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ANCA vasculitis is a small-vessel vasculitis (SVV) resulting in inflammation of small- and medium-sized blood vessels. Since the initial description of SVV, there have been tremendous advances in our understanding of its pathogenesis. Over the last decade, we have made significant progress in understanding the pathogenesis and improving the treatment and prognosis of patients with ANCA vasculitis. Patient and renal survival has improved, and treatment is moving toward individualizing care, minimizing severe adverse events, and preventing relapse. This review focuses on treatment updates in ANCA vasculitis, duration of therapy, and management of relapses. We also describe the existing treatment protocols used at our institution.

Background: Antineutrophil cytoplasmic antibodies (ANCAs) have been reported to occur in 7% to 10% of patients with idiopathic pulmonary fibrosis (IPF), but their clinical relevance remains unclear. The aim of this study was to estimate the prevalence of ANCAs in a North American population with IPF and evaluate their clinical significance., Methods: This was a retrospective study of two independent cohorts of patients diagnosed with IPF at the University of California San Francisco (discovery cohort) and the University of Chicago (replication cohort). Myeloperoxidase (MPO) and proteinase 3 (PR3) ANCAs were measured in all patients. Prevalence and associations of ANCAs with clinical characteristics and transplant-free survival were evaluated., Results: A total of 14 of 353 (4.0%; 95% CI, 2.2-6.5) and 20 of 392 (5.1%; 95% CI, 3.1-7.8) patients with IPF were positive for ANCAs at the time of diagnosis in the discovery and replication cohorts, respectively. Among those positive for MPO antibodies, two of six (33%) in the discovery cohort and three of 12 (25%) in the replication cohort developed vasculitis. None of the patients who were PR3-positive developed vasculitis. Patients who were ANCA-positive were more likely to be women than patients who were ANCA-negative, and were more likely to have some ground-glass opacities on CT scan. In the combined cohort of 745 patients, median transplant-free survival was not significantly different in patients who were ANCA-positive vs ANCA-negative (P = .57)., Conclusions: ANCA positivity is uncommon in North American patients with IPF and not associated with baseline disease severity or transplant-free survival; however, a significant proportion of patients who are MPO-positive with IPF develop clinical vasculitis., (Copyright © 2019 American College of Chest Physicians. All rights reserved.)

ANCA mediated vasculitis mainly occur between the fourth and fifth decade of life; therefore, it is very uncommon to see pregnant patients with the disease. Vasculitis may affect significantly the course of pregnancy; in turn pregnancy can change the course of vasculitis. We report a 20 years old woman with ANCA-mediated renal vasculitis lasting 10 years who consulted with a pregnancy of 15 weeks. She was in remission and had amenorrhea attributed to ovarian toxicity due to cyclophosphamide. Pregnancy had an uneventful course with spontaneous delivery at the 37th week, giving birth to a healthy newborn. Proteinuria increased during the course of pregnancy with a mild deterioration of kidney function. During the year after delivery, she had nephrotic proteinuria and a worsening of renal function.

A 21-year-old woman, with a background of asthma, presented to medical admissions ward, with diarrhoea and vomiting; the clinical picture during her admission evolved to include acute shortness of breath, seizures, unsteadiness, low mood and apathy. Investigations revealed pericardial, pleural effusions, myocardial infiltration and vasculitic lesions in the brain. Although serological tests for autoantibodies were negative, an eventual diagnosis of eosinophilic granulomatosis with polyangiitis, formerly known as Churg-Strauss syndrome, was performed based on the clinical picture. The multiorgan involvement meant that the initial diagnosis and effective management required multidisciplinary input from cardiology, neurology, rheumatology, psychiatry, immunology and occupational and physiotherapy., (2015 BMJ Publishing Group Ltd.)

We report the case of a 69-year-old male patient who was admitted for fever, dry cough, recurrent sinusitis with epistaxis, anorexia with weight loss of 20 kg over a 3-month period, myalgia, and mononeuritis multiplex. He was diagnosed with pANCA/anti-MPO associated vasculitis and rectal adenocarcinoma. The tumor was treated by surgical resection. Recurrence of vasculitis occurred during steroid tapering which prompted us to add Mycophenolate mofetyl. A complete remission was achieved. We conclude that in the present case the vasculitis was an independent disease, not a paraneoplastic phenomenon. We discuss the value of different ANCA serologies for diagnostics and follow-up, the epidemiology of vasculitis associated with malignancy, and the concept of vasculitis as a paraneoplastic syndrome.

