Systemic vasculitis: one year in review 2024.

Systemic vasculitides comprise a collection of rare and heterogeneous disorders capable of impacting any organ and system, posing a considerable burden of mortality and comorbidity. As with previous annual reviews of this series, this review will offer a critical overview of the latest literature on pathogenesis, biomarkers, and treatment options in both small- and large-vessel vasculitis.

Impaired immunogenicity to COVID-19 vaccines in autoimmune systemic diseases. High prevalence of non-response in different patients' subgroups.

Autoimmune systemic diseases (ASD) may show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed to evaluate the seroconversion after the vaccination cycle and at 6-12-month follow-up, as well the safety and efficacy of vaccines in preventing COVID-19. The study included 478 unselected ASD patients (mean age 59 ± 15 years), namely 101 rheumatoid arthritis (RA), 38 systemic lupus erythematosus (SLE), 265 systemic sclerosis (SSc), 61 cryoglobulinemic vasculitis (CV), and a miscellanea of 13 systemic vasculitis. The control group included 502 individuals from the general population (mean age 59 ± 14SD years). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was evaluated by measuring serum IgG-neutralizing antibody (NAb) (SARS-CoV-2 IgG II Quant antibody test kit; Abbott Laboratories, Chicago, IL) on samples obtained within 3 weeks after vaccination cycle. The short-term results of our prospective study revealed significantly lower NAb levels in ASD series compared to controls [286 (53-1203) vs 825 (451-1542) BAU/mL, p < 0.0001], as well as between single ASD subgroups and controls. More interestingly, higher percentage of non-responders to vaccine was recorded in ASD patients compared to controls [13.2% (63/478), vs 2.8% (14/502); p < 0.0001]. Increased prevalence of non-response to vaccine was also observed in different ASD subgroups, in patients with ASD-related interstitial lung disease (p = 0.009), and in those treated with glucocorticoids (p = 0.002), mycophenolate-mofetil (p < 0.0001), or rituximab (p < 0.0001). Comparable percentages of vaccine-related adverse effects were recorded among responder and non-responder ASD patients. Patients with weak/absent seroconversion, believed to be immune to SARS-CoV-2 infection, are at high risk to develop COVID-19. Early determination of serum NAb after vaccination cycle may allow to identify three main groups of ASD patients: responders, subjects with suboptimal response, non-responders. Patients with suboptimal response should be prioritized for a booster-dose of vaccine, while a different type of vaccine could be administered to non-responder individuals.

ROS-producing immature neutrophils in giant cell arteritis are linked to vascular pathologies.

Giant cell arteritis (GCA) is a common form of primary systemic vasculitis in adults, with no reliable indicators of prognosis or treatment responses. We used single cell technologies to comprehensively map immune cell populations in the blood of patients with GCA and identified the CD66b+CD15+CD10lo/-CD64- band neutrophils and CD66bhiCD15+CD10lo/-CD64+/bright myelocytes/metamyelocytes to be unequivocally associated with both the clinical phenotype and response to treatment. Immature neutrophils were resistant to apoptosis, remained in the vasculature for a prolonged period of time, interacted with platelets, and extravasated into the tissue surrounding the temporal arteries of patients with GCA. We discovered that immature neutrophils generated high levels of extracellular reactive oxygen species, leading to enhanced protein oxidation and permeability of endothelial barrier in an in vitro coculture system. The same populations were also detected in other systemic vasculitides. These findings link functions of immature neutrophils to disease pathogenesis, establishing a clinical cellular signature of GCA and suggesting different therapeutic approaches in systemic vascular inflammation.

Systemic vasculitis successfully treated with decitabine in a high-risk myelodysplastic syndrome patient: a case report and literature review.

Aim: Epidemiological studies have reported the association between myelodysplastic syndrome (MDS) and autoimmune diseases (AIDs). Immune dysregulation appears as the common driving force between MDS and AIDs pathogenesis. Low-dose hypomethylating agents might suppress tumor growth and regulate immune balance via its epi-immunomodulatory role. Materials & methods: A high-risk MDS patient presented with systemic vasculitis and was successfully treated with ultra-low-dose decitabine (7 mg/m2/d for 5 days). Results: He achieved complete remission of both MDS and AIDs after two cycles of decitabine treatment, and his overall survival duration was 45 months. Conclusion: Future studies should assess the application of ultra-low-dose decitabine among some high-risk MDS patients, especially among those with comorbid AIDs or in cases warranting the prevention of decitabine-mediated myelosuppression.

Is it Kawasaki shock syndrome, Kawasaki-like disease or pediatric inflammatory multisystem disease? The importance of semantic in the era of COVID-19 pandemic.

