Background

Antineutrophil cytoplasmic antibody (ANCA) vasculitis comprises a spectrum of diseases, including Wegener's granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome (ANCA-associated vasculitis: AAV), characterised by the presence of ANCA in the serum of patients. These autoantibodies were first discovered by Davies et al. in 1982 when they were studying immunofluorescence staining in serum samples from patients with segmental necrotising glomerulonephritis.1 Instead of the classical nuclear staining, a cytoplasmic pattern was seen. In 1985 van der Woude et al. observed that cytoplasmic ANCA mainly developed in patients with Wegener's granulomatosis.2 ANCA are predominantly autoantibodies to proteinase-3 (PR3) and myeloperoxidase (MPO), which are enzymes residing within the azurophilic granules of human neutrophils. In vitro, these autoantibodies can result in activation and degranulation of primed neutrophils, with resulting damage to endothelial cells.3

Typically, patients with Wegener's granulomatosis have an immunoglobulin G (IgG) antibody to proteinase-3 (PR3 IgG) and those with microscopic polyangiitis are IgG positive for myeloperoxidase (MPO IgG). The discovery of ANCA revolutionised the study of small-medium vessel vasculitis as it provided a laboratory test to accurately identify this subgroup of patients. The subsequent improvements in the detection of ANCA by enzyme-linked immunosorbent assay (ELISA) have paralleled the advances in the medical treatment of AAV. The international consensus statement on reporting ANCA levels recommends that all serum samples should first undergo indirect immunofluorescence (IIF) testing using normal peripheral blood neutrophils. Should this screening test show the presence of perinuclear or cytoplasmic fluorescence an ELISA, to detect ANCA specific for PR3 or MPO, should be performed.4

The value and limitations of these two methods as diagnostic and predictive tools for AAV have been extensively studied. Harris et al. compared the diagnostic performance of ELISA and IIF, and found the highest sensitivity with combined testing (92%) and the highest positive predictive value with combined ELISA and IIF (73%).5 It has been shown that the ANCA test is best used in cases with a high index of clinical suspicion of AAV to further reduce the rate of false-positive results.6 Furthermore a study examining antigen-specific ANCA ELISAs has found different sensitivities for active and treated vasculitic disease. It found that the PR3-ANCA and MPO-ANCA ELISAs were all highly sensitive and specific for the diagnosis of active small vessel vasculitis, but varied in their ability to detect ANCA in treated AAV.7

Criteria defining AAV involving clinical features and histological findings have been published by the American College of Rheumatology and the Chapel Hill group.8,9 The precise classification of AAV has allowed individuals with this disease to be identified and studied exclusively in clinical trials.

This commentary aims to review the major published international collaborative studies regarding the treatment of AAV and discuss their findings according to the level of renal function in the individuals studied. The publications discussed were identified from Pubmed, The European Vasculitis Study Group (EUVAS) website (http://www.vasculitis.org) and published abstracts from 14th International Vasculitis and ANCA Workshop. Each paper was critically reviewed and the type of trial and therapeutic intervention, number of patients enrolled, duration of follow up and renal function of the patients were considered when evaluating each paper. While this commentary does not attempt to be a meta-analysis, the authors believe that at the time of publication most relevant studies are included in this review.

Clinical features and outcomes of AAV

Antineutrophil cytoplasmic antibody-associated vasculitis is a life-threatening, systemic disease that requires prompt diagnosis and therapeutic intervention. Multiple organ systems can be affected, particularly the kidneys, lungs, upper respiratory tract, gut, skin and brain. AAV has an annual incidence in Europe of 10-20 per million, per year. There is an increased incidence with age, with a median age of onset of 56 years.10 Men are more often affected than women. Epidemiological studies have found that there is an association between exposure to silica dust and an increased risk of developing disease.11 There has also been reported a possible association between farming and developing AAV.12 Before the availability of medical therapy the mortality rate of Wegener's granulomatosis was 80% at 1 year and 100% in the presence of systemic disease.13 Recent studies have reported 1- and 5-year survival rates of 85% and 75%, respectively.14 Age and serum creatinine at diagnosis are the strongest predictors of both patient and renal survival.14

The kidneys are the most frequently involved vital organ with 70% of patients having renal involvement.15 Those who present with advanced renal failure have poorer outcomes, with only 50% of those who survive having independent renal function at 1 year.14 Approximately 20% of surviving patients who had histological renal involvement at the time of diagnosis developed end-stage renal disease.16 It is estimated that AAV accounts for around 5% of all causes of renal failure requiring renal replacement therapy.17,18

