Endothelial dysfunction and complement activation are independently associated with disease duration in patients with systemic vasculitis.

OBJECTIVES: Systemic vasculitis is a heterogenous group of autoimmune diseases characterized by enhanced cardiovascular mortality. Endothelial dysfunction is associated with accelerated vascular damage, representing a core pathophysiologic mechanism contributing to excess CV risk. Recent studies have also shown that complement activation holds significant role in the pathogenesis of Anti-Neutrophilic Cytoplasmic Autoantibody (ANCA) -associated vasculitis (AAV). Given the potential crosstalk between the endothelium and complement, we aimed to assess, for the first time simultaneously, easily accessible biomarkers of endothelial dysfunction and complement activation in SV. METHODS: We measured circulating endothelial microvesicles (EMVs) and soluble complement components representative of alternative, classical and terminal activation (C5b-9, C1q, Bb fragments, respectively) in a meticulously selected group of patients with systemic vasculitis, but without cardiovascular disease. Individuals free from systemic diseases, who were matched with patients for cardiovascular risk factors(hypertension, diabetes, smoking, dyslipidemia), comprised the control group. RESULTS: We studied 60 individuals (30 in each group). Patients with systemic vasculitis had elevated EMVs, higher levels of C5b-9 [536.4(463.4) vs 1200.94457.3), p = 0.003] and C1q [136.2(146.5 vs 204.2(232.9), p = 0.0129], compared to controls [232.0 (243.5) vs 139.3(52.1), p < 0.001]. In multivariate analysis both EMVs and C5b-9 were independently associated with disease duration (p = 0.005 and p = 0.004 respectively), yet not with disease activity. CONCLUSION: Patients with systemic vasculitis exhibit impaired endothelial function and complement activation, both assessed by easily accessible biomarkers, even in the absence of cardiovascular disease manifestations. EMVs and soluble complement components such as C5b-9 and C1q could be used as early biomarkers of endothelial dysfunction and complement activation, respectively, in clinical practice during the course of SV, yet their predictive value in terms of future cardiovascular disease warrants further verification in appropriately designed studies.

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.

Retiform purpura: Workup and therapeutic considerations in select conditions.

In this article we focus on updates in select etiologies of retiform purpura. These causes of retiform purpura, in addition to bacterial or fungal sepsis, disseminated intravascular coagulation, purpura fulminans, and catastrophic antiphospholipid syndrome, are important diagnoses with potential for morbidity and mortality. Important aspects in the pathophysiology, patient demographics and risk factors, updates in the diagnostic workup, histopathology, and treatment of these specific conditions are discussed.

Association of serum high mobility group box 1 levels with disease activity and renal involvement in patients with systemic vasculitis.

High mobility group box 1 (HMGB1) is a kind of proinflammatory mediator that acts as an alarmin when released by dying, injured or activated cells. Previous studies have reported that HMGB1 are closely linked to antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The present study aimed to evaluate whether serum HMGB1 levels were associated with systemic vasculitis (VAs).The study population consisted of 51 patients with VAs, 46 patients with essential hypertension (EH) and 46 healthy controls (HC). Thirty-five patients with VAs had in active stage and 16 patients with VAs in an inactive stage. Furthermore, 31 patients with VAs had renal involvement, the other 20 patients were selected for without renal involvement. Serum HMGB1 levels were measured by enzyme-linked immunosorbent assay. Associations between serum HMGB1 levels with clinical and laboratory parameters were analyzed.Serum HMGB1 levels in patients with VAs were significantly higher than in EH and HC (all P < .05), and no difference regarding serum HMGB1 levels could be found between EH and HC (P = .208). Serum HMGB1 levels in VAs patients with active stage were significantly higher than those in HC and VAs patients with inactive stage (all P < .05). Patients with renal involvement and non-renal involvement had increased HMGB1 levels compared with HC (all P < .05). In addition, serum HMGB1 levels were significantly higher in patients with renal involvement compared with non-renal involvement patients (P = .001). Correlation analysis showed that serum HMGB1 levels were positive significant correlated with the Birmingham Vasculitis Activity Score, hypersensitive C reactive protein (Hs-CRP), serum creatinine (Scr) and 24-hour proteinuria (all P < .05). Among the subsets of VAs, serum HMGB1 levels were significantly higher in AAV, polyarteritis nodosa (PAN) and takayasu arteritis (TA) than in HC (all P < .05). More interestingly, serum HMGB1 were significantly higher in patients with PAN compared with AAV and TA patients (all P < .05). Furthermore, there was positive correlation between serum HMGB1 levels and Hs-CRP, Scr, and 24-hour proteinuria in patients with PAN (all P < .05).Serum HMGB1 levels are increased in patients with VAs compared with HC and EH and can reflect the disease activity and renal involvement.

