The ANCA-associated vasculitides include granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis. The clinical presentation, diagnosis, pathophysiology, and treatment of these entities are discussed below.
Granulomatosis with Polyangiitis: Clinical Presentation and Diagnosis
GPA is the most common form of vasculitis to involve the lung. The Chapel Hill Consensus Conference defined GPA as “necrotizing granulomatous inflammation usually involving the respiratory tract, and necrotizing vasculitis affecting predominantly small- to medium-sized vessels.”1 However, it is important to recognize that GPA is a systemic disease that can affect almost any organ (Table 74-2). The most frequently involved sites are the upper airways, lungs, and kidneys.4 Symptoms and clinical disease manifestations are the result of necrotizing granulomatous inflammation and small vessel vasculitis that occur in variable degrees of combination.
Table 74-2Organ Systems Affected by ANCA-Associated Vasculitis |Favorite Table|Download (.pdf) Table 74-2Organ Systems Affected by ANCA-Associated Vasculitis
|Feature ||Granulomatosis with Polyangiitis (formerly Wegener’s) ||Microscopic Polyangiitis ||Eosinophilic Granulomatosis with Polyangiitis (formerly Churg–Strauss) |
|Upper airway disease ||90–95% ||No ||50–60% |
|Pulmonary parenchymal disease ||54–85% ||20% ||30% |
|Alveolar hemorrhage ||5–15% ||10–50% ||<3% |
|Glomerulonephritis ||51–80% ||60–90% ||10%–25% |
|Gastrointestinal tract ||<5% ||30% ||30–50% |
|Eyes ||35–52% ||<5% ||<5% |
|Nervous system ||20–50% ||60–70% ||70%–80% |
|Heart ||8–16% ||10–15% ||10–15% |
|Skin ||33–46% ||62% ||50–60% |
|Eosinophilia ||Rare ||Rare ||Yes |
|Asthma ||Noa ||Noa ||Yes |
|Granulomatous inflammation ||Yes ||No ||Yes |
In the 1960s the term “limited Wegener granulomatosis” was introduced to indicate patients with GPA who lacked renal disease. The use of this term and its implications have evolved over the last two decades. Even in the absence of renal involvement, patients may have life-threatening pulmonary or neurological disease requiring aggressive immunosuppressive treatment. For instance, a patient who “only” has alveolar hemorrhage in the absence of glomerulonephritis should never be classified as having “limited” GPA. Consequently, today, the use of the term “limited GPA” implies that (a) the pathology is predominantly a necrotizing granulomatous inflammation, and the vasculitis seen on biopsy is of lesser clinical significance; and (b) there is no immediate threat either to the patient’s life or that the affected organ is at risk for irreversible damage. In this sense, the terms “limited” or “nonsevere” GPA are now used interchangeably as distinction from “severe” GPA, which by definition either threatens the patient’s life (alveolar hemorrhage) or a vital organ with the risk of irreversible damage (rapidly progressive glomerulonephritis, scleritis, or mononeuritis multiplex). These definitions and distinctions form the basis for stratification of current standard therapy.
Over 90% of patients with GPA first seek medical attention for symptoms arising from either the upper and/or lower airway. Nasal and sinus disease is characterized by congestion and epistaxis due to mucosal friability, ulceration, and thickening. Patients may also have features of chronic sinusitis and recurrent or chronic serous otitis. Perforation of the nasal septum and/or saddle nose deformity may result from ischemia of the nasal cartilage (Fig. 74-3). Oral manifestations include gingival hyperplasia (Fig. 74-4) and oropharyngeal ulcerations. Subglottic stenosis occurs in approximately 20% of patients and can cause life-threatening compromise of the airway. Subglottic stenosis may occur in the absence of other features of active GPA, and its symptoms may be nonspecific, for example, dyspnea, hoarseness, cough or stridor; the latter is occasionally mistaken for wheezing.
Saddle nose deformity of granulomatosis with polyangiitis.
Strawberry or mulberry gums in a patient with granulomatosis with polyangiitis.
GPA involving the lower airways can affect the pulmonary parenchyma, the bronchi, and rarely the pleura. Presenting features of parenchymal involvement may include cough, dyspnea, chest pain, or hemoptysis. However, some patients may be completely asymptomatic. Patients with diffuse alveolar hemorrhage usually present with progressive dyspnea and anemia (Fig. 74-5). Hemoptysis is absent in about one-third of patients. Patients with diffuse alveolar hemorrhage may deteriorate rapidly and experience respiratory failure, which has a mortality rate up to 50%.
