anca vasculitis.pdf

Clinical Practice: Review Article
Nephron 2022;146:121–137
Antineutrophil Cytoplasmic
Antibody-Associated Vasculitis: Toward
an Individualized Approach
Javier Villacorta
a
Laura Martinez-Valenzuela
b
Irene Martin-Capon
a
Juliana Bordignon-Draibe
b
aNephrology Department, Ramón y Cajal University Hospital, IRYCIS, Alcala University, Madrid, Spain;
b
Nephrology Department, Bellvitge University Hospital, IDIBELL Biomedical Research Institute, Hospitalet de
Llobregat, Barcelona, Spain
Received: September 14, 2021
Accepted: October 29, 2021
Published online: December 15, 2021
Correspondence to:
Javier Villacorta, javier.villacorta@salud.madrid.org
© 2021 S. Karger AG, Basel
karger@karger.com
www.karger.com/nef
DOI: 10.1159/000520727
Keywords
Glomerulonephritis · Antineutrophil cytoplasmic antibody ·
Vasculitis
Abstract
Antineutrophil cytoplasmic antibody (ANCA)-associated
vasculitis (AAV), characterized by the presence of autoanti-
bodies to neutrophil cytoplasmic antigens, proteinase 3
(PR3), and myeloperoxidase (MPO), typically involves small
blood vessels of the respiratory tract and kidneys. It includes
distinct clinical syndromes: microscopic polyangiitis (MPA),
granulomatosis with polyangiitis (GPA), and eosinophilic
GPA. GPA is commonly associated with PR3-ANCA, while
MPA is associated with MPO-ANCA. AAVs have a complex
pathogenesis, influenced by genetics and environmental
factors. There is evidence for a loss of tolerance to neutrophil
proteins, which leads to ANCA-mediated neutrophil activa-
tion and injury, with effector T cells and activation of the al-
ternative pathway of the complement also involved. Ad-
vances in immunosuppressive treatment have drastically re-
duced mortality of AAV in the past decades, opting for a
more individualized approach. Careful assessment of ANCA
specificity, disease activity, organ damage, and quality of life
allows for a tailored immunosuppressive therapy. Contem-
porary AAV treatment is characterized by regimens that min-
imize the cumulative exposure to glucocorticoids and cyclo-
phosphamide, and novel approaches including comple-
ment blockage and immunosuppressant combinations
might be the standard of care in the future. In this review, we
examine the pathogenesis, clinical approach, and evidence-
based treatment options for the management of AAV pa-
tients. © 2021 S. Karger AG, Basel
Introduction
Antineutrophil cytoplasmic antibody (ANCA)-associ-
ated vasculitis (AAV) is a group of disorders character-
ized by inflammation and destruction of small- and me-
dium-sized blood vessels and the presence of circulating
ANCAs [1]. It comprises distinct clinical syndromes: mi-
croscopic polyangiitis (MPA), granulomatosis with poly-
angiitis (GPA), and eosinophilic GPA (EGPA) [2]. Sero-
logical classification of AAV into proteinase 3-ANCA
(PR3-ANCA) disease and myeloperoxidase-ANCA
(MPO-ANCA) disease is crucial [3]. GPA is commonly

Villacorta/Martinez-Valenzuela/
Martin-Capon/Bordignon-Draibe
Nephron 2022;146:121–137
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DOI: 10.1159/000520727
associated with PR3-ANCA, while MPA is associated
with MPO-ANCA. However, differences in genetics,
pathogenesis, risk factors, treatment responses, and out-
comes associate closely with ANCA specificity (PR3 vs.
MPO-ANCA) than with clinical syndrome [4]. There-
fore, the ANCA serotype may guide clinical and thera-
peutic approaches, leading to a more personalized medi-
cine for AAV patients. Renal involvement is present in
the majority of patients with AAV, and the consequences
of a missed or delayed diagnosis of renal vasculitis are po-
tentially life-threatening. Advances in immunosuppres-
sive treatment have drastically reduced mortality of AAV
in the past decades with higher rates of remission ob-
served in recent trials [5]. However, infection rates are
still high, and current regimens aim to minimize the cu-
mulative exposure to glucocorticoids and cyclophospha-
mide (CYC). In this review, we discuss the pathogenesis,
clinical classification, diagnostic approach, potential bio-
markers, and evidence-based treatment regimens for pa-
tients with AAV.
Epidemiology
AAV is an infrequent disease with an incidence of
about 20 per million population per year in North Amer-
ica and Europe [6]. Incidence increases with age, with a
peak incidence during the seventh decade of life and a
marked predominance of male patients. AAV has a high-
er prevalence in Caucasic and Asian populations than Af-
rican-American populations [7]. There is notable geo-
graphic variation, with GPA being more common in
Northern Europe and Pacific area countries, whereas
MPA is more common in Southern Europe and Asia [8].
Infection with Staphylococcus aureus may trigger epi-
sodes of AAV since chronic nasal carriage of S. aureus has
been associated with an increased risk for disease relapse
[9]. Other environmental factors include silica exposure,
hydrocarbon exposure, pesticides, and medications such
as hydralazine and propylthiouracil [10–12].
Genetic Studies
Two genome-wide association studies in North Amer-
ican and European populations have identified disease
susceptibility loci in AAV [4]. GPA is associated with sin-
gle-nucleotide polymorphisms in HLA-DP, PRTN3 (en-
coding PR3), and SERPINA1 (encoding α1-antitrypsin, a
protease acting as the major inhibitor of PR3). PR3-AN-
CA disease-associated variants in PRTN3 and SERPINA1
support the hypothesis that PR3-ANCA is not merely an
epiphenomenon in AAV but plays a central role in the
pathogenesisofthisdisease.Bycontrast,MPAwasassoci-
atedwithHLA-DQpolymorphisms.Notably,thestrength
of these genetic associations was greater with respect to
ANCA specificity (PR3-ANCA or MPO-ANCA) than for
the clinical phenotype (GPA or MPA) [13]. These data
support for the concept that PR3-AAV and MPO-AAV
are distinct autoimmune syndromes.
Pathogenesis
AAV pathogenesis has classically been focused on the
activity and interactions of the neutrophil. They have a
double role as the target of the ANCAs and effectors of
the tissue damage after degranulation induced by these
antibodies. The exposure of MPO and PR3 in the surface
of the cellular membrane of the neutrophils is necessary
for the binding of the ANCA and requires a pre-activa-
tion process known as priming. Various microbial, en-
dogenous, or environmental agents and pro-inflammato-
ry cytokines such as interleukin (IL)-1, IL-18, and TNF-α
can prime neutrophils. Once primed, neutrophils achieve
their maximal phagocytic potential and response more
intensively to a second stimulus such as ANCA binding.
Proteolytic enzymes and free oxygen radicals are released
from neutrophil granules into the damage site. Neutro-
phils also release chemokines that recruit more neutro-
phils and other inflammatory cells [14]. Moreover, MPO
and PR3 can exert direct damage on endothelial cells [15].
In addition, neutrophils from AAV patients are more
prone to NETosis, spontaneously or induced by ANCA,
and tissular deposition of NETs also contributes to vas-
cular endothelial damage [16] (Fig. 1).
How ANCAs are produced is debated. MPO and PR3
are mostly circumscribed to the primary granules of the
neutrophil’s cytoplasm and are rapidly eliminated by spe-
cific inhibitors after neutrophil degranulation, thus stay-
ing out of reach of the immune system [17]. Several hy-
potheses have been drawn regarding how these proteins
can become immunogenic, such as the molecular mim-
icry with bacterial antigens hypothesis [18], the comple-
mentary peptide hypothesis [19], or the exposure of MPO
and PR3 as components of the NETs in NETosis process-
es [16].
In recent years, this neutrophil-focused view of the
AAV pathogenesis is being abandoned in favor of the
consideration of the disease as a multistep process with

ANCA Vasculitis: An Individualized
Approach
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the involvement of other immune cells. In this line, ex-
tensive T-cell infiltrates have been identified in damaged
tissue from AAV patients, as well as forming part of the
characteristic granulomas [20]. Moreover, preclinical
models of AAV are attenuated in the absence of different
T-cell subsets, thus suggesting the importance of these
cells for the induction of the disease [21]. The ameliora-
tion of the disease after T-cell directed therapies is also a
proof of concept of the T-cell involvement [22]. The aber-
rant T-cell response in AAV consists on the polarization
toward predominant Th1 [23] and Th17 [24] phenotypes
during the acute phase of the disease, together with a nu-
merical and functional impairment in T regulatory lym-
phocytes [25]. Some authors described a higher propor-
tion of activated CD8+ T cells in AAV patients together
with a higher expression of IL-7 and T-cell receptor sig-
naling pathways in these cells [26]. Altered T-cell co-
stimulation has also been described in AAV, consisting of
a decreased CD28 expression and CTLA4 overexpression
with diminished inhibitory ability, thus resulting in resis-
tance to anergy and contributing to a more pronounced
pro-inflammatory state [27].
The participation of the alternate pathway of the
complement has been demonstrated in AAV. Despite
the paucity of the immune deposits in AAV lesions, el-
evated serum C5a levels have been described in active
AAV [28]. C5a acts as a powerful neutrophil priming
agent via the C5a receptor present in this cell. At the
same time, neutrophils release properdin that promotes
further generation of C5a [29]. Based on this rationale,
the utility of the C5a receptor inhibitor as induction to
remission treatment in active AAV has recently been
published [30].
Resting neutrophil
Plasma leakage and
fibrinoid necrosis
Endothelial damage
Chemotaxis of
inflammatory cells
Proteolytic enzymes release
NETosis
Direct ANCA damage
ANCA binding
Microbial, environmental or
endogenous agents,
proinflammatory cytokines,
C5a complement fraction
Primed neutrophil
ROS release
Molecular mimicry with bacterial antigens
Immune response to complementary
peptides
Exposure of MPO and PR3 after netosis
ANCA production
Fig. 1. Pathophysiology. MPO and PR3 are inside cytoplasmic
granules in resting neutrophils. Pre-activation (priming) of the
neutrophils by environmental, infectious, or pro-inflammatory
agents is required to expose MPO and PR3 in the cell surface. Once
exposed, ANCAs can bind to MPO and PR3. ANCA binding leads
to neutrophil degranulation that releases ROS and proteolytic en-
zymes that cause endothelial damage. The rupture of the endothe-
lium allows plasma leakage that causes fibrinoid necrosis. MPO,
myeloperoxidase; PR3, proteinase 3; ANCA, antineutrophil cyto-
plasmic antibody; ROS, reactive oxygen species.

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Clinical Presentation
AAV is a heterogeneous group of autoimmune multi-
system conditions that can present with a wide variety of
signs and symptoms. Clinical manifestations depend on
the size, number, and type of affected vessels and the or-
gans involved, disease stage, and activity [5]. In addition
to organ-specific manifestations, patients often present
with constitutional symptoms such as fever, malaise,
weight loss, anorexia, myalgias, and arthralgias which re-
late to the systemic autoimmune pathophysiology [1].
The upper respiratory tract is usually compromised of de-
structive inflammatory lesions causing nasal, sinus, tra-
cheal, and/or ear abnormalities [31]. Upper respiratory
tract and ear-nose-throat (ENT) involvement frequently
is manifested by recurrent epistaxis, mucosal ulceration,
nasal septum deformities and perforation, sinusitis, otitis
media, or subglottic stenosis [32]. Pulmonary manifesta-
tions of AAV include pulmonary nodules and diffuse al-
veolar hemorrhage. Alveolar hemorrhage occurs as a re-
sult of pulmonary capillaritis and presents with hemop-
tysis and dyspnea. The most reported ocular involvement
in AAV includes orbital disease and scleritis [33]. Cuta-
neous [34], neurological [35], or enteric [36] involvement
is also frequent (Table 1).
Regarding to kidney involvement in AAV, it manifests
as a rapidly progressive glomerulonephritis. Usually, it is
accompanied by a nephritic syndrome with hematuria
and proteinuria. Less frequently, renal involvement in
AAV presents as subacute or chronic nephritis. Renal
AAV can lead to end-stage renal disease.
The different AAV disease phenotypes are composed of
adifferentialpatternofassociationsoforgandamage.Prev-
alence of renal involvement ranges between 75 and 90%
and is higher in MPA than inGPA or EGPA [1]. Necrotiz-
ing glomerulonephritis is present in >80% patients diag-
nosed with MPA and up to 50% patients present with pul-
monaryinvolvement.ThirtypercentofMPApatientspres-
ent with neurological, skin, or gastrointestinal symptoms.
In GPA patients, necrotizing vasculitis is accompanied by
granulomatous inflammation. ENT and upper airway in-
volvement are more frequent in GPA patients than in MPA
patients. EGPA presents on a background of eosinophilia
and asthma, and sinuses abnormalities are commonly as-
sociated. Around one-third of patients have renal manifes-
tations. Some patients with GPA or MPA present with vas-
culitis limited to a single organ, such as the kidneys or
lungs, which may represent the early stages of AAV. How-
ever, in MPO-ANCA+ patients with MPA, isolated renal
disease or isolated pulmonary fibrosis is not infrequent.
Classification Criteria and Diagnosis
The classification of the systemic vasculitis has been
controversial for several decades. The American College
of Rheumatology Criteria (ACR) was published in 1990
and included only GPA and EGPA but not MPA [37].
Lately, the Chapel Hill Consensus Conference (CHCC)
definitions developed in 1994 and revised in 2012 added
the knowledge of the etiopathogenesis of vasculitis. A
new tree hierarchy was developed which recognized that
some conditions cannot be simply classified by vessel size
and suggested the use of surrogate markers of the disease,
such as ANCAs. AAV was recognized as a specific type of
small-vessel vasculitis along with immune complex-me-
diated vasculitis (Fig. 2) [2].
In clinical practice, AAV serological diagnosis is based
on the finding of ANCA positivity in sera from patients
with consistent signs and symptoms. The presence of
ANCA can be evaluated by means of the indirect immuno-
fluorescence(IIF)testonhumanethanol-fixedneutrophils
[38] by enzyme-linked immunoassay and more recently by
chemiluminescent immunoassay. C-ANCA describes an
IIF pattern consisting on a diffuse granular cytoplasmic
staining predominantly associated to the presence of auto-
antibodies targeting PR3. On the contrary, the IIF pattern
P-ANCA consists on a perinuclear staining related to the
presence of autoantibodies against MPO [39]. Results re-
Table 1. Serological and clinical features of AAV
GPA, % MPA, % EGPA, %
PR3/C-ANCA 80–90 10–20 10–30
MPO/P-ANCA 10–15 70–80 40–60
Negative ANCA 5 10–20 10–50
Cutaneous 40 40 50
Kidney 80 90 40
Pulmonary 90 50 70
ENT 90 30 50
Neurological 50 30 70
Gastrointestinal 30–50 30–50 30–50
Musculoskeletal 60 60 50
Eyes 30 20 10
ANCA, antineutrophil cytoplasmic antibody; PR3, proteinase 3;
MPO, myeloperoxidase; GPA, granulomatosis with polyangiitis;
MPA, microscopic polyangiitis; EGPA, eosinophilic granulomatosis
with polyangiitis; RLV, renal-limited vasculitis; ORL, otorhinolaryn-
gological; AAV, antineutrophil cytoplasmic antibody-associated
vasculitis; ENT, ear, nose, and throat.

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trieved from the IIF test, as a screening test, should be con-
firmed by enzyme-linked immunoassay [40]. In the recent
years, chemiluminescent immunoassay has been devel-
oped in order to improve sensitivity and specificity in the
detection and titration of ANCAs [39].
Regarding the clinical syndrome, MPA-AAV patients
often show a P-ANCA pattern associated to the presence
of anti-MPO antibodies [41], but they can also exhibit
anti-PR3 antibodies. The IIF pattern most commonly as-
sociated with GPA, but not exclusive, is C-ANCA, related
to anti-PR3 antibodies [42]. In EGPA, <50% of patients
have detectable ANCAs, more frequently anti-MPO an-
tibodies [43].
More recently, results from epidemiological outcomes
and genetic studies in AAV suggest that patients should be
classified by ANCA specificity rather by the clinical syn-
drome [4]. The new Diagnostic and Classification Criteria
of Vasculitis Study aims to provide new validated classifi-
cation and diagnostic criteria for systemic vasculitis [44].
Disease Activity and Damage Scores
Validated tools to assess disease activity are Birming-
ham Vasculitis Activity Score (BVAS) and the Five-Fac-
tor Score. The BVAS includes 10 categories of new or
worsening symptoms presented <4 weeks until the re-
cord. A BVAS score of 0 represents remission, ≥1 repre-
sents active disease, and refractory disease is active dis-
ease despite treatment [45]. The 2009 Five-Factor Score
for EGPA comprises serum creatinine, age (>65 years),
cardiomyopathy, gastrointestinal involvement, and the
absence of ENT manifestations [46]. On the other hand,
the Vasculitis Damage Index is used to assess chronic
damage from the disease and treatment and includes
musculoskeletal, skin, and mucous membranes and ocu-
lar, ENT, pulmonary, cardiovascular, the peripheral vas-
culature, gastrointestinal, renal, and neuropsychiatric
systems, with an eleventh category for other systems [47].
Biomarkers
There is a rising interest in the use of biomarkers in
screening disease, diagnosing, staging, monitoring thera-
peutic interventions, predicting outcomes or adverse
events, or identifying cell types in AAV. Although con-
troversial, the most accepted classical biomarker of active
AAV is the ANCA titer. In a subgroup of 104 AAV pa-
tients with renal involvement, Kemna et al. [48] found a
correlation between ANCA titer rise and disease relapse.
Lionaki et al. [49] described that ANCA-PR3 specificity
Large vessel
Takayasu arteritis
Giant cell arteritis
Medium vessel
Polyarteritis nodosa
Kawasaki disease
Cryoglobulinaemic vasculitis
lgA vasculitis
Hypocomplementemic urticarial vasculitis
Anti-GBM disease
ANCA-associated vasculitis
Small vessel
Fig. 2. Classification of AAV. AAV, antineutrophil cytoplasmic antibody-associated vasculitis; Ig, immunoglobulin.

Nephron 2022;146:121–137
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DOI: 10.1159/000520727
predicts relapse in AAV patients with kidney involve-
ment, conferring almost twice the relapse risk compared
to ANCA-MPO vasculitis.
Based on the disease pathophysiology, neutrophil ac-
tivation biomarkers are of special interest in AAV. After
ANCA binding and full activation of these cells, neutro-
phil microparticles and NETs are released and can be
measured in the serum of AAV patients for the assess-
ment of disease activity [50, 51]. Calprotectin is contained
in the cytoplasmic granules of neutrophils and released
after degranulation in active AAV. Calprotectin binds en-
dothelial cells and amplifies endothelial damage and in-
flammation, by increasing IL8, ICAM1, and leukocyte re-
cruitment [52]. Pepper et al. [52] demonstrated calpro-
tectin expression by immunohistochemistry in kidney
biopsies from AAV patients localized in crescents and ar-
eas of endocapillary proliferation. They also found that
serum calprotectin is elevated in patients in the acute
phase of AAV compared to patients in remission [53].
Our group described higher serum calprotectin levels in
remission in those patients with worse renal outcomes
during the follow-up and found higher urinary calprotec-
tin levels in the acute patients than in the remission pa-
tients [54]. Also, in the field of urinary biomarkers,
suCD163 has shown promising results. suCD163 is pro-
duced by macrophages composing the inflammatory in-
filtrates in AAV, released to the urinary space, and mea-
sured in the urine. Higher suCD163 levels have been no-
ticedinacuteAAVwithrenalinvolvementthanremission
[55]. In a prospective study, suCD163 consistently in-
creased compared to previous levels during the follow-up
of patients in remission who experienced relapse [56].
suCD163 has been evaluated in combination with sCD25
[57] or MCP1 [58], showing an improved performance as
a disease activity biomarker.
Due to their emerging role in disease pathogenesis,
some T-cell subpopulations or byproducts have been de-
scribed as AAV biomarkers. Our group found higher fre-
quencies of MPO/PR3-specific Th17 cells in acute AAV
than remission and suggested higher specific Th17 count
in remission as a surrogate marker of subclinical activity
[59]. Morgan et al. [60] found that patients with a higher
Treg count at presentation entered earlier in remission
than those with a lower Treg count and a negative corre-
lation between Tregs and the disease relapse rate. In the
same line, Yoshimura et al. [61] correlated a lower FOXP3
staining – a key transcription factor for the suppressive
ability of Tregs – in AAV renal biopsies with the require-
ment of maintenance. McKinney et al. [26] found that the
higher expression of a particular subgroup of genes re-
lated to T-cell survival, and expansion of memory CD8 T
cells was strongly associated with a shorter time to relapse
after induction to remission treatment and identified
those individuals with a greater propensity for relapse, al-
lowing the customization of the therapy.
Inthesettingoftherisinginterestinthealternatepath-
way of the complement as a therapeutic target in AAV,
complement fractions have also been studied as biomark-
ers. Villacorta et al. observed that serum C3 at baseline
was predictive of renal and global survival in AAV pa-
tients, with the worse outcomes associated with C3 con-
sumption [62] and that C3d-positive staining in diagnos-
tic kidney biopsy was associated with the severity of renal
impairment and with a lower response rate to treatment
[63].
