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Treatment of ANCA-associated vasculitis

Ulf Schnermarck, Wolfgang L. Gross and Kirsten de Groot
Abstract | Antineutrophil cytoplasmic autoantibody (ANCA)-associated diseases are small-vessel vasculitides, encompassing granulomatosis with polyangiitis (formerly Wegeners granulomatosis), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis. Once considered life-threatening diseases, the introduction of stage-adapted immunosuppressive therapy and medications with decreased toxicity has improved patients survival. Treatment is biphasic, consisting of induction of remission (36months) for rapid control of disease activity and maintenance of remission (at least 18months) to prevent disease relapse using therapeutic alternatives that have reduced toxicity. This Review summarizes current treatment strategies for these diseases, with a special focus on long-term follow-up data from key randomized controlled trials and new developments in remission induction and maintenance therapy. Current treatment strategies have substantial short-term and long-term adverse effects, and relapses are frequent; thus, less-toxic and more-effective approaches are needed. Moreover, the optimal intensity and duration of maintenance therapy remains under debate. Clinical trials have traditionally considered ANCA-associated vasculitides as a single disease entity. However, future studies must stratify participants according to their specific disease, clinical features (differenttypes of organ manifestation, PR3-ANCA or MPO-ANCA positivity) and disease severity.
Schnermarck, U. etal. Nat. Rev. Nephrol. 10, 2536 (2014); published online 5 November 2013; doi:10.1038/nrneph.2013.225

Introduction
Antineutrophil cytoplasmic autoantibody (ANCA)associated diseases are small-vessel vasculitides, encompassing granulomatosis with polyangiitis (GPA, formerly known as Wegeners granulomatosis), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (formerly known as ChurgStrauss syndrome). These diseases are characterized by no or few immune complexes in the tissue and the presence of specific types of ANCAs, upon which the nomenclature of these diseases is now based.1 Eosinophilic granuloma tosis with polyangiitis is characterized by differences in pathogenetic mechanisms, genetic associations and a much lower frequency of kidney involvement and ANCA positivity than is observed in GPA and MPA; therefore, in this Review, we focus on the treatment of patients with GPA and MPA. For many years, GPA and MPA were considered to be part of a single disease spectrum because they share many clinical and histopathological features. ANCAs are thought to contribute to the pathogenesis of both GPA and MPA, with proteinase 3 (PR3)-ANCA commonly occurring in patients with GPA and myelo peroxidase (MPO)ANCA frequently occurring in patients with MPA. However, patients with PR3-ANCA and MPO-ANCA (but not those with the clinical disease entities GPA and MPA) can be distinguished by genetic associations,
Competing interests W. L. Gross declares associations with the following companies: GlaxoSmithKline, Hoffmann-La Roche. K. de Groot declares an association with the following company: HoffmannLa Roche. U.Schnermarck declares no competing interests.

Medizinische Klinik undPoliklinik IV, Nephrologisches Zentrum, University Hospital Munich, Campus Grosshadern, Ludwig-MaximiliansUniversity, Marchioninstrasse 15, Munich D81377, Germany (U.Schnermarck). University Hospital Schleswig-Holstein, Campus Lbeck, Ratzeburger Allee 160, Lbeck D23538, Germany (W. L. Gross). IIIrd Medical Department, Klinikum Offenbach GmbH, Starkenburgring 66, KfH Renal Center Starkenburgring 70, Offenbach/Main D63069, Germany (K.de Groot). Correspondence to: K. de Groot kirsten@de-groot.de

epigenetic control of MHC and antigen expression, function and localization of antigens, and also outcome.2,3 Differences between PR3-ANCA-associated and MPOANCA-associated diseases have also been identi fied in clinical manifestations, histology, relapse rate, and renal and patient survival.4 These two groups also had different genetic associations in a genome-wide association study;5 PR3-ANCA was associated with polymorphisms in HLA-DP and the genes encoding PR3 (PTN3) and its inhibitor 1-antitrypsin (SERPINA1), whereas MPOANCA was associated with HLA-DQ. These observations provide evidence for a genetic contribution to disease susceptibility. Despite their distinct genetic risk factors, PR3ANCA-associated and MPO-ANCA-associated diseases have overlapping clinical phenotypes and similarities in their pathogenesis. Consequently, and to enroll reasonable patient numbers in clinical trials of drugs to treat ANCA-associated diseases, patients with MPA and GPA have been uniformly treated so far. MPA and GPA were once considered life-threatening diseases, but immunosuppressive therapy has substantially improved the survival of affected patients. Treatment is biphasic and tailored according to disease stage and severityinduction of remission (36months) for rapid control of disease activity and maintenance of remission (for at least 18months; Table1). Maintenance therapy aims to prevent disease relapse using less-toxic agents than are required for induction of remission. However, relapsesare frequent and require prolonged or repeated therapy. Moreover, current treatment strategies have substantial short-term and long-term adverse effects;6,7 patients in the first year of treatment are three times
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Key points
Treatment of antineutrophil cytoplasmic autoantibody-associated vasculitides is tailored according to disease stage and severity Current treatments for granulomatosis with polyangiitis and microscopic polyangiitis do not reflect the fact they are genetically distinct diseases For remission induction, dose reduction and avoidance of prolonged use of cyclophosphamide have been successfully implemented; the addition of plasma exchange has increased the rate of renal recovery in patients with rapidly progressive glomerulonephritis Maintenance of remission treatment to prevent relapse is even more important when reduced amounts of cyclophosphamide are used during induction of remission Rituximab is noninferior to cyclophosphamide for remission induction, but its use as maintenance therapy is currently under investigation in randomized trials In patients with life-threatening disease, severe renal involvement and/or alveolar haemorrhage, plasma exchange can be successfully used as adjunctive therapy

more likely to die from treatment-related adverse events than from the disease itself.8 The mortality of patients with ANCA-associated vasculitides (AAV) consequently remains increased compared with that of the general population, with a standardized mortality ratio of 2.0 in the first year of developing the disease and 1.3 in subsequent years,9 owing to increased rates of infections, malignancies and cardiovascular events.10 However, improved outcomes have been reported in a single-centre cohort of patients with GPA who had little renal involvement,11 as well as in patients with severe renal disease.12 Effective treatment of AAV must balance the risk from therapy against the risk from disease activity. Clinical trials have, therefore, focused on optimizing therapy and minimization of treatment-related short-term and long-term toxicity. This Review summarizes the current treatment strat egies for ANCA-associated vasculitides. In particular, we focus on long-term follow-up data from randomized controlled trials and new developments in remission induction and maintenance therapy.

