REVIEWS

Treatment of ANCA-associated vasculitis

Ulf Schönermarck, Wolfgang L. Gross and Kirsten de Groot
Abstract | Antineutrophil cytoplasmic autoantibody (ANCA)-associated diseases are small-vessel vasculitides,
encompassing granulomatosis with polyangiitis (formerly Wegener’s 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 (3–6 months) for rapid control of disease
activity and maintenance of remission (at least 18 months) 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
(different types of organ manifestation, PR3-ANCA or MPO-ANCA positivity) and disease severity.
Schönermarck, U. et al. Nat. Rev. Nephrol. advance online publication 5 November 2013; doi:10.1038/nrneph.2013.225

Introduction
Antineutrophil cytoplasmic autoantibody (ANCA)- epigenetic control of MHC and antigen expression, func-
associated diseases are small-vessel vasculitides, encom- tion and localization of antigens, and also outcome.2,3
passing granulomatosis with polyangiitis (GPA, formerly Differences between PR3-ANCA-associated and MPO-
known as Wegener’s granulomatosis), microscopic ANCA-associated diseases have also been identi­fied in
polyangiitis (MPA) and eosinophilic granulomatosis clinical manifestations, histology, relapse rate, and renal
with polyangiitis (formerly known as Churg–Strauss and patient survival.4 These two groups also had differ-
syndrome). These diseases are characterized by no or ent genetic associations in a genome-wide association
few immune complexes in the tissue and the presence of study;5 PR3-ANCA was associated with polymorphisms
specific types of ANCAs, upon which the nomenclature in HLA-DP and the genes encoding PR3 (PTN3) and its
of these diseases is now based.1 Eosinophilic granuloma­ inhibitor α‑1-antitrypsin (SERPINA1), whereas MPO-
Medizinische Klinik tosis with polyangiitis is characterized by differences in ANCA was associated with HLA-DQ. These observations
und Poliklinik IV,
Nephrologisches pathogenetic mechanisms, genetic associations and a provide evidence for a genetic contribution to disease sus-
Zentrum, University much lower frequency of kidney involvement and ANCA ceptibility. Despite their distinct genetic risk factors, PR3-
Hospital Munich,
Campus Grosshadern, positivity than is observed in GPA and MPA; therefore, ANCA-associated and MPO-ANCA-associated diseases
Ludwig-Maximilians- in this Review, we focus on the treatment of patients with have overlapping clinical phenotypes and similarities in
University,
Marchioninstrasse 15,
GPA and MPA. their pathogenesis. Consequently, and to enroll reason-
Munich D‑81377, For many years, GPA and MPA were considered to able patient numbers in clinical trials of drugs to treat
Germany be part of a single disease spectrum because they share ANCA-associated diseases, patients with MPA and GPA
(U. Schönermarck).
University Hospital many clinical and histopathological features. ANCAs are have been uniformly treated so far.
Schleswig-Holstein, thought to contribute to the pathogenesis of both GPA and MPA and GPA were once considered life-threatening
Campus Lübeck,
Ratzeburger Allee 160,
MPA, with proteinase 3 (PR3)-ANCA commonly occur- diseases, but immunosuppressive therapy has substan-
Lübeck D‑23538, ring in patients with GPA and myelo­peroxidase (MPO)- tially improved the survival of affected patients. Treatment
Germany (W. L. Gross). ANCA frequently occurring in patients with MPA. is biphasic and tailored according to disease stage and
IIIrd Medical
Department, Klinikum However, patients with PR3-ANCA and MPO-ANCA severity—induction of remission (3–6 months) for rapid
Offenbach GmbH, (but not those with the clinical disease entities GPA control of disease activity and maintenance of remission
Starkenburgring 66,
KfH Renal Center
and MPA) can be distinguished by genetic associations, (for at least 18 months; Table 1). Maintenance therapy
Starkenburgring 70, aims to prevent disease relapse using less-toxic agents
Offenbach/Main
than are required for induction of remission. However,
D‑63069, Germany
(K. de Groot).
Competing interests relapses are frequent and require prolonged or repeated
W. L. Gross declares associations with the following companies:
GlaxoSmithKline, Hoffmann-La Roche. K. de Groot declares an
therapy. Moreover, current treatment strategies have
Correspondence to:
K. de Groot association with the following company: Hoffmann–La Roche. substantial short-term and long-term adverse effects;6,7
kirsten@de-groot.de U. Schönermarck declares no competing interests. 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 pop-
ulation, 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 EUVAS and EULAR definition53,61
Localized Upper and/or lower respiratory tract
disease without further systemic
involvement or constitutional symptoms
Early systemic Any disease without organ-threatening or
life-threatening involvement
Generalized Renal or other organ-threatening disease
Severe Renal or other vital organ failure
Refractory Progressive disease unresponsive to
standard therapy
Abbreviations: ANCA, antineutrophil cytoplasmic autoantibody; ENT, ear, nose, throat; EULAR, European League Against Rheumatism; EUVAS, European
Vasculitis Study Group.
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18 months13 to 80% at 8 years of follow-up.14 However,
treatment with oral cyclophosphamide (2–4 mg/kg/d) for
a prolonged period, as occurs when this agent is used
for both remission induction and maintenance therapy, is
associated with substantial treatment-related short-term
and long-term morbidity from infectious complications,
myelosuppression, infertility, cardiovascular disease
and malignancy.8–10,14
Treatment with cyclophosphamide and glucocorti-
coids 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 1 year and up to 75%
at 10 years.9 Furthermore, alternative treatments adapted
to each disease stage have been developed to minimize,
or even avoid, the use of cyclophosphamide (Tables 2
and 3). Pulse cyclophosphamide is noninferior to daily
oral cyclophosphamide in terms of the remission rate
(Table 2). However, in a retrospective long-term follow-
up study, pulse cyclophosphamide was associated with
a significantly higher relapse rate than daily oral cyclo-
phosphamide after a median of 4.3 years (39.5% versus
20.8%, HR 0.50, 95% CI 0.26–0.93; P = 0.029).15 No dif-
ferences 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 effec-
tive 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 cyclophospha-
mide. Standardized dose reduction of intravenous pulse
cyclophosphamide, according to age and renal impair-
ment, has improved the safety of this regimen (Table 3).
When using daily oral cyclophosphamide, dose reduc-
tion according to age and renal function is also advised.
Oral doses should be reduced by 25% for patients
>60 years and by 50% for patients over 70 years. 16
Furthermore, prophylaxis with co-trimoxazole (to
prevent Pneumocystis jirocevii pneumonia) should be
applied to all patients with generalized disease receiving
remission induction (Figure 1).
Systemic vasculitis Threatened vital Serum creatinine
outside ENT or lung organ function (μmol/l)
No No <120
Yes No <120
Yes Yes <500
Yes Organ failure >500
Yes Yes Any
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Table 2 | Randomized controlled trials for induction of remission in AAV using cytotoxic or biological agents
Disease Trial Inclusion Treatment groups Primary end Outcome
stage (patients) criteria (dose) points
Early NORAM18 New diagnosis Methotrexate (0.3 mg/kg once Remission Methotrexate not inferior
systemic (100) of GPA or MPA, weekly) versus daily oral Time to to cyclophosphamide
and creatinine cyclophosphamide relapse Time to relapse shorter with
<150 μmol/l methotrexate
Generalized CYCLOPS16 New diagnosis Intravenous pulse Remission Pulse cyclophosphamide not
(149) of GPA, MPA, cyclophosphamide (15 mg/kg) Time to inferior to oral
or relapse with versus daily oral relapse cyclophosphamide
renal involvement, cyclophosphamide (2 mg/kg) Less leucopenia and trend
creatinine towards more relapses with
150–500 μmol/l pulse cyclophosphamide
Generalized RITUXVAS32 New diagnosis Rituximab (four 375 mg/m² Sustained Rituximab not inferior to
(44) of AAV and severe infusions) plus two intravenous remission pulse cyclophosphamide
renal involvement pulses of cyclophosphamide,
versus intravenous pulse
cyclophosphamide only
Generalized RAVE33 New or relapsing Rituximab (4 × 375 mg/m² Complete Rituximab not inferior to oral
(198) GPA or MPA infusions) versus daily oral remission and cyclophosphamide
cyclophosphamide cessation of Rituximab better in patients
glucocorticoids with relapse than after first
at 6 months diagnosis
Generalized MEPEX24 New diagnosis Plasma exchange and oral Renal survival Better renal survival with
with RPGN (137) of GPA or MPA cyclophosphamide versus at 3 months plasma exchange
and creatinine 3 × intravenous 24% risk reduction for ESRD
>500 μmol/l methylprednisolone pulse with plasma exchange
and oral cyclophosphamide
MPA, GPA MYCYC22 New diagnosis Mycophenolate mofetil (2–3 g Remission at Preliminary data: noninferiority
(140) of GPA, MPA daily) versus intravenous pulse 6 months not proven for mycophenolate
and major organ cyclophosphamide (15 mg/kg) Relapse mofetil versus pulse
involvement cyclophosphamide
MPA, GPA, CORTAGE46 New diagnosis Rapid glucocorticoid tapering Severe Preliminary data: less severe
EGPA or PAN (104) of MPA, GPA, and reduced-dose intravenous adverse adverse events with reduced
EGPA, PAN and pulse cyclophosphamide events immunosuppression, no
age >65 years (500 mg) versus standard difference in remission and
intravenous pulse relapse rates
cyclophosphamide (500 mg/m²)
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 appar-
ent relapse rate will be.17 Prolonged use of maintenance
therapy (>12 months) 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
<150 μmol/l) were treated with either oral cyclophospha-
mide (2 mg/kg daily) or oral methotrexate (20–25 mg
per week) for 12 months. Both groups also received
prednisolone.18 After 18 months of follow-up, remis-
sion rates were similar in both groups. However, in the
methotrexate group, time to remission was significantly
longer in patients with extensive disease or pulmonary
involvement. Furthermore, the relapse rate at 18 months
was higher (69.5% versus 46.5%) and the time from
remission to relapse shorter (13 versus 15 months, HR
1.85, 95% CI 1.06–3.25, 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 6 years)
follow-up data from the NORAM18 trial further sup-
ports these results;19 patients who were initially treated
with methotrexate experienced less-effective long-
term disease control, and required a longer duration
of glucocorticoid therapy than did those who received
cyclophosphamide.19–21 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 pro-
longed use of effective maintenance therapies.21 However,
the risk of ESRD seems to be low in patients with early
systemic AAV.

