BMJ 2020;368:m421 doi: 10.1136/bmj.
m421 (Published 18 March 2020)
Clinical Review
STATE OF THE ART REVIEW
Management of ANCA associated vasculitis
1 2 3
Zachary S Wallace assistant professor of medicine
2 3
medicine
1
Clinical Epidemiology Program, Division of Rheumatology, Allergy, and Immunology, Mongan Institute, Department of Medicine, Massachusetts
General Hospital, Boston, MA, USA; 2Rheumatology Unit, Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts
General Hospital, Boston, MA, USA; 3Harvard Medical School, Boston, MA, USA
Abstract
ABSTRACT
Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV)
is a small to medium vessel vasculitis associated with excess morbidity
and mortality. This review explores how management of AAV has evolved
over the past two decades with pivotal randomized controlled trials
shaping the management of induction and maintenance of remission.
Contemporary AAV care is characterized by approaches that minimize
the cumulative exposure to cyclophosphamide and glucocorticoids,
increasingly use rituximab for remission induction and maintenance, and
consider therapies with less toxicity (for example, methotrexate,
mycophenolate mofetil) for manifestations of AAV that do not threaten
organ function or survival. Simultaneously, improvements in outcomes,
such as renal and overall survival, have been observed. Additional trials
and observational studies evaluating the comparative effectiveness of
agents for AAV in various patient subgroups are needed. Prospective
studies are necessary to assess the effect of psychosocial interventions
on patient reported outcomes in AAV. Despite the expanding array of
treatments for AAV, little guidance on how to personalize AAV care is
available to physicians.
Introduction
Anti-neutrophil cytoplasmic antibody (ANCA) associated
vasculitis (AAV) is a necrotizing vasculitis primarily affecting
small to medium sized vessels.1 AAV is a heterogeneous
condition that includes three clinicopathologic conditions:
granulomatosis with polyangiitis (GPA, formerly Wegener’s
granulomatosis), microscopic polyangiitis, and eosinophilic
granulomatosis with polyangiitis (EGPA).1 It affects men and
women from a wide age spectrum and diverse racial
backgrounds (fig 1). The most commonly affected organs
include the respiratory tract, eyes, kidneys, skin, and nervous
system.
Correspondence to: zswallace@mgh.harvard.edu (or @zach_wallace_md on Twitter)
Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason
they are written predominantly by US authors
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CLINICAL REVIEW
, Eli M Miloslavsky assistant professor of
Most patients with AAV are ANCA positive at some point in
their clinical course, with antibodies targeting either proteinase
3 (PR3-ANCA positive) or myeloperoxidase (MPO-ANCA
positive).3-5 Mounting evidence suggests that phenotyping
patients according to ANCA type (PR3-ANCA positive or
MPO-ANCA positive), rather than as GPA or microscopic
polyangiitis, may better identify homogeneous groups that share
similar genetics, pathogenesis, organ involvement, and response
to treatment (fig 1).6-10
Pivotal trials (table 1 and table 2) over the past several decades
have shaped contemporary strategies for induction and
maintenance of remission, which have led to improvements in
relapse rates, renal outcomes, quality of life, morbidity, and
overall survival.26-33 However, AAV remains associated with a
higher risk of death than the general population,34 35 and patients
continue to accrue organ damage from disease activity and
treatment.36
Here, we focus on clinical trials that have shaped the
contemporary management of induction and maintenance of
remission in AAV, specifically GPA and microscopic
polyangiitis; EGPA is considered a distinct disease with different
approaches to management. We consider how the increasing
amount of data from trials and observational studies might
inform a personalized approach to AAV care.
Incidence and prevalence of AAV
A population based study conducted in Olmstead County,
Minnesota, USA, estimated the annual incidences of GPA and
microscopic polyangiitis to be 1.3 (95% confidence interval 0.8
to 1.8) per 100 000 and 1.6 (1.0 to 2.2) per 100 000, respectively.
The prevalence of AAV in that study was 42.1 (29.6 to 54.6)
per 100 000.37 Similar estimates of annual incidence of GPA
were reported in a large US health insurance claims database
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BMJ 2020;368:m421 doi: 10.1136/bmj.m421 (Published 18 March 2020)
(1.3 (1.2 to 13.4) per 100 000),38 as well as the UK General
Practice Research Database (0.8 (0.8 to 0.9) per 100 000).39
Natural history
Severity of AAV varies widely, leading many people to
differentiate between severe and non-severe disease (fig 2).
Severe disease is characterized by manifestations that threaten
the function of vital organs, such as diffuse alveolar hemorrhage,
glomerulonephritis, mononeuritis multiplex, sensorineural
deafness, scleritis, or gangrene.41-44 Non-severe disease, in
contrast, is characterized by disease affecting the sinuses, nares,
and/or mucocutaneous surfaces, as well as pulmonary nodules,
tracheobronchial disease, and arthritis. Despite this
dichotomization, manifestations considered severe may be
indolent and non-severe manifestations may contribute
significantly to disease morbidity.
Sinonasal, pulmonary, and musculoskeletal manifestations are
the most common presenting symptoms. A minority of patients
present with chronic non-severe disease, often limited to the
sinuses and the upper airway. More often, patients with
non-severe disease develop severe disease, after months to years
of non-severe manifestations.45 This highlights the importance
of early recognition and treatment initiation. Severe disease,
however, may be fulminant and unheralded. Renal involvement
is the most common severe manifestation and can lead to end
stage renal disease (ESRD), which is estimated to affect 30%
of patients with renal involvement after five years.26
Generally, severe AAV is fatal if left untreated.46 Even with
treatment, excess mortality remains. A recent meta-analysis
found that the standardized mortality ratio of death in AAV
compared with the general population was 2.7 (95% confidence
interval 2.3 to 3.2).35 47
Pathogenesis of ANCA associated
vasculitis
The cause of AAV is unknown, but approximately 20% of
disease risk is due to genetic factors, which differ between
PR3-ANCA positive and MPO-ANCA positive patients.10 48 49
The role of MPO-ANCA in pathogenesis is well established
given observations that the transfer of MPO-ANCA antibodies
into experimental mouse models induces vasculitis.50 51 Evidence
supporting the pathogenic role of PR3-ANCA is less strong but
is inferred from certain observations: PR3-ANCA antibodies
appear years before clinical presentation; genetic variants in
proteinase 3 (the antigenic target of PR3-ANCA) are seen in
PR3-ANCA positive AAV; PR3-ANCA titers correlate with
disease activity in some patients; and B cell targeted therapy is
efficacious in PR3-ANCA positive patients.52 As such, current
therapies include broad immunosuppression and B cell targeted
treatment.
However, as our understanding of the pathogenesis of AAV
expands, so do the therapeutic options. Myeloperoxidase and
proteinase 3 are enzymes found in neutrophils, which are the
targets of ANCA antibodies and play a key role in
pathogenesis.50 Neutrophil extracellular traps (NETs) have been
recently recognized as important in the pathogenesis.53
Moreover, although immunoglobulins and complement are
infrequently observed in biopsy specimens, the alternative
pathway is now considered pathogenically important, and
complement inhibitors (such as anti-C5a) may have efficacy in
AAV.54 55
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Sources and selection criteria
We identified relevant studies for inclusion by a search of
PubMed, Embase, and Cochrane databases from 2009 to 2019.
We searched for the following phrases: “ANCA-associated
vasculitis”, “Wegener’s granulomatosis”, “granulomatosis with
polyangiitis”, and/or “microscopic polyangiitis”. We reviewed