With the development of successful medical therapy AAV has become a chronic medical illness. Many patients suffer from problems due to end-organ damage from the vasculitic disease process and the side-effects of pharmacological therapy. The long-term follow up of patients with Wegener's granulomatosis by the National Institutes of Health found that 86% of patients had permanent end-organ damage as a consequence of the disease, and 42% of patients experienced permanent treatment-related morbidity.19 In a more recent cohort study 180 patients were followed for a median of 25 months as part of the Wegener's granulomatosis Etanercept trial.20 At the time of enrolment in the trial the median time since diagnosis was 4.7 months. At the commencement of the trial 40.2% had ear, nose or throat damage and 15.5% had kidney impairment. After 12 months of follow up, only 11% of the patients had not developed any permanent health problems due to either AAV, or the medical treatment received. It was estimated by the authors that three-quarters of the medical problems reported were directly due to the Wegener's granulomatosis disease process. They also found that as a patient developed more medical complications, there was a measurable decline in the patients' quality of life.20

Goals of therapy

Ideally AAV would be diagnosed early in the course of disease to reduce the risk of permanent end-organ damage and the amount of immunosuppression required. For instance, the higher the serum creatinine at presentation, the greater the likelihood of developing end-stage renal failure, and the higher the mortality rate.16 Like other autoimmune diseases, AAV can be a great mimic and present in many ways, further complicating and delaying the initial diagnosis and subsequent treatment. The discovery of ANCA, and the implementation of laboratory test for its detection have assisted with the earlier diagnosis of AAV. Nevertheless, strategies to reduce the time to the initial diagnosis and treatment are still important to reduce exposure to immunosuppressive agents and to reduce end-organ damage.

The treatment of AAV has been divided into two distinct phases. The initial induction phase involves the administration of potent immunosuppressive agents for 3-6 months. Maintenance pharmacological therapy then follows and uses less toxic immunosuppression. The change from induction to maintenance therapy needs to be assessed individually and should proceed when there is clinical evidence that the disease is in remission. Recently EUVAS has published guidelines on the management of AAV according to the clinical stage of the disease and phase of treatment.21

Another aim when treating patients with AAV is to minimise the toxicity of treatment. This can be done by limiting the duration and dose of immunosuppressive agents, but needs to be balanced against the risk of relapse and achieving disease control. Immunosuppressive drugs such as prednisolone, cyclophosphamide, methotrexate and azathioprine have been the mainstay of therapy for many years. The side-effects of these therapies are numerous, and include bone marrow suppression, diabetes mellitus, infertility, cystitis and malignancy.

Induction therapy

The first trial evidence for medical induction therapy for the treatment of AAV began with the retrospective findings from the National Institutes of Health using a prolonged course of oral prednisolone and cyclophosphamide, regardless of renal function.19 The relapse rate from this study was around 50% and side-effects were significant and included glucocorticoid-induced diabetes mellitus (8%), cyclophosphamide cystitis (43%), bone fractures (11%) and myelodysplasia (2%).19 Following this initial report further prospective randomised controlled intervention studies have been conducted. To further determine which subgroups of AAV patients may benefit from different treatments more recent trials have further identified specific patient subgroups by including measures such as serum creatinine to define renal function. This has identified that some treatment options are more beneficial for those patients with preserved renal function compared with those who require dialysis therapy.

Induction therapy for patients with AAV and a serum creatinine less than 500 [micro]mol/L

The current recommended induction therapy for patients with organ-threatening AAV is a potent immunosuppressive regime consisting of a cytotoxic drug such as cyclophosphamide, with prednisolone, as first-line therapy. Recent clinical trials have used prednisolone as induction therapy at 1 mg/kg per day (maximum of 60 mg/day). The European League Against Rheumatism (EULAR) recommends that the dose of glucocorticoids be maintained at this high dose for 1 month followed by a stepwise reduction to less than 15 mg/day after 3 months of therapy.21

In order to reduce the side-effects of cyclophosphamide and prednisolone therapy, and reduce the risk of relapse, various trials were established to compare pulse intravenous cyclophosphamide with continuous oral cyclophosphamide therapy.22-24 In all three of these trials patients with normal renal function and those with significant renal impairment (creatinine >500 [micro]mol/L, and/or requiring dialysis at commencement) were enrolled. The trial by Adu et al. (n = 54 patients enrolled) and Guillevin et al. (n = 50) were prospective; however, the trial by Haubitz et al. (n = 35) was retrospective. Despite the different methodologies of these three trials a meta-analysis was performed and concluded that intravenous therapy was more likely to successfully induce remission than oral therapy. There was also a lower risk of infection and leucopenia with intravenous therapy.25 However, there was an increased risk of disease relapse in those treated with intravenous therapy, but this failed to reach statistical significance. The incidence of death and end-stage renal failure was no different between the two treatment modalities. The authors concluded that intravenous cyclophosphamide was less toxic than continuous oral cyclophosphamide and an effective induction regime to achieve remission, but potentially resulted in a higher risk of relapse. As the total number of patients included in the meta-analysis was only n = 149, the group suggested that further trials were needed.25

