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Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a group of rare diseases with a chronic and relapsing course. Recent treatment guidelines offer many therapeutic options depending mainly on the type of diagnosis and disease manifestations. Areas that remain under discussion include whether all patients diagnosed with AAV belong to a homogeneous group with a similar prognosis at baseline or if the type and duration of remission-inducing treatment should depend on factors other than just diagnosis and disease severity. The aim of this review is to present the recent literature on the tools available to use while evaluating the risk of relapse in patients upon presentation as well as potential biomarkers of proceeding flare in patients upon remission.

Objective: To characterize the eosinophilic granulomatosis with polyangiitis (EGPA) population from the POLVAS registry depending on ANCA status and diagnosis onset, including their comparison with the granulomatosis with polyangiitis (GPA) subset with elevated blood eosinophilia (min. 400/ μ l) (GPA HE) to develop a differentiating strategy., Methods: A retrospective analysis of the POLVAS registry., Results: The EGPA group comprised 111 patients. The ANCA-positive subset ( n  = 45 [40.54%]) did not differ from the ANCA-negative one in clinics. Nevertheless, cardiovascular manifestations were more common in ANCA-negative patients than in those with anti-myeloperoxidase (MPO) antibodies (46.97% vs. 26.92%, p  = 0.045). Patients diagnosed before 2012 ( n  = 70 [63.06%]) were younger (median 41 vs. 49 years, p   < 0.01), had higher blood eosinophilia at diagnosis (median 4,946 vs. 3,200/ μ l, p   < 0.01), and more often ear/nose/throat (ENT) and cardiovascular involvement. GPA HE comprised 42 (13.00%) out of 323 GPA cases with reported blood eosinophil count. Both GPA subsets had a lower prevalence of respiratory, cardiovascular, and neurologic manifestations but more often renal and ocular involvement than EGPA. EGPA also had cutaneous and gastrointestinal signs more often than GPA with normal blood eosinophilia (GPA NE) but not GPA HE. The model differentiating EGPA from GPA HE, using ANCA status and clinical manifestations, had an AUC of 0.92, sensitivity of 96%, and specificity of 95%., Conclusion: Cardiovascular symptoms were more prevalent in the ANCA-negative subset than in the MPO-ANCA-positive one. Since EGPA and GPE HE share similarities in clinics, diagnostic misleading may result in an inappropriate therapeutic approach. Further studies are needed to optimize their differentiation and tailored therapy, including biologics., Competing Interests: All authors have declared no conflicts of interest., (Copyright © 2024 Anna Drynda et al.)

Introduction: Nervous system involvement is common in antineutrophil cytoplasmic antibody-associated vasculitides (AAV). While the involvement of the peripheral and central nervous system is well described, it is still unclear how and to what extent the autonomic nervous system (ANS) is affected. Functional magnetic resonance imaging (fMRI) can provide information on both structure and potential damage of the brain, as well as on the function of selected brain centers., Objectives: The aim of this study was to investigate the ANS dysfunction in AAV patients and its correlation with the results of fMRI performed during the Valsalva maneuver., Patients and Methods: A total of 31 patients with AAV and 30 healthy controls were enrolled in the study. Each participant completed the Composite Autonomic Symptom Score (COMPASS)-31 questionnaire. MRI was performed using a 3T scanner. The participants were asked to perform the Valsalva maneuver according to the fixed protocol, and their airway pressure was monitored. During the maneuver, fMRI data were collected. The generalized least‑ squares time series analysis and the region of interest (ROI) analysis were subsequently performed., Results: The patients with AAV had a higher median COMPASS‑ 31 score than the controls (12.86 vs 2.99, respectively; P <0.01). Structural MRI investigation did not reveal any significant differences between the groups. The brain centers involved in ANS function were detected during fMRI; however, the ROI analysis showed no differences between the study patients and controls., Conclusions: The patients with AAV reported symptoms related to the ANS dysfunction; however, no differences with respect to the functioning of the ANS brain centers were demonstrated between these patients and healthy controls in the fMRI study during the Valsalva maneuver.

Introduction: Granulomatosis with polyangiitis (GPA) is a small vessel vasculitis with a complex pathomechanism. Organ damage in GPA is also mediated by extracellular trap formation (NETosis). We analyzed the functional status of phosphoproteins modulating NETosis in neutrophils by the mammalian target of rapamycin (mTOR) pathway in GPA along with NETosis biomarkers., Methods: Phosphoproteins levels measured in isolated neutrophils from 42 patients with GPA (exacerbation n=21; remission n=21) and 21 healthy controls were compared to serum biomarkers of the disease., Results: Neutrophils in active disease manifested lowered levels of phosphorylated mTOR (Ser2448), PTEN (Ser380) and ULK1 (Ser555) , whereas phosphorylated GSK-3α/β (Ser21/Ser9) was elevated. Exacerbation of GPA was characterized by elevated neutrophil dsDNA in serum, circulating mitochondrial DNA, and DNA-MPO complexes. A significant negative correlation between mTOR or PTEN phosphoproteins and biomarkers of GPA activity was also present, reflecting the clinical activity score of GPA. Positive correlations between phosphorylated GSK-3 α/β and circulating mtDNA, DNA-MPO complexes, neutrophil-released dsDNA, or circulating proteins were also significant. Increased serum levels of IGFBP-2, TFF-3, CD147, and CHI3L1 accompanied GPA exacerbation, whereas DPP-IV levels were the lowest in active GPA. Using a principal component analysis basigin, PTEN and mTOR had the highest loadings on the discrimination function, allowing classification between active, remission, and control subjects with 98% performance., Conclusions: We present evidence that inhibited mTOR signaling accompanies NETosis in patients with GPA. The functional status of phosphoproteins suggests simultaneous activation of NETosis and autophagy. These results give rise to the study of autophagy as a mechanism underlying granuloma formation in GPA., 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 © 2023 Surmiak, Wawrzycka-Adamczyk, Kosałka-Węgiel, Włudarczyk, Sanak and Musiał.)