approximately 500 abstracts of systematic reviews,
meta-analyses, randomized controlled trials (RCTs), and
observational studies that were published in English. We also
reviewed published management guidelines after reviewing
websites and publications from professional rheumatology (for
example, American College of Rheumatology, British Society
of Rheumatology), nephrology, and other specialty societies.
In addition to studies identified using these approaches, we also
included landmark studies. With the exception of high profile
RCTs recently reported in abstract form, only peer reviewed
studies were eligible for inclusion.25 56 We prioritized
meta-analyses and RCTs with the exception of the management
of specific manifestations (for example, sinus disease) for which
data are more limited to case series. We generally excluded
studies that enrolled patients with other forms of vasculitis (for
example, polyarteritis nodosa) unless results from stratified
analyses were available.
Evolution of clinical trial design in ANCA
associated vasculitis
Case series from the US National Institutes of Health shaped
the initial AAV treatment paradigm. Subsequently, recognition
of the importance of multicenter studies in AAV and related
conditions led to the formation of the Glomerular Disease
Collaborative Network (GDCN), the French Vasculitis Study
Group (FVSG), the European Vasculitis Study Group (EUVAS),
and the Vasculitis Clinical Research Consortium (VCRC).57 The
success of clinical trials organized by these groups confirmed
that large, well designed studies in AAV were feasible and
transformed AAV treatment. However, review of this experience
reveals challenges to designing AAV trials that affect our ability
to compare results across studies. Firstly, although recent efforts
have been made to standardize trial design, trials historically
relied on variable enrollment criteria, primary outcome
measures, and definitions of remission and relapse.58 Secondly,
the doses and durations of glucocorticoid regimens have varied
widely.42 Considering these limitations is important as we review
AAV clinical trials from the past 20 years.
Induction of remission
Glucocorticoids in AAV remission induction
Glucocorticoids bind to cytosolic glucocorticoid receptors,
causing decreased expression of pro-inflammatory proteins and
rapid non-genomic effects.59 Their quick onset of action and
robust anti-inflammatory effects have made them a cornerstone
of AAV care.60 However, significant toxicity (table 3) and
incomplete efficacy as monotherapy necessitate a second
immunosuppressive agent.61
The optimal dose, route, and duration of glucocorticoids remains
uncertain. Intravenous methylprednisolone, typically in doses
of 1000 mg daily for three days, is often used for severe end
organ involvement, although the evidence base supporting this
practice is weak.62 Ongoing uncertainty about the role of
intravenous glucocorticoids is shown by the design of clinical
trials for severe AAV, with some studies requiring their use and
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BMJ 2020;368:m421 doi: 10.1136/bmj.m421 (Published 18 March 2020)
others using oral glucocorticoids or leaving the decision to the
discretion of the investigator.13 15-17
Similar variation exists in the dose and duration of
glucocorticoid therapy, with trials using courses ranging from
5.5 months to more than 24 months.42 Oral glucocorticoids are
typically started at prednisone equivalent 1 mg/kg/day and
tapered to 30-40 mg/day by one month and 10-20 mg/day by
three months.44 63
Only recently have studies assessed the optimal duration of oral
glucocorticoids. The PEXIVAS trial, which enrolled 704
patients, used a two-by-two factorial design comparing plasma
exchange versus no plasma exchange and standard dose versus
reduced dose glucocorticoids in a non-blinded manner. The
primary outcome was death or ESRD. The reduced
glucocorticoid dose arm used 55% of the standard dose regimen
over the first six months of therapy,64 achieving the same
efficacy as the standard dose arm with fewer serious infections.56
Additional studies are needed to optimize the use of
glucocorticoids to balance their efficacy and toxicity. This has
been facilitated by the development of a novel tool, the
glucocorticoid toxicity index, now being used in clinical trials.65
Refining cyclophosphamide to minimize
toxicity
Prospective case series describing the efficacy of oral daily
cyclophosphamide in combination with prednisone for GPA
heralded the modern era of AAV treatment.45 46 66
Cyclophosphamide is an alkylating agent that causes broad
immunosuppression, including B cell depletion.67-70 Despite
good response rates, the risk of relapse and toxicity (table 3)
became evident with growing experience, leading to multiple
studies comparing oral daily with intravenous pulse
cyclophosphamide.11 46 71 72
Of these, the CYCLOPS trial was the first remission induction
trial to use the contemporary regimen in which azathioprine is
substituted for cyclophosphamide after three to six months of
therapy (see section on remission maintenance).19 CYCLOPS
was an unblinded controlled trial that randomized 149 patients
with renal disease due to ANCA positive (99%) GPA or
microscopic polyangiitis to daily or pulse cyclophosphamide
(table 1).15 The primary outcome, time to remission over 18
months, was no different between the daily and pulse groups
(hazard ratio 1.1, 95% confidence interval 0.8 to 1.6). The
median time to remission was three months in both groups. The
daily group received double the amount of cyclophosphamide
as the pulse group (16 g v 8 g; P=0.001). No difference was
seen in the proportion achieving remission at nine months (88%
in both groups).
In a retrospective follow-up study of CYCLOPS, the daily group
had a 50% reduction in the risk of relapse (hazard ratio 0.5, 0.3
to 0.9) over a median of 4.3 years compared with the pulse
group, independent of ANCA type.73 Leukopenia was more
common in the daily group than the pulse group (45% v 26%;
P=0.02). In both the 18 month analysis and a long term
follow-up study, no difference was seen in risk of malignancy,
severe infection, death, or change in renal function between the
two treatment arms.
Rituximab versus cyclophosphamide
For patients with complications or for whom cyclophosphamide
treatment was not successful, an alternative was needed. Case
series reported the efficacy of peripheral CD20+ B cell
depletion,74-76 motivating the design of the Rituximab in
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ANCA-Associated Vasculitis (RAVE) trial,16 which transformed
the management of AAV (table 1).
RAVE randomized 197 patients with newly diagnosed or
relapsing severe ANCA positive GPA or microscopic
polyangiitis to a 5.5 month glucocorticoid taper plus either
rituximab (four weekly 375 mg/m2 doses) or oral daily
cyclophosphamide for three to six months followed by
azathioprine. Patients in the rituximab arm received no
prescribed treatment beyond glucocorticoids and the first four
doses of rituximab. In contrast to other AAV trials, this was a
double blind, double dummy, non-inferiority trial which had a
primary outcome that required patients to be off glucocorticoids
by six months. Most patients were PR3-ANCA positive (68%)
and classified as GPA (77%); 48% had no major renal
involvement. RAVE excluded patients with diffuse alveolar
hemorrhage requiring ventilatory support and/or renal failure
with a creatinine concentration greater than 4.0 mg/dL (354
μmol/L).
The primary outcome, complete remission off glucocorticoids
at six months, was reached by 64% of patients randomized to
rituximab compared with 53% of those randomized to
cyclophosphamide (P<0.001 for non-inferiority). Rituximab
was not statistically superior to cyclophosphamide (P=0.09)
overall but was found to be superior among patients with
relapsing disease at baseline (odds ratio 1.40, 95% confidence
interval 1.03 to 1.91) and, in a post hoc analysis, among those
who were PR3-ANCA positive (odds ratio 2.11, 1.04 to 4.30).7
Rituximab without additional remission maintenance therapy
remained non-inferior to cyclophosphamide-azathioprine at 18
