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BRIEF REVIEW www.jasn.org
Proteinase 3-ANCA Vasculitis versus Myeloperoxidase-ANCA Vasculitis
Marc Hilhorst, Pieter van Paassen, and Jan Willem Cohen Tervaertfor the Limburg Renal Registry
Clinical and Experimental Immunology, Maastricht University, Maastricht, The Netherlands
ABSTRACTIn patients with GN or vasculitis, ANCAs are directed against proteinase 3 (PR3) ormyeloperoxidase (MPO). The differences between PR3-ANCA-associated vasculitis(AAV) andMPO-AAV described in the past have been supplemented during the lastdecade. In this review, we discuss the differences between these two small-vesselvasculitides, focusing especially on possible etiologic and pathophysiologic differ-ences. PR3-AAV is more common in northern parts of the world, whereasMPO-AAVis more common in southern regions of Europe, Asia, and the Pacific, with theexception of New Zealand and Australia. A genetic contribution has been exten-sively studied, and there is a high prevalence of the HLA-DPB1*04:01 allele inpatients with PR3-AAV as opposed to patients with MPO-AAV and/or healthy con-trols. Histologically, MPO-AAV and PR3-AAV are similar but show qualitative differ-ences when analyzed carefully. Clinically, both serotypes are difficult to distinguish,but quantitative differences are present. More organs are affected in PR3-AAV,whereas renal limited vasculitis occurs more often in patients with MPO-AAV. Forfuture clinical trials, we advocate classifying patients by ANCA serotype as opposedto the traditional disease type classification.
J Am Soc Nephrol 26: 2314–2327, 2015. doi: 10.1681/ASN.2014090903
ANCA were first described more than50 years ago.1 Later, these antibodieswere discovered in the context of GN2
and vasculitis.3 The discovery of theseantibodies in granulomatosis with poly-angiitis (GPA; formerly known asWegener’s granulomatosis) marked abreakthrough in diagnostics, since GPAhad been known for at least half a cen-tury without a serologic marker.4,5 Sub-sequently, ANCA were found in twoother forms of small-to-medium-vesselvasculitis, i.e., microscopic polyangiitis(MPA)6 and eosinophilic GPA (formerlyknown as Churg–Strauss syndrome).7
ANCA were traditionally tested with animmunofluorescence test on fixed neu-trophils. Three patterns can be found:cytoplasmic (cANCA), perinuclear
(pANCA), and atypical.8 ANCA, asdetected by immunofluorescence tech-niques, have been found in many differ-ent diseases.9
In addition to detecting cANCA orpANCA by immunofluorescence, a testto detect proteinase 3 (PR3)-ANCA ormyeloperoxidase (MPO)-ANCA ismandatory for the diagnosis of ANCA-associated vasculitis (AAV).8 In the case ofGN and/or vasculitis, ANCA are almostalways directed against PR3 or MPO,and PR3-ANCA and MPO-ANCA arespecific for GPA and MPA.8 The distinc-tion betweenGPAandMPA in the contextof ANCA serotype is far from perfect8,10
and underlines the discordance betweendisease categorization and ANCA sero-type categorization. Most patients are
single-positive, meaning that only oneANCA serotype can be detected.11
Many differences exist between patientswith PR3-AAV and MPO-AAV,12–16
which were highlighted in a review byFranssen et al. more than a decadeago.17 Since then, more differences be-tween PR3-AAV and MPO-AAV havebeen discovered.
The aim of the current review is todiscuss differences between PR3-AAVand MPO-AAV in the light of the dis-coveries that took place during the lastdecade.
CONCISE METHODS
Medline and Embase were searched for com-
binations of the following indexed subject
headings [MeSH]: vasculitis, antibodies, an-
tineutrophil cytoplasmic, anti-neutrophil cy-
toplasmic antibody-associated vasculitis,
“ANCA [text word]”, granulomatosis with
polyangiitis, Wegener’s granulomatosis, mi-
croscopic polyangiitis, “pauci-immune [text
word]”. Eosinophilic GPA was not included
in this review. The rating of the quality of
evidence as depicted in Table 1 is based on
Published online ahead of print. Publication dateavailable at www.jasn.org.