Chest radiograph of a patient with granulomatosis with polyangiitis displaying an alveolar filling pattern indicative of diffuse alveolar hemorrhage.
The clinical presentation of alveolar hemorrhage is caused by pulmonary capillaritis (Fig. 74-6). The predominant inflammatory cells are neutrophils. However, eosinophils or monocytes may also be present. Capillaritis usually causes fibrinoid necrosis of alveolar and vessel walls and may culminate in the destruction of the underlying architecture of the lung. An important hallmark of capillaritis is the presence of pyknotic cells and nuclear fragments from neutrophils undergoing apoptosis, a feature called leukocytoclasis. This hallmark enables distinction between true capillaritis and margination of neutrophils related to surgical trauma. Depending on the acuteness and duration of alveolar hemorrhage, hemosiderin-laden macrophages and interstitial hemosiderin deposits may be present.
Alveolar capillaritis causing pulmonary hemorrhage in granulomatosis with polyangiitis.
The most common form of pulmonary involvement in GPA is caused by necrotizing granulomatous inflammation and presents radiographically as nodules or mass lesions, which may cavitate (Figs. 74-7–74-9). These lesions may be incidental findings on thoracic imaging studies as they cause little symptoms and do not result in significant abnormalities of pulmonary function. Prominent air–fluid levels can be seen when the necrotic center of the inflammatory lesion gets superinfected (Fig. 74-8). These necrotizing granulomatous lesions are a disease-defining feature of GPA. Their presence easily separates GPA from MPA. In the absence of other features of small vessel vasculitis in other organs, the differential diagnosis of these lesions consists primarily of infections, particularly caused by fungal or mycobacterial organisms, and less likely of malignancies or necrotizing sarcoid granulomatosis.
Chest radiograph of a patient with granulomatosis with polyangiitis displaying multiple nodules with and without cavitation.
Chest radiograph of a patient with granulomatosis with polyangiitis showing multiple large cavities, some with air–fluid levels.
Computed tomography scan of a patient with granulomatosis with polyangiitis showing multiple nodules, some with cavitation. There are also small bilateral pleural effusions.
The lung nodules of GPA have very characteristic histopathological features. Small necrotizing microabscesses appear to be the earliest lesion. They enlarge and coalesce until the typical geographic and basophilic appearance of the necrosis has developed (Fig. 74-10). The necrotic center is surrounded by palisading histiocytes and scattered giant cells. Occasionally the necrosis may be bronchocentric. When this type of necrotizing granulomatous inflammation extends into the walls of small vessels it is referred to as granulomatous vasculitis (Fig. 74-11). In contrast to capillaritis, this type of vasculitis seems to be a secondary phenomenon of the necrotizing granulomatous inflammation affecting the lung parenchyma. The inflammatory background of the granulomatous necrosis and vasculitis consists of a mixed cellular infiltrate containing lymphocytes, plasma cells, scattered giant cells, and eosinophils. It may cause extensive parenchymal consolidation mimicking organizing pneumonia. Well-defined sarcoid-like nonnecrotizing granulomas are not found in GPA.
Geographic basophilic necrosis with palisading histiocytes and giant cells from a lung nodule in a patient with granulomatosis with polyangiitis.
Granulomatous vasculitis with giant cells in a lung biopsy of a patient with granulomatosis with polyangiitis.
Inflammation and stenosis of the tracheobronchial tree occur in at least 15% of patients with lung involvement.5,6 Endobronchial disease may be an incidental finding on bronchoscopy or present with cough, hemoptysis, wheezing, dyspnea, or symptoms related to parenchymal collapse or postobstructive infection. Spirometry including inspiratory and expiratory flow–volume loops may show characteristic abnormalities indicative of degree and location of airway narrowing. Subglottic stenosis represents a fixed airway obstruction resulting in flattening of both the inspiratory and expiratory loops. If the intrathoracic trachea, or more commonly, one or both mainstem bronchi are affected, flattening of the expiratory curve can be found. Pleural effusions may occur, but are usually small, asymptomatic, and incidental findings (Fig. 74-9). Other thoracic manifestations of GPA include inflammatory pleural pseudotumors or hilar adenopathy. The latter should raise the suspicion of infection, sarcoidosis, or lymphoma.