months when rates of sustained completion remission were
compared (39% v 33%).77 Over 18 months, 74% of patients
achieved complete remission off glucocorticoids at any time.
No difference was seen between rituximab and
cyclophosphamide with respect to the frequency, severity, or
time to relapse over 18 months. Outcomes were similar among
patients with major renal involvement at baseline regardless of
whether they were randomized to cyclophosphamide or
rituximab.16 78 No significant difference was seen in the rates of
adverse events between the two treatment arms, although
cyclophosphamide was associated with more pneumonias
(P=0.03).16 This equivalency was surprising but likely reflects
the countering effects of glucocorticoid exposure and reduced
cyclophosphamide exposure on risk of infection.
A companion EUVAS trial, RITUXVAS, randomized 44
patients (3:1) with severe AAV associated renal vasculitis to
rituximab plus two intravenous cyclophosphamide infusions or
intravenous cyclophosphamide for three to six months followed
by azathioprine.17 Both groups achieved sustained remission at
similar rates (76% v 82%; P=0.7) and had similar rates of severe
adverse events (42% v 36%; P=0.8).
Given the efficacy and comparable safety profile of rituximab,
rituximab is often chosen for induction of remission.79 The
optimal dosing regimen has not been studied, but the most
common regimens include 375 mg/m2 weekly for four weeks
or 1000 mg twice over two weeks. Cyclophosphamide remains
a cornerstone of therapy for many providers,80 especially where
rituximab is prohibitively expensive.81 The relatively short
follow-up in RAVE limited an assessment of differences in long
term outcomes, such as malignancy and survival, between the
two treatment arms, but recent observational data suggest that
rituximab, in contrast to cyclophosphamide, is not associated
with an increased risk of malignancy.32
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BMJ 2020;368:m421 doi: 10.1136/bmj.m421 (Published 18 March 2020)
Other approaches to remission induction:
methotrexate and mycophenolate mofetil
Methotrexate and mycophenolate mofetil have also been studied
for induction of remission. Methotrexate has its effects by
increasing extracellular adenosine, whereas mycophenolate
mofetil inhibits DNA synthesis.82 The NORAM trial was
designed following studies suggesting that methotrexate may
have efficacy in non-severe AAV.83-86 NORAM was an open
label, non-inferiority EUVAS trial that randomized 100 patients
with non-severe GPA or microscopic polyangiitis to either
methotrexate or daily cyclophosphamide for 12 months (table
1).12 Patients with organ threatening or life threatening disease
were excluded.
Most patients in NORAM were PR3-ANCA positive (74%) and
had GPA (94%). The primary outcome, the proportion in
remission at six months, was achieved by a similar proportion
of patients in the methotrexate and cyclophosphamide arms
(90% v 94%), and the median time to remission was also similar
(3 v 2 months; P=0.3). However, methotrexate was associated
with a longer time to remission among patients with more
extensive disease and a shorter time to relapse among all patients
than was cyclophosphamide (hazard ratio 1.9, 95% confidence
interval 1.1 to 3.3). Over 18 months, methotrexate was
associated with more flares than cyclophosphamide (70% v
47%). Compared with cyclophosphamide, methotrexate was
associated with fewer episodes of leukopenia (3 v 14; P=0.01)
but more episodes of liver dysfunction (7 v 1: P=0.04).
NORAM has two significant limitations. Firstly, it used 12
months of oral cyclophosphamide, so how methotrexate would
compare with contemporary three to six month
cyclophosphamide regimens is unclear. Secondly, all therapy
was tapered and discontinued by 12 months, after which many
of the flares occurred. Prolonged methotrexate treatment may
have prevented flares and been well tolerated. Methotrexate is
commonly used in rheumatology because of its favorable safety
profile, as confirmed in a recent large trial evaluating its efficacy
for secondary prevention of cardiovascular disease,87 but should
be avoided in patients with a glomerular filtration rate below
30 mL/min/1.73 m2.
MYCYC was an open label, non-inferiority, randomized
controlled EUVAS trial that compared mycophenolate mofetil
with cyclophosphamide for induction of remission (table 1).18
It followed several small prospective studies that found
mycophenolate mofetil to be efficacious in MPO-ANCA positive
AAV.88-90 In MYCYC, 140 patients newly diagnosed as having
GPA or microscopic polyangiitis (59% PR3-ANCA positive,
38% MPO-ANCA positive) were randomized to either
mycophenolate mofetil (76% on 2 g/day of mycophenolate) or
pulse cyclophosphamide; both arms received azathioprine
following remission. Patients with life threatening disease and
those with rapidly declining renal function were excluded, but
most (81%) had renal disease and the severity of renal disease
was generally worse than in those enrolled in NORAM.
A similar proportion of patients in the mycophenolate mofetil
and cyclophosphamide groups achieved remission at six months
(67% v 61%), showing non-inferiority (risk difference 5.7%,
90% confidence interval −7.5% to 19%). However, more
patients in the mycophenolate mofetil group relapsed after
remission (33% v 19%; incidence rate ratio 1.97, 95%
confidence interval 0.96 to 4.23). This difference was strongly
driven by differences in response according to ANCA type;
48% of PR3-ANCA positive patients in the mycophenolate
mofetil group compared with 24% of PR3-ANCA positive
patients in the cyclophosphamide group relapsed. Notably, the
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rates of serious infection were similar between the
mycophenolate mofetil and cyclophosphamide arms (26% v
17%; odds ratio 1.7, 0.68 to 4.19), as were the rates of other
adverse events (for example, ESRD and death).
NORAM and MYCYC show that methotrexate and
mycophenolate mofetil can induce remission in selected patients
but may be associated with a higher risk of relapse. They may
be particularly useful for patients in whom conventional
therapies have failed or are contraindicated and/or in those at
lower risk of flare (such as MPO-ANCA). They may not be
ideal for patients in whom a relapse could portend organ failure,
significant effect on quality of life, serious toxicity from excess
glucocorticoids, or life threatening disease. Of note,
mycophenolate mofetil received the lowest grade of endorsement
by members of EUVAS in their recommendations for the
management of AAV, although these were published before the
publication of MYCYC.44
RAVE, NORAM, and MYCYC highlight the relative safety
from an infection perspective of contemporary
cyclophosphamide regimens. However, these observations are
derived from clinical trials in which patient selection and close
monitoring may influence infection rates. Observational data
may better assess these risks and be used to compare the relative
efficacy of different regimens (for example, methotrexate,
mycophenolate mofetil) versus rituximab in patients with less
severe disease.
Plasma exchange in ANCA associated
vasculitis
In cases of diffuse alveolar hemorrhage, rapidly progressive
glomerulonephritis, or both, plasma exchange is sometimes
used in conjunction with other therapies. Until recently, MEPEX
was the only large trial evaluating the efficacy of plasma
exchange in AAV patients with biopsy proven
glomerulonephritis associated with a creatinine concentration
above 5.8 mg/dL (table 1).14 MEPEX was a EUVAS trial that
randomized 137 patients (43% PR3-ANCA positive, 52%
MPO-ANCA positive) to oral cyclophosphamide and a
glucocorticoid taper with either seven plasma exchanges or three
days of pulse methylprednisolone. Patients randomized to
plasma exchange were more likely to be alive and free of
dialysis and to have a creatinine concentration below 5.8 mg/dL
at three months than were those randomized to pulse
methylprednisolone (69% v 49%; P=0.02). However, four years
after randomization, a post hoc analysis found that differences
in ESRD and death were not sustained.91 A subsequent
meta-analysis concluded that insufficient evidence was available
to assess the efficacy of plasma exchange for preventing ESRD
and/or death in AAV.92
To assess the ongoing uncertainty about the efficacy of plasma
exchange, PEXIVAS randomized AAV patients with
glomerulonephritis (with a glomerular filtration rate <50
mL/min/1.73 m2), diffuse alveolar hemorrhage, or both to
standard therapy (rituximab or cyclophosphamide and
glucocorticoids) plus plasma exchange or standard therapy
only.56 64 PEXIVAS enrolled 704 patients (41% PR3-ANCA
positive, 59% MPO-ANCA positive), 98% of whom had renal
disease. In contrast to MEPEX, both arms received pulse
methylprednisolone. No difference was seen in the rate of ESRD
or death from any cause (co-primary endpoints) between patients
randomized to plasma exchange and those randomized to
standard therapy (28% v 31%; hazard ratio 0.86, 0.65 to 1.13)
at seven years. No difference was seen when the outcomes of
ESRD and death were analyzed separately.
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BMJ 2020;368:m421 doi: 10.1136/bmj.m421 (Published 18 March 2020)
Despite differences in inclusion criteria and treatment, both
PEXIVAS and MEPEX suggest that plasma exchange does not
provide a long term benefit over standard of care in AAV. Post
hoc analyses of PEXIVAS and other trials are needed to clarify
the potential utility of plasma exchange in subgroups of patients.
Patients who are positive for both ANCA and anti-glomerular
basement membrane should continue to receive plasma
exchange.93-95
Summary of remission induction
Induction of remission has evolved considerably over the past
few decades (table 1). Today, high dose glucocorticoids plus
either rituximab or cyclophosphamide are used more often. Case
series using combination rituximab and cyclophosphamide to
spare glucocorticoid exposure have been published, but the
evidence base supporting this practice remains weak.96 97 The
main limitation to use of rituximab is its cost,98 although
biosimilar rituximab may cost less.99 Toxicity from
cyclophosphamide may be minimized by reducing the dose in
patients with renal impairment and with advancing age, as well
as by limiting duration of treatment. Plasma exchange does not
seem to add efficacy for severe disease. In cases of non-severe
disease, methotrexate or mycophenolate mofetil may be options,
but neither has been compared with rituximab.
Additional studies comparing long term outcomes between
treatments, stratified by ANCA type and other disease features,
are warranted in addition to cost effectiveness analyses. The
cost effectiveness of regimens for induction of remission needs
to be evaluated from multiple societal perspectives, considering
the impact of biosimilar rituximab costs and incorporating long
term observational outcome data as they become available.100
Maintenance of remission
The vast majority of patients with AAV will achieve remission
with contemporary regimens, but approximately a third of
patients will relapse by 18 months and less than a third will
remain in relapse-free remission for more than a decade.77 101 A
personalized approach to maintenance of remission based on
patient specific and disease specific factors would balance the
benefits of disease quiescence with the cost and morbidity of
prolonged immunosuppression. This is particularly important
given that most deaths occurring more than a year after the
diagnosis of AAV are due to infection, malignancy, and
cardiovascular disease rather than active vasculitis.34 The past
20 years have greatly advanced the approach to maintenance of
remission, with several effective agents and treatment strategies
now in use.
Oral agents
Cyclophosphamide, azathioprine, methotrexate, and
mycophenolate mofetil have been investigated in randomized
trials of maintenance therapy (table 2). All studies induced
remission with prednisone and cyclophosphamide, but
cyclophosphamide dosing strategies (daily v pulse, duration)
varied between trials.
CYCAZAREM was an unblinded, controlled EUVAS trial that
randomized 144 patients with newly diagnosed severe AAV
(57% PR3-ANCA positive, 39% MPO-ANCA positive) to
azathioprine or continued cyclophosphamide for maintenance
of remission (table 2). Azathioprine is thought to have efficacy
because of its effect on DNA synthesis. Over 18 months, the
relapse rate (severe and non-severe) was similar between
azathioprine and cyclophosphamide (15.5% v 13.7%; P=0.65).19
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CYCAZAREM changed the treatment paradigm in AAV,
limiting cyclophosphamide treatment to three to six months to
avoid serious morbidity associated with prolonged
cyclophosphamide exposure (table 3).102-104
Azathioprine was compared with methotrexate in WEGENT
(table 2), a randomized, controlled, unblinded FVSG trial of
126 patients with newly diagnosed systemic AAV (60%
PR3-ANCA positive, 31% MPO-ANCA positive).20
Methotrexate was hypothesized to have fewer adverse events
than azathioprine, but both were found to have similar rates of
adverse events (19% v 11%; P=0.21). The surprisingly high
adverse event rate in the methotrexate arm may have resulted
from a lack of dose adjustment for renal impairment. At 24
months, methotrexate and azathioprine had similar rates of
severe and non-severe relapse-free survival (hazard ratio 0.92,
0.52 to 1.65), but the trial was not powered to assess this
outcome.20
Azathioprine was found to be superior to mycophenolate mofetil
for maintenance of remission in the IMPROVE trial conducted
by EUVAS (table 2).21 This was an open label RCT that enrolled
156 patients with newly diagnosed AAV (58% PR3-ANCA
positive, 33% MPO-ANCA positive). Over a median of 39
months, participants randomized to mycophenolate mofetil
relapsed (severe and non-severe) more often than did those
randomized to azathioprine (hazard ratio 1.80, 1.10 to 2.93).21
Given these observations, both azathioprine and methotrexate
are considered effective oral agents for maintenance of remission
in AAV.44 Mycophenolate mofetil remains a potential alternative
agent, particularly given its efficacy in MYCYC, but may be
inferior to azathioprine.18 Notable aspects of this evidence base
are that most patients had GPA, were PR3-ANCA positive, and
had severe disease.
Rituximab
Rituximab’s efficacy in inducing remission,16 combined with
the experience of long term B cell depletion in rheumatoid
arthritis,105 led to several reports of its use for AAV remission
maintenance.106-108 Subsequently, two RCTs compared rituximab
with azathioprine for maintenance of remission.
MAINRITSAN 1 (table 2), an unblinded, randomized, controlled
FVSG trial of 115 newly diagnosed or relapsing patients with
AAV (70% PR3-ANCA positive, 23% MPO-ANCA positive),
compared rituximab (500 mg twice over 14 days followed by
infusions every six months until month 18) with azathioprine
(for 22 months). All patients were treated with pulse
cyclophosphamide for induction of remission. Azathioprine was
associated with more severe relapses than rituximab (29% v
5%; hazard ratio 6.61, 1.56 to 27.96).22
At five years, 42 months after the last rituximab infusion,
rituximab remained superior to azathioprine but relapse-free
survival was reduced in both groups (58% v 37%; P=0.01).109
Although few deaths occurred, rituximab was associated with
better survival at five years (100% v 93%; P=0.045).109
Moreover, a cost effectiveness analysis from the French societal
perspective found rituximab to be cost effective compared with
azathioprine.110 A notable criticism of MAINRITSAN 1 is that
the dose of azathioprine was decreased from 2 mg/kg to 1.5
mg/kg at 12 months and to 1 mg/kg at 18 months, whereas the
rituximab exposure remained unchanged.
The RITAZAREM study randomized 170 patients (72%
PR3-ANCA positive, 28% MPO-ANCA positive) with relapsing
disease to rituximab 1 g every four months or azathioprine for
maintenance of remission after induction with rituximab (table
2). Preliminary data presented in abstract form showed that
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BMJ 2020;368:m421 doi: 10.1136/bmj.m421 (Published 18 March 2020)