A few weeks after the peak of the global 2019 novel coronavirus disease pandemic, cases of shock, multisystem inflammation and severe myocarditis have occurred in children and adolescents, generating some concerns and above all many questions. An almost immediate association raised with shock syndrome related to Kawasaki disease (KD). However, in light of bo/th experience and literature have taught us about severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection, and what already known on the epidemiology of KD, we suggest here the hypothesis of a new 'post-viral' systemic inflammatory disease related to excessive adaptive immune response rather than a form of KD caused by SARS-COV-2. We discuss analogies and differences between the two forms.

Cardiovascular Disease in the Systemic Vasculitides.

The vasculitides are a heterogeneous group of disorders, characterized by inflammatory cell infiltration and necrosis of blood vessels that cause vascular obstruction or aneurysm formation, affecting various organs such as lungs, kidneys, skin and joints. Cardiac involvement is commonly encountered in primary systemic vasculitis and it is associated with increased morbidity and mortality. Depending on the dominant pathophysiological mechanism, heart complications may manifest in different ways, including myocardial ischemia due to impaired micro- or macrovascular circulation, progressive heart failure following valvular heart disease and myocardial dysfunction, (sub) clinical myocarditis, pericarditis, pulmonary hypertension as well as arteritis of coronary vessels. Beyond cardioprotective regimens, aggressive immunosuppression reduces the inflammatory burden and modulates the progression of cardiovascular complications. Perioperative management of inflammation, when surgical treatment is indicated, improves surgical success rates and postoperative long-term prognosis. We aim to provide an overview of the pathogenetic, diagnostic and therapeutic principles of cardiovascular involvement disease in the various forms of systemic vasculitis.

Role of Neutrophils in Systemic Vasculitides.

Neutrophils and neutrophil extracellular traps (NETs) contribute to the pathogenesis of many autoimmune diseases, including vasculitis. Though neutrophils, and NETs, can break self-tolerance by being a source of autoantigens for autoantibodies in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, playing a key role in driving the autoimmune response, the role of neutrophils and NETs in large vessel vasculitis, including giant cell arteritis (GCA), is not well understood. In this review, we summarize the current insight into molecular mechanisms contributing to neutrophil-mediated pathology in small and medium vessel vasculitis, as well as provide potential translational perspectives on how neutrophils, and NETs, may partake in large vessel vasculitis, a rare disease entity of unclear pathogenesis.

Formation and glomerular deposition of immune complexes in mice administered bovine serum albumin: Evaluation of dose, frequency, and biomarkers.

In preclinical toxicity studies, species-foreign proteins administered to animals frequently leads to formation of anti-drug antibodies (ADA). Such antibodies may form circulating immune complexes (CIC) with the administered protein. These CIC can activate the classical complement pathway, thereby forming complement-bound CIC (cCIC); if large of amounts of CIC or cCIC is formed, the clearance mechanism may become saturated which potentially leads to vascular immune complex (IC) deposition and inflammation. Limited information is available on the effect of different treatment related procedures as well as biomarkers of IC-related vascular disease. In order to explore the effect of different dose regimens on IC formation and deposition, and identification of possible biomarkers of IC deposition and IC-related pathological changes, C57BL/6J and BALB/c mice were dosed subcutaneously twice weekly with bovine serum albumin (BSA) for 13 weeks without adjuvant. After 6 and 13 weeks, CIC and cCIC were detected in plasma; after 13 weeks, IC deposition was detected in kidney glomeruli. In particular immunohistochemistry double-staining was shown to be useful for detection of IC deposition. Increasing dosing frequency or changing BSA dose level on top of an already established CIC and cCIC response did not cause changes in IC deposition, but CIC and cCIC concentrations tended to decrease with increased dose level, and increased cCIC formation was observed after more frequent dosing. The presence of CIC in plasma was associated with glomerular IC deposits in the dose regimen study; however, the use of CIC or cCIC as potential biomarkers for IC deposition and IC-related pathological changes, needs to be explored further.

Advances in Therapies and Imaging for Systemic Vasculitis.

Vasculitis is a systemic disease characterized by immune-mediated injury of blood vessels. Current treatments for vasculitis, such as glucocorticoids and alkylating agents, are associated with significant side effects. Furthermore, the management of both small and large vessel vasculitis is challenging because of a lack of robust markers of disease activity. Recent research has advanced our understanding of the pathogenesis of both small and large vessel vasculitis, and this has led to the development of novel biologic therapies capable of targeting key cytokine and cellular effectors of the inflammatory cascade. In parallel, a diverse range of imaging modalities with the potential to monitor vessel inflammation are emerging. Continued expansion of combined structural and molecular imaging using positron emission tomography with computed tomography or magnetic resonance imaging may soon provide reliable longitudinal tracking of vascular inflammation. In addition, the emergence of radiotracers able to assess macrophage activation and immune checkpoint activity represents an exciting new frontier in imaging vascular inflammation. In the near future, these advances will allow more precise imaging of disease activity enabling clinicians to offer more targeted and individualized patient management.