Glomerulonephritis is among the most concerning disease manifestations of GPA as it can progress to complete renal failure in the absence of symptoms. It is usually detected by the presence of abnormal laboratory results such as active urine sediment with microscopic hematuria and red cell casts, proteinuria, and declining renal function. Continued vigilance for glomerulonephritis is essential as it is present at diagnosis in less than half of all patients. However, over the course of their disease, the kidneys are affected in 80% of patients.
A renal biopsy is useful to establish a diagnosis of ANCA-associated vasculitis and to determine the renal prognosis. The glomeruli are not affected uniformly (focal) by segmental, necrotizing inflammation (Fig. 74-12), and cellular crescents (Fig. 74-13) are frequently found. The number of glomeruli affected, degree of crescent formation, and destruction of individual glomeruli as well as the amount of sclerosis found determine the chance of recovery of renal function. In addition, tubular fibrosis and atrophy affect renal outcomes. Direct immunofluorescence reveals no or only scant immune deposits (pauci-immune glomerulonephritis). Granulomatous inflammation affecting the renal parenchyma and tubulointerstitial nephritis can also be found rarely.
Focal necrotizing glomerulitis of granulomatosis with polyangiitis.
Rapidly progressive crescentic glomerulonephritis in granulomatosis with polyangiitis.
A wide spectrum of ocular manifestations has been observed in GPA, which may threaten vision by affecting the eye directly or involving its contiguous structures. Manifestations may include conjunctivitis, episcleritis, scleritis, keratitis, corneal ulceration, uveitis, and retinal vasculitis. Involvement of the lacrimal system may result in epiphora, dacryocystitis, and fistula. Retro-orbital inflammatory pseudotumors may affect one or both the eyes, threaten the vision, and represent the most difficult challenge in the management of GPA (Figs. 74-14 and 74-15). Any patient with GPA who presents with eye pain or redness, proptosis, change in visual acuity, diplopia, or loss of visual field should be referred for emergent ophthalmological consultation.
External ophthalmoplegia of the left eye due to orbital involvement with granulomatosis with polyangiitis.
Computed tomography scan of the orbits in a patient with granulomatosis with polyangiitis showing a mass in the right orbit causing external ophthalmoplegia.
Nervous system involvement may occur in up to one-third of patients. Mononeuritis multiplex of the peripheral nervous system caused by inflammation of the vasa nervorum as well as central nervous system vasculitis and pachymeningitis represent severe disease manifestations with substantial risk of irreversible damage, persisting even after the acute inflammation is adequately controlled.
Cardiac involvement may be occult. Regional wall motion abnormalities with a noncoronary distribution pattern are frequent echocardiographic findings.7 It is unclear whether this type of cardiomyopathy is the result of small vessel disease or inflammatory infiltration of the cardiac muscle. Pericarditis, valvulitis, and inflammatory pseudotumor have also been described.
A wide spectrum of cutaneous manifestations may be observed in GPA. Leukocytoclastic vasculitis presenting as palpable purpura is most common, followed by pyoderma gangrenosum–like lesions (Fig. 74-16) and so-called Churg–Strauss granulomas.
Pyoderma gangrenosum of the leg in a patient with granulomatosis with polyangiitis.
Microscopic Polyangiitis: Clinical Presentation and Diagnosis
Histopathologically, the necrotizing small vessel vasculitis of MPA causing necrotizing crescentic glomerulonephritis and pulmonary capillaritis is indistinguishable from that encountered in GPA.8 Consequently, there is substantial overlap in organ manifestations and symptoms between the two syndromes (Table 74-2). A timely diagnosis of MPA may be delayed by a gradual onset or the nonspecific nature of symptoms such as fever, malaise, and weight loss. All organ systems may be involved. The kidneys are most commonly affected in up to 80% of patients. Other commonly encountered disease manifestations include diffuse alveolar hemorrhage due to pulmonary capillaritis affecting 10% to 30% of patients. MPA is the most frequent cause of pulmonary renal syndrome. Several cases of MPA in association with severe obstructive airway disease or bronchiectasis have also been described. More recently, several case series have highlighted an association between usual interstitial pneumonia and MPO-ANCA–positive MPA. In these cases, the fibrotic changes either precede the development of MPA or are already present at the time of diagnosis of MPA.
