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.

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.

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.

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.

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.

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.

Occlusive vasculopathy in human immunodeficiency virus (HIV)-associated vasculitis: unusual clinical and imaging course.

Human immunodeficiency virus (HIV)-associated vasculitis is a rare secondary systemic vasculitis involving small and medium arteries. We report a 42-year-old man with uncontrolled HIV infection presenting with long-lasting abdominal pain. An abdominal CT angiography revealed multiple microaneurysms and stenoses in intrarenal arteries, with involvement of mesenteric and hepatic arteries. HIV-associated vasculitis was diagnosed and glucocorticoids and raltegravir-based antiretroviral therapy were administered with good initial clinical and virological response. Several episodes of acute intestinal ischaemia were later developed requiring bowel resections of which histological examination showed vascular occlusive fibrotic changes without active vasculitic lesions. Vasculitis persisted in remission and intrarenal microaneurysms disappeared.

Distinct phenotypic subpopulations of circulating CD4+CXCR5+ follicular helper T cells in children with active IgA vasculitis.

BACKGROUND: Circulating follicular helper T (Tfh) cells are a heterogeneous population of CD4+ helper T cells that promotes pathogenic immune responses in autoimmune diseases. In this study, we examined the status of different subpopulations of Tfh cells in peripheral circulation and their associations with various clinical characteristics of IgA vasculitis (IgAV). METHODS: According to the phenotypic expressions of different molecules, focus was given on six subpopulations of Tfh cells: CD4+CXCR5+, CD4+CXCR5+ICOS+, CD4+CXCR5+ICOS+PD-1+, CD4+CXCR5+ICOShighPD-1high, CD4+CXCR5+ICOS-PD-1+, and CXCR5+CD45RA-IL-21+. The frequencies of these six subpopulations and the circulating level of Tfh-related cytokine interleukin 21 (IL-21) were measured from 27 patients with IgAV and 15 healthy controls (HC) by flow cytometry and flow cytometric bead array, respectively. RESULTS: Significantly higher frequencies of CD4+CXCR5+, CD4+CXCR5+ICOS+, CD4+CXCR5+ICOS+PD-1+, CD4+CXCR5+ICOShighPD-1high and CXCR5+CD45RA-IL-21+ Tfh cells, as well as higher levels of plasma IL-21, were detected in IgAV patients compared to HC. The level of each Tfh subpopulation varied by the presenting symptoms of IgAV, but did not differ between patients treated or not treated with glucocorticoids. When the disease entered the remission stage following treatment, circulating levels of CD4+CXCR5+, CD4+CXCR5+ICOS+, CD4+CXCR5+ICOS+PD-1+, CD4+CXCR5+ICOShighPD-1high and CXCR5+CD45RA-IL-21+ Tfh cells, as well as plasma IL-21 levels were reduced. Among the six subpopulations of Tfh cells, both CD4+CXCR5+ICOS+ and CXCR5+CD45RA-IL-21+ significantly and positively correlated with serum IgA and plasma IL-21 levels, but only CXCR5+CD45RA-IL-21+ significantly and negatively correlated with the serum C4 level. CONCLUSIONS: Tfh cells may differentially contribute to the development of IgAV or predict disease progression. These findings provide novel insights in the pathogenesis of IgAV and may benefit treatment development targeting organ-specific presenting symptoms of IgAV.

Usefulness of antineutrophil cytoplasmic autoantibodies in diagnosing and managing systemic vasculitis.

PURPOSE OF REVIEW: Antineutrophil cytoplasmic autoantibodies (ANCAs) are considered important diagnostic tests in the work-up of patients suspected of vasculitis. Here we discuss new developments in the methodology of testing, the pitfalls in using these tests as diagnostic tools, and the value of serial ANCA testing for the follow-up of patients with ANCA-associated vasculitis including treatment decisions. RECENT FINDINGS: Both the indirect immunofluorescence (IIF) test and antigen-specific assays should be performed. New methodologies include automated reading in the IIF test and third-generation assays (anchor ELISA and bead-based multiplex assay) for the antigenic-specific assays. ANCA testing should be done in the right clinical context as positive results for PR3-ANCA and MPO-ANCA do occur in other conditions than vasculitis as well. These ANCAs develop in about 10% of patients with infective endocarditis. The occurrence of drug-induced ANCA and ANCA, also directed against elastase, following use of levamisole-adulterated cocaine should be recognized. In the right clinical context, ANCA are highly sensitive and specific for their associated disease. The value of serial ANCA testing for the follow-up of patients with ANCA-associated vasculitis is still under discussion but may be relevant in patients with renal involvement and in patients treated with rituximab. SUMMARY: The techniques for ANCA testing improve further but new tests should be standardized and validated. Their diagnostic value in the right clinical context is undisputed. Their value for the follow-up of patients is still under discussion.

