antineutrophil cytoplasmic antibody-associated vasculitis with renal involvement: the evidence for...

C O M M E N T A R Y

Antineutrophil cytoplasmic antibody-associated vasculitiswith renal involvement: the evidence for treatmentjbr_149 18..27

Lisa S Jeffs MB BS(Hons) FRACP, Plinio R Hurtado MD PhD, Randall J Faull MB BS FRACPPhD and Chen Au Peh MB BS FRACP PhDRenal Unit, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia

AbstractAntineutrophil cytoplasmic antibody-associated vasculitis is an autoimmune disease involving small to medium bloodvessels. It is an uncommon illness, but can have devastating consequences, particularly on kidney function and othervital organs. Exciting progress has been made in the treatment of the disease largely because of internationalcollaboration in randomised clinical trials. Patient survival has improved dramatically with advancements in diseasediagnosis and medical treatment. The long-term morbidity from the disease, although improving, remains substan-tial with up to 10% of survivors requiring dialysis or kidney transplantation. Clinical trials are underway using morespecifically targeted immunosuppressants in the hope to improve the long-term patient outcomes. Advancementsare also being made in understanding the pathogenesis of the disease and this will further assist disease treatmentand outcomes in the future.

Key words: antineutrophil cytoplasmic antibodies (ANCA), ANCA-associated vasculitis (AAV), microscopic poly-angiitis, vasculitis, Wegener’s granulomatosis.

Background

Antineutrophil cytoplasmic antibody (ANCA) vasculitis com-prises a spectrum of diseases, including Wegener’s granulo-matosis, microscopic polyangiitis and Churg-Strausssyndrome (ANCA-associated vasculitis: AAV), characterisedby the presence of ANCA in the serum of patients. Theseautoantibodies were first discovered by Davies et al. in 1982when they were studying immunofluorescence staining inserum samples from patients with segmental necrotisingglomerulonephritis.1 Instead of the classical nuclear staining,a cytoplasmic pattern was seen. In 1985 van der Woudeet al. observed that cytoplasmic ANCA mainly developed inpatients with Wegener’s granulomatosis.2 ANCA are pre-dominantly autoantibodies to proteinase-3 (PR3) andmyeloperoxidase (MPO), which are enzymes residing withinthe azurophilic granules of human neutrophils. In vitro, theseautoantibodies can result in activation and degranulation ofprimed neutrophils, with resulting damage to endothelialcells.3

Typically, patients with Wegener’s granulomatosis have animmunoglobulin G (IgG) antibody to proteinase-3 (PR3 IgG)

and those with microscopic polyangiitis are IgG positive formyeloperoxidase (MPO IgG). The discovery of ANCA revo-lutionised the study of small-medium vessel vasculitis as itprovided a laboratory test to accurately identify this sub-group of patients. The subsequent improvements in thedetection of ANCA by enzyme-linked immunosorbent assay(ELISA) have paralleled the advances in the medical treat-ment of AAV. The international consensus statement onreporting ANCA levels recommends that all serum samplesshould first undergo indirect immunofluorescence (IIF)testing using normal peripheral blood neutrophils. Shouldthis screening test show the presence of perinuclear or cyto-plasmic fluorescence an ELISA, to detect ANCA specific forPR3 or MPO, should be performed.4

The value and limitations of these two methods as diag-nostic and predictive tools for AAV have been extensivelystudied. Harris et al. compared the diagnostic performanceof ELISA and IIF, and found the highest sensitivity with com-bined testing (92%) and the highest positive predictivevalue with combined ELISA and IIF (73%).5 It has beenshown that the ANCA test is best used in cases with a highindex of clinical suspicion of AAV to further reduce the rateof false-positive results.6 Furthermore a study examiningantigen-specific ANCA ELISAs has found different sensitivitiesfor active and treated vasculitic disease. It found that thePR3-ANCA and MPO-ANCA ELISAs were all highly sensitive

Correspondence: Dr Lisa S Jeffs, Renal Unit, Level 6, EmergencyBuilding, Royal Adelaide Hospital, North Terrace, Adelaide, SA5000, Australia. Email: [email protected]

doi:10.1111/j.1744-1609.2010.00149.x Int J Evid Based Healthc 2010; 8: 18–27

© 2010 The AuthorsJournal Compilation © Blackwell Publishing Asia Pty Ltd

and specific for the diagnosis of active small vessel vasculitis,but varied in their ability to detect ANCA in treatedAAV.7

Criteria defining AAV involving clinical features and histo-logical findings have been published by the AmericanCollege of Rheumatology and the Chapel Hill group.8,9 Theprecise classification of AAV has allowed individuals with thisdisease to be identified and studied exclusively in clinicaltrials.

This commentary aims to review the major publishedinternational collaborative studies regarding the treatmentof AAV and discuss their findings according to the level ofrenal function in the individuals studied. The publicationsdiscussed were identified from Pubmed, The EuropeanVasculitis Study Group (EUVAS) website (http://www.vasculitis.org) and published abstracts from 14th Interna-tional Vasculitis and ANCA Workshop. Each paper wascritically reviewed and the type of trial and therapeutic inter-vention, number of patients enrolled, duration of follow upand renal function of the patients were considered whenevaluating each paper. While this commentary does notattempt to be a meta-analysis, the authors believe that at thetime of publication most relevant studies are included in thisreview.

Clinical features and outcomes of AAV

Antineutrophil cytoplasmic antibody-associated vasculitis isa life-threatening, systemic disease that requires promptdiagnosis and therapeutic intervention. Multiple organsystems can be affected, particularly the kidneys, lungs,upper respiratory tract, gut, skin and brain. AAV has anannual incidence in Europe of 10–20 per million, per year.There is an increased incidence with age, with a medianage of onset of 56 years.10 Men are more often affectedthan women. Epidemiological studies have found that thereis an association between exposure to silica dust and anincreased risk of developing disease.11 There has also beenreported a possible association between farming and devel-oping AAV.12 Before the availability of medical therapy themortality rate of Wegener’s granulomatosis was 80% at1 year and 100% in the presence of systemic disease.13

Recent studies have reported 1- and 5-year survival rates of85% and 75%, respectively.14 Age and serum creatinine atdiagnosis are the strongest predictors of both patient andrenal survival.14

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

With the development of successful medical therapy AAVhas become a chronic medical illness. Many patients sufferfrom problems due to end-organ damage from the vasculitic

disease process and the side-effects of pharmacologicaltherapy. The long-term follow up of patients with Wegener’sgranulomatosis by the National Institutes of Health foundthat 86% of patients had permanent end-organ damage asa consequence of the disease, and 42% of patients experi-enced permanent treatment-related morbidity.19 In a morerecent cohort study 180 patients were followed for a medianof 25 months as part of the Wegener’s granulomatosis Etan-ercept trial.20 At the time of enrolment in the trial the mediantime since diagnosis was 4.7 months. At the commence-ment of the trial 40.2% had ear, nose or throat damage and15.5% had kidney impairment. After 12 months of followup, only 11% of the patients had not developed any per-manent health problems due to either AAV, or the medicaltreatment received. It was estimated by the authors thatthree-quarters of the medical problems reported weredirectly due to the Wegener’s granulomatosis diseaseprocess. They also found that as a patient developed moremedical complications, there was a measurable decline inthe patients’ quality of life.20

Goals of therapy

Ideally AAV would be diagnosed early in the course ofdisease to reduce the risk of permanent end-organ damageand the amount of immunosuppression required. Forinstance, the higher the serum creatinine at presentation,the greater the likelihood of developing end-stage renalfailure, and the higher the mortality rate.16 Like otherautoimmune diseases, AAV can be a great mimic and presentin many ways, further complicating and delaying the initialdiagnosis and subsequent treatment. The discovery ofANCA, and the implementation of laboratory test for itsdetection have assisted with the earlier diagnosis of AAV.Nevertheless, strategies to reduce the time to the initialdiagnosis and treatment are still important to reduce expo-sure to immunosuppressive agents and to reduce end-organdamage.

The treatment of AAV has been divided into two distinctphases. The initial induction phase involves the administra-tion of potent immunosuppressive agents for 3–6 months.Maintenance pharmacological therapy then follows and usesless toxic immunosuppression. The change from inductionto maintenance therapy needs to be assessed individuallyand should proceed when there is clinical evidence that thedisease is in remission. Recently EUVAS has published guide-lines on the management of AAV according to the clinicalstage of the disease and phase of treatment.21

Another aim when treating patients with AAV is to mini-mise the toxicity of treatment. This can be done by limitingthe duration and dose of immunosuppressive agents, butneeds to be balanced against the risk of relapse and achiev-ing disease control. Immunosuppressive drugs such asprednisolone, cyclophosphamide, methotrexate and aza-thioprine have been the mainstay of therapy for many years.The side-effects of these therapies are numerous, andinclude bone marrow suppression, diabetes mellitus, infer-tility, cystitis and malignancy.

Vasculitis with renal involvement 19


Induction therapy

The first trial evidence for medical induction therapy for thetreatment of AAV began with the retrospective findings fromthe National Institutes of Health using a prolonged course oforal prednisolone and cyclophosphamide, regardless of renalfunction.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 randomisedcontrolled intervention studies have been conducted. Tofurther determine which subgroups of AAV patients maybenefit from different treatments more recent trials havefurther identified specific patient subgroups by includingmeasures such as serum creatinine to define renal function.This has identified that some treatment options are morebeneficial for those patients with preserved renal functioncompared with those who require dialysis therapy.

Induction therapy for patients with AAV and aserum creatinine less than 500 mmol/LThe current recommended induction therapy for patientswith organ-threatening AAV is a potent immunosuppressiveregime consisting of a cytotoxic drug such as cyclophospha-mide, with prednisolone, as first-line therapy. Recent clinicaltrials have used prednisolone as induction therapy at1 mg/kg per day (maximum of 60 mg/day). The EuropeanLeague Against Rheumatism (EULAR) recommends that thedose of glucocorticoids be maintained at this high dose for1 month followed by a stepwise reduction to less than15 mg/day after 3 months of therapy.21

In order to reduce the side-effects of cyclophosphamideand prednisolone therapy, and reduce the risk of relapse,various trials were established to compare pulse intravenouscyclophosphamide with continuous oral cyclophosphamidetherapy.22–24 In all three of these trials patients with normalrenal function and those with significant renal impairment(creatinine >500 mmol/L, and/or requiring dialysis at com-mencement) were enrolled. The trial by Adu et al. (n = 54patients enrolled) and Guillevin et al. (n = 50) were prospec-tive; however, the trial by Haubitz et al. (n = 35) was retro-spective. Despite the different methodologies of these threetrials a meta-analysis was performed and concluded thatintravenous therapy was more likely to successfully induceremission than oral therapy. There was also a lower risk ofinfection and leucopenia with intravenous therapy.25

However, there was an increased risk of disease relapse inthose treated with intravenous therapy, but this failed toreach statistical significance. The incidence of death andend-stage renal failure was no different between the twotreatment modalities. The authors concluded that intrave-nous cyclophosphamide was less toxic than continuous oralcyclophosphamide and an effective induction regime toachieve remission, but potentially resulted in a higher risk ofrelapse. As the total number of patients included in themeta-analysis was only n = 149, the group suggested thatfurther trials were needed.25

The EUVAS group conducted a prospective trial of newlydiagnosed patients with AAV and renal involvement (butserum creatinine less than 500 mmol/L). One hundred andsixty patients were enrolled and n = 149 were treated withprednisolone and randomised to daily oral cyclophospha-mide (2 mg/kg/day) or pulse intravenous cyclophospha-mide (15 mg/kg with 2 weeks between the first two dosesand then 3-weekly). Azathioprine was commenced at3 months after remission was achieved in both groups. Theprimary end-point of the study was the time to achieveremission. Importantly this study was underpowered todetect differences in relapse rates between groups, non-blinded and the duration of follow up only 18 months. Theresults showed that there was no difference in remissionrates for AAV for patients who received a pulse cyclophos-phamide regimen compared with those who received a dailyoral cyclophosphamide regimen. There was no significantdifference in glomerular filtration rate, or the developmentof end-stage renal failure between the two groups. Therewas a reduced cumulative cyclophosphamide dosage for thepulse compared with the oral route of administration, andthere were fewer cases of leucopenia.26

In an attempt to find alternative agents and improverelapse rates, other agents have been investigated. Etaner-cept is a recombinant, soluble, human tumour necrosisfactor (TNF)-receptor fusion protein. Etanercept was trialledas induction and maintenance therapy for Wegener’s granu-lomatosis Etanercept trial (WGET trial). One hundred andeighty patients were randomised to receive either etanerceptor placebo as induction therapy in conjunction with stan-dard induction therapy of prednisolone and cyclophospha-mide or methotrexate.27 All patients enrolled in this trial hada serum creatinine of less than 500 mmol/L. The primaryoutcome was sustained disease remission for at least6 months. Etanercept failed to show a benefit when used inaddition to standard therapy for induction or maintenancetherapy. Notably, six solid cancers were observed in thosepatients treated with both etanercept and cyclophospha-mide, thus raising concern about this pharmacological com-bination. The authors concluded that etanercept was noteffective for the maintenance of remission of patients withWegener’s granulomatosis. Sustainable remissions were onlyachieved in the minority of patients and there was a highrate of treatment-related complications.

Cyclophosphamide and methotrexate have also beencompared as induction therapy in early AAV, althoughpatients with a serum creatinine greater than 150 mmol/L orurinary red cell casts or proteinuria greater than 1 g/daywere excluded from this trial. The use of methotrexate inpatients with renal impairment in practice is difficult becauseof the significant risk of pancytopenia. Patients with organ orlife-threatening manifestations were also excluded. Eventhough remission rates were similar in both groups, signifi-cantly more disease relapses were observed in the methotr-exate group as compared with the cyclophosphamidegroup.28 Methotrexate may have a role as induction therapyin patients with AAV with very early disease and little end-organ damage.

20 LS Jeffs et al.


Hu et al. enrolled 35 Chinese patients in a clinical trial tocompare mycophenolate mofetil (MMF) and pulse cyclo-phosphamide as induction treatment for patients with MPO-AAV and moderate renal involvement. Patients were eligiblefor the study if their serum creatinine was less than500 mmol/L. They found that MMF was as effective an induc-tion agent as cyclophosphamide, although the remissionrates for both agents were lower than in previous studies.There was no difference in adverse events between thegroups.29 However, the patient number was small in thistrial, and larger trials with the inclusion of PR3 patients areneeded. The EUVAS group is currently conducting a clinicaltrial to compare the use of MMF and cyclophosphamide asan induction agent for AAV (MYCYC trial). However, patientswith rapidly progressive glomerulonephritis, a glomerularfiltration rate less than 15 mL/min, and patients on dialysis atentry will all be excluded from this trial.

Induction therapy for patients with AAV and aserum creatinine greater than 500 mmol/LThe early trials using cyclophosphamide and prednisolone asinduction therapy for AAV all enrolled patients with serumcreatinine >500 mmol/L, or requiring dialysis therapy.22–24

Importantly a reduction in the dose of cyclophosphamideneeds to be made for patients with renal impairment as theparent drug and the metabolites are excreted in the urine.30

Cyclophosphamide and prednisolone therapy are recom-mended as first-line induction therapy for patients withserum creatinine greater than 500 mmol/L, although there islimited evidence in this patient subgroup.

Plasma exchange was first successfully used for rapidlyprogressive glomerulonephritis in the treatment of anti-glomerular basement membrane (anti-GBM) disease.31

Plasma exchange removes the plasma from the patient’scirculation and replaces it with either donated fresh frozenplasma or albumin. There may also be immunomodulatorybenefits as part of plasma exchange therapy with theremoval of cytokines, inflammatory reactants and coagula-tion and complement factors.32 In 1991, following the dis-covery of ANCA antibodies, Pusey et al. trialled plasmaexchange therapy for the treatment AAV. They found that ifpatients did not require dialysis, there was no additionalbenefit of plasma exchange in addition to immunosuppres-sive therapy. However, for a small subgroup that was dialysisdependent there was a significant short-term benefit ofplasma exchange.33 Further small randomised controlledtrials failed to show any benefit of plasma exchange in thetreatment of non-anti-GBM antibody-mediated rapidly pro-gressive glomerulonephritis.34–36 However, subset analysisagain suggested that plasma exchange may be beneficial forthose patients presenting with severe disease or dialysisdependency.37

The EUVAS group subsequently performed a randomisedtrial of plasma exchange versus high-dosage methylpred-nisolone as adjunctive therapy for severe renal vasculitis(Plasma exchange (PEX) versus pulse methylprednisolone(MEP) trial). The trial was designed to examine whetherthere was any benefit for those patients with AAV and severe

renal failure (creatinine � 500 mmol/L, or requiring dialysis)to receive plasma exchange compared with intravenousmethylprednisolone.38 This study randomised 137 individu-als to either intravenous methylprednisolone or plasmaexchange. Both groups received similar regimes of cyclo-phosphamide and oral prednisolone. The investigatorsfound a higher rate of renal recovery and dialysis inde-pendence in the group that received plasma exchangecompared with those who received intravenous methylpred-nisolone. However, disappointingly there was no differencein the rates of adverse effects, infections or patient survivalbetween the two groups.38

A possible reason for these findings may be that once renalfailure is so advanced plasma exchange cannot alter thedisease outcome. To determine whether earlier commence-ment of plasma exchange may improve patient and renaloutcomes, and to determine if exposure to lower dosages ofcorticosteroids may be as effective as conventional dosagesof corticortisteroids, the EUVAS group has designed a two-by-two factorial design randomised clinical trial of high-versus low-dose steroid regimens, and adjunctive plasmaexchange versus no plasma exchange in AAV [(PEXIVAS trial– Plasma exchange and glucocorticoids for the treatment ofANCA-associated vasculitis)]. The trial will specifically recruitpatients with renal disease (creatinine > 200 mmol/L or risein serum creatinine of 30% within 60 days), but will excludethose with end-stage disease defined as requiring dialysis formore than 2 weeks before trial entry. The trial hopes to showthe efficacy of adjunctive plasma exchange for moderate tosevere AAV by measuring primary end-points of end-stagerenal disease and all-cause mortality. The other aim of thistrial is to examine the dosage of steroids needed to treatAAV.

Maintenance therapy

Given the side-effects of long-term cyclophosphamide use,there has been a desire to reduce the cumulative exposure tocyclophosphamide. This strategy uses cyclophosphamide toinduce remission over a 3- to 6-month period, followed by aless toxic immunosuppressant such as azathioprine or meth-otrexate.39 In 1997 Adu et al. randomised 54 patients withvasculitis to receive remission maintenance therapy withcyclophosphamide or azathioprine and found no significantdifference in adverse events.22 However there was a non-significant trend towards increased toxicity in patients treatedwith cyclophosphamide as maintenance therapy comparedwith those treated with azathioprine. A follow-up study of alarger cohort of 155 patients followed over 18 months ran-domised the patients to either azathioprine or cyclophospha-mide after at least 3 months of oral cyclophosphamide andprednisolone [(CYCAZAREM trial – cyclophosphamide vs aza-thioprine for early remission of vasculitis)]. They found that inpatients with AAV the withdrawal of cyclophosphamide andthe substitution of azathioprine after remission did notincrease the risk of relapse, and there were no increases inadverse events.40 Notably this study excluded patients with aserum creatinine of greater than 500 mmol/L at enrolment.



More recent studies have compared the safety and effi-cacy of azathioprine and methotrexate combined withprednisolone as maintenance therapy in AAV patients inremission.39 In a prospective, open-label, multicentre trialpatients with AAV in remission were randomised to receiveoral azathioprine or methotrexate for 12 months. Theprimary end-point was an adverse event requiring discon-tinuation of the study drug or causing death. Patients withrenal impairment were enrolled in the study, but at entryall had a serum creatinine of less than 500 mmol/L. Theauthors found that methotrexate and azathioprine appearto be similar immunosuppressive alternatives for mainte-nance therapy for patients with AAV after initial remissionis achieved. There was no significant difference inthe side-effects or rate of relapse between the twodrugs and the authors concluded that either agentcould be used depending on the patients’ individualcharacteristics.39

Mycophenolate and leflunomide were suggested by theBritish Society for Rheumatology as alternatives to meth-otrexate and azathioprine as maintenance therapy only ifthe more conventional therapy is ineffective or not toler-ated.41 Other authors have suggested that these agentsshould be used with caution as experience and evidence islimited. Importantly, there is no evidence that these agentsare superior to the conventional azathioprine and methotr-exate therapy, and leflunomide in particular is associatedwith significant side-effects.42 The EUVAS group has com-pleted a clinical trial comparing MMF with a standard aza-thioprine regime for remission maintenance after inductionwith cyclophosphamide and glucocorticoids in AAV(IMPROVE trial, NCT00307645). There are no publishedresults, but preliminary oral results presented at the 14thInternational ANCA and vasculitis workshop in June 2009suggested that azathioprine was perhaps a superior agentto MMF in maintaining remission in patients with AAV.43

The renal function of this group of patients was notreported in the printed abstract and final publication of theresults is awaited.

The length of time to continue maintenance therapy isunclear, and tailoring of therapy to the individual patient isrequired. The British Society for Rheumatology recommendsthat patients should continue maintenance therapy for atleast 24 months following successful disease remission.Patients with Wegener’s granulomatosis or those whoremain ANCA positive should continue immunosuppressionfor up to 5 years.41 De Groot et al. found that discontinuingmaintenance therapy after 12 months in a group of patientswith early AAV showed a higher relapse rate at 18 monthscompared with patients in other trials using the same immu-nosuppressive agents but for a longer period.28 The EUVASgroup is conducting a clinical trial to help determine theduration of maintenance therapy. The group is conductinga randomised trial of prolonged remission-maintenancetherapy in systemic vasculitis (REMAIN trial, BMH – CT93-1078), in which 2 years versus 4 years of azathioprine andprednisolone are being compared in patients with renalvasculitis.44

Treatment of refractory disease

Refractory disease is defined as disease that fails to respondto conventional remission induction therapy. The evidence islimited for all levels of renal function due to small patientnumbers and practical difficulties in performing trials in thisarea. About 10–20% of patients with AAV are refractoryto conventional cyclophosphamide and prednisolonetherapy.32,45 Intravenous immunoglobulin (IVIg) has beenused for patients who continue to have active diseasedespite conventional remission-induction therapy.46,47 Thehypothesis is that IVIg may be effective in inhibiting thebinding of ANCA to their antigens and Fc receptors, andthereby inhibit ANCA-mediated neutrophil activation. In aplacebo-controlled trial of IVIg, the addition improveddisease control initially, but this was not sustained beyond3 months. Other treatments that have been investigatedinclude the blockade of TNFa with infliximab. Booth et al.found in a prospective uncontrolled trial of infliximab thatnearly 90% of the 16 patients studied initially responded,but 20% developed a relapse of disease within 17 months offollow up. Twenty-one per cent of patients who receivedinfliximab developed a severe infection.48 Further ran-domised controlled trials are therefore required to determinewhether there is a role for infliximab in the treatment of AAV.