Palpable purpura caused by leukocytoclastic vasculitis of the skin, and musculoskeletal complaints, such as arthralgias and myalgias, are also common. Gastrointestinal involvement occurs in about one-third of patients. This is in contrast to GPA, in which gastrointestinal involvement is very rare. Visceral angiography is generally not helpful for the evaluation of abdominal symptoms as the vessels involved are too small to be visualized. CT with or without contrast injection may be more helpful if gastrointestinal involvement is suspected. However, the use of contrast is relatively contraindicated in patients with active renal involvement. Sinusitis and asthma are rarely found in MPA, and should lead to the consideration of an alternative diagnosis.
Most patients with MPA have ANCA, and in 40% to 80% they are of the P-ANCA variety, reacting with MPO. C-ANCA reacting with PR3 is seen less frequently. Occasionally patients with MPA later develop granulomatous inflammation and are reclassified as having GPA; this is more likely to occur in patients with C-ANCA.
As in GPA, a histopathological diagnosis may be necessary to confirm the diagnosis before the patient is committed to prolonged immunosuppressive therapy. The biopsy specimen should be sought from the most accessible site. Renal biopsy shows pauci-immune focal segmental–necrotizing glomerulonephritis, with extracapillary proliferation forming crescents. In contrast to GPA, granulomatous inflammation is not a feature of MPA. All other histopathological features are indistinguishable from those of GPA. Treatment of MPA should follow the principles applied to the management of GPA. Consequently, most cases of MPA require immunosuppressive therapy used for patients with severe GPA.
Eosinophilic Granulomatosis with Polyangiitis: Clinical Presentation and Diagnosis
EGPA is the third type of vasculitis that commonly affects the lung. The 2012 Chapel Hill Consensus definition for the disease is “eosinophil-rich and necrotizing granulomatous inflammation often involving the respiratory, and necrotizing vasculitis predominantly affecting small- to medium-sized vessels, and associated with asthma and eosinophilia.”1 EGPA is included among the ANCA-associated vasculitides even though only 40% to 70% of patients with active EGPA are ANCA positive.9–11 EGPA is primarily distinguished from GPA and MPA by a high prevalence of asthma and peripheral blood and tissue eosinophilia. Three distinct phases of the disease have been described. The first is a prodromal allergic phase with asthma. This phase may last for a number of years. The second is an eosinophilic phase with prominent peripheral and tissue eosinophilia. This phase may also last a number of years and the manifestations may remit and recur over this time period. The differential diagnosis for patients in this phase of the disease includes parasitic infection and chronic eosinophilic pneumonia. The third vasculitic phase consists of systemic vasculitis and may be life threatening. The three phases are not seen in all patients and do not necessarily occur in this order; they may even concur. However, asthma usually predates vasculitic symptoms by a mean of 7 years (range 0–61). Formes frustes of EGPA have also been described with eosinophilic vasculitis and/or eosinophilic granulomas in isolated organs without evidence of systemic disease.
Pulmonary parenchymal involvement occurs in 38% of patients. Transient alveolar-type infiltrates are most common (Fig. 74-17). These have a predominantly peripheral distribution and are indistinguishable from infiltrates seen in chronic eosinophilic pneumonia. Occasionally, nodular lesions may be seen in EGPA. In contrast to GPA and MPA, alveolar hemorrhage is exceedingly rare. Renal involvement in EGPA is less prominent than in GPA and MPA and does not generally lead to renal failure. In contrast, peripheral nerve involvement, typically in the form of mononeuritis multiplex, is more frequent. The peripheral nerve involvement can result from both capillaritis and direct toxicity from eosinophil granule proteins. Skin, heart, central nervous system, and abdominal viscera may also be involved.
Chest radiographs of patients with eosinophilic granulomatosis with polyangiitis (Churg–Strauss): (A) Nonspecific gnomonic infiltrates; (B) Multiple vague, patchy infiltrates. (Reproduced with permission from Chumbley LC, Harrison EG, DeRemee RA. Allergic Granulomatosis and angiitis (Churg-Strauss syndrome): report and analysis of 30 cases. Mayo Clin Proc. 1977;52(8):477–484.)
The classic histopathological picture consists of necrotizing vasculitis, eosinophilic tissue infiltration, and extravascular granulomas. However, not all features are found in every case, and they are not pathognomonic of the condition. Particularly the finding of a “Churg–Strauss granuloma” on skin biopsy should not be confused with the diagnosis of EGPA. While this type of necrotizing extravascular granuloma may be seen in EGPA, it may occur in other systemic autoimmune diseases, including GPA and rheumatoid arthritis.