Correspondence: Dr. Jan Willem Cohen Tervaert,Clinical and Experimental Immunology, Maas-tricht University, Universiteitssingel 40, PO Box616, 6200MD Maastricht, The Netherlands. Email:jw.cohentervaert@maastrichtuniversity
Copyright © 2015 by the American Society ofNephrology
2314 ISSN : 1046-6673/2610-2314 J Am Soc Nephrol 26: 2314–2327, 2015
the Grading of Recommendations Assess-
ment, Development and Evaluation sys-
tem.18
EpidemiologyThe AAV form a group of rare autoimmune
diseases with an increasing annual inci-
dence,19 currently reported as 20 per mil-
lion/year.20 Several studies have shown that
themale to female ratio is higher in PR3-AAV
(1.3–1.9) than in MPO-AAV (0.3–0.8).12,16
In our cohort of patients with renal involve-
ment the male to female ratio was 3.0 in
PR3-AAV patients and 1.9 in MPO-AAV
patients.21
The incidenceofPR3-AAVandMPO-AAV
varies worldwide, possibly as the result of
a combination of genetic pools and certain
environmental factors. For example, the in-
cidence of PR3-AAV in the United Kingdom
has been reported as 11.3 permillion/year and
3.0 per million/year in Spain, whereas the
incidence of MPO-AAV has been reported as
5.9 and 7.9 per million/year, respectively.22,23
In Japan, the incidence of AAV is 22.6 per
million/year with 84% of patients being
MPO-ANCA positive.24 Although population-
based data from China are lacking, the
majority of patients in China are also MPO-
ANCA positive.25 In general, PR3-AAV is
more common in northern parts of the
world whereas MPO-AAV is more common
in southern Europe, Asia and the Pacific,
with the exception of New Zealand and
Australia.26–32 This distribution has led to
genetic and environmental hypotheses on
the etiology of AAV, which are discussed in
the next sections.
Genetic FeaturesA genetic contribution in AAV has been
extensively studied.33 Many polymorphisms
have been researched and linked—or not
linked—to the MHC.34–37 Two large genome-
wide studies have recently been per-
formed,38,39 which confirmed the presence
of single nucleotide polymorphisms in the
HLA-DPB region on chromosome 6 in a
large percentage of patients with PR3-AAV
as opposed to patients with MPO-AAV.38,39
The association between this particular single
nucleotide polymorphism and PR3-ANCA
was stronger than with the clinical diagnosis
of GPA.39 A weaker association was found
betweenMPO-AAVand HLA-DQ. Polymor-
phisms in the genes IL-10, CTLA-4, CD226,
ITGB2, PTPN22, IL2RA, and PRTN3,40–42
previously reported to play a role in AAV,
were included.39 However, none of these
had an odds ratio that was significant
genome-wide (P value ,531028). Lyons
et al.39 found a higher prevalence of SERPINA1
polymorphisms in patients with PR3-AAV
compared with those with MPO-AAV. The
association between SERPINA1 and GPA
was confirmed by Xie et al..38 Although
not significant genome-wide, PRTN3 in the
study by Lyons et al.39 was associated with
PR3-AAV but not with MPO-AAV. Xie et al.38
Table 1. Completed clinical trials in ANCA-associated vasculitis
Name Treatment Studied Patients Primary Outcomes
CYCAZAREM168 Azathioprineversus cyclophosphamide inremission maintenance
GPA and MPA Azathioprine is as effective as cyclophosphamide and reducescumulative cyclophosphamide doses for maintenance ofremission
CYCLOPS169 IV cyclophosphamide versus oralcyclophosphamide in remissioninduction
GPA, MPA andRLV
IV cyclophosphamide is as effective as oral cyclophosphamideand reduces cumulative cyclophosphamide doses forinduction therapy
IMPROVE170 Mycophenolate mofetil versusazathioprine in remission maintenance
GPA and MPA Mycophenolate mofetil is less effective than azathioprine formaintenance of remission
MAINRITSAN154 Rituximab versus azathioprine inremission maintenance
GPA and MPA Rituximab is more effective to prevent relapse compared withazathioprine whereas adverse events are similarly frequent
MEPEX171 Plasma exchange versusmethylprednisolone in remissioninduction
GPA and MPA Renaloutcome isbetterwhenplasmaexchangewasperformedin patients with severe renal disease but patient survival issimilar
MTX versus LEF172 Oral methotrexate versus leflunomide forremission maintenance
GPA Less relapses occur with leflunomide as compared withmethotrexate for remission maintenance but more adverseevents occur with leflunomide
NORAM173 Methotrexate versus cyclophosphamidefor remission induction
GPA and MPA Methotrexate is less effective than cyclophosphamide inpatients with non-renal AAV for disease control
RAVE135,153 Rituximab versus cyclophosphamide inremission induction
GPA and MPA A single course of rituximab is as effective and as safe astreatment with cyclophosphamide followed by azathioprine
RITUXVAS152 Rituximab with cyclophosphamide versuscyclophosphamide in remissioninduction
GPA and MPA In patients with severe renal disease, rituximab in combinationwith two pulses of cyclophosphamide is as effective and assafe for remission induction as cyclophosphamide pulsetherapy
WEGENT174 Methotrexate versus azathioprine inremission maintenance
GPA and MPA Methotrexate is as effective and as safe for remissionmaintenance as azathioprine
WGET175 Etanercept with standard therapy versusstandard therapy in remission inductionand maintenance
GPA Etanercept is not effective for maintenance of remission andwhen combined with standard therapy results in a high rate oftreatment related complications (e.g., malignancies)
IV, intravenous; RLV, renal-limited vasculitis.
