ANCA-Positive Vasculitis

Inflammation and necrosis of blood vessel wall occurs in a dozen or so primary vasculitic disorders. An attempt to classify these diverse forms of vasculitis resulted in the Chapel Hill international consensus definitions, which used the vessel size as the determinant of classification (1). Wegener granulomatosis, microscopic polyangiitis, and Churg Strauss syndrome are described as small-vessel vasculitides and are acknowledged to be commonly associated with antineutrophil cytoplasm antibodies (ANCA). These diseases share a common pathology with focal necrotizing lesions, which affect many different vessels and organs; in the lungs, a capillaritis may cause alveolar hemorrhage; within the glomerulus of the kidney, a crescentic glomerulonephritis may cause acute renal failure; in the dermis, a purpuric rash or vasculitic ulceration may occur. Wegener granulomatosis and Churg Strauss syndrome have additional granulomatous lesions (for further review, see reference 2). The incidence of these diseases is increasing, with more than 20 per million affected and occurring more often in an elderly population (peak age, 55 to 70 yr) (3). Pathogenesis Understanding the pathogenesis of ANCA-associated vasculitis is important for the development of novel therapeutic agents, and important advances have been made in recent years (4,5). ANCA are thought to contribute to the pathogenesis of these small-vessel vasculitides, activating cytokine-primed neutrophils and monocytes, which express the ANCA antigens, proteinase 3 and myeloperoxidase, on their surface. Neutrophils respond by developing the capability of adhering to cytokine-activated endothelial cells, generating a respiratory burst, releasing proteolytic granule contents, and secreting proinflammatory cytokines. ANCA also interfere with the normal processes of resolution of inflammation. Neutrophil apoptosis is dysregulated by ANCA activation of neutrophils, preventing apoptotic cell removal, which in turn allows progression to secondary necrosis, a highly phlogistic event. Electron microscopy studies show the presence of necrotic leukocytes within the intracapillary space (as schematically shown in Figure 1). Figure 1. : Initiation of vasculitic lesions in small vessels by ANCA-activating cytokine-primed neutrophils in the wrong place and at the wrong time. Local release of inflammatory cytokines such as tumor necrosis factor (TNF), both prime neutrophils so that target antigens for ANCA are expressed on the cell surface and locally activate endothelial cells to upregulate their expression of adhesion molecules. ANCA can then bind and activate neutrophils (AcPMN) leading to (a) enhanced adhesion of activated neutrophils to activated endothelial cells (AcEC), (b) dysregulated apoptosis, secondary necrosis (nPMN), and (c) enhanced neutrophil migration across the endothelial barrier. Endothelial cells may be damaged directly by inflammatory mediators released from activated neutrophils, or they may be damaged as neutrophils undergo secondary necrosis in the vascular lumina, amplifying inflammation. After initiation of the vasculitic lesion by the interactions of neutrophils, ANCA, and endothelial cells, further mononuclear leukocytes are recruited, further enhancing vascular inflammation and injury.The endothelial cell is also important in localizing inflammation. Endothelial cells develop an activated phenotype in ANCA-associated vasculitis with enhanced expression of adhesion molecules that promotes interaction with circulating inflammatory cells. ANCA activation can convert rolling neutrophils to stationary adherent cells that are well placed to mediate endothelial injury. Release of proinflammatory mediators, including nitric oxide, reactive oxygen species, and proteolytic enzymes, all might contribute to directly damaging the endothelial cell. Proteinase 3 and myeloperoxidase can bind to endothelial cells; indeed endothelial cells express receptors for proteinase 3. Myeloperoxidase can induce endothelial cell detachment, whereas proteinase 3 can cause direct apoptosis of these cells. Furthermore, ANCA can bind to the endothelial-bound antigens, inducing endothelial cell cytotoxicity. Activation of endothelial cells and neutrophils is important for the early development of vasculitic lesions, and progression of these lesions is accompanied by T cell and monocyte recruitment. T cell-mediated immunity is thought to contribute to the pathogenesis of ANCA-associated vasculitis. Several studies have documented the ability of peripheral