Antineutrophil cytoplasmic autoantibodies (ANCAs) are the probable cause of a distinct form of vasculitis that can be accompanied by necrotizing granulomatosis. Clinical and experimental evidence supports a pathogenesis that is driven by ANCA-induced activation of neutrophils and monocytes, producing destructive necrotizing vascular and extravascular inflammation. Pathogenic ANCAs can originate from precursor natural autoantibodies. Pathogenic transformation might be initiated by commensal or pathogenic microbes, legal or illegal drugs, exogenous or endogenous autoantigen complementary peptides, or dysregulated autoantigen expression. The ANCA autoimmune response is facilitated by insufficient T-cell and B-cell regulation. A putative pathogenic mechanism for vascular inflammation begins with ANCA-induced activation of primed neutrophils and monocytes leading to activation of the alternative complement pathway, which sets in motion an inflammatory amplification loop in the vessel wall that attracts and activates neutrophils with resultant respiratory burst, degranulation, extrusion of neutrophil extracellular traps, apoptosis and necrosis. The pathogenesis of extravascular granulomatosis is less clear, but a feasible scenario proposes that a prodromal infectious or allergic condition positions primed neutrophils in extravascular tissue in which they can be activated by ANCAs in interstitial fluid to produce extravascular necrotizing injury that would initiate an innate granulomatous inflammatory response to wall off the necrotic debris.

A 16-year-old female with fever was admitted to our hospital. On admission, her serum IgM antibody against Epstein-Barr virus (EBV) was positive. Then, the disease aggravated and acute kidney injury occurred gradually. Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) was confirmed by serum test and kidney biopsy. The patient was treated with oral methylprednisolone. Along with the disappearance of the IgM anti-EBV antibody, the AAV also relieved without relapse during follow-up for half a year. Although a previous study indicated that there was a high positive rate of ANCA in the sera positive for IgM antibodies to EBV and EBV infection might trigger the relapse of AAV, this is the first case of incipient AAV associated with acute EBV infection. One possible explanation might be that EBV infection stimulated the production of ANCA.

We present a 47-year-old Caucasian fire fighter who developed multisystem organ failure in the setting of a positive antineutrophil cytoplasmic autoantibody (myeloperoxidase) as well as confirmed Rocky Mountain spotted fever by skin biopsy PCR. This case provided a diagnostic challenge, a rare association of a Rickettsia infection and autoimmune vasculitis as well as a unique management approach.

The transformation of the antineutrophil cytoplasmic antibody (ANCA) specificity in the absence of specific drug treatment has not been reported in the literature. A few studies have suggested changes in the epitopes recognized by the ANCAs. We describe two patients who switched from myeloperoxidase-positive to PR3 (proteinase 3)-positive ANCA during the course of their disease process and subsequently remained unchanged. One patient developed ulcerative colitis following the appearance of PR3-ANCA while the other remains quiescent. Regular follow-up and close monitoring of ANCA specificity are essential. A change of specificity may indicate the development of a new ANCA-related disease.

Objective: To report the first case of concomitant drug- and infection-induced antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) in a patient treated with propylthiouracil (PTU) and suffering from tuberculosis., Presentation and Intervention: A 28-year-old woman with PTU-treated hyperthyroidism presented with fever, purpura, pulmonary cavitations and ANCA to myeloperoxidase, bactericidal/permeability-increasing protein (BPI), proteinase-3 and elastase. Skin histopathology confirmed vasculitis. However, sputum examination revealed Mycobacterium tuberculosis. Remission was achieved after PTU withdrawal and treatment with antituberculosis drugs., Conclusion: Our case confirmed that BPI-ANCA are elevated in active tuberculosis. Multispecific ANCA were helpful for the diagnosis of concomitant PTU- and M. tuberculosis-induced AAV., (Copyright © 2012 S. Karger AG, Basel.)

Diffuse alveolar hemorrhage (DAH) in primary and secondary vasculitis occurs when capillaritis is present. The diagnosis of DAH is considered in patients who develop progressive dyspnea with alveolar opacities on chest imaging (with density ranging from ground glass to consolidation) that cannot be explained otherwise. Hemoptysis, a valuable sign, is often absent. A decline of blood hemoglobin level over a few days without hemolysis or any hemorrhage elsewhere should be an alert for DAH. Bronchoalveolar lavage, retrieving bright red fluid, is the best diagnostic clue. Lung biopsy is not recommended. A search for anti-neutrophil cytoplasmic autoantibodies (ANCAs) is mandatory. Once DAH is diagnosed and hemodynamic as well as infectious causes have been excluded, ANCA-associated vasculitis is taken into account (mainly microscopic polyangiitis or Wegener granulomatosis, and, exceptionally, Churg-Strauss syndrome). Drug-induced DAH, especially antithyroid drugs such as propylthiouracil may be coupled with ANCA. Isolated DAH with capillaritis with or without ANCA is rare. DAH in systemic lupus erythematosus is either associated or not with capillaritis. Treatment of DAH should target the underlying disorder. In the primary vasculitides, corticosteroids and immunosuppressants, especially cyclophosphamide, are the mainstay of therapy, but plasma exchange, particularly in severe DAH, is the rule, although evidence of its effectiveness is awaited., (© Thieme Medical Publishers.)

