Search

The spectrum of inflammatory blood vessel diseases includes both atherosclerosis and the primary systemic vasculitides. Although the inciting triggers differ, significant overlap exists in the mechanisms that contribute to sustained inflammation and vascular damage in both entities. With improvement in therapeutics to control acute vasculitis leading to longer survival, cardiovascular morbidity and mortality has emerged as the leading cause of death for vasculitis patients. Cardiovascular events likely occur as a consequence of vasculitis, vascular damage from prior inflammation causing a sustained procoagulant state, and accelerated atherosclerosis. In this review, we discuss the latest evidence regarding risk of cardiovascular events in patients with major forms of primary systemic vasculitis, and review the mechanisms by which accelerated atherosclerosis may occur., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Levamisole-contaminated cocaine can induce severe systemic vasculitis. The diagnosis can be challenging, especially when substance abuse is uncertain. We present the case of a 42-year-old woman suffering from vasculitis due to levamisole-contaminated cocaine, who persistently denied substance abuse. Symptoms included ulcerating skin lesions, arthralgia and myalgia, and the occurrence of an ileal intussusception. The definitive diagnosis was made using hair testing for toxins. She recovered through cocaine abstinence, but re-exposure resulted in a severe relapse with glomerulonephritis. Importantly, at time of the relapse, the patient became positive for both myeloperoxidase-antineutrophil cytoplasmic antibody (ANCA) and proteinase 3-ANCA. Cocaine-levamisole-induced vasculitis poses a great clinical challenge. The proper diagnostic strategy and therapy is still controversial. We highlight our diagnostic and therapeutic considerations, including hair testing for definitive proof of exposure., (2015 BMJ Publishing Group Ltd.)

Cerebral small vessel disease (CSVD) is considered to be caused by an increased permeability of the blood-brain barrier and results in enlargement of Virchow Robin spaces (VRs), white matter lesions, brain microbleeds, and lacunar infarcts. The increased permeability of the blood-brain barrier may relate to endothelial cell activation and activated monocytes/macrophages. Therefore, we hypothesized that plasma markers of endothelial activation (adhesion molecules) and monocyte/macrophage activation (neopterin) relate to CSVD manifestations. In 163 first-ever lacunar stroke patients and 183 essential hypertensive patients, we assessed CSVD manifestations on brain magnetic resonance imaging (MRI) and levels of C-reactive protein (CRP), neopterin, as well as circulating soluble adhesion molecules (sICAM-1, sVCAM-1, sE-selectin, sP-selectin). Neopterin, sICAM-1 and sVCAM-1 levels were higher in patients with extensive CSVD manifestations than in those without (p < 0.01). Neopterin levels independently related to higher numbers of enlarged Virchow Robin spaces (p < 0.001). An inflammatory process with activated monocytes/macrophages may play a role in the increased permeability of the blood brain barrier in patients with CSVD., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In this study we assess the presence of antibodies against infectious agents as well as for a variety of autoantibodies in an attempt to establish associations between various vasculitides and infections in order to shed light on the etiopathogenesis of these diseases and perhaps implicate a potential cure. Sera from patients with Wegener's granulomatosis (WG), polyarteritis nodosa, microscopic polyangiitis, Churg Strauss, and giant cell arteritis were compared to healthy control sera. Serum samples were assessed, using the Bio-Rad BioPlex 2200, for the presence of Toxoplama gondii, cytomegalovirus (CMV), Epstein-Barr virus (EBV), Treponema pallidum, and Saccharomyces cerevisiae. Hepatitis B virus (HBV), hepatitis C virus (HCV), and anti-Helicobacter pylori antibodies were assessed by ELISA. In addition, sera were tested for a panel of antibodies associated with thrombophilia as well as various autoantibodies. The prevalence of antibodies toward HCV and H. pylori was significantly higher among patients with WG. IgG antibodies toward T. gondii and IgM antibodies toward CMV were significantly more common among WG patients than among controls. WG patients exhibited more antibodies toward EBV viral capsid antigen IgG and EBV early antigen IgG compared to sera from healthy controls. In WG, positive associations were disclosed between CMV IgG antibodies and the presence of gastrointestinal manifestations and renal involvement, and there was a higher Birmingham vasculitis activity score in association with elevated titers of EBV viral capsid antigen IgG antibodies. Otorhinolaryngeal manifestations were more common in those with positive IgG antibodies for EBV early antigen. Our results unveil novel associations between WG and various infectious agents, including HCV, H. pylori, T. gondii, CMV, and EBV. In addition to putative roles in initiation and exacerbation of the vasculitic process, it seems that these infectious agents also modulate the clinical phenotype of the disease.

Background: Dendritic cells (DCs) maintain immune tolerance and are able to initiate immune responses. Their involvement in ANCA-associated vasculitis (AAV) is unknown. In this study, the participation of DC subsets is investigated in renal biopsies of AAV patients., Method: A total of 25 patients with biopsy-proven AAV and five healthy controls (HC) with normal renal histology were included. Renal biopsies were stained for mature (CD208), immature (CD209), plasmacytoid (CD303) and Langerhans (CD1a) DC subsets. Furthermore, T-cells were stained using a T-cell marker (CD3). The interstitial cellular infiltrate was graded semi-quantitatively from 0+ (= absence of cells) to 3+ (= numerous cells). Within the glomeruli, an absolute count was performed for positive cells., Results: CD208+ and CD209+ cells were found within patients' glomeruli but not in HC (1 +/- 0.3 versus 0.08 +/- 0.1 cells/glom; 2 +/- 0.3 versus 0.1 +/- 0.07 cells/glom). An average of 0.3 +/- 0.1 cell/glom expressed CD3 in patients while few cells were found in HC (0.1 +/- 0.7 cell/glom). Focal interstitial cellular infiltrates were observed in patients' biopsies but not in HC. Interstitial infiltration with CD3+ and CD209+ cells was assessed at an average of 1+, but some glomeruli and tubuli were surrounded by CD3+ and CD209+ cells forming clusters. Serial sections revealed that CD209+ cells were present in CD3+ rich areas., Conclusion: Both mature and immature glomerular DCs are found in renal biopsies of patients with AAV. Immature DCs cluster with T-cells in interstitial infiltrates in these biopsies. Since DCs form aggregates in T-cell areas, we hypothesize that these cells interact with each other and are involved in lymphoid neogenesis.