Treatment
Remission Induction Therapy
Advances in immunosuppressive treatment have dras-
tically reduced mortality of AAV in the past decades. Re-
mission rates obtained in different clinical trials range be-
tween 53 and 90% [64] (Table 2). However, mortality
rates despite immunosuppressive treatment are not neg-
ligible, especially in those patients presenting with severe
organ involvement, such as renal failure or alveolar hem-
orrhage [65]. Infection constitutes the major cause of
death within the first year after the onset, followed by ac-
tive vasculitis damage. Therefore, AAV therapy should
try to control disease activity but minimize side-effect de-
velopment, mainly infections.
The goal of induction therapy is to achieve remission
within the first 3 months, by employing more intensive
immunosuppression. Before initiation of therapy, careful
assessment of disease activity, organ damage, and quality
of life is crucial and may guide the use of potentially tox-
ic therapies. Remission has been defined as improvement
or stability of renal function, resolution of hematuria, and
the absence of extrarenal features of disease activity.
Treatment should be initiated as soon as AAV with organ
and life-threatening manifestations are suspected, even in
the absence of histological confirmation of vasculitis
since a delay in treatment can lead to worse outcomes.
CYC-Based Remission Induction Treatment
AAV with organ and life-threatening manifestations
has been classically treated with combination therapy of
glucocorticoids and CYC for 3–6 months. CYC can be
given orally or intravenously. Both routes of administra-

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Table
2.
Induction
immunosuppressive
protocol
according
to
different
trials
Study
Drug
comparison
Induction
immunosuppressive
protocol
Maintenance
therapy
Results
immunosuppressive
drug
doses
and
duration
corticosteroid
dose
corticosteroid
tapering
CYCLOPS
RCT
(2009)
ivCYC
versus
oral
CYC
ivCYC
15
mg/kg
every
2–3
weeks
for
3–6
months
Oral
prednisolone
1
mg/kg
Tapering
to
12.5
mg/
day
at
month
3
and
to
5
mg
at
month
18
Oral
AZA
2
mg/kg/day
since
month
3–6
to
month
18
No
differences
in
remission
rates.
Less
cumulative
dose
in
the
ivCYC
group
Oral
CYC
2
mg/kg/day
for
3–6
months
RAVE
RCT
(2010)
RTX
versus
oral
CYC
RTX
375
mg/m
2
/week
for
4
weeks
1–3
pulses
1
g
iv
methylprednisolone,
followed
by
oral
prednisolone
at
1
mg/kg/day
Tapering
to
zero
at
month
5
Placebo
maintenance
RTX
noninferior
to
oral
CYC
for
induction
remission
RTX
superior
for
relapsing
vasculitis
or
PR3-positive
patients
Oral
CYC
2
mg/kg/day
for
3–6
months
Oral
AZA
2
mg/kg/day
since
month
3–6
to
month
18
RITUXVAS
RCT
(2010)
RTX
versus
ivCYC
RTX
+
2
doses
ivCYC±PEX/
SDS
RTX
375
mg/m
2
/week
for
4
weeks
+
CYC
15
mg/kg
with
the
first
and
third
RTX
1
pulse
1
g
iv
methylprednisolone,
followed
by
oral
prednisolone
at
1
mg/kg/day
Tapering
to
5
mg/day
at
month
6
Withdrawn
at
month
12
No
maintenance
RTX
noninferior
to
ivCYC
for
induction
remission
ivCYC
15
mg/kg
every
2
weeks
for
3–6
months
Oral
AZA
2
mg/kg/day
since
month
3–6
to
month
24
Pepper
et
al.
[86]
Cohort
study
(2019)
LDS
versus
SDS
from
historic
cohort
of
EUVAS
trials
RTX
+
ivCYC
RTX
1
g
at
day
0
and
day
7
CYC
500
mg,
6
doses
every
2
weeks
2
pulses
250–500
mg
methylprednisolone
at
days
0
and
7,
followed
by
0.5
mg/kg/day
(max
30
mg)
days
2–6
Withdrawn
at
day
7
(maximum
duration
3
weeks)
Oral
AZA
2
mg/kg/day
No
differences
in
remission
rates
RTX
1
g
at
day
0
and
day
14
CYC
500
mg,
6
doses
every
2
weeks
1
pulse
250–1,000
mg
methylprednisolone,
followed
by
60
mg/day
1
week,
followed
by
45
mg/day
1
week
Withdrawn
at
week
2
(5
patients
received
>30
days
of
prednisolone)
MYCYC
RCT
(2019)
Oral
MMF
versus
ivCYC
Oral
MMF
2
g/day
until
remission
Oral
prednisolone
1
mg/kg
Tapering
to
5
mg/day
at
month
6
Prednisolone
5
mg/day
+
oral
AZA
2
mg/kg/day
since
remission
to
month
18
No
differences
in
remission
rates
At
18
months:
more
relapses
with
MMF,
especially
in
PR3-
ANCA
patients
IvCYC
15
mg/kg
every
2–3
weeks
until
remission
CYCLOWVAS
Cohort
study
(2019)
LDS
versus
SDS
from
historic
cohort
of
EUVAS
trials
RTX
+
ivCYC
RTX
1
g
at
day
0
and
day
14
CYC
10
mg/kg
to
maximum
of
500
mg,
6
doses
every
2
weeks
Oral
prednisolone
1
mg/kg
(maximum
dose
60
mg)
Tapering
to
10
mg/day
at
week
13
Oral
AZA
2
mg/kg/day
since
month
3
to
month
18–24
High
rate
remission
Reduced
risk
of
death,
ESRD
and
relapses
compared
with
the
historic
cohort
PEXIVAS
RCT
(2020)
LDS
versus
SDS
RTX/ivCYC±PEX
RTX/ivCYC
according
to
local
practitioner
PEX
according
to
the
PEXIVAS
trial
randomization
1–3
pulses
1
g
iv
methylprednisolone,
followed
by
oral
prednisolone
at
1
mg/kg/day
Tapering
to
5
mg/day
at
week
23–52
No
maintenance
specified
No
differences
in
remission
rates
between
groups
1–3
pulses
1
g
methylprednisolone,
followed
by
oral
prednisolone
at
1
mg/kg/day
Tapering
to
5
mg/day
at
week
15–16
ADVOCATE
RCT
(2021)
Avacopan
versus
prednisone
RTX
+
ivCYC
RTX
(375 mg/m
2
weekly
for
4
weeks)
or
CYC
orally
(2
mg/
kg
daily
for
14
weeks)
or
IV
(15
mg/kg
every
2–3
weeks
for
13
weeks
Prednisone:
60 mg
versus
avacopan:
30 mg
orally
twice
daily
for
52
weeks
without
prednisone
Taper
over
21
weeks
Oral
AZA
2
mg/kg/day
since
month
3–6
to
month
18
after
CYC
The
RTX
arm
did
not
receive
maintenance
At
weeks
26
and
52:
Noninferior
remission
rate
in
the
avacopan
group
compared
to
prednisone
CYC,
cyclophosphamide;
ivCYC,
intravenous
cyclophosphamide;
AZA,
azathioprine;
RTX,
rituximab;
MMF,
mycophenolate
mofetil;
PEX,
plasma
exchange;
SDS,
standard
dose
of
steroids;
LDS,
low
dose
of
steroids;
EUVAS,
European
Renal
Association
and
the
European
Vasculitis
Society.

