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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.

Background Citrullinated histone H3 (CitH3), a hallmark component of neutrophil extracellular traps, has emerged as a circulating indicator of pathological neutrophil activation. We evaluated the utility of serum CitH3 as a biomarker for disease activity and risk of end-stage kidney disease (ESKD) development in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). Methods A total of 65 patients with MPA and GPA were included. At diagnosis, serum CitH3 levels were measured and disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS). Correlation between serum CitH3 level and BVAS was assessed using Pearson’s correlation coefficient. Discriminatory performance of serum CitH3 for severe disease (BVAS ≥ 20) and low disease activity states (BVAS ≤ 3) was evaluated using receiver operating characteristic curve analysis. The association between serum CitH3 level and ESKD risk was assessed using multivariable Cox regression analysis. Results Serum CitH3 levels significantly correlated with BVAS ( r  = 0.393, p  = 0.001). Moreover, serum CitH3 demonstrated excellent discriminatory performance (area under the curve [AUC] 0.905, 95% confidence interval [CI] 0.825–0.984, p  < 0.001) for severe disease (BVAS ≥ 20), and acceptable discriminatory performance (AUC 0.703, 95% CI 0.558–0.848, p  = 0.013) for low disease activity states (BVAS ≤ 3). During a mean follow-up of 38.3 ± 32.8 months, eight (12.3%) patients developed ESKD. After adjusting for age and serum creatinine, higher serum CitH3 levels were independently associated with an increased risk of ESKD (adjusted hazard ratio 1.181, 95% CI 1.033–1.352, p  = 0.015). Conclusion Serum CitH3 correlated with disease activity, demonstrated strong discriminatory performance for severe disease and acceptable discriminatory performance for low disease activity states, and was associated with an increased risk of ESKD. These findings support serum CitH3 as a potential biomarker for identifying severe disease and low disease activity states, and stratifying ESKD risk in MPA and GPA.

Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a rare systemic vasculitis with eosinophilic inflammation and variable clinical presentations. Although skin manifestations are frequent, current classification criteria do not include them, which may underestimate their diagnostic value. This prospective observational study aimed to assess systemic and skin involvement as well as eosinophilia, anti-neutrophil cytoplasmic antibody (ANCA), and Anti-nuclear antibodies (ANA) serum levels in 20 EGPA patients followed for one year at the University Hospital of Messina, Italy, before starting Mepolizumab, 300 mg. Eosinophilia, ANCA status, systemic and skin involvement were also evaluated at 6 and 12 months; a literature review on these data supplements our findings. Skin involvement was present in 55% of patients, including purpura, urticarial vasculitis, angioedema, maculopapular rash, and nodules, mostly in ANCA-negative patients, though purpura was more frequent in ANCA-positive cases but without any statistically significant correlation. ANAs were present in 50% of patients, together with ANCA in two subjects and without in eight. Mepolizumab significantly reduced eosinophil levels, BVASs, and corticosteroid dependence, with notable improvement in skin symptoms. In conclusion, skin manifestations are common in EGPA and may represent useful indicators of disease activity. Their integration with ANCA status, eosinophil counts, and positivity to other autoantibodies could enhance diagnostic and monitoring strategies identifying different clusters of EGPA patients even if the small sample size limits the generalizability of the findings.

Eosinophilic granulomatosis with polyangiitis (EGPA) was a rare systemic vasculitis characterized by eosinophilia, asthma, and necrotizing vasculitis. Metabolic dysregulation had been shown to participate in the pathogenesis of autoimmune diseases, but the plasma metabolic profile of EGPA remained unclear. This work was designed to systematically characterize the plasma metabolomic profiles of EGPA patients, identify differential metabolites that distinguish EGPA from bronchial asthma (BA), and explore their potential as biomarkers for differential diagnosis. Ten patients with EGPA, ten patients with BA, and ten age- and gender-matched healthy controls (HCs) were enrolled. Untargeted metabolomics based on liquid chromatography/mass spectrometry (LC/MS) was performed to analyze the metabolic profiles of the three groups. Differential metabolites were identified using VIP > 1 and P < 0.05. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed on the differential metabolites, with statistical significance defined as P < 0.05. A total of 971 metabolites were differentially expressed between EGPA patients and HCs. KEGG pathway enrichment analysis identified 59 pathways, five of which were statistically significant (P < 0.05): caffeine metabolism; valine, leucine and isoleucine biosynthesis; alanine, aspartate and glutamate metabolism; arginine and proline metabolism; and glyoxylate and dicarboxylate metabolism. Comparison of EGPA with BA patients revealed 161 altered metabolites and 102 enriched pathways, three of which were significant (P < 0.05): caffeine metabolism, basal cell carcinoma, and Fc gamma R-mediated phagocytosis. Receiver operating characteristic (ROC) curve analysis demonstrated that 21 of the 24 metabolites identified from the five key EGPA-HC pathways exhibited strong diagnostic performance (area under the curve [AUC] > 0.8). Four metabolites (cholesterol, 5-acetylamino-6-formylamino-3-methyluracil, 5-acetylamino-6-amino-3-methyluracil, and 3-methylxanthine) showed high diagnostic potential (AUC > 0.8) for distinguishing EGPA from BA. This study revealed, for the first time, a distinct plasma metabolic profile in EGPA patients, with key pathways and candidate biomarkers identified. The metabolites with high diagnostic efficacy (AUC > 0.8) might serve as candidate diagnostic biomarkers for EGPA and its differentiation from BA. These observations provided novel insights into the metabolic basis of EGPA pathogenesis and might provide valuable references for the clinical management of this rare disease.

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. 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. 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. In anti-MPO AAV patients, serum level of ceruloplasmin at diagnosis seems to be associated with a significant impact on survival.

Objectives Peripheral helper T (Tph) cells, a recently identified Th cell subset, have been implicated in various autoimmune diseases. However, their role in granulomatosis with polyangiitis (GPA) remains unclear. This study aimed to investigate the potential clinical significance of circulating Tph cells (cTph) in GPA. Methods Peripheral blood mononuclear cells were collected from 74 remission GPA-patients, 26 active GPA-patients and 22 age- and sex-matched healthy controls. Flow cytometry was used to quantify cTph cells and their subset distribution. Single-cell multi-omics profiling was performed in an independent cohort (5 remission GPA-patients, 5 active GPA-patients and 5 healthy controls). Plasma IL-21 levels were measured by enzyme-linked immunosorbent assay, and associations between cTph cells and clinical parameters were evaluated. Results active GPA-patients showed an increased frequency and absolute number of cTph compared to remission GPA-patients, and both GPA groups exhibited cTph2-skewed distribution compared to healthy controls. Remission GPA-patients with generalized disease exhibited higher cTph frequencies than those with localized disease. cTph cells from active GPA-patients displayed an activated phenotype and a transcriptional profile marked by pro-inflammatory and survival-associated genes. Plasma IL-21 levels did not differ significantly between the three groups. Notably, absolute counts of memory cTph and cTph2 cells correlated positively with clinical markers of disease activity, and were significantly elevated in GPA patients with higher cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) titers. Conclusions cTph cells are expanded and exhibit an activated, pro-inflammatory profile with a cTph2-skewed distribution in active GPA-patients. Their association with disease activity may support a potential role in disease pathogenesis and highlight their potential as therapeutic targets, warranting further investigation.

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.

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.

ObjectivesWe 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.MethodsWe 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.ResultsTwenty-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).ConclusionsElevated 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.