Clinical, electrophysiological and laboratory parameters, and outcome in patients with biopsy proven systemic and nonsystemic vasculitic neuropathy.

AIM: To describe the clinical and laboratory findings of patients with biopsy proven vasculitic neuropathy. INTRODUCTION: Peripheral neuropathies form one of the most common disorders of the nervous system. However, more than 50% of them are labelled as 'idiopathic' and, therefore, treatment options become less. In this study, we tried to evaluate the phenotypic as well as laboratory characteristics and outcome of patients with biopsy proven vasculitic neuropathy. PATIENTS AND METHODS: Review of biopsy proven definite or probable vasculitic neuropathy was done. RESULTS: The cohort consisted of 67 subjects. There were 21 patients of systemic vasculitis (SVS) and 46 of non-systemic vasculitic neuropathy (NSVN). The nerve biopsy revealed definite vasculitis in 37 and probable vasculitis in 30 patients. The symptoms at onset were paraesthesia (68.7%), and paraesthesia and weakness (28.4%). Diffuse polyneuropathy occurred in 70.1% patients. The course was chronic in the majority (80.59%) of patients. Electrophysiology revealed mononeuritis multiplex in 32.84%, and polyneuropathy in 67.16% of patients. Pure sensory neuropathy was present in 16.42%. Among the patients who had undergone bilateral nerve conduction studies, the majority (71.05%) of patients had an asymmetric neuropathy. An elevated erythrocyte sedimentation rate (ESR) was observed in 80.59% (mean 71.57 ± 30.81 mm/1hr [in SVS] and 35.24 ± 21.62mm/1 hr in NSVN) of patients. The treatment included steroids, other immunomodulators, and symptomatic medications. The mean follow up was 10.98 ± 9.58 months. The outcome was good in 73.46% (43.8% with SVS and 87.88% with NSVN) patients, with those having a NSVN having a significantly better outcome. CONCLUSION: Vasculitis is a potentially treatable cause of peripheral neuropathy. The clinical features, electrophysiology, laboratory results and nerve biopsy may help in the diagnosis and categorization of patients into non-systemic and systemic vasculitic neuropathies. The long-term outcome is better in patients with NSVN compared to those with systemic vasculitis.

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

Impact of vasculitis on employment and income.

OBJECTIVES: Work disability associated with rheumatic diseases accounts for a substantial financial burden. However, few studies have investigated disability among patients with vasculitis. The purpose of this study was to examine the impact of vasculitis on patient employment and income. METHODS: Patients enrolled in the Vasculitis Clinical Research Consortium (VCRC) Patient Contact Registry, living in the USA or Canada, and followed for >1 year post-diagnosis, participated in an online survey-based study. RESULTS: 421 patients with different systemic vasculitides completed the survey between June and December 2015. The majority of patients were female (70%) and Caucasian (90%); granulomatosis with polyangiitis (GPA) was the most common type of vasculitis (49%), and the mean age at the time of diagnosis was 53 years. At the time of their diagnosis of vasculitis 76% of patients were working a paid job, 6% were retired, and 2% were on disability. Over the course of their disease, and with a mean follow-up of 8±6.4 years post-diagnosis, 26% of participants became permanently work disabled or had to retire early due to vasculitis. Variables that were independently associated with permanent work disability included work physicality, less supportive work environment, and symptoms such as respiratory disease, pain, and cognitive impairment. Overall, patients reported a mean productivity loss of 6.9% and income was reduced by a median of 45%. CONCLUSIONS: Due to their vasculitis, patients frequently suffer substantial limitations in work and productivity, and personal income loss.

Cutaneous and systemic vasculitides in dermatology: a histological perspective.