J Am Soc Nephrol 26: 2314–2327, 2015 PR3-AAV versus MPO-AAV 2315
www.jasn.org BRIEF REVIEW
did not include PRTN3 in their analysis. The
findings of Lyons et al. support a pathogenic
role for ANCA—which implicates the MHC,
the PR3 antigen itself, and a1-antitrypsin—so
further diminishing the possibility of ANCA
being an epiphenomenon. Although CTLA4
polymorphisms are more prevalent in patients
compared with healthy controls, no difference
can be found between ANCA serotypes.39 Our
group, however, has found that patients with
MPO-AAV tend to more often be G-allele
carriers of a polymorphism in CTLA4 com-
pared with patients with PR3-AAV.34 Re-
cently, we extended this study and found
that 76.4% of the patients with MPO-AAV
(n=72) were G-allele carriers compared with
58.8% of patients with PR3-AAV (n=80) and
55.1% of healthy controls (n=185; P=0.01;
M. Hilhorst et al, unpublished data).
In the North American genome-wide
studies, a link between SEMA6A and GPA
was found,38 but this was not confirmed in
an independent cohort of European pa-
tients.43
Interestingly, the alleleHLA-DRB1*15has
been associated with PR3-AAV in African
Americans, but not with MPO-AAV in these
patients or with Caucasian patients in gen-
eral.44 Such findings further support a strong
genetic background of AAV, which may sup-
port categorization of patients based on
ANCA serotypes rather than on clinical di-
agnosis.
EtiologyIncidence and prevalence of AAVare different
at different latitudes.27 The geographical pat-
tern can be explained by factors such as ge-
netic background and/or environmental
factors.45 Especially in MPO-AAV, silica ex-
posure is thought to play a role.46,47 Macro-
phages phagocytosing silica, e.g., in the
lung, produce proinflammatory cytokines
which attract neutrophils. The silica parti-
cles are then transported to regional lymph
nodes, resulting in chronic activation of T
cells and triggering autoimmune reactions
in susceptible patients.48–50 A higher inci-
dence of MPO-AAV was reported after the
Kobe earthquake in Japan, possibly related
to increased silica exposure.51 After closure
of the last coal mine in the region of Maas-
tricht, the Netherlands, MPO-AAV diagno-
ses appeared to decrease compared with the
number of PR3-AAV diagnoses.52 Whether
this observation supports the etiologic con-
tribution of silica exposure is, however, spec-
ulative.
Bacterial infections have been thought to
be an important factor in the initiation of
AAV.53–56 It is known that PR3-ANCA-
positive patients who carry nasal Staphylococ-
cus aureus chronically are at higher risk for
disease relapse.54 While MPO-AAV in associ-
ation with S. aureus infection has been men-
tioned,57,58 so far no studies on the role of
nasal S. aureus carriage in MPO-AAV have
been performed. A sequence homology be-
tween PR3 and parts of the S. aureus genome
has been suggested, but evidence that such
interaction is operative in vivo is lacking.59
Furthermore, a homology between comple-
mentary PR3 and S. aureus was found.60 Var-
ious possible mechanisms by which S. aureus
contributes to the pathophysiology of AAV
have been postulated.55 These mechanisms,
however, fail to explain a difference between
PR3-AAV and MPO-AAV. Importantly,
ANCA directed against human lysosome-
associated membrane protein 2, present
in both PR3-ANCA– and MPO-ANCA–
associated GN,61 were found to react with
the bacterial adhesin FimH, supporting an
autoimmune model of molecular mimicry
in ANCA-associated GN.62
Pathophysiology: In Vitro Data andAnimal ModelsIn vitro dataWhile neutrophils express low levels of PR3
andMPO on their cell surface, PR3 andMPO
are expressed extensively upon stimulation
(e.g., with TNF-a),63–65 making it possible
for ANCA to bind. It has been shown that
PR3 and MPO levels are aberrantly increased
in patients with AAV compared with healthy
controls,66 possibly because of epigenetic
factors.67 Both ANCA serotypes are able to ac-
tivate neutrophils via Fab as well as Fcg en-
gagement,68 resulting in the release of
inflammatory mediators.69 Subsequently,
PR3 and MPO are both released into the cir-
culation and bind to endothelial cells.70 Both
enzymes can be internalized by endothelial
cells, yet exert different effects. PR3 induces
apoptosis of the endothelial cell whereas
MPO induces the production of intracellular
oxidants.71 It is currently unknown whether
PR3-ANCA and MPO-ANCA induce differ-
ent pathways of inflammation. During active
disease, an increase in the antiangiogenic
factor sFlt1 (also known as sVEGFR-1) can
be observed in patients with PR3-AAV and
to a much lesser extent in those with MPO-
AAV. Monocytes were shown to be the main
source of sFlt1, releasing this factor upon
stimulation with serum from patients with
PR3-AAV but not after stimulation with se-
rum from patients with MPO-AAV.72 It has
been suggested that C5a is a major driver of
sFlt1 release by monocytes.73 Complement
activation may therefore differ between
PR3-ANCA and MPO-ANCA.74
Animal ModelsTo demonstrate pathogenicity of ANCA in
vivo, several animal models have been devel-
oped.75 The development of an animal model
for AAV was most successful for MPO-AAV.