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Table 3 | Recommendations for inducing remission of AAV according to EULAR and BSR 59,60
Disease stage Treatment Dose Trial
Localized Co-trimoxazole with or without 960 mg, twice daily Stegeman et al.78
glucocorticoids
Localized Methotrexate and glucocorticoids Methotrexate 15 mg per week (oral or subcutaneous), increasing to NA
20–25 mg per week, plus folic acid and glucocorticoids
Early systemic Methotrexate and glucocorticoids Methotrexate 15 mg per week (oral or subcutaneous), increasing to NORAM18
20–25 mg per week, plus folic acid and glucocorticoids
Generalized Cyclophosphamide and Intravenous pulse cyclophosphamide (three pulses of 15 mg/kg every 2 weeks, CYCLOPS16
glucocorticoids then every 3 weeks, for a total of 6–9 pulses) and glucocorticoids or
Oral cyclophosphamide 2 mg/kg and glucocorticoids, duration 3–6 months
Generalized Rituximab and glucocorticoids Rituximab four infusions of 375 mg/m² once a week RAVE33
RITUXVAS32
Severe Plasma exchange as adjunctive Seven rounds of plasma exchange 60 ml/kg bodyweight MEPEX24
therapy to cyclophosphamide
or rituximab (standard therapy)
Refractory Rituximab Four infusions of 375 mg/m², once a week Holle et al.55
Refractory Intravenous immunoglobulin 2 g/kg or 0.5 g/kg/d for 4 days Jayne et al.56
Refractory Infliximab 3–5 mg/kg infusions, once or twice monthly Lamprecht et al.88
Refractory Mycophenolate mofetil 2 g daily Joy et al.89
Refractory 15-deoxyspergualin 0.5 mg/kg daily for six cycles (adjusted to leucocyte count) Birck et al.90
Refractory Antithymocyte globulin Intravenous 2.5 mg/kg daily for 10 days (adjusted to leucocyte count) 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 Publication of the final results, with long-term follow-up

Early systemic Generalized Severe
data, should enable firm conclusions to be drawn.

Plasma exchange
In patients with severe or life-threatening disease,
Remission
induction

Methotrexate + Cyclophosphamide Cyclophosphamide

glucocorticoid* + glucocorticoid* or + glucocorticoid* or rapid disease control is warranted. The rationale for
rituximab + glucocorticoid* rituximab + glucocorticoid* using plasma exchange to treat active AAV includes the
and plasma exchange
removal of pathological circulating factors (for example
ANCA) and excess amounts of physiological circulating
Failure to respond components (that is, complement, coagulation factors
and cytokines).23
Continue methotrexate Switch to azathioprine + Refractory The randomized controlled MEPEX 24 trial com-
+ glucocorticoid glucocorticoid (alternative ■ Switch to cyclophosphamide pared seven plasma exchange sessions with three
Co-trimoxazole methotrexate/leflunomide) or rituximab methylprednis­olone pulses in 137 patients with newly
maintenance

Continue rituximab every

Remission

■ Other treatment options

4–6 months 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 18–24 months. *Add co-
trimoxazole 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 cyclo-
phosphamide 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
6 months, but thereafter the risk of relapse seems to
be substantially higher with mycophenolate mofetil.
diagnosed AAV who had serum creatinine levels
>500 μmol/l at presentation. Both treatment groups
also received oral cyclophosphamide and predniso-
lone. The primary end point was renal recovery at
3 months and secondary end points were renal and
patient survival at 12 months. At 3 months, the pro-
portion of dialysis-­independent patients was signifi-
cantly 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 12 months (43% versus 19%). Severe
adverse event rates and 1‑year patient survival (76%
versus 73%) were similar in both groups. However, at a
median follow-up of 4 years, 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 0.40–1.05).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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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 treat-
ment, which is associated with a high morbidity and
socioeconomic burden.
Further questions remain unanswered in the MEPEX
study. For example, the now frequently used combin­
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
PEXIVAS trial.26
Pulse cyclophosphamide rather than daily oral cyclo-
phosphamide is typically used in conjunction with
plasma exchange in general clinical practice. In a retro-
spective 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 stand-
ard immunosuppression only in 32 patients with GPA,
demonstrated improved renal survival among patients
who presented with serum creatinine levels >250 μmol/l
and were treated with additional plasma exchange, even
after 5 years of follow-up. Plasma exchange had no
in­fluence 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 indi-
viduals with refractory or relapsing disease that affects
other organs. A large international randomized con-
trolled trial has begun recruiting patients with GPA or
MPA who present with an estimated glomerular filtra-
tion rate (GFR) <50 ml/min and/or alveolar haemor-
rhage (PEXIVAS, n = 500).26 This study will have a 2 × 2
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REVIEWS
factorial design, and will also assess whether gluco-
corticoids can be tapered more rapidly in the patients
receivin­g plasma exchange.26
B‑cell depletion
Given the proposed pathogenic role of B lymphocytes
and ANCAs in AAV, the use of targeted anti‑B-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 anti-
body rituximab and cyclophosphamide for remission
induction in patients with GPA and MPA.32,33
In the RITUXVAS trial,32 44 patients with newly diag-
nosed, severe AAV accompanied by renal involvement
were randomly assigned in a 3:1 ratio to receive a stand-
ard glucocorticoid regimen plus rituximab (four infu-
sions of 375 mg/m² body surface area) and either one or
two pulses of intravenous cyclophosphamide (15 mg/kg;
rituximab group), or intravenous cyclophosphamide
for 3–6 months (control group). Glucocorticoids were
reduced to 5 mg daily after 6 months and maintained at
this dose for the remainder of the study. The primary
end points, the rates of sustained remission at 12 months
(rituximab group 76%, control group 82%) and severe
adverse events (rituximab group 42%, control group
36%), were not statistically different. Notably, 18% of
the patients died within the first 12 months (six of 33
in the rituximab group and two of 11 in the control
group).32 At 2 years of follow-up, the relapse rate was
similar in both groups (rituximab 21%, cyclophospha-
mide 18%) as were rates of adverse events, such as infec-
tions, 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 effec-
tive as standard therapy (intravenous cyclophospha-
mide for induction and ­azathioprine for maintenance
of r­emission) in severe AAV.
In the RAVE 33 study, a double-blind placebo-
controlled­multicentre 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 375 mg/m²) or oral cyclo-
phosphamide 2 mg/kg daily (control group).33 Patients
with severe alveolar haemorrhage requiring ventilator
support and advanced renal failure (creatinine levels
>354 µmol/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 5 months. The primary end point—disease remis-
sion off prednisone at 6 months—was 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 (rituxi-
mab 60%, control group 65%). Adverse events were simi-
larly frequent in both groups. However, after 18 months
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Table 4 | Pulse cyclophosphamide reduction based on renal function and age16
Age (years) Cyclophosphamide dose reduction (per pulse, mg/kg)
Creatinine <300 μmol/l Creatinine 300–500 μmol/l
<60 15 12.5
60–70 12.5 10
>70 10 7.5
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 rituxi-
mab was as effective as 18 months 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, PR3-
ANCA-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
demon­strate that rituximab is as effective as cyclophos-
phamide therapy (either intravenous or oral) at indu­
cing remission in ANCA-positive patients with GPA and
MPA. Intriguingly, patients with relapse who were PR3-
ANCA-positive did better on rituximab than on cyclo-
phosphamide. These results add rituximab as a valuable
therapeutic option, especially for patients who cannot
tolerate cyclophosphamide, those who are of reproduc-
tive 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, 1 year mortality, relapse rate
and adverse effects remain unchanged.32,34,37 The optimal
treatment regimen for rituximab remains to be deter-
mined. Both commonly used rituximab protocols (four
once-weekly infusions of 375 mg/m² or two 1 g infusions,
2 weeks apart) seem to be equally effective for induc-
tion 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, long-
term 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.32,39–41 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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combination of rituximab and cyclophosphamide pulses
(as opposed to cyclophosphamide alone) will be associ-
ated 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 60 years
About one-third of patients with ANCA-associated
necrotizing glomerulonephritis are over 60 years 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 83 years) with ANCA-
associated glomerulonephritis, immunosuppression had
a ben­eficial effect over supportive treatment only with
regard to renal and patient outcomes.45 Moreover, cyclo-
phosphamide doses should be reduced in patients aged
>60 years, owing to an increased rate of adverse effects
and impaired renal function (Table 4). In a prospective
randomized controlled trial of patients with AAV and
polyarteritis nodosa, reduced doses of cyclophos­phamide
(500 mg) and prednisolone in patients >65 years old
proved no less effective than standard doses in terms of
remission and relapse rates, according to preliminary
results.46 In summary, less-intensive immunosuppres-
sive therapy seems justified and beneficial with regard
to patient and organ outcomes in patients >60 years 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 sulfamethoxa-
zole) alone or in combination with glucocorticoids or
immunosuppressive therapy.49–51 The positive effect of
these antibiotics might be due to the elimination of nasal
carriage of Staphylococcus aureus, which has been impli-
cated in the pathogenesis of GPA, or to their immuno-
suppressive 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 co-
trimoxazole alone as first-line therapy. During long-
term 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 remis-
sion with co-trimoxazole, alone or in combination with
glucocorticoids. Controlled randomized trials of this
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agent are lacking; however, co-trimoxazole alone or in
combin­ation with glucocorticoids can be recommended
to induce remission in patients with localized GPA,
e­specially when limited to the upper respiratory tract.
Refractory vasculitis
Refractory AAV has been defined by the EUVAS and
EULAR consensus study group (Box 1).53,54 According to
the EUVAS/EULAR definition, the frequency of refrac-
tory AAV among participants in randomized controlled
trials (CYCLOPS,15 MEPEX,24 NORAM,18 RITUXVAS,32
RAVE33) is low, affecting only 4–5% of patients.54 No ran-
domized 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; autol­ogous 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 refrac-
tory 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 glomerulo-
nephritis 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 2 g/kg,
Table 5 | Recommendations for maintenance of remission of AAV according to EUVAS disease stage 59,60
Disease stage Treatment
Localized Co-trimoxazole
Early systemic Methotrexate
Early systemic with severe upper Co-trimoxazole
respiratory tract involvement
Generalized Azathioprine
Generalized Methotrexate
Generalized Leflunomide
Generalized Rituximab
Abbreviations: AAV, antineutrophil cytoplasmic antibody-associated vasculitis; EUVAS, European Vasculitis Study Group; NA, not available.
NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION  |  7
© 2013 Macmillan Publishers Limited. All rights reserved
REVIEWS
Box 1 | Refractory AAV as defined by EUVAS and EULAR
■■ Unchanged or increased disease activity in acute stage
after 4 weeks of treatment with standard therapy (daily
oral cyclophosphamide, 2–3 mg/kg, or intermittent high-
dose intravenous pulse cyclophosphamide 15 mg/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
4–6 weeks of treatment
■■ Chronic, persistent disease with presence of at least
one major or three minor items on the disease activity
score* list despite 8 weeks (>12 weeks) of treatment
■■ Intolerance of, or contraindications to, cyclophosphamide
and glucocorticoids
*Birmingham vasculitis activity score, or granulomatosis with
polyangiitis (formerly Wegener’s granulomatosis)-specific
Birmingham vasculitis activity score. Abbreviations: AAV, ANCA-
associated vasculitis; EULAR, European League Against
Rheumatism; EUVAS, European Vasculitis Study Group.
or 0.5 g/kg daily for 4 days) can be considered. Although
this treatment is effective for inducing remission and
has good safety and tolerance profiles, the effect is not
sustained beyond 3 months, and monthly re-treatment
might be required. 56,57 Confirmation of which treat-
ment strategy 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.58–60
Consensus guidelines suggest continuation of maint­
enance immunosuppression for at least 18–24 months
(Table 5).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.
Dose Trial
960 mg twice daily NA
20–25 mg per week and low-dose glucocorticoids NORAM18
WEGENT64
LEM92
960 mg twice daily or three times per week Stegeman et al.78
Zycinska et al.79
2 mg/kg daily for 12 months, thereafter 1.5 mg/kg CYCAZAREM63
daily and low-dose glucocorticoids
20–25 mg per week and low-dose glucocorticoids WEGENT64
20 mg daily and low-dose oral glucocorticoids LEM92
375 mg/m² or 0.5 g or 1 g infusions every 4–6 months Ongoing
REVIEWS

Table 6 | Randomized controlled trials for maintenance of remission in AAV

Trial (number Inclusion criteria Treatment groups (dose) Primary end points Outcome
of patients)
CYCAZAREM63 GPA, MPA or Oral azathioprine (2 mg/kg) versus oral Relapse No difference in relapse
(144) relapse and renal cyclophosphamide (1.5 mg/kg daily) Adverse events
or vital organ
involvement
IMPROVE65 New diagnosis of Oral mycophenolate mofetil (2 g daily) Time without relapse More relapses with
(165) GPA or MPA versus oral azathioprine (2 mg/kg) Adverse events mycophenolate mofetil than
azathioprine, trend towards more
adverse events with azathioprine
WEGENT64 GPA or MPA Methotrexate (0.3 mg/kg once weekly) Adverse events No difference between groups in
(126) and renal versus azathioprine (2 mg/kg) with consecutive primary end point and relapses
or multiorgan treatment
involvement cessation or death
LEM67 Generalized GPA Leflunomide (30 mg daily) versus Relapse More relapses with methotrexate
(54) and creatinine methotrexate (up to 20 mg per week) than leflunomide, trend towards
<1.3 mg/dl more adverse events with
leflunomide
WGET66 GPA and BVAS >3 Etanercept and methotrexate or Sustained No benefit with etanercept, more
(174) cyclophosphamide versus placebo and remission for cancers in etanercept group
methotrexate or cyclophosphamide >6 months
Abbreviations: AAV, antineutrophil cytoplasmic antibody-associated vasculitis; BVAS, Birmingham vasculitis activity score for GPA; GPA, granulomatosis with
polyangiitis (formerly Wegener’s granulomatosis); MPA, microscopic polyangiitis.

