ANCA are associated with pauci-immune necrotizing crescentic glomerulonephritis and small vessel vasculitis.1 Since their discovery in 1982,2 much has been learned about these autoantibodies, their target antigens, and association with a spectrum of clinicopathologic syndromes such as systemic vasculitis, respiratory tract disease, and necrotizing glomerulonephritis. Disease descriptions include Wegener granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and renal-limited pauci-immune necrotizing and crescentic glomerulonephritis.
There have been substantial advances in the basic understanding and treatment of ANCA diseases in the past 20 years. In the 1980s and early 1990s, questions focused on ANCA diseases, the target autoantigens for ANCA, and whether ANCA participate in the pathogenesis of these diseases. Myeloperoxidase (MPO) and proteinase 3 (PR3) were soon discovered as major antigenic targets for ANCA in neutrophils and monocytes.1,3 In the 1990s, in vitro observations suggested that ANCA participate in the pathogenesis of vascular inflammation.4–9 The controversy over whether MPO-ANCA causes necrotizing glomerulonephritis and small vessel vasculitis dissipated with the development of convincing animal models.10–13 The pathogenic potential of ANCA is supported by observations in patients, multiple levels of in vitro experimental evidence, and animal models, all confirming that antibodies to MPO cause glomerulonephritis and small vessel vasculitis in mice and rats.10,12–15 Abundant in vitro evidence demonstrates that PR3-ANCA also cause leukocyte activation and endothelial cell destruction, although a convincing animal model has not been developed for PR3-ANCA glomerulonephritis or vasculitis.16
Clinical comparative efficacy and observational studies revealed effective treatment for induction and maintenance therapy, discussed later in this review.17–27 The quantity and quality of these clinical studies are a consequence of the clarification of nomenclature provided by the Chapel Hill Consensus Conference28 and the successes of collaborative efforts within the European Vasculitis Study Group (EUVAS),29 the European League Against Rheumatism (EULAR),30 and the Vasculitis Clinical Research Consortium (VCRC).31,32 Despite rapid and remarkable progress, further elucidation of this autoimmune disorder is needed to identify better treatment regimens that result in more effective, durable responses, if not cures, for these diseases.
Nomenclature: What Is in a Name?
In 1994, the now routinely used Chapel Hill nomenclature28 provided names and definitions for these vasculitides, including microscopic polyangiitis, Wegener granulomatosis, and Churg-Strauss syndrome. The Chapel Hill nomenclature was not intended to establish diagnostic criteria. To date, no widely adopted diagnostic criteria have been published to distinguish ANCA-associated disease from other vasculitides or to separate ANCA disease into clinicopathologic subcategories. There are a number of ongoing problems and controversies with nomenclature and diagnosis.
In practice, the clinical differentiation between Wegener granulomatosis and microscopic polyangiitis is difficult because of similarities in their clinical and pathologic features, particularly the indistinguishable necrotizing glomerulonephritis. Where there are differences, as in the presence or absence of respiratory tract granulomatous inflammation, pathologic confirmation of granulomatous inflammation before implementing treatment is often unnecessary or unrewarding. Diagnosis of a patient's disease is not always based on rigorous, widely adopted criteria but rather is influenced by diverse personal and regional practices. For example, if one believes all patients with ear, nose, and throat disease have Wegener granulomatosis, then all such patients will carry that diagnosis, notwithstanding that some may not have or ever develop granulomatous inflammation. In reality, pathologic confirmation of a granulomatous process has become less important for patient treatment because of the similarity of therapy for microscopic polyangiitis and Wegener granulomatosis. The presence of a positive ANCA and pathologic confirmation of pauci-immune small vessel vasculitis or glomerulonephritis is sufficient to warrant immunosuppressive induction therapy, even if there is uncertainty about whether the patient should be diagnosed as having Wegener granulomatosis or microscopic polyangiitis.
In fact, the names microscopic polyangiitis and Wegener granulomatosis describe a clinicopathologic phenotype but are poor predictors of natural history of these two diseases compared with the predictive capacity of the ANCA serotype PR3-ANCA or MPO-ANCA.33,34 PR3-ANCA, lung disease, and, to a lesser extent, upper respiratory tract disease predict the propensity for relapse better than a diagnosis of Wegener granulomatosis versus microscopic polyangiitis.