Induction of remission
Cyclophosphamide-based therapy Remission induction with cyclophosphamide in combin ation with glucocorticoids has dramatically improved patients survival in these previously fatal diseases. Survival improved over the past decades from 20% after
Table 1 | Disease stages in ANCA-associated vasculitis Disease stage
Localized

18months13 to 80% at 8years of follow-up.14 However, treatment with oral cyclophosphamide (24mg/kg/d)for a prolonged period, as occurs when this agent is used forboth remission induction and maintenance therapy, is associated with substantial treatment-related short-term and long-term morbidity from infectious complications, myelosuppression, infertility, cardiovascular disease andmalignancy.810,14 Treatment with cyclophosphamide and glucocorticoids has emerged as the standard of care for remission induction in patients with generalized AAV. Treatment modifications have further increased remission rates, and patient survival is now 90% at 1year and up to 75% at 10years.9 Furthermore, alternative treatments adapted to each disease stage have been developed to minimize, or even avoid, the use of cyclophosphamide (Tables2 and 3). Pulse cyclophosphamide is noninferior to daily oral cyclophosphamide in terms of the remission rate (Table2). However, in a retrospective long-term followup study, pulse cyclophosphamide was associated with a significantly higher relapse rate than daily oral cyclophosphamide after a median of 4.3years (39.5% versus 20.8%, HR 0.50, 95% CI 0.260.93; P=0.029).15 No differences in mortality, renal function, end-stage renal disease (ESRD), overall duration of immunosuppressive therapy or adverse events were observed between the treatment groups. These findings indicate that remission induction with intravenous pulse cyclophosphamide is as effective as daily oral cyclophosphamide, and results in a lower cumulative dose of cyclophosphamide; however, intravenous pulse cyclophosphamide is associated with a higher risk of relapse than is daily oral cyclophosphamide. Standardized dose reduction of intravenous pulse cyclophosphamide, according to age and renal impairment, has improved the safety of this regimen (Table3). When using daily oral cyclophosphamide, dose reduction according to age and renal function is also advised. Oral doses should be reduced by 25% for patients >60years and by 50% for patients over 70years. 16 Furthermore, prophylaxis with co-trimoxazole (to prevent Pneumocystis jirocevii pneumonia) should be applied to all patients with generalized disease receiving remission induction (Figure1).

EUVAS and EULAR definition53,61

Upper and/or lower respiratory tract disease without further systemic involvement or constitutional symptoms Any disease without organ-threatening or life-threatening involvement Renal or other organ-threatening disease Renal or other vital organ failure Progressive disease unresponsive to standard therapy

Systemic vasculitis outside ENT or lung

No

Threatened vital organ function

No

Serum creatinine (mol/l)

<120

Early systemic Generalized Severe Refractory

Yes Yes Yes Yes

No Yes Organ failure Yes

<120 <500 >500 Any

Abbreviations: ANCA, antineutrophil cytoplasmic autoantibody; ENT, ear, nose, throat; EULAR, European League Against Rheumatism; EUVAS, European Vasculitis Study Group.

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Table 2 | Randomized controlled trials for induction of remission in AAV using cytotoxic or biological agents Disease stage
Early systemic

Trial (patients)
NORAM18 (100)

Inclusion criteria
New diagnosis ofGPA or MPA, and creatinine <150mol/l New diagnosis ofGPA, MPA, orrelapse with renalinvolvement, creatinine 150500mol/l New diagnosis ofAAV and severe renal involvement

Treatment groups (dose)

Methotrexate (0.3mg/kg once weekly) versus daily oral cyclophosphamide Intravenous pulse cyclophosphamide (15mg/kg) versus daily oral cyclophosphamide (2mg/kg)

Primary end points

Remission Time to relapse Remission Time to relapse

Outcome
Methotrexate not inferior tocyclophosphamide Time to relapse shorter with methotrexate Pulse cyclophosphamide not inferior to oral cyclophosphamide Less leucopenia and trend towards more relapses with pulse cyclophosphamide Rituximab not inferior to pulse cyclophosphamide

Generalized

CYCLOPS16 (149)

Generalized

RITUXVAS32 (44)

Rituximab (four 375mg/m infusions) plus two intravenous pulses of cyclophosphamide, versus intravenous pulse cyclophosphamide only Rituximab (4375mg/m infusions) versus daily oral cyclophosphamide

Sustained remission

Generalized

RAVE33 (198)

New or relapsing GPA or MPA

Complete remission and cessation of glucocorticoids at 6months Renal survival at 3months

Rituximab not inferior to oral cyclophosphamide Rituximab better in patients with relapse than after first diagnosis Better renal survival with plasma exchange 24% risk reduction for ESRD with plasma exchange Preliminary data: noninferiority not proven for mycophenolate mofetil versus pulse cyclophosphamide Preliminary data: less severe adverse events with reduced immunosuppression, no difference in remission and relapse rates

Generalized with RPGN

MEPEX24 (137)

New diagnosis ofGPA or MPA and creatinine >500mol/l New diagnosis ofGPA, MPA andmajor organ involvement New diagnosis ofMPA, GPA, EGPA, PAN and age >65years

Plasma exchange and oral cyclophosphamide versus 3intravenous methylprednisolone pulse andoral cyclophosphamide Mycophenolate mofetil (23g daily) versus intravenous pulse cyclophosphamide (15mg/kg) Rapid glucocorticoid tapering and reduced-dose intravenous pulse cyclophosphamide (500mg) versus standard intravenous pulse cyclophosphamide (500mg/m)

MPA, GPA

MYCYC22 (140)

Remission at 6months Relapse Severe adverse events

MPA, GPA, EGPA or PAN

CORTAGE46 (104)

Abbreviations: AAV, antineutrophil cytoplasmic antibody-associated vasculitis; EGPA, eosinophilic granulomatosis with polyangiitis; ESRD, end-stage renal disease; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; PAN, polyarteritis nodosa; RPGN, rapidly progressive glomerulonephritis.

Alternative treatments for remission induction For disease that is neither severe nor life-threatening, alternative treatments for induction of remission have been evaluated in randomized controlled trials. The results of these trials show that the less cyclophosphamide is used for remission induction, the higher the apparent relapse rate will be.17 Prolonged use of maintenance therapy (>12months) is, therefore, warranted in patients receiving these alternative therapies, especially those with GPA, as recurrent disease is frequent in such patients.
Methotrexate In early systemic disease, methotrexate is effective at inducing remission. In the NORAM,18 which included 100 patients, the vast majority (94%) of patients with GPA but without organ-threatening disease (creatinine <150mol/l) were treated with either oral cyclophosphamide (2mg/kg daily) or oral methotrexate (2025mg per week) for 12months. Both groups also received prednisolone.18 After 18months of follow-up, remission rates were similar in both groups. However, in the methotrexate group, time to remission was significantly longer in patients with extensive disease or pulmonary
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involvement. Furthermore, the relapse rate at 18months was higher (69.5% versus 46.5%) and the time from remission to relapse shorter (13 versus 15months, HR 1.85, 95% CI 1.063.25, P=0.023) with methotrexate than with cyclophosphamide, respectively. Leucopenia was more frequent in the cyclophosphamide group, whereas liver dysfunction was more common in the methotrexate group. The high relapse rate in both groups was attributed to suboptimal maintenance treatment. A retrospective analysis of long-term (median 6years) follow-up data from the NORAM18 trial further supports these results;19 patients who were initially treated with methotrexate experienced less-effective longterm disease control, and required a longer duration of glucocorticoid therapy than did those who received cyclophosphamide.1921 In addition, patients with early systemic AAV are likely to experience recurrent disease, especially with early cessation of immunosuppressive therapy. The overall higher relapse rate in the NORAM18 study as compared with other studies supports the prolonged use of effective maintenance therapies.21 However, the risk of ESRD seems to be low in patients with early systemicAAV.
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Table 3 | Recommendations for inducing remission of AAV according to EULAR and BSR 59,60 Disease stage
Localized Localized Early systemic Generalized

Treatment
Co-trimoxazole with or without glucocorticoids Methotrexate and glucocorticoids Methotrexate and glucocorticoids Cyclophosphamide and glucocorticoids Rituximab and glucocorticoids Plasma exchange as adjunctive therapy to cyclophosphamide orrituximab (standard therapy) Rituximab Intravenous immunoglobulin Infliximab Mycophenolate mofetil 15-deoxyspergualin Antithymocyte globulin

Dose
960mg, twice daily Methotrexate 15mg per week (oral or subcutaneous), increasing to 2025mg per week, plus folic acid and glucocorticoids Methotrexate 15mg per week (oral or subcutaneous), increasing to 2025mg per week, plus folic acid and glucocorticoids Intravenous pulse cyclophosphamide (three pulses of 15mg/kg every 2weeks, then every 3weeks, for a total of 69 pulses) and glucocorticoidsor Oral cyclophosphamide 2mg/kg and glucocorticoids, duration 36months Rituximab four infusions of 375mg/m once a week Seven rounds of plasma exchange 60ml/kg bodyweight

Trial
Stegeman etal.78 NA NORAM18 CYCLOPS16

Generalized Severe

RAVE33 RITUXVAS32 MEPEX24

Refractory Refractory Refractory Refractory Refractory Refractory

Four infusions of 375mg/m, once a week 2g/kg or 0.5g/kg/d for 4days 35mg/kg infusions, once or twice monthly 2g daily 0.5mg/kg daily for six cycles (adjusted to leucocyte count) Intravenous 2.5mg/kg daily for 10days (adjusted to leucocyte count)

Holle et al.55 Jayne et al.56 Lamprechtetal.88 Joy et al.89 Birck et al.90 Schmitt et al.91

Abbreviations: AAV, antineutrophil cytoplasmic antibody-associated vasculitis; BSR, British Society of Rheumatology; EULAR, European League Against Rheumatism; NA, not available.

AAV Early systemic Generalized Severe

Publication of the final results, with long-term follow-up data, should enable firm conclusions to be drawn.
Plasma exchange In patients with severe or life-threatening disease, rapid disease control is warranted. The rationale for using plasma exchange to treat active AAV includes the removal of pathological circulating factors (for example ANCA) and excess amounts of physiological circulating components (that is, complement, coagulation factors and cytokines).23 The randomized controlled MEPEX 24 trial compared seven plasma exchange sessions with three methylprednis olone pulses in 137 patients with newly diagnosed AAV who had serum creatinine levels >500mol/l at presentation. Both treatment groups also received oral cyclophosphamide and prednisolone. The primary end point was renal recovery at 3months and secondary end points were renal and patient survival at 12months. At 3months, the proportion of dialysis- independent patients was significantly higher in the plasma exchange group than in the methylprednisolone group (69% versus 49%; P=0.02). Plasma exchange was also associated with a decreased risk of ESRD at 12months (43% versus 19%). Severe adverse event rates and 1year patient survival (76% versus 73%) were similar in both groups. However, at a median follow-up of 4years, plasma exchange conferred no significant advantage with regard to rates of death, ESRD or relapse, although a trend towards a decreased frequency of ESRD was noted with plasma exchange (HR 0.64, 95% CI 0.401.05).25 The lack of statistical significance in the long-term follow-up results of the MEPEX24 trial was attributed to an insufficient number
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Remission induction

Methotrexate + glucocorticoid*

Cyclophosphamide + glucocorticoid* or rituximab + glucocorticoid*

Cyclophosphamide + glucocorticoid* or rituximab + glucocorticoid* and plasma exchange

Failure to respond Continue methotrexate + glucocorticoid Co-trimoxazole Switch to azathioprine + glucocorticoid (alternative methotrexate/leflunomide) Continue rituximab every 46 months

Remission maintenance

Refractory Switch to cyclophosphamide or rituximab Other treatment options IVIG, infliximab, mycophenolate motefil Relapse Repeat induction therapy Switch to rituximab

Figure 1 | Treatment strategies for remission induction and maintenance of AAV. Maintenance treatment should be continued for at least 1824months. *Add cotrimoxazole for prophylaxis of Pneumocystis jirovecii pneumonia. Abbreviations: AAV, antineutrophil cytoplasmic antibody-associated vasculitis; IVIG, intravenous immunoglobulin.

Mycophenolate mofetil A trial to compare mycophenolate mofetil with cyclophosphamide for remission induction in patients with AAV is currently underway (MYCYC).22 Preliminary results suggest that mycophenolate mofetil is noninferior to pulse cyclophosphamide for remission induction at 6months, but thereafter the risk of relapse seems to be substantially higher with mycophenolate mofetil.
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of remaining patients included in the analysis. The trial was insufficiently powered to demonstrate differences in the rate of death and ESRD over a longer follow-up period. However, even without reducing mortality, this finding could potentially represent a substantial reduction of ESRD requiring long-term dialysis treatment, which is associated with a high morbidity and socioeconomicburden. Further questions remain unanswered in the MEPEX study. For example, the now frequently used combi n ation of intravenous steroid pulses with plasma exchange was not tested, and the results of kidney biopsies were not used to stratify patients according to the severity of pre-existing irreversible kidney damage. Furthermore, whether plasma exchange might be more beneficial early in the course of AAV than it is thereafter is not yet clear. This question is the subject of the ongoing PEXIVAStrial.26 Pulse cyclophosphamide rather than daily oral cyclophosphamide is typically used in conjunction with plasma exchange in general clinical practice. In a retrospective study, the outcomes of a cohort of 41 patients with AAV who required haemodialysis at presentation were compared to those of the patients treated with plasma exchange and daily oral cyclophosphamide in the MEPEX24 trial. The combination of plasma exchange and pulse cyclophosphamide was noninferior (in terms of achieving remission, renal and patient survival) compared with plasma exchange and daily oral cyclophosphamide.27 A small randomized controlled trial of standard immunosuppression plus plasma exchange versus standard immunosuppression only in 32 patients with GPA, demonstrated improved renal survival among patients who presented with serum creatinine levels >250mol/l and were treated with additional plasma exchange, even after 5years of follow-up. Plasma exchange had no in fluence on mortality or relapse rates.28 Evidence supporting the additional use of plasma exchange to treat AAV in patients with severe renal disease has been summarized in a meta-analysis of nine randomized controlled trials, which included 387 patients.29 The analysis revealed a trend towards a decrease in the combined end point of death and ESRD, as well as some evidence that plasma exchange decreases the risk of kidney failure.29 However, so far, no evidence suggests that plasma exchange also lowers the risk of mortality. Furthermore, the researchers concluded that the optimal dose, the use of highly selective immuno adsorption procedures, and the combination of plasma exchange with other immune-modulating drugs all need to be explored further.29 Currently, plasma exchange is recommended as an adjunctive treatment for patients with severe renal and/or alveolar haemorrhage,30,31 and might be used in individuals with refractory or relapsing disease that affects other organs. A large international randomized controlled trial has begun recruiting patients with GPA or MPA who present with an estimated glomerular filtration rate (GFR) <50ml/min and/or alveolar haemorrhage (PEXIVAS, n=500).26 This study will have a 22
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factorial design, and will also assess whether glucocorticoids can be tapered more rapidly in the patients receivin g plasma exchange.26

Bcell depletion Given the proposed pathogenic role of B lymphocytes and ANCAs in AAV, the use of targeted antiB-cell therapy that could interfere with this pathogenic process is a logical step. Two randomized controlled trials have demonstrated equal effectiveness of the anti-CD20 antibody rituximab and cyclophosphamide for remission induction in patients with GPA and MPA.32,33 In the RITUXVAS trial,32 44 patients with newly diagnosed, severe AAV accompanied by renal involvement were randomly assigned in a 3:1 ratio to receive a standard glucocorticoid regimen plus rituximab (four infusions of 375mg/m body surface area) and either one or two pulses of intravenous cyclophosphamide (15mg/kg; rituximab group), or intravenous cyclophosphamide for 36months (control group). Glucocorticoids were reduced to 5mg daily after 6months and maintained at this dose for the remainder of the study. The primary end points, the rates of sustained remission at 12months (rituximab group 76%, control group 82%) and severe adverse events (rituximab group 42%, control group 36%), were not statistically different. Notably, 18% of thepatients died within the first 12months (six of 33 in the rituximab group and two of 11 in the control group).32 At 2years of follow-up, the relapse rate was similar in both groups (rituximab 21%, cyclophosphamide 18%) as were rates of adverse events, such as infections, leukopenia, and anaemia.34 From this study we can conclude that a rituximab-based regimen, with only one or two pulses of cyclophosphamide, was as effective as standard therapy (intravenous cyclophosphamide for induction and azathioprine for maintenance of r emission) in severe AAV. In the RAVE 33 study, a double-blind placebocontrolledmulticentre trial, 197 ANCA-positive patients with newly diagnosed or relapsing GPA or MPA were randomly assigned to receive either rituximab (four once-weekly infusions of 375mg/m) or oral cyclophosphamide 2mg/kg daily (control group).33 Patients with severe alveolar haemorrhage requiring ventilator support and advanced renal failure (creatinine levels >354mol/l) were excluded. As in the RITUXVAS trial,32 treatment with azathioprine for maintenance of remission was only applied to patients in the control group. Glucocorticoid dosages were tapered to zero by 5months. The primary end pointdisease remission off prednisone at 6monthswas reached by 64% of patients in the rituximab group, compared with 53% in the control group, meeting the prespecified criterion of noninferiority. The rituximab-containing regimen was more efficacious than oral cyclophosphamide for inducing remission in patients with relapsing disease (rituximab 67%, control group 42%, P=0.01), but equally effective in patients with newly diagnosed AAV (rituximab 60%, control group 65%). Adverse events were similarly frequent in both groups. However, after 18months
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Table 4 | Pulse cyclophosphamide reduction based on renal function and age16 Age (years)
<60 6070 >70 15 12.5 10

Cyclophosphamide dose reduction (per pulse, mg/kg) Creatinine <300mol/l Creatinine 300500mol/l
12.5 10 7.5

combination of rituximab and cyclophosphamide pulses (as opposed to cyclophosphamide alone) will be associated with a reduced time to remission, improved preser vation of organ function and reduction of persistent organ damage.

Modifications for specific subgroups

Patients aged over 60years About one-third of patients with ANCA-associated necrotizing glomerulonephritis are over 60years old at the time of their diagnosis.44 The majority of these older patients are MPO-ANCA-positive and have reduced kidney function compared with younger patients. As advanced age and severely impaired renal function are predictors of high mortality from infections within the first year of treatment for this disorder,8 the value of immunosuppressive treatment in this population needs to be explored. In a retrospective analysis of data from 61 patients (median age 83years) with ANCAassociated glomerulonephritis, immunosuppression had a ben eficial effect over supportive treatment only with regard to renal and patient outcomes.45 Moreover, cyclophosphamide doses should be reduced in patients aged >60years, owing to an increased rate of adverse effects and impaired renal function (Table4). In a prospective randomized controlled trial of patients with AAV and polyarteritis nodosa, reduced doses of cyclophosphamide (500mg) and prednisolone in patients >65years old proved no less effective than standard doses in terms of remission and relapse rates, according to preliminary results.46 In summary, less-intensive immunosuppressive therapy seems justified and beneficial with regard to patient and organ outcomes in patients >60years old. Localized GPA Patients with localized, primarily granulomatous AAV that is restricted to the upper respiratory tract, lung or eye, and who do not experience progression to systemic disease, represent ~5% of patients with GPA.47,48 Some reports suggest that these patients respond favourably to co-trimoxazole (trimethoprim and sulfamethoxazole) alone or in combination with glucocorticoids or immunosuppressive therapy.4951 The positive effect of these antibiotics might be due to the elimination of nasal carriage of Staphylococcus aureus, which has been implicated in the pathogenesis of GPA, or to their immunosuppressive properties,49 which result from interference with folic acid metabolism. The results of nonrandomized, single-centre studies show complete remission rates of up to 50% in patients with localized AAV receiving co-trimoxazole. 51,52 However, the rate of relapse or the need for further immunosuppressive therapy owing to persistent disease activity was high among patients who received cotrimoxazole alone as first-line therapy. During longterm follow-up only seven of 50 patients in the cohort study from Germany 47 and four of 16 patients from the French Vasculitis Study Group48 maintained remission with co-trimoxazole, alone or in combination with glucocorticoids. Controlled randomized trials of this
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no differences were observed in the remission rate at any time point, relapse severity and rate, or adverse effects (including infection risk and frequency).35 The study authors concluded that four weekly infusions of rituximab was as effective as 18months of standard therapy (oral cyclophosphamide for induction and azathioprine for maintenance of remission). Relapsing disease at baseline and PR3-ANCA positivity were associated with an increased number of disease flares. However, PR3ANCA-positive patients experienced fewer flares when treated with rituximab (14% versus 32%, P=0.02).36 In summary, the RAVE 33 and RITUXVAS 32 trials demon strate that rituximab is as effective as cyclophosphamide therapy (either intravenous or oral) at indu cing remission in ANCA-positive patients with GPA and MPA. Intriguingly, patients with relapse who were PR3ANCA-positive did better on rituximab than on cyclophosphamide. These results add rituximab as a valuable therapeutic option, especially for patients who cannot tolerate cyclophosphamide, those who are of reproductive age, or whose disease activity is poorly controlled or relapse while taking cyclophosphamide. Since 2011, rituximab has been licensed for the treatment of AAV in many countries in North America and Europe. However, the two studies highlight several limitations of treatment with rituximab; for example, 1year mortality, relapse rate and adverse effects remain unchanged.32,34,37 The optimal treatment regimen for rituximab remains to be determined. Both commonly used rituximab protocols (four once-weekly infusions of 375mg/m or two 1g infusions, 2weeks apart) seem to be equally effective for induction of remission, but have not been formally compared. Moreover, the concomitant glucocorticoid regimen that is most appropriate for use with any remission-inducing agent is unclear. The results of a meta-analysis suggest that prolonged courses of low-dose glucocorticoid therapy might significantly decrease disease activity in patients with AAV and reduce relapse.38 However, longterm treatment with glucocorticoids has also been linked to increased morbidity.10 For patients with imminently organ-threatening or life-threatening disease, treatment with rituximab alone has not yet been tested. Cyclophosphamide might be added to rituximab therapy in patients with severe and/or life-threatening AAV.32,3941 By contrast, rituxi mab might not be needed at all in patients with mild forms of AAV. However, several case reports suggest that rituximab can be successfully used as rescue therapy for patients with refractory and/or relapsing AAV, and can be recommended where conventional therapy has failed.42,43 Future studies will determine whether the
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Box 1 | Refractory AAV as defined by EUVAS and EULAR
Unchanged or increased disease activity in acute stage after 4weeks of treatment with standard therapy (daily oral cyclophosphamide, 23mg/kg, or intermittent highdose intravenous pulse cyclophosphamide 15mg/kg and glucocorticoids) No response (defined as <50% reduction in disease activity score* and lack of improvement in at least one major item on the disease activity score list) after 46weeks of treatment Chronic, persistent disease with presence of at least one major or three minor items on the disease activity score* list despite 8weeks (>12weeks) of treatment Intolerance of, or contraindications to, cyclophosphamide and glucocorticoids
*Birmingham vasculitis activity score, or granulomatosis with polyangiitis (formerly Wegeners granulomatosis)-specific Birmingham vasculitis activity score. Abbreviations: AAV, ANCAassociated vasculitis; EULAR, European League Against Rheumatism; EUVAS, European Vasculitis Study Group.