If ANCA are present, they are usually P-ANCA reacting with MPO. The ANCA status appears to correlate with disease activity. Recent studies suggest a more vasculitic disease phenotype in the presence of ANCA, with ANCA being particularly frequent among patients with glomerulonephritis. Patients with heart involvement are less likely to be ANCA positive. However, not all studies have found this consistently, and there remains substantial overlap of organ manifestations between patients with EGPA who are ANCA positive and those who are ANCA negative.
In recent years significant attention has been devoted to EGPA detected in patients using leukotriene receptor antagonists. Available case studies and limited population-based incidence estimates suggest that these agents may lead to unmasking of vasculitic symptoms in asthmatics, by allowing dose reductions or discontinuation of oral glucocorticoid therapy. There is no evidence suggesting that these agents cause EGPA.
The prognosis of EGPA is better than that of GPA and MPA, as the overall mortality is lower and not significantly different from the normal population. Most deaths are secondary to cardiac involvement.
Pathophysiology of ANCA-Associated Vasculitis
The etiology of ANCA-associated vasculitis remains unknown. Several different pathways and mechanisms have been proposed for the pathogenesis.12 A genetic predisposition for autoimmunity, epigenetic factors and environmental triggers seem to play a role in the development of ANCA-associated vasculitis. Currently available clinical and experimental evidence support that infections or other environmental exposures can lead to the loss of tolerance and an inflammatory environment that is conducive for the production of autoantibodies (ANCA) in predisposed patients. In the context of an inflammatory milieu, ANCA can cause specific tissue inflammation and injury by a variety of different mechanisms which involve direct interactions with PR3 or MPO.
Multiple studies have reported skewing in polymorphisms of a variety of immune response genes and genes encoding for ANCA-target antigens and α1-proteinase inhibitor with potential effects on disease outcome. A recent genome-wide association study found major histocompatibility complex (MHC) and non-MHC associations with GPA and MPA and that these syndromes are genetically distinct.13 Moreover, the associations with the specific ANCA types (PR3-ANCA vs. MPO-ANCA) and the differences between them were stronger than those between patients diagnosed with GPA versus MPA. For PR3-ANCA–positive patients strong associations were found with HLA-DP, the serpin A1 gene (SERPINA1), which codes for the α1-antitrypsin, the major inhibitor of PR3, and with the PRTN3 gene which encodes PR3. In patients with MPO-ANCA only an association with HLA-DQ was found.
The expression of ANCA-target antigens on the neutrophil surface, particularly PR3, is increased in patients with GPA and genetically determined. Moreover, epigenetic modifications that interfere with the normal silencing of genes coding for the ANCA autoantigens in mature neutrophils may also contribute to the observed inappropriately increased expression of PR3 or MPO by these cells in patients with GPA or MPA.
Many clinical observations suggest that the presence or absence of ANCA as well as the specific type of ANCA (PR3-ANCA vs. MPO-ANCA) defines the disease phenotype. Patients with limited GPA who remain ANCA negative rarely develop systemic vasculitic disease manifestations. Patients with glomerulonephritis and PR3-ANCA lose their renal function much more rapidly than patients with MPO-ANCA. Patients with PR3-ANCA also have a higher relapse rate than patients with MPO-ANCA. Experimental data and animal models support a pathogenic role of ANCA in the development of vasculitis. A couple of recent studies have also suggested a different clinical phenotype of ANCA-positive patients with Churg–Strauss syndrome compared with ANCA-negative patients.
In GPA, the presence of PR3-ANCA appears most closely related to the development of vasculitic complications. Furthermore, systemic vasculitic relapses without recurrence of ANCA are extremely rare. Yet, remission may be maintained for extended periods of time in up to one-half of the patients despite the presence of ANCA. These clinical observations suggest that ANCA alone are not sufficient to cause disease activity, but ANCA seem to be required for the development of vasculitic complications of GPA and systemic relapses.