blood T cells from patients with either active or quiescent disease to proliferate in response to proteinase 3 or myeloperoxidase. T cell activation has also been shown to persist after disease remission with reduced CD28, a costimulatory molecule for T cell activation, and increased CD69, an early marker of T cell activation. These and other studies (see reference 6 for review) suggest that T cells may contribute to the remitting/relapsing nature of ANCA-associated vasculitis and show the failure of current therapies to suppress immune disease processes and induce tolerance. Clinical Features Constitutional symptoms, such as fever, myalgia, anorexia, weight loss, malaise, and night sweats, are common in vasculitis. In Wegener granulomatosis, there is a predilection for the upper and lower respiratory tracts and the kidneys to be involved. Upper respiratory tract symptoms include rhinorrhea, epistaxis, sinusitis, otitis media, collapse of the nasal bridge, and tracheal stenosis. Lung disease presents with cough, hemoptysis, and dyspnea and can progress to life-threatening pulmonary hemorrhage. Renal manifestations are common in the form of hematuria, proteinuria, and red cell casts, and there can be a rapid deterioration in renal function. Severe ocular abnormalities, such as episcleritis, uveitis, proptosis, and optic nerve ischemia, can also occur. The disease can involve the gut, causing ischemia and hemorrhage, the heart, causing myocardial ischemia, and the peripheral nervous system, causing mononeuritis multiplex. A detailed review of the clinical findings and presentations may be found in references 7–9. Microscopic polyangiitis is very similar to Wegener granulomatosis. Renal involvement is very common, and pulmonary hemorrhage can also occur. However, no granuloma formation is seen, and upper airway involvement is rare. In Churg-Strauss syndrome, the disease is characterized by hypereosinophilia, asthma, and necrotizing vasculitis. Vasculitis can affect the skin, peripheral nerves, muscles, and the intestine. Renal involvement is usually mild, and severe renal failure is uncommon. The vascular pathology is shared between the disorders. In the kidney, early lesions show focal segmental necrosis of the glomeruli, which later progress to crescent formation. Granulomatous inflammation is predominant in Wegener disease, and these lesions are common in the respiratory tract. In addition, Churg-Strauss syndrome has eosinophilic infiltrates. Diagnosis The diagnosis of ANCA-associated vasculitis is made on the basis of the clinical findings, by biopsy of a relevant involved organ (typically kidney, nasal mucosa, or occasionally lung) and the presence of ANCA. Testing for ANCA using both indirect immunofluorescence and antigen-specific enzyme-linked immunosorbent assay is recommended and provides a high sensitivity (approximately 99%) and good specificity (approximately 70%) (10,11). Treatment in ANCA-Associated Vasculitis The prognosis of untreated ANCA-associated vasculitis is poor, with up to 90% of patients dying within 2 yr, usually due to respiratory failure (12). The introduction of cyclophosphamide and high-dose corticosteroids by Hoffman et al. (12) and Fauci et al. (13) in the 1970s markedly reduced the mortality. Cyclophosphamide alkylates DNA guanidine nucleotides, induces lymphopenia, particularly of B lymphocytes, and suppresses Ig responses. The combination of prednisolone and cyclophosphamide, now viewed as standard therapy, leads to control of disease in 80 to 90% of patients. However, these regimes are associated with treatment-related morbidity in over 50% of patients, including steroid-induced diabetes, bladder and lymphoproliferative malignancy, and infertility (12,14) There appears to be little role for prednisolone alone. When compared with combined cyclophosphamide and prednisolone, prednisolone alone is associated with a lower remission rate (56 versus 85% in one study), a higher relapse rate, and a higher mortality rate (15). Treatment has converted this acutely fatal disease into a chronic relapsing disorder with accumulating morbidity. Current treatment is toxic and contributes to morbidity and mortality. Treatment must be tailored to the stage and severity of disease to balance the dangers of disease against those of treatment. For successful treatment vasculitis must be recognized and treated early before permanent scarring occurs. Disease monitoring tools have been developed to aid distinction of tissue damage by active disease that would be amenable to treatment from that