Best Practice & Research Clinical Rheumatology 27 (2013) 317

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Best Practice & Research Clinical

Rheumatology
journal homepage: www.elsevierhealth.com/berh

Update on the classication of vasculitis

Rosemary Waller, MBBS MRCP *, Azeem Ahmed, MB ChB 1,
Ishita Patel, MBBS MRCP MSc 1, Raashid Luqmani,
DM FRCP FRCP(E) 1
Department of Rheumatology, Nufeld Orthopaedic Centre, Windmill Road, Headington,
Oxford OX3 7HE, UK

Keywords:
Vasculitis
Classication criteria
ANCA
MPA
GPA
EGPA
ANCA-associated vasculitis
Takayasus vasculitis
GCA

Classication criteria have an important role and practical use in

everyday rheumatology. Improvement in therapy and our understanding of the aetiopathogenesis of vasculitis have driven the need to
have better descriptors and groupings of diseases. This in turn will allow
newer therapy and further understanding to have a greater impact.
The American College of Rheumatology (ACR) classication criteria
have been an important advance but have limitations. There remains confusion between classication and diagnostic criteria and
denitions. We hope to resolve this using evidence-based improvements in classication and diagnostic criteria. Further understanding of the underlying causative mechanisms could lead to
diagnostic testing, eliminating the need for classication criteria.
2012 Elsevier Ltd. All rights reserved.

Introduction
The vasculitides are an uncommon heterogeneous group of diseases that share the pathological
hallmark of blood vessel-wall inammation. The objective of classication criteria is to classify a specic patient into a standardised category for research with an aim to improve patient management [1].
Given the wide variability in the aetiology, pathological features, clinical expression, prevalence and
prognosis of these diseases the classication of vasculitis has proved problematic.
Zeek in 1952 was the rst to propose a classication for vasculitis [2]. She adopted the term of
necrotising angiitis and described ve distinct vasculitides from a review of the literature. These forms
included hypersensitivity angiitis, granulomatous allergic angiitis (recognisable as eosinophilic

* Corresponding author. Tel.: 44 01865 741155; fax: 44 01865 738058.

E-mail addresses: [email protected] (R. Waller), [email protected] (A. Ahmed), [email protected]
(I. Patel), [email protected] (R. Luqmani).
1
Tel.: 44 01865 741155; fax: 44 01865 738058.
1521-6942/$ see front matter 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.berh.2012.12.002

R. Waller et al. / Best Practice & Research Clinical Rheumatology 27 (2013) 317

granulomatosis with polyangiitis (EGPA)), rheumatic arteritis, periarteritis nodosa (polyarteritis

nodosa (PAN)) and temporal arteritis (GCA). Recognition of various other types of vasculitides,
including Takayasus arteritis (TAK) and granulomatosis with polyangiitis (GPA, Wegners granulomatosis), in subsequent years led to development of various other classication systems [37] as
outlined in Table 1. Through the years, these classication systems slowly built upon Zeeks criteria and
separated the vasculitides by distinct parameters including size of vessel involvement, histological
features and primary or secondary forms.
The most commonly used classication criteria within clinical trial research are adapted from the
American College of Rheumatology (ACR)-proposed criteria. The Chapel Hill Consensus Conference
(CHCC) nomenclature is also frequently used in studies. These are a set of denitions rather than
classication or diagnostic criteria but are often mistakenly used as such. These two systems are not
without their limitations and both are used incorrectly as diagnostic criteria, which was not their
primary design. There are no widely used diagnostic tools for vasculitis.
Within the scope of this review we will argue the need to update the classication criteria, particularly in light of our increased understanding of the underlying pathogenesis and improved diagnostic techniques. We will also outline the current international collaborative efforts underway which
are attempting to do this.
Throughout this review we have used the new denitions of vasculitis as outlined in the updated
2012 CHCC [8]. Eponyms have been replaced with suitable non-eponymous terminology. This terminology is summarised in Table 2. In particular CHCC 2012 adopted the recommendations of the ACR,
American Society of Nephrology (ASN) and European League Against Rheumatism (EULAR) to replace
Wegeners granulomatosis with granulomatosis with polyangiitis(GPA) [9]. ChurgStrauss syndrome
was replaced with the term eosinophilic granulomatosis with polyangiitis to provide continuity
within the anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis group. HenochSchnlein
purpura was replaced by the name IgA vasculitis (IgAV) based on the established acceptance and
evidence that the dening pathological feature is of abnormal IgA deposition in vessel walls.
Historical perspective
Why do we need classication criteria? Classication criteria aim to differentiate patients known to
have a form of vasculitis in order to create homogenous cohorts for clinical research. This prevents
heterogeneous patients being assessed for the same outcome and leading to erroneous conclusions.
One example of this was when Leib et al., in 1979 reported outcomes of 64 cases of PAN [10]. Patients
were treated with steroid and immunosuppressant, steroid alone or no treatment. They reported that
survival was signicantly increased in the combination group. Nine patients had renal biopsies. The
histology included patients with focal proliferative glomerulonephritis suggesting that most patients
actually had microscopic polyangiitis (MPA) or GPA. Forty-eight percent of patients also had eosinophilia and almost certainly some patients will have had EGPA, especially those accepted on clinical
grounds alone. Treatment strategies for ANCA-associated vasculitis are now different from PAN. In the
latter, corticosteroids and immunosuppressive agents can enhance viral replication if related to

Table 1
Summary of historical classication criteria [27].
Author(s)/date

Key points

Zeek, 1954

First classication system, and has served as the basis for all subsequent
classication systems
Similar scheme as Zeek, but GPA and IgAV added

Alaron-Segovