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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 Tervaert for the Limburg Renal Registry Clinical and Experimental Immunology, Maastricht University, Maastricht, The Netherlands ABSTRACT In patients with GN or vasculitis, ANCAs are directed against proteinase 3 (PR3) or myeloperoxidase (MPO). The differences between PR3-ANCA-associated vasculitis (AAV) and MPO-AAV described in the past have been supplemented during the last decade. In this review, we discuss the differences between these two small-vessel vasculitides, focusing especially on possible etiologic and pathophysiologic differ- ences. PR3-AAV is more common in northern parts of the world, whereas MPO-AAV is more common in southern regions of Europe, Asia, and the Pacic, with the exception 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 in patients 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 difcult 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. For future clinical trials, we advocate classifying patients by ANCA serotype as opposed to the traditional disease type classication. J Am Soc Nephrol 26: 23142327, 2015. doi: 10.1681/ASN.2014090903 ANCA were rst described more than 50 years ago. 1 Later, these antibodies were discovered in the context of GN 2 and vasculitis. 3 The discovery of these antibodies in granulomatosis with poly- angiitis (GPA; formerly known as Wegeners granulomatosis) marked a breakthrough in diagnostics, since GPA had been known for at least half a cen- tury without a serologic marker. 4,5 Sub- sequently, ANCA were found in two other forms of small-to-medium-vessel vasculitis, i.e., microscopic polyangiitis (MPA) 6 and eosinophilic GPA (formerly known as ChurgStrauss syndrome). 7 ANCA were traditionally tested with an immunouorescence test on xed neu- trophils. Three patterns can be found: cytoplasmic (cANCA), perinuclear (pANCA), and atypical. 8 ANCA, as detected by immunouorescence tech- niques, have been found in many differ- ent diseases. 9 In addition to detecting cANCA or pANCA by immunouorescence, a test to detect proteinase 3 (PR3)-ANCA or myeloperoxidase (MPO)-ANCA is mandatory for the diagnosis of ANCA- associated vasculitis (AAV). 8 In the case of GN and/or vasculitis, ANCA are almost always directed against PR3 or MPO, and PR3-ANCA and MPO-ANCA are specic for GPA and MPA. 8 The distinc- tion between GPA and MPA in the context of ANCA serotype is far from perfect 8,10 and underlines the discordance between disease categorization and ANCA sero- type categorization. Most patients are single-positive, meaning that only one ANCA serotype can be detected. 11 Many differences exist between patients with PR3-AAV and MPO-AAV, 12 16 which were highlighted in a review by Franssen et al. more than a decade ago. 17 Since then, more differences be- tween PR3-AAV and MPO-AAV have been discovered. The aim of the current review is to discuss differences between PR3-AAV and MPO-AAV in the light of the dis- coveries that took place during the last decade. 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, Wegeners 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 date available at www.jasn.org. Correspondence: Dr. Jan Willem Cohen Tervaert, Clinical and Experimental Immunology, Maas- tricht University, Universiteitssingel 40, PO Box 616, 6200MD Maastricht, The Netherlands. Email: jw.cohentervaert@maastrichtuniversity Copyright © 2015 by the American Society of Nephrology 2314 ISSN : 1046-6673/2610-2314 J Am Soc Nephrol 26: 23142327, 2015

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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

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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

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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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