The EUVAS group conducted a prospective trial of newly diagnosed patients with AAV and renal involvement (but serum creatinine less than 500 [micro]mol/L). One hundred and sixty patients were enrolled and n = 149 were treated with prednisolone and randomised to daily oral cyclophosphamide (2 mg/kg/day) or pulse intravenous cyclophosphamide (15 mg/kg with 2 weeks between the first two doses and then 3-weekly). Azathioprine was commenced at 3 months after remission was achieved in both groups. The primary end-point of the study was the time to achieve remission. Importantly this study was underpowered to detect differences in relapse rates between groups, non-blinded and the duration of follow up only 18 months. The results showed that there was no difference in remission rates for AAV for patients who received a pulse cyclophosphamide regimen compared with those who received a daily oral cyclophosphamide regimen. There was no significant difference in glomerular filtration rate, or the development of end-stage renal failure between the two groups. There was a reduced cumulative cyclophosphamide dosage for the pulse compared with the oral route of administration, and there were fewer cases of leucopenia.26

In an attempt to find alternative agents and improve relapse rates, other agents have been investigated. Etanercept is a recombinant, soluble, human tumour necrosis factor (TNF)-receptor fusion protein. Etanercept was trialled as induction and maintenance therapy for Wegener's granulomatosis Etanercept trial (WGET trial). One hundred and eighty patients were randomised to receive either etanercept or placebo as induction therapy in conjunction with standard induction therapy of prednisolone and cyclophosphamide or methotrexate.27 All patients enrolled in this trial had a serum creatinine of less than 500 [micro]mol/L. The primary outcome was sustained disease remission for at least 6 months. Etanercept failed to show a benefit when used in addition to standard therapy for induction or maintenance therapy. Notably, six solid cancers were observed in those patients treated with both etanercept and cyclophosphamide, thus raising concern about this pharmacological combination. The authors concluded that etanercept was not effective for the maintenance of remission of patients with Wegener's granulomatosis. Sustainable remissions were only achieved in the minority of patients and there was a high rate of treatment-related complications.

Cyclophosphamide and methotrexate have also been compared as induction therapy in early AAV, although patients with a serum creatinine greater than 150 [micro]mol/L or urinary red cell casts or proteinuria greater than 1 g/day were excluded from this trial. The use of methotrexate in patients with renal impairment in practice is difficult because of the significant risk of pancytopenia. Patients with organ or life-threatening manifestations were also excluded. Even though remission rates were similar in both groups, significantly more disease relapses were observed in the methotrexate group as compared with the cyclophosphamide group.28 Methotrexate may have a role as induction therapy in patients with AAV with very early disease and little end-organ damage.

Hu et al. enrolled 35 Chinese patients in a clinical trial to compare mycophenolate mofetil (MMF) and pulse cyclophosphamide as induction treatment for patients with MPO-AAV and moderate renal involvement. Patients were eligible for the study if their serum creatinine was less than 500 [micro]mol/L. They found that MMF was as effective an induction agent as cyclophosphamide, although the remission rates for both agents were lower than in previous studies. There was no difference in adverse events between the groups.29 However, the patient number was small in this trial, and larger trials with the inclusion of PR3 patients are needed. The EUVAS group is currently conducting a clinical trial to compare the use of MMF and cyclophosphamide as an induction agent for AAV (MYCYC trial). However, patients with rapidly progressive glomerulonephritis, a glomerular filtration rate less than 15 mL/min, and patients on dialysis at entry will all be excluded from this trial.

Induction therapy for patients with AAV and a serum creatinine greater than 500 [micro]mol/L

The early trials using cyclophosphamide and prednisolone as induction therapy for AAV all enrolled patients with serum creatinine >500 [micro]mol/L, or requiring dialysis therapy.22-24 Importantly a reduction in the dose of cyclophosphamide needs to be made for patients with renal impairment as the parent drug and the metabolites are excreted in the urine.30 Cyclophosphamide and prednisolone therapy are recommended as first-line induction therapy for patients with serum creatinine greater than 500 [micro]mol/L, although there is limited evidence in this patient subgroup.