Objectives: As the HLA system is involved in recognition of self and non-self, an association with the development of ANCA-associated vasculitis (AAV) seems probable. In this study, the relation between HLA antigens and AAV and it's severity were investigated., Methods: Consecutive patients diagnosed with AAV at our centre, who were followed for at least 2 years, were included. The frequency of HLA antigens of AAV and WG patients was compared with 5872 healthy blood donors from the same region and with 4000 healthy Dutch controls originating from a Eurotransplant database., Results: From 304 AAV patients, sufficient data were available. We found DR13(6) to be less prevalent and both DR4 and the ancestral haplotype A1B8DR3 more prevalent in patients with AAV compared with controls, particularly in patients with WG. In addition, DR1 was less prevalent in patients with WG in comparison with controls. Further, DR8 was more prevalent in patients with CSS compared with other forms of vasculitis and controls. There were no associations between HLA antigens and disease characteristics or course of AAV or WG., Conclusions: AAV is associated with increased prevalence of DR4 and the ancestral haplotype A1B8DR3 and with decreased prevalence of DR13(6), particularly in patients with WG. In patients with WG, prevalence of DR1 was decreased, whereas in patients with CSS DR8 was increased. No associations between HLA antigens and disease characteristics or course of AAV were found.

Premature atherosclerosis has been observed during the course of different systemic inflammatory diseases such as rheumatoid arthritis and sytemic lupus erythematosus. Remarkably, relatively few studies have been published on the occurrence of accelerated atherosclerosis in patients with vasculitis. In giant cell arteritis (GCA), mortality because of ischaemic heart disease is not increased. In addition, intima media thickness (IMT) is lower in patients with GCA than in age-matched controls. In contrast, IMT is increased significantly in Takayasu arteritis, another form of large vessel vasculitis occurring in younger patients. In Takayasu arteritis and in Kawasaki disease, a form of medium-sized vessel vasculitis, accelerated atherosclerosis has been well documented. In small vessel vasculitis because of anti-neutrophil cytoplasmic autoantibodies-associated vasculitis, cardiovascular diseases are a major cause of mortality. IMT measurements reveal conflicting results. During active disease these patients experience acceleration of the atherosclerotic process. However, when inflammation is controlled, these patients have atherosclerotic development as in healthy subjects. Several risk factors, such as diabetes and hypertension, are present more often in patients with vasculitis compared with healthy controls. In addition, steroids may be pro-atherogenic. Most importantly, many patients have impaired renal function, persistent proteinuria and increased levels of C-reactive protein, well-known risk factors for acceleration of atherosclerosis. Enhanced oxidation processes, persistently activated T cells and reduced numbers of regulatory T cells are among the many pathophysiological factors that play a role during acceleration of atherogenesis. Finally, autoantibodies that may be relevant for acceleration of atherosclerosis are found frequently in elevated titres in patients with vasculitis. Because patients have an increased risk for cardiovascular events, vasculitis should be treated with as much care as possible. In addition, treatment should be considered with angiotensin-converting-enzyme inhibitors and/or angiotensin receptor-1 blockers, statins and acetylsalicyl acid. Finally, classical risk factors for cardiovascular disease should be monitored and treated as much as possible.

Background: Antineutrophil cytoplasmic antibodies (ANCA) with a C-ANCA or P-ANCA pattern are detected in ANCA-associated vasculitis (AAV). While in most patients with AAV a C-ANCA pattern is due to reactivity with proteinase-3 (PR3)-ANCA, some C-ANCA-positive sera do not react with PR3., Objective: The development and evaluation of a direct enzyme-linked immunosorbent assay (ELISA) for PR3-ANCA with increased sensitivity., Methods: A mixture of human native (hn) and human recombinant (hr) PR3 was used as antigen coating. The resulting ELISA (anti-PR3-hn-hr) was compared with ELISAs using directly coated hn-PR3 or hr-PR3, as well as with a hn-PR3 capture ELISA. Assay characteristics were determined in patients with AAV (n = 248), with special attention for those patients with C-ANCA (n = 132), as well as disease controls (n = 585) and healthy controls (n = 429). Additionally, for prediction of relapses serial samples of 46 patients with PR3-AAV were analysed., Results: At a predefined specificity of 99% both ELISAs containing hr-PR3 revealed a substantial increase in sensitivity. For the prediction of relapses by rises in PR3-ANCA titres the capture ELISA was most optimal (odds ratio 12.5). With an odds ratio of 8.9 the novel anti-PR3-hn-hr ELISA was second best., Conclusions: Owing to the very high sensitivity of the novel anti-PR3-hn-hr ELISA for the detection of PR3-ANCA in C-ANCA-positive samples of patients with AAV this assay has an excellent diagnostic performance. This feature is combined with a good predictability of clinical relapses in patients with PR3-AAV. These characteristics challenge the dogma that, for detection of PR3-ANCA, capture ELISAs are superior for diagnosis and follow-up.

Objectives: We undertook a systematic literature review as a background to the European League Against Rheumatism (EULAR) recommendations for conducting clinical trials in anti-neutrophil cytoplasm antibody associated vasculitis (AAV), and to assess the quality of evidence for outcome measures in AAV., Methods: Using a systematic Medline search, we categorised the identified studies according to diagnoses. Factors affecting remission, relapse, renal function and overall survival were identified., Results: A total of 44 papers were reviewed from 502 identified by our search criteria. There was considerable inconsistency in definitions of end points. Remission rates varied from 30% to 93% in Wegener granulomatosis (WG), 75% to 89% in microscopic polyangiitis (MPA) and 81% to 91% in Churg-Strauss syndrome (CSS). The 5-year survival for WG, MPA and CSS was 74-91%, 45-76% and 60-97%. Relapse (variably defined) was common in the first 2 years but the frequency varied: 18% to 60% in WG, 8% in MPA, and 35% in CSS. The rate of renal survival in WG varied from 23% at 15 months to 23% at 120 months., Method: used to assess morbidity varied between studies. Ignoring the variations in definitions of the stage of disease, factors influencing remission, relapse, renal and overall survival included immunosuppressive therapy used, type of organ involvement, presence of ANCA, older age and male gender., Conclusions: Factors influencing remission, relapse, renal and overall survival include the type of immunosuppressive therapy used, pattern of organ involvement, presence of ANCA, older age and male gender. Methodological variations between studies highlight the need for a consensus on terminology and definitions for future conduct of clinical studies in AAV.

T cell activation is regulated by inhibitory molecules such as PD-1 and CTLA-4, whose expression may be affected by gene polymorphisms. Increased T cell activation is present in patients with ANCA-associated vasculitis (AAV). We investigated two single-nucleotide polymorphisms (SNPs) in PDCD1 and five polymorphisms in CTLA4 in 102 patients with AAV and 188 healthy controls (HC). The distributions of the PD-1.3 and PD-1.5 SNPs, and the distributions of the CTLA4 promoter polymorphisms -1722T/C, -1661A/G, -318 C/T, and the (AT)(n) microsatellite in the 3'-untranslated region of CTLA4, did not differ between patients and HC. However, the +49 G allele was significantly more often present in patients with AAV. Furthermore, the co-occurrence of the PD-1.5 T allele with CTLA4 +49 AA homozygosity (i.e., the absence of a G allele) was less often present in patients compared to HC. These genetic polymorphisms may lead to hyperreactivity of T cells and thus may contribute to the pathogenesis of AAV.