Cutaneous vasculitides encompass a wide and heterogeneous group of diseases affecting skin blood vessels that are clinically characterized by polymorphic skin lesions, particularly including palpable purpura as well as urticarial and necrotic-ulcerative lesions, with possible, albeit rare, extracutaneous involvement. Cutaneous leukocytoclastic angiitis and urticarial vasculitis, which are the two prototypic and most common variants of this group, are usually idiopathic but may also be induced by different triggers, notably drugs and infections, or may manifest in association with systemic disorders, particularly lupus erythematosus. Vasculitis skin lesions can also occur during the chronic-relapsing course of systemic vasculitides, such as granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis, with which cutaneous vasculitides can share clinical and histological features. In order to make the diagnosis of a specific form of vasculitis, the cutaneous picture and clinical history of the patient have to be correlated with the histological pattern, direct immunofluorescence findings, laboratory data and possible presence of extracutaneous manifestations. Histology is pivotal for the diagnosis of vasculitis and timing of the biopsy is relevant to correctly evaluate the characteristics of the inflammatory infiltrate. In this review, we will focus in particular on the histological features of cutaneous vasculitides in order to differentiate them from the systemic forms and to avoid misdiagnosis when skin involvement is the presenting sign of a multisystem vasculitis.

Accelerated atheromatosis and arteriosclerosis in primary systemic vasculitides: current evidence and future perspectives.

PURPOSE OF REVIEW: Primary systemic vasculitides (PSV) encompass a subset of autoimmune diseases, characterized by inflammation of blood vessels. Atheromatosis and arteriosclerosis may be accelerated in several PSV and account for the increased rate of cardiovascular morbidity that some exhibit. We aimed to summarize recent studies reporting on the acceleration of atheromatosis and/or arteriosclerosis in each type of PSV, using state-of-the-art noninvasive vascular biomarkers with clinical value as end points. RECENT FINDINGS: Limited number of PSV patients and methodology limitations reduce the value of many published studies. Accelerated atheromatosis, as measured by the use of carotid ultrasonagraphy (plaques and intimal-medial thickening) and increased arterial stiffening, as measured by the use of applanation tonometry (carotid to femoral pulse wave velocity), are currenly well established in Takayasu arteritis, Kawasaki disease and Behcet's disease. The association of atheromatosis and arteriosclerosis with polyarteritis nodosa and small vessel vasculitides remains less established and studied, so far. SUMMARY: Accelerated atheromatosis and arteriosclerosis or arteriosclerosis are established in some PSV. The potential clinical value of easy-to-measure and clinically useful noninvasive vascular biomarkes prompts the need for large prospective cohorts in order to provide useful future guidance regarding the prognosis and treatment of PSV patients.

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.

Investigational drugs in systemic vasculitis.

INTRODUCTION: Treatment of systemic vasculitis is based on glucocorticoids (GC) in association with immunosuppressive therapy. There are still unmet needs, including earlier onset of response, more targeted therapies, reduction of relapse-risk and decrease of long-term GC and classic immunosuppressants toxicities. Areas covered: In this review, we discuss investigational drugs in early phase clinical trials for induction of remission in vasculitis. We focus on ANCA-associated vasculitis, Behçet's disease, giant cell arteritis, Takayasu arteritis, and cryoglobulinemic vasculitis. We performed a comprehensive review of articles published on pubmed and a review of clinical trials registered online ( https://clinicaltrials.gov ) for each vasculitis. Expert opinion: Recent progress in the pathogenesis identifies new therapeutic targets. Some of these therapies are promising in GC sparing effects, in reducing relapse rate, and for their safety profile. These results need to be confirmed in large-scale phase III studies.

Gastrointestinal aspects of vasculitides.

Systemic vasculitides are caused by inflammation of blood vessels and can affect any organ and any part of the gastrointestinal tract, hepatic and biliary system, as well as the pancreas. These disorders can cause a wide array of gastrointestinal manifestations, from asymptomatic elevated transaminase levels and mild abdominal pain to potentially life-threatening bowel perforations and peritonitis. A diagnosis based solely on gastrointestinal symptoms is challenging as these manifestations are not specific. Conversely, diagnostic and therapeutic delays can be rapidly detrimental. In this article, we review the epidemiology, characteristics and management of the main gastrointestinal manifestations of systemic vasculitides, including polyarteritis nodosa and antineutrophil cytoplasm antibody-associated vasculitides, as well as isolated vasculitides limited to the gastrointestinal tract.

Respiratory manifestations of eosinophilic granulomatosis with polyangiitis (Churg-Strauss).