agent are lacking; however, co-trimoxazole alone or in combin ation with glucocorticoids can be recommended to induce remission in patients with localized GPA, e specially when limited to the upper respiratory tract.
Refractory vasculitis Refractory AAV has been defined by the EUVAS and EULAR consensus study group (Box1).53,54 According to the EUVAS/EULAR definition, the frequency of refractory AAV among participants in randomized controlled trials (CYCLOPS,15 MEPEX,24 NORAM,18 RITUXVAS,32 RAVE33) is low, affecting only 45% of patients.54 No randomized trials have yet investigated this topic. However, open-label studies suggest a variety of medical treatment options for this group: switching from intravenous to oral cyclophosphamide; the use of rituximab, antithymocyte globulin or alemtuzumab; autol ogous haematopoietic stem cell transplantation; high-dose azathioprine; tumour necrosis factor (TNF) antagonists; mycophenolate mofetil; 15-deoxyspergualin; or intravenous immunoglobulins.54 Current data from case reports suggest a response rate of 85% for rituximab in patients with refractory AAV (complete remission ~60%, partial response ~25%). 55

Rituximab can, therefore, be considered an effective and well-tolerated second-line therapy for this group of patients, and might be the first choice after the failure of cyclophosphamide treatment. One study suggests that response rates for vasculitic manifestations were excellent (complete remission or improvement in 90.6% of patients), whereas granulomatous manifestations (especially orbital masses) showed a high rate of failure to respond to rituximab (unchanged activity or refractory disease in 41.8% of patients) or might even progress despite this treatment.55 In patients who do not respond to first-line use of rituximab, the addition of plasma exchange (especially for rapidly progressive glomerulonephritis and/or alveolar haemorrhage), or alternatively, switching to cyclophosphamide, may be considered. However, the risk of infection must be monitored even more thoroughly with such a combined treatment. For patients with infectious complications, in whom the use of immunosuppressive therapies is restricted, intravenous immunoglobulins (a single dose of 2g/kg, or 0.5g/kg daily for 4days) can be considered. Although this treatment is effective for inducing remission and has good safety and tolerance profiles, the effect is not sustained beyond 3months, and monthly re-treatment might be required.56,57 Confirmation of which treatmentstrategy is optimal for patients with refractory AAV in a prospective multicentre trial, using a protocolized approach (that is, standard protocols for the various drugs as well as a rank order in which to use the drugs presented) would also be helpful.

Maintenance of remission
Current treatment strategies are highly efficient at inducing remission, with response rates of up to 90% in patients with AAV.58 However, relapses are frequent if maintenance therapy is not used, although the rate of relapse and time to first relapse varies considerably.5860 Consensus guidelines suggest continuation of main tenance immunosuppression for at least 1824months (Table5).61,62 After induction of remission, the use of a less-potent immunosuppressive regimen to prevent relapses and accrual of damage related to disease activity must be balanced against the toxicity of the treatment.

Table 5 | Recommendations for maintenance of remission of AAV according to EUVAS disease stage 59,60 Disease stage
Localized Early systemic

Treatment
Co-trimoxazole Methotrexate

Dose
960mg twice daily 2025mg per week and low-dose glucocorticoids

Trial
NA NORAM18 WEGENT64 LEM92 Stegeman etal.78 Zycinska etal.79 CYCAZAREM63 WEGENT64 LEM92 Ongoing

Early systemic with severe upper respiratory tract involvement Generalized Generalized Generalized Generalized

Co-trimoxazole Azathioprine Methotrexate Leflunomide Rituximab

960mg twice daily or three times per week 2mg/kg daily for 12months, thereafter 1.5mg/kg daily and low-dose glucocorticoids 2025mg per week and low-dose glucocorticoids 20mg daily and low-dose oral glucocorticoids 375mg/m or 0.5g or 1g infusions every 46months

Abbreviations: AAV, antineutrophil cytoplasmic antibody-associated vasculitis; EUVAS, European Vasculitis Study Group; NA, not available.

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Table 6 | Randomized controlled trials for maintenance of remission in AAV Trial (number ofpatients)
CYCAZAREM63 (144)

Inclusion criteria
GPA, MPA or relapse and renal or vital organ involvement New diagnosis of GPA or MPA

Treatment groups (dose)

Oral azathioprine (2mg/kg) versus oral cyclophosphamide (1.5mg/kg daily)

Primary end points

Relapse Adverse events

Outcome
No difference in relapse

IMPROVE65 (165)

Oral mycophenolate mofetil (2g daily) versus oral azathioprine (2mg/kg)

Timewithoutrelapse Adverse events

More relapses with mycophenolate mofetil than azathioprine, trend towards more adverse events with azathioprine No difference between groups in primary end point and relapses

WEGENT64 (126)

GPA or MPA andrenal ormultiorgan involvement Generalized GPA and creatinine <1.3mg/dl GPA and BVAS >3

Methotrexate (0.3mg/kg once weekly) versus azathioprine (2mg/kg)

Adverse events withconsecutive treatment cessation or death Relapse

LEM67 (54)

Leflunomide (30mg daily) versus methotrexate (up to 20mg per week)

More relapses with methotrexate than leflunomide, trend towards more adverse events with leflunomide No benefit with etanercept, more cancers in etanercept group

WGET66 (174)

Etanercept and methotrexate or cyclophosphamide versus placebo and methotrexate or cyclophosphamide

Sustained remission for >6months

Abbreviations: AAV, antineutrophil cytoplasmic antibody-associated vasculitis; BVAS, Birmingham vasculitis activity score for GPA; GPA, granulomatosis with polyangiitis (formerly Wegeners granulomatosis); MPA, microscopic polyangiitis.

Cytotoxic agents The gold-standard treatment for remission maintenance is 2mg/kg daily of azathioprine for at least 18months after onset of remission, 63 which has replaced longterm cyclophosphamide treatment without increasing the relapse rate. This non-inferiority of azathioprine in maintenance of remission as compared to cyclophosphamide was maintained throughout follow-up (median 8.5years), although a trend towards more relapses was noted in the az athioprine group (David Jayne, personalcommunication). A number of immunosuppressive agents have now been directly compared with azathioprine,6466 but none has shown a substantial benefit over azathioprine (Table6). Methotrexate can be used as an alternative to azathioprine, and has similar efficacy; however, methotrexate should be avoided in patients with renal insuf ficiency, because the drug is excreted via the kidneys and accumulates in response to decreasing renal function, thereby causing severe cytopenia and mucositis.64 Mycophenolate mofetil was less effective than azathioprine for maintaining remission (unadjusted HR 1.69) in the IMPROVE trial. 65 Relapses were more common in the myco phenolate mofetil group than in the azathioprine group (occurring in 42 of 76 patientstakingmyco phenolate mofetil, versus 30 of 80 patients taking azathioprine), but the results showed no significant differences in adverse event rates, estimated GFR or proteinuria. Mycophenolate mofetil is not, therefore, considered the first choice for maintenance treatment; however, it is used as a second line agent in patients with impaired renal function who are intolerant to azathioprine and cannot be given methotrexate. Another trial comparing low-dose methotrexate with leflunomide for maintenance of remission was terminated prematurely, owing to a higher than expected relapse rate in patients taking methotrexate. Moreover,
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four of the 13 patients who relapsed had rapidly progressive glomerulonephritis at relapse, suggesting that patients on a maintenance regimen of methotrexate need to be closely monitored for signs of glomerulonephritis, (for example, regular controls of dipstick urine tests and creatinine measurements).67 Adverse effects, (such as infection or nausea) were also common and should be taken into account if methotrexate-based maintenance therapy is being considered. Azathioprine is currently the first choice for maintenance treatment based on cytotoxic agents, although the performance of this treatment is far from perfect. The optimal duration of maintenance therapy remains unclear and is currently being investigated in the EUVASinitiated Randomized Trial of Prolonged Remission and Maintenance Therapy in Systemic Vasculitis (REMAIN) trial. 68 However, even with the use of maintenance t reatment, the relapse rate might be as high as 50%.15