A 55-year-old man, with no previous history, presented with extreme fatigue and fever and was admitted to hospital. He had progressive renal dysfunction and his serum anti-neutrophil cytoplasmic antibodies (ANCA) were markedly elevated. Renal histology was consistent with ANCA-associated vasculitis. The patient was successfully treated with cyclophosphamide and prednisolone. The classification and management of the ANCA-associated vasculitides are described. The classification was guided by the clinical presentation, serology and results of tissue biopsies. The ANCA inflammation had affected the middle sized and small vessels of especially the upper and lower airways, and the kidneys. The antibodies were directed at proteinase-3 (PR3) or myeloperoxidase (MPO). PR3-ANCA is predominantly found in Wegener's granulomatosis, while MPO-ANCA is related to microscopic polyangiitis. Tissue studies showed granulomatous inflammation of the airways which is typical of Wegener's disease. This type of inflammation is absent in microscopic polyangiitis. The initial treatment schedule consists of prednisone 1 mg/kg daily and oral cyclophosphamide 2 mg/kg daily. In the remission phase, the cyclophosphamide is replaced by azathioprine. It is not yet known how long maintenance treatment should be continued and which parameters have prognostic value.

The first description of what is now known as antineutrophil cytoplasmic autoantibody-associated necrotizing vasculitis appeared more than 140 yr ago. Since then, many aspects of the pathogenic pathway have been elucidated, indicating the involvement of antineutrophil cytoplasmic autoantibodies, but why antineutrophil cytoplasmic autoantibodies are produced in the first place remains unknown. Over the years, many hypotheses have emerged addressing the etiology of antineutrophil cytoplasmic antibody production, but no exclusive factor or set of factors can so far be held responsible. Herein is reviewed the most influential hypotheses regarding the causes of antineutrophil cytoplasmic antibody-associated vasculitis with the aim of placing in an epidemiologic background the different hypotheses that are centered on environmental and genetic influences.

Many patients surviving vasculitis are prone to accelerated atherosclerosis and often have enhanced levels of antibodies to oxidized low-density lipoprotein (oxLDL). To measure anti-oxLDL antibodies, oxidation of LDL is achieved with copper (Cu) or malondialdehyde (MDA). Because, in vivo, LDL may be oxidized with myeloperoxidase (MPO) or its product hypochlorite, we measured anti-hypochlorite LDL antibodies in patients with vasculitis, haemodialysis patients and healthy controls. A newly developed enzyme-linked immunosorbent assay (ELISA) was used to detect antibodies to oxLDL as modified by hypochlorite. Results are compared with data obtained by standard LDL oxidation using MDA-LDL or Cu-LDL as substrate. Results were compared between anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) patients (n = 93), haemodialysis (HD) patients (n = 59) and healthy controls (HC; n = 43). Furthermore, patients with MPO-ANCA-associated vasculitis (n = 47) were compared with patients with proteinase 3 (PR3)-ANCA associated vasculitis (n = 46). Optimal cut-off points were determined by receiver operator characteristic (ROC) curve analysis. Anti-oxLDL antibodies are enhanced in AAV patients (MDA-LDL and hypochlorite-LDL) and in HD patients (hypochlorite-LDL), when compared to HC. Furthermore, patients with MPO-ANCA-associated vasculitis had higher levels of antibodies to hypochlorite-LDL than patients with PR3-ANCA-associated vasculitis. Our newly developed assay, in which hypochlorite-LDL is used as substrate, seems a more sensitive assay than traditional assays to measure oxLDL antibodies. Furthermore, our results suggest that enhanced MPO-mediated LDL oxidation occurs in patients with MPO-ANCA.

We have evaluated a new-multiplex immunoassay (FIDIS Vasculitis) for simultaneous detection and quantification of anti-MPO, -PR3, and -glomerular basement membrane (GBM) antibodies in diagnosis and follow-up of ANCA-associated vasculitides (AAV) and Goodpasture's disease. ANCA were determined in sera of (a) 87 consecutive patients with biopsy-proven pauci-immune NCGN and 72 controls; (b) 9 patients with Goodpasture's disease; and (c) 60 WG patients and 60 controls, previously used in a multicenter comparison of direct and capture ELISA for PR3-ANCA. Finally, for prediction of relapses, PR3-ANCA was measured in samples preceding relapse in 23 PR3-AAV patients and in 23 matched PR3-AAV patients without relapse. The relative sensitivity of the FIDIS Vasculitis assay was 97.4% for MPO-ANCA and 92.3% for PR3-ANCA; specificity was 100% and 97.2%, respectively. Evaluation of the anti-GBM antibody detection revealed a sensitivity of 100% and a specificity of 99.6%. The sensitivity for WG of the PR3-ANCA detection (71.6%) approached the performance of capture ELISA (74%), although at the cost of specificity (96.7% versus 100%). For prediction of relapses a rise of 50% in ANCA level by FIDIS Vasculitis appeared optimal (ROC curve) for prediction of relapses. However, as compared to capture ELISA, both positive (63% versus 76%) and negative (68% versus 72%) predictive values were reduced. In conclusion, simultaneous detection of anti-MPO, -PR3, and -GBM antibodies in the multiplex FIDIS Vasculitis assay has excellent performance in terms of diagnosis of patients with AAV or Goodpasture's disease. However, detection of rises in PR3-ANCA for prediction of relapses gives less optimal results when compared to capture ELISA.

Background: Active anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is commonly treated with cyclophosphamide, a drug with serious side effects, and with corticosteroids., Objective: To determine the efficacy of a possible alternative drug for cyclophosphamide, oral mycophenolate mofetil (MMF) 1000 mg twice daily and oral prednisolone 1 mg/kg once daily as remission induction treatment., Methods: 32 consecutive patients with 34 episodes of active vasculitis who could not be treated with cyclophosphamide were diagnosed for a median (range) of 6.0 (0.3-22) years and experienced 4 (0-14) relapses prior to the current episode. Treatment response and relapse-free survival were analysed., Results: Complete remission (CR) was obtained in 25 (78%) patients, partial remission (PR) in 6 (19%), whereas 1 (3%) patient did not respond. 19 patients relapsed, 13 (52%) after CR, 14 (3-58) months after starting the treatment and 6 (100%) after PR, 6 (2-10) months after starting the treatment. The median relapse-free survival was 16 months, comparable with the interval between the previous relapse and the current MMF-treated relapse (17 (3-134) months). Relapse-free survival at 1, 3, and 5 years was 63%, 38% and 27%, respectively. Patients who had been treated successfully with cyclophosphamide before responded better (CR 84%, relapse 50%) than those who had not (CR 50%, relapse 100%). Minor gastrointestinal side effects and infections occurred frequently. MMF was prematurely discontinued due to adverse effects in two patients., Conclusion: MMF, in combination with prednisolone, can induce remission in patients with relapses of AAV intolerant to cyclophosphamide.