rituximab was superior to azathioprine for preventing disease
relapse (13% v 38%; hazard ratio 0.30, 0.15 to 0.60; P<0.001),
further supporting the efficacy of rituximab for maintaining
remission.25
Timing of rituximab
MAINRITSAN 1 and RITAZAREM used a fixed interval of
rituximab retreatment. However, observations that relapses are
less frequent in patients with undetectable peripheral B cells
and that rising ANCA titers may predict a flare led to
MAINRITSAN 2 (table 2).77 111 112 This open label RCT
conducted by the FVSG compared fixed interval rituximab (as
used in MAINRITSAN 1) with retreatment only when peripheral
B cells became detectable or a significant rise in the ANCA titer
occurred (that is, tailored therapy).113 MAINRITSAN 2 enrolled
162 patients with newly diagnosed or relapsing AAV (47%
PR3-ANCA positive, 31% MPO-ANCA positive). Fixed interval
and tailored approaches were equivalent with regard to the risk
of severe and non-severe relapse over 28 months (10% v 17%;
P=0.22). Patients in the tailored arm received significantly fewer
rituximab infusions than those in the fixed interval arm (median
3 (interquartile range 2-4) versus 5 (5-5)). Safety was similar
in the fixed interval and tailored arms (85% v 91% severe events;
P=0.5), but numerically fewer patients had infections in the
tailored arm (9 v 16). Although the optimal timing and dose of
rituximab retreatment remain uncertain, personalization of
retreatment regimens holds promise.
Duration of treatment
The optimal duration of AAV maintenance therapy remains
unknown.114 Although some patients can remain in drug-free
remission, the prevalence of relapse increases steadily over
time.101 109 REMAIN, an open label RCT that enrolled 117
patients with severe AAV (52% PR3-ANCA positive, 44%
MPO-ANCA positive), found that discontinuing azathioprine
and prednisone after 24 months of treatment was associated
with a higher risk of non-severe and severe relapse (63% v 22%;
odds ratio 6.0, 2.6 to 13.8) and ESRD (7.8% v 0%; P=0.01)
compared with continued treatment for 48 months (table 2).23
Similarly, a meta-analysis of 13 studies which included 983
patients with diverse AAV manifestations found that prolonged
treatment with glucocorticoids was associated with fewer
relapses than shorter durations (hazard ratio 0.4, 0.3 to 0.5).115
Being able to stratify patients according to risk of relapse is
necessary to eventually personalize care in a way that optimally
balances the risk of relapse and potential toxicity of various
regimens. Several risk factors for relapse have been identified
(table 4). Multiple studies have shown that PR3-ANCA positive
patients have an approximately twofold higher risk of relapse
than MPO-ANCA positive patients.16 101 More severe renal
damage has been associated with a reduced risk of
relapse.122 129 130 Potential serum and urine biomarkers of disease
activity have been identified but need further study before
clinical use.123 127 Risk stratification and development of
biomarkers able to predict relapse are critical to personalizing
the approach to maintenance therapy.
Treatment challenges associated with
specific manifestations
Sinus involvement, tracheobronchial disease, orbital
pseudotumor, and interstitial lung disease are particularly
challenging manifestations of AAV because they can be the
sole manifestation, can be hard to diagnose and treat, and can
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cause significant, irreversible damage. Studies of these
manifestations are limited to case series, providing a limited
evidence base for recommendations.
Sinonasal disease
Sinusitis is common in GPA.36 45 Evaluation by an experienced
otolaryngologist is useful in patients with sinusitis and suspected
GPA, because up to 40% of patients with disease limited to the
sinuses and respiratory tract may be ANCA negative and an
otolaryngologist can help to differentiate active sinus disease
from damage.45 Nasal septal perforation and saddle nose
deformity are well described manifestations of AAV damage,
but bony erosion, persistent nasal congestion, crusting, and
epistaxis may persist after appropriate treatment. Distinguishing
between damage and active disease is important, as treating
damage with immunosuppression may unnecessarily increase
the risks of infection and other complications.
No studies have investigated the optimal treatment regimen for
sinonasal manifestations, but all agents that have been
investigated for induction of remission are thought to be
efficacious. In addition, topical treatment with saline and
corticosteroids, as recommended for general chronic sinusitis,131
can be helpful.
Tracheobronchial manifestations
Subglottic stenosis, tracheobronchitis, and bronchial masses are
uncommon manifestations of GPA but cause substantial
morbidity.132-134 Tracheobronchial manifestations are often
decoupled from disease activity elsewhere and can occur during
immunosuppressive therapy, suggesting that these manifestations
may not respond to immunomodulation.132-134 In general,
bronchial masses are treated with immunosuppression, but the
management of subglottic stenosis is controversial. One case
series of 21 patients observed that a series of intralesional
glucocorticoid and dilations over a mean follow-up of 41 months
did not result in any tracheostomies, a marked improvement
from previous reports.135 Other case series of up to 43 patients,
in contrast, have reported variable success of
immunosuppressives (methotrexate, cyclophosphamide,
rituximab) in combination with prednisone.132 133 136
Orbital inflammatory disease
Orbital inflammatory disease is challenging to treat because it
often does not fully respond to immunosuppression and relapses
are common.137 138 One of the largest case series of 59 patients
with orbital masses suggested improved outcomes with
rituximab compared with cyclophosphamide (91% v 52%
response).138 However, the study’s small sample size and
retrospective nature limit the generalizability of these findings.
Interstitial lung disease
Interstitial lung disease (ILD) is increasingly observed in
association with MPO-ANCA antibodies with or without other
manifestations of AAV.139-141 Whereas treatment of ILD in
patients with other AAV manifestations follows the typical
approaches described earlier, the management of ILD and a
positive ANCA test without other AAV manifestations is
uncertain. In a small case series that included 36 patients,
approximately 20-30% of patients with ANCA positivity and
ILD went on to develop AAV, especially those who were
MPO-ANCA positive.142 A case series of 12 patients with usual
interstitial pneumonia associated with ANCA positivity reported
improvement in ILD with immunosuppression,143 but other series
(n<20) did not report a benefit.144 145 Additional studies of this
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BMJ 2020;368:m421 doi: 10.1136/bmj.m421 (Published 18 March 2020)
unique AAV subgroup are needed. The role of nintedanib in
fibrotic lung disease associated with ANCA is of interest, given
its efficacy in idiopathic pulmonary fibrosis and scleroderma
lung disease.146
Supplementary therapies in AAV
Trimethoprim-sulfamethoxazole is an important treatment
adjunct for preventing Pneumocystis jirovecii pneumonia (PCP)
in patients with AAV (table 3). Although no randomized studies
exist to guide PCP prophylaxis in patients with rheumatologic
disease, the American Thoracic Society suggests treatment in
patients receiving 20 mg or more of prednisone for four weeks
or longer, especially if combined with another
immunosuppressive agent.147 Uncertainty exists as to whether
trimethoprim-sulfamethoxazole has a role in preventing relapse
of GPA, based on a randomized study in 81 patients that showed
benefit in those with upper airway involvement.148 However, its
efficacy is not thought to be sufficient for it to be used as
monotherapy.44
In addition to calcium and vitamin D, postmenopausal women
and men aged over 50 who are receiving prednisone equivalent
of at least 7.5 mg for three months or more or are at high risk
for major osteoporotic fracture (based on FRAX tool) should
