This article provides an update on the diagnosis and management of the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides, granulomatosis with polyangiitis (formerly Wegener), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss). Focus is on new schemes of classification and the importance of ANCAs in the diagnosis and prognosis of these systemic vasculitides. Current therapeutic strategies consisting of glucocorticoids in conjunction with conventional or biologic agents for both induction of remission and remission maintenance are outlined. Future research directions include investigation of the optimal duration and frequency of maintenance therapy and development of targeted therapeutic agents.
Key points
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Antineutrophil cytoplasmic antibody (ANCA) positivity by immunofluorescence should be confirmed with ELISA for proteinase-3 (PR3) or myeloperoxidase (MPO) in the diagnosis of ANCA-associated vasculitides (AAVs). Tissue biopsy for histologic confirmation should be obtained whenever possible.
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ANCA specificity may be associated with different prognostic and phenotypic features in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Additionally, in eosinophilic granulomatosis with polyangiitis (EGPA), different clinical manifestations may be observed in those with ANCA positivity compared with those who are ANCA negative.
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Treatment of AAVs, which is divided into an induction phase followed by remission maintenance, should be tailored to disease activity and severity. Optimal duration of maintenance therapy is unknown.
Introduction
The AAVs include GPA, formerly Wegener’s granulomatosis; MPA; and EGPA, formerly Churg-Strauss syndrome. These 3 primary systemic vasculitides are multisystem diseases characterized by pauci-immune necrotizing vasculitis of small- to medium-sized blood vessels and an association with serologically detectable ANCAs in a majority of cases. Change has transformed the field of AAVs in recent years with the introduction of new nomenclature for these diseases, novel insights into the genetic underpinnings of AAVs, and advances in therapeutic approach, including the use of biologics. This article focuses on the current understanding of AAV diagnosis and management and highlights existing controversies and unmet needs in the care of patients with AAVs. Because of differences in clinical phenotype, disease course, and serologic positivity, EGPA is discussed separately at the end of this article.
Introduction
The AAVs include GPA, formerly Wegener’s granulomatosis; MPA; and EGPA, formerly Churg-Strauss syndrome. These 3 primary systemic vasculitides are multisystem diseases characterized by pauci-immune necrotizing vasculitis of small- to medium-sized blood vessels and an association with serologically detectable ANCAs in a majority of cases. Change has transformed the field of AAVs in recent years with the introduction of new nomenclature for these diseases, novel insights into the genetic underpinnings of AAVs, and advances in therapeutic approach, including the use of biologics. This article focuses on the current understanding of AAV diagnosis and management and highlights existing controversies and unmet needs in the care of patients with AAVs. Because of differences in clinical phenotype, disease course, and serologic positivity, EGPA is discussed separately at the end of this article.
Classification and nomenclature
The 1990 American College of Rheumatology (ACR) classification criteria for the systemic vasculitides proposed a series of criteria meant to enable discrimination between the various forms of systemic vasculitis. At the time the ACR criteria were created, MPA was not recognized as a distinct entity; thus, classification criteria for MPA were not created. As such, the ACR criteria for GPA are of limited value in differentiating between GPA and MPA. These classification criteria were created before ANCA testing was widely available, so ANCAs, which have an undisputed role in the diagnosis of AAVs, were excluded from classification criteria.
Despite high sensitivity and specificity, ACR criteria are of limited value in AAVs, especially in distinguishing between GPA and MPA, which have certain clinical and histologic differences. GPA is characterized by necrotizing small vessel vasculitis with extravascular granulomatous inflammation, which is not present in MPA. Although pulmonary and renal involvement is common in both GPA and MPA, granulomatous involvement of the upper and lower airway occurs exclusively in GPA. Otolaryngologic manifestations, including rhinosinusitis, serous otitis media, and subglottic inflammation, are present in an estimated 90% of patients with GPA, making this the most commonly involved organ system in GPA, whereas glomerulonephritis is the most frequent manifestation in MPA. These phenotypic distinctions may confer important prognostic and therapeutic differences, discussed later.