Objectives: To develop the European League Against Rheumatism (EULAR) recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis., Methods: An expert consensus group was formed consisting of rheumatologists, nephrologists and specialists in internal medicine representing five European countries and the USA, a clinical epidemiologist and representatives from regulatory agencies. Using an evidence-based and expert opinion-based approach in accordance with the standardised EULAR operating procedures, the group identified nine topics for a systematic literature search through a modified Delphi technique. On the basis of research questions posed by the group, recommendations were derived for conducting clinical studies and/or clinical trials in systemic vasculitis., Results: Based on the results of the literature research, the expert committee concluded that sufficient evidence to formulate guidelines on conducting clinical trials was available only for anti-neutrophil cytoplasm antibody-associated vasculitides (AAV). It was therefore decided to focus the recommendations on these diseases. Recommendations for conducting clinical trials in AAV were elaborated and are presented in this summary document. It was decided to consider vasculitis-specific issues rather than general issues of trial methodology. The recommendations deal with the following areas related to clinical studies of vasculitis: definitions of disease, activity states, outcome measures, eligibility criteria, trial design including relevant end points, and biomarkers. A number of aspects of trial methodology were deemed important for future research., Conclusions: On the basis of expert opinion, recommendations for conducting clinical trials in AAV were formulated. Furthermore, the expert committee identified a strong need for well-designed research in non-AAV systemic vasculitides.

Background: The classification of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and polyarteritis nodosa (PAN) for epidemiology studies is confusing. The existing schemes such as American College of Rheumatology (ACR) criteria, Chapel Hill Consensus Conference (CHCC) definitions and Lanham criteria produce overlapping and conflicting classifications, making it difficult to compare incidence figures., Aim: To develop a consensus method of using these criteria and definitions for epidemiological studies to permit comparison without confounding by classification., Methods: A stepwise algorithm was developed by consensus between a group of doctors interested in the epidemiology of vasculitis. The aim was to categorise patients with Wegener's granulomatosis, microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS) and PAN into single clinically relevant categories. The ACR and Lanham criteria for CSS, and ACR criteria for Wegener's granulomatosis were applied first, as these were considered to be the most specific. Surrogate markers for Wegener's granulomatosis were included to distinguish Wegener's granulomatosis from MPA. MPA was classified using the CHCC definition and surrogate markers for renal vasculitis. Finally, PAN was classified using the CHCC definition. The algorithm was validated by application to 20 cases from each centre and 99 from a single centre, followed by a paper case exercise., Results: A four-step algorithm was devised. It successfully categorises patients into a single classification. There was good correlation between observers in the paper case exercise (91.5%; unweighted kappa = 0.886)., Conclusion: The algorithm achieves its aim of reliably classifying patients into a single category. The use of the algorithm in epidemiology studies should permit comparison between geographical areas.

Both the innate and the acquired immune system are involved in the pathophysiology of renal vasculitis. However, anti-neutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis is characterized by a 'pauci-immune' pattern of immunofluorescence during kidney biopsy, indicating the relative lack of immunoglobulin and complement deposition within the kidney. On the other hand, evidence is accumulating that ANCA, autoantibodies against constituents of primary granules of neutrophils and the lysosomes of monocytes, play a pathogenic role in renal vasculitis. In this review we will discuss both in vitro and in vivo experimental data providing compelling evidence that ANCA are a primary pathogenic factor in renal vasculitis, mainly by augmenting leukocyte-endothelial interactions. We will also address novel data, pointing at the role of, in addition to ANCA, non-specific proinflammatory signals. Finally, we propose a working hypothesis of the pathogenesis of ANCA-associated renal vasculitis., (Copyright 2007 S. Karger AG, Basel.)

Most frequent reasons for intensive care unit (ICU) admission in vasculitis patients are severe respiratory insufficiency due to diffuse alveolar haemorrhage, sepsis and/or pneumonia and an acute abdomen due to bowel infarction. Other reasons are massive gastrointestinal bleeding, thromboembolism and/or scissures. In a patient, not previously diagnosed as having vasculitis, diagnosis can be difficult and must be made as soon as possible, since immunosuppressive therapy should be instituted immediately. Immunosuppressive therapy in severe cases consists of high-dose corticosteroids and cyclophosphamide. In addition, in many cases plasma exchange has to be instituted as well. Prognosis is related to disease activity scores of vasculitis and of severity of illness as measured by the APACHE III scoring system and/or the SOFA score. Septic shock is still the leading cause of death in patients with vasculitis. Nowadays, death due to active untreated vasculitis is rare in experienced clinics.

Antiendothelial cell antibodies (AECA) are a heterogeneous family of antibodies reacting with endothelial cell antigens. These antibodies are found in various diseases and recognise several antigen determinants. Different pathophysiological effects have been observed in in vitro experiments, which include direct or indirect cytotoxicity and endothelial cell apoptosis. Furthermore, some AECA activate endothelial cells, resulting in increased leucocyte adhesiveness, activation of coagulation and vascular thrombosis. In animal models, it has been shown that AECA could promote vascular damage. Neither the endothelial cell antigens nor their precise role in the pathogenecity of different diseases in which AECA are found is well characterised. Nowadays, it is not known whether AECA are an epiphenomenon accompanying vascular injury or whether they are pathogenic. It is controversial whether fluctuations in AECA titres are associated with disease activity during follow-up studies. This review summarises the present knowledge about AECA, AECA antigens and their potential role in the pathogenecity of vasculitis and connective tissue diseases.

Objective: Standard therapy for antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV) with cyclophosphamide (CYC) and prednisolone is limited by toxicity. This unblinded, prospective, randomized, controlled trial was undertaken to determine whether methotrexate (MTX) could replace CYC in the early treatment of AASV., Methods: Patients with newly diagnosed AASV, with serum creatinine levels <150 mumoles/liter, and without critical organ manifestations of disease were randomized to receive either standard oral CYC, 2 mg/kg/day or oral MTX, 20-25 mg/week; both groups received the same prednisolone regimen. All drug treatments were gradually tapered and withdrawn by 12 months. Followup continued to 18 months. The primary end point was the remission rate at 6 months (noninferiority testing)., Results: One hundred patients were recruited from 26 European centers; 51 patients were randomized to the MTX group and 49 to the CYC group. At 6 months, the remission rate in patients treated with MTX (89.8%) was not inferior to that in patients treated with CYC (93.5%) (P = 0.041). In the MTX group, remission was delayed among patients with more extensive disease (P = 0.04) or pulmonary involvement (P = 0.03). Relapse rates at 18 months were 69.5% in the MTX group and 46.5% in the CYC group; the median time from remission to relapse was 13 months and 15 months, respectively (P = 0.023, log rank test). Two patients from each group died. Adverse events (mean 0.87 episodes/patient) included leukopenia, which was less frequent in the MTX versus the CYC group (P = 0.012), and liver dysfunction, which was more frequent in the MTX group (P = 0.036)., Conclusion: MTX can replace CYC for initial treatment of early AASV. The MTX regimen used in the present study was less effective for induction of remission in patients with extensive disease and pulmonary involvement and was associated with more relapses than the CYC regimen after termination of treatment. The high relapse rates in both treatment arms support the practice of continuation of immunosuppressive treatment beyond 12 months.