Glucocorticoids The results of a meta-analysis suggest that prolonged courses of low-dose corticosteroid therapy might significantly alter disease activity and reduce relapse in patients with AAV.38 However, long-term treatment with glucocorticoids has been linked to increased morbidity. The concomitant steroid regimen that should be used with any remission-induction agent or maintenance therapy is also currently unclear. The duration of maintenance glucocorticoid treatment, and steroid dosages during the early post-induction and long-term remission periods, is currently being investigated in international trials (PEXIVAS and REMAIN).26,68 Biological agents The use of biological agents has also been investigated for maintenance of remission in patients with AAV.
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TNF blockade improves vasculitis in animal models.69 However, in the WGET trial,66 treatment with the soluble TNF receptor etanercept did not improve the sustained remission rate when added to standard treatment (cyclophosphamide or methotrexate in c ombination with glucocorticoids), in patients with GPA.66 Although rituximab is effective for induction of remission in patients with AAV, relapse is still common, especially in patients with refractory or relapsing disease. In three published trials, the median time to relapse after rituximab-based induction therapy was 11.5months (range 437months),42 8.5months70and 13.5 months (range 354 months). 55 The RAVE 33 andRITUXVAS32trials did not address the need for postrituximab maintenance treatment, nor what drug should be used. So far, only retrospective analyses of pre-emptive re-treatment with rituximab as maintenance therapy have been published, albeit with encouraging results.7072 However, the dose, timing and duration of rituximab retreatment show considerable variation within the different studies. In 39 patients who were in complete or partial remission at the time of initiation of rituximab main tenance treatment (1g infusion every 4months), discontinuation of immunosuppression and glucocorticoids was possible in a substantial number (among the patients with 2year follow-up 8 of 20 patients [40%, P=0.039 versus time 0] were completely off cytotoxic therapy and prednisone), without occurrence of relapses and with a favourable safety profile.71 Moreover, in 53 patients with GPA who received rituximab as induction therapy during a 10-year period, pre-emptive re-treatment with this agent after the return of B-cells and/or ANCA in peripheral blood was effective and seemed safe.70 In another retrospective analysis of data from 73 patients, re-treatment with rituximab at fixed intervals (1g every 6months for 2years) was associated with reduced relapse rates during the re-treatment period and a prolonged period of remission during subsequent follow-up in patients with refractory and relapsing AAV, regardless of Bcell count and ANCA status.72 Data concerning the long-term safety of repeated use of rituximab in patients with AAV are still lacking. Severe hypogammaglobulinaemia is rare, but if this does occur, reconstitution with intravenous immunoglobulins might be required. The risk of progressive multi focal leuco encephalopathy, late-onset neutropenia and malignancy needs to be considered. Long-term safety data from patients treated with rituximab for rheumatoid arthritis do not suggest an increased rate of malignancy or an increasing risk of infection over time.73,74 Preliminary data from a prospective randomized controlled trial (MAINRITSAN) 75 comparing two forms of maintenance treatment: standard azathioprine and fixed-dose infusions of rituximab (500mg every 6months for 18months) have been published. This study provides evidence for the superiority of rituximab over azathio prine as maintenance therapy (relapse rates were 3.6% with rituximab versus 27% with azathioprine), although the complete results are not yet available.76 Afurther international randomized controlled
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trial is underway, which will compare rituximab with azathioprine for m aintaining remission in patients withAAV(RITAZAREM).77 In summary, pre-emptive re-treatment with rituximab might reduce relapse rates in patients with AAV, although the optimal timing, dosing and duration of such therapy remain to be determined. Prospective controlled trials with long-term follow-up are needed to show not only the efficacy of this approach, but also the safety of repeated administration of rituximab for maintaining remission.

Co-trimoxazole Two randomized studies have compared co-trimoxazole treatment with placebo for maintenance of remission in patients with GPA after remission induction with standard immunosuppressive therapy (cyclophosphamide and glucocorticoids). In the larger of the two studies, 91 patients were randomly assigned to receive either co-trimoxazole 960mg twice per day (n=41) or placebo (n=40) for 24months.78 Eight of 41 patients (20%) stopped treatment with co-trimoxazole because of adverse events, such as nausea, rash, interstitial nephritis or hepatotoxicity. However, relapses were significantly less frequent in the co-trimoxazole group than the placebo group (18% versus 40%; relative risk of relapse 0.40 with co-trimoxazole). This benefit of cotrimoxazole therapy was evident for relapses involving the upper respiratory tract, but not for relapses in other organs. In the other randomized study, 31 patients were assigned to receive either co-trimoxazole 960mg three times a week (n=16) or placebo (n=15) for 18months as maintenance therapy, after remission induction with cyclophosphamide and glucocorticoids. 79 Treatment with co-trimoxazole was associated with a trend towards reduced incidence of relapses versus placebo (25% versus 47%, respectively, HR 0.8, 95% CI 0.211.20). Treatment with co-trimoxazole is safe and usually well tolerated. This agent can, therefore, be used alone or in combination with glucocorticoids to maintain remission in patients with disease limited to the upper respiratory tract, particularly those who are chronic carriers of Staphylococcus aureus. However, although the cotrimoxazole dose should be adjusted according to renal function, the optimal dosage and duration of treatment is unclear. For patients receiving rituximab (or cyclophosphamide) as maintenance therapy, the addition of cotrimoxazole is advocated for prophylaxis of Pneumocystis jirovecii pneumonia.61

Relapse of vasculitis
Relapse has been defined as the reoccurrence or new onset of disease attributable to active vasculitis.52 A major relapse is defined as a potentially organ-threatening or life-threatening disease, whereas a minor relapse is considered neither organ-threatening nor life-threatening. In patients receiving maintenance treatment for at least 18months, the majority of relapses occur during tapering of glucocorticoids and cytotoxic agents or after the discontinuation of maintenance medication.18,64
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Risk factors Patients at risk of relapse should be identified. Those with PR3-ANCA positivity or a diagnosis of GPA have a higher risk of relapse than do those with MPO-ANCA positivity or a diagnosis of MPA.50,80,81 Suboptimal intensity of induction therapy 58 and early withdrawal of immunosuppression or glucocorticoids might also be associated with an increased risk of relapse.38 However, even when adequate maintenance therapy has been administered, relapse during long-term follow-up is common, albeit highly variable timing and severity. Furthermore, the involvement of certain organs (ear, nose and throat, or lung and heart) is associated with an increased risk of relapse in some, but not all studies (HR 1.53.0).60,80,81 Conversely, in two studies, reduced renal function (GFR <30ml/min81 or creatinine levels >200mol/l) at the time of diagnosis60 was strongly associated with a decreased risk of relapse (HR 0.4). Persistence of ANCA after induction of remission,7,82 a rise in ANCA titres83 or chronic nasal carriage of Staphylococcus aureus are also associated with relapsing disease.82 However, serial ANCA testing for prediction of relapse remains controversial.84,85 According to a meta-analysis, a rise in ANCA titre during remission is associated with an increased risk of subsequent relapse (positive likelihood ratio 2.84, 95% CI 1.654.90). However, this association was not seen in all studies. Furthermore, relapses might occur without a preceding rise in ANCA titre.86 Patients who are PR3-ANCA positive, have GPA with granulomatous involvement of the upper and lower respiratory tract, and do not have renal impairment at the time of diagnosis, are at the highest risk of relapse.60,80,81 For these patients, extension of maint enance treatment beyond 24months might be beneficial and is commonly practiced.61,62 However, relapses in these patients commonly only affect the ear, nose and throat, without threatening vital organ functions. Whether the benefits of prolonged and intensive maintenance treatment outweigh the risk of therapy-related adverse effects in this population is as yet unknown. The results of the REMAIN trial,68 which will compare relapse rates in patients receiving either 24months or 48months of maintenance therapy, will hopefully answer this question. Relapse rates are also high in patients who have one or more of the risk factors outlined above in the absence of maintenance treatment.18 Treatment The first-line agent used for successful induction treatment might be reintroduced in patients who relapse, according to the severity of the relapse. For mild relapses,a temporary increase of the glucocorticoid dose (to 0.5mg/kg of body weight) might be sufficient. Rituximab seems to be superior to cyclophosphamide in the treatment of relapsing disease, as suggested in the RAVE trial.33 Re-treatment with rituximab is also recommended for relapse following rituximab-induced remission. 41 Future treatment strategies must also address whether the presence of certain risk factors can guide the type and duration of maintenance treatment,
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to individualize therapy for the diverse population of patients with AAV.