Cytotoxic agents
The gold-standard treatment for remission maintenance
is 2 mg/kg daily of azathioprine for at least 18 months
after onset of remission, 63 which has replaced long-
term cyclophosphamide treatment without increasing
the relapse rate. This non-inferiority of azathioprine
in maintenance of remission as compared to cyclo-
phosphamide was maintained throughout follow-up
(median 8.5 years), although a trend towards more
relapses was noted in the az­athioprine group (David
Jayne, personal communication).
A number of immunosuppressive agents have now been
directly compared with azathioprine,64–66 but none has
shown a substantial benefit over azathioprine (Table 6).
Methotrexate can be used as an alternative to azathio-
prine, and has similar efficacy; however, methotrexate
should be avoided in patients with renal insuf­ficiency,
because the drug is excreted via the kidneys and accu-
mulates in response to decreasing renal function, thereby
causing severe cytopenia and mucositis.64 Mycophenolate
mofetil was less effective than azathioprine for maintain-
ing 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 patients taking myco­phenolate
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 metho-
trexate. Another trial comparing low-dose methotrexate
with leflunomide for maintenance of remission was ter-
minated prematurely, owing to a higher than expected
relapse rate in patients taking methotrexate. Moreover,
four of the 13 patients who relapsed had rapidly pro-
gressive 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 main-
tenance 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 EUVAS-
initiated Randomized Trial of Prolonged Remission and
Maintenance Therapy in Systemic Vasculitis (REMAIN)
trial. 68 However, even with the use of maintenance
t­reatment, 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 signifi-
cantly alter disease activity and reduce relapse in patients
with AAV.38 However, long-term treatment with gluco-
corticoids 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 (cyclo-
phosphamide or methotrexate in c­ombination 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
11.5 months (range 4–37 months),42 8.5 months70 and
13.5  months (range 3–54  months). 55 The RAVE 33
and RITUXVAS32 trials did not address the need for post-
rituximab 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.70–72
However, the dose, timing and duration of rituximab re-
treatment show considerable variation within the different
studies. In 39 patients who were in complete or partial
remission at the time of initiation of rituximab maint­
enance treatment (1g infusion every 4 months), discon-
tinuation of immunosuppression and glucocorticoids
was possible in a substantial number (among the patients
with 2‑year 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 retro-
spective analysis of data from 73 patients, re-treatment
with rituximab at fixed intervals (1g every 6 months for
2 years) was associated with reduced relapse rates during
the re-treatment period and a prolonged period of remis-
sion during subsequent follow-up in patients with refrac-
tory and relapsing AAV, regardless of B‑cell 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 multi­focal leuco­
encephalopathy, late-onset neutropenia and malignancy
needs to be considered. Long-term safety data from
patients treated with rituximab for rheumatoid arthri-
tis 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 (500 mg every
6 months for 18 months) have been published. This
study provides evidence for the superiority of rituximab
over azathio­prine as maintenance therapy (relapse rates
were 3.6% with rituximab versus 27% with azathio-
prine), although the complete results are not yet avail-
able.76 A further international randomized controlled
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© 2013 Macmillan Publishers Limited. All rights reserved
REVIEWS
trial is underway, which will compare rituximab with
azathioprine for ­m aintaining remission in patients
with AAV (RITAZAREM).77
In summary, pre-emptive re-treatment with rituxi-
mab 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 (cyclophospha-
mide and glucocorticoids). In the larger of the two
studies, 91 patients were randomly assigned to receive
either co-trimoxazole 960 mg twice per day (n = 41) or
placebo (n = 40) for 24 months.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 co-
trimoxazole 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 960 mg three
times a week (n = 16) or placebo (n = 15) for 18 months
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 0.21–1.20).
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 car-
riers of Staphylococcus aureus. However, although the co-
trimoxazole dose should be adjusted according to renal
function, the optimal dosage and duration of treatment is
unclear. For patients receiving rituximab (or cyclophos-
phamide) as maintenance therapy, the addition of co-
trimoxazole 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 con-
sidered neither organ-threatening nor life-threatening.
In patients receiving maintenance treatment for at least
18 months, the majority of relapses occur during taper-
ing of glucocorticoids and cytotoxic agents or after the
discontinuation of maintenance medication.18,64
REVIEWS
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 positiv-
ity or a diagnosis of MPA.50,80,81 Suboptimal intensity of
induction therapy 58 and early withdrawal of immuno-
suppression 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 1.5–3.0).60,80,81
Conversely, in two studies, reduced renal function (GFR
<30 ml/min81 or creatinine levels >200 μmol/l) at the time
of diagnosis60 was strongly associated with a decreased
risk of relapse (HR 0.4). Persistence of ANCA after induc-
tion 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 remis-
sion is associated with an increased risk of subsequent
relapse (positive likelihood ratio 2.84, 95% CI 1.65–4.90).
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 res-
piratory 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 maint­enance treatment
beyond 24 months might be beneficial and is com-
monly practiced.61,62 However, relapses in these patients
commonly only affect the ear, nose and throat, without
threatening vital organ functions. Whether the ben-
efits 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 24 months or 48 months of
maintenance therapy, will hopefully answer this ques-
tion. 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 treat-
ment 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 0.5 mg/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,
10  |  ADVANCE ONLINE PUBLICATION
© 2013 Macmillan Publishers Limited. All rights reserved
to individualize therapy for the diverse population of
patients with AAV.
Conclusions
Over the past 20 years, 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 medi-
cations 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 cumu-
lative organ damage.9,10,58,59 We urgently need improved
predictors of treatment resistance, prognosis and relapse
risk. Finally, improved tools for measurement of patient-
related outcomes, and long-term follow-up of clinical
trials to define the risk of malignancy and toxic effects
of new 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 cyclophos-
phamide and/or glucocorticoids) are still required. For
patients without organ-threatening disease, metho-
trexate can be used. Rituximab is equally effective as
cyclophosphamide for remission induction and should
be considered the first choice in patients of reproduc-
tive age, in patients who have received cyclophospha-
mide treatment in 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 combi-
nation therapies and the long-term risks are still lacking.
The use of adjunctive treatments should also be consid-
ered, 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 18–24 months,
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 mani-
festation, genetic associations, histology, rate of relapse as
well as renal and patient survival, individuals with GPA
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 REVIEWS

and MPA (or PR3-ANCA and MPO-ANCA positivity) Review criteria

should be studied separately in future trials. Moreover,
stratification of patients in clinical trials should not only
consider the individual’s phenotype or genotype, but
also the different types of organ or disease manifesta-
tion. As an example granulomatous and vasculitic organ
manifestations behave differently with regard to treat-
ment 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 i­ndividualized strategies has to be
proven in future studies.
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.