In 2012, the International Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitides (CHCC) was convened with a goal of redefining the vasculitic syndromes with nomenclature reflective of the underlying pathogenesis, pathology, and clinical characteristics. The 2012 CHCC nosology eliminated eponyms from the AAV nomenclature and cemented presence of granulomatous inflammation in the respiratory tract as the key difference between GPA and MPA. This nomenclature fails to account for ANCA antigen specificity, which some experts think should be included with clinicopathologic phenotype in classification of AAVs. Efforts to create more comprehensive classification and diagnostic criteria for AAV are under way with an international observational study designed to develop and validate classification and diagnostic criteria for primary systemic vasculitis, including the AAVs.
Antineutrophil cytoplasmic antibody
Antineutrophil Cytoplasmic Antibody Detection
Circulating ANCAs with different immunofluorescence patterns and antigen specificities characterize GPA and MPA. ANCAs, which have demonstrated pathogenicity in animal, in vitro, and ex vivo models, are also an important diagnostic tool. In making a diagnosis of AAVs, the utility of ANCAs depends on the clinical setting and on the assay used. A perinuclear (p-ANCA) or cytoplasmic (c-ANCA) pattern may be seen by indirect immunofluorescence; however, this technique is hampered by potential for interference by antinuclear antibodies and subjective interpretation. Positive immunofluorescence should be followed by ELISA for ANCAs specifically directed against PR3 or MPO, which are associated with GPA and MPA, respectively, in greater than 80% of cases. New methodology for autoantigen detection, including new-generation ELISA and multiplex technology, will improve ANCA detection in the future. C-ANCA pattern with PR3 positivity can be found in 90% of patients with active GPA, and a majority of MPA patients have p-ANCA with positive MPO. In the appropriate clinical setting, only combinations of c-ANCA with PR3 or p-ANCA with MPO have a positive predictive value for diagnosis of GPA or MPA.
An atypical ANCA pattern on immunofluorescence, multiple positive autoantigens, or discordance between ANCA pattern and antigen specificity should alert suspicion for drug-induced disease, in particular cocaine. The most common autoantibody in cocaine-induced disease, which can mimic the destructive sinonasal disease of GPA, is directed against human neutrophil elastase. This atypical ANCA is not found in patients with AAVs.
The clinical and pathogenic significance of additional ANCAs, other than the commercially available PR3 and MPO, are under investigation in AAVs. One such autoantibody is human lysosomal-associated membrane protein 2 (LAMP-2). LAMP-2 is coexpressed with MPO and PR3 in neutrophils; however, unlike MPO and PR3, LAMP-2 is also expressed in glomerular endothelial cells, a key site of injury in AAVs. LAMP-2 autoantibodies were initially reported to be present in 85% of patients with untreated AAVs, a finding that was duplicated by the same investigators in a different cohort of AAV patients with glomerulonephritis where LAMP-2 positivity was specific for AAVs and paralleled disease activity. Another group found LAMP-2 in only 20% of AAV patients, however, which approached the frequency in their control population. Given these conflicting results and lack of commercial grade assays, the value of LAMP-2 detection in AAVs remains unknown.
Implications of Antineutrophil Cytoplasmic Antibody Specificity
There has been increasing appreciation of phenotypic distinction between AAV patients with PR3 and MPO positivity. A recent genome-wide association study identified distinct genetic subsets of AAV patients, determined by ANCA antigen specificity and not clinical syndrome; different HLA correlations were noted in those with PR3-ANCA and MPO-ANCA. Additionally, PR3 positivity was associated with genes coding for PR3 and α 1 -antitrypsin. Exploring these genetic associations may allow for better appreciation of distinctions between disease pathogenesis depending on autoantigen subtype and possibly provide a platform for future genetic markers to aid diagnosis.