In this study we have evaluated a new, fully automated fluorescent-enzyme immuno-assay (FEIA) for detection and quantification of anti-PR3 and anti-MPO ANCA in diagnosis and follow-up of ANCA-associated small vessel vasculitis (AAV). PR3- and MPO-ANCA were determined by FEIA technology in (1) sera of 87 consecutive patients with biopsy-proven, pauci-immune necrotizing crescentic glomerulonephritis (NCGN) and 72 controls; (2) 120 sera (60 patients with Wegener's granulomatosis and 60 controls) that were previously used in a multicentre comparison of direct and capture ELISAs for PR3-ANCA; (3) in samples preceding relapse in 23 PR3-AAV patients with and 23 matched PR3-AAV patients without relapse for prediction of relapses. PR3- and/or MPO-ANCA detection in pauci-immune NCGN by FEIA revealed an overall sensitivity of 82.8%. The FEIA specificity was 96% and 100% for PR3- and MPO-ANCA, respectively. The overall sensitivity of MPO- and PR3-ANCA could be increased to 88.5% by lowering the cut-off values without affecting the specificity (ROC-curve analysis), which is similar to a multistep ANCA procedure that combines indirect immunofluorescence with direct and capture ELISAs. The sensitivity for Wegener's granulomatosis (WG) of the PR3-ANCA FEIA (60%) was more comparable to direct ELISAs (64%) than to capture ELISAs (74%). A rise of 100% in ANCA level as measured by FEIA appeared optimal (ROC-curve) for prediction of relapses and such a rise was observed in 26 patients. In 18 of these 26 patients the rise was followed by a relapse (PPV 69%), whereas in 15 of the 20 patients without a rise no relapse was observed (NPV 75%). In conclusion, detection of PR3- and MPO-ANCA by FEIA has excellent performance in terms of diagnosis of AAV patients. Furthermore, detection of rises in PR3-ANCA by FEIA for prediction of relapses gives results comparable to other techniques.

Objective: To test whether antineutrophil cytoplasmic antibodies (ANCA) and ANCA-associated vasculitis (AAV) are not only induced during treatment with antithyroid drugs, but can also become evident when medication has been ceased, possibly after years., Methods: Patients who visited our hospital for the treatment of hyperthyroidism were included (n = 207). Treatment consisted of antithyroid medications, radioactive iodide, thyroidectomy, or a combination of these treatment options. Patients were retested 3-6 years later to evaluate long-term effects of antithyroid drugs. Patients were tested for the presence of ANCA and, if positive, evaluated for the presence of AAV., Results: Of 209 patients with hyperthyroidism, 12 patients (6%) were positive for myeloperoxidase- (MPO-), proteinase 3-, or human leukocyte elastase-ANCA. Seventy-seven of 209 patients were retested; 1 patient who had not been treated with antithyroid drugs had developed MPO-ANCA. In 3 of 6 patients previously positive, ANCA could still be detected. The presence of ANCA was highly associated with treatment with antithyroid drugs (odds ratio 11.8 [95% confidence interval 1.5-93.3]). Of 13 patients with a positive ANCA result on enzyme-linked immunosorbent assay, AAV with glomerulonephritis was diagnosed in 4 (31%)., Conclusion: The presence of ANCA with or without vasculitis is associated with previous treatment with antithyroid drugs, possibly after years.

The strong association of antineutrophil cytoplasmic autoantibodies (ANCA) with certain forms of small vessel vasculitis suggests a pathogenic role of these autoantibodies in the disease process. In vitro, ANCA can activate neutrophils and monocytes to produce reactive oxygen intermediates, to release lysosomal enzymes, and to secrete proinflammatory cytokines. More recently, it was demonstrated that antimyeloperoxidase ANCA can induce systemic vasculitis and glomerulonephritis in mice. Taken together, these data provide convincing evidence that ANCA are indeed pathogenic.

Objective: To analyze disease-free survival in patients with antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis (AAV) treated with cyclophosphamide only or switched to azathioprine after 3 months of full remission while taking cyclophosphamide., Methods: We analyzed disease-free survival in all consecutive patients diagnosed with AAV between 1990 and 2000 at our center. Patients were treated with cyclophosphamide only (1990-1996) or switched to azathioprine after 3 months of remission while taking cyclophosphamide (1997-2000). All patients received at least 12 months of followup., Results: Of the total 128 patients, 53 (41%) relapsed. Forty-four of the 128 patients (34%) had been switched to azathioprine therapy. Disease-free survival at 2 and 4 years was 76% and 65% in the cyclophosphamide group compared with 76% and 51% in the azathioprine group. In patients with proteinase 3 (PR3) classic ANCA (C-ANCA)-associated vasculitis who were switched to azathioprine (n = 33), a positive C-ANCA titer at the moment of treatment switch (n = 13) was significantly associated with relapse (RR 2.6, 95% confidence interval 1.1-8.0; P = 0.04). In patients with a negative ANCA titer at the time of switch to azathioprine, disease-free survival at 2 and 4 years was 80% and 62%, which was identical to that for patients treated with cyclophosphamide only. In patients who were ANCA-positive at the time of treatment switch, disease-free survival at 2 and 4 years was only 58% and 17%., Conclusion: Switching cyclophosphamide to azathioprine after induction of remission in patients with PR3-ANCA-associated vasculitis who are still ANCA-positive at the time of treatment switch is associated with a high risk of relapse.