Awareness of Friedrich Wegener's Nazi connections has prompted efforts to remove his name from the eponym Wegener granulomatosis.35–39 Although no definitive “smoking gun” has been discovered documenting Wegener's participation in Nazi war crimes, available records indicate he was an early member of the Nazi party and a member of the brownshirts (Strum Abteilung), the paramilitary storm troopers of the early Nazi movement. As a pathologist in Lodz during World War II, his office was located a few blocks from the Lodz ghetto that was established to rid that city of Jews by deporting them to death or work camps. Reasonable evidence suggests that Wegener also served as a pathologist in the municipal health agency that issued reports on 50 to 100 autopsies a month on deaths in that municipality.
It is untenable to imagine that Wegener was unaware of Nazi atrocities. After 1945, Wegener was included on lists of war criminals, although the reasons are unknown. There is no evidence that he ever publicly renounced or apologized for his involvement with the Nazi party. In 2007, as a consequence of a careful review of the available data, the American College of Chest Physicians rescinded their Master Clinician Award given to Friedrich Wegener in 1989 and called for the removal of his eponymous distinction.38 It is noteworthy that the most important advocacy organization for patients with Wegener granulomatosis, the Vasculitis Foundation, is thinking about dropping Wegener's name from their organization, in 2006 stating, “As patients and family members, we would prefer a different name for our disease” (Dianne Shaw, past president of the Vasculitis Society, personal communication, January 2008). It is time for the medical community studying vasculitis to agree on an alternative name for Wegener granulomatosis.
Wegener granulomatosis occurs as a systemic process with granulomatous inflammation, usually involving the respiratory tract, accompanied by necrotizing vasculitis affecting small- to medium-sized vessels including capillaries, venules, arterioles, and arteries.28 Necrotizing glomerulonephritis is common, and Wegener granulomatosis also occurs in a localized or limited form in the upper and/or lower respiratory tract with no evidence of accompanying vasculitis. Thus, the granulomatosis and not the vasculitis is the sine qua non of this disease; therefore, a descriptive name for diagnosis should emphasize the granulomatosis and exclude the term vasculitis if the name is to be used as an alternative designation for both the systemic and the limited expressions of this disease.
Wegener initially used the term “rhinogenic granulomatosis” for what is now called Wegener granulomatosis.40 Churg and Strauss used the term “allergic granulomatosis” for what is now called Churg-Strauss syndrome.41 Thus, the term granulomatosis has substantial historical precedence, which supports its retention in a noneponymous alternative for Wegener granulomatosis. One approach would be to use the term granulomatosis with polyangiitis (GPA) for disease with evidence of vasculitis (Figure 1, Table 1). The term respiratory granulomatosis could be used for disease limited to the respiratory tract but with no clinical or pathologic evidence of vasculitis.
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Figure 1: A proposed nomenclature for ANCA disease.
Table 1: ANCA-associated disease
The term ANCA-associated vasculitis (AAV) has been used to refer to the full spectrum of disease, including Wegener granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and pauci-immune necrotizing glomerulonephritis. This is with the realization that some patients are ANCA-negative but have a clinically and pathologically identical disease to ANCA-positive patients. AAV is a problematic term for patients who have limited Wegener granulomatosis or limited Churg-Strauss syndrome, who have no evidence of vasculitis.
We propose that the most generic name for microscopic polyangiitis, Wegener granulomatosis, and Churg-Strauss syndrome could be ANCA disease, which is analogous to anti–glomerular basement membrane disease. If serologic data are known, then the designation could be PR3-ANCA disease, MPO-ANCA disease, or seronegative ANCA disease. Seronegative ANCA disease is conceptually analogous to seronegative systemic lupus erythematosus and seronegative rheumatoid arthritis. Clinicopathologic phenotypes could be designated ANCA granulomatosis (limited Wegener granulomatosis), ANCA granulomatosis with polyangiitis (GPA; Wegener granulomatosis), microscopic polyangiitis, or Churg-Strauss syndrome (Table 1). For example, GPA could be further classified as PR3-ANCA GPA, MPO-ANCA GPA, or ANCA-negative GPA.