Prognostic differences between PR3 and MPO positivity also exist. Compared with MPO-ANCA, PR3-ANCA is associated with a higher mortality (relative risk >3). Additional studies have identified PR3 positivity as an independent predictor of disease relapse. In a cohort of more than 500 patients with AAVs and biopsy-proved glomerulonephritis, PR3 specificity conferred a 2-fold risk for relapse compared with MPO. ANCA specificity for PR3 was independently associated with relapse regardless of pathology or clinical classification using the CHCC definitions of AAVs. Those with PR3-ANCA and renal disease may also have a faster decline in renal function compared with MPO-ANCA patients, although these data reflect deterioration prior to initiation of treatment. A recent cluster analysis of approximately 700 patients enrolled in AAV treatment trials identified 5 subgroups of AAV patients based on several clinical variables and ANCA specificity. Two of these subgroups were defined by renal involvement with or without PR3 positivity; patients in the renal AAVs with PR3 subgroup had higher relapse risk but lower mortality rate than those with renal disease and no PR3.
Serial Antineutrophil Cytoplasmic Antibody Measurements and Correlation with Disease Activity
Although ANCA detection has diagnostic and prognostic importance in AAVs, the utility of serial ANCA measurements is less certain. Considerable variability exists in the available literature addressing the value of serial ANCAs, with differences in ANCA detection methodology, follow-up intervals, and definitions of disease activity, which makes drawing definitive conclusions difficult. Observational cohorts have failed to show a definitive correlation between ANCA levels and disease activity or flare. A longitudinal analysis of 156 GPA patients participating in the Wegener’s Granulomatosis Etanercept Trial (WGET) showed that changes in ANCAs accounted for less than 10% of changes in disease activity; relapse within 1 year of increasing PR3 titer was seen in only 40% of patients.
A 2012 meta-analysis examining the value of serial ANCA measurements during remission to predict relapse included 18 articles looking at patients with either rising ANCA titer or persistently positive ANCAs. Trying to account for heterogeneity between studies, the investigators found that rising ANCAs or persistently positive ANCAs was associated with flare (positive likelihood ratios 2.84 and 1.97, respectively); however, they concluded that ANCA titer alone was insufficient to guide treatment decisions. Persistently negative ANCAs in a patient who was previously ANCA positive do not guarantee disease quiescence. In a study of 100 AAV patients followed prospectively with serial ANCAs, 13 of the 37 patients who relapsed were ANCA negative at time of relapse. In the right clinical setting and with supporting pathology when available, ANCAs remain a cornerstone for AAV diagnosis but are insufficiently sensitive or specific for monitoring disease activity, predicting relapse, or guiding immunosuppressive treatment. On an individual level, in patients in whom a relationship between ANCA level and disease activity has been established, serial ANCA testing may have a role in disease monitoring and therapeutic decision making.
Tissue biopsy
Guided tissue biopsies are important in defining the character and extent of the inflammatory process in the diagnosis of AAVs. Histologic confirmation of AAVs with tissue biopsy should be attempted whenever possible, but treatment should not be delayed in a critically ill patient with high suspicion for disease in whom tissue is not readily or safely accessible. Individual clinical presentation should dictate the biopsy location with the overall aim of performing the safest procedure with the highest potential yield. Diagnostic yield varies depending on organ system biopsied, especially because inflammatory changes may be patchy and examination of large amount of tissue may be required to make a histopathologic diagnosis. In conjunction with clinical and serologic information, histologic evidence of necrotizing vasculitis with accompanying granulomatous inflammation is used to differentiate GPA from MPA.
Although upper airway disease is noted in three-quarters of GPA patients at disease onset, tissue biopsy of these regions has low yield for identifying the classical pathologic necrotizing vasculitis with granulomatous inflammation. One study noted necrotizing vasculitis with concurrent extravascular granulomatosis in only 16% of upper airway biopsies. Other studies have found diagnostic yield of minimally invasive endonasal biopsy to approach 50%, especially in early or localized ENT disease, although this depends on location, depth, and number of samples biopsied. In routine practice, however, even when performed by an experienced surgeon, upper airway biopsy is rarely diagnostic.