Vasculitides that affect the lung represent a diverse group of diseases with various systemic clinical manifestations, and include microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis), Churg-Strauss syndrome (CSS), and anti-glomerular basement membrane (anti-GBM) disease (Goodpasture syndrome). The etiologies of these diseases remain largely unknown. Although the pathogenic mechanisms of each differ, these diseases overlap by the presence of anti-neutrophil cytoplasmic autoantibodies in the vast majority of patients with MPA and GPA, and a substantial minority of patients with CSS and anti-GBM disease. This article reviews the current understanding of the pathogenesis of these four disease entities., (© Thieme Medical Publishers.)

Purpose of Review: Antineutrophil cytoplasmic autoantibodies (ANCAs) are associated with vasculitis. Current therapy involves administration of toxic therapy that is not optimally effective. This review will summarize evidence for the pathogenicity of ANCAs, which will suggest possible strategies for improving treatment., Recent Findings: Pauci-immune small vessel vasculitis is associated with antibodies against myeloperoxidase (MPO-ANCA) and proteinase 3 (PR3-ANCA). One research group has reported a high frequency of autoantibodies against lysosomal-associated membrane protein 2 (LAMP-2) in patients with MPO-ANCA or PR3-ANCA. Epigenetic dysregulation appears to be the basis for increased MPO and PR3 neutrophil gene expression in ANCA disease. Release of neutrophil extracellular traps may be involved in initiating the ANCA autoimmune response and causing vessel injury. Generation of C5a by alternative pathway activation is involved in pathogenesis in mouse models. Intervention strategies in mice that target antigens, antibodies and inflammatory signaling pathways may translate into novel therapies. Animal models of LAMP-ANCA and PR3-ANCA disease have been proposed. Molecular mimicry and responses to complementary peptides may be initiating events for ANCAs. T cells, including regulatory T cells, have been implicated in the origin and modulation of the ANCAs, as well as in the induction of tissue injury., Summary: Our basic understanding of the origins and pathogenesis of ANCA disease is advancing. This deeper understanding already has spawned novel therapies that are being investigated in clinical trials. This brief review shows that there are more questions than answers, and new questions are emerging faster than existing questions are being answered.

We report the case of a 59-year-old woman who presented with a persistent papular and nodular cutaneous eruption and new-onset asthma, with normal renal function but persistent haematuria and proteinuria. Investigations revealed eosinophilia, both antineutrophil cytoplasmic antibodies and antiglomerular basement membrane antibodies on serological testing (double-positive vasculitis), and a focal necrotizing glomerulonephritis on renal biopsy. Histological examination of a skin biopsy showed a dense neutrophilic infiltrate with focal fibrinoid necrosis and few eosinophils. The clinical and pathological features suggested a double-positive vasculitis/Churg-Strauss overlap syndrome presenting with a predominantly neutrophilic dermatosis. Specific cutaneous features in patients with double-positive vasculitis have not been documented previously. The patient has responded extremely well to immunosuppressive treatment and her disease is currently in remission.

Vasculitides associated with serum positivity for anti-neutrophil cytoplasmic antibodies (ANCAs) that affect small- to medium-sized vessels are commonly known as ANCA-associated vasculitis (AAV) and include Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. Evidence derived from both in vitro studies and recent animal models points to a pathogenic role of ANCAs in AAV. In 2002, the first in vivo breakthrough in the pathogenesis of ANCAs showed that mouse ANCAs against myeloperoxidase (MPO) led to intrinsic pauci-immune renal vasculitis in mice. In 2004, a report using both in vitro and in vivo studies proposed that proteinase 3 (PR3)-directed autoimmunity involved the complementary peptide of PR3 (cPR3), which is encoded by the antisense strand of the PR3 gene. The last breakthrough came in October 2008 with a previously undescribed molecular explanation for the origin and development of injury in pauci-immune renal vasculitis, with potential clinical implications. This report showed that infection by fimbriated bacteria may trigger cross-reactive autoimmunity to a previously characterized ANCA antigen, lysosomal membrane protein-2, which is contained in the same vesicles that harbor MPO and PR3. Infection by fimbriated bacteria resulted in the production of autoantibodies, which activated neutrophils and killed human microvascular endothelium in vitro and caused renal vasculitis in rats. Although the evidence for a pathogenic role of ANCAs, mainly MPO-ANCAs, is striking, various questions remain unanswered. Understanding the key pathogenic mechanisms of AAV may provide a safer, more rational therapeutic approach than the traditional (ie, corticosteroids and immunosuppressants) treatment strategy.