Etiology and Pathogenesis of ANCA Disease
Although the close clinical association of ANCA with a distinctive type of small vessel inflammation raises the possibility of a pathogenic role for ANCA, the best support for this comes from animal models and in vitro experimental observations. Numerous in vitro studies reported by multiple research groups demonstrated that both MPO-ANCA and PR3-ANCA antibodies are capable of activating neutrophils and monocytes through both Fab′2 and Fc engagement, which initiates signal transduction pathways that are similar in neutrophils and monocytes (Figure 2).42–44 Activation of these leukocytes results in adhesion to endothelial cells, causing endothelial damage in both cell culture and flow conditions.45–47 Studies in mouse and rat models provide conclusive evidence that anti-MPO antibodies induce necrotizing and crescentic glomerulonephritis and systemic small vessel vasculitis.10–12 Anti-MPO antibodies in the absence of functional T cells are capable of causing glomerulonephritis and vasculitis,10 and the induction of this disease is dependent on neutrophils.48 It can be aggravated by a variety of cytokines, is dependent on activation of the alternative pathway of complement,49 and is abrogated by inhibition of the alternative pathway and by anti-C5 receptor antibodies.49,50 These studies provide a basis for exploring novel therapeutic strategies in human ANCA disease, such as inhibitors of alternative pathway activation, Fc receptors, or signaling pathways activated by ANCA.
Figure 2: Immune mechanisms for ANCA. Depicted are hypothetical pathways for the immunogenesis of the ANCA autoimmune response (left) and the pathogenesis of ANCA vasculitis by ANCA (right). In the top left, we hypothesize the initial immunologic event in the induction of the ANCA autoimmune response is an immune response to an epitope with a structure that is complementary (antisense) to the autoantigen. This immunogen could be endogenous (e.g., an antisense transcript) or exogenous (e.g., an antisense mimic brought in by a microbe). The anti-idiotypic immune response to this initial antibody produces anti-idiotypic antibodies that cross-react with the autoantigen. We hypothesize the normal protection against autoimmunity is circumvented by dysregulated B cells and Th17 T cells (bottom left), allowing the autoimmune response to persist. We further hypothesize yet another event that fosters ANCA disease is the abnormal expression of genes in neutrophils that produce ANCA antigens (MPO and PR3; top right) and that this abnormality results from epigenetic dysregulation. These events set the stage for activation of neutrophils and resultant injury to vessels (bottom right), which begins with priming of neutrophils with TNF-α or C5a, resulting in expression of target antigens (MPO or PR3) at the cell surface, where they are available to interact with ANCA. This results in neutrophil activation by both Fc receptor engagement and Fab′2 binding. Activated neutrophils release factors that engage the alternative complement pathway amplification loop with resultant chemotactic recruitment of neutrophils and additional neutrophil priming. Destructive factors released by activated neutrophils and generated by complement activation cause inflammatory injury to vessel walls (bottom left corner).
Although multiple robust animal models of anti-MPO–induced disease have been developed, investigators have not been able to create a convincing animal model of anti-PR3–induced disease, despite the ample in vitro data showing that PR3-ANCA cause leukocyte activation. Why this has proved so difficult raises a number of possibilities, including that PR3-ANCA alone are not capable of inducing small vessel vasculitis and need some as-yet-unidentified synergistic factor.
Need for a “Second Hit”
More than one event is required for activation of neutrophils by ANCA (Figure 2). The autoantibodies must be present, but alterations in neutrophils also are required. In in vitro studies, neutrophils must be primed with TNF or other cytokines to drive MPO and PR3 to the cell surface for interaction with ANCA.4 If the autoantibody is the first hit, then a second hit requires autoantigen availability in the pathogenesis of ANCA disease. In vivo, an antecedent inflammatory process, such as a respiratory tract infection, could provide the necessary cytokines for increased autoantigen availability. A possible mechanism permitting ANCA to recognize antigens on the cell surface is suggested by studies from France and Germany showing that a genetically determined increase in membrane expression of PR3 could serve as the source of target antigen.51–55 Another potential source for increased availability of autoantigens is aberrant transcription of neutrophil genes as a consequent loss of epigenetic silencing of MPO and PR3 genes.56,57
Patients with ANCA disease aberrantly express genes encoding neutrophil granules, including PR3 and MPO, and this expression profile correlates with disease activity.58 Furthermore, despite that MPO and PR3 genes exist on different chromosomes, their respective levels of expression are upregulated during active disease and downregulated during remission.58 Epigenetic changes as a result of loss of recruitment of the histone methylase PRC2 by Runx3 for both MPO and PR3 genes de-repress their transcription. Silencing is further diminished by the induction of the histone demethylase Jumonji D3.57
Origin of ANCA
ANCA cause disease, but what causes the appearance of ANCA? At least three different theories regarding the origin of the ANCA immune response have been proposed since 2004. The theory of autoantigen complementarity posits that a protein complementary (antisense) to the autoantigen (sense) initiates an immune response; and the anti-idiotypic counterresponse cross-reacts with the autoantigen (Figure 2).59 This complementary protein could be derived endogenously by aberrant antisense transcription or exogenously from a pathogen using a complementary, antisense, mimicking protein that binds to and inhibits the antimicrobial properties of PR3 or MPO. The presence of PR3 anti-complementary specificity has been identified in both human antibodies and T cells. Moreover, this theory of autoantigen complementarity led to the discovery that protein complementary to the middle portion of PR3 is the endogenous protein plasminogen.60 Antibodies to plasminogen are detected in patients with ANCA disease, inhibit fibrinolysis, and associate with increased risk for thrombosis.