In patients with evidence of renal involvement based on urinalysis or reduced creatinine clearance, kidney biopsy remains the gold standard for diagnosis of glomerulonephritis. Kidney biopsy has a high yield with varying degrees of segmental necrotizing pauci-immune glomerulonephritis in greater than 80% of specimens. Renal histopathology also has prognostic implications, according to a 2010 classification system of glomerular lesions, with sclerosis and tubular atrophy correlated with progression to end-stage renal disease.
Pulmonary involvement occurs in approximately 85% of AAV patients. Pulmonary lesions in GPA are commonly nodules and cavitary changes whereas MPA patients present more frequently with pulmonary infiltrates or diffuse alveolar hemorrhage. Targeted biopsy of radiographically abnormal lung parenchyma via a thoracoscopic or open lung biopsy is usually of high yield for AAV diagnosis. The efficacy of transbronchial biopsy, however, in establishing the diagnosis of pulmonary vasculitis is less than 10%, and a negative transbronchial specimen should not exclude the diagnosis of AAVs. Transbronchial specimens can be used to exclude infection or neoplasia, and bronchial alveolar lavage is helpful in confirming alveolar hemorrhage.
Treatment
Historical Perspective
The past several decades have seen major therapeutic advances in the management of AAVs. Primarily, recognition that a regimen of daily oral cyclophosphamide (CYC) and high-dose corticosteroids was effective for inducing remission in a vast majority of patients transformed AAVs from a uniformly fatal disease to a chronic relapsing disease with a dramatically reduced mortality of 25% at 5 years. Although the initial observational data supporting the use of CYC reflects the experience of physicians at the National Institutes of Health caring for a cohort of GPA patients, similar trends are evident in MPA. Progress has also been made in identification of various immunosuppressive agents with more favorable safety profiles than CYC, which can be used maintain remission; multiple randomized trials comparing maintenance regimens are discussed later ( Table 1 ). In an effort to minimize toxicity related to CYC, there was the additional insight that some patients could be successfully treated with CYC-free regimens. The past decade has seen the last major advance in AAV treatment born out of the search for more targeted therapy, with multicenter collaborations investigating the use of various biologic therapies. Targeting of B cells with rituximab (RTX), the monoclonal anti-CD20 antibody, has been demonstrated as an effective therapy for remission induction and maintenance in severe AAVs. In 2011, RTX became the first therapy approved by the Food and Drug Administration for GPA and MPA.
| Trial Name | Design | Primary Endpoint | Results |
|---|---|---|---|
| Induction | |||
| CYCLOPS | po-CYC vs IV-CYC in newly diagnosed AAVs with renal involvement | Time to remission | IV-CYC noninferior to po-CYC, lower cumulative dose and less leukopenia with IV, long-term follow-up suggested higher relapse rate with IV |
| NORAM | MTX vs po-CYC in patients with limited disease | Remission at 6 mo | No difference in remission rates at 6 mo between groups, in long-term follow-up, lower rate of relapse-free survival in MTX group |
| RAVE | RTX vs po-CYC, new or relapsing AAVs | Steroid-free remission at 6 mo | RTX noninferior to CYC for induction of remission and may be more effective in relapsing disease |
| RITUXIVAS | IV-CYC + RTX vs IV-CYC + placebo in newly diagnosed AAVs with renal involvement | Remission at 12 mo | RTX + IV-CYC noninferior to IV-CYC alone with similar rates of adverse events |
| Maintenance | |||
| CYCAZAREM | AZA vs po-CYC in new or relapsing AAVs after induction with po-CYC | Relapse rate | No difference in rates of relapse between the treatment groups |
| WEGENT | AZA vs MTX after induction with IV-CYC | Adverse events requiring discontinuation of treatment or death | No difference in adverse events and similar relapse rate in both treatment arms, majority of relapses occurred after study medication tapered off |