Context: The clinical characteristics of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis caused by antithyroid drugs are still unclear because most reports describe only a small number of patients., Objective: The objective was to analyze a large number of patients with MPO-ANCA-associated vasculitis to determine the time of onset, the drug and dose taken, the clinical symptoms, the relationship between the clinical symptoms and the MPO-ANCA titer, and the incidence., Design: We analyzed 92 patients in whom the adverse reaction of MPO-ANCA-associated vasculitis was reported to Chugai Pharmaceutical, a company that markets antithyroid drugs., Results: Of the 92 patients, 41 (44.6%) had single-organ failure, 32 (34.8%) had two-organ failure, 13 (14.1%), had three-organ failure, and two (2.2%) had four-organ failure. The number of organs involved was unknown in the other four patients (4.3%). The median time of onset was 42 months (range, 1-372 months) after starting drug treatment. The median dose at onset of MPO-ANCA-associated vasculitis was 15 mg/d (range, 2.5-45 mg/d) for methimazole and 200 mg/d (50-450 mg/d) for propylthiouracil. The severity and number of organs involved were not correlated with the MPO-ANCA titer. The incidence was between 0.53 and 0.79 patients per 10,000, and the ratio of the estimated incidences for methimazole and propylthiouracil was 1:39.2., Conclusions: The time of onset of MPO-ANCA-associated vasculitis and the dose at onset varied. The severity and number of organs involved were not correlated with the MPO-ANCA titer, indicating a need for vigilance even when the MPO-ANCA titer is only weakly positive.

Anti-neutrophil cytoplasmic autoantibodies (ANCA) with a specificity for myeloperoxidase or proteinase 3 are closely associated with small vessel vasculitides (SVV). In vitro, ANCA activate primed neutrophils to release toxic substances that destroy endothelial cells, suggesting a pathogenic role for these autoantibodies in disease development. However, to study the complex interplay between ANCA, neutrophils, and the local environment in vivo, animal models are required. Here, we will review the animal models developed for ANCA-SVV and discuss how these models have been applied to study ANCA-SVV pathogenesis. In addition, some directions for future research pertaining to unresolved issues relevant for the pathogenesis and immunogenesis of ANCA-SVV are proposed.

Much has been learnt over the last 30 years to optimize the use of immunosuppressive and glucocorticoid therapies that has allowed the publication of treatment guidelines. However, major unmet needs remain in the treatment of ANCA-associated vasculitis (AAV) and include refractory disease, only partial efficacy and toxicity of current drugs and the need for long-term regimens. Newer therapies, including mycophenolate mofetil, leflunomide and rituximab, are providing a real opportunity for improved outcomes of AAV in the future. The development of therapy has been facilitated by international clinical research networks but delayed by the complexities of studying an uncommon, multi-system disease.

Because of their multiple overlapping clinical characteristics, Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) have increasingly been conceptualized as different expressions of a unique anti-neutrophil cytoplasm antibodies (ANCA)-associated vasculitis (AAV) disease spectrum. However, this continuum theory remains hindered by uncertainty surrounding a potentially common etiology. This review sheds light on our current understanding of the epidemiology of WG and MPA with the aim of weighing the evidence supporting whether or not these two vasculitis forms are distinct diseases. At present, some epidemiological evidence exists that WG and MPA might correspond to mere variants of a single AAV entity.

The inflammation of blood vessel walls that is associated with autoimmune disorders characterized by anti-neutrophil cytoplasm antibodies (ANCA) represents dysregulation of normal physiological processes, whereby neutrophils recruited to the vessel wall by cytokine-activated endothelium show destructive behaviours that initiate damage with endothelial apoptosis and denudation. Anti-endothelial cell antibodies may also help to focus and escalate injury. Understanding the molecular mechanisms underlying the interplay between ANCA, aberrant neutrophil behaviour and vascular damage will allow development of more focused therapies.

The pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is unknown but is most consistent with a primary role for neutrophils in the acute injury. Thus, neutrophils are cardinal cells in the pathophysiological process in AAV because they are both effector cells responsible for endothelial damage and targets of autoimmunity. In addition, because of their capacity to synthesize a wide variety of cytokines and chemokines, neutrophils can be considered as important modulators of the inflammatory and potentially of the autoimmune process. ANCA directed against two main autoantigens, namely proteinase 3 and myeloperoxidase, are likely to play a modulatory role in the inflammatory process. Interestingly, neutrophils are an important source of lymphocyte stimulator (BLy), a cytokine that plays a fundamental role in B-cell physiology, including differentiation, proliferation and immunoglobulin production. The issue of B-cell activation and/or dysregulation in vasculitis will be discussed.

Renal involvement in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is characterized by focal segmental crescentic and/or necrotizing glomerulonephritis. Here, we report the case of a 66-year-old woman showing myeloperoxidase (MPO)-ANCA positivity and mononeuritis multiplex whose kidney biopsy revealed severe and diffuse tubulointerstitial nephritis despite the fact that crescentic necrotizing glomerulonephritis was focal. The mechanism of tubulointerstitial injury in ANCA-associated vasculitis remains unclear. Further studies are necessary to confirm the relationship between diffuse tubulointerstitial nephritis and ANCA-associated vasculitis.