Initially, Brown-Norway rats were immu-
nized with MPO and their kidneys were per-
fused with H2O2 and a lysosomal extract
containing MPO and elastinolytic enzymes.
This resulted in a severe pauci-immune necro-
tizing crescentic GN (NCGN) with up to 80%
fibrinoid necrosis and 70% crescentic lesions,
and localization of MPO along the glomerular
basement membrane. This proves that anti-
MPO antibodies cause severe damage when
initial immune complex formation occurs.76
Injecting mice with anti-MPO antibodies
(raised in Mpo2/2 mice) results in a mild
form of NCGN77 whereas an additional injec-
tion with LPS causes a more severe NCGN.78
Finally, it has been demonstrated that human
MPO immunization in WKY rats results in
anti-MPO antibody binding to rat leucocytes,
causing vasculitis and GN.79
Similar approaches were used to develop
an animal model for PR3-AAV but these
proved unsuccessful. Immunization of mice
and rats with chimeric human/mouse PR3
induced anti-PR3 antibodies, but no dis-
ease.80 Similarly, nonobese diabetic (NOD)
mice immunized with recombinant mouse
PR3 developed anti-PR3 antibodies but no
signs of autoimmune disease. In fact, vascu-
litis could only be induced when splenocytes
from these immunized NOD mice were
transferred into NOD-SCID mice.81 A more
recent study using humanized NOD-SCID-
IL-2Rg2/2 mice injected with LPS and hu-
man IgG containing anti-PR3 antibodies
showed the development of lung hemorrhage
and mild kidney disease, characterized by
2316 Journal of the American Society of Nephrology J Am Soc Nephrol 26: 2314–2327, 2015
BRIEF REVIEW www.jasn.org
mesangial hypercellularity and leukocyte influx.
This supports the pathogenicity of PR3-
ANCA.82 Induction of an inflammatory reaction
with granulomatous features in a PR3-AAVani-
mal model has, however, been unsuccessful to
date. One hypothesis on why PR3-AAV animal
models are more difficult to develop than
MPO-AAV animal models is that mouse PR3
is undetectable on isolated mouse neutrophils,
probably as the result of a different interaction
between PR3 and NB1 (CD177) in mice.83
This makes the antigen unavailable to the
circulating antibodies.84
The differences in animalmodels for PR3-
AAV and MPO-AAV could indicate a differ-
ence between mice and men and may not
necessarily reflect a difference in pathophys-
iology.
Histopathologic FeaturesA biopsy showing necrotizing vasculitis con-
firms the presence of AAV. A hallmark of GPA
is granulomatous inflammation. Granuloma
formation is thought to be initiated by small
aggregates of neutrophils surrounding ne-
crotic areas (microabscess).85–87 In GPA,
granulomatous inflammation can be found
in several affected organs, a feature not found
in MPA.88 Granuloma formation can be
found in both PR3-ANCA–positive patients
and MPO-ANCA–positive patients diag-
nosed with GPA.11 Therefore, granuloma
formation—including periglomerularly
(Figure 1)—does not discriminate PR3-
AAV from MPO-AAV (Figure 2). In our
study, for those patients with a renal biopsy,
23 of 92 PR3-AAV patients (25.0%) and 17
of 89 MPO-AAV patients (19.1%) had peri-
glomerular granulomas. Whether granulomas
in PR3-AAV differ from granulomas in MPO-
AAV is at present unknown.
Renal histology in PR3-AAV and MPO-
AAV does not discriminate, because similar
abnormalities are recorded: NCGN with
fibrinoid necrosis upon light microscopy in
combination with pauci-immunity (,2+
on a scale of 0 to 4+) upon immunofluores-
cence.89 The ANCA-associated GN classifi-
cation90 classifies renal biopsies based on
percentage of glomeruli involved. A distinc-
tion between four groups can be made: when
.50% of glomeruli are normal, the renal bi-
opsy is classified as focal; when .50% of
glomeruli contain cellular crescents, the bi-
opsy is termed crescentic; when .50% of
glomeruli are sclerosed, the biopsy is classi-
fied as sclerotic; and when the biopsy is not
classified in the other groups, it is classified as
mixed. This classification has prognostic
value91 with the best renal survival in the fo-
cal group, followed by the mixed and cres-
centic groups and the worst renal survival
in the sclerotic group.21 Although renal his-
tology between PR3-AAV and MPO-AAV is
similar, significant quantitative differences
can be observed.92 An important difference
is the presence of more normal glomeruli in
PR3-AAV compared with MPO-AAV (31%–
40% and 26%–28%, respectively), with a
comparable eGFR between these groups at
the time of renal biopsy.52,90,93 In contrast,
more fibrotic changes are recorded in
MPO-AAV,93,94 reported as interstitial fibro-
sis in addition to fibrous crescents (19% in
MPO-AAV versus 10% in PR3-AAV)52 and
obliterated glomeruli (25% in MPO-AAV
versus 15% in PR3-AAV).90 Since chronic
features are known to be associated with
bad renal outcome52,95 patients with MPO-
AAV may have worse renal survival than pa-
tients with PR3-AAV. Data on this matter
remain, however, inconclusive.92,96–98 In addi-
tion to renal fibrosis, an association between
lung fibrosis and MPO-ANCA has been ob-
served.99–101 Pulmonary fibrosis in PR3-AAV
seems to occur less often.102 It has been pos-
tulated that fibrotic changes in MPO-AAVare
either due to a delayed diagnosis93 or due to a
more profibrotic pathogenesis.103,104
Although ANCA-associated GN is by defi-
nition pauci-immune, a subset of renal biopsies
were found to have complement and immuno-
globulin depositions, as well as electron-dense
deposits ultrastructurally.105 Electron-
dense deposits were found as frequently in
PR3-AAV as in MPO-AAV.105,106 In the
Limburg Renal Registry,107 we found C3 depo-
sition in more than half of renal biopsies. C3d
depositions were more prevalent in patients
with MPO-AAV compared with patients with
PR3-AAV (M. Hilhorst et al, unpublished data).
There is some evidence to support a
different role for complement between the
two ANCA serotypes108–110 (vide supra).
Clinical FeaturesMost AAV patients are diagnosed between
ages 50 and 70 years, without clear differences
between ANCA serotypes. AAV is a systemic
disease that involves the ear, nose, and throat,
the lungs, the kidneys, the heart, the digestive
Figure 1. Light microscopy picture of a renal biopsy from a patient with ANCA vasculitis.Around the almost obliterated glomerulus an active granulomatous inflammation can beseen (hematoxylin and eosin staining; original magnification 340).
J Am Soc Nephrol 26: 2314–2327, 2015 PR3-AAV versus MPO-AAV 2317
www.jasn.org BRIEF REVIEW
system, the nervous system, the eyes, the skin,
the musculoskeletal tract and, infrequently,
other organs.111 All organ systems involved
are summarized in the Birmingham Vasculitis
Activity Score, enabling the clinician to assess
disease severity.112,113 Clinical features differ
between PR3-AAVandMPO-AAV. The combi-
nation of upper and/or lower respiratory tract
involvement with renal involvement is fre-
quently seen in PR3-AAVas opposed to vascu-
litis limited to the kidney in MPO-AAV.13,114
The frequency of pulmonary involvement is
similar in both serotypes, but differs in nature.
While fibrosing lesions are more frequent in
MPO-AAV, cavitating lesions are more often
found in PR3-AAV.13,115 Nodules and masses
on chest radiography are more often observed
inPR3-AAVandpatchy infiltratesmore often in
MPO-AAV.116 Initially, alveolar lung hemor-
rhage was reported more frequently in MPO-
AAV13 but more recent studies have reported it
to be more frequent in PR3-AAV.117,118
Differences in ear, nose, and throat in-
volvement have been reported with more
necrotizing lesions in PR3-AAV compared
with MPO-AAV. Granulomatous inflamma-
tion in the ear, nose, and throat region is rare
in MPO-AAV but polyps occur.14,119
Renal disease is common in AAV—
estimated at 80%—and the overall prevalence
does not differ between PR3-AAV and MPO-
AAV.103 Renal function at baseline has been
shown to be more severely impaired in
MPO-AAV in some studies98,120 but our studies
included patients with similar renal function at
baseline.21,52
Nervous system involvement in AAV has
been reported equally frequently in PR3-AAV
patients (7%) compared with MPO-AAV
patients (7%).121–124
Twenty to forty percent of patients with
AAV have skin lesions upon presentation,
irrespective of ANCA serotype.125
When analyzing patients with GPA and
patients with MPA without including those
with eosinophilic GPA, cardiac involvement
in AAV appears similar in both ANCA sero-
types, but data are scarce.120
Ophthalmologic manifestations such as
orbital inflammatory disease are observed
more often in PR3-AAV than in MPO-
AAV.126,127
OutcomeOutcome differs according to ANCA sero-
type. Patients with PR3-AAV relapse signifi-
cantly more often (hazard ratio 1.6–3.2) than
patients withMPO-AAV.52,98,128–130 Risk fac-
tors for relapse other than ANCA serotype
are ear, nose, and throat involvement, nasal
carriage of S. aureus in PR3-AAV, cardiovas-
cular involvement and a rise in ANCA titers
in patients with renal involvement.54,131
Worse renal involvement has been reported
to be associated with a lower risk for re-
lapse.54,129 Most studies have not analyzed
risk factors for relapse stratifying by ANCA
serotype.