Conclusions
Over the past 20years, the results of multicentre ran domized controlled trials have changed the treatment options for AAV. Stage-adapted induction and maint enance therapies, and the introduction of effective medications with decreased toxicity have optimized AAV treatment and improved patient survival. These and other improvements in the management of patients with AAV, including increased awareness and prompt diagnosis, have also substantially improved renal survival over the past four decades. However, AAV should still be considered a chronic disease that involves frequent relapses and requires prolonged or repeated therapy. The improved outcomes are also counterbalanced by substantial short-term and long-term treatment-related adverse effects.6,87 Moreover, the benefits of therapy have to be weighed against the risk of death as well as relapse. Important predictors of mortality are severe renal insufficiency, advanced age, low haemoglobin levels, high disease activity levels and cumulative organ damage.9,10,58,59 We urgently need improved predictors of treatment resistance, prognosis and relapse risk. Finally, improved tools for measurement of patientrelated outcomes, and long-term follow-up of clinical trials to define the risk of malignancy and toxic effects ofnew therapeutic drugs, are both lacking. Cyclophosphamide and glucocorticoids are still an effective therapy for induction of remission in patients with generalized or severe disease. Dose reductions and avoidance of prolonged use of these agents have also been successfully implemented, although less-toxic regimens (especially ones that reduce the need for cyclophosphamide and/or glucocorticoids) are still required. For patients without organ-threatening disease, methotrexate can be used. Rituximab is equally effective as cyclophosphamide for remission induction and should be considered the first choice in patients of reproductive age, in patients who have received cyclophosphamide treatmentin the past, and especially in those with relapsing disease, in whom rituximab might be superior to cyclophosphamide. However, data regarding the most effective rituximab dose, the efficacy and safety of combination therapies and the long-term risks are still lacking. The use of adjunctive treatments should also be considered, including plasma exchange in patients with severe, life-threatening disease (such as renal failure or alveolar haemorrhage) and co-trimoxazole for individuals with ear, nose and throat involvement. The optimal type, amount and duration of maintenance therapy remain under debate. Maintenance therapy is currently recommended for at least 1824months, and azathioprine is the drug of choice for this purpose. However, rituximab might be equally effective or even better than azathioprine. In all clinical trials conducted to date, AAV has been treated as a single disease entity. However, because of the clear differences in clinical manifestation, genetic associations, histology, rate of relapse as well as renal and patient survival, individuals with GPA
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and MPA (or PR3-ANCA and MPO-ANCA positivity) should be studied separately in future trials. Moreover, stratification of patients in clinical trials should not only consider the individuals phenotype or genotype, but also the different types of organ or disease manifestation. As an example granulomatous and vasculitic organ manifestations behave differently with regard to treatment response and relapse rate. Better individual risk stratification in future trials could allow the tailoring of more intense therapy to those with aggressive and life- threatening disease, whereas prolonged therapy would be given only to patients with a high risk of relapse. However, the success of these i ndividualized strategies has to be proven in future studies.
1. Jennette, J.C. etal. 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculitides. Arthritis Rheum. 65, 111 (2013). Jennette, C.J. & Falk, R.J. L1. Pathogenesis of ANCA-associated vasculitis: observations, theories and speculations. Presse Med. 42, 493498 (2013). Pepper, R.J. & Salama, A.D. Classifying and predicting outcomes in ANCA-associated glomerulonephritis. Nephrol. Dial. Transplant. 27, 21352137 (2012). Jayne, D. L27. Antibodies versus phenotypes: aclinicians view. Presse Med. 42, 579582 (2013). Lyons, P .A. etal. Genetically distinct subsets within ANCA-associated vasculitis. N. Engl. J. Med. 367, 214223 (2012). Hoffman, G.S., Leavitt, R.Y., Kerr, G.S. &Fauci,A.S. The treatment of Wegeners granulomatosis with glucocorticoids and methotrexate. Arthritis Rheum. 35, 13221329 (1992). Slot, M.C., Tervaert, J.W., Boomsma, M.M. &Stegeman, C.A. Positive classic antineutrophil cytoplasmic antibody (C-ANCA) titer at switch to azathioprine therapy associated with relapse in proteinase 3related vasculitis. Arthritis Rheum. 51, 269273 (2004). Little, M.A. etal. Early mortality in systemic vasculitis: relative contribution of adverse events and active vasculitis. Ann. Rheum. Dis. 69, 10361043 (2010). Flossmann, O. etal. Long-term patient survival in ANCA-associated vasculitis. Ann. Rheum. Dis. 70, 488494 (2011). Wall, N. & Harper, L. Complications of long-term therapy for ANCA-associated systemic vasculitis. Nat. Rev. Nephrol. 8, 523532 (2012). Holle, J.U. etal. Improved outcome in 445 patients with Wegeners granulomatosis in a German vasculitis center over four decades. Arthritis Rheum. 63, 257266 (2011). Hilhorst, M. etal. Improved outcome in antineutrophil cytoplasmic antibody (ANCA)associated glomerulonephritis: a 30-year follow-up study. Nephrol. Dial. Transplant. 28, 373379 (2013). Walton, E.W. Giant cell granuloma of the respiratory tract (Wegeners Granulomatosis). BMJ 2, 265270 (1958). Hoffman, G.S. etal. Wegeners granulomatosis: an analysis of 158 patients. Ann. Intern. Med. 116, 488498 (1992). Harper, L. etal. Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up. Ann. Rheum. Dis. 71, 955960 (2012).