Aim: The prevalence of anti-endothelial cell autoantibodies (AECA) in patients with anti-neutrophil cytoplasmic autoantibody-associated systemic vasculitis (ASV) has been reported by several groups with conflicting results ranging from 8% to 100%. Types of substrate cells used for AECA testing partially explain this variation. Endothelial cells from kidney origin have been reported to be predominant in AECA binding. Therefore, we investigated AECA prevalence using a human glomerular endothelial cell line compared with primary human umbilical vein endothelial cells, which have frequently been used for AECA detection., Methods: Sera from 43 ASV patients (29 Wegener's granulomatosis (WG), 14 microscopic polyangiitis (MPA)) with active disease were assessed for AECA positivity using cell-based enzyme-linked immunosorbent assay. Forty serum samples from healthy controls were tested in parallel. To evaluate endothelial activation levels, soluble intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 were measured with capture enzyme-linked immunosorbent assay., Results: The AECA were detected in 4 of 29 WG patients (14%), but none of 14 MPA patients was positive for AECA using glomerular endothelial cell as a substrate, whereas AECA were positive in 10% of WG patients and 14% of MPA patients on human umbilical vein endothelial cells. No significant differences were found between ASV patients and controls in AECA test. Serum levels of vascular cell adhesion molecule-1 and soluble intercellular cell adhesion molecule-1 in ASV patients were significantly higher than in controls. However, there were no differences between AECA-positive and -negative patients for both of the activation markers., Conclusion: The AECA, directed against glomerular endothelial cells, have a low prevalence in ASV patients with active disease and are not correlated with endothelial activation.

Summary: Small-vessel vasculitides associated with anti-neutrophil cytoplasmic auto-antibodies (ANCA) are severe systemic diseases that may affect any organ. Increasing evidence from clinical, animal and in vitro studies indicates that ANCA are causally involved in disease pathogenesis mainly through activation of neutrophils resulting in endothelial cell injury. Recent studies suggest a previously unsuspected but crucial role for alternative pathway complement activation in ANCA disease pathogenesis. In this brief review, we will discuss the evidence for complement system activation in ANCA-associated vasculitides and propose a working model that links ANCA, neutrophils and complement activation in causing an inflammatory amplification loop that may explain the severe leukocytoclastic inflammation that is typical for ANCA-associated vasculitis.

A recent development in the field of vasculitis is the increasing recognition that certain medications such as propylthiouracil can induce anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). This review focuses on the data on causal drugs, possible pathogenesis, clinical description, diagnosis, treatment and prognosis of patients with drug-induced AAV. The pathogenesis of drug-induced AAV might be multifactorial. The clinical manifestations are similar to those of primary AAV, but ANCA with multi-antigenicity may help to differentiate it from primary AAV. The diagnosis of drug-induced AAV is based on the temporal relationship between clinically evident vasculitis and administration of the offending drugs, and excluding medical conditions that mimic vasculitis and other definable types of vasculitis. After the diagnosis of drug-induced AAV was made, the offending drugs should be withdrawn immediately, and appropriate immunosuppressive therapy should be administered only for patients with vital organ involvement. The duration of immunosuppressive therapy should be much shorter than that in primary AAV and long-term maintenance therapy might not be necessary. The prognosis of patients with drug-induced AAV is good as long as the offending drug is discontinued in time.

Antineutrophil cytoplasmic autoantibody (ANCA)-associated systemic vasculitis (AASV) constitutes a group of primary vasculitides associated with antineutrophil cytoplasmic autoantibodies, which are either directed to proteinase-3 or myeloperoxidase. In contrast to other forms of vasculitis, immuohistologic evaluation of affected tissues in patients with AASV, particularly the kidneys, demonstrated an absence or paucity of immunoglobulins, which could suggest involvement of cell-mediated injury in this disorder. Several studies have shed light on T cell-mediated immune responses playing a role in the pathophysiology of AASV. Imbalance of CD4(+) T-cell subsets has been demonstrated in the peripheral blood of patients with AASV. The trigger that leads to this imbalance remains to be defined, but clinical evidence shows that nasal carriage of Staphylococcus aureus constitutes a risk factor for disease exacerbation. Recent data show that superantigens and peptidoglycans from these Gram-positive bacteria can induce skewing of T-cell responses towards pathogenic interleukin (IL)-17-producing T-helper cells (Th17). Overproduction of IL-17 in response to this infection might aggravate inflammatory responses and contribute to the production of autoantibodies as well as to granuloma formation and tissue injury in patients with AASV. Next to Th17 cells, memory CD4(+) T cells with the effector cytotoxic phenotype (CD4(+) T(EM)) have also been demonstrated to constitute a major effector pathway of tissue injury in patients with pauci-immune glomerulonephritis. Therefore, future perspectives for treatment of AASV could be built on neutralization of IL-17 and depletion of CD4(+) T(EM) cells.