Patient survival in AAV has improved
substantially over the last three decades,52
with mortality rates currently at 2%–30%
at 1 year and 19%–50% at 5 years, strongly
depending on renal involvement and/or age
at onset.96,132–135 A systematic review dem-
onstrated worse patient survival in patients
with MPA compared with patients with
GPA.136 In our patients with AAV who had
renal involvement, patient survival was
worse in patients with MPO-AAV (n=92)
compared with patients with PR3-AAV
(n=89), whereas renal survival was similar
(P50.28). Various studies, however, could
not find a clear difference in patient survival
between PR3-AAV and MPO-AAV pa-
tients,98,137 whereas one study reported a
worse patient survival in patients with PR3-
AAV.138 Three studies found no difference in
renal survival between ANCA sero-
types,92,96,139 whereas several recent studies
reported a worse renal survival in patients
with MPO-AAV.98,140–142 Survival in pa-
tients with PR3-AAV may be largely deter-
mined by diffuse alveolar hemorrhage at
presentation and renal relapses in follow-
up,98,143 whereas renal and/or patient sur-
vival in MPO-AAV is probably related to
smoldering disease94 causing end-stage renal
disease.
With improving treatment and survival,
long-term morbidity plays an increasingly
important role in AAV. Within the first year
after diagnosis, infection forms the most
important risk of death.144,145 Thereafter,
Figure 2. Pathogenic model highlighting the differences between PR3-ANCA and MPO-ANCAvasculitis. PR3-AAV ismorecommon in thenorthernpartsof theworldwhereasMPO-AAV ismorecommon in thesouthernparts.Differentgeneticbackgroundshavebeen foundanddifferent etiologic factors are considered.Clinically and histologically both vasculitidesdiffer. On the cellular level, PR3 andMPOexert different effects on endothelial cells. Thesedifferences possibly point out separate pathogenic pathways.
2318 Journal of the American Society of Nephrology J Am Soc Nephrol 26: 2314–2327, 2015
BRIEF REVIEW www.jasn.org
cardiovascular disease, malignancies and
infections are the main causes of death.145
The occurrence rate of infection does not
seem to differ between PR3-AAV or MPO-
AAV.
Cardiovascular disease in AAV has been
described as being increased, occurring in
14%of patients within 5 years of diagnosis,146
with patients with MPO-AAV at a higher
risk.146,147
Patients with AAV tend to develop more
venous thromboembolic events compared
with healthy controls,148–150 with no clear
distinction between patients with PR3-AAV
and MPO-AAV.
No difference in the occurrence of malig-
nancies has been shown between MPO-AAV
and PR3-AAV patients,151 but more long-
term data are needed.
TreatmentThe treatment of AAV has been an important
research topic during the last twodecades and
has shown continuous improvement in out-
come. The introduction of B-cell targeting
therapy for remission induction marked an
important milestone. The RITUXVAS trial
showed that in newly diagnosed patients with
severe renal involvement, rituximab in com-
bination with two pulses of cyclophospha-
mide induced remission as effectively as a
standard regimen of cyclophosphamide
pulses, with no significant difference in ad-
verse events.152 In the RAVE trial, rituximab
was shown to be noninferior to cyclophos-
phamide in newly diagnosed patients and
superior to cyclophosphamide in relapsing
patients153 after 6months follow-up, whereas
at 18 months follow-up it became apparent
that a single course of rituximab was as effec-
tive for inducing sustained remission as con-
ventional immunosuppressive treatment
with cyclophosphamide followed by azathio-
prine.135 The MAINRITSAN trial showed
that patients in remission (after induction
Table 2. Currently planned or ongoing clinical trials in ANCA-associated vasculitis
Name Treatment Studied Status Patients Primary Outcomes Clinical Trial no.