Plasma exchange was first successfully used for rapidly progressive glomerulonephritis in the treatment of anti-glomerular basement membrane (anti-GBM) disease.31 Plasma exchange removes the plasma from the patient's circulation and replaces it with either donated fresh frozen plasma or albumin. There may also be immunomodulatory benefits as part of plasma exchange therapy with the removal of cytokines, inflammatory reactants and coagulation and complement factors.32 In 1991, following the discovery of ANCA antibodies, Pusey et al. trialled plasma exchange therapy for the treatment AAV. They found that if patients did not require dialysis, there was no additional benefit of plasma exchange in addition to immunosuppressive therapy. However, for a small subgroup that was dialysis dependent there was a significant short-term benefit of plasma exchange.33 Further small randomised controlled trials failed to show any benefit of plasma exchange in the treatment of non-anti-GBM antibody-mediated rapidly progressive glomerulonephritis.34-36 However, subset analysis again suggested that plasma exchange may be beneficial for those patients presenting with severe disease or dialysis dependency.37

The EUVAS group subsequently performed a randomised trial of plasma exchange versus high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis (Plasma exchange (PEX) versus pulse methylprednisolone (MEP) trial). The trial was designed to examine whether there was any benefit for those patients with AAV and severe renal failure (creatinine >= 500 [micro]mol/L, or requiring dialysis) to receive plasma exchange compared with intravenous methylprednisolone.38 This study randomised 137 individuals to either intravenous methylprednisolone or plasma exchange. Both groups received similar regimes of cyclophosphamide and oral prednisolone. The investigators found a higher rate of renal recovery and dialysis independence in the group that received plasma exchange compared with those who received intravenous methylprednisolone. However, disappointingly there was no difference in the rates of adverse effects, infections or patient survival between the two groups.38

A possible reason for these findings may be that once renal failure is so advanced plasma exchange cannot alter the disease outcome. To determine whether earlier commencement of plasma exchange may improve patient and renal outcomes, and to determine if exposure to lower dosages of corticosteroids may be as effective as conventional dosages of corticortisteroids, the EUVAS group has designed a two-by-two factorial design randomised clinical trial of high- versus low-dose steroid regimens, and adjunctive plasma exchange versus no plasma exchange in AAV [(PEXIVAS trial - Plasma exchange and glucocorticoids for the treatment of ANCA-associated vasculitis)]. The trial will specifically recruit patients with renal disease (creatinine > 200 [micro]mol/L or rise in serum creatinine of 30% within 60 days), but will exclude those with end-stage disease defined as requiring dialysis for more than 2 weeks before trial entry. The trial hopes to show the efficacy of adjunctive plasma exchange for moderate to severe AAV by measuring primary end-points of end-stage renal disease and all-cause mortality. The other aim of this trial is to examine the dosage of steroids needed to treat AAV.

Maintenance therapy

Given the side-effects of long-term cyclophosphamide use, there has been a desire to reduce the cumulative exposure to cyclophosphamide. This strategy uses cyclophosphamide to induce remission over a 3- to 6-month period, followed by a less toxic immunosuppressant such as azathioprine or methotrexate.39 In 1997 Adu et al. randomised 54 patients with vasculitis to receive remission maintenance therapy with cyclophosphamide or azathioprine and found no significant difference in adverse events.22 However there was a non-significant trend towards increased toxicity in patients treated with cyclophosphamide as maintenance therapy compared with those treated with azathioprine. A follow-up study of a larger cohort of 155 patients followed over 18 months randomised the patients to either azathioprine or cyclophosphamide after at least 3 months of oral cyclophosphamide and prednisolone [(CYCAZAREM trial - cyclophosphamide vs azathioprine for early remission of vasculitis)]. They found that in patients with AAV the withdrawal of cyclophosphamide and the substitution of azathioprine after remission did not increase the risk of relapse, and there were no increases in adverse events.40 Notably this study excluded patients with a serum creatinine of greater than 500 [micro]mol/L at enrolment.