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128
DOI: 10.1159/000520727
tion were evaluated in the CYCLOPS trial, in which pa-
tients with a new diagnosis of AAV were randomly as-
signed to receive either oral CYC or intravenous CYC
[66]. There was no difference in remission rates between
the 2 groups (88.1% vs. 87.7%), but the cumulative dose
was significantly higher in the oral CYC group (15.2 vs.
8.2 g) and was associated with a higher incidence of leu-
kopenia. Long-term follow-up of the trial showed that al-
though the oral CYC group was at lower risk for relapse,
this did not translate into differences in renal or overall
survival [67]. For this reason, several clinical guidelines
recommend intravenous CYC as induction therapy [67,
68].
CYC is associated with several serious adverse effects
such as infection, bone marrow suppression, hemorrhag-
ic cystitis, and infertility [68]. Several studies have linked
CYC therapy with an increased incidence of malignances,
mainly skin cancer, myeloid malignancies, and bladder
cancer [69, 70]. This increased risk for the development
of tumors is especially evident when the cumulative dose
is >20 gr [71]. Therefore, induction treatment with CYC
should be avoided in patients with cancer history, those
with high risk or active infection, and young patients with
gestational desire.
Rituximab-Based Remission Induction Treatment
Given the substantial toxicity associated with cumula-
tive CYC use and the relapsing nature of AAV, the use of
rituximab (RTX), a chimeric anti-CD20 monoclonal an-
tibody, has been widely employed as induction therapy
[71]. Two randomized controlled trials, RAVE and
RITUXVAS, evaluated the efficacy of RTX for remission
induction in GPA and MPA [72, 73]. In the RAVE trial,
mainly composed by PR3-ANCA patients with both new
and relapsing diseases, but without severe renal failure,
the RTX arm received methylprednisolone pulses, and
the prednisone dosage was tapered to zero within 6
months. On the other hand, the RITUXVAS trial enrolled
only patients with newly diagnosed vasculitis with more
severe kidney disease, including patients requiring dialy-
sis (20%). In contrast to the RAVE trial, the RTX arm re-
ceived 2 doses of intravenous CYC, and the use of plas-
mapheresis was allowed. Both studies demonstrated that
RTX therapy was noninferior to CYC for remission in-
duction, with comparable rates of mortality and adverse
events. A subanalysis of the RAVE trial performed among
patients with relapsing disease concluded that RTX was
superior to CYC in PR3-ANCA patients with relapsing
disease since a higher rate of remission in the RTX arm
was observed [74]. Based on this, current guidelines rec-
ommend RTX as first-line treatment for PR3-ANCA pa-
tients, relapsing disease, refractory disease, and those
with contraindications to CYC [75, 76] (Fig. 3).
Specific measures such as prevention of hepatitis B vi-
rus reactivation and hypogammaglobulinemia surveil-
lance must be taken when receiving RTX therapy [77]. Up
to 25% of patients with AAV present hypogammaglobu-
linemia at the onset of AAV disease and after RTX ther-
apy low levels of immunoglobulin (Ig) G are observed in
up to 50–60% of patients [78]. In most cases, hypogam-
maglobulinemia is mild and transient, and IgG levels re-
turntonormalwithoutspecificmeasureswithin6months
after RTX infusion. However, severe hypogammaglobu-
linemia occurs in 4.2% of patients and contributes to re-
current infections, requiring the use of intravenous Ig.
Therefore, Ig levels should be checked at baseline and at
least before each RTX infusion [79].
Individuals with chronic hepatitis B and previously in-
fected but serologically cleared HBV infection are both
susceptible to HBV reactivation after RTX therapy [80].
Identification of patients at risk and institution of pro-
phylactic antiviral therapy prior to initiation of RTX is
essential [81]. Finally, late-onset neutropenia is a rare side
effect of RTX observed among AAV patients that mani-
fests as abrupt and severe neutropenia within 2–6 months
following the last dose of RTX and may require filgrastim
administration in some cases [82].
Mycophenolate-Based Remission Induction Treatment
The use of mycophenolate mofetil (MMF) for induc-
tion remission therapy was evaluated in a randomized
controlled trial (MYCYC) which compared intravenous
CYC versus oral MMF (2–3 g/d) for treatment of newly
diagnosed AAV patients without severe kidney failure
[83]. The remission rates observed at 6 months were com-
parable between both groups (67% vs. 61%). However,
relapses were more common in the MMF group, mostly
in PR3-ANCA-positive patients. Therefore, the study
suggests that MMF and glucocorticoids can be used as a
first-line induction therapy, mainly in patients with
MPO-ANCA who have mild to moderate renal involve-
ment without life-threatening extrarenal vasculitis.
Novel Strategies for Remission Induction Therapy:
Steroid Minimization Regimens
Classically, oral glucocorticoids have constituted a
cornerstone of AAV induction therapy due to its rapid
effect which allows disease control in the meanwhile oth-
er immunosuppressives to have an effect. However, glu-
cocorticoids have an extensive side-effect profile, includ-

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DOI: 10.1159/000520727
ing hypertension, hyperglycemia, weight gain, bone dis-
ease, psychiatric disorders, gastrointestinal bleeding, and
long-term risks for cardiovascular disease [84].
Although intravenous pulse methylprednisolone at
the onset of therapy for severe disease is conventionally
administered, its benefits have not been adequately stud-
ied. In recent years, several studies have explored the em-
ploy of lower dose regimens of steroids for induction
therapy and similar efficacy with a reduced risk of severe
infections was observed. The CYCLOWVAS study pro-
posed a combination of RTX with quinquennial low-dose
pulses of CYC associated with a rapid taper of glucocor-
ticoids within the first month [85]. A high remission rate
was observed in this study and when compared with an
European Renal Association and the European Vasculitis
Society (EUVAS) historic cohort, a reduction of the risk
of progression to end-stage renal disease and death was
shown. Another observational study employing this im-
munosuppression protocol represented a step forward
toward glucocorticoid withdrawal [86]. In this study,
prednisone was discontinued within the first 2 weeks of
therapy. Patients with severe renal failure were not ex-
cluded, and however, the remission rates observed were
very high (>90%). The rapid withdrawal of prednisone
was associated with a significant lower incidence of car-
diovascular events and diabetes. However, further trials
are needed to confirm the safety and superiority of this
combination regimen. Finally, the recent PEXIVAS trial
demonstrated that a reduction of the prednisone dose to
20 mg daily by 7 weeks and 5 mg daily by 20 weeks was as
Mild to moderate kidney failure
New onset
MPO PR3/MPO
Relapsed disease
Severe kidney failure
New onset/relapsed disease
PR3/MPO
RTX + SDS a)
RTX + ivCYC + LDS (*) e) RTX + ivCYC + SDS g)
RTX + ivCYC + LDS (*) h)
PR3
RTX + SDS a)/LDS d)
No remission Remission No remission No remission No remission
Consider stop
treatment and/or
dialysis
Swich therapy
Remission Remission
Maintenance therapy
RTX 500 mg every 4–6 months i) (+)
AZA j)
ivCYC ivCYC
RTX + SDS a)/LDS d)
ivCYC + SDS b)/LDS d)
MMF + SDS c)
RTX + iv CYC + LDS (*) e)
Avacopan + RTX/ivCYC f)
Fig. 3. Treatment algorithm for AAV. Mild to moderate kidney
failure: GFR >15 mL/min/1.73 m2
; severe kidney failure: GFR <15
mL/min/1.73 m2
. a) RAVE RCT protocol; b) CYCLOPS RCT pro-
tocol; c) MYCYC RCT protocol; d) PEXIVAS trial; e) CYCLOW-
VAS case-control trial protocol (RTX + quinquennial low-dose
CYC); f) AVACOPAN RCT protocol; g) RITUXVAS RCT proto-
col (RTX + quinquennial low-dose CYC); h) case control study
protocol from Pepper et al. [86]; i) MAINRITSAN 1 RCT protocol;
j) CYCAZREM RCT protocol. (*) Patients with intolerance or
contraindication to corticosteroids (+) or according to ANCA sta-
tus or CD19 B-cell repopulation (MAINRITSAN 2 protocol).