The respiratory manifestations of eosinophilic granulomatosis with polyangiitis (EGPA) have not been studied in detail.In this retrospective multicentre study, EGPA was defined by asthma, eosinophilia and at least one new onset extra-bronchopulmonary organ manifestation of disease.The study population included 157 patients (mean±sd age 49.4±14.1 years), with a mean±sd blood eosinophil count of 7.4±6.4×109 L-1 at diagnosis. There was a mean±sd of 11.8±18.2 years from the onset of asthma to the diagnosis of EGPA, of 1.4±8.4 years from the first onset of peripheral eosinophilia to the diagnosis of EGPA, and of 7.4±6.4 years from EGPA diagnosis to the final visit. Despite inhaled and oral corticosteroid treatment, the severity of asthma increased 3-6 months before the onset of the systemic manifestations. Asthma was severe in 57%, 48%, and 56% of patients at diagnosis, at 3 years, and at the final visit, respectively. Persistent airflow obstruction was present in 38%, 30%, and 46% at diagnosis, at 3 years, and at the final visit, respectively.In EGPA, asthma is severe, antedates systemic manifestations by a mean of 12 years, and progresses to long-term persistent airflow obstruction despite corticosteroids in a large proportion of patients, which affects long-term management and morbidity.

Assessment of work limitations and disability in systemic vasculitis.

OBJECTIVES: Despite advances in the management of systemic vasculitis (SV), direct consequences of the disease, leading to impairments in physical and mental function can cause disability. The objective of this study was to assess work limitations in SV. METHODS: SV patients were recruited from a tertiary care clinic. Work disabled (WD) was defined as not working, early retirement, or reduced hours at work. Participants who were working at the time of enrolment completed the Work Limitations Questionnaire (WLQ). Other work-related measures were self-reported by questionnaire. Disease outcome measures (Vasculitis Damage Index (VDI), Health Assessment Questionnaire-Disability Index (HAQ) and pain visual analogue score (VAS)) were obtained at time of WLQ. RESULTS: 103 participants were enrolled with mean age 58 (SD17), 60% females, 48% with anti-neutrophilic cytoplasmic antibody-associated vasculitis (AAV), 26% with large vessel vasculitis (LVV) and 26% with other types of SV. 22 (21%) were WD secondary to SV, 29 (28%) were working and 52 (51%) subjects were not working for reasons other than SV. SV-related WD subjects were more likely to have a lower level of education (p=0.003) than non-WD subjects. The VDI was higher in SV-related WD vs. non-WD subjects: 1.9 (SD 2.7) vs. 2.9 (SD 1.4); p=0.015. 38 subjects were working in some capacity and completed the WLQ; their productivity loss was 8.2% and this was highly correlated with HAQ and pain VAS (rho=0.585 and rho=0.458, respectively). CONCLUSIONS: SV-related work disability occurred in 21% and was associated with lower levels of education, higher disease severity and worse functional outcomes.

Percutaneous Coronary Intervention in a Patient With Severe Systemic Vasculitis and Myocardial Infarction.

A 72-year-old woman presented with acute coronary syndrome. There was diffuse coronary ectasia and severe stenosis in the proximal left anterior descending artery consistent with coronary vasculitis. Despite treatment with high-dose immunosuppression, she underwent percutaneous coronary intervention for refractory angina.

Pediatric Vasculitis.

Vasculitis is defined as inflammation of the blood vessels and can result in stenosis or aneurysm, which may in turn lead to occlusion or rupture of the vessel compromising tissue perfusion. The manifestations of these diseases depend on the size and site of the vessels effected. Vasculitis can be secondary to numerous inflammatory and infectious diseases but this review will concentrate on the systemic primary vasculitides and aims to discuss the presentations and approaches to management of a number of these conditions.

Innate immune cells in the pathogenesis of primary systemic vasculitis.

Innate immune system forms the first line of defense against foreign substances. Neutrophils, eosinophils, erythrocytes, platelets, monocytes, macrophages, dendritic cells, γδ T cells, natural killer and natural killer T cells comprise the innate immune system. Genetic polymorphisms influencing the activation of innate immune cells predispose to development of vasculitis and influence its severity. Abnormally activated innate immune cells cross-talk with other cells of the innate immune system, present antigens more efficiently and activate T and B lymphocytes and cause tissue destruction via cell-mediated cytotoxicity and release of pro-inflammatory cytokines. These secreted cytokines further recruit other cells to the sites of vascular injury. They are involved in both the initiation as well as the perpetuation of vasculitis. Evidences suggest reversal of aberrant activation of immune cells in response to therapy. Understanding the role of innate immune cells in vasculitis helps understand the potential of therapeutic modulation of their activation to treat vasculitis.