Antineutrophil cytoplasmic antibodies (ANCA) are predominantly IgG autoantibodies directed against constituents of primary granules of neutrophils and monocytes lysosomes. Although several antigenic targets have been identified, those ANCA directed to proteinase 3 or myeloperoxidase are clinically relevant, whereas the importance of other ANCA remains unknown. Both are strongly associated with small vessel vasculitides, the ANCA-associated vasculitides, which include Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome, and the localised forms of these diseases (eg, pauci-immune necrotising and crescentic glomerulonephritis). ANCA is a useful serological test to assist in diagnosis of small-vessel vasculitides. 85-95% of patients with Wegener's granulomatosis, microscopic polyangiitis, and pauci-immune necrotising and crescentic glomerulonephritis have serum ANCA. ANCA directed to either proteinase 3 or myeloperoxidase are clinically relevant, yet the relevance of other ANCA remains unknown. Besides their diagnostic potential, ANCA might be valuable in disease monitoring. In addition, data seem to confirm the long-disputed pathogenic role of these antibodies. There is increasing evidence that myeloperoxidase-ANCA are directly involved in the pathogenesis of necrotizing vasculitis. This is less clear for proteinase 3-ANCA, markers for Wegener's granulomatosis. With respect to proteinase 3-ANCA, complementary proteinase 3, a peptide translated from the antisense DNA strand of proteinase 3 and homologous to several microbial peptides, may be involved in induction of proteinase 3-antineutrophil cytoplasmic autoantibodies.

A 50-year-old man with chronic HCV infection had been received the injections of 12MU of Consensus-Interferon (C-IFN) three times a week in a previous hospital. Six months later, C-IFN therapy was terminated because of fever and massive ascites. Diuretics and antibiotics had not been effective against these symptoms. In the meantime, skin symptoms of purpura and giant ulcers in the extremities developed, and he was transferred to our hospital. Because skin biopsy revealed vasculitis and serum MPO-ANCA was positive, the diagnosis of ANCA associated vasculitis was made. Methylpredonizoron pulse therapy improved skin symptoms and massive ascites, and the skin ulcers eventually disappeared. ANCA is suggested to be responsible for this rare complication.

The case is reported of a 68-year-old man with perinuclear anti-neutrophil cytoplasmic antibody (pANCA)-associated glomerulonephritis who developed antibodies to glomerular basement membrane (anti-GBM) resulting in end stage renal failure. His pANCA titre on admission was 1:1024 IgG and he was anti-myeloperoxidase positive. A renal biopsy showed advanced sclerosing necrotising glomerulonephritis consistent with a pauci-immune ANCA-positive glomerulonephritis. He was treated with steroids and cyclophosphamide. His serum creatinine profile improved. He had a relapse of disease 16 months later, which was successfully treated. After a further 16 months, he presented with acute renal failure (creatinine 1060 micromol/l). His pANCA titre on admission was 1:64 IgG. This was treated as a further relapse of ANCA-positive vasculitis. He became oliguric and his haemoglobin concentration fell. Eight days after admission, he was found to be strongly positive for anti-GBM (138 U/ml). Despite receiving cyclophosphamide, steroids and plasma exchange, he remained dialysis-dependent.

Wegener's granulomatosis (WG) is a necrotizing granulomatous vasculitis involving the nose, paranasal sinuses, lungs, and kidneys. There are two types of WG-systemic, which is characterized by focal segmental necrotizing glomerulonephritis and limited in which the kidneys are spared. Without proper immunosuppression, WG can be aggressive and often fatal. There are very few reports on WG presenting as parotitis and lacrimal gland involvement. We report a lady who presented recurrent parotitis, focal segmental glomerulosclerosis, and orbital cellulitis, in whom the final diagnosis was revealed after an open lung biopsy.

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.

Despite advances in the diagnosis and treatment of the antineutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitides, renal morbidity is common. End-stage renal disease occurs in up to 20% of patients with these diagnoses, which include Wegener's granulomatosis and microscopic polyangiitis. As the mortality of patients with ANCA-associated vasculitis continues to improve, our ability to address the consequences of renal failure in this patient population becomes paramount. Renal transplantation is an important therapeutic option for these patients. Graft and patient survival rates among patients with ANCA-associated vasculitis are comparable to those observed in nondiabetic patients. This review summarizes our current knowledge of indications and contraindications for renal transplantation in these patients, the recurrence of vasculitis after transplantation and the impact of posttransplant immunosuppression on the clinical course of these patients.

Microscopic polyangiitis was initially considered a "microscopic" form of polyarteritis nodosa and was not definitively distinguished from it until the Chapel Hill nomenclature (1994). Microscopic polyangiitis is a systemic necrotizing vasculitis of small vessels. Its typical clinical manifestations are rapidly progressive glomerulonephritis and alveolar hemorrhage. Other possible symptoms resemble those encountered in polyarteritis nodosa. Microscopic polyangiitis belongs to the group of ANCA-associated vasculitides, and 75-80% of patients have pANCA to myeloperoxidase (MPO). Anti-MPO ANCA pathogenicity has been established in animal models, and a recent report describes transplacental transfer of these antibodies in humans, resulting in pulmonary hemorrhage and renal involvement in the newborn. Patients with no poor prognostic factors, as defined by a five-factor score, can be treated with corticosteroids alone, with immunosuppressants added only in case of treatment failure. Patients with one or more poor prognostic factors must receive a combination of corticosteroids and immunosuppressants, mainly intravenous pulsed cyclophosphamide, with plasma exchange as an adjuvant therapy for those with severe renal involvement. Once remission is achieved, maintenance therapy can replace cyclophosphamide by azathioprine or methotrexate. Biological therapies are under evaluation. The remission rate is above 80% with these regimens, and the relapse rate is around 30% at 5 years, lower than for Wegener's granulomatosis.