caused by healing scars or treatment. For example, the Birmingham Vasculitis Activity Score (BVAS) and vasculitis damage index (VDI) score active disease and chronic damage respectively (for review, see reference 16). These tools have been particularly useful in clinical studies, contributing to definitions of clinical remission and relapse, which are necessary end points of therapeutic trials. Induction Therapy Initial therapy requires high-dose cyclophosphamide and corticosteroids, with additional therapy in those with life-threatening or organ-threatening disease. In those with non-organ-threatening renal involvement (creatinine <5.6 mg/100 ml; 500 μmol/L), a commonly used approach is prednisolone (1 mg/kg per d to a maximum of 80 mg, with reducing doses over time to 12.5 to 15 mg by 3 mo) and cyclophosphamide (2 mg/kg, adjusted for age, renal function, and the prevailing white cell count), in which the cyclophosphamide is maintained for 3 mo. A recently reported multicenter randomized controlled trial (CYCAZAREM) comparing 3-mo or 12-mo therapy with cyclophosphamide followed by conversion to azathioprine for remission therapy supported this approach (17); the patients converted to azathioprine at 3 mo entered remission as readily as those receiving more protracted cyclophosphamide therapy. Encouraged by the success of pulsed cyclophosphamide in the treatment of systemic lupus erythematosus, several studies have addressed the question of efficacy of a pulsed regime in ANCA-associated vasculitis (for review, see reference 18). A recent meta-analysis suggested that pulsed cyclophosphamide is less toxic with fewer adverse effects than continuous oral cyclophosphamide and that it is at least as potent an inducer of remission, but possibly at the expense of a higher relapse rate (18). The existing studies were, however, flawed, and there is a need for a large multicenter randomized controlled trial. The most important indicators of prognosis are pulmonary hemorrhage and severity of renal failure at diagnosis. Patients who present with fulminant disease require intensification of induction therapy with the addition of methylprednisolone or plasma exchange. In one study, plasma exchange that removes ANCA IgG and other inflammatory mediators from the circulation conferred additional benefit when patients were dialysis-dependent (19). Neutrophils from patients with ANCA-associated vasculitis have a greater inflammatory potential compared with healthy controls, producing more oxygen free radicals (20). Methylprednisolone may improve inflammation by increasing the production of the antioxidant, superoxide dismutase, normalizing superoxide anion production and reducing damage by neutrophils (21). Plasma exchange has theoretic advantages over methylprednisolone in reducing morbidity; at least one study (22) suggests that a high total steroid dose increases the likelihood of intercurrent infection. A comparative study of plasma exchange (7 × 3 to 4 L exchanges within 14 d) versus intravenous methylprednisolone (1 g daily for 3 d) in severe disease (creatinine >5.7 mg/100 ml; 500 μmol/L) is in progress; the MEPEX trial has been organized by the European Vasculitis Study Group (EUVAS) and has completed recruitment. Intravenous Ig has also been used as adjuvant therapy, but a randomized placebo-controlled trial of 34 patients suggested only a transient improvement (23). Intravenous Ig is associated with significant side effects, including acute renal failure, and further studies are required to prove efficacy. Cyclophosphamide may induce neutropenia that can be severe and protracted. A small study (24) suggested that the use of granulocyte colony-stimulating factor, a neutrophil-activating agent, does not carry a high risk of inducing a flare of vasculitis. Maintenance Therapy The risks of maintenance therapy have to be balanced against the risks of disease relapse, which varies from 25 to 50% over 3 to 5 yr. Azathioprine has been extensively used for maintenance. It blocks synthesis of inosinic acid, a precursor of the purines, adenylic and guanylic acid, in the S phase of the cell cycle, reducing T and B cell proliferation. In the recently reported CYCAZAREM study, which compared azathioprine and cyclophosphamide as maintenance treatments, azathioprine was as effective as continued cyclophosphamide in the maintenance of remission (17). Prednisolone was maintained at low levels in both limbs. Adverse events were frequent in both limbs, although with a nonsignificant trend toward less severe adverse events with