Many in vitro studies have demonstrated proinflammatory effects of PR3-ANCA and MPO-ANCA on neutrophils, monocytes, and endothelial cells, which enhance and perpetuate endothelial cell and tissue damage. ANCA may increase the adhesion of neutrophils to endothelial cells by enhancing the expression of cell adhesion molecules on endothelial cells. ANCA can activate primed neutrophils, resulting in the release of oxygen radicals and proteolytic enzymes. The latter may in turn induce endothelial cell apoptosis. ANCA-mediated neutrophil activation involves both Fc-γ–receptor engagement and recognition of expressed target antigen on the surface of primed neutrophils. ANCA may also cause endothelial cell damage by direct cytotoxicity or localized immune complex formation with target antigens bound to the endothelial cell surface. The latter may initiate localized complement activation. Finally, ANCA are thought to contribute to the recruitment of more inflammatory cells to the area of tissue injury by stimulating the release of chemotactic chemokines and agents from neutrophils, monocytes, and endothelial cells. For a detailed description of pathways and mechanisms by which ANCA may directly and indirectly contribute to damage of the vascular endothelium, the reader is referred to other recent reviews.
Many patients with ANCA-associated vasculitis relate the onset or recurrence of their disease to preceding infectious episodes. The following link to infection has been hypothesized. Most ANCA-mediated effects on neutrophils and monocytes require priming of the cells. This cytokine-dependent process is not unique to vasculitis. Cytokine stimulation of neutrophils and monocytes, typically by tumor necrosis factor (TNF), with resulting increased surface expression of ANCA-target antigens, occurs normally in the context of infections. Patients with active vasculitis have indeed been shown to have both increased expression of ANCA-target antigens on the surface of their neutrophils and elevated levels of TNF. In combination, these observations allow the hypothesis that neutrophil priming, which occurs in response to cytokine stimulation during infection, enables ANCA to interact with their target antigen on the neutrophil surface. This in turn sets the documented proinflammatory effects of ANCA in motion, which aggravate and perpetuate the inflammatory reaction at the endothelial cell interphase.
Rodent models of MPO-ANCA–associated vasculitis support this hypothesis of a pathogenic role of ANCA. They clearly indicate that ANCA contribute directly to the development of vasculitis and glomerulonephritis, and that the interaction of ANCA with its target antigen is required for the development of lesions. Furthermore, the localization of lesions is determined by the site of this interaction. At the same time, animal models support the significance of genetic determinants for the development of autoimmunity, vasculitis, and a specific phenotype with characteristic organ involvement and histopathological features. Finally, animal model studies indicate that infections may be significant disease modifiers. Even though proinflammatory effects of murine PR3-ANCA could also be documented in vivo, the animals did not develop organ pathology typical for GPA or MPA, and good animal model for PR3-ANCA–associated vasculitis remains elusive. This may be due to substantial differences between human and murine PR3, as the latter behaves more like human elastase than human PR3.
To date, the causes of the production and persistence of ANCA remain poorly understood. Yet infections may be instrumental for the development of this specific type of autoimmunity. ANCA directed against a broad variety of target antigens have been documented in association with viral, fungal, bacterial, and protozoal infections. In the rare instances of C-ANCA/PR3-ANCA observed in infections, the ANCA disappeared with appropriate antimicrobial therapy. These observations may suggest that ANCA can occur transiently in the setting of infection, and that the persistent ANCA response in patients with vasculitis may be the result of molecular mimicry in susceptible hosts. Subsequent diversification of T- and B-cell responses (“epitope spreading”) may lead to responses against different epitopes on the same target molecule (intramolecular spreading) or extend to other molecules (intermolecular spreading. Bacterial superantigens have also been implicated in the pathogenesis of ANCA-associated vasculitis. GPA patients colonized with superantigen-producing Staphylococcus aureus are at high risk for relapse. GPA patients had expansion of T-cell clones expressing Vβ genes specific for S. aureus superantigens more frequently than controls. This supports the theory that S. aureus contributes to the pathogenesis of vasculitis. By inducing potent T- and B-cell activity, superantigens produced during an S. aureus infection could initiate and maintain both ANCA production and cytokine release, thought to be required for the cascade that results in necrotizing granulomatous inflammation and vasculitis.
Treatment of ANCA-Associated Vasculitis
Treatment of granulomatosis with polyangiitis and microscopic polyangiitis, including management of patients who are refractory to standard therapy, is described below. In addition, treatment of eosinophilic granulomatosis with polyangiitis is considered.