Evolving concepts in classification of systemic vasculitis: where are we and what is the way forward?

The classification of the systemic vasculitides has been controversial for several decades. The Chapel Hill consensus Conference definitions originally developed in 1994, but revised and extended in 2012 are now widely accepted. The American College of Rheumatology (ACR) criteria were first published in 1990, are now generally accepted to be out of date and new criteria are needed. More recently the classical division of the ANCA vasculitides using clinical phenotype has come under scrutiny with evidence from epidemiological, genetic and outcome studies that perhaps these conditions should be classified on the basis of ANCA specificity into PR3-ANCA positive and MPO-ANCA positive groups. The traditional distinction between giant cell arteritis and Takayasu arteritis has been questioned and some recent studies of GCA have included patients with only extra-cranial disease. The Diagnostic and Classification Criteria of Vasculitis study (DCVAS) will provide new validated classification criteria for the systemic vasculitides.

One year in review 2018: systemic vasculitis.

Systemic vasculitis are heterogeneous, complex and disabling disorders. Following the previous annual reviews of this series, this paper gives a brief overview on current knowledge about recent literature on small- and large-vessel systemic vasculitis, with a specific focus on pathogenetic and clinical aspects, novel possible disease-related biomarkers and current and future therapies that are in the pipeline.

Cross-phenotype analysis of Immunochip data identifies KDM4C as a relevant locus for the development of systemic vasculitis.

OBJETIVE: Systemic vasculitides represent a heterogeneous group of rare complex diseases of the blood vessels with a poorly understood aetiology. To investigate the shared genetic component underlying their predisposition, we performed the first cross-phenotype meta-analysis of genetic data from different clinically distinct patterns of vasculitis. METHODS: Immunochip genotyping data from 2465 patients diagnosed with giant cell arteritis, Takayasu's arteritis, antineutrophil cytoplasmic antibody-associated vasculitis or IgA vasculitis as well as 4632 unaffected controls were analysed to identify common susceptibility loci for vasculitis development. The possible functional consequences of the associated variants were interrogated using publicly available annotation data. RESULTS: The strongest association signal corresponded with an intergenic polymorphism located between HLA-DQB1 and HLA-DQA2 (rs6932517, P=4.16E-14, OR=0.74). This single nucleotide polymorphism is in moderate linkage disequilibrium with the disease-specific human leucocyte antigen (HLA) class II associations of each type of vasculitis and could mark them. Outside the HLA region, we identified the KDM4C gene as a common risk locus for vasculitides (highest peak rs16925200, P=6.23E-07, OR=1.75). This gene encodes a histone demethylase involved in the epigenetic control of gene expression. CONCLUSIONS: Through a combined analysis of Immunochip data, we have identified KDM4C as a new risk gene shared between systemic vasculitides, consistent with the increasing evidences of the crucial role that the epigenetic mechanisms have in the development of complex immune-mediated conditions.

How Should We Classify Kawasaki Disease?

The exact classification of Kawasaki disease (KD) has been debated. Infectious disease specialists have claimed it as an infection with a classic immune responses to an as yet unidentified pathogen that localizes to the coronary arteries. Others have favored an autoreactive hypothesis that KD is triggered by an antigen that shares homology with structures in the vascular wall, and molecular mimicry resulting in an immune response directed to that tissue. Rheumatologists have classified it as a systemic vasculitis, while some immunologists have stressed the robust nature of the innate immune response that causes both systemic inflammation as well as damage to the coronary arterial wall and questioned whether KD falls within the spectrum of autoinflammatory diseases. This review will describe the evidences available up to now regarding these hypotheses.

Early obesity leads to increases in hepatic arginase I and related systemic changes in nitric oxide and L-arginine metabolism in mice.

