Progress in treatment of ANCA-associated vasculitis

Autoantibodies to neutrophil cytoplasmic antigen-associated vasculitis (AAV) is characterised by inflammation of blood vessels. The introduction of immunosuppressive therapy with glucocorticoids and cyclophosphamide transformed AAV from a fatal condition to a largely treatable condition. Over the past 30 years, considerable progress has been made refining immunosuppressive regimens with a focus on minimising toxicity. There is, however, a high unmet need in the treatment of AAV. A proportion of patients are refractory to current therapies; 50% experience a relapse within 5 years and treatment toxicity contributes to mortality and chronic disability. As knowledge of the pathogenesis of vasculitis grows, it is mirrored by the availability of biological agents, which herald a revolution in the treatment of vasculitis. Lymphocyte-targeted and cytokine-targeted agents have been evaluated for the treatment of AAV and are entering the routine therapeutic arena with the potential to improve patient outcomes. As rare diseases, treatment advances in vasculitis depend on international collaborative research networks both to establish an evidence base for newer agents and to develop recommendations for patient management.     

Reactivity against complementary proteinase-3 is not increased in patients with PR3-ANCA-associated vasculitis

The etiology of anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitides (AAV) is unknown, but the association between infections and autoimmunity has been studied extensively. In 2004, a novel theory was proposed that could link infection and autoimmunity. This 'theory of autoantigen complementarity' was based on the serendipitous finding of antibodies against complementary-PR3 (cPR3) in patients with PR3-ANCA-associated vasculitis. cPR3 demonstrated homology to several bacterial proteins, and it was hypothesized that PR3-ANCA develop in response to anti-cPR3 antibodies, as a consequence of the anti-idiotypic network. These data have not been confirmed in other patient cohorts. We investigated the presence of anti-cPR3 antibodies in a Dutch cohort of PR3-ANCA-associated vasculitis patients. Anti-cPR3 reactivity was determined in serum using ELISA. Two separate batches of cPR3 were used to determine reactivity in two separate cohorts of PR3-ANCA-associated vasculitis patients. We found that anti-cPR3-reactivity was not increased in our PR3-ANCA-associated vasculitis patients, in comparison to control groups. Further research will be necessary to prove the concept of autoantigen complementarity in autoimmune diseases.     

Intense immunostaining of heat shock protein 70 within renal interstitium associates with long-term renal survival in an ANCA-associated vasculitis cohort

In anti-neutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV) genetic predisposition, ANCA autoantibodies, neutrophil extracellular traps (NETs), complement activation, and toll-like receptor signaling are implicated in AAV pathogenesis. Heat shock proteins (HSPs), a highly conserved group of small-sized molecular chaperones, take part in protein folding during cellular stress. Although HSPs were initially observed intracellularly, it has been shown that they can be secreted in the extracellular space and modulate the immune response in various autoimmune diseases including AAV. The scope of the present study is to investigate the role of heat shock protein 60 (HSP60) and 70 (HSP70) in the long renal effects in an ANCA vasculitis cohort. In this cohort of ANCA-associated vasculitis, 29 patients were followed up over 20 years. At diagnosis, immunohistochemistry was performed for HSP60 and HSP70 within the various nephron compartments. Higher renal HSP60 expression was associated with increased interstitial inflammatory infiltrates at diagnosis, while HSP70 expression was associated with a greater extent of interstitial fibrosis at diagnosis. Notably, intense tissue expression of HSP70 at the time of biopsy was associated with a worsened kidney survival. Renal HSP70 expression was associated with poor renal outcomes during long-term follow-up. This finding may indicate a role of HSPs in renal disease progression in ANCA vasculitis. Further validating studies are needed to verify a causative association between HSP70 expression and renal outcomes in ANCA-associated vasculitis.     

Ocular disease in patients with ANCA-positive vasculitis

Anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis—the term recently applied to Wegener's granulomatosis—is a rare multi-system inflammation characterized by necrotizing granulomas and vasculitis. We investigated the ocular manifestations of this disease in a group of patients drawn from five inflammatory eye disease clinics across the United States. Of 8,562 persons with ocular inflammation, 59 individuals were diagnosed with ANCA-positive vasculitis; 35 males and 21 females, aged 16 to 96 years, were included in this study. Ocular diagnoses were scleritis (75.0%), uveitis (17.9%), and other ocular inflammatory conditions (33.9%) including peripheral ulcerative keratitis and orbital pseudotumor. Mean duration of ocular disease was 4.6 years. Oral corticosteroids and other systemic immunosuppressive agents were used by 85.7% and 78.5% of patients, respectively. Over time, patients with ANCA-positive vasculitis experienced 2.75-fold higher mortality than other patients with inflammatory eye disease.     