1. Jennette, J. C. et al. 2012 revised International
Chapel Hill Consensus Conference nomenclature
of vasculitides. Arthritis Rheum. 65, 1–11 (2013).
2. Jennette, C. J. & Falk, R. J. L1. Pathogenesis of
ANCA-associated vasculitis: observations,
theories and speculations. Presse Med. 42,
493–498 (2013).
3. Pepper, R. J. & Salama, A. D. Classifying and
predicting outcomes in ANCA-associated
glomerulonephritis. Nephrol. Dial. Transplant. 27,
2135–2137 (2012).
4. Jayne, D. L27. Antibodies versus phenotypes:
a clinician’s view. Presse Med. 42, 579–582
(2013).
5. Lyons, P. A. et al. Genetically distinct subsets
within ANCA-associated vasculitis. N. Engl. J.
Med. 367, 214–223 (2012).
6. Hoffman, G. S., Leavitt, R. Y., Kerr, G. S.
& Fauci, A. S. The treatment of Wegener’s
granulomatosis with glucocorticoids and
methotrexate. Arthritis Rheum. 35, 1322–1329
(1992).
7. 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 3‑related vasculitis. Arthritis Rheum.
51, 269–273 (2004).
8. Little, M. A. et al. Early mortality in systemic
vasculitis: relative contribution of adverse
events and active vasculitis. Ann. Rheum. Dis.
69, 1036–1043 (2010).
9. Flossmann, O. et al. Long-term patient survival in
ANCA-associated vasculitis. Ann. Rheum. Dis.
70, 488–494 (2011).
10. Wall, N. & Harper, L. Complications of long-term
therapy for ANCA-associated systemic vasculitis.
Nat. Rev. Nephrol. 8, 523–532 (2012).
11. Holle, J. U. et al. Improved outcome in 445
patients with Wegener’s granulomatosis in a
German vasculitis center over four decades.
Arthritis Rheum. 63, 257–266 (2011).
12. Hilhorst, M. et al. Improved outcome in anti-
neutrophil cytoplasmic antibody (ANCA)-
associated glomerulonephritis: a 30-year
follow-up study. Nephrol. Dial. Transplant. 28,
373–379 (2013).
13. Walton, E. W. Giant cell granuloma of the
respiratory tract (Wegener’s Granulomatosis).
BMJ 2, 265–270 (1958).
14. Hoffman, G. S. et al. Wegener’s granulomatosis:
an analysis of 158 patients. Ann. Intern. Med.
116, 488–498 (1992).
15. Harper, L. et al. Pulse versus daily oral
cyclophosphamide for induction of remission in
ANCA-associated vasculitis: long-term follow-up.
Ann. Rheum. Dis. 71, 955–960 (2012).
16. de Groot, K. et al. Pulse versus daily oral
cyclophosphamide for induction of remission in
antineutrophil cytoplasmic antibody-associated
vasculitis: a randomized trial. Ann. Intern. Med.
150, 670–680 (2009).
17. Neumann, I. et al. Histological and clinical
predictors of early and late renal outcome in
ANCA-associated vasculitis. Nephrol. Dial.
Transplant. 20, 96–104 (2005).
18. de Groot, K. et al. Randomized trial of
cyclophosphamide versus methotrexate for
induction of remission in early systemic
antineutrophil cytoplasmic antibody-associated
vasculitis. Arthritis Rheum. 52, 2461–2469
(2005).
19. Faurschou, M. et al. 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, 3472–3477
(2012).
20. Faurschou, M. et al. 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 et al.
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, 678–679
(2013).
23. Casian, A. & Jayne, D. Plasma exchange in the
treatment of Wegener’s granulomatosis,
microscopic polyangiitis, Churg-Strauss
syndrome and renal limited vasculitis. Curr. Opin.
Rheumatol. 23, 12–17 (2011).
24. Jayne, D. R. et al. Randomized trial of plasma
exchange or high-dosage methylprednisolone
as adjunctive therapy for severe renal vasculitis.
J. Am. Soc. Nephrol. 18, 2180–2188 (2007).
25. Walsh, M. et al. Long-term follow-up of patients
with severe ANCA-associated vasculitis
comparing plasma exchange to intravenous
methylprednisolone treatment is unclear. Kidney
Int. 84, 397–402 (2013).
26. US National Library of Medicine. Clinicaltrials.gov
[online], http://clinicaltrials.gov/ct2/show/
NCT00987389 (2013).
27. Pepper, R. J. et al. Intravenous cyclophosphamide
and plasmapheresis in dialysis-dependent ANCA-
associated vasculitis. Clin. J. Am. Soc. Nephrol. 8,
219–224 (2013).
28. Szpirt, W. M., Heaf, J. G. & Petersen, J. Plasma
exchange for induction and cyclosporine A for
maintenance of remission in Wegener’s
granulomatosis—a clinical randomized
controlled trial. Nephrol. Dial. Transplant. 26,
206–213 (2011).
29. Walsh, M. et al. Plasma exchange for renal
vasculitis and idiopathic rapidly progressive
glomerulonephritis: a meta-analysis. Am. J.
Kidney Dis. 57, 566–574 (2011).
30. Casian, A. & Jayne, D. Management of alveolar
hemorrhage in lung vasculitides. Semin. Respir.
Crit. Care Med. 32, 335–345 (2011).
31. Hruskova, et al. Long-term outcome of severe
alveolar haemorrhage in ANCA-associated
vasculitis: a retrospective cohort study. Scand. J.
Rheumatol. 42, 211–214 (2013).
32. Jones, R. B. et al. Rituximab versus
cyclophosphamide in ANCA-associated renal
vasculitis. N. Engl. J. Med. 363, 211–220 (2010).
33. Stone, J. H. et al. Rituximab versus
cyclophosphamide for ANCA-associated
vasculitis. N. Engl. J. Med. 363, 221–232 (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. et al. Efficacy of remission-induction
regimens for ANCA-associated vasculitis.
N. Engl. J. Med. 369, 417–427 (2013).
36. Miloslavsky, E. M. et al. Clinical outcomes of
remission induction therapy for severe
antineutrophil cytoplasmic antibody-associated
vasculitis. Arthritis Rheum. 65, 2441–2449
(2013).
37. Clain, J. M. & Specks, U. S1. Rituximab for ANCA-
associated vasculitis: the experience in the
United States. Presse Med. 42, 530–532 (2013).
38. Walsh, M., Merkel, P. A., Mahr, A. & Jayne, D.
The effects of duration of glucocorticoid
therapy on relapse rate in anti-neutrophil
cytoplasm antibody associated vasculitis:
a meta-analysis. Arthritis Care Res. 62,
1166–1173 (2010).
39. Cohen Tervaert, J. W. Rituximab in ANCA-
associated vasculitis: a revolution? Nephrol.
Dial. Transplant. 26, 3077–3079 (2011).
40. Mansfield, N. et al. Prolonged disease-free
remission following rituximab and low-dose
cyclophosphamide therapy for renal ANCA-
associated vasculitis. Nephrol. Dial. Transplant.
26, 3280–3286 (2011).
41. Guerry, M. J. et al. Recommendations for the use
of rituximab in anti-neutrophil cytoplasm
antibody-associated vasculitis. Rheumatology
(Oxford) 51, 634–643 (2012).

NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION  |  11

© 2013 Macmillan Publishers Limited. All rights reserved
REVIEWS
42. Jones, R. B. et al. A multicenter survey of
rituximab therapy for refractory antineutrophil
cytoplasmic antibody-associated vasculitis.
Arthritis Rheum. 60, 2156–2168 (2009).
43. Martinez Del Pero, M. et al. B‑cell depletion with
rituximab for refractory head and neck Wegener’s
granulomatosis: a cohort study. Clin. Otolaryngol.
34, 328–335 (2009).
44. Hamour, S. M. & Salama, A. D. ANCA comes of
age-but with caveats. Kidney Int. 79, 699–701
(2011).
45. Bomback, A. S. et al. ANCA-associated
glomerulonephritis in the very elderly. Kidney Int.
79, 757–764 (2011).
46. Pagnoux, C. et al. Treatment of systemic
necrotizing vasculitides in patients >65 years
old: results of the multicentre randomized
CORTAGE trial [abstract]. Presse Med. 42,
679–680 (2013).
47. Holle, J. U. et al. Prospective long-term follow-up
of patients with localised Wegener’s
granulomatosis: does it occur as persistent
disease stage? Ann. Rheum. Dis. 69, 1934–1939
(2010).
48. Pagnoux, C. et al. Wegener’s granulomatosis
strictly and persistently localized to one organ is
rare: assessment of 16 patients from the French
Vasculitis Study Group database. J. Rheumatol.
38, 475–478 (2011).
49. DeRemee, R. A., McDonald, T. J. & Weiland, L. H.
Wegener’s granulomatosis: observations on
treatment with antimicrobial agents. Mayo Clin.
Proc. 60, 27–32 (1985).
50. DeRemee, R. A. The treatment of Wegener’s
granulomatosis with trimethoprim/
sulfamethoxazole: illusion or vision? Arthritis
Rheum. 31, 1068–1074 (1988).
51. Reinhold-Keller, E. et al. Response to
trimethroprim-sulfamethoxazole (T/S) in
Wegener’s granulomatosis (WG) depends on the
phase of disease. QJM 89, 15–23 (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, 29–32
(2008).
53. Hellmich, B. et al. 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, 605–617 (2007).
54. Rutgers, A. & Kallenberg, C. G. Refractory
disease in antineutrophil cytoplasmic antibodies
associated vasculitis. Curr. Opin. Rheumatol. 24,
245–251 (2012).
55. Holle, J. U. et al. Rituximab for refractory
granulomatosis with polyangiitis (Wegener’s
granulomatosis): comparison of efficacy in
granulomatous versus vasculitic
manifestations. Ann. Rheum. Dis. 71, 327–333
(2012).
56. Jayne, D. R. et al. Intravenous immunoglobulin
for ANCA-associated systemic vasculitis with
persistent disease activity. QJM 93, 433–439
(2000).
57. Martinez, V. et al. 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, 308–317 (2008).
58. Mukhtyar, C. et al. Outcomes from studies of
antineutrophil cytoplasm antibody associated
vasculitis: a systematic review by the European
League Against Rheumatism systemic vasculitis
task force. Ann. Rheum. Dis. 67, 1004–1010
(2008).
12  |  ADVANCE ONLINE PUBLICATION
59. Booth, A. D. et al. Outcome of ANCA-associated
renal vasculitis: a 5‑year retrospective study. Am.
J. Kidney Dis. 41, 776–784 (2003).
60. Walsh, M. et al. Risk factors for relapse of
antineutrophil cytoplasmic antibody-associated
vasculitis. Arthritis Rheum. 64, 542–548 (2012).
61. Mukhtyar, C. et al. EULAR recommendations for
the management of primary small and medium
vessel vasculitis. Ann. Rheum. Dis. 68, 310–317
(2009).
62. Lapraik, C. et al. BSR and BHPR guidelines for the
management of adults with ANCA associated
vasculitis. Rheumatology (Oxford) 46, 1615–1616
(2007).
63. Jayne, D. et al. A randomized trial of
maintenance therapy for vasculitis associated
with antineutrophil cytoplasmic autoantibodies.
N. Engl. J. Med. 349, 36–44 (2003).
64. Pagnoux, C. et al. Azathioprine or methotrexate
maintenance for ANCA-associated vasculitis.
N. Engl. J. Med. 359, 2790–2803 (2008).
65. Hiemstra, T. F. et al. Mycophenolate mofetil vs
azathioprine for remission maintenance in
antineutrophil cytoplasmic antibody-associated
vasculitis: a randomized controlled trial. JAMA
304, 2381–2388 (2010).
66. WGET Research Group. Etanercept plus
standard therapy for Wegener’s granulomatosis.
N. Engl. J. Med. 352, 351–361 (2005).
67. Metzler, C. et al. Elevated relapse rate under
oral methotrexate versus leflunomide for
maintenance of remission in Wegener’s
granulomatosis. Rheumatology (Oxford) 46,
1087–1091 (2007).
68. European Vasculitis Study Group. Clinical
Trial Protocol: REMAIN. [online], http://
www.vasculitis.nl/media/documents/remain.pdf
(2006).
69. Little, M. A. et al. Therapeutic effect of anti‑TNF‑α
antibodies in an experimental model of anti-
neutrophil cytoplasm antibody-associated
systemic vasculitis. J. Am. Soc. Nephrol. 17,
160–169 (2006).
70. Cartin-Ceba, R. et al. Rituximab for remission
induction and maintenance in refractory
granulomatosis with polyangiitis (Wegener’s):