Purpose of Review: Since the discovery of antineutrophil cytoplasmic autoantibodies (ANCA) and their association with the occurrence of several types of small-vessel vasculitis, a causal relation between the two has been suggested. Various in vitro and in vivo experimental data provide indirect evidence in support of this view. This article comprises a review of the animal models that have been used to investigate the pathogenesis of ANCA-associated vasculitis, and focuses on recent developments in this field., Recent Findings: Xiao et al. provide definite proof of the pathogenic potential of ANCA in a novel mouse model of myeloperoxidase (MPO)-ANCA-associated vasculitis, in which transfer of splenocytes or IgG from MPO-/- mice immunized with murine MPO, to naive wild-type or Rag2-/- (lacking mature B and T lymphocytes) mice causes a disease remarkably similar to its human counterpart. In addition, preliminary studies by Smyth et al. show that immunization of Wistar Kyoto rats with human MPO induces antihuman MPO antibodies that cross-react with rat MPO, as well as a disease closely resembling human small-vessel vasculitis. Another murine ANCA model is the SCG/Kj mouse. A recent publication by Neumann et al., however, puts an important limitation on the use of this mouse model for the study of ANCA-associated vasculitis, demonstrating multiple immune complex deposits in the spontaneously occurring vascular lesions. SUMMARY Recently developed animal models of MPO-ANCA-associated vasculitis convincingly demonstrate that MPO-ANCA are pathogenic. Whether similar strategies can be used to develop an appropriate model for proteinase 3-ANCA-associated vasculitis remains to be investigated.

The strong relation between antineutrophil cytoplasmic autoantibodies (ANCA) and primary vasculitic syndromes suggests a pathophysiological role for ANCA. Experimental evidence for the pathogenic potential of ANCA has been derived from in vitro studies that demonstrate that ANCA can activate tumour necrosis factor alpha primed neutrophils, monocytes and/or endothelial cells. The binding of ANCA to primed neutrophils results in activation of these cells by a process that is largely dependent on engagement of beta-2 integrins and on the interaction of the Fc portion of ANCA. An Fc-independent mechanism is, however, also operative. In experimental animal models, it has been demonstrated that immunisation with myeloperoxidase (MPO) induces MPO-ANCA. The induction of ANCA, however, is not sufficient to induce vasculitis in rats since immune complexes first have to be deposited along the vessel wall before lesions develop. When MPO-deficient mice are, however, immunised with murine MPO, anti-MPO immunoglobulins are purified and subsequently injected into mice that are not deficient for MPO, systemic vasculitis and glomerulonephritis is induced. These experiments suggest that ANCA indeed induces vasculitis. Risk factors for breaking self-tolerance to ANCA antigens are genetic factors, drugs, chemical substances and/or infectious agents.

Standard therapy of Wegener's granulomatosis is prednisolone in combination with cyclophosphamide. Cyclophosphamide is continued for 15-18 months after diagnosis. During therapy 26% of the patients have severe or life-threatening side effects, mostly infections. Furthermore, there are multiple long-term side effects such as an increased incidence of malignancies, especially bladder carcinoma. During the last 10 years the European vasculitis study group (www.vasculitis.org) organized several randomized clinical trials to determine optimal treatment. Recently, it was demonstrated in one of these trials that in patients with generalized ANCA-associated vasculitis (vasculitis associated with antineutrophil cytoplasmic autoantibodies) withdrawal of cyclophosphamide and substitution by azathioprine after remission did not increase the rate of relapse and was safe. Wegner's granulomatosis is not a fatal disease anymore. Sometimes, however, patients lose their job. Fortunately, this occurs only in a small percentage of patients.

Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and idiopathic pauci-immune necrotizing crescentic glomerulonephritis are strongly associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). These ANCA-associated vasculitides can serologically be separated into myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA positive patients. The unique properties of the antigen targeted by the anti-MPO antibodies could help to explain the specific characteristics of MPO-ANCA associated disease. Recently, an animal model has been developed that proves that anti-mouse MPO immunoglobulins alone are capable of causing disease similar to that in humans. Also, the in vitro pathologic effects of binding of MPO-ANCA to MPO are better understood. MPO-ANCA can activate (primed) neutrophils directly causing extensive reactive oxygen species formation and degranulation of neutrophil constituents, including MPO, resulting in a destructive inflammatory response towards the vessel wall. MPO-ANCA can prevent the clearing and inactivation of MPO by ceruloplasmin as well, resulting in increased myeloperoxidase activity. Myeloperoxidase produces not only the strong oxidant bleach (hypochlorous acid) out of hydrogen peroxide and chloride ions but also oxidizes LDL into a macrophage high-uptake form, inactivates protease inhibitors, and consumes nitric oxide. These may contribute to endothelial dysfunction and add to the chronic renal lesions observed in patients with MPO-ANCA. MPO levels are influenced by genetic factors including two, MPO463 and MPO129, single nucleotide polymorphisms. The MPO 463 polymorphism has been associated with an increased risk of development of MPO-ANCA associated disease.

Background: The primary systemic vasculitides usually associated with autoantibodies to neutrophil cytoplasmic antigens include Wegener's granulomatosis and microscopic polyangiitis. We investigated whether exposure to cyclophosphamide in patients with generalized vasculitis could be reduced by substitution of azathioprine at remission., Methods: We studied patients with a new diagnosis of generalized vasculitis and a serum creatinine concentration of 5.7 mg per deciliter (500 micromol per liter) or less. All patients received at least three months of therapy with oral cyclophosphamide and prednisolone. After remission, patients were randomly assigned to continued cyclophosphamide therapy (1.5 mg per kilogram of body weight per day) or a substitute regimen of azathioprine (2 mg per kilogram per day). Both groups continued to receive prednisolone and were followed for 18 months from study entry. Relapse was the primary end point., Results: Of 155 patients studied, 144 (93 percent) entered remission and were randomly assigned to azathioprine (71 patients) or continued cyclophosphamide (73 patients). There were eight deaths (5 percent), seven of them during the first three months. Eleven relapses occurred in the azathioprine group (15.5 percent), and 10 occurred in the cyclophosphamide group (13.7 percent, P=0.65). Severe adverse events occurred in 15 patients during the induction phase (10 percent), in 8 patients in the azathioprine group during the remission phase (11 percent), and in 7 patients in the cyclophosphamide group during the remission phase (10 percent, P=0.94 for the comparison between groups during the remission phase). The relapse rate was lower among the patients with microscopic polyangiitis than among those with Wegener's granulomatosis (P=0.03)., Conclusions: In patients with generalized vasculitis, the withdrawal of cyclophosphamide and the substitution of azathioprine after remission did not increase the rate of relapse. Thus, the duration of exposure to cyclophosphamide may be safely reduced., (Copyright 2003 Massachusetts Medical Society)