The protein tyrosine phosphatase nonreceptor 22 C1858T polymorphism and vasculitis: a meta-analysis

The aim of this study was to determine whether the functional protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism (rs2476601) confers susceptibility to vasculitis. A meta-analysis was conducted on the PTPN22 C1858T polymorphism across nine comparative studies containing 1,922 vasculitis patients and 11,505 normal control subjects. Meta-analysis showed no association between the T allele and vasculitis in all subjects [odds ratio (OR) 1.046, 95 % confidence interval (CI) 0.755-1.1.451, p = 0.786], and analysis after stratification by ethnicity indicated that the T allele was not associated with vasculitis in Europeans (OR 1.104, 95 % CI 0.798-1.528, p = 0.551). However, meta-analysis showed a significant association between the T allele and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) (OR 1.415, 95 % CI 1.228-1.630, p = 1.59 × 10(-6)) and Wegener's granulomatosis (WG) (OR 1.829, 95 % CI 1.377-2.431, p = 3.09 × 10(-5)). In addition, meta-analysis showed an association between the T allele and WG in ANCA-positive subjects (OR 2.042, 95 % CI 1.534-2.719, p = 1.02 × 10(-6)), but not in ANCA-negative WG patients (OR 0.595, 95 % CI 0.199-1.781, p = 0.353). This meta-analysis does not show that the PTPN22 C1858T polymorphism is associated with vasculitis susceptibility, but does show that this polymorphism is associated with susceptibility to AAV, WG, and ANCA status in WG.     

Evidence for defect of complement-mediated phagocytosis by monocytes from patients with rheumatoid arthritis and cutaneous vasculitis.

In-vitro measurements of the rate of monocyte phagocytosis of heat-killed yeast preopsonised in human AB serum from 14 patients with rheumatoid arthritis and 14 normal controls showed a significant reduction in five patients with active vasculitis but no change in nine with active arthritis alone. Further studies of complement- and Fc-mediated monocyte phagocytosis in which the rate constants (Kc and KFc respectively) were determined using complement-coated Saccharomyces cerevisiae and Candida albicans opsonised with IgG in monocytes from nine patients with rheumatoid vasculitis and 12 controls showed a significant reduction in Kc (p less than 0.01) but normal KFc. Kc was normal in three patients with inactive vasculitis. Low Kc was correlated with low serum C3 concentrations but not with Clq binding or anticomplementary activity, and no evidence of intracytoplasmic or membrane-bound immune complexes was detected in monocytes from patients with active vasculitis. These results show that cutaneous vasculitis in rheumatoid arthritis is associated with selective impairment of complement-mediated monocyte phagocytosis, which does not appear to result from receptor blockade by immune complexes.     

Crescentic glomerulonephritis requiring hemodialysis and elevated MPO-ANCA level and vasculitis allergica cutis in a 21-year-old girl

Microscopic polyangiitis (mPA) is a systemic necrotizing nongranulomatous vasculitis that affects small blood vessels. Clinical features include constitutional symptoms such as fever, anorexia, fatigue, and weight loss. Skin lesions include purpura and splinter hemorrhages, which occur in 50% of patients. Another characteristic feature is rapidly progressive glomerulonephritis, which often affects the kidneys in the early stages of the condition. Diagnosis is based on typical clinical features, biopsy, and presence of antineutrophil cytoplasmic antibodies (ANCA). This disorder tends to involve middle-aged and older persons, with a predilection for males; it is very rare in children. A 21-year-old female patient with mPA who did not respond well to treatment, required hemodialysis, developed vasculitis allergica cutis (VAC) later, and had a relatively short-term survival is reported herein.     