Granulomatosis with polyangiitis is a chronic systemic inflammation of small vessels characterized by circulating anti-proteinase 3 antibodies. MicroRNAs are short transcripts specifically inhibiting protein translation. Neutrophils can release extracellular vesicles (EVs). In this study, we characterized profile of microRNA trafficked by EVs in GPA. Fifty patients with GPA were enrolled in the study, 25 at acute phase and 25 in remission. EVs were isolated from the blood serum, characterized by their number, size distribution. Following unbiased screening for microRNA expression, differentially expressed candidates were measured by quantitative real-time PCR. Circulating DNA-myeloperoxidase complexes and apoptosis-related transcripts in peripheral blood neutrophils were quantified. We identified four differentially expressed microRNAs from EVs in granulomatosis with polyangiitis (GPA). MirRs-223-3p, 664a-3p, and 200b-3p were overexpressed and miR-769-5p suppressed in the disease. A distinction between GPA and healthy controls was the best for miR-223-3p, whereas miR-664a-3p discriminated between active vs. remission of GPA. Correct classification of the disease based on multivariate discriminant analysis was between 92% for acute phase and 85% for all study participants. Bioinformatics tools identified genes transcripts potentially targeted by the microRNAs belonging to pathways of focal adhesion, mTOR signaling and neutrophil extracellular traps formation. Two microRNAs positively correlating with the disease activity were involved in neutrophil extracellular traps formation and apoptosis inhibition. A comprehensive characteristics of microRNAs trafficked in bloodstream inside EVs correlates well with our understanding of the mechanisms of GPA and suggests the importance of EVs in progression of the disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology.)

Introduction: Patients with granulomatosis with polyangiitis (GPA) show increased tendency toward thromboembolic phenomena in exacerbation of their disease., Objectives: The aim of the study was to evaluate thrombin generation potential and fibrinolytic plasma activity in patients with GPA, both in exacerbation and in remission., Patients and Methods: We included 38 patients with GPA: 18 with exacerbated GPA and 20 in remission. The control group included 39 healthy participants matched for age and sex. Plasma thrombogenic potential was assessed using calibrated automated thrombography. Plasma fibrinolytic potential was assessed using clot lysis time (CLT). We also measured levels of inflammatory markers, thrombomodulin, and fibrinolysis proteins in all participants., Results: In the whole group of patients with GPA, endogenous thrombin potential was higher by about 25% (P <0.001), while CLT was lower by about 20% (P = 0.02) when compared with controls. The endogenous thrombin potential was higher, the CLT lower, and the levels of thrombomodulin and inflammation markers (C‑reactive protein, fibrinogen, factor VIII) higher both in patients with exacerbation and in remission than in the control group; no such differences were noted when comparing those with exacerbation and those in remission, however. The only parameter that differentiated patients with GPA exacerbation from those in remission was the D‑dimer level (median [interquartile range], 1151 [597.2-2468.7] ng/ml vs 340.4 [255.1-500.7] ng/ml; P <0.001), a marker of lysis of intravascularly formed fibrin., Conclusions: Patients with GPA show an increased prothrombotic state, regardless of the disease phase. This is probably related to ongoing low-grade inflammation and endothelial injury. Large clinical studies are required to address the need for, and appropriate type of, antithrombotic prophylaxis during the course of GPA.

Activation of neutrophils is an important mechanism in the pathology of granulomatosis with polyangiitis (GPA). In this study, we evaluated whether extracellular vesicles (EVs) circulating in the plasma of GPA patients could contribute to this process. EVs from the plasma of GPA patients in the active stage of the disease (n = 10) and healthy controls (n = 10) were isolated by ultracentrifugation and characterized by flow cytometry (CD63, CD8) and nanoparticle tracking analysis. Targeted oxylipin lipidomics of EVs was performed by HPLC-MS/MS. EV/oxylipin-induced neutrophil extracellular traps (NETs) were analyzed by confocal microscopy, and released double-stranded DNA (dsDNA) was quantified by PicoGreen fluorescent dye. Reactive oxygen species (ROS) production and neutrophils' EV binding/uptake were evaluated by flow cytometry. Brief priming with granulocyte-macrophage colony-stimulating factor was required for EV-mediated ROS production and dsDNA release. It was observed that priming also increased EV binding/uptake by neutrophils only for EVs from GPA patients. EVs from GPA patients had higher concentrations of leukotriene (LT)B 4 and 5-oxo-eicosatetraenoic acid (5-oxo-ETE) as compared with EVs from healthy controls. Moreover, neutrophils stimulated with LTB 4 or 5-oxo-ETE produced ROS and released dsDNA in a concentration-dependent manner. These results reveal the potential role of EVs containing oxylipin cargo on ROS production and NET formation by activated neutrophils., (Copyright © 2020 Surmiak et al.)