| IMPROVE | MMF vs AZA in newly diagnosed AAV patients after induction in CYCLOPS trial | Relapse-free survival | Relapse more common in MMF group with similar rates of adverse events |
| German Network of Rheumatic Diseases Study | LEF vs MTX in GPA after induction with po-CYC | Relapse rate | Study terminated early because of high incidence of major relapses in MTX arm, although increased frequency of adverse events in LEF arm (LEF dose 30 mg/d) |
| Dutch Co-Trimoxazole Wegener Study | TMP-SMX vs placebo, in GPA patients during/after remission induction with po-CYC | Disease-free interval | Fewer relapses in patients receiving TMP-SMX, although 20% patients discontinued TMP-SMX due to side effects |
| WGET | Etanercept vs placebo in addition to CYC (severe) or MTX (limited) for active GPA | Sustained remission for ≥6 mo | Etanercept not effective for remission maintenance, 6 malignancies in etanercept group (all in patients on prior CYC) |
Treatment Principles
As AAV therapies evolve, several fundamental treatment principles continue to guide patient management. First, patients should be stratified by disease severity with treatment tailored to severity of disease. Severe disease, defined as life- or organ-threatening manifestations, includes features, such as rapidly progressive glomerulonephritis, pulmonary hemorrhage, mesenteric ischemia, scleritis, and nervous system involvement and typically requires more aggressive therapy. Limited disease, which encompasses all non–life- or organ-threatening manifestations, including mild renal or pulmonary disease, may not require as potent immunosuppression as severe disease. Similarly, disease flares or relapses should be characterized as limited or severe based on organ systems involved, and this distinction must be taken into account when choosing therapy.
The treatment paradigm is conceptualized in 2 components, namely induction of remission followed by institution of maintenance therapy. This principle arose from recognition of CYC toxicity and desire to minimize and/or avoid CYC exposure if possible. Corticosteroids remain part of all induction regimens in active or relapsing disease and are usually tapered once remission is attained. Some patients are maintained on low-dose corticosteroids during the maintenance period, although at most centers, the aim is for complete discontinuation after remission induction. The optimal tapering regimen and duration of glucocorticoid treatment is not established.
Once remission is induced, structured clinical assessments with urinalysis and basic laboratory tests should be performed regularly to monitor for new organ involvement, treatment response, and drug toxicity. Relapse is common in AAVs, especially after discontinuation of immunosuppression. The optimal duration of maintenance therapy is unknown. Approaching 55% in some studies, relapse rates are highest in the first few years after diagnosis; thus, maintenance immunosuppression is generally continued for approximately 2 years in most patients. Duration of maintenance therapy should be individualized and balance the individual risk of relapse with treatment morbidity. The main cause of death in the first year of AAV diagnosis is infection, accounting for 48% of deaths compared with 19% of deaths due to active vasculitis, so the risk of immunosuppression is not trivial.
Damage, which can be the sequelae of both previous disease activity and treatment-related toxicity, occurs frequently in AAVs. Treatment should be directed to avoid accrual of permanent damage while ensuring immunosuppressive therapy is aimed only at manifestations of active disease, not those reflecting prior damage. Reliable biomarkers that would allow for distinction of active disease from damage or infection, portend relapse, or predict treatment response are lacking in AAVs. Ideally, therapy should be individualized based on a patient’s history, comorbidities, disease severity, and pattern of organ involvement.