B-cell-targeted therapy in systemic vasculitis.

PURPOSE OF REVIEW: The present review discusses the evidence supporting the use of B-cell-targeted therapy in the treatment of various forms of systemic vasculitis with a focus on the use of rituximab (RTX), in the antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV). RECENT FINDINGS: Long-term follow-up of the two studies establishing the efficacy of a RTX-based induction regimen for severe AAV have demonstrated noninferiority of a single course of RTX compared with conventional therapy for remission maintenance. In addition, these observations highlight an association between relapse and B-cell reconstitution in patients treated with RTX. The maintenance of remission using rituximab in systemic ANCA-associated vasculitis trial compared a regimen of RTX infusions every 6 months to azathioprine for remission maintenance and concluded that serial RTX lead to higher rates of sustained remission.RTX is also an established therapy for cryoglobulinemic vasculitis associated with hepatitis C viral (HCV) infection. Recently published data support the long-term efficacy and safety of RTX for cryoglobulinemic vasculitis. SUMMARY: B-cell depletion with RTX is an established therapy for both remission induction and maintenance in severe AAV and in HCV-related cryoglobulinemic vasculitis. There are limited data to support use of B-cell-targeted therapy in refractory cases of other forms of systemic vasculitis such as eosinophilic granulomatosis with polyangiitis and Takayasu's arteritis.

Antineutrophil cytoplasmic antibody negative pauci-immune extracapillary glomerulonephritis.

AIM: Pauci-immune extracapillary glomerulonephritis (PEGN) is one of the most common causes of rapidly progressive glomerulonephritis and is usually associated with circulating anti-neutrophil cytoplasmic antibodies (ANCAs). However, a significant number of individuals with PEGN test negative for ANCA and this study aimed to analyze the characteristics of this subgroup of patients. METHODS: Patients from two centres who were diagnosed with PEGN between 1997 and 2014 were studied retrospectively. Clinicopathological characteristics and renal outcome were compared between patients presenting with pauci-immune necrotizing extracapillary glomerulonephritis associated or not with the presence of circulating ANCA. RESULTS: Among the 114 patients with PEGN, 29 (25.4%) were ANCA negative. Compared with the 85 ANCA-positive patients, ANCA-negative patients were younger at the onset (54.8 ± 17.2 vs. 62 ± 14.0 years; P < 0.05). The median level of urinary protein excretion was significantly higher among ANCA-negative patients (3.1 vs. 1 g/24 h; P < 0.001), whereas no differences were found in renal function and need for dialysis between ANCA-negative and positive groups. Extrarenal involvement was present independently of ANCA status. Histological analysis showed that ANCA-negative patients were more likely to have mesangial proliferation (P < 0.05). Renal and global survival were similar between ANCA-negative and positive patients, and treatment response and relapse rates were comparable in both groups. CONCLUSIONS: ANCA-negative pauci-immune extracapillary glomerulonephritis is not a rare condition and is part of a systemic vasculitis disease. Although ANCA-negative patients have renal and histological characteristics that differ from ANCA-positive patients, renal survival and treatment response in PEGN are independent of ANCA status.

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.

Immune- and ribosome-related genes were associated with systemic vasculitis.

This study aimed to investigate the molecular mechanism of systemic vasculitis via bioinformatics analysis. Gene express profile of E-GEOD-16945 (13 Takayasu arteritis samples and 13 control samples) was downloaded from European Bioinformatics Institute (EBI) database. Differentially expressed genes (DEGs) were screened between Takayasu arteritis and normal controls (|log FC| > 1). Basic local alignment search tool (BLASTX) was used for the Clusters of Orthologous Groups (COG) classification of DEGs. Gene ontology analysis was performed for the DEGs (P < 0.05). A gene expression network was built with DEGs. Mcode in Cytoscape software was used to extract modules from the network (degree ≥ 2, K-core ≥ 2 and adjusted P-value < 0.05) followed by pathway analysis using GenMAPP (false discovery rate < 0.05). A total of 747 DEGs were identified. There were 16 significant GO function terms enriched with DEGs, of which immune and defence response was the most significant GO term. Totally, three modules were extracted from gene expression network, including one module constituted with upregulated genes and two modules constituted with downregulated genes. Furthermore, human leucocyte antigen (HLA)-DRB1, HLA-DPA1, HLA-DPB1, HLA-DOA and HLA-DRA in the downregulated modules were significantly linked to immune-related pathways (intestinal immune network for IgA production and systemic lupus erythematosus pathways), while ribosomal protein L 31 (RPL31), RPS3A and RPL9 in the upregulated module were enriched in ribosome pathway. The immune-related pathways, ribosome pathway, immune-related genes including (HLA-DRB1, HLA-DPA1, HLA-DPB1, HLA-DOA and HLA-DRA) and ribosome-related genes (RPL31, RPS3A and RPL9) might be involved in systemic vasculitis.