receive treatment with a bisphosphonate or another agent.149
Finally, reviewing and completing appropriate vaccinations is
of particular importance in patients with AAV.
Organ transplantation in AAV
Rapidly progressive glomerulonephritis and interstitial lung
disease are two manifestations of AAV that can cause
irreversible organ failure. Renal transplantation is safe and
effective in appropriately selected patients with ESRD due to
AAV.150-152 Among AAV patients with ESRD who are waitlisted
for a transplant, renal transplantation is associated with a 70%
reduction in the risk of all cause death (relative risk 0.30, 95%
confidence interval 0.25 to 0.37), largely driven by a reduction
in the risk of death due to cardiovascular disease (0.10, 0.06 to
0.16).153 Although recommendations vary, patients with a low
glomerular filtration rate (<20 mL/min/1.73 m2) without
expected recovery should be evaluated for transplantation
candidacy, ideally before dialysis.154 AAV should be in remission
for at least 12 months and the ANCA titer should be negative
before transplantation.155 156 In contrast to renal disease, outcomes
in lung transplantation for AAV are poorly described.157
Quality of life in AAV
AAV is associated with depression and anxiety, as well as a
worse quality of life compared with the general population.158-161
These differences often persist in disease remission and highlight
the challenges of managing both the physical and psychosocial
aspects of living with AAV. When reported, quality of life
outcomes in AAV trials have not differed between treatment
arms. Differences in quality of life observed in MAINRITSAN
1 are difficult to interpret because completion of the survey was
optional and a significant amount of data is missing.162 The
recent development of an AAV specific patient reported outcome
measure will enable the assessment of AAV specific quality of
life (for example, AAV symptoms, side effects, emotional
impact, uncertainty) in future studies.163 No studies have
evaluated psychosocial interventions in AAV.
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Emerging treatments
The development of novel agents and optimization of the use
of existing therapeutics are rapidly evolving research areas in
AAV. Given the recognition of the importance of the
complement pathway in the pathogenesis of AAV, several agents
targeting the complement activation product C5a are being
studied, including a phase III trial of avacopan, an oral C5a
receptor inhibitor, for induction of remission. Two phase II
studies, CLEAR and CLASSIC, showed the potential efficacy
of avacopan in inducing remission in combination with
rituximab or cyclophosphamide.55 164 The CLEAR study
suggested that avacopan may have a dramatic steroid sparing
effect, which would be a tremendous advance.55 IFX-1, a
monoclonal antibody targeting C5a, is being studied in phase
II trials.165 In addition to complement pathway targets, a phase
III trial is studying abatacept, a cytotoxic T lymphocyte
associated protein 4 antagonist, for non-severe GPA.166 167
The optimal dose and duration of glucocorticoid treatment
remains an area of active investigation in both induction and
maintenance of remission.125 167-170 For example, a single center
study of 49 patients found that the combination of rituximab
and cyclophosphamide with two weeks or less of glucocorticoids
led to 96% of patients achieving remission at six months.125
A growing evidence base suggests that personalized approaches
to treatment of AAV may be possible. Identifying optimal
strategies that balance the adverse events and cost of
maintenance therapy against morbidity associated with active
disease and treatment is a critical area of future investigation.
In particular, remission induction and maintenance studies
stratified by ANCA type can further elucidate whether
PR3-ANCA positive and MPO-ANCA positive patients respond
differently to treatment. Additional studies of non-severe AAV
are essential to assess the efficacy of less toxic treatment options.
Guidelines
The European League Against Rheumatism (EULAR) and the
British Society for Rheumatology (BSR) have published
guidelines on the management of AAV.44 81 Notably, both were
written before the publication of several recent pivotal trials, so
their recommendations should be interpreted cautiously. General
agreement exists between the EULAR and BSR guidelines.
Both reflect the growing therapeutic options that clinicians have
for induction and maintenance of remission in AAV. Both
guidelines advocate for prolonged glucocorticoid exposure,
which remains controversial. The EULAR and BSR guidelines
emphasize the need to routinely assess patients for disease
related and treatment related toxicities, including cardiovascular
disease, diabetes, and hypogammaglobulinemia, which could
not be covered in this review.
Conclusion
Management of AAV has evolved considerably in recent
decades, a period characterized by substantial improvements in
outcomes, including renal outcomes and overall survival. As
our understanding of the pathogenesis of AAV expands, so too
does the pipeline of therapeutic options for AAV, especially
those with the potential to substantially reduce glucocorticoid
exposure. Additional studies are needed to define personalized
approaches to the management of AAV.
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BMJ 2020;368:m421 doi: 10.1136/bmj.m421 (Published 18 March 2020)
Research questions
1.Should induction and maintenance of remission be managed differently
for patients with ANCA associated vasculitis (AAV) who are PR3-ANCA
positive and those who are MPO-ANCA positive?
2.What are the risks and benefits of reducing the cumulative exposure to
and/or duration of glucocorticoid therapy used during induction and
maintenance of remission?
3.What is the comparative effectiveness of methotrexate, mycophenolate
mofetil, and rituximab for non-severe AAV?
4.What interventions can effectively improve the quality of life of patients
with AAV and meet their psychosocial needs?
Glossary of abbreviations
AAV—ANCA associated vasculitis
ANCA—anti-neutrophil cytoplasmic antibody
BSR—British Society for Rheumatology
EGPA—eosinophilic granulomatosis with polyangiitis
ESRD—end stage renal disease
EULAR—European League Against Rheumatism
EUVAS—European Vasculitis Study Group
FVSG—French Vasculitis Study Group
GDCN—Glomerular Disease Collaborative Network
GPA—granulomatosis with polyangiitis
ILD—interstitial lung disease
MPO—myeloperoxidase
NET—neutrophil extracellular trap
PCP—Pneumocystis jirovecii pneumonia
PR3—proteinase 3
RCT—randomized controlled trial
VCRC—Vasculitis Clinical Research Consortium
Patient involvement
Three patients from our practice kindly volunteered to review this manuscript.
In response to their feedback, minor edits were made to the manuscript. One
was a 40 year old man with ANCA associated vasculitis (AAV) who has
cutaneous vasculitis, arthritis, and pulmonary masses. He suggested
highlighting the importance of early diagnosis and treatment recommendation
and appreciated our proposal to study psychosocial interventions for AAV.
The second patient was a 60 year old man with AAV who has sinusitis,
pulmonary nodules, and neuropathy. He suggested highlighting the balance
of costs and benefits of fixed rituximab maintenance therapy. The third patient
was a 67 year old man with AAV causing scleritis, sialadenitis, hearing loss,
pancreatitis, sinusitis, and lung nodules. He appreciated the value of this
manuscript but did not recommend any specific changes.
Contributors: ZSW had the idea for the article. Both authors did the literature search
and planned and wrote the article. ZSW accepts full responsibility for the finished
article, had access to any data, and controlled the decision to publish; he is the
guarantor.
Funding: ZSW receives funding from NIH/NIAMS (K23AR073334 and L30
AR070520).
Competing interests: We have read and understood the BMJ Group policy on
declaration of interests and declare the follow interests: none.
Provenance and peer review: Commissioned; externally peer reviewed.
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Tables