Maintenance for 24 months in patients with low risk of relapse and
up to 48 months in PR3-ANCA patients and those with high risk
for relapsing. PR3, proteinase 3; MPO, myeloperoxidase; RTX,
rituximab; SDS, standard dose of steroids; LDS, low dose of ste-
roids; ivCYC, intravenous cyclophosphamide; MMF, mycopheno-
late mofetil; AZA, azathioprine; RCT, randomized clinical trial;
AAV, antineutrophil cytoplasmic antibody-associated vasculitis;
CYC, cyclophosphamide.

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130
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effective as a higher dose regimen and implied a substan-
tial reduction in the infection rates [87].
Complement Blockage: Betting on the Future
Given the knowledge of the crucial role of complement
activation in the pathogenesis of AAV, therapies target-
ing the alternative pathway and particularly the anaphyl-
atoxin C5a have emerged [28]. The ADVOCATE trial
was a phase 3 study which analyzed standard immuno-
suppression with CYC or RTX combined with a selective
C5a receptor inhibitor avacopan or oral prednisone on a
tapering schedule [30]. At week 26, the proportion of pa-
tients in disease remission (BVAS = 0) in the avacopan
group was comparable to the prednisone group (72.3%
vs. 70.1%) [29]. Sustained remission at week 52 was ob-
served in 65.7% of the patients receiving avacopan and in
54.9% receiving prednisone. Therefore, avacopan nonin-
feriority was met at weeks 26 and 52 (p < 0.001), and su-
periority was met at week 52 only (p = 0.007). Avacopan
patients reported better health-related quality of life in
several measures (physical health, health perception,
emotional health, and vitality).
However, the study had some limitations. First, the
large number of patients in the avacopan arm (86%) who
received nonstudy-supplied glucocorticoids within the
first 6 months may have had an impact on the study drug
effect. Second, the lack of maintenance therapy in the
RTX subgroup may also have had some positive impact
outcome for the avacopan arm since the difference for
long-term disease remission was only observed among
patients treated with RTX. Finally, similar infection rates
were observed in both groups of treatment, but a greater
proportion of avacopan-treated patients had adverse
events associated with hepatic abnormalities. Despite
these concerns, the avacopan groups were noninferior to
the standard prednisone group in the study, highlighting
a potential approach in which glucocorticoid doses can be
minimized. Another phase II study is currently analyzing
the employ of vilobelimab (IFX-1), a first-in-class anti-
C5a antibody, added to standard of care and will certain-
ly provide further information about complement inhibi-
tion in AAV induction therapy [88].
Plasma Exchange: Unlearning What Has Been
Learned?
The benefit for considering plasma exchange (PEX) in
treatment of patients AAV is that the removal of ANCAs
and other inflammatory mediators could promote earlier
reversal of the immunological response and minimize tis-
sue damage. However, PEX is an invasive therapeutic
method which could increase the risk of infection, hem-
orrhage, and catheter-related complications and when
frozen plasma is employed, transfusion-related adverse
reactions [89]. The MEPEX trial showed that adjuvant
therapywithPEXaddedtoCYCinAAVpatientspresent-
ing with severe kidney failure was associated with a 24%
risk reduction in progression to end-stage kidney disease
[90]. However, the longer term follow-up data showed no
difference in mortality or end-stage kidney disease [91].
The PEXIVAS enrolled a total of 704 MPO and PR3-AAV
patients with renal involvement and with or without pul-
monary compromise [87]. Treatment with PEX associ-
ated to standard immunosuppression (RTX or CYC) was
compared with no PEX, and a standard dose oral gluco-
corticoid regimen was compared with a reduced dose reg-
imen. Notably, serious adverse events, including serious
infections, were comparable among patients treated with
and without PEX but were less frequent among patients
receiving a low dose of steroids. After a median follow-up
of 3 years, the study showed no difference in primary end
points (death from any cause or kidney failure) between
groups receiving or not PEX, and subgroup analysis failed
to show a benefit among those patients requiring dialysis
at the onset (20%).
However, similarly to the MEPEX study, the analysis
at the 1-year follow-up showed a nonsignificant advan-
tage of PEX (HR, 0.77; 95% CI, 0.56–1.06), whereas sta-
tistical assessment at 3 and 6 months was not provided
despite short-term clear separation between survival
curves. Therefore, many nephrologists consider that a
short-term benefit of PEX leading to a free dialysis period
within the first year, as well as the absence of serious tech-
nique-related complications in the study, still justifies
PEX employ among patients presenting with severe renal
failure.
In the PEXIVAS trial, 61 (9%) patients with severe pul-
monary hemorrhage, defined as oxygen saturation ≤85%
or requirement of mechanical ventilation, were included.
Although PEX did not show a statistically significant ef-
fect on the primary outcome in these patients, a trend
toward the beneficial effect of PEX could be observed
(HR,0.67;95%CI,0.28–1.6).However,theimpactofPEX
on mortality alone was not provided, and the study had
not powerful enough to evaluate the true effect of PEX in
these patients.
Maintenance Therapy: Which One and for How Long?
AAV constitutes a chronic disease with a relapsing
course. Up to 30–60% of patients will present a relapse in
the course of the disease, mainly within the first 2 years

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Table
3.