azathioprine. It is unclear whether continuation of immunosuppression beyond 18 to 24 mo improves relapse rates. There is evidence that Wegener granulomatosis is more likely to relapse than microscopic polyangiitis (17) and, if confirmed, may imply a need for a different approach to therapy in those with Wegener granulomatosis. An alternative to azathioprine is methotrexate weekly. Methotrexate inhibits the enzyme, dihydrofolate reductase, which is essential for the synthesis of purines and pyrimidines. Methotrexate has been used as induction/remission therapy in Wegener granulomatosis without threatened vital organ function (25,26). Its use to control renal vasculitis is more controversial; of 21 patients who had active glomerulonephritis in the original study by Sneller et al. (27), those who had normal or near normal serum creatinines showed no in renal function. However, in study, a of patients with more than 50% of the Methotrexate is when the serum is mg/100 at which time there is a risk of and has been used as an alternative to azathioprine. is an with high after requires the synthesis inhibits a of the has effects on and cells and inhibits by of and expression of endothelial adhesion molecules A study of patients receiving standard induction therapy, showed that it was well one in the with all patients followed for 15 mo. was to disease and that had been present at the end of induction therapy other studies in form also the use of in ANCA-associated vasculitis. In these studies, patients who had or disease were treated with 15 2 and was of treatment Patients who are of cyclophosphamide and who relapse on azathioprine may also respond well to treatment with A large multicenter trial of as maintenance therapy has been by of are by the kidneys so may have an important on the therapeutic efficacy in acute renal In there is large of plasma of the between monitoring of plasma of be The use of as an alternative was suggested after the use in patients who had remission and renal function. However, a randomized trial found a higher relapse rate in patients to compared with those maintained on cyclophosphamide Furthermore, of Wegener in patients receiving disease to of and of cyclophosphamide is further evidence of the efficacy of in acute vasculitis. of the upper respiratory tract by may the risk of disease relapse, and use of reduced the risk of respiratory relapse compared with when to therapy. There however, a high rate of and it is not whether efficacy of the to of is not recommended for use at the expense of immunosuppression Therapy for and Disease induction therapy to induce remission in of patients. A further those who relapse, use of these have a high risk of side effects from cyclophosphamide, due to the high dose of cyclophosphamide that is have involved the use tumor necrosis factor or cell The success of in has the for the use of similar therapeutic in patients with ANCA-associated vasculitis. There are for that may be in the inflammation in systemic vasculitis that is associated with ANCA. circulating levels have been active vasculitis and and are markedly increased at vasculitic The of by T cells from patients with active Wegener granulomatosis is increased when T cells are with or in expression in peripheral blood mononuclear cells in patients with systemic vasculitis and serum levels of and have been found also for this include neutrophils and endothelial cells. of neutrophils increases the surface expression of and neutrophils from patients with ANCA-associated vasculitis are more likely to have high proteinase 3 expression on the neutrophil surface Neutrophils in systemic vasculitis have been shown to be evidence of circulating but not neutrophils was shown by the of the activation and but no in adhesion molecule with and with disease and increased of superoxide (20). is also required for an effective respiratory with superoxide release Furthermore, neutrophils can undergo and dysregulated apoptosis after activation by ANCA, which may to the of the apoptotic neutrophil secondary necrosis is also a potent endothelial cell inducing increased adhesion molecule expression and a for neutrophils and other in ANCA-associated of adhesion and vascular cell adhesion on endothelial cells with disease with in patients with showed significant in vascular adhesion molecules and There was a in the and inflammatory score of with a in and cells from the monocyte These studies that therapy leads to a in the of leukocytes In ANCA-associated that lesions are and that T cell and occurs as a secondary In a