Treatment of Granulomatosis with Polyangiitis and Microscopic Polyangiitis
The first goal of therapy for patients with ANCA-associated vasculitis is to induce a remission as quickly as possible, so that irreversible organ damage is minimized. To this end, early diagnosis and prompt application of an appropriate immunosuppressive regimen are crucial. At the same time the treatment plan needs to include the prevention of treatment-related toxicity. Once remission has been induced, the second goal of therapy is to maintain remission with as few side effects as possible. Finally, once the patient has enjoyed a stable remission, surgical interventions aiming to repair damage may proceed as necessary. These overarching principles apply to the therapy of both GPA and MPA.
Remission Induction Therapy
Remission induction therapy is best tailored to the patient’s degree of disease severity, extent, and acuity. Patients who present with indolent GPA localized to the upper and/or lower airways and who are ANCA negative can be treated with trimethoprim/sulfamethoxazole (T/S) at a dose of 160/800 mg twice daily. The mechanism of action of T/S is unclear, but possibly related to antimicrobial effects on S. aureus, the organism most frequently cultured from the nostrils of patients with GPA. It is also possible that this agent has immune-modulatory effects not shared with other antibiotics. T/S monotherapy should not be used in ANCA-positive patients, in the setting of glomerulonephritis or any other severe disease manifestation, and patients treated with T/S need continued long-term observation, as some will later develop more severe disease manifestations requiring immunosuppressive therapy.
Standard remission induction therapy for most patients categorized as having “limited” or “nonsevere” or “early-systemic” GPA or MPA consists of oral prednisone at doses of 0.5 to 1 mg/kg per day (generally not to exceed 80 mg/d) in combination with methotrexate with a target dose of 20 to 25 mg once a week.14,15 This dose can be applied orally or subcutaneously. To minimize toxicity and the risk of Pneumocystis pneumonia (PCP), this immunosuppressive regimen should be supplemented by folic acid, 1 mg/d and standard PCP prophylaxis.
For the last four decades standard remission induction therapy for patients with severe disease (also called “generalized” or “organ-threatening” disease) has consisted of oral prednisone in combination with oral cyclophosphamide at a dose of 2 mg/kg daily for 3 to 6 months.16 One randomized controlled trial has shown that intravenous pulse therapy with cyclophosphamide consisting of three pulses of 15 mg/kg given 2 weeks apart followed by 15 mg/kg pulses given every 3 weeks for 6 months, is equally effective to induce remission in severe GPA or MPA.17 Based on results from a large multicenter randomized double-dummy–controlled trial that compared four once-weekly doses (375 mg/m2 of body surface) of rituximab to standard oral cyclophosphamide for remission induction in severe ANCA-associated vasculitis, rituximab has now been approved for this indication by most regulatory agencies across the globe.18 The long-term follow-up of this study has shown that the efficacy of a single course of four once-weekly doses of rituximab (375 mg/m2 of body surface) remains equivalent to continued standard daily oral immunosuppressive therapy with cyclophosphamide followed by azathioprine for 18 months.19 These three remission induction regimens have been shown to be equivalent for newly diagnosed patients with severe GPA or MPA. Remission can be achieved in up to 90% of patients with either of these regimens. For patients presenting with a severe disease relapse, rituximab was found to be superior to cyclophosphamide.18,19 Rituximab is also the preferred agent for young patients in whom fertility needs to be preserved. If oral cyclophosphamide is used, patients need to be monitored carefully to minimize the risk of bone marrow toxicity. The dose of cyclophosphamide should be adjusted in patients with impaired renal function, and the patient’s complete blood counts need to be monitored at least biweekly for the duration of therapy. Optimal dosing with oral cyclophosphamide is achieved when the lymphocyte count is reduced, but the total white blood count is maintained above 3500. To avoid bladder toxicity of cyclophosphamide, the entire dose is applied in the morning and patients are instructed to drink at least 3 L of fluid per day.