15-Deoxyspergualin (DSG) is a peptidomimetic com-pound that has immunosuppressive properties and has beenused in animal models of transplantation and autoimmunedisease.49 Flossmann et al. recruited 44 patients with activeWegener’s granulomatosis, who despite treatment withcyclophosphamide or methotrexate did not have adequatedisease control.50 Complete remission was achieved in 45%of patients and partial remission in 95%. Relapses occurredin 43% of patients. Significantly, 53% of patients developedsevere or life-threatening treatment-related adverse events.This rate of adverse events was much higher than previouslyreported in a smaller trial.49 The EULAR group recommendsthat given the significant risk of severe side-effects DSGshould only be used as a treatment option in the event ofrefractory disease.21

Relapsing disease

Disease relapse after achieving successful disease control isnot uncommon. Patients with Wegener’s granulomatosis aremore likely to relapse (50–80%) than those with microscopicpolyangiitis (30%).40 Three main factors have been found tobe associated with relapse of AAV. The first was treatment:receiving <10 g (compared with �10 g) of cyclophospha-mide in the first 6 months was associated with an increasedrelapse rate.51 Maintaining a high dose of prednisolone(>20 mg/day) for less than 2.75 months increased therisk of relapse.52 The adjunctive use of trimethoprim/sulfamethoxazole (160/800 mg) twice a day maintainedremission for longer in patients with Wegner’s granuloma-tosis.53 Withdrawal of immunosuppression is also a risk factorfor disease relapse, and most relapses occur within the firstyear of withdrawal of immunosuppressive therapy.54 The

22 LS Jeffs et al.


second factor affecting relapse was a positive ANCA titre.The presence of a positive PR3-ANCA titre at diagnosis con-ferred an increased risk of relapse.55 Patients who remainedANCA positive after induction therapy, or became ANCApositive again while in remission, had a significantlyincreased risk of relapse compared with those patients whowere ANCA negative.55 The third factor was target organinvolvement. The presence of lung, cardiac or upper-airwaydisease is also associated with a higher risk of relapse inAAV.40,51 Patients with a creatinine clearance greater than60 mL/min were also more likely to relapse.56

Rituximab

A novel therapy under investigation for use in AAV is ritux-imab. Rituximab is an IgG mouse/human chimeric mono-clonal antibody that targets the B-cell-specific surface markerCD20. Binding of the antibody to this cell surface markerresults in the depletion of peripheral B-cells, but not plasmacells. Various mechanisms have been found to account forB-cell depletion, including B-cell apoptosis induced by ritux-imab and complement activation.57 The hypothesis under-lying the use of rituximab is that B-cells play a role in thepathogenesis of AAV. Circulating ANCA reactive B-cells canbeen found in peripheral blood patients with vasculitis.58

B-cells produce the ANCA antibody and there is some evi-dence in animal models to suggest that the ANCA antibodyitself is pathogenic.59 B-cells also interact with T-cells, den-dritic cells and play an integral role in the immune response.B-cells are antigen specific and capable of clonal expansionand amplifying immune responses. As B-cells play a centralrole in the immune response, their depletion has widespreadimmunological effects.60

Rituximab was first licensed for use in 1997 for the treat-ment of B-cell lymphomas, and in 2006 for rheumatoidarthritis.61,62 Preliminary studies on patients with otherautoimmune diseases, including systemic lupus erythemato-sus and multiple sclerosis, have also shown encouragingclinical results with the use of rituximab.63–65 Published datain the use of rituximab in AAV consist mainly of small non-randomised trials and case reports when used for refractoryor frequently relapsing disease.66–70 Recently a retrospective,multicentre clinical survey of 65 patients receiving rituximabfor refractory AAV was published.71 This study was observa-tional, unblinded, uncontrolled and patients received ritux-imab using different regimes. Despite these limitations therates of complete remission (75%) and relapse (57%)achieved were comparable to other reported studies.14,25

Importantly patients who underwent a relapse were able tosafely receive a second course of rituximab and 84% of thesepatients achieved remission. A total of 46 serious adverseevents occurred in 25 patients; however, only transient neu-tropenia in two individuals were thought to be directlyattributable to rituximab.71

Two large clinical trials [(RITUXVAS – Rituximab versusstandard cyclophosphamide/azathioprine in the treatmentof active AAV)] and [(RAVE – Rituximab for AAV)] comparingrituximab and cyclophosphamide as induction therapy for

AAV have been performed and full publication of the resultsis awaited. The RITUXVAS trial (EUDRACT – European UnionDrug Regulating Authorities Clinical trials; number: 2005-003610-15), conducted by EUVAS, compared an open-labelrituximab regime with standard intravenous cyclophospha-mide therapy as induction therapy for 44 patients withnewly diagnosed AAV with renal involvement. The resultswere reported in abstract form at the 14th InternationalANCA and vasculitis workshop in June 2009. They showedthat after 12 months of follow up, 76% of those treated withrituximab had achieved sustained remission and 82% ofthose treated with cyclophosphamide, with no significantstatistical difference between the two groups. Severe adverseevents were 42% for rituximab and 36% for cyclophospha-mide and again no significant difference between thegroups. The authors concluded that there was no evidencethat a rituximab-based regime was less effective than intra-venous cyclophosphamide for the induction of remission inAAV with renal involvement.72 An American group has alsoinvestigated the role of rituximab as induction therapy forAAV, RAVE trial (http://clinicaltrials.gov, NCT00104299).They have performed a randomised, double-blind studycomparing rituximab with standard oral cyclophophamide/azathioprine regimen and evaluated the outcomes at 6 and18 months. Patients were excluded from this trial if theirserum creatinine was greater than 350 mmol/L or if theywere ventilator dependent. The 6-month data of 180patients were presented orally by Dr J Stone on behalf of theinvestigators at the 2009 ANCA and vasculitis workshop.They found that after 6 months of therapy 61% in the rit-uximab group and 55% in the cyclophosphamide groupwere in complete remission. The RAVE investigators con-cluded that at 6 months rituximab as induction therapy wasnot inferior, nor superior to oral cyclophosphamide therapy.The possibility of rituximab becoming the standard induc-tion therapy for AAV is exciting, but further published dataon the risk of relapse, infections, long-term complicationsand patient survival will be required to determine its role inthe treatment of AAV.