similar to that shown in patients, treatment of patients from ANCA-associated systemic vasculitis with may in of the reducing interactions between endothelial adhesion molecules and the expressed on reducing of circulating leukocytes in evidence has shown benefit of in an of acute crescentic a of renal vasculitis are for clinical use in and a of receptors to the of and a is a and is clinical An study of 20 patients with Wegener granulomatosis was to the of in combination with standard therapy, which cyclophosphamide patients had disease, of which had active The time from original diagnosis was mo. a disease for Wegener granulomatosis the was patients had the of of the 20 patients and of although active disease was in 15 patients. The daily prednisolone was reduced from mg to mg after 6 mo. Adverse were mild, with patients required but in was it due to with severe developed and a infection. A randomized placebo-controlled study has been in the to efficacy the of The for the Study of Vasculitis has also been used in the treatment of although there are as no reported trials. have treated patients with patients had severe or renal and the had relapsing disease 1). patients to treatment within 6 The patients with disease had remission by 6 and who had disease, remission by 4 to 3 dialysis-dependent however, renal biopsy showed significant chronic patients had a and 3 developed and but both were by patients Patients treated with with the recently successful use of in patients with Wegener granulomatosis, findings the that is a inflammation in ANCA-associated vasculitis. appears to be an effective novel therapy for life-threatening disease or for those of T cells a role in the pathogenesis of vasculitis. is against surface antigens of activated and in has been used for and treatment of renal has been used as therapy for patients with Wegener granulomatosis with cyclophosphamide and patients showed a response to with or remission of disease a of 5 to mo. had which resulted in of the effects of treatment were mild, with no A further suggested that may also be useful in patients with Wegener granulomatosis who are dialysis-dependent at diagnosis cell antibodies have also shown remission in small studies The use of these requires further study, but they the of T cells in the pathogenesis of ANCA-associated vasculitis. is a that has been used in acute renal and of disease. The of is not It has been shown to interfere with the by 70 and the activation of It leads to of early B T and neutrophil in may be not only it may also induce tolerance. the with failure to express and and are required for of T cells to an immune In an of renal of the was using also has a on which has been in the pathogenesis of Wegener granulomatosis. In an multicenter study, was used to induce remission in patients with active Wegener granulomatosis, all of were or had for standard therapy were receiving cyclophosphamide before Patients mg/kg daily white blood cells to 3 × they were then a before over 6 to mo. remission was in patients and remission in patients. the patients who had active disease receiving cyclophosphamide, one remission, remission, and within the treatment Treatment was well with no or of may be a useful alternative for cyclophosphamide, but further studies are using high-dose followed by cell has to remission in a of vasculitis However, in one of patients receiving cell both within 3 that may as enhanced studies are required and are very on the of this remission, azathioprine and methotrexate are but both are and often not by patients. Furthermore, methotrexate is in renal is a that as a of In was shown to have similar to methotrexate and It does not in renal failure and does not cause was used to remission in Wegener granulomatosis for therapy may also include of other proinflammatory including using These have been used with success in T cell is necessary for activation. may be by the use of the A between and Wegener granulomatosis has been that this novel therapeutic may have an important role in for therapy of vasculitis include which of B cells; successful use to induce remission in a with chronic relapsing has been reported the of the use of cyclophosphamide and corticosteroids in patients with ANCA-associated the for patients has The current in the of immunosuppression to morbidity and mortality without organ therapeutic agents, including and agents, are to large randomized controlled using the standard of cyclophosphamide and corticosteroids as controls, the evidence for treatment of this disease and the for patients.