Induction Therapy
Severe disease
As discussed previously, CYC in combination with high-dose corticosteroids was long considered the standard of care for remission induction therapy in severe AAVs. Complete remission is attainable in greater than 75% of patients treated with oral CYC at doses of 2 mg/kg/d (with dose reductions made for older age and renal insufficiency). Treatment-related morbidity, including hemorrhagic cystitis, malignancy, and infertility, occurs in 50% of patients and is related to cumulative dose. In an attempt to minimize CYC exposure, use of pulse intravenous CYC (IV-CYC) was investigated in the CYCLOPS (pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis) trial. In this study comparing daily oral CYC to pulse IV-CYC (15 mg/kg every 2–3 weeks) in newly diagnosed AAVs with renal involvement, there was no difference in time to remission or remission rates between the 2 treatment groups. Patients treated with IV-CYC received lower cumulative doses of CYC and had one-third fewer occurrences of leukopenia. Although this initial study was not powered to detect a difference in relapse rates, long-term follow-up of study participants suggested an increased rate of relapse in those treated with IV-CYC. Thus, CYC regimens are similar in their ability to induce remission with possibly higher relapse rates in IV-CYC, which must be balanced with higher rates of leukopenia and potential infection in daily oral regimens. Deciding between CYC route of administration needs to be an individualized decision between the patient and the treating physician.
B lymphocytes are implicated in the pathogenesis of AAVs by giving rising to autoantibody-producing plasma cells, by contributing to local cytokine production, by acting as antigen-presenting cells, and through the T cell costimulatory pathway. Specific targeting of B lymphocytes with RTX has been shown an effective treatment strategy in severe AAVs. Two randomized trials, including patients with both newly diagnosed and relapsing severe AAVs, demonstrated that RTX was noninferior to CYC for remission induction. In the double-blind, double-dummy randomized controlled Rituximab for ANCA-Associated Vasculitis (RAVE) trial, a single course of RTX (375 mg/m 2 weekly for 4 weeks) was compared with CYC followed by azathioprine (AZA) in 197 AAV patients; all patients received high-dose IV corticosteroids at the beginning of the induction regimen. Patients with serum creatinine greater than 4 mg/dL or alveolar hemorrhage requiring mechanical ventilatory support were excluded from RAVE. The primary endpoint of complete remission and tapering of prednisone at 6 months was achieved by 64% of patients receiving RTX compared with 53% of those receiving CYC, meeting the criteria for noninferiority with similar rates of flare and serious adverse events noted in both groups. In the subset of patients with relapsing disease at trial enrollment, RTX seemed superior to CYC in inducing remission.
Published concurrent with RAVE, the Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis (RITUXIVAS) study was an open-label trial in newly diagnosed AAVs with renal involvement. Patients were randomized 3:1 to receive RTX (375 mg/m 2 weekly for 4 weeks) plus 2 doses of IV-CYC or pulse IV-CYC alone along with background corticosteroids in both groups. At 12 months, 76% of patients in the RTX-CYC group and 82% of the CYC-only treated patients had achieved sustained remission. Like RAVE, RITUXIVAS concluded an RTX-based regimen was noninferior to a standard CYC induction regimen with similar rates of adverse events. With these studies demonstrating efficacy of RTX as induction therapy, there has been increasing use of RTX as initial therapy in AAVs, especially in patients with concerns about infertility or malignancy. Because those with severe renal dysfunction and respiratory failure were excluded from RAVE, and RITUXIVAS used RTX in combination with CYC, the efficacy of RTX-only regimens in these critically ill patients is not well studied.
Plasma exchange, in conjunction with standard induction therapy, has been used in patients with severe renal disease and/or alveolar hemorrhage. Data suggest plasma exchange may improve renal recovery in those with severe renal disease (creatinine >5.8 mg/dL) or dialysis dependence without any overall mortality benefit. The MEPEX (randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis) trial was an open-label study of 1 g pulse methylprednisolone daily for 3 days compared with 7 sessions of plasma exchange for newly diagnosed AAVs with severe renal disease, with all patients getting oral corticosteroids and CYC. At 3 months, 69% of those treated with plasma exchange compared with 49% of those treated with methylprednisolone were alive and dialysis independent. There have been no controlled trials of diffuse alveolar hemorrhage treated with plasma exchange, although retrospective data suggest there may be a benefit. To more definitely answer questions about the role of plasma exchange in AAVs with alveolar hemorrhage and/or severe renal disease, the Plasma Exchange and Glucocorticoids for Treatment of ANCA-Associated Vasculitis (PEXIVAS) is an ongoing randomized, controlled, international study evaluating adjunctive plasma exchange and 2 oral glucocorticoid regimens.