A second theory for the genesis of ANCA disease is based on the observation that patients with both MPO-ANCA and PR3-ANCA have antibodies to another neutrophil protein, lysosome-associated membrane protein 2 (LAMP2), that are capable of neutrophil activation and endothelial damage in vitro. LAMP2 has homology to a protein expressed by fimbriated bacteria (FimH). Antibodies to either FimH peptides or LAMP2 peptides are capable of inducing necrotizing and crescentic glomerulonephritis in rats. Hypothetically, anti-LAMP2 antibodies could result from molecular mimicry as a result infection with Gram-negative organisms making FimH.61 Other research groups have not yet confirmed the association of LAMP2 antibodies with ANCA disease.
A third theory of causation is that neutrophils are surrounded by what are known as neutrophil nets that are a platform on which MPO and PR3 may be available to initiate an autoimmune response.62
Treatment: Movement toward Consensus
Although previously diverse and controversial, therapy for ANCA disease has become more standardized today. Many studies now describe the results of randomized and controlled clinical trials addressing various aspects of ANCA disease management, including induction and maintenance therapies.17,19–23,26,27 Induction of remission is aimed at quelling inflammation quickly. Pulses of methylprednisolone combined with immunosuppression effectively induce remission. Plasmapheresis is beneficial in patients with pulmonary hemorrhage63 and in patients with severe kidney disease.20 Entry serum creatinine and pulmonary hemorrhage are predictors of higher mortality.33
For many years, debate centered on whether daily oral or pulse intravenous cyclophosphamide therapy results in the best short- or long-term outcomes.21,64,65 In a meta-analysis of three randomized trials (totaling approximately 150 patients), intravenous pulse cyclophosphamide resulted in a significantly smaller cumulative dosage of cyclophosphamide, a nonsignificantly higher rate of remission, and a lower rate of leukopenia and serious adverse events, particularly infections.66 These benefits were mitigated by a higher rate of relapse in the pulse cyclophosphamide group that did not reach statistical significance. A EUVAS study has probably answered the debate.27 A total of 149 patients who had newly diagnosed generalized AAV with renal involvement were randomly assigned to receive either pulse cyclophosphamide or daily oral cyclophosphamide. Cyclophosphamide was continued for 3 months beyond the time of remission, and patients were then switched to azathioprine. The two treatment groups did not differ in time to remission or proportion of patients who achieved remission or had a relapse. Absolute cumulative cyclophosphamide dosage in the daily oral group was almost twice that of the pulse group. At last, the oral cyclophosphamide debate may be drawing to a close. Without a clear advantage of daily oral cyclophosphamide, we favor the pulse regimen as first-line induction therapy with a lower cumulative dosage and risks from severe leukopenia.