Experimental therapy andfuture directions

Given the promise of rituximab in the treatment of AAV,other B-cell therapies are being developed. A humanisedanti-CD20 monoclonal antibody is available and currentlyundergoing clinical trials in systemic lupus erythematosusand rheumatoid arthritis.73 B-cells are also being targeted asspecific targets in other ways in the treatment of autoim-mune disease. The B-cell cytokine BLyS is critical in B-celldevelopment. Monoclonal antibodies against BLyS (beli-mumab) have been trialled in rheumatoid arthritis, but theresults were disappointing.74 There may be more hope forthe use of belimumab in AAV, as levels of BLyS have beenfound to be elevated in these patients.75 There are no trials todate using belimumab in the treatment of AAV.

Anti-T-cell therapies have also been trialled in the treat-ment of AAV, as autoreactive T-cells are thought to play a



major role in the pathogenesis of AAV.76 The largest trial ofanti-T-cell therapy was using alemtuzumab (CAMPATH-1H),a humanised anti-CD52 antibody that depletes circulatinglymphocytes and macrophages. The trial enrolled 71patients with refractory or relapsing AAV and all receivedCAMPATH-1H. Over the mean follow-up time of 5 years,CAMPATH-1H induced remission in 65% of patients, but61% of patients underwent a relapse. The side-effects of thedrug were noteworthy, with 39% of patients developing aninfection, 11% developed Graves disease and 4% developeda malignancy within 1 year of treatment.77 Antithymocyteglobulin (ATG), which targets activated T-cells, has beenused in the treatment of Wegener’s granulomatosis inpatients who were unresponsive to cyclophosphamideinduction therapy. The side-effects of using ATG in this trialwere significant, with infections in 40% and significantserum sickness requiring plasma exchange in 2/15patients.45 There are no randomised controlled trials usingATG to determine its role in the treatment of refractory AAV.

In rheumatoid arthritis, cytokine-blocking therapies suchas anti-TNF have shown encouraging results. However thetrial using etanercept (TNF-receptor fusion protein) as partof induction therapy in patients with Wegener’s granuloma-tosis mentioned above was disappointing.27 Pallan et al.have speculated that tocilizumab, a humanised monoclonalantibody against the interleukin-6 receptor, may have somepromise in the treatment of AAV.73 There are no trials usingtocilizumab in AAV.

The standard current therapy for AAV uses non-specificimmunosuppressive agents, which have widespread effectson the immune system, and as a result significant side-effects. Therapies for AAV in the future are more likely tospecifically target cell-signalling pathways. Pallan et al. havewritten a recent review and discussed future potential thera-pies in the treatment of AAV. They suggest that agents suchas imatinib mesylat, a tyrosine kinase inhibitor, spleentyrosine kinase inhibition with a Syk kinase inhibitor, and theinhibition of Ras with farnesylthiosalicylic acid, all showpotential as future novel therapies.73

Long-term outcomes and supportive care

Although there have been significant reduction in the initialmortality rate from AAV, there are still significant long-termcomplications that develop and reduce patient quality oflife.40 Today, AAV is a chronic illness and needs to be treatedholistically. Permanent disease-related morbidity occurred inthe vast majority of patients in long-term follow up, andmost had more than one chronic medical condition as acomplication of AAV and its treatment.19 Patients requireongoing monitoring for disease control, the development ofpotential side-effects with drug therapy, careful changes indrug dose and management of chronic problems caused bythe 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 particu-larly susceptible to the development of infections. Overlong-term follow up, 46% of patients developed a serious

infection that required hospitalisation and intravenous anti-biotics.19 During the first 6 months of induction therapy,it is recommended that patients receive trimethoprim/sulfamethoxazole to prevent the development of Pneu-mocystis pneumonia. An added benefit, treatment withtrimethoprim/sulfamethoxazole reduces the disease relapsein 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 recom-mended. 2-MercaptoEthane Sulfonate sodium (Mesna)should be used in association with intravenous cyclophos-phamide to reduce the incidence of haemorrhagic cystitisand haematuria. The dose of cyclophosphamide should bereduced for older patients and in those with severe renalfailure, and regular complete blood examinations need to beperformed. Patients should receive a gastric acid suppressantto reduce the risk of peptic ulceration while on glucocorti-coid therapy. Antifungal prophylaxis treatment should beused in the first 12 weeks. Women should be screened forcervical intraepithelial neoplasia. Patients receiving immuno-suppression should be vaccinated against pneumococcalinfection and influenza. Prophylaxis against osteoporosisshould be used in all patients receiving high-dose corticos-teroids. Before administering cyclophosphamide to patients,they should be informed about the possibility of infertility,and the options of storing sperm or oocytes offered asappropriate.