Limited disease
Methotrexate (MTX) can be used to induce remission in limited AAVs as demonstrated in an open-label, randomized trial comparing MTX to CYC. The NORAM (randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis) trial randomized patients with newly diagnosed limited AAVs, including patients with mild renal disease, to MTX (15–25 mg weekly) or oral CYC. The primary endpoint of remission at 6 months was achieved in 90% of MTX-treated patients and 94% of CYC-treated patients. Patients receiving MTX took a longer time to achieve remission. At 18 months, higher rates of relapse were seen in those who had been treated with MTX compared with CYC, although a majority of relapses occurred after therapy had been tapered off. The observation of high relapse rates after discontinuation of therapy has led to the standard continuation of maintenance immunosuppression for greater than 12 months in most patients. Follow-up of these patients at a median of 6 years after induction therapy revealed the patients initially treated with MTX had lower rates of relapse-free survival and were treated with immunosuppressive therapy for a longer period of time than those in the CYC group.
Maintenance Therapy
AZA and MTX are the principle conventional immunosuppressive agents used for maintenance remission in AAVs. The CYCAZAREM (A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies) trial randomized 155 patients with newly diagnosed AAVs who had achieved remission on oral CYC to continue treatment with CYC at a lower dose or to switch to AZA. All patients were placed on AZA at 12 months. The primary endpoint of this study was relapse rate at 18 months, which was not significantly different between the 2 treatment groups nor was there a difference in adverse events observed. WEGENT (Azathioprine or methotrexate maintenance for ANCA-associated vasculitis) was a prospective, open-label maintenance trial comparing MTX to AZA in 159 AAV patients, all of whom received IV-CYC for induction. The primary endpoint of this trial was adverse events requiring discontinuation of therapy, with the hypothesis that MTX would better tolerated than AZA. Rates of adverse events and relapse rates were similar between both groups of patients; echoing previous results, a majority of relapses in this trial occurred after discontinuation of maintenance therapy. Thus, MTX and AZA seem comparably efficacious and safe maintenance agents in AAVs. Given renal clearance of MTX, use of MTX in patients with permanent renal damage and reduced creatinine clearance should be avoided, and AZA is likely a safer option in these patients. Similarly, MTX is a known teratogen, making AZA a better option in woman of childbearing potential.
Leflunomide (LEF) is an alternative maintenance agent in AAVs. A trial comparing LEF (30 mg daily) to MTX was terminated early due to a higher incidence of major relapse in the MTX arm, although patients in the LEF arm experienced a significantly higher rate of adverse events. High rates of adverse events and discontinuation of therapy due to intolerability limit the use of LEF as first-line maintenance therapy.
Hypothesizing that mycophenolate mofetil (MMF) would be more effective than AZA in preventing relapse, the IMPROVE (Mycophenolate mofetil versus azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis) trial randomized 154 newly diagnosed AAV patients to MMF (2000 mg daily) and AZA (2 mg/kg daily) after remission was induced with CYC. At a median follow-up of 36 months, relapse rates were higher in the MMF treatment arm, with a hazard ratio of 1.69 and with no difference in serious adverse events. There have been no head-to-head comparisons of MMF and MTX. Because MMF is less efficacious than AZA in preventing relapse, it is not routinely used as a first-line maintenance therapy in AAVs, although it may have a role in treating patients with refractory disease or those intolerant of other agents.