Correlations between plasma levels of a fibronectin isoform subpopulation and C-reactive protein in patients with systemic inflammatory disease

Surrogate markers to detect vasculitic processes prior to organ compromise are lacking. To determine if specific populations among the fibronectin (FN) family of alternatively spliced proteins correlate with parameters of vasculitis in at-risk patients, we retrospectively evaluated the association of plasma levels of total FN (TFN) and FN bearing the alternatively spliced EIIIA segment (A⁺FN) with clinical vasculitis status and with levels of two putative vasculitis markers (C-reactive protein (CRP) and von Willebrand factor) in a previously studied cohort of 27 patients with systemic inflammatory disease. We found that the percentage of TFN composed by A⁺FN (%A⁺) and A⁺FN, but not TFN, correlated with plasma levels of CRP, the prototypic inflammation biomarker used to detect vasculitis. These findings suggest that different FNs may confer distinct clinical information, and that their simultaneous measurement merits further investigation in our efforts to identify soluble biomarker systems to detect vasculitis.     

Potential roles of NLRP3 inflammasome in the pathogenesis of Kawasaki disease

There is a heterogeneous group of rare illnesses that fall into the vasculitis category and are characterized mostly by blood vessel inflammation. Ischemia and disrupted blood flow will cause harm to the organs whose blood arteries become inflamed. Kawasaki disease (KD) is the most prevalent kind of vasculitis in children aged 5 years or younger. Because KD's cardiovascular problems might persist into adulthood, it is no longer thought of as a self-limiting disease. KD is a systemic vasculitis with unknown initiating factors. Numerous factors, such as genetic predisposition and infectious pathogens, are implicated in the etiology of KD. As endothelial cell damage and inflammation can lead to coronary endothelial dysfunction in KD, some studies hypothesized the crucial role of pyroptosis in the pathogenesis of KD. Additionally, pyroptosis-related proteins like caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC), proinflammatory cytokines like IL-1 and IL-18, lactic dehydrogenase, and Gasdermin D (GSDMD) have been found to be overexpressed in KD patients when compared to healthy controls. These occurrences may point to an involvement of inflammasomes and pyroptotic cell death in the etiology of KD and suggest potential treatment targets. Based on these shreds of evidence, in this review, we aim to focus on one of the well-defined inflammasomes, NLRP3, and its role in the pathophysiology of KD.     

Antineutrophil Cytoplasmic Antibody-Positive Vasculitis in A Patient with Graves Disease: Cross-Reaction Between Propylthiouracil and Methimazole

ObjectiveTo alert clinicians about the risk of vasculi- tis and cross-reactivity of antithyroid medication.MethodsWe describe the clinical course and medical management of the study patient.ResultsA 25-year-old woman with hyperthyroid- ism developed antineutrophil cytoplasmic antibody-posi- tive vasculitis after 15 months of propylthiouracil therapy. Her condition improved when propylthiouracil was with- drawn, but recurred when she was prescribed methimazole. Propylthiouracil and methimazole are commonly used an- tithyroid medications, and propylthiouracil is a well-rec- ognized cause of drug-induced vasculitis. Cross-reactivity between the 2 drugs is likely, but it has not been reported previously with regard to vasculitis. Many patients with propylthiouracil-induced vasculitis have been switched to methimazole.ConclusionsAwareness of this rare, but potentially serious, adverse drug reaction is important because prompt discontinuation of medication is essential. Cross-reactivity between propylthiouracil and methimazole must be consid- ered when selecting alternative therapies. (Endocr Pract. 2010;16:449-451)     

Retinal vasculitis--a primer.

Retinal vasculitis is a diagnosis that is generally suggested by an ophthalmologist. Frequently patients with the disorder are referred to nonophthalmologists for further diagnostic evaluation or treatment. The criteria for defining vasculitis differ greatly between ophthalmologists and other physicians. To facilitate collaboration between ophthalmologists and their colleagues, we have sought to clarify the term "retinal vasculitis" by discussing its subcategories, the potential role of antiphospholipid antibodies, and the etiology of retinal vasculitis. We offer guidelines for evaluating the disorder and treating patients.     

Place de la tomographie par émission de positons (TEP) au [18F]FDG dans l’exploration des vascularites

[¹⁸F]fluorodeoxyglucose (¹⁸FDG) positron emission tomography (PET) is a noninvasive metabolic imaging modality that is well suited to the assessment of activity and extent of large vessel vasculitis, such as giant cell arteritis and Takayasu arteritis. PET could be more effective than magnetic resonance imaging in detecting the earliest stages of vascular wall inflammation. The visual grading of vascular [¹⁸F]FDG uptake makes it possible to discriminate arteritis from atherosclerosis, providing therefore high specificity. High sensitivity can be achieved provided scanning is performed during active inflammatory phase, preferably before starting corticosteroid treatment. Large scale prospective studies are needed to determine the exact value of PET imaging in assessing the large vessel vasculitis outcome and response to immunosuppressive treatment.     

Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system

Evidence is lacking for direct pathogenicity of human anti-proteinase-3 (PR3) antibodies in development of systemic vasculitis and granulomatosis with polyangiitis (GPA, Wegener''s granulomatosis). Progress in study of these antibodies in rodents has been hampered by lack of PR3 expression on murine neutrophils, and by different Fc-receptor affinities for IgG across species. Therefore, we tested whether human anti-PR3 antibodies can induce acute vasculitis in mice with a human immune system. Chimeric mice were generated by injecting human haematopoietic stem cells into irradiated NOD-scid-IL2Rγ^−/− mice. Matched chimera mice were treated with human IgG from patients with: anti-PR3 positive renal and lung vasculitis; patients with non-vasculitic renal disease; or healthy controls. Six-days later, 39% of anti-PR3 treated mice had haematuria, compared with none of controls. There was punctate bleeding on the surface of lungs of anti-PR3 treated animals, with histological evidence of vasculitis and haemorrhage. Anti-PR3 treated mice had mild pauci-immune proliferative glomerulonephritis, with infiltration of human and mouse leukocytes. In 3 mice (17%) more severe glomerular injury was present. There were no glomerular changes in controls. Human IgG from patients with anti-PR3 autoantibodies is therefore pathogenic. This model of anti-PR3 antibody-mediated vasculitis may be useful in dissecting mechanisms of microvascular injury.     

Rituximab treatment in hepatitis C infection: an in vitro model to study the impact of B cell depletion on virus infectivity

Hepatitis C virus (HCV) infected patients with vasculitis are often treated with the B-cell-depleting anti-CD20 antibody rituximab. Treatment reduces the cryoglobulins that cause vasculitis, yet it also leads to a transient increase in liver enzymes and HCV genomic RNA in the periphery. The mechanism underlying the increased viral load is unclear and both direct and indirect roles have been proposed for B cells in HCV infection. We previously reported that HCV can associate with B cells and can trans-infect hepatocytes. We established an in vitro assay to study the effect(s) of rituximab on B cell-associated HCV infectivity. Rituximab-mediated lysis of B cells in vitro increases the level of infectious HCV released from B cells. Our results, using a model where virus does not replicate in B cells, recapitulate observations seen in patients and may explain in part the rapid increase in blood HCV RNA observed after rituximab treatment.     

Hepatitis C virus-associated mixed cryoglobulinemia. Clinical manifestations, histopathological changes, mechanisms of cryoprecipitation and options of treatment

Chronic hepatitis C virus (HCV) infection is frequently associated with a variety of autoimmune phenomenons. Mixed cryoglobulinemia (MC) appears in up to 50% of chronic HCV-infected patients. Cryoglobulins consist of immunoglobulin complexes precipitating in vitro when cooled below body temperature. In most cases IgM with rheumatoid factor activity is found in cryoprecipitates which could lead to vasculitis induced by the deposition of immnuocomplexes in small vessels. This vasculitis is thought to cause clinical symptoms called Meltzer's triad. This triad is represented by purpura, arthralgia and weakness. One third of patients suffering from HCV-associated mixed cryoglobulinemia are developing typical symptoms during their course of disease. The striking association between HCV infection and MC has conduced to the hypothesis that HCV is of major importance in the production of MC with followed vasculitis. Both hepatrophism and lymphotrophism have been reported for the hepatitis C virus. Infection of B-cells by HCV could probably lead to a bcl-2 translocation and immunoglobulin gene rearrangement which results in clonal lymphoproliferation and in synthesis of monoclonal IgM with rheumatoid factor activity. These IgM form immunocomplexes with IgG in the cold, which are finally responsible for the described vasculitis. Histopathological changes of the liver are dominated by chronic HCV infection. The majority of times mild activity of hepatitis or mild fibrosis could be found. Nevertheless, cirrhosis is more often found in HCV-infected patients suffering from MC compared to patients without MC. Conventional treatment of MC is aimed to reduce circulating immune complexes by immunosupression and plasmapheresis. With the emerging concept of a viral pathogenesis the therapeutic approach has changed during the last decade. Interferon treatment of MC, particularly of HCV-associated MC is well established nowadays.     