Background/purpose: Granulomatosis with polyangiitis (GPA) is a type of primary systemic vasculitis associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). GPA mainly affects medium and small vessels and may manifest in different organs, most commonly upper respiratory tract. Oral lesions occur in 6-13% of GPA patients and might be the first symptom observed by the patient. This study presents the evaluation of orofacial manifestations of patients with GPA., Materials and Methods: Prospective study was conducted between June 2014 and November 2017 in Department of Allergy and Immunology at University Hospital in Krakow. Patients diagnosed with GPA, after medical assessment, were examined including precise dental inspection, bacterial and fungal flora of oral cavity evaluation and Cone Beam Computed Tomography (CBCT) imaging., Results: Nine patients were enrolled in the study. Characteristic for GPA strawberry gingivitis was observed in one patient. Bone destruction and inflammatory lesions in paranasal sinuses was confirmed by CBCT in 55.6% of patients. Fungal infection was revealed in 66.7% of patients., Conclusion: These findings oblige dentists to consult patient with laryngologist or internal medicine physician to establish further diagnostic approach, because early diagnosis of GPA is crucial for implementing appropriate treatment and preventing chronic organ damage.

Objectives: Granulomatosis with polyangiitis (GPA) is an autoimmune disease with still unknown etiology. Recent studies indicate that neutrophils extra-cellular traps participate in the pathophysiology of GPA. This study investigates the levels of circulating NET formation markers and neutrophil-platelet interaction in patients with GPA., Methods: We enrolled 40 GPA patients (20 in the active stage of the disease and 20 in remission). Twenty sex- and age-matched healthy subjects served as a control group. Serum/plasma levels of serine proteases, and histone-, myeloperoxidase-, proteinase-3 DNA complexes and sP-selectin were measured using ELISA or Luminex assays. Circulating platelet-neutrophil aggregates and neutrophils activation markers expression was measured by flow cytometry., Results: Patients in active stage of GPA had higher circulating levels of serine proteases, DNA-histone and myeloperoxidase -DNA complexes. In addition, platelet-neutrophil aggregates and sP-selectin were also elevated in this group. Platelet-neutrophil aggregates and myeloperoxidase -DNA complexes correlated positively with the disease activity score (BVAS)., Conclusions: NETs production and activation of platelets in GPA is supported by elevated myeloperoxidase-DNA complexes and platelet-neutrophil aggregates correlating positively with the disease activity score. This mechanism justifies laboratory measurements of myeloperoxidase-DNA complexes and plasma sP-selectin as biomarkers for studying GPA activity.

A 73-year-old male with marked emphysema was admitted to the 2nd Department of Internal Medicine, University Hospital in Krakow because of chronic obstructive pulmonary disease (COPD) exacerbation. His medical history was significant for total laryngectomy due to laryngeal cancer in 2010.

Granulomatosis with polyangiitis is a rare chronic inflammatory disease. In this multisystem autoimmune disorder neutrophils cause small vessels necrosis and infiltrate perivascular tissue to form granulomas. Progression of the disease is evaluated by the symptoms score and by a titer of anti-neutrophil cytoplasm antibodies. Despite glucocorticoid and immunosuppressive therapy, prognosis is complicated by chronic renal insufficiency, hearing loss and skin ulceration. In this preliminary study we tested the hypothesis that altered neutrophil expression of miRNAs can contribute to the cell activation, extracellular traps formation and decreased apoptosis. First we compared a profile of 728 miRNAs expressed in circulating neutrophils of patients with active disease and matched healthy donors. Subsequently, candidate miRNAs were quantified in neutrophils from 16 subjects with active disease, 16 asymptomatic patients at the remission and in 16 healthy controls. Out of 11 candidate miRNAs, only miR-128-3p was both biologically (relative quantity < 30% control or remission patients) and statistically (p<0.01) decreased in the cells during active stage of the disease. This miRNA correlated with a clinical score of the disease well. A set of 10 transcripts involved in the mechanism of the disease was quantified from the same neutrophils RNA. Relative expression of MMP9 was higher in neutrophils from the patients with active disease and correlated negatively with miR-128-3p. The opposite finding was present for MTA1 transcripts. Despite surprisingly scarce changes in the expression of neutrophil miRNAs, miR-128-3p is the best candidate for deciphering etiology of granulomatosis with polyangiitis.