Bacterial colonization, such as nasal carriage of Staphylococcus aureus , has been suggested to play a role in disease induction and relapse in GPA. The role of antistaphylococcal therapy with trimethoprim-sulfamethoxazole (TMP-SMX) was investigated as an adjunctive remission maintenance agent in GPA in a double-blind study of 81 patients, stratified by renal involvement, who were randomized to TMP-SMX (800 mg/160 mg twice daily) or placebo. At 24 months, 82% of TMP-SMX treated patients were in remission compared with 60% of the placebo group with a relative risk of relapse for TMP-SMX of 0.4, although TMP-SMX was discontinued in 20% of patients due to intolerability. The benefit of TMP-SMX seemed most apparent in patients with upper airway disease. Treatment doses of TMP-SMX can be considered an alternative maintenance therapy for GPA patients with mild, localized upper airway disease or an adjunctive therapy in those on other immunosuppressive agents to reduce risk of relapse.
WGET was the first clinical trial in which a biologic was evaluated as a treatment of vasculitis and was based on experimental data suggesting that tumor necrosis factor α (TNF-α) may be an important inflammatory mediator in GPA. WGET randomized 180 GPA patients to received etanercept, an anti–TNF-α agent, or placebo in addition to standard therapy for remission maintenance. Patients with limited disease received MTX as standard therapy and those with severe disease at enrollment were given CYC. There was no difference in rates of sustained remission in those receiving etanercept compared with placebo, and flares were common in both groups. WGET concluded etanercept is not effective for remission maintenance in GPA. Furthermore, 6 patients in the etanercept group developed solid malignancies compared with no malignancies in the placebo group. All of the patients who developed malignancy had received prior CYC; whether TNF blockade had an additive effect on malignancy risk in AAVs is unknown. Given the WGET data, however, anti–TNF-α therapy does not have a routine role in treatment of AAVs.
RTX is an effective maintenance therapy for AAVs. A follow-up of RAVE reported that 48% and 39% of the patients receiving the single course of RTX remained in complete remission at 12 and 18 months, respectively, compared with 39% and 33% of those in the CYC group, again meeting the criteria for noninferiority; RTX again seemed superior in those with relapsing disease with no difference in adverse events between the groups observed. These data suggest that given the prolonged duration of its biologic effects, a single course of RTX has comparable safety and efficacy to continuous conventional immunosuppressive therapy in remission induction and maintenance out to 18 months. Additionally, RTX has proved effectiveness for treatment of severe disease flares regardless of previous treatment history.
The ideal dose and frequency of administration of RTX maintenance remain unknown. An observational study of Mayo Clinic’s decade-long experience with repeated RTX treatment of refractory GPA suggests utility in the combination of B-lymphocyte reconstitution and ANCA level in predicting relapse. In this cohort of chronically relapsing patients, all observed relapses occurred after B-cell reconstitution and were temporally accompanied by an increase in PR3 levels (except in 1 patient who was ANCA negative) suggesting that RTX retreatment can be individualized. Other investigators have demonstrated effectiveness of preemptive retreatment approach with RTX. A study comparing RTX maintenance at a fixed-dose and interval (1 g every 6 months) to those treated at time of relapse found reduced relapse rates and longer periods of remission in the preemptive retreatment group without an increase in adverse events during the observational period. A trial comparing 2 RTX-based maintenance regimens, 1 based on reconstitution of B lymphocytes and rising ANCAs and the other a strategy of fixed-interval retreatment every 6 months, is ongoing.
There are no controlled studies of RTX expressly for limited disease manifestations. As previously noted, upper airway involvement occurs frequently in GPA and is an independent risk factor for disease relapse. Additionally, persistent, grumbling otolaryngologic disease is common and can lead to accrual of permanent damage, such as nasal bridge collapse, hearing loss, and subglottic stenosis, making treatment of these disease manifestations crucial. The efficacy of RTX for the granulomatous compared with vasculitic manifestations of GPA is debated, with several case series offering conflicting results In the largest reported observational cohort looking at RTX solely for otolaryngologic manifestations of GPA, patients given RTX for active ENT disease were greater than 10 times less likely to have active ENT disease compared with patients treated with other therapies ; results of this retrospective study suggest RTX may be a useful therapy for granulomatous otolaryngologic disease in GPA.
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