Table 1| Randomized controlled trials of remission induction therapy in ANCA associated vasculitis (AAV)

Name Date Intervention Cohort* Primary outcome Results

Pulse v daily 1997 Pulse v daily CYC for 2 Pulse CYC: 100% GPA v 0% MPA; Remission rate and Remission rate similar for pulse and daily CYC
CYC†11 years‡ daily CYC: 100% GPA v 0% MPA; mortality at 6 months (89% v 78%; P>0.05) but pulse
ANCA type not reported group had less CYC (28 g v 44 g; P<0.001). 5
year survival was similar between pulse and
daily CYC arms (66% v 57%; P>0.05)
NORAM†12 2005 Daily CYC v MTX in MTX: 76% PR3 v 11% MPO, 94% Remission rate at 6 MTX was non-inferior to CYC for remission
non-severe AAV GPA v 6% MPA; CYC: 72% PR3 months (90% v 94%; P=0.04). Secondary: MTX was
v 15% MPO, 93% GPA v 7% MPA associated with shorter time to relapse than
CYC (13 v 15 months; HR 1.9, 95% CI 1.1 to
3.3; P=0.02)
WGET13 2005 Etanercept v placebo in Etanercept: 71% PR3 v 17% MPO, Sustained remission No difference in sustained remission rate
addition to glucocorticoids 100% GPA v 0% MPA; placebo: for ≥6 months between etanercept and placebo arms (70% v
with daily CYC or MTX 75% PR3 v 7% MPO, 100% GPA 75%; HR 0.86, 0.6 to 1.2; P=0.4)
(MTX or AZA added for v 0% MPA
maintenance)
MEPEX†14 2007 Plasma exchange v pulse Methylprednisolone: 46% PR3 v Dialysis independence Plasma exchange more effective at dialysis
intravenous glucocorticoid 46% MPO, 36% GPA v 64% MPA; at 3 months independence (percentage difference 20%, 95%
in severe renal AAV plasma exchange: 37% PR3 v CI 18% to 35%; P=0.02) but differences not
57% MPO, 26% GPA v 74% MPA sustained at long term follow-up
CYCLOPS†15 2009 Pulse CYC v daily CYC‡ in Pulse CYC: 39% PR3 v 50% MPO, Time to remission No significant difference in time to remission
non-life threatening AAV 39% GPA v 50% MPA; daily CYC: (median 3 months in both groups) between
41% PR3 v 51% MPO, 42% GPA pulse and daily CYC (HR 1.1, 0.8 to 1.6; P=0.6);
v 45% MPA 61 (92%) v 55 (92%) achieved remission at 6
months
RAVE16 2010 RTX v daily CYC in severe RTX: 67% PR3 v 32% MPO, 75% Remission and RTX non-inferior (P<0.001) to CYC (64% v
AAV GPA v 24% MPA; CYC: 66% PR3 completion of steroid 53%). Secondary: remission on <10 mg/day of
v 34% MPO, 76% GPA v 24% taper at 6 months prednisone more common with RTX than CYC
MPA (71% v 62%); RTX more effective for primary
outcome in relapsing disease (67% v 42%;
P=0.01)
RITUXVAS†17 2010 RTX with two intravenous RTX: 61% PR3 v 39% MPO, 55% Sustained remission No significant difference in proportion achieving
CYC courses v intravenous GPA v 36% MPA; CYC: 45% PR3 and rates of severe sustained remission with RTX (76%) v CYC
CYC followed by AZA in v 55% MPO, 36% GPA v 36% adverse events at 12 (82%); absolute difference −6%, 95% CI −33%
severe AAV associated MPA months to 21%. Severe adverse events occurred with
renal disease similar frequency in RTX (42%) and CYC (35%)
groups
MYCYC†18 2019 MMF v pulse CYC in MMF: 59% PR3 v 40% MPO, 67% Remission with MMF non-inferior to CYC (67% v 61%; risk
non-life threatening AAV GPA v 33% MPA; CYC: 60% PR3 prednisone dose at 5 difference 5.7%, 90% CI −7.5 to 19%).
without rapidly declining v 37% MPO, 63% GPA v 37% mg/day by 6 months Secondary: relapses more common with MMF
renal function MPA than CYC (37% v 20%; P=0.049), driven by
patients with PR3-ANCA+ AAV
PEXIVAS†56 2020 Plasma exchange v no Plasma exchange: 41% PR3 v Death from any cause No significant difference in primary outcome
plasma exchange and 59% MPO; no plasma exchange: or end stage renal with plasma exchange (28%) v no plasma
reduced dose glucocorticoid 41% PR3 v 59% MPO; reduced disease exchange (31%; HR 0.86, 0.65-1.13; P=0.27).
v standard dose dose glucocorticoid: 41% PR3 v Reduced dose glucocorticoids was non-inferior
glucocorticoid in severe 60% MPO, standard dose to standard dose glucocorticoids with respect
AAV glucocorticoid: 41% PR3 v 59% to primary outcome (28% v 26%); absolute risk
MPO difference, 2.3 percentage points (90% CI −3.4
to 8.0; 95% CI −4.5 to 9.1). Secondary: reduced
dose glucocorticoids had lower rate of severe
infection than standard dose (incidence rate
ratio 0.69, 0.52 to 0.93)

ANCA=anti-neutrophil cytoplasmic antibody; AZA=azathioprine; CYC=cyclophosphamide; GPA=granulomatosis with polyangiitis; HR=hazard ratio;
MMF=mycophenolate mofetil; MPA=microscopic polyangiitis; MPO=myeloperoxidase; MTX=methotrexate; PR3=proteinase-3.
* GPA/MPA totals do not always equal 100% because some patients had renal limited vasculitis or disease that could not be further defined.
† Open label.
‡ Pulse CYC refers to intermittent intravenous CYC treatments; daily refers to daily oral CYC.

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Table 2| Randomized controlled trials* of maintenance therapy in ANCA associated vasculitis

Name Date Intervention Cohort Primary outcome Results

CYCAZAREM19 2003 Continued daily CYC v AZA AZA: 54% PR3 v 39% MPO, 61% Relapse over ~14 No difference in % relapsing: 16% AZA v
after induction (3-6 months of GPA v 39% MPA; CYC: 59% PR3 months 14% CYC (P=0.65); difference 1.8%, 95%
daily CYC) v 34% MPO, 62% GPA v 38% CI −9.9% to 13.0%
MPA
WEGENT20 2008 AZA v MTX after induction (~7 AZA: 65% PR3 v 29% MPO, 76% Treatment ending No difference in adverse event for MTX v
months) with pulse CYC GPA v 24% MPA; MTX: 56% PR3 adverse event AZA: HR 1.65, 95% CI 0.65 to 4.18;
v 33% MPO, 76% GPA v 24% P=0.29. Secondary: % of relapse for MTX
MPA v AZA: 36% and 33%; P=0.71)
IMPROVE21 2010 MMF v AZA after ≤6 months MMF: 54% PR3 v 37% MPO, 59% Relapse-free survival Relapses were more common in MMF
of induction therapy with pulse GPA v 41% MPA; AZA: 61% PR3 over ~39 months group than AZA group (55% v 38%; HR
or daily CYC v 29% MPO, 69% GPA v 31% 1.80, 1.10 to 2.93; P=0.02)
MPA
MAINRITSAN 122 2014 RTX v AZA for maintenance in RTX: 77% PR3 v 16% MPO, 82% Major relapse at Major relapse more common with AZA
newly diagnosed patients after GPA v 14% MPA†; AZA: 62% PR3 month 28 than RTX (29% v 5%; HR 6.61, 1.56 to
4-6 months of induction with v 31% MPO, 69% GPA v 26% 27.96; P=0.002). Secondary: RTX was
pulse CYC MPA† associated with better survival than AZA
(100% v 93%; P=0.045)
REMAIN23 2017 AZA/prednisone for 48 months Withdrawal: 59% PR3 v 41% Relapse rate over Relapse more common in withdrawal
v 24 months after induction MPO, 47% GPA v 53% MPA; ~925 days group than continuation group (63% v
with CYC continuation: 46% PR3 v 47% 22%; HR 2.8, 1.7 to 4.9; P<0.001).
MPO, 47% GPA v 53% MPA Secondary: major relapse more common
with withdrawal than continuation (35% v
14%; P=0.007)
MAINRITSAN224 2018 Individually tailored v fixed Individually tailored: 49% PR3 v Relapse at month 28 No statistically significant difference in
schedule RTX for remission 34% MPO, 69% GPA v 31% MPA; relapse rates between individually tailored
maintenance after induction fixed schedule: 48% PR3 v 30% and fixed schedule RTX (17% v 10%;
with CYC, MTX, or RTX MPO, 75% GPA v 25% MPA P=0.2). Secondary: tailored arm received
fewer RTX infusions (median 3 (IQR 2-4)
v 5 (5-5)) and had numerically fewer
infections (9 v 16)
RITAZAREM25 2019 RTX v AZA for maintenance in RTX: 72% PR3 v 28% MPO; AZA: Relapse at 24 RTX led to fewer relapses than AZA (13%
relapsing patients after 71% PR3 v 27% MPO months v 38%; HR 0.30, 0.15 to 0.60; P<0.001)
induction with RTX

ANCA=anti-neutrophil cytoplasmic antibody; AZA=azathioprine; CYC=cyclophosphamide; GPA=granulomatosis with polyangiitis; HR=hazard ratio; IQR=interquartile
range; MPA=microscopic polyangiitis; MPO=myeloperoxidase; MTX=methotrexate; MMF=mycophenolate mofetil; PR3=proteinase 3; RTX=rituximab.
* All were open label studies.
† Total of MPA and GPA does not equal 100% because some patients had renal limited vasculitis that could not be further classified.