Maintenance
immunosuppressive
protocol
according
to
different
trials
Study
Immunosuppressive
drug
induction
Maintenance
comparison
Maintenance
drug
Doses
and
duration
Steroid
maintenance
Results
CYCAZAREM
RCT
(2003)
Oral
CYC
+
SDS
Oral
CYC
versus
AZA
Oral
CYC
1.5
mg/kg/day
until
month
12,
followed
by
AZA
1.5
mg/kg/day
Prednisolone
10
mg/day
until
month
12,
then
tapering
to
7.5
mg/day
No
differences
in
relapse
rates
AZA
2
mg/kg/day
until
month
12,
then
tapering
to
1.5
mg/kg/day
IMPROVE
RCT
(2010)
CYC
+
SDS
MMF
versus
AZA
MMF
2
g/kg/day,
tapering
to
1.5
g/kg/day
after
12
months,
1
g/kg/day
after
18
months,
withdrawn
after
42
months
Prednisolone
15
mg/day
at
the
start
of
maintenance,
tapering
to
5
mg/day
after
12
months,
withdrawn
after
24
months
Higher
relapse
rates
in
the
MMF
group
AZA
2
mg/kg/day,
tapering
to
1.5
mg/kg/day
after
12
months,
1
mg/kg/day
after
18
months,
withdrawn
after
42
months
MAINRITSAN
RCT
(2014)
ivCYC
+
SDS
RTX
versus
AZA
RTX
500
mg
at
days
0
and
14,
then
at
months
6,
12,
and
18
Prednisone
tapering
to
5
mg/day
until
18
months,
then
withdrawn
according
to
physician
criteria
Greater
sustained
remission
in
the
RTX
group
AZA
2
mg/kg/day
for
12
months,
1.5
mg/kg/
day
for
6
months,
1
mg/kg/day
for
4
months
REMAIN
RCT
(2017)
CYC
+
SDS
AZA
+
LDS
for
24
months
versus
AZA
+
LDS
for
48
months
AZA
+
LDS
for
24
months
Withdrawn
AZA
at
month
24
Withdrawn
steroids
at
month
24
Greater
sustained
remission
in
the
prolonged
AZA
group
AZA
+
LDS
for
48
months
AZA
1
mg/kg/day
until
month
48
Tapering
prednisolone
from
5
to
7.5
mg/day
to
zero
at
month
48
MAINRITSAN
2
RCT
(2018)
CYC
+
SDS
Fixed
RTX
dosing
versus
tailored
RTX
dosing
Fixed
500 mg
IV
at
days
0
and
14
and
then
at
6,
12,
and
18
months
No
significant
difference
in
the
relapse
rate.
Less
RTX
infusions
in
the
tailored
group
Individualized
500 mg
IV
at
randomization
and
then
reinfusion
only
if
reappearance
of
CD19
or
ANCA
or
increased
titer
of
ANCA
Prednisone
tapering
to
5
mg/day
until
18
months,
then
withdrawn
according
to
physician
criteria
MAINRITSAN
3
RCT
(2020)
CYF/MTX/RTX
+
SDS*
RXT
for
18
months
(5
doses)
versus
RTX
for
36
months
(9
doses)
RTX
18
months
500
mg
at
day
0
and
14,
then
at
months
6,
12,
and
18
Prednisone
tapering
to
5
mg/day
until
18
months,
then
withdrawn
according
to
physician
criteria
Greater
sustained
remission
in
the
prolonged
RTX
group
RTX
46
months
500
mg
at
days
0
and
14,
then
at
months
6,
12,
and
18,
then
at
months
28,
34,
40,
and
46
CYC,
cyclophosphamide;
AZA,
azathioprine;
RTX,
rituximab;
MMF,
mycophenolate
mofetil;
MTX,
methotrexate;
SDS,
standard
dose
of
steroids;
LDS,
low
dose
of
steroids.
*Patients
in
the
MAINRITSAN
2
trial.

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after the withdrawal of immunosuppression. The appear-
ance of relapses implies a substantial increase in the mor-
bidity in these patients. Risk factors for relapse include
PR3-ANCA serotype, GPA phenotype, ENT involve-
ment, persistent ANCA-positive titers, and persistent mi-
crohematuria [86, 92].
The use of maintenance immunosuppression for re-
lapse prevention following successful remission induc-
tion is standard (Table 3). The first study to compare 2
maintenance regimens was the CYCAZAREM trial, in
which patients with AAV who achieved remission with
oral CYC were randomly assigned at 6 months to con-
tinue CYC therapy or switch to azathioprine (AZA) [93].
At 18 months, relapse rates were similar between both
arms (15.5 vs. 13.7%) but with less side effects in the AZA
group. The IMPROVE trial compared MMF to AZA and
showed higher rates of relapse in patients treated with
MMF. Therefore, MMF may be considered for remission
maintenance in patients who have intolerance to AZA.
Subsequently, the employ of RTX as maintenance
therapy showed dramatically lower rates of relapse. In the
MAINRITSAN 1 trial, patients who achieved remission
after CYC induction regimen were randomized to receive
either AZA or biannual semestral RTX infusions (500
mg) as maintenance therapy [94]. In the RTX arm, only
5% of treated patients experienced a major relapse com-
pared to 29% in the AZA group. This beneficial effect of
RTX in the prevention of relapses was independent of the
ANCA serotype, and no difference in side effects or infec-
tion rates was observed between groups. The ongoing
RITAZAREM trial analyzes another RTX maintenance
regimen (1 g every 4 months for 2 years) with conven-
tional maintenance therapy with AZA in patients with
relapsing AAV who received RTX for induction. The first
report of the trial showed a high level of efficacy (90%)
with RTX in conjunction with glucocorticoids for the re-
induction of remission in patients with AAV who have
relapsed [95]. An approach to individualized mainte-
nance therapy employing RTX dosing tailored to B-cell
reappearance and/or increase in ANCA titers was evalu-
ated in the MAINRITSAN 2 trial [96]. In this study, the
median number of infusions was reduced (3 vs. 5) in the
tailored-dosegroupcomparedtopatientsreceivingfixed-
dose RTX every 6 months. Although not significant, a
trend toward a higher rate of relapse in patients with
RTX-tailored dosing (17.3%) compared with patients re-
ceiving fixed-dose RTX (9.9%) was observed. Interesting-
ly, 50% of the relapses in this study occurred in patients
without B-lymphocyte reconstitution and 30% with neg-
ative ANCA, highlighting the limitation of these bio-
markers to predict relapse. Notably, up to 30% of patients
experienced a relapse 38 months after the last RTX infu-
sion, putting into debate the optimal duration of mainte-
nance immunosuppression.
In this sense, the REMAIN trial was a randomized con-
trolled trial that tested whether continuing AZA and
prednisone treatment for 48 months was more effective
in relapse prevention than withdrawal at 24 months [97].
Results from this study showed a significant decrease in
both major and minor relapses and better renal survival
in the continuation group. More recently, the MAINRIT-
SAN 3 trial included PR3 and MPO-AAV patients who
were in complete remission after receiving an 18-month
RTX maintenance regimen in the MAINRITSAN 2 study
[98], and participants were randomly assigned to receive
prolonged maintenance therapy with either intravenous
RTX (500 mg every 6 months) or a placebo for a further
18 months. Relapse-free survival rates at month 28 were
significantly higher among patients given prolonged RTX
(96%) than patients given the placebo (74%), and long-
term RTX maintenance therapy did not increase the
number of adverse events. Notably, relapses occurred
more frequently in PR3-ANCA patients than in MPO pa-
tients in the placebo arm (40% vs. 12%). On the basis of
these results, prolonged maintenance treatment (4–5
years) with RTX may be employed at high-risk patients
for relapses, such as those with PR3-ANCA, those who
have already had a relapse, or with persistent hematuria
or high ANCA titers despite treatment.