Recent studies provided new insights into the pathogenesis of vasculitides associated with antineutrophil cytoplasm antibodies (ANCA). They yield more information about the pathogenic role of ANCA, the initiation of the immune response against proteinase 3, the expression of ANCA target antigens on neutrophil surfaces, endothelial damage and the mechanisms of vasculitis associated with propylthiouracil. The pathogenic role of antimyeloperoxidase antibodies has been established in vitro and in vivo in animal models and in human. A pathogenic role for antiproteinase 3 antibodies has not yet been clearly established in vivo although it is well documented in vitro.

Biological therapies enable us to apply highly selective targeting components to modulate the immune response. Until now, a few controlled studies investigated the efficacy of TNF-alpha blocking agents in systemic vasculitis have been carried out, but, in general, they were falling short of expectations. However, there is conducive evidence that TNF-alpha blockers are advantageous in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis, at least in selected disease stages. Likewise, although the efficacy of the monoclonal CD20 antibody rituximab in ANCA-associated vasculitis is obvious, the effect on predominantly granulomatous disease activity in Wegener's granulomatosis is less clear. In addition, interferon-alpha is used for induction treatment particularly in Churg-Strauss syndrome. Even though the effectiveness and safety of short-term administration was confirmed by case series, severe side effects after long-term treatment relativized the initial results. This review presents the recent data on the use of biologicals in vasculitis and appraises the knowledge in the clinical context.

Purpose of Review: This review focuses on recent advances in the diagnosis, pathogenesis and treatment of antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis., Recent Findings: Antineutrophil cytoplasmic autoantibodies are closely associated with Wegener's granulomatosis and microscopic polyangiitis. Within the Churg-Strauss syndrome, antineutrophil cytoplasmic autoantibodies, mostly directed towards myeloperoxidase, characterize patients with glomerulonephritis and small-vessel vasculitis. There is increasing evidence that myeloperoxidase-antineutrophil cytoplasmic autoantibodies are directly involved in the pathogenesis of necrotizing vasculitis. This is less clear for proteinase 3-antineutrophil cytoplasmic autoantibodies, markers for Wegener's granulomatosis. With respect to proteinase 3-antineutrophil cytoplasmic autoantibodies, complementary proteinase 3, a peptide translated from the antisense DNA strand of proteinase 3 and homologous to several microbial peptides, may be involved in induction of proteinase 3-antineutrophil cytoplasmic autoantibodies. Currently, various controlled trials have been initiated. Methotrexate has been shown to be effective for induction of remission in locoregional Wegener's granulomatosis. Other trials are underway., Summary: Apart from its diagnostic potential, antineutrophil cytoplasmic autoantibodies, particularly myeloperoxidase-antineutrophil cytoplasmic autoantibodies, are directly involved in the pathogenesis of the associated vasculitides. New treatment modalities, supposedly more efficacious and less toxic than daily oral cyclophosphamide, are being tested in randomized controlled trials.

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.)

Clinical and experimental evidence indicate that ANCA cause pauci-immune necrotizing and crescentic glomerulonephritis (NCGN) and systemic small vessel vasculitis in humans. One of the major target antigens for ANCA is myeloperoxidase (MPO). An animal model that closely resembles the human disease is induced by intravenous injection of anti-MPO IgG into mice. The likely primary pathogenic targets for the anti-MPO IgG are circulating neutrophils and monocytes, although other cells have been implicated, including endothelial cells and epithelial cells. Herein is reported a new model for anti-MPO-mediated glomerulonephritis and vasculitis that further documents the pathogenic potential of ANCA and demonstrates that bone marrow (BM)-derived cells are sufficient targets to cause anti-MPO disease in the absence of MPO in other cell type. MPO knockout (Mpo-/-) mice that were immunized with mouse MPO were exposed to irradiation and received a transplant of Mpo+/+ or Mpo-/- BM. Engraftment in mice with circulating anti-MPO resulted in development of pauci-immune NCGN in all mice and pulmonary capillaritis and splenic necrotizing arteritis in some. Anti-MPO IgG also was introduced intravenously into chimeric mice by transplantation of Mpo+/+ BM into irradiated Mpo-/- mice or Mpo-/- BM into irradiated Mpo+/+ mice. Chimeric Mpo-/- mice with circulating MPO-positive neutrophils developed NCGN, whereas chimeric Mpo+/+ mice with circulating MPO-negative neutrophils did not, thereby indicating that BM-derived cells are not only sufficient but also necessary for induction of anti-MPO disease. This novel animal model further documents ANCA IgG interactions with neutrophils as a cause of ANCA-associated glomerulonephritis and vasculitis.