Review criteria
Selection of articles for this review focused on randomized studies conducted by the European Vasculitis Society (formerly the European Vasculitis Study Group, EUVAS), the Vasculitis Clinical Research Consortium and the French Vasculitis Study Group, as well as analyses of long-term follow-up data from these studies. Further references were found by searching PubMed for articles published between 1990 and September 2013 with the following terms: ANCA-associated vasculitis and randomized trial, rituximab, plasma exchange or cotrimoxazole. We included mainly full-text papers written in English and abstracts presented at the 16th Vasculitis & ANCA Meeting.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16. de Groot, K. etal. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann. Intern. Med. 150, 670680 (2009). 17. Neumann, I. etal. Histological and clinical predictors of early and late renal outcome in ANCA-associated vasculitis. Nephrol. Dial. Transplant. 20, 96104 (2005). 18. de Groot, K. etal. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 52, 24612469 (2005). 19. Faurschou, M. etal. Brief report: long-term outcome of a randomized clinical trial comparing methotrexate to cyclophosphamide for remission induction in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 64, 34723477 (2012). 20. Faurschou, M. etal. Reply. Arthritis Rheum. 65, 844 (2013). 21. Langford, C.A. & Hoffman, G.S. Methotrexate remains a valuable option for remission induction of nonsevere antineutrophil cytoplasmic antibody-associated vasculitis: comment on the article by Faurschou etal. Arthritis Rheum. 65, 843 (2013). 22. Jones, R.B. A randomized trial of mycophenolate mofetil versus cyclophosphamide for remission induction of ANCA-associated vasculitis: MYCYC. On behalf of the European vasculitis study group [abstract]. Presse Med. 42, 678679 (2013). 23. Casian, A. & Jayne, D. Plasma exchange in the treatment of Wegeners granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and renal limited vasculitis. Curr. Opin. Rheumatol. 23, 1217 (2011). 24. Jayne, D.R. etal. Randomized trial of plasma exchange or high-dosage methylprednisolone asadjunctive therapy for severe renal vasculitis. J. Am. Soc. Nephrol. 18, 21802188 (2007). 25. Walsh, M. etal. Long-term follow-up of patients with severe ANCA-associated vasculitis comparing plasma exchange to intravenous methylprednisolone treatment is unclear. Kidney Int. 84, 397402 (2013). 26. US National Library of Medicine. Clinicaltrials.gov [online], http://clinicaltrials.gov/ct2/show/ NCT00987389 (2013). 27. Pepper, R.J. etal. Intravenous cyclophosphamide and plasmapheresis in dialysis-dependent ANCAassociated vasculitis. Clin. J. Am. Soc. Nephrol. 8, 219224 (2013).

28. Szpirt, W.M., Heaf, J.G. & Petersen, J. Plasma exchange for induction and cyclosporine A for maintenance of remission in Wegeners granulomatosisa clinical randomized controlled trial. Nephrol. Dial. Transplant. 26, 206213 (2011). 29. Walsh, M. etal. Plasma exchange for renal vasculitis and idiopathic rapidly progressive glomerulonephritis: a meta-analysis. Am. J. Kidney Dis. 57, 566574 (2011). 30. Casian, A. & Jayne, D. Management of alveolar hemorrhage in lung vasculitides. Semin. Respir. Crit. Care Med. 32, 335345 (2011). 31. Hruskova, et al. Long-term outcome of severe alveolar haemorrhage in ANCA-associated vasculitis: a retrospective cohort study. Scand. J. Rheumatol. 42, 211214 (2013). 32. Jones, R.B. etal. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N. Engl. J. Med. 363, 211220 (2010). 33. Stone, J.H. etal. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N. Engl. J. Med. 363, 221232 (2010). 34. Jones, R.B., Walsh, M. & Jayne, D.R. Two year follow up results from a randomised trial of RTX versus CyP for ANCA-associated vasculitis: RITUXVAS [abstract]. Clin. Exp. Immunol. 164, 57 (2011). 35. Specks, U. etal. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N.Engl. J. Med. 369, 417427 (2013). 36. Miloslavsky, E.M. etal. Clinical outcomes of remission induction therapy for severe antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 65, 24412449 (2013). 37. Clain, J.M. & Specks, U. S1. Rituximab for ANCAassociated vasculitis: the experience in the United States. Presse Med. 42, 530532 (2013). 38. Walsh, M., Merkel, P .A., Mahr, A. & Jayne, D. Theeffects of duration of glucocorticoid therapyon relapse rate in anti-neutrophil cytoplasm antibody associated vasculitis: ameta-analysis. Arthritis Care Res. 62, 11661173 (2010). 39. Cohen Tervaert, J.W. Rituximab in ANCAassociated vasculitis: a revolution? Nephrol. Dial. Transplant. 26, 30773079 (2011). 40. Mansfield, N. etal. Prolonged disease-free remission following rituximab and low-dose cyclophosphamide therapy for renal ANCAassociated vasculitis. Nephrol. Dial. Transplant. 26, 32803286 (2011). 41. Guerry, M.J. etal. Recommendations for the use of rituximab in anti-neutrophil cytoplasm antibody-associated vasculitis. Rheumatology (Oxford) 51, 634643 (2012).

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42. Jones, R.B. etal. A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 60, 21562168 (2009). 43. Martinez Del Pero, M. etal. Bcell depletion with rituximab for refractory head and neck Wegeners granulomatosis: a cohort study. Clin. Otolaryngol. 34, 328335 (2009). 44. Hamour, S.M. & Salama, A.D. ANCA comes of age-but with caveats. Kidney Int. 79, 699701 (2011). 45. Bomback, A.S. etal. ANCA-associated glomerulonephritis in the very elderly. Kidney Int. 79, 757764 (2011). 46. Pagnoux, C. et al. Treatment of systemic necrotizing vasculitides in patients >65years old: results of the multicentre randomized CORTAGE trial [abstract]. Presse Med. 42, 679680 (2013). 47. Holle, J.U. etal. Prospective long-term follow-up of patients with localised Wegeners granulomatosis: does it occur as persistent disease stage? Ann. Rheum. Dis. 69, 19341939 (2010). 48. Pagnoux, C. etal. Wegeners granulomatosis strictly and persistently localized to one organ is rare: assessment of 16 patients from the French Vasculitis Study Group database. J. Rheumatol. 38, 475478 (2011). 49. DeRemee, R.A., McDonald, T.J. & Weiland, L.H. Wegeners granulomatosis: observations on treatment with antimicrobial agents. Mayo Clin. Proc. 60, 2732 (1985). 50. DeRemee, R.A. The treatment of Wegeners granulomatosis with trimethoprim/ sulfamethoxazole: illusion or vision? Arthritis Rheum. 31, 10681074 (1988). 51. Reinhold-Keller, E. etal. Response to trimethroprim-sulfamethoxazole (T/S) in Wegeners granulomatosis (WG) depends on the phase of disease. QJM 89, 1523 (1996). 52. Kallenberg, C.G. & Tadema, H. Vasculitis and infections: contribution to the issue of autoimmunity reviews devoted to autoimmunity and infection. Autoimmun. Rev. 8, 2932 (2008). 53. Hellmich, B. etal. EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis: focus on anti-neutrophil cytoplasm antibody-associated vasculitis. Ann. Rheum. Dis. 66, 605617 (2007). 54. Rutgers, A. & Kallenberg, C.G. Refractory disease in antineutrophil cytoplasmic antibodies associated vasculitis. Curr. Opin. Rheumatol. 24, 245251 (2012). 55. Holle, J.U. etal. Rituximab for refractory granulomatosis with polyangiitis (Wegeners granulomatosis): comparison of efficacy in granulomatous versus vasculitic manifestations. Ann. Rheum. Dis. 71, 327333 (2012). 56. Jayne, D.R. etal. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. QJM 93, 433439 (2000). 57. Martinez, V. etal. Intravenous immunoglobulins for relapses of systemic vasculitides associated with antineutrophil cytoplasmic autoantibodies: results of a multicenter, prospective, open-label study of twenty-two patients. Arthritis Rheum. 58, 308317 (2008). 58. 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