Obesity is a risk factor for vascular endothelial cell dysfunction characterized by low-grade, chronic inflammation. Increased levels of arginase I and concomitant decreases in L-arginine bioavailability are known to play a role in the pathogenesis of vascular endothelial cell dysfunction. In the present study, we focused on changes in the systemic expression of arginase I as well as L-arginine metabolism in the pre-disease state of early obesity prior to the onset of atherosclerosis. C57BL/6 mice were fed a control diet (CD; 10% fat) or high-fat diet (HFD; 60% fat) for 8 weeks. The mRNA expression of arginase I in the liver, adipose tissue, aorta, and muscle; protein expression of arginase I in the liver and plasma; and systemic levels of L-arginine bioavailability and NO2- were assessed. HFD-fed mice showed early obesity without severe disease symptoms. Arginase I mRNA and protein expression levels in the liver were significantly higher in HFD-fed obese mice than in CD-fed mice. Arginase I levels were slightly increased, whereas L-arginine levels were significantly reduced, and these changes were followed by reductions in NO2- levels. Furthermore, hepatic arginase I levels positively correlated with plasma arginase I levels and negatively correlated with L-arginine bioavailability in plasma. These results suggested that increases in the expression of hepatic arginase I and reductions in plasma L-arginine and NO2- levels might lead to vascular endothelial dysfunction in the pre-disease state of early obesity.

Apheresis to treat systemic vasculitis.

Apheresis has been used in the treatment of severe systemic vasculitides, in conjunction with immunosuppressive therapies, for over 40 years. The aim is to rapidly remove autoantibodies or circulating immune complexes from the plasma. The two main indications at present are vasculitis associated with Antineutrophil Cytoplasmic Antibodies (ANCAs) manifesting as severe renal involvement and/or intraalveolar hemorrhage and antiglomerular basement membrane disease (Goodpasture syndrome). The ongoing PEXIVAS randomized controlled trial is assessing plasmapheresis to treat ANCA-associated vasculitis with or without severe renal involvement or intraalveolar hemorrhage. The two main apheresis techniques used to treat systemic vasculitis are plasmapheresis (by filtration, centrifugation, or double filtration) and immunoadsorption. The advantages and drawbacks of each technique are discussed here. Whether one technique is superior over the other in the current indications has not been proven.

HCV-unrelated cryoglobulinaemic vasculitis: the results of a prospective observational study by the Italian Group for the Study of Cryoglobulinaemias (GISC).

OBJECTIVES: To investigate the clinical and laboratory patterns of HCV-unrelated cryoglobulinaemic vasculitis (CV), and the factors influencing its outcome. METHODS: Prospective study of all anti-HCV and HCV-RNA negative patients with CV who have been observed since January 2004 in 17 centres participating in the Italian Group for the Study of Cryoglobulinaemias (GISC). RESULTS: 175 enrolled were followed up for 677 person-years. The associated conditions were primary Sjögren's syndrome (21.1%), SLE (10.9%), other autoimmune disorders (10.9%), lymphoproliferative diseases (6.8%), solid tumours (2.3%) and HBsAg positivity (8.6%), whereas 69 patients (39.4%) had essential CV. There were significant differences in age (p<0.001), gender (p=0.002), the presence of purpura (p=0.005), arthralgia (p=0.009), liver abnormalities (p<0.001), sicca syndrome (p<0.001), lymphadenopathy (p=0.003), splenomegaly (p=0.002), and rheumatoid factor titres (p<0.001) among these groups. Type II mixed cryoglobulins were present in 96 cases (54.9%) and were independently associated with purpura and fatigue (odds ratio [OR]4.3; 95% confidence interval [CI] 1.8-10.2; p=0.001; and OR2.8; 95%CI 1.3-6.3; p=0.012). Thirty-one patients died during follow-up, a mortality rate of 46/1000 person-years. Older age (for each additional year, adjusted hazard ratio [aHR] 1.13; 95%CI 1.06-1.20; p<0.001), male gender (aHR 3.45; 95%CI 1.27-9.40; p=0.015), type II MCG (aHR 3.31; 95%CI 0.09-1.38; p=0.047) and HBsAg positivity (aHR 7.84; 95%CI 1.20-36.04; p=0.008) were independently associated with greater mortality. CONCLUSIONS: HCV-unrelated CV is a multifaceted and often disabling disorder. The associated conditions influence its clinical severity, giving rise to significantly different clinical and laboratory profiles and outcomes.

One year in review 2017: systemic vasculitis.

Systemic vasculitis is a group of heterogeneous, disabling disorders. Great interest has recently arisen in pathophysiology, clinical phenotypes and therapy of large- and small-vessel vasculitis. The general work hypothesis has been to promote research focused on disease-related pathogenetic pathways, with the ultimate goal of identifying novel diagnostic and prognostic biomarkers, thus leading towards more effective targeted treatments. Following the previous annual reviews of this series, we will hereby provide a critical digest of the recent literature on small- and large-vessel systemic vasculitis, with a specific focus on novel possible disease-related biomarkers and their impact on current and future therapies.