Whether cyclophosphamide can be further reduced or avoided completely by the use of rituximab was addressed in two randomized, controlled trials (soon to be published). In the Randomised Trial of Rituximab versus Cyclophosphamide for ANCA Associated Renal Vasculitis (RITUXVAS) trial, 44 patients with newly diagnosed ANCA vasculitis were randomly assigned 3:1 either to rituximab plus cyclophosphamide or to cyclophosphamide alone.24 Rituximab for the treatment of Wegener granulomatosis and microscopic polyangiitis (Rituximab for ANCA-associated Vasculitis [RAVE] trial)67 is a multicenter, double-blind, randomized, placebo-controlled trial of 197 patients to assess the noninferiority of rituximab plus corticosteroids versus cyclophosphamide plus corticosteroids in patients with new-onset and relapsing disease. In both trials, rituximab seems noninferior to cyclophosphamide. In the RITUXVAS, remissions were common (approximately 90%), whereas in the RAVE trial, the remission rate was much lower. In the RITUXVAS, severe adverse events were common, affecting 45% of patients in the rituximab group and 36% in the cyclophosphamide group alone. The 1-year mortality rate was elevated in both groups (18%). In the RAVE trial, the rate of adverse effects was similar. The evaluation of rituximab compared with cyclophosphamide awaits analysis of long-term outcomes, sustained remission, rate of relapses, and safety data. Importantly, rituximab may eventually become a useful tool worthy of therapeutic consideration, although it is unclear whether rituximab will be any safer than cyclophosphamide.
A variety of maintenance therapies have also been evaluated in several trials, including the CYClophosphamide or AZathioprine As a REMission therapy for vasculitis (CYCAZAREM) trial19 (cyclophosphamide versus azathioprine), Wegener's Granulomatosis–Entretien (WEGENT) trial23 (azathioprine versus methotrexate), Leflunomide versus Methotrexate in the Therapy of ANCA Vasculitis (LEM) study,25 and Azathioprine versus Mycophenolate Mofetil in the therapy of ANCA Vasculitis (IMPROVE) study.26 All of these approaches work, although azathioprine seems to be one of the best agents. Interestingly, the duration of glucocorticoid use remains controversial. Our own practice stops prednisone therapy in most patients by 16 weeks, whereas investigators in Europe continue low-dosage glucocorticoids for years.
Many drug combinations are effective in inducing and maintaining remission, but with all of these combinations, there should be concern about too much immunosuppression. In the CYCAZAREM trial,19 eight patients died during induction and severe adverse events occurred in 10% of patients in the induction phase and in 10% of both study arms during the remission phase. In the Methylprednisolone versus Plasma Exchange as Additional Therapy for Severe ANCA Associated Glomerulonephritis (MEPEX) trial,20 25% of patients died in the first 3 months. In the Wegener's Granulomatosis Etanercept Trial (WGET),22,68 the use of anti-TNF drugs resulted in significant cancers in a remarkable number of patients. In the RITUXVAS and the RAVE trial, adverse events also abound. Finding the most effective and least toxic regimens remains a major unmet need.
Looking to the Future
The biology of remission and relapse in ANCA disease is poorly understood. Clinical tools can predict disease relapse and remission, but they have limitations. The Birmingham Vasculitis Activity Score69 is an efficient approach to defining disease remission at a given point in time but does not ensure that the patient will stay in remission. Multiple attempts have been made to predict propensity for relapse. Patients with PR3-ANCA; lung disease; and/or ear, nose, and throat disease have a higher likelihood of disease relapse.34 A replication study demonstrated the predictive value of positive PR3-ANCA and lung disease, yet patients without these markers also experience relapse, although less frequently. We know so little about the biology of individuals who have a single-shot disease or experience only a single relapse when compared with individuals who have repetitive relapses with or without remission maintenance therapy. We only partially understand the biology of remission and relapse in autoimmune disease and certainly not in ANCA disease. To alter fundamentally the clinical approach to maintenance therapy, we need to discover the mechanism underpinning relapse and what permits a long-term remission. A better understanding would directly benefit all therapeutic strategies. For example, patients who are likely to have long-term stable remission without therapy should not be exposed to needless maintenance immunosuppressive therapy. Biomarkers of remission and relapse would permit clinicians to withhold immunosuppressive therapy safely. Patients who are destined to relapse should have targeted therapy on the basis of the disease mechanisms causing their relapse.
Conclusions
Since the first report of ANCA in 1982,2 tremendous advances have been made in understanding the clinical, pathologic, and pathogenic nature of ANCA disease, and substantial improvements have been made in the treatment of ANCA disease; however, recently emerging insights into pathogenesis and the value of novel immunomodulatory therapies portend more important advances in the near future. We seem to be heading in the right direction.
Disclosures
None.
Published online ahead of print. Publication date available at www.jasn.org.
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