Progressive renal failure requiring renal replacementtherapy is an important long-term complication of AAV.Westman et al. found there was significantly better renalsurvival in patients with a lower serum creatinine at presen-tation than those with a higher creatinine. Those with a highPR3 titre at diagnosis were more likely to have worse renaloutcome than those with a lower titre at diagnosis. Patientswhose serum creatinine was higher at the time of referralhad a significantly higher mortality rate than those with alower serum creatinine at presentation.16 Among Hoffmanet al.’s prospective cohort, 11% went on to require dialysisand 42% developed chronic renal failure.19

Malignancies are also more common in patients withAAV and this is most likely because of the cytotoxic therapythey have received. Hoffmann et al. found a 2.4-foldoverall increase in all malignancies, a 33-fold increase inbladder cancers and an 11-fold increase in lymphomas.19

In a Swedish cohort with AAV there was a 10.4 timeshigher risk of developing skin cancer than the expectedcancer incidence in a matched population. Patients whowere treated with cyclophosphamide, azathioprine or cor-ticosteroids for greater than 12 months had a significantlyhigher risk of developing a malignancy.16 Because of therisk of long-term malignancies it is recommended thatpatients undergo regular dermatological examinations.Because of the risk of bladder neoplasia patients associatedwith cyclophosphamide use, patients who have receivedthis agent should undergo regular urine cytologicalexaminations and haematuria should be investigated bycystoscopy.78

24 LS Jeffs et al.


It is suspected that patients with AAV also have higherrates of cardiovascular disease than those in the generalcommunity.79 However there are no cohort studies tosupport this hypothesis. Certainly patients with renal diseasefrequently develop hypertension. It is accepted that patientswith renal disease of any aetiology have a higher rate ofcardiovascular disease than age-matched control individu-als.80 Blood pressure control is an important part of thelong-term management of patients with AAV.

Patients are frequently followed by clinicians with serialANCA measurements. There have been numerous trials thatfollowed serial ANCA measurements in the hope that diseaserelapse may be predicted by a rise in ANCA titre beforedisease relapse occurring. Some studies have found a strongassociation between rising ANCA titres and disease relapse,while other studies did not find the ANCA titre predic-tive.81,82 To clarify the significance of a changing ANCA titrea meta-analysis was performed.83 A total of 22 studies wereincluded with 950 patients. Because of the methodologicaland clinical heterogeneity of the studies, the authors werenot able to determine a conclusion concerning the clinicalvalue of serial ANCA monitoring from the available literature.

Other markers, such as serial testing of the inflammatorymarkers C-reactive protein and erythrocyte sedimentationrate, do provide limited information of the immediatedisease activity, but do not provide any prognostic value.54

Other markers for evidence of increased likelihood of vascu-litis relapse are available in the research laboratory, but noneis available for general clinical use. Patients in clinical remis-sion from AAV, but who subsequently develop a rise in ANCAtitre, show evidence of increased T-cell activation as mea-sured 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 researchand these have been translated through international col-laborative trials into improvements in patient care. Futureaims include the discovery of less toxic and more selectiveimmunosuppressive agents to treat AAV. Prednisolone andcyclophosphamide remains the mainstay of inductiontherapy and azathioprine as maintenance therapy forpatients with AAV and renal involvement, irrespective ofrenal function. Most clinical trials for induction and mainte-nance therapy for AAV have been performed on patientswith a serum creatinine of less than 500 mmol/L and theresults extrapolated to those with more significant renaldisease. The degree of renal impairment at the time oftreatment reflects the extent of end-organ involvement.Accordingly in the future clinical trials may involve sub-groups of patients specifically defined by their renal functionto determine what the most appropriate therapy is for thosewith early disease and little renal involvement, comparedwith those with advanced end-organ disease. Further trialsare also needed to improve the long-term outcomes inpatients and reduce the associated morbidity. The role andsafety of novel agents are yet to be defined and long-term

follow-up studies are needed. Other advances in the clinicalcare of patients are likely to originate from the laboratory,and will target specific molecules involved in the pathogen-esis of AAV.

Acknowledgements

Dr Jeffs’ work is supported by the NH & MRC (NationalHealth and Medical Research Council) scholarship; Drs Pehand Hurtado’s work is supported by financial grants from theHanson Centre and Royal Adelaide Hospital.

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