In patients with rapidly progressive fulminant disease, such as those presenting with alveolar hemorrhage or rapidly deteriorating renal function, intravenous methylprednisolone, 1000 mg per day for 3 to 5 days may be necessary for effective control of inflammation. If this therapy does not generate the desired effects, plasma exchange should be implemented.20,21
Remission Maintenance Therapy
Once remission has been induced the prednisone dose is tapered gradually over the course of 5 to 6 months with the goal of complete discontinuation. Patients with limited or “nonsevere” disease should be maintained on methotrexate for remission maintenance.15 Patients treated with cyclophosphamide for remission induction should be switched to either methotrexate or azathioprine for remission maintenance.22 Azathioprine is preferred in patients with any degree of renal insufficiency. Mycophenolate mofetil is an alternative for patients who cannot tolerate either methotrexate or azathioprine for remission maintenance. However, mycophenolate mofetil appears less effective than azathioprine for remission maintenance. Remission maintenance therapy is continued for at least 12 months beyond achievement of remission, and longer in patients who have suffered relapses. Early discontinuation of immunosuppressive therapy is associated with an unduly high relapse rate. The need for remission maintenance therapy following remission induction with rituximab in newly diagnosed patients remains unclear. Over 18 months a single remission induction course of rituximab is as effective as oral cyclophosphamide followed by azathioprine, but PR3-ANCA–positive patients with GPA are at risk for relapse once peripheral blood B lymphocytes are reconstituted (after 6–12 months) and may benefit from long-term remission maintenance therapy.23
Long-term remission maintenance therapy with T/S beyond immunosuppression may also be beneficial. In one study, patients who received T/S at a dose of 160/800 mg twice daily had a lower rate of disease relapse than those who received placebo.24
Treatment of Patients Refractory to Standard Therapy
About 10% of patients do not respond adequately to therapy with cyclophosphamide and fail to achieve remission. These patients are particularly challenging. Anti–TNF-α agents have not been shown to be effective in such patients. One large multicenter, double-blind, placebo-controlled, randomized trial conducted in GPA, has shown no efficacy of etanercept when added to standard therapy.25 Moreover, a higher frequency of malignancies was observed in the treatment arm compared with the control arm of that trial. All patients with malignancies had also received cyclophosphamide. For this reason, the use of etanercept in patients who have received cyclophosphamide is now strongly discouraged. Smaller, uncontrolled open-label studies with infliximab conducted in Europe have suggested some efficacy of that agent, but many complicated infections were observed in these patients. Over the last decade many cohort studies have found rituximab to be very effective in such patients, and rituximab has now become the de facto standard of care for refractory GPA.26
PCP still carries a mortality of up to 35%. Therefore, PCP with T/S is recommended for all non–sulfa allergic patients with ANCA-associated vasculitis receiving immunosuppressive therapy including rituximab. Patients who have a sulfa allergy manifesting itself with a skin rash can be desensitized against the drug. Those who fail this approach or have other contraindications for the use of this drug should be given other agents for PCP prophylaxis. Patients receiving methotrexate for remission induction or maintenance should also receive PCP. This can be safely accomplished with T/S at recommended doses for this purpose, provided that folic acid, 1 mg daily, is also given. Patients undergoing intense immunosuppression during the remission induction phase may also benefit from prophylactic antifungal therapy. Finally, every patient treated with glucocorticoids for ANCA-associated vasculitis should receive osteoporosis prophylaxis with calcium and vitamin D supplements and possibly bisphosphonates.
Treatment of Eosinophilic Granulomatosis with Polyangiitis
Even though mortality of EGPA is lower than that of GPA or MPA, the management of EGPA remains a challenge. Systemic glucocorticoids are the cornerstone of therapy. There are no clinical trials that provide clear guidance. The reports from the French Vasculitis Study Group are difficult to interpret with respect to this disease, because patients with EGPA were not separated from those with polyarteritis nodosa and MPA, two diseases with distinct clinical manifestations, pathophysiology, and prognosis.27,28 Yet, these studies suggest that it is appropriate to treat EGPA according to the principles applied to the management of GPA and MPA. Accordingly, cyclophosphamide should be added to glucocorticoids for remission induction in all patients with disease manifestations that threaten the patient’s life or the function of a vital organ, that is, particularly those with central or peripheral nerve involvement, glomerulonephritis, heart involvement, or alveolar hemorrhage. Methotrexate, azathioprine, and mycophenolate mofetil have been used as glucocorticoid-sparing agents in less severe disease and for remission maintenance. Refractory disease and disease dominated by difficult-to-control eosinophilic inflammation may respond to interferon-α therapy.29 However, continued long-term interferon-α therapy may be necessary, and this treatment carries the risk of substantial toxicity. More recently, small case series and a formal pilot trial have shown beneficial effects of rituximab, particularly in ANCA-positive patients with renal involvement.30,31 Two pilot trials have documented substantial glucocorticoid-sparing effects of anti–interleukin-5 therapy with mepolizumab.32,33