More recent studies have compared the safety and efficacy of azathioprine and methotrexate combined with prednisolone as maintenance therapy in AAV patients in remission.39 In a prospective, open-label, multicentre trial patients with AAV in remission were randomised to receive oral azathioprine or methotrexate for 12 months. The primary end-point was an adverse event requiring discontinuation of the study drug or causing death. Patients with renal impairment were enrolled in the study, but at entry all had a serum creatinine of less than 500 [micro]mol/L. The authors found that methotrexate and azathioprine appear to be similar immunosuppressive alternatives for maintenance therapy for patients with AAV after initial remission is achieved. There was no significant difference in the side-effects or rate of relapse between the two drugs and the authors concluded that either agent could be used depending on the patients' individual characteristics.39

Mycophenolate and leflunomide were suggested by the British Society for Rheumatology as alternatives to methotrexate and azathioprine as maintenance therapy only if the more conventional therapy is ineffective or not tolerated.41 Other authors have suggested that these agents should be used with caution as experience and evidence is limited. Importantly, there is no evidence that these agents are superior to the conventional azathioprine and methotrexate therapy, and leflunomide in particular is associated with significant side-effects.42 The EUVAS group has completed a clinical trial comparing MMF with a standard azathioprine regime for remission maintenance after induction with cyclophosphamide and glucocorticoids in AAV (IMPROVE trial, NCT00307645). There are no published results, but preliminary oral results presented at the 14th International ANCA and vasculitis workshop in June 2009 suggested that azathioprine was perhaps a superior agent to MMF in maintaining remission in patients with AAV.43 The renal function of this group of patients was not reported in the printed abstract and final publication of the results is awaited.

The length of time to continue maintenance therapy is unclear, and tailoring of therapy to the individual patient is required. The British Society for Rheumatology recommends that patients should continue maintenance therapy for at least 24 months following successful disease remission. Patients with Wegener's granulomatosis or those who remain ANCA positive should continue immunosuppression for up to 5 years.41 De Groot et al. found that discontinuing maintenance therapy after 12 months in a group of patients with early AAV showed a higher relapse rate at 18 months compared with patients in other trials using the same immunosuppressive agents but for a longer period.28 The EUVAS group is conducting a clinical trial to help determine the duration of maintenance therapy. The group is conducting a randomised trial of prolonged remission-maintenance therapy in systemic vasculitis (REMAIN trial, BMH - CT93-1078), in which 2 years versus 4 years of azathioprine and prednisolone are being compared in patients with renal vasculitis.44

Treatment of refractory disease

Refractory disease is defined as disease that fails to respond to conventional remission induction therapy. The evidence is limited for all levels of renal function due to small patient numbers and practical difficulties in performing trials in this area. About 10-20% of patients with AAV are refractory to conventional cyclophosphamide and prednisolone therapy.32,45 Intravenous immunoglobulin (IVIg) has been used for patients who continue to have active disease despite conventional remission-induction therapy.46,47 The hypothesis is that IVIg may be effective in inhibiting the binding of ANCA to their antigens and Fc receptors, and thereby inhibit ANCA-mediated neutrophil activation. In a placebo-controlled trial of IVIg, the addition improved disease control initially, but this was not sustained beyond 3 months. Other treatments that have been investigated include the blockade of TNF[alpha] with infliximab. Booth et al. found in a prospective uncontrolled trial of infliximab that nearly 90% of the 16 patients studied initially responded, but 20% developed a relapse of disease within 17 months of follow up. Twenty-one per cent of patients who received infliximab developed a severe infection.48 Further randomised controlled trials are therefore required to determine whether there is a role for infliximab in the treatment of AAV.

15-Deoxyspergualin (DSG) is a peptidomimetic compound that has immunosuppressive properties and has been used in animal models of transplantation and autoimmune disease.49 Flossmann et al. recruited 44 patients with active Wegener's granulomatosis, who despite treatment with cyclophosphamide or methotrexate did not have adequate disease control.50 Complete remission was achieved in 45% of patients and partial remission in 95%. Relapses occurred in 43% of patients. Significantly, 53% of patients developed severe or life-threatening treatment-related adverse events. This rate of adverse events was much higher than previously reported in a smaller trial.49 The EULAR group recommends that given the significant risk of severe side-effects DSG should only be used as a treatment option in the event of refractory disease.21

Relapsing disease

Disease relapse after achieving successful disease control is not uncommon. Patients with Wegener's granulomatosis are more likely to relapse (50-80%) than those with microscopic polyangiitis (30%).40 Three main factors have been found to be associated with relapse of AAV. The first was treatment: receiving <10 g (compared with >=10 g) of cyclophosphamide in the first 6 months was associated with an increased relapse rate.51 Maintaining a high dose of prednisolone (>20 mg/day) for less than 2.75 months increased the risk of relapse.52 The adjunctive use of trimethoprim/sulfamethoxazole (160/800 mg) twice a day maintained remission for longer in patients with Wegner's granulomatosis.53 Withdrawal of immunosuppression is also a risk factor for disease relapse, and most relapses occur within the first year of withdrawal of immunosuppressive therapy.54 The second factor affecting relapse was a positive ANCA titre. The presence of a positive PR3-ANCA titre at diagnosis conferred an increased risk of relapse.55 Patients who remained ANCA positive after induction therapy, or became ANCA positive again while in remission, had a significantly increased risk of relapse compared with those patients who were ANCA negative.55 The third factor was target organ involvement. The presence of lung, cardiac or upper-airway disease is also associated with a higher risk of relapse in AAV.40,51 Patients with a creatinine clearance greater than 60 mL/min were also more likely to relapse.56