Background: Severe renal disease is a feature of anti-neutrophil cytoplasmic antibodies (ANCA)-associated small-vessel vasculitis. We evaluated patient and renal survival and prognostic factors in patients with PR3-ANCA associated vasculitis with renal involvement at diagnosis during long-term follow-up., Methods: Eighty-five patients were diagnosed between 1982 and 1996 and followed until 2001 allowing >or=5 years of follow-up. All patients were treated with prednisolone and cyclophosphamide. Univariate and multivariate analyses with patient and renal survival as dependent variables were performed., Results: Of the 85 patients in this study, 17 (20%) died within one year after diagnosis. Of the 25 patients (29%) who were dialysis dependent at diagnosis, two remained dependent and two again became dialysis dependent after less than one year; nine died early without renal recovery. Risk factors for death occurring within one year in univariate analysis (RR, 95% CI) were age>65 years (6.5, 1.6-13.7) and dialysis dependency at diagnosis (3.6, 1.0-13). Twenty patients died beyond one year during the long-term follow-up. Male gender (4.7, 1.6-10) and developing dialysis dependency during follow-up (4.1, 1.4-12) were associated with poor outcome. Risk factor for renal failure within one year was dialysis dependency at diagnosis (29, 3.6-229). Of 64 patients dialysis independent one year after diagnosis, 12 patients became dialysis dependent during follow-up. A renal relapse was strongly associated with development of renal failure in long-term follow-up (17, 3.5-81)., Conclusions: Early death and failure to recover renal function in PR3-ANCA associated vasculitis is associated with age> 65 years and dialysis dependency at diagnosis. Long-term renal survival is determined by renal relapses during follow-up only. Slow, progressive renal failure without relapses is rarely observed in this group.

Wegener's granulomatosis, microscopic polyangiitis, and Churg Strauss syndrome are forms of systemic vasculitides in which neutrophils and monocyte macrophages infiltrate the walls of small blood vessels, leading to destruction and occlusion. These diseases are associated with autoantibodies directed against granular components of neutrophils and monocytes, i.e., antineutrophil cytoplasmic antibodies (ANCA). The most common target antigens of ANCA in these vasculitides are myeloperoxidase (MPO) and proteinase 3 (PR3). ANCA-stimulated neutrophils injure endothelial cells, a process that is dependent upon the production of reactive oxygen radicals and the release of granular components such as MPO and PR3. Here we investigate whether a common functional MPO promoter polymorphism (-463 G/A) is associated with increased incidence and clinical aspects of ANCA-associated small vessel vasculitis. Genotyping was carried out for 142 patients with ANCA-associated small vessel vasculitis and 129 ethnically matched controls. The GG genotype was found to be associated with an increased risk for MPO-ANCA-associated vasculitis in females (86% GG, P = 0.045), but not males (64% GG, P = 1.0). Interestingly, the MPO A allele is associated with an increased incidence of relapses (P = 0.012) and an earlier age at diagnosis (P = 0.03) of MPO-ANCA-associated vasculitis. Both these associations are specific for MPO-ANCA and are not observed in patients with PR3-ANCA-associated vasculitis. These findings suggest that MPO expression levels influence the disease course of MPO-ANCA-associated vasculitis and further support the view that genetic factors are involved in the pathophysiology of this autoimmune disease., ((c) 2002 Elsevier Science (USA).)

Various forms of vasculitis may result in mesenteric ischaemia, ischaemic colitis or aneurysm formation in the aorta or intestinal blood vessels. Vasculitides may involve large- and/or medium-sized vessels, medium- and/or small-sized vessels, or small-sized vessels only. It is essential to differentiate between the different forms of vasculitis since diagnostic tests and therapies differ greatly. Gastrointestinal manifestations of vasculitis can generally be detected using angiography, digital subtraction angiography and/or magnetic resonance angiography (MRA). Various laboratory tests are helpful in establishing the diagnosis in patients in whom vasculitis is clinically suspected. In addition, the diagnosis should be confirmed using histology or angiography if possible. Treatment of vasculitis not caused by chronic infection consists of high dose corticosteroids and, in the case of polyarteritis nodosa or vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA), cyclophosphamide.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a relapsing-remitting disease, which is treated with corticosteroids (CS) in combination with cyclophosphamide. One of the major side-effects of this treatment is osteoporosis, which may result in the increased occurrence of fractures. In the present study we measured the prevalence of reduced bone mineral density (BMD) in a cross-sectional cohort of patients and correlated BMD findings with cumulative doses of CS and/or cyclophosphamide. BMD was measured by dual-energy X-ray absorptiometry (DXA) of the lumbar spine, radius and proximal femur between January 1998 and December 1999. Cumulative doses of CS and cyclophosphamide were calculated by chart review. Ninety-nine consecutive patients (48 men, 51 women) aged 55 +/- 16 years (mean +/- SD) were studied 50 months (median; range 0-400 months) after a diagnosis of ANCA-associated vasculitis had been made. Sixty-nine patients were treated with 10.7 g (median cumulative dose; range 0.4-67.2 g) of CS, and 88 patients were treated with 34.1 g (median cumulative dose; range 0.8-324.3 g) of cyclophosphamide. Fifty-seven percent of the patients had osteopenia (T-score: -1 to -2.5 SD), and 21% had osteoporosis (T-score: <-2.5 SD) at least at one site. Thirty-four of 37 (92%) postmenopausal women, 9 of 14 (64%) premenopausal women, and 34 of 48 (71%) men had either osteopenia or osteoporosis. The mean age- and sex-adjusted BMD (Z-score) of the proximal femur in men was found to be significantly lower than zero. Cumulative dose of CS therapy showed an inverse relation with Z-scores at the lumbar spine (p = 0.035) and proximal femur (p = 0.011). Cumulative dose of cyclophosphamide was not correlated with Z-scores. Osteopenia and osteoporosis are thus frequently observed in patients with ANCA-associated vasculities. However, only in men is the mean Z-score significantly lower than zero. Cumulative dose of CS therapy is significantly associated with bone loss at the spine and femur.

The role of ICs in ANCA-associated vasculitides remains controversial. The ANCA-associated vasculitides are described as being pauci-immune. We hypothesize that the absence of ICs is a result of an exaggerated inflammatory response caused by the presence of ANCAs. We present evidence indicating that ICs may play a role in the initiation or relapses of the disease. The nature of the involved antigen(s) is not yet known. Possible candidates are reviewed and include ANCA antigens, AECA antigens, and staphylococcal antigens.

High-dose corticosteroids in combination with cytotoxic drugs are universally accepted as the initial approach in vasculitides that are associated with anti-neutrophil cytoplasmic antibodies. Cyclophosphamide is the most effective cytotoxic drug and is used in more severe cases. Because cyclophosphamide has more severe short- and long-term side-effects than methotrexate, methotrexate is used in less severe cases. New prospects for the treatment of vasculitis include novel immunosuppressive agents (e.g. mycophenolate, 15-deoxyspergualin, and leflunomide), sequential chemotherapy (e.g. cyclophosphamide followed by azathioprine or cyclophosphamide followed by methotrexate), intravenous immunoglobulin, tumour necrosis factor-alpha directed therapy, anti-lymphocyte directed therapy (e.g. antithymocyte globulin or anti CD52/anti CD4 antibodies), anti-adhesion molecule directed therapy (e.g. anti-CD18 or intercellular adhesion molecule-1 antisense) or immunoablation using high-dose cytotoxic medication with or without stem cell rescue.