ABROGATE Abatacept (CTLA-4immunoglobulin)
Not yetrecruiting
GPA Treatment failure after 12 monthsof treatment
NCT02108860
Evaluate the efficacy of achieving glucocorticoid-free remission in patients with relapsing non-severe GPAALEVIATE Alemtuzumab (monoclonal
anti-CD52)Unknown GPA and MPA Complete or partial remission after
6 months; adverse eventNCT01405807
Evaluating whether alemtuzumab induces sustained remission in refractory patientsBIANCA-SC Blisibimod (selective
antagonist of BAFF)Not yetrecruiting
GPA and MPA Induction of clinical remission NCT01598857
Evaluate efficacy of blisibimod when taken with methotrexate to induce remissionBREVAS Belimumab (human
monoclonal anti-BAFF)Recruiting GPA and MPA Time to first relapse NCT01663623
Assessing efficacy of belimumab in maintenance of remission following a standard induction regimenCLASSIC CCX168 (C5a inhibitor) Recruiting GPA and MPA Safety and efficacy of two-dose
regimenNCT02222155
Studying the safety and efficacy of CCX168 for induction therapy (low versus high dose) with conventional therapyCLEAR CCX168 (C5a inhibitor) Recruiting GPA and MPA Safety (adverse events) and
efficacy (BVAS)NCT01363388
Studying the safety and efficacy of CCX168 versus placebo for induction therapy on a background of conventional therapyLoVAS Rituximab with
glucocorticoidsRecruiting GPA and MPA Remission induction NCT02198248
Comparing rituximab with low-dose glucocorticoids versus rituximab with high-dose glucocorticoidsMAINRITSAN-2 Rituximab (two strategies) Active, not
recruitingGPA and MPA Number of minor and major
relapsesNCT01731561
Assess efficacy of a rituximab regimen based on rate of ANCA and CD19 lymphocytes for maintenance of remissionPEXIVAS Plasma exchange Recruiting GPA and MPA All-cause mortality; end-stage
renal diseaseNCT00987389
Determining whether plasma exchange with immunosuppressive therapy are effective in reducing death and ESRDRAVELOS Rituximab (chimeric
monoclonal anti-CD20)Recruiting byinvitation
GPA and MPA Long-term safety and effects ofrituximab
NCT01586858
Following the patients included in the RAVE study to study long-term outcome after rituximab treatmentRITAZAREM Rituximab Recruiting GPA and MPA Time to first relapse NCT01697267Evaluating whether repeated rituximab will maintain remissionSCOUT Glucocorticoids and
rituximabRecruiting GPA and MPA Complete remission NCT02169219
Studying whether an 8-week course of glucocorticoids with rituximab is effective as remission inductionTAPIR Glucocorticoids Recruiting GPA Increase of the glucocorticoid
dose for disease relapseNCT01933724–NCT01940094
Evaluating the effects of low-dose glucocorticoids (5 mg/day) versus stopping completely in GPA in remission
J Am Soc Nephrol 26: 2314–2327, 2015 PR3-AAV versus MPO-AAV 2319
www.jasn.org BRIEF REVIEW
therapy with cyclophosphamide and cortico-
steroids) treated with rituximab for mainte-
nance of remission had a lower risk for relapse
compared with the conventional maintenance
therapy of azathioprine154 (Table 1). Whether
rituximab-based responses differ between pa-
tients with PR3-AAV and patients with MPO-
AAV is at present unknown.
Different new treatments in AAV are
currently being studied.155 Importantly, in
patients with more limited forms of AAV
(mainly limited GPA) remissions can be
achieved with methotrexate and possibly
abatacept (CTLA4-immunoglobulins).156
Also, for patients with refractory forms of
AAV, plasma exchange,157 intravenous im-
munoglobulins,158 deoxyspergualin,159 my-
cophenolate mofetil,160 alemtuzumab161
and/or mizoribine162 may be effective. Fur-
thermore, blocking complement activation
via C5a or its receptor, effective in animal
models, may be an appealing option.163,164
Besides exploring new treatment strate-
gies, many questions remain to be answered
with regard to the traditional treatment
regimens. One example is whether gluco-
corticoids need to bemaintained at low dose
when patients attain remission or whether
they need to be stopped completely. Another
question is how patients who never had a
relapse should be treated in the long-
term.165 Currently ongoing trials may pro-
vide answers to these essential questions
(Table 2).
Despite the differences between PR3-
AAVandMPO-AAV, treatment protocols are
the same (Figure 3).Nevertheless, because
patients with PR3-AAV relapse more fre-
quently, retreatment in these patients is
more common. In agreement with Furuta
and Jayne,166 we advocate segregating AAV
by ANCA serotype in future clinical trials as
opposed to by the disease type classifica-
tion.
New ClassificationThe differences in presentationwith regard to
PR3-AAV and MPO-AAV aided the develop-
ment of a cluster analysis of 673 patients with
AAV. This cluster analysis showed that GPA
and MPA are difficult to distinguish and that
their distinction is more subjective than the
distinction based on ANCA serotype.120,130
Based on clinical and outcome data, patients
with AAV can be clustered as nonrenal AAV
patients, renal PR3-ANCA–positive patients
and renal PR3-ANCA–negative patients.120
This cluster analysis supports a break-up
into PR3 and MPO-ANCA, rather than into
GPA and MPA. Also, based on the clear ge-
netic distinctions between ANCA serotypes,
categorization of patients based on ANCA
serotype is appealing. At present, however,
patients are still categorized according to a
clinical diagnosis.167 The difference of diag-
nosing GPA or MPA is based on, sometimes
subtle, clinical features and is less objective
Figure 3. Flow diagram for treatment in AAV. Evidence for every step is given as follows, linked to the symbols in the diagram. (A) Silvaet al.176 and Stassen et al.160 (B) NORAM trial173; (C) MEPEX trial171; (D) PEXIVAS trial (table 2); (E ) RAVE trial153 and RITUXVAS trial135; (F)LoVAS trial and RAVELOS study (table 2); (G) CYCLOPS trial169; (V) WEGENT trial174; (W) CYCAZAREM trial168; (X) IMPROVE trial170; (Y)MAINRITSAN154 (table 1), RITAZAREM and SCOUT trials (table 2); (Z) TAPIR trial (table 2).