Crosstalk between intestinal microbiota, adipose tissue and skeletal muscle as an early event in systemic low-grade inflammation and the development of obesity and diabetes.

Obesity is associated with a systemic chronic low-grade inflammation that contributes to the development of metabolic disorders such as cardiovascular diseases and type 2 diabetes. However, the etiology of this obesity-related pro-inflammatory process remains unclear. Most studies have focused on adipose tissue dysfunctions and/or insulin resistance in skeletal muscle cells as well as changes in adipokine profile and macrophage recruitment as potential sources of inflammation. However, low-grade systemic inflammation probably involves a complex network of signals interconnecting several organs. Recent evidences have suggested that disturbances in the composition of the gut microbial flora and alterations in levels of gut peptides following the ingestion of a high-fat diet may be a cause of low-grade systemic inflammation that may even precede and predispose to obesity, metabolic disorders or type 2 diabetes. This hypothesis is appealing because the gastrointestinal system is first exposed to nutrients and may thereby represent the first link in the chain of events leading to the development of obesity-associated systemic inflammation. Therefore, the present review will summarize the latest advances interconnecting intestinal mucosal bacteria-mediated inflammation, adipose tissue and skeletal muscle in a coordinated circuitry favouring the onset of a high-fat diet-related systemic low-grade inflammation preceding obesity and predisposing to metabolic disorders and/or type 2 diabetes. A particular emphasis will be given to high-fat diet-induced alterations of gut homeostasis as an early initiator event of mucosal inflammation and adverse consequences contributing to the promotion of extended systemic inflammation, especially in adipose and muscular tissues.

Small-vessel vasculitis with prominent IgG4 positive plasma cell infiltrates as potential part of the spectrum of IgG4-related disease: a case report.

IgG4-related disease (IgG4-RD) is a systemic entity characterised by multiorgan inflammatory lesions with abundant IgG4+ plasma cells, obliterative phlebitis, and storiform fibrosis. Involvement of several organs such as the pancreas, gastrointestinal tract, salivary glands, periorbital tissue and lymph nodes has been described. Up to now, vascular involvement by IgG4-RD has been thought to be essentially confined to large vessels. We present a patient with small-vessel systemic vasculitis involving muscle, peripheral nerve and kidney (glomerulonephritis) in the context of IgG4-RD diagnosed on the basis of elevated serum IgG4+ concentrations and histologically consistent signs in all biopsied tissues. Thoracic and abdominal aortic aneurysms in addition to aortitis, suggestive of large-vessel involvement, were also present. This observation expands the spectrum of vascular involvement in the context of IgG4-RD and supports the inclusion of IgG4-RD in the category of vasculitis associated with systemic disorder.

Venous thromboembolism in systemic autoimmune diseases: A narrative review with emphasis on primary systemic vasculitides.

Venous thromboembolism (VTE) is a prevalent multifactorial health condition associated with significant morbidity and mortality. Population-based epidemiological studies have revealed an association between systemic autoimmune diseases and deep venous thrombosis (DVT)/VTE. The etiopathogenesis of increased risk of VTE in systemic autoimmune diseases is not entirely clear but multiple contributors have been explored, especially in the context of systemic inflammation and disordered thrombogenesis. Epidemiologic data on increased risk of VTE in patients with primary systemic vasculitides (PSV) have accumulated in recent years and some of these studies suggest the increased risk while patients have active diseases. This could lead us to hypothesize that venous vascular inflammation has a role to play in this phenomenon, but this is unproven. The role of immunosuppressive agents in modulating the risk of VTE in patients with PSV is not yet clear except for Behçet's disease, where most of the studies are retrospective. Sensitizing physicians to this complication has implications for prevention and optimal management of patients with these complex diseases. This review will focus on the epidemiology and available evidence regarding pathogenesis, and will attempt to summarize the best available data regarding evaluation and treatment of these patients.

Small-Medium Vessel Vasculitides: is the Complement System a Potential Forgotten Target?

Systemic vasculitides are a group of uncommon diseases characterized by blood vessel inflammation. The complement system is involved in the pathogenesis and clinical manifestations of several autoimmune diseases, including systemic vasculitides. This enzymatic system is a component of the innate immune system. Its main function was initially believed to be limited to the recognition and elimination of pathogens, but research in recent years has demonstrated the important role that complement proteins play in modulating adaptive immunity and in bridging innate and adaptive responses. Its activation is also critical for the development of T cell immunity and natural antibodies as well as for the regulation of autoreactive B cells. In systemic vasculitides, particularly small-medium vesselvasculitides, the complement system has been shown to contribute to the development of inflammatory damage. In view of these crucial functions, the complement system represents an attractive therapeutic target for a wide range of diseases. including vasculitic disorders.