Much like other autoantibodies (eg, anti-double stranded DNA in systemic lupus erythematosus or antiglomerular basement membrane antibodies in Goodpasture's syndrome), antineutrophil cytoplasmic antibodies (ANCA) have provided doctors with a useful serological test to assist in diagnosis of small-vessel vasculitides, including Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and their localised forms (eg, pauci-immune necrotising and crescentic glomerulonephritis). 85-95% of patients with Wegener's granulomatosis, microscopic polyangiitis, and pauci-immune necrotising and crescentic glomerulonephritis have serum ANCA. ANCA directed to either proteinase 3 or myeloperoxidase are clinically relevant, yet the relevance of other ANCA remains unknown. Besides their diagnostic potential, ANCA might be valuable in disease monitoring. In addition, data seem to confirm the long-disputed pathogenic role of these antibodies. Present treatments for ANCA-associated vasculitis are not free from side-effects and as many as 50% of patients relapse within 5 years. Accurate understanding of the key pathogenic points of ANCA-associated vasculitis can undoubtedly provide a more rational therapeutic approach.

Background: Exposure to silica dust is considered to be one of etiological factors of antineutrophil cytoplasmic antibodies (ANCA) -associated vasculitis (AAV)., Methods: Subjects exposed to silica dust in Central Bohemia and followed in the Department of Occupational Medicine, Charles University, were selected for study. A group of 86 men exposed to SiO2 for at least 5 years were examined. The association between occupational exposure to silica dust and ANCA positivity is analyzed., Results: The subjects had a mean age of 66.7 years, and mean exposure to silica of 22.3 years. ANCA were detected significantly more frequently in patients group (17.1%; P-ANCA 18x, C-ANCA 3x) than in controls (n = 28, mean age 64.2 years, P-ANCA 1x, i.e., 3.6%). ANCA positivity was found less frequently (7.1%) in the group with history of SiO2 exposure without signs of pronounced silicosis, than in the group with simple (30.3%) or complicated silicosis (36.0%). Odds ratio for ANCA positivity and relative risk estimate in patients with silicosis were highly significant. Among possible predictor factors for ANCA positivity, silicosis and tuberculosis were relevant. No typical AAV was present among the patients., Conclusion: Long-term silica exposure may be one of the exogenous factors contributing to ANCA production, however, silica exposure alone, without typical silicosis, was not associated with ANCA positivity., ((c) 2006 Wiley-Liss, Inc.)

Macrophage migration inhibitory factor (MIF) is a central proinflammatory cytokine that regulates innate and adaptive immune responses. To evaluate its role in primary vasculitides, we determined MIF by enzyme-linked immunoassay in the sera of patients with Wegener's granulomatosis (WG; n=26), microscopic polyangiitis (MPA; n=10), polyarteritis nodosa (PAN; n=9) and giant cell arteritis (GCA; n=11). Healthy controls (n=26) and patients with sarcoidosis (n=14) were studied in parallel. Serum levels of MIF were significantly higher in patients with WG (median 41.1, range 3.2-120 ng/ml) than those in healthy controls (6.0, 0.015-36.5 ng/ml; P<0.001) and in patients with sarcoidosis (13.8, 0.015-67.1 ng/ml; P<0.05). MIF values were higher in MPA patients (29.5, 9.9-69.4 ng/ml; P<0.01) in comparison with those in healthy controls. In particular, increased levels of MIF were associated with active disease as assessed by the Birmingham Vasculitis Activity Score. Sequential studies showed decreased levels of MIF after initiation of immunosuppressive therapy, with clinical improvement in WG and MPA patients. In contrast, serum levels of MIF were not significantly elevated in patients with PAN and GCA. The results suggest that MIF contributes to the inflammatory process and correlates with disease activity in antineutrophil cytoplasmic antibody-associated vasculitides.

The pathogenicity of anti-neutrophil cytoplasmic antibodies (ANCAs) in ANCA-associated vasculitis has been debated for some time. Animal models have recently demonstrated that ANCAs are a transferable cause of disease and this is supported by studies of the effects of ANCAs on neutrophil-endothelial cell interactions under flow. ANCAs activate neutrophils by cross-linking target antigens on the neutrophil surface with Fc receptors, thereby recruiting signal transduction pathways that promote neutrophil adhesion, degranulation and respiratory burst. Activated neutrophils in proximity with endothelial cells are believed to initiate injury.

Myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic antibodies (MPO-ANCA) are involved in the development of vasculitis microscopic polyangiitis, a systemic vasculitis etc. We have showed a correlation of MPO-ANCA epitopes in vasculitis concerning contribution of N and C terminus of MPO to severity of the diseases. On the other hand, a role of activated neutrophils in inflammatory nephritis renal lesions using SCG/Kj mice. In the phase of nephritis with a low grade of proteinuria, the spontaneous release of MPO from peripheral neutrophils increased, indicating that neutrophils are activated and contribute to the development of active crescentic lesions in SCG/Kj mice. In addition, we have investigated that mice having CADS/CAWS-induced vasculitis also are good model animals for the analysis of the production of MPO-ANCA. Furthermore, we have clarified that MPO is a major antigen for MPO-ANCA production using MPO knock mice.