2320 Journal of the American Society of Nephrology J Am Soc Nephrol 26: 2314–2327, 2015
BRIEF REVIEW www.jasn.org
when compared with a distinction by ANCA
serotype. With some evidence for a worse re-
nal and patient outcome for MPO-AAV
compared with PR3-AAV, there is increasing
support to categorize patients based on their
ANCA serotype. Finally, categorizing
patients by ANCA serotype instead of clinical
diagnosis may decrease a selection bias for
including patients in clinical trials.
Table 3. Similarities and differences between PR3-AAV and MPO-AAV with quality of evidence
Feature Evidence PR3-AAV MPO-AAV
Epidemiology♂/♀ ratio B Higher LowerGeographical distribution A More prevalent in northwestern Europe
and North AmericaMore prevalent in southern
Europe, Asia and the PacificIncidence 11.3/million/yr in UK and 3/
million/yr in SpainIncidence 5.9/million/yr in UK and
7.9/million/yr in SpainGeneticsHLA-DPB1 A More prevalent Less prevalentHLA-DQ B Less prevalent More prevalentPRTN3 B More prevalent Less prevalentCTLA-4 C Less prevalent More prevalentHLA-DRB*15 C More prevalent in African Americans Not prevalent
Renal histopathology C In both serotypes granuloma formation can be seenNormal glomeruli A More LessFibrosis C Less MoreElectron-dense deposits D Not differentImmunofluorescence C Less C3 deposition More C3 deposition
Clinical presentationAge at onset A Not differentOrgan involvement in general B More ear, nose, and throat involvement More renal-limitedPulmonary C Cavitating lesions Fibrosing lesionsAlveolar lung hemorrhage C More LessEar, nose, and throat B Necrotizing lesions PolypsNervous system C Similar frequencySkin C Not differentCardiac C Not differentOphthalmologic C More ophthalmologic involvement Less ophthalmologic involvement
Follow-upRelapse rate A Higher LowerPatient survival C Similar/better Similar/worseRenal survival C Similar/better Similar/worseInfection D Not differentCardiovascular C Fewer events More eventsVenous thromboembolism D Not differentMalignancies D Not differentTreatment C Not different
Etiology C S. aureusa Silica associateda
Low vitamin D levelsa
PathophysiologyIn vitro interaction of ANCAwith
neutrophilsD Not different
Endothelial cells D PR3 induces apoptosis of endothelial cell MPO induces production ofintracellular oxidants
Monocytes D PR3-ANCA induces release of sFlt1 bymonocytes
MPO-ANCA does not inducerelease of sFlt1
In vivo animal models D Less successful models, possibly due todifferent interaction of PR3 with NB1 inmice
Successful mouse and rat modelsresulting in vasculitis andnecrotizing crescentic GN
Quality of evidence was based on the GRADE system as follows: A, Further research is very unlikely to change our confidence in the estimate of effect; B, Furtherresearch is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; C, Further research is very likely to have animportant impact on our confidence in the estimate of effect and is likely to change the estimate; D, Any estimate of effect is very uncertain). GRADE, Grading ofRecommendations Assessment, Development and Evaluation.aThese etiologic factors remain speculative due to insufficient evidence.
J Am Soc Nephrol 26: 2314–2327, 2015 PR3-AAV versus MPO-AAV 2321
www.jasn.org BRIEF REVIEW
CONCLUSION
Evidence that PR3-AAV and MPO-AAVare two distinct diseases of one entity hasaccumulated since our review in 2000(Table 3). It remains, however, difficultto distinguish characteristic clinical dif-ferences, despite a clearly different ge-netic basis of both vasculitides. Whenconsidering genetic differences and clus-ter analyses data, it is appealing to breakup the ANCA-associated vasculitidesinto PR3-ANCA vasculitis and MPO-ANCA vasculitis. This discriminationmight prove of great significance in thescope of clinical trials and could aid thefurther improvement of treatment.
ACKNOWLEDGMENTS
We gratefully thank N. Bijnens, H. van Rie,
and P. Heerings-Rewinkel (Laboratory of
Clinical Immunology, Maastricht University
Medical Center, Maastricht) for assistance.
We also thank all participating nephrologists
of the Limburg Renal Registry: F. de Heer,
M.M.E. Krekels, and G.H. Verseput (Orbis
Medisch Centrum, Sittard); S. Boorsma, W.
Grave, and J.Wirtz (St. Laurentiusziekenhuis,
Roermond); W.E. Boer, L.A.M. Frenken, and
J. Wolters (Atrium Medisch Centrum, Heer-
len); and K.M.L. Leunissen, J.P.Kooman, and
F.M. van der Sande (Department of Internal
Medicine, Division of Nephrology, Maas-
tricht University Medical Center, Maas-
tricht). The authors thank the Dutch Kidney
Foundation for supporting M. Hilhorst and
J.W. Cohen Tervaert.
DISCLOSURESNone.
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J Am Soc Nephrol 26: 2314–2327, 2015 PR3-AAV versus MPO-AAV 2327
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