The ANCA-associated systemic vasculides are, in many cases, life-threatening conditions. Combined treatment with corticosteroids and cyclophosphamide has improved their prognosis considerably. Five year survival does, however, still not exceed 75%, due to the occurrence of treatment resistant cases and the severe adverse effects of this treatment regimen. In this review new treatment modalities are discussed. In cases resistant to conventional therapy high dose intravenous immunoglobulin and T-cell directed biologicals, that is anti-thymocyte globulin (ATG) and humanised monoclonal antibodies to CD4 and CDw52, may be effective. Also, TNF-directed treatment is being used. Less severe cases may benefit from methotrexate treatment instead of cyclophosphamide. For maintenance of remission azathioprine has been proven to be as effective as cyclophosphamide so preventing the toxicity of long-term cyclophosphamide treatment. Relapses may also be prevented by treatment based on changes in ANCA-titers or by elimination of Staphylococcus aureus carriage which is associated with relapsing disease in Wegener's Granulomatosis. Several of those new treatment modalities are now being tested in controlled studies by the European Vasculitis Study Group (EUVAS).

Antiproteinase 3- and antimyeloperoxidase-associated vasculitis. Wegener's granulomatosis, microscopic polyangiitis, and idiopathic pauci-immune necrotizing crescentic glomerulonephritis (NCGN) are strongly associated with antineutrophil cytoplasmic autoantibodies (ANCAs) directed against either proteinase 3 (anti-PR3) or myeloperoxidase (anti-MPO). This has led some investigators to prefer combining these diseases under the common heading of ANCA-associated vasculitides. However, it is increasingly recognized that there are characteristic differences between patients with anti-PR3 and those with anti-MPO-associated vasculitis. This review focuses on the clinical, histopathologic, and possibly pathophysiologic differences between anti-PR3- and anti-MPO-associated vasculitis. Although there is considerable overlap, the anti-PR3- and anti-MPO-associated vasculitides are each characterized by particular clinical and histopathological findings. Extrarenal organ manifestations and respiratory tract granulomas occur more frequently in patients with anti-PR3 than in those with anti-MPO. Anti-PR3-positive patients with NCGN generally have a more dramatic deterioration of their renal function compared with anti-MPO-positive patients. The term "ANCA-associated vasculitis" is considered as a useful concept in the presence of systemic vasculitis. Likewise, in the presence of vasculitis, the terms "anti-PR3-associated vasculitis" and "anti-MPO-associated vasculitis" are useful concepts.

Background: Objective scoring systems of disease activity and disease-associated damage have proven useful in the management of patients with systemic vasculitis., Patients and Methods: We used the recently designed Birmingham vasculitis activity score (BVAS; maximum score 63) and vasculitis damage index (VDI; maximum score 59) to assess initial activity and long-term damage, respectively, in ANCA positive patients from one center over a 3-year period. Thirty-two patients with ANCA vasculitis were identified and analyzed as an historic cohort. The median BVAS for all vasculitis patients at first presentation was 19 (range 6 - 36). Patients with Wegener's granulomatosis had a significantly higher total score and respiratory BVAS score compared to the 15 with microscopic polyangiitis. The majority of patients received standard cyclophosphamide/steroid treatment., Results: At the end of follow-up (mean 24.9 months), 4 patients had died; all patients had evidence of permanent organ damage. The median total VDI score at last follow-up was 4.0 (range 0-11), with no differences between patients with Wegener's granulomatosis and microscopic polyangiitis. The VDI was not associated with the number of relapses. A high initial BVAS was found to correlate with a later high vasculitis damage index (r = 0.56). Initial renal or respiratory involvement was also associated with longterm damage in the same organ system., Conclusion: Although mortality from ANCA-associated vasculitis has decreased, morbidity remains a common problem. High early-disease activity may identify patients at high risk of long-term organ damage, allowing more effective individualized therapy. This hypothesis requires validation in a prospective, controlled study.

Anti-neutrophil cytoplasmic antibodies, as detected by indirect immunofluorescence, have limited diagnostic significance as they occur in a variety of inflammatory disorders. The presence of antibodies to defined target antigens of anti-neutrophil cytoplasmic antibodies, that is proteinase 3 and myeloperoxidase, is, however, highly specific for one of the systemic vasculitides, in particular Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and idiopathic pauci-immune necrotizing crescentic glomerulonephritis. In general, anti-proteinase-3-positive patients show more widespread organ involvement, more granuloma formation, and a more severe initial course of their renal lesions than anti-myeloperoxidase-positive patients; however, there is considerable overlap, and either antibody specificity may be found in the different clinical syndromes. In vitro, anti-neutrophil cytoplasmic antibodies are able further to activate pre-activated neutrophils and monocytes, which can result in endothelial damage. A direct activating effect of anti-neutrophil cytoplasmic antibodies on endothelial cells has been suggested, but those studies should be confirmed. In vivo, experimental data support a pathogenetic role for anti-neutrophil cytoplasmic antibodies, particularly anti-myeloperoxidase, but besides anti-neutrophil cytoplasmic antibodies a second pro-inflammatory stimulus seems to be required to induce lesions. Whether anti-neutrophil cytoplasmic antibodies can be a direct target for treatment has still to be proved. Current immunosuppressive treatment regimens for the anti-neutrophil cytoplasmic antibody-associated vasculitides are, however, unsatisfactory because of side-effects, that is opportunistic infections and malignancies. New treatment regimens, based on new pathogenetic concepts, are currently being tested.

Multiple risk factors are involved in susceptibility to vasculitis. Inherited determinants may increase the risk but are insufficient to induce the disease. Environmental factors, such as infections, are important modulators and probably trigger the disease in most cases. One of the possible triggers may be a bacterial superantigen (SAg). SAgs may activate autoreactive T cells that mediate autoimmune vessel wall destruction. Furthermore, SAgs may activate autoreactive B cells to produce autoantibodies that are involved in the pathophysiology of vasculitis, such as antineutrophil cytoplasmic autoantibodies or anti-endothelial cell antibodies. In patients with Kawasaki disease, Wegener's granulomatosis, and infection-related forms of vasculitis, SAg-producing microorganisms have regularly been found. Activation of circulating T cells and skewing of the T-cell repertoire have been reported in most forms of vasculitis. In the past year, for the first time, patients were described in which T-cell receptor V beta expansions were documented simultaneously with the typing of the microbial SAgs, providing evidence that the observed changes in the T-cell repertoire could be caused by these bacterial SAgs. In the future, elucidation of the immunologic mechanisms by which SAgs may play a role in the pathophysiology of vasculitis will provide more effective methods for the treatment of vasculitis.