Rituximab

A novel therapy under investigation for use in AAV is rituximab. Rituximab is an IgG mouse/human chimeric monoclonal antibody that targets the B-cell-specific surface marker CD20. Binding of the antibody to this cell surface marker results in the depletion of peripheral B-cells, but not plasma cells. Various mechanisms have been found to account for B-cell depletion, including B-cell apoptosis induced by rituximab and complement activation.57 The hypothesis underlying the use of rituximab is that B-cells play a role in the pathogenesis of AAV. Circulating ANCA reactive B-cells can been found in peripheral blood patients with vasculitis.58 B-cells produce the ANCA antibody and there is some evidence in animal models to suggest that the ANCA antibody itself is pathogenic.59 B-cells also interact with T-cells, dendritic cells and play an integral role in the immune response. B-cells are antigen specific and capable of clonal expansion and amplifying immune responses. As B-cells play a central role in the immune response, their depletion has widespread immunological effects.60

Rituximab was first licensed for use in 1997 for the treatment of B-cell lymphomas, and in 2006 for rheumatoid arthritis.61,62 Preliminary studies on patients with other autoimmune diseases, including systemic lupus erythematosus and multiple sclerosis, have also shown encouraging clinical results with the use of rituximab.63-65 Published data in the use of rituximab in AAV consist mainly of small non-randomised trials and case reports when used for refractory or frequently relapsing disease.66-70 Recently a retrospective, multicentre clinical survey of 65 patients receiving rituximab for refractory AAV was published.71 This study was observational, unblinded, uncontrolled and patients received rituximab using different regimes. Despite these limitations the rates of complete remission (75%) and relapse (57%) achieved were comparable to other reported studies.14,25 Importantly patients who underwent a relapse were able to safely receive a second course of rituximab and 84% of these patients achieved remission. A total of 46 serious adverse events occurred in 25 patients; however, only transient neutropenia in two individuals were thought to be directly attributable to rituximab.71

Two large clinical trials [(RITUXVAS - Rituximab versus standard cyclophosphamide/azathioprine in the treatment of active AAV)] and [(RAVE - Rituximab for AAV)] comparing rituximab and cyclophosphamide as induction therapy for AAV have been performed and full publication of the results is awaited. The RITUXVAS trial (EUDRACT - European Union Drug Regulating Authorities Clinical trials; number: 2005-003610-15), conducted by EUVAS, compared an open-label rituximab regime with standard intravenous cyclophosphamide therapy as induction therapy for 44 patients with newly diagnosed AAV with renal involvement. The results were reported in abstract form at the 14th International ANCA and vasculitis workshop in June 2009. They showed that after 12 months of follow up, 76% of those treated with rituximab had achieved sustained remission and 82% of those treated with cyclophosphamide, with no significant statistical difference between the two groups. Severe adverse events were 42% for rituximab and 36% for cyclophosphamide and again no significant difference between the groups. The authors concluded that there was no evidence that a rituximab-based regime was less effective than intravenous cyclophosphamide for the induction of remission in AAV with renal involvement.72 An American group has also investigated the role of rituximab as induction therapy for AAV, RAVE trial (http://clinicaltrials.gov, NCT00104299). They have performed a randomised, double-blind study comparing rituximab with standard oral cyclophophamide/azathioprine regimen and evaluated the outcomes at 6 and 18 months. Patients were excluded from this trial if their serum creatinine was greater than 350 [micro]mol/L or if they were ventilator dependent. The 6-month data of 180 patients were presented orally by Dr J Stone on behalf of the investigators at the 2009 ANCA and vasculitis workshop. They found that after 6 months of therapy 61% in the rituximab group and 55% in the cyclophosphamide group were in complete remission. The RAVE investigators concluded that at 6 months rituximab as induction therapy was not inferior, nor superior to oral cyclophosphamide therapy. The possibility of rituximab becoming the standard induction therapy for AAV is exciting, but further published data on the risk of relapse, infections, long-term complications and patient survival will be required to determine its role in the treatment of AAV.