Refractory Disease and Other Therapies
Refractory disease in AAV can be defined as progres-
sive disease within the first 3 months or lack control of
vasculitis activity by 6 months despite standard of care
therapy. An increase in the glucocorticoid dose is used in
severe disease, but prolonged use of high-dose oral gluco-
corticoids should be avoided due to the associated risks.
Switching from CYC to RTX and vice versa or a combina-
tion of both immunosuppressants could be considered in
refractory cases.
The development of anti-RTX antibodies has been de-
scribed to neutralize RTX B-cell cytotoxicity and may im-
pact the clinical outcome of autoimmune diseases [99].
Ofatumumab, a fully humanized antibody directed
against a distinct extracellular epitope of CD20 has slow-
er dissociation kinetics than that of RTX and has been
shown to be a more potent activator of complement-de-
pendent cytotoxicity in vitro. It was successfully em-
ployed in small series of AAV cases [100], but its role in
refractory AAV disease requires further investigation.

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The efficacy and safety of mepolizumab, a human
monoclonal antibody against IL-5, for the treatment of
relapsing or refractory EGPA, were investigated in a ran-
domized, placebo-controlled study which included pa-
tients on a stable corticosteroid therapy [101]. Patients
treated with mepolizumab achieved a significantly higher
rate of remission than patients who received the placebo.
Also beneficial effects of IL-6 receptor blockade therapy
with tocilizumab in association with steroids have been
observed in small series of MPA patients [102], but larger
and prospective studies are desirable to confirm these re-
sults.
Given the considerable evidence for the role of TNF-α
in pathogenesis of AAV, several anti-TNF-α agents have
been explored for AAV therapy. The WGET study was a
randomized, placebo-controlled study which examined
the use of etanercept as add-on therapy to conventional
treatment, for maintenance of remission, in a large cohort
of patients with GPA [103]. This study found no addi-
tional benefit of etanercept, and excess of solid cancers
was observed, but this risk could not be attributed solely
to etanercept treatment since previous history of malig-
nancy and CYC exposure previous to etanercept could
have also played a role. Another anti-TNF agent, inflix-
imab, was evaluated as adjuvant therapy with CYC and
corticosteroids in a prospective clinical trial [104]. Inflix-
imab was effective at inducing remission in 88% of pa-
tients and permitted reduction in steroid doses. However,
severe infections were seen in 21% of patients, and despite
continued infliximab, 20% of initial responders experi-
enceddiseaseflares.Adalimumabwassimilarlyemployed
as adjuvant therapy showing high rates of early remission
(80% at 3 months) and the ability to significantly reduce
the steroid dose during induction treatment [105].
Other therapeutic approaches include the combina-
tion of the BLyS/BAFF blockade with RTX, which is now
being evaluated in the “Rituximab and Belimumab Com-
bination Therapy in PR3 Vasculitis” trial [106]. Alemtu-
zumab, a humanized anti-CD52 (CAMPATH-1H)
monoclonal antibody, was evaluated in combination with
prednisone for patients with AAV refractory to conven-
tional treatment [107]. In this study, 85% of patients
achieved remission, but 71% of these had relapsed by 9.2
months and adverse events were common.
Leflunomide was reported efficacious for remission
induction among 62 out of 93 patients (67%) with differ-
ent vasculitic disorders (64% with GCA, 89% with TAK,
80% with PAN, 69% with GPA, 75% with MPA, and 33%
with EGPA) [108]. In this study, 20% of patients discon-
tinued leflunomide before achieving remission because of
persistent disease activity and adverse events (gastroin-
testinal symptoms being the most common) led to drug
discontinuation in 18 (19%) patients.
Antithymocyte globulin (ATG) was also employed as
adjuvant therapy in a small cohort of patients with refrac-
tory GPA [109]. The majority of patients achieved remis-
sion after therapy, and treatment with ATG allowed a fur-
ther reduction in immunosuppression. However, authors
recommended avoiding ATG therapy if simultaneous in-
fections, fluid overload, or alveolar hemorrhage were
present. Also in GPA patients with refractory disease, a
6-month course of the immunosuppressant 15-deoxys-
pergualin was successfully employed in 7 patients [110].
However, most patients relapsed after 15-deoxyspergua-
lin discontinuation.
There is little experience with agents targeting plasma
cells in AAV. Experimental studies showed that bortezo-
mib depleted MPO-specific plasma cells and prevented
anti-MPO IgG-mediated necrotizing crescentic glomeru-
lonephritis in mice [111]. Interestingly, a favorable effect
of proteasome inhibition was reported in 1 patient with
AAV [112].
Finally, the use of the Ig was analyzed in a randomized,
placebo-controlled trial that investigated the efficacy of a
single course of intravenous Ig (IVIg) (total dose 2 g/kg)
in previously treated AAV patients, showing persistent
disease activity [113]. A single course of IVIg reduced dis-
ease activity in these patients, but the effect was not main-
tained beyond 3 months. Therefore, IVIg may be an alter-
native treatment option for AAV with persistent disease
activity after standard therapy. In this sense, the ongoing
Endurance 1 trial is a randomized and prospective study
which aims to prove the superiority of combination treat-
ment RTX with CYC compared to standard of care ther-
apy in AAV patients showing persistent disease activity
[114].
Conclusions
AAVs have a complex pathogenesis, influenced by ge-
netics and environmental factors. There is evidence for a
loss of tolerance to neutrophil proteins, which leads to
ANCA-mediated neutrophil activation, recruitment, and
injury, with effector T cells and activation of alternative
pathway of complement also involved. NETs containing
MPO and PR3 contribute to the pathogenesis through
different mechanisms, including antigen presentation
that promotes autoimmunity as well as direct vascular
damage.

Nephron 2022;146:121–137
134
DOI: 10.1159/000520727
Data from epidemiological outcomes and genetic
studies in AAV suggest that patients should be classified
by ANCA specificity (MPO-ANCA vs. PR3-ANCA) rath-
er than by the clinical syndrome. Novel biomarkers for
screening disease, monitoring therapeutic interventions
and identifying relapses include neutrophil activation
markers such as calprotectin, macrophage activation-de-
rived products (uCD163 and MCP), T-cell subpopula-
tions, and alternative pathway of complement fractions.
The treatment of AAV is rapidly evolving, and mortal-
ity and remission rates have improved over the years.
However, high infection rates are still observed, and cur-
rent strategies are focused on reducing treatment toxicity.
RTX-based regimens are the cornerstone for induction
therapy among PR3 and relapsing patients as well as for
maintenance therapy. Novel therapeutic strategies in-
clude blockage of complement and combination of im-
munosuppressants, which allow minimization of cumu-
lative steroids exposure. Individualization of treatment
according to ANCA specificity, disease phenotype, and
risk of relapse is a key for offering a personalized care to
AAV patients.
Acknowledgments
We thank all the members of the Spanish Group for the Study
of Glomerular Diseases (GLOSEN) for their valuable contribution
to research in glomerular diseases.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
There were no funding sources for this work.
Author Contributions
All the authors contributed equally to this study, revised the
paper, and approved the final version of the manuscript.
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