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BMJ 2020;368:m421 doi: 10.1136/bmj.m421 (Published 18 March 2020)
Table 3| Adverse effects of commonly used medications to treat ANCA associated vasculitis
Treatment Adverse effects
Glucocorticoids Infection; osteoporosis; diabetes mellitus;
hypertension; psychosis, depression, anxiety,
insomnia; skin thinning, bruising, striae
Cyclophosphamide Infection including reactivation of latent infection
(eg, hepatitis B, human polyomavirus 2 (JC virus));
cytopenias; hypogammaglobulinemia; malignancy,
especially bladder cancer; hemorrhagic cystitis;
infertility, premature menopause in women;
teratogenicity
Rituximab Infection including reactivation of latent infection Risk of PCP may be reduced by prophylactic use of trimethoprim/sulfamethoxazole,
(eg, hepatitis B, human polyomavirus 2 (JC virus)); atovaquone, or dapsone. With severe hypogammaglobulinemia or
hypogammaglobulinemia; late onset neutropenia
Methotrexate Infection; gastrointestinal upset; fatigue; oral ulcers; Folic acid supplementation may reduce risk of certain adverse effects (eg,
alopecia; transaminitis; pneumonitis; cytopenias;
teratogenicity
Azathioprine Infection; gastrointestinal upset, pancreatitis;
cytopenias; rash; transaminitis
Mycophenolate mofetil Infection; gastrointestinal upset; cytopenias;
transaminitis; teratogenicity
Pre-treatment
screening and
prevention
ANCA=anti-neutrophil cytoplasmic antibody; PCP=pneumocystis pneumonia.
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Comments
Risk of PCP may be reduced by prophylactic use of trimethoprim/sulfamethoxazole,
atovaquone, or dapsone. Baseline bone density examination may be considered.
Calcium and vitamin D supplementation as well as prophylaxis for glucocorticoid
induced osteoporosis should be considered for bone health. Proton pump inhibitors
or H blockers can be considered in patients with dyspepsia
2
Risk of PCP may be reduced by prophylactic use of trimethoprim/sulfamethoxazole,
atovaquone, or dapsone. Toxicity risk may be attenuated by dose adjustment in renal
failure and older age. Treatment with mesna may reduce risk of hemorrhagic cystitis
when used intravenously. After treatment, patients should be monitored for bladder
cancer with periodic urinalysis. In patients who are hoping to conceive in future,
consultation with reproductive endocrinology and/or infertility specialists is needed to
review options for egg or semen preservation and/or ovarian suppression for women
of childbearing age
hypogammaglobulinemia in setting of infection, intravenous immunoglobulin may be
indicated. Late onset neutropenia can be idiosyncratic and may occur at any time
during or after period of B cell depletion
mucocutaneous). Patients should limit alcohol consumption while taking methotrexate.
Methotrexate should be avoided when glomerular filtration rate is reduced below 30
mL/min/1.73 m2
Screening for thiopurine methyltransferase enzyme activity can identify patients with
low enzyme activity who are at high risk of azathioprine toxicity. Considered safe for
use in pregnancy
Mycophenolic acid delayed release formulation may be associated with fewer
gastrointestinal adverse effects
Test all patients for hepatitis B virus, hepatitis C virus, and tuberculosis infection before
administering these drugs and consult with infectious disease specialist before
treatment if evidence of infection (active or latent) is present. Vaccinations against
influenza virus, pneumococcus, and varicella virus should be considered for
immunosuppressed patients according to local recommendations
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Table 4| Potential biomarkers of and/or risk factors for relapse

Potential risk factor Direction of association Comments

ANCA testing:
Rising ANCA titer ±Association between increased titer or
seroconversion (negative to positive) and risk of
relapse. Serial monitoring of PR3-ANCA+ and
MPO-ANCA+ needs further study
PR3-ANCA+ v MPO-ANCA+ PR3-ANCA+ increases risk of relapse
Renal disease Renal involvement decreases risk of relapse113 114 Risk of relapse 60% lower in patients with renal disease (HR 0.4, 0.2 to 0.8).
B cell detection Major and minor relapses less likely during
periods of B cell depletion
Serum biomarkers Increased levels associated with disease activity MMP-3, TIMP-1, and CXCL-13 discriminate between disease activity (AUC>0.8)
compared with remission. Only sIL-6 has been
studied as predictor of flare
Urine biomarkers Increased levels associated with active renal
disease. These have not been studied as
predictors of flare
No association between ANCA titer and risk of relapse observed in RAVE.77
Meta-analysis found increase in ANCA is modestly associated with future
relapse112 (+LR of 2.8, 95% CI 1.7 to 4.9) and highlighted heterogeneity of data,
limited number of MPO-ANCA studies. PR3-ANCA titer increase may predict
relapse after RTX for remission induction.114 116 MPO-ANCA seroconversion from
negative to positive after remission induction may be associated with increased
risk of flare (OR 26, 95% CI 8.2 to 101.0)117
Compared with MPO-ANCA+, PR3-ANCA+ patients have approximately twofold
higher risk of relapse16 109 118-121
Cluster of patients with renal involvement had 40-60% reduction in relapse risk
(HR 0.4 (0.3 to 0.5) in minimal extrarenal disease and 0.6 (0.4 to 0.9) in extensive
extrarenal disease. Relapse rate is reduced from 0.20 (0.13 to 0.26) per patient
year to 0.08 (0.04 to 0.11) per patient year after ESRD compared with before122
12% of RTX treated patients and 30% of CYC treated patients in RAVE had
relapse without detectable B cells.77 B cells detectable in most RTX treated
patients during flare, especially once off fixed schedule RTX109
and remission as well as healthy states (AUC>0.9).123 124 Increases in calprotectin
(S100A8/A9) are associated with risk of relapse, especially in PR3-ANCA+
patients after RTX treatment.125 After RTX treatment, increasing sIL-6 may predict
relapse (HR 7.2, 1.5 to 34.9)126
Soluble CD163 above cut-off had AUC of 0.9 for distinguishing active renal
vasculitis.127 Increase in MCP-1 had AUC of 0.9 for distinguishing active renal
disease from remission128

ANCA=anti-neutrophil cytoplasmic antibody; AUC=area under curve; CYC=cyclophosphamide; ESRD=end stage renal disease; HR=hazard ratio; LR=likelihood
ratio; MCP-1=monocyte chemoattractant protein 1; MMP-3=matrix metallopeptidase 3; MPO=myeloperoxidase; OR=odds ratio; PR3=proteinase 3; RTX=rituximab;
sIL-6=soluble interleukin 6; TIMP-1=tissue inhibitor matrix metalloproteinase 1.

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Figures

Fig 1 Features of ANCA associated vasculitis (AAV), PR3-ANCA+ AAV, and MPO-ANCA+ AAV.2 ANCA=anti-neutrophil
cytoplasmic antibody; CVD=cardiovascular disease; CYC=cyclophosphamide; DVT=deep venous thrombosis;
ESRD=end stage renal disease; gCSF=granulocyte colony stimulating factor; GPA=granulomatosis with polyangiitis;
IL=interleukin; mCSF=macrophage colony stimulating factor; MPA=microscopic polyangiitis; MPO=myeloperoxidase;
NET=neutrophil extracellular trap; PMN=polymorphonuclear neutrophil; PR3=proteinase 3; RTX=rituximab; sIL=soluble
interleukin; sTNF=soluble tumor necrosis factor

Fig 2 Diagnostic and remission induction treatment algorithm for anti-neutrophil cytoplasmic antibody (ANCA) associated
vasculitis (AAV). *Biopsy of non-renal tissue often shows non-specific chronic inflammation rather than granuloma
or vasculitis16 40; open lung biopsy preferred over transbronchial biopsy. †Strong evidence on combination of rituximab
(RTX) and cyclophosphamide (CYC) compared with either treatment alone in combination with glucocorticoids and
on use of plasma exchange is lacking. ‡Methotrexate (MTX) should be avoided in patients with renal disease because
it is renally cleared and can lead to toxicity. RTX, mycophenolate mofetil (MMF), and MTX have not been compared
with one another for induction of remission of non-severe disease; MMF use is controversial. DAH=diffuse alveolar
hemorrhage; GC=glucocorticoid; GN=glomerulonephritis; RPGN=rapidly progressive glomerulonephritis; UA=urinalysis

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