ten-year experience at a single center. Arthritis
Rheum. 64, 3770–3778 (2012).
71. Rhee, E. P., Laliberte, K. A. & Niles, J. L. Rituximab
as maintenance therapy for anti-neutrophil
cytoplasmic antibody-associated vasculitis. Clin. J.
Am. Soc. Nephrol. 5, 1394–1400 (2010).
72. Smith, R. M. et al. Rituximab for remission
maintenance in relapsing antineutrophil
cytoplasmic antibody-associated vasculitis.
Arthritis Rheum. 64, 3760–3769 (2012).
73. van Vollenhoven, R. F. et al. Longterm safety of
patients receiving rituximab in rheumatoid
arthritis clinical trials. J. Rheumatol. 37,
558–567 (2010).
74. van Vollenhoven, R. F. et al. Long-term safety of
rituximab in rheumatoid arthritis: 9.5-year
follow-up of the global clinical trial programme
with a focus on adverse events of interest in RA
patients. Ann. Rheum. Dis. (2012).
75. US National Library of Medicine. Clinicaltrials.gov
[online], http://clinicaltrials.gov/ct2/show/
NCT00748644 (2013).
76. Charles, P. & Guillevin, L. S3. Rituximab for
ANCA-associated vasculitides: the French
experience. Presse Med. 42, 534–536 (2013).
77. US National Library of Medicine. Clinicaltrials.gov
[online], http://clinicaltrials.gov/ct2/show/
NCT01697267 (2013).
78. Stegeman, C. A., Cohen Tervaert, J. W.,
De Jong, P. E. & Kallenberg, C. G. Trimethoprim-
sulfamethoxazole (co-trimoxazole) for the
© 2013 Macmillan Publishers Limited. All rights reserved
prevention of relapses of Wegener’s
granulomatosis. N. Engl. J. Med. 335, 16–20
(1996).
79. Zycinska, K., Wardyn, K. A., Zielonka, T. M.,
Krupa, R. & Lukas, W. Co-trimoxazole and
prevention of relapses of PR3-ANCA positive
vasculitis with pulmonary involvement. Eur. J.
Med. Res. 14 (Suppl. 4), 265–267 (2009).
80. Pagnoux, C. et al. Predictors of treatment
resistance and relapse in antineutrophil
cytoplasmic antibody-associated small-vessel
vasculitis: comparison of two independent
cohorts. Arthritis Rheum. 58, 2908–2918 (2008).
81. Pierrot-Deseilligny Despujol, C., Pouchot, J.,
Pagnoux, C., Coste, J. & Guillevin, L. Predictors
at diagnosis of a first Wegener’s granulomatosis
relapse after obtaining complete remission.
Rheumatology (Oxford) 49, 2181–2190 (2010).
82. Stegeman, A. C. et al. Association of chronic
nasal carriage of staphylococcus aureus and
higher relapse rates in Wegener’s granulomatosis.
Ann. Intern. Med. 120, 12–17 (1994).
83. Boomsma, M. M. et al. Prediction of relapses
in Wegener’s granulomatosis by measurement
of antineutrophil cytoplasmic antibody levels:
a prospective study. Arthritis Rheum. 43,
2025–2033 (2000).
84. Birck, R., Schmitt, W. H., Kaelsch, I. A.
& van der Woude, F. J. Serial ANCA
determinations for monitoring disease activity
in patients with ANCA-associated vasculitis:
systematic review. Am. J. Kidney Dis. 47, 15–23
(2006).
85. Finkielman, J. D. et al. Antiproteinase 3
antineutrophil cytoplasmic antibodies and
disease activity in Wegener granulomatosis.
Ann. Intern. Med. 147, 611–619 (2007).
86. Tomasson, G., Grayson, P. C., Mahr, A. D.,
Lavalley, M. & Merkel, P. A. Value of ANCA
measurements during remission to predict a
relapse of ANCA-associated vasculitis—a meta-
analysis. Rheumatology (Oxford) 51, 100–109
(2012).
87. Faurschou, M. et al. Malignancies in Wegener’s
granulomatosis: incidence and relation to
cyclophosphamide therapy in a cohort of 293
patients. J. Rheumatol. 35, 100–105 (2008).
88. Lamprecht, P., et al. Effectiveness of TNF-alpha
blockade with infliximab in refractory Wegener’s
granulomatosis. Rheumatology (Oxford) 41,
1303–1307 (2002).
89. Joy, M. S., Hogan, S. L., Jennette, J. C., Falk, R. J.
& Nachman, P. H. A pilot study using
mycophenolate mofetil in relapsing or resistant
ANCA small vessel vasculitis. Nephrol. Dial.
Transplant. 20, 2725–2732 (2005).
90. Birck, R. et al. 15-Deoxyspergualin in patients with
refractory ANCA-associated systemic vasculitis:
a six-month open-label trial to evaluate safety and
efficacy. J. Am. Soc. Nephrol. 14, 440–447 (2003).
91. Schmitt, W. H., et al. Treatment of refractory
Wegener’s granulomatosis with antithymocyte
globulin (ATG): an open study in 15 patients.
Kidney Int. 65, 1440–1448 (2004).
92. Metzler, C., Fink, C., Lamprecht, P., Gross, W. L.
& Reinhold-Keller, E. Maintenance of remission
with leflunomide in Wegener’s granulomatosis.
Rheumatology (Oxford) 43, 315–320 (2004).
Author contributions
U. Schönermarck and K. de Groot researched data
for the article, made substantial contribution to
discussion of the content, and wrote, reviewed and
edited the manuscript before submission. W. L. Gross
made a substantial contribution to discussion of the
content and reviewed/edited the manuscript
before submission.
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