Effects of thalidomide on the local Shwartzman reaction in mice and rabbits

Abstract The Shwartzman reaction is an animal model displaying histopathological vasculitis phenomena. Extravasation and swelling due to increased vascular permeability and cellular infiltration, which are hallmarks of the Shwartzman reaction, were evaluated as leakage of i.v.-injected Evans Blue dye and by histological and immunohistological characteristics in rabbits and mice. (±)-Thalidomide, (−)-thalidomide, (+)-thalidomide and dexamethasone inhibited the increase of vascular permeability in the local Shwartzman reaction. Histologically, the intensity of the Shwartzman reaction was reduced. In mice thrombus formation and leukocytoclastic vasculitis was inhibited by (±)-thalidomide and (+)-thalidomide. ICAM-1 expression was markedly reduced after (+)-thalidomide injection. Thalidomide and dexamethasone pretreatment reduced Mac-1 expression on perivascular infiltrated granulocytes. The inhibitory effect of thalidomide on vasculitis of the Shwartzman reaction may thus be related to reduction of adhesion molecule expression.     

What you should know about PR3-ANCA. Evidence for the role of T cells in the pathogenesis of systemic vasculitis

The pathogenesis of systemic vasculitis is complex and is likely to involve many mechanisms. There is a growing body of evidence that T cells may contribute to the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Predominantly, T cells and monocytes are found in inflammatory infiltrates in patients with Wegener's granulomatosis (WG). The production of ANCA appears to be T-cell-dependent. T lymphocytes from the peripheral blood of patients with ANCA-associated vasculitis have been shown to proliferate in response to proteinase 3 (PR3). These and other findings outlined in this review indicate T-cell involvement, although further studies are still needed to elucidate the exact contribution of T cells to the pathogenesis of systemic vasculitis.     

What you should know about PR3-ANCA: Evidence for the role of T cells in the pathogenesis of systemic vasculitis

The pathogenesis of systemic vasculitis is complex and is likely to involve many mechanisms. There is a growing body of evidence that T cells may contribute to the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Predominantly, T cells and monocytes are found in inflammatory infiltrates in patients with Wegener's granulomatosis (WG). The production of ANCA appears to be T-cell-dependent. T lymphocytes from the peripheral blood of patients with ANCA-associated vasculitis have been shown to proliferate in response to proteinase 3 (PR3). These and other findings outlined in this review indicate T-cell involvement, although further studies are still needed to elucidate the exact contribution of T cells to the pathogenesis of systemic vasculitis.     

Trafficking of QD-conjugated MPO-ANCA in murine systemic vasculitis and glomerulonephritis model mice

In systemic vasculitis, the serum level of myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic autoantibodies (MPO-ANCA) is significantly elevated with the progression of disease. We have established a model of murine systemic vasculitis by administration of MPO-ANCA and fungal mannoprotein to C57BL/6 mice. We examined the role of MPO and MPO-ANCA in the pathogenesis of glomerulonephritis and systemic vasculitis in this model using quantum dots (QDs). We demonstrated that QD-conjugated MPO-ANCA (ANCA-QD) visualized the translocation of MPO on the neutrophil membrane surface after stimulation with proinflammatory cytokines. We also observed that MPO translocation on neutrophils in both patients with rapid progressive glomerulonephritis and these model mice without any stimulation, suggesting that MPO translocation is certain to contribute to the development of glomerular lesion. In addition, blood flow on the kidney surface vessel was significantly decelerated in both SCG/Kj mice and this model, suggesting that ANCA induces the damage of blood vessel. These results indicate that MPO-ANCA and surface-translocated MPO on the activated neutrophils coordinately plays essential roles in the initial steps of the glomerulonephritis.     

Vascular involvement in relapsing polychondritis.

Review of four cases of relapsing polychondritis (RP) seen at one hospital in the 12-year period 1963 to 1974 revealed that one patient had aortic insufficiency with large artery involvement, two others had involvement of medium and large arteries and the fourth may have had mucocutaneous vasculitis. Valvular disease has occurred in 9% of all cases of RP reported in the literature and, if vasculitis beyong the aortic root is included, 25% of cases of RP manifested inflammatory vascular disease. The frequency of pseudotumour of the orbit and cochlear-labyrinthine dysfunction is also high and may be a manifestation of vasculitis.