Experimental therapy and future directions

Given the promise of rituximab in the treatment of AAV, other B-cell therapies are being developed. A humanised anti-CD20 monoclonal antibody is available and currently undergoing clinical trials in systemic lupus erythematosus and rheumatoid arthritis.73 B-cells are also being targeted as specific targets in other ways in the treatment of autoimmune disease. The B-cell cytokine BLyS is critical in B-cell development. Monoclonal antibodies against BLyS (belimumab) have been trialled in rheumatoid arthritis, but the results were disappointing.74 There may be more hope for the use of belimumab in AAV, as levels of BLyS have been found to be elevated in these patients.75 There are no trials to date using belimumab in the treatment of AAV.

Anti-T-cell therapies have also been trialled in the treatment of AAV, as autoreactive T-cells are thought to play a major role in the pathogenesis of AAV.76 The largest trial of anti-T-cell therapy was using alemtuzumab (CAMPATH-1H), a humanised anti-CD52 antibody that depletes circulating lymphocytes and macrophages. The trial enrolled 71 patients with refractory or relapsing AAV and all received CAMPATH-1H. Over the mean follow-up time of 5 years, CAMPATH-1H induced remission in 65% of patients, but 61% of patients underwent a relapse. The side-effects of the drug were noteworthy, with 39% of patients developing an infection, 11% developed Graves disease and 4% developed a malignancy within 1 year of treatment.77 Antithymocyte globulin (ATG), which targets activated T-cells, has been used in the treatment of Wegener's granulomatosis in patients who were unresponsive to cyclophosphamide induction therapy. The side-effects of using ATG in this trial were significant, with infections in 40% and significant serum sickness requiring plasma exchange in 2/15 patients.45 There are no randomised controlled trials using ATG to determine its role in the treatment of refractory AAV.

In rheumatoid arthritis, cytokine-blocking therapies such as anti-TNF have shown encouraging results. However the trial using etanercept (TNF-receptor fusion protein) as part of induction therapy in patients with Wegener's granulomatosis mentioned above was disappointing.27 Pallan et al. have speculated that tocilizumab, a humanised monoclonal antibody against the interleukin-6 receptor, may have some promise in the treatment of AAV.73 There are no trials using tocilizumab in AAV.

The standard current therapy for AAV uses non-specific immunosuppressive agents, which have widespread effects on the immune system, and as a result significant side-effects. Therapies for AAV in the future are more likely to specifically target cell-signalling pathways. Pallan et al. have written a recent review and discussed future potential therapies in the treatment of AAV. They suggest that agents such as imatinib mesylat, a tyrosine kinase inhibitor, spleen tyrosine kinase inhibition with a Syk kinase inhibitor, and the inhibition of Ras with farnesylthiosalicylic acid, all show potential as future novel therapies.73

Long-term outcomes and supportive care

Although there have been significant reduction in the initial mortality rate from AAV, there are still significant long-term complications that develop and reduce patient quality of life.40 Today, AAV is a chronic illness and needs to be treated holistically. Permanent disease-related morbidity occurred in the vast majority of patients in long-term follow up, and most had more than one chronic medical condition as a complication of AAV and its treatment.19 Patients require ongoing monitoring for disease control, the development of potential side-effects with drug therapy, careful changes in drug dose and management of chronic problems caused by the disease itself or the side-effects of therapy.

General supportive measures are also critical in the long-term management of patients with AAV. Patients are particularly susceptible to the development of infections. Over long-term follow up, 46% of patients developed a serious infection that required hospitalisation and intravenous antibiotics.19 During the first 6 months of induction therapy, it is recommended that patients receive trimethoprim/sulfamethoxazole to prevent the development of Pneumocystis pneumonia. An added benefit, treatment with trimethoprim/sulfamethoxazole reduces the disease relapse in patients who carry Staphylococcus aureus in their nares.53 For nasal Staphylococcal aureus carriers, treatment with long-term nasal mupirocin should be considered.

Other general supportive measures are also recommended. 2-MercaptoEthane Sulfonate sodium (Mesna) should be used in association with intravenous cyclophosphamide to reduce the incidence of haemorrhagic cystitis and haematuria. The dose of cyclophosphamide should be reduced for older patients and in those with severe renal failure, and regular complete blood examinations need to be performed. Patients should receive a gastric acid suppressant to reduce the risk of peptic ulceration while on glucocorticoid therapy. Antifungal prophylaxis treatment should be used in the first 12 weeks. Women should be screened for cervical intraepithelial neoplasia. Patients receiving immunosuppression should be vaccinated against pneumococcal infection and influenza. Prophylaxis against osteoporosis should be used in all patients receiving high-dose corticosteroids. Before administering cyclophosphamide to patients, they should be informed about the possibility of infertility, and the options of storing sperm or oocytes offered as appropriate.

Progressive renal failure requiring renal replacement therapy is an important long-term complication of AAV. Westman et al. found there was significantly better renal survival in patients with a lower serum creatinine at presentation than those with a higher creatinine. Those with a high PR3 titre at diagnosis were more likely to have worse renal outcome than those with a lower titre at diagnosis. Patients whose serum creatinine was higher at the time of referral had a significantly higher mortality rate than those with a lower serum creatinine at presentation.16 Among Hoffman et al.'s prospective cohort, 11% went on to require dialysis and 42% developed chronic renal failure.19

Malignancies are also more common in patients with AAV and this is most likely because of the cytotoxic therapy they have received. Hoffmann et al. found a 2.4-fold overall increase in all malignancies, a 33-fold increase in bladder cancers and an 11-fold increase in lymphomas.19 In a Swedish cohort with AAV there was a 10.4 times higher risk of developing skin cancer than the expected cancer incidence in a matched population. Patients who were treated with cyclophosphamide, azathioprine or corticosteroids for greater than 12 months had a significantly higher risk of developing a malignancy.16 Because of the risk of long-term malignancies it is recommended that patients undergo regular dermatological examinations. Because of the risk of bladder neoplasia patients associated with cyclophosphamide use, patients who have received this agent should undergo regular urine cytological examinations and haematuria should be investigated by cystoscopy.78

It is suspected that patients with AAV also have higher rates of cardiovascular disease than those in the general community.79 However there are no cohort studies to support this hypothesis. Certainly patients with renal disease frequently develop hypertension. It is accepted that patients with renal disease of any aetiology have a higher rate of cardiovascular disease than age-matched control individuals.80 Blood pressure control is an important part of the long-term management of patients with AAV.

Patients are frequently followed by clinicians with serial ANCA measurements. There have been numerous trials that followed serial ANCA measurements in the hope that disease relapse may be predicted by a rise in ANCA titre before disease relapse occurring. Some studies have found a strong association between rising ANCA titres and disease relapse, while other studies did not find the ANCA titre predictive.81,82 To clarify the significance of a changing ANCA titre a meta-analysis was performed.83 A total of 22 studies were included with 950 patients. Because of the methodological and clinical heterogeneity of the studies, the authors were not able to determine a conclusion concerning the clinical value of serial ANCA monitoring from the available literature.

Other markers, such as serial testing of the inflammatory markers C-reactive protein and erythrocyte sedimentation rate, do provide limited information of the immediate disease activity, but do not provide any prognostic value.54 Other markers for evidence of increased likelihood of vasculitis relapse are available in the research laboratory, but none is available for general clinical use. Patients in clinical remission from AAV, but who subsequently develop a rise in ANCA titre, show evidence of increased T-cell activation as measured by serum levels of soluble interleukin-2 receptor, soluble CD30 and interleukin-10.84,85

Conclusions

Many advances have been made in the field of AAV research and these have been translated through international collaborative trials into improvements in patient care. Future aims include the discovery of less toxic and more selective immunosuppressive agents to treat AAV. Prednisolone and cyclophosphamide remains the mainstay of induction therapy and azathioprine as maintenance therapy for patients with AAV and renal involvement, irrespective of renal function. Most clinical trials for induction and maintenance therapy for AAV have been performed on patients with a serum creatinine of less than 500 [micro]mol/L and the results extrapolated to those with more significant renal disease. The degree of renal impairment at the time of treatment reflects the extent of end-organ involvement. Accordingly in the future clinical trials may involve subgroups of patients specifically defined by their renal function to determine what the most appropriate therapy is for those with early disease and little renal involvement, compared with those with advanced end-organ disease. Further trials are also needed to improve the long-term outcomes in patients and reduce the associated morbidity. The role and safety of novel agents are yet to be defined and long-term follow-up studies are needed. Other advances in the clinical care of patients are likely to originate from the laboratory, and will target specific molecules involved in the pathogenesis of AAV.

Acknowledgements

Dr Jeffs' work is supported by the NH & MRC (National Health and Medical Research Council) scholarship; Drs Peh and Hurtado's work is supported by financial grants from the Hanson Centre and Royal Adelaide Hospital.

References