted of 10 proteins considerably contributed to the discrimination between MPA and GPA. This is the first to demonstrate that protein profiles of PMNs are different among MPA, GPA and healthy control. The 10 proteins we identified in this study would be new biomarkers for the diagnosis of the diseases, and may be reflect the pathology difference between MPA and GPA., (© 2013.)

Aim: To identify autoantibodies useful in the diagnosis of primary vasculitides., Methods: The presence of antibodies against proteins in the lysate of mouse blood vessels was examined by two-dimensional electrophoresis followed by Western blotting for the pooled serum sample from patients with various forms of vasculitis: polyarteritis nodosa (PAN), microscopic polyangiitis (MPA), Wegener's granulomatosis (WG) and Takayasu's arteritis (TA). Autoantigenicity in patients with vasculitides was examined by Western blotting and enzyme-linked immunosorbent assay (ELISA). Clinicopathological correlations between the positivity of the autoantibodies and clinical status of patients with the vasculitis were examined., Results: The autoantigen detected in the lysate of pooled sera from patients with vasculitides was identified by mass spectrometry as carbonic anhydrase III (CAIII). ELISA showed significantly higher prevalence of anti-CAIII antibodies in MPA patients (MPA, 11/23 [47.8%]; healthy controls, 2/32 [6.3%]; P < 0.001). Further, anti-CAIII antibody-positive MPA patients had higher vasculitis activity scores compared to anti-CAIII antibody-negative patients, and a weak and not significant negative correlation was observed between anti-CAIII antibody levels and myeloperoxidase - anti-nuclear cytoplasmic antibody (MPO-ANCA) levels. No significant differences were found in anti-CAIII autoantibody levels between MPA and the other primary vasculitides., Conclusion: We found significantly high prevalence of anti-CAIII antibody levels in sera from MPA patients. Although the number of samples available in this study is small and anti-CAIII autoantibodies display weak specificity for MPA, anti-CAIII antibodies may be useful for diagnosing MPA in patients who have no ANCA, as well as for assessing disease activity., (© 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

The JMAAV study was an open-labeled prospective clinical trial, which proposed severity-based treatment protocols for patients with microscopic polyangiitis (MPA). The results suggest that the proposed protocols are useful (remission rate: 89.4%), but are also indicative of relapse or patient demise regardless of the treatment (recurrence rate: 19.0%; mortality rate: 10.6%). The aim of this study is to develop the method to predict response to the treatment in patients with MPA. In the present study, transcriptome analysis was performed using peripheral blood from patients enrolled in the JMAAV study before and 1-week after the beginning of treatment. The gene expression profile before treatment was not directly related to the response to the treatment. However, when the samples from 9 patients with good response (persistent remission for 18 months) were examined, the expression of 88 genes was significantly altered by the treatment. Thirty statistically reliable genes were selected, and then the alteration of expression by the treatment was examined among 22 patients, including 17 with good response, which was defined as persistent remission for 18 months and 5 with poor response, which was defined as relapse after remission or no remission. Discrimination analysis between the alteration of expression of the 30 genes by the treatment and the response identified a combination of 16 genes as the most valuable gene set to predict the response to the treatment. This preliminary study identified IRF7, IFIT1, IFIT5, OASL, CLC, GBP-1, PSMB9, HERC5, CCR1, CD36, MS4A4A, BIRC4BP, PLSCR1, DEFA1/DEFA3, DEFA4, and COL9A2 as the important genes that can predict the response to the treatment in patients with MPA at an early point during the therapy.

Introduction: The present study aimed to explore a possible role for IL-21 producing Th-cells in the immunopathogenesis of granulomatosis with polyangiitis (GPA)., Methods: Peripheral blood from 42 GPA patients in remission and 29 age-matched healthy controls (HCs) were stimulated in vitro, and the frequencies of IL-21 producing Th-cells were determined by flow cytometry. Since Th17-cells produce a low level of IL-21, IL-17 was also included in the analysis. Given that IL-21 is a hallmark cytokine for T follicular helper cells (T(FH)), we next evaluated the expression of their key transcription factor BCL-6 by RT-PCR and flow cytometry. To investigate the effect of IL-21 on autoantibody-production, PBMCs from GPA patients were stimulated in vitro with BAFF/IL-21 and total IgG and ANCA levels were measured in supernatants. In addition, the expression of IL-21-receptor on B-cells was analyzed., Results: Percentages of IL-21 producing Th-cells were significantly elevated in GPA-patients compared to HCs, and were restricted to ANCA-positive patients. The expression of BCL-6 was significantly higher in ANCA-positive GPA-patients, as compared with ANCA-negative patients and HCs. IL-21 enhanced the production of IgG and ANCA in vitro in stimulated PBMCs from GPA patients. No difference was found in the expression of the IL-21-receptor on B-cells between ANCA-negative patients, ANCA-positive patients, and HCs., Conclusion: The increased frequency of circulating IL-21 producing Th-cells in ANCA-positive GPA patients and the stimulating capacity of IL-21 on ANCA-production suggest a role for these cells in the immunopathogenesis of GPA. Blockade of IL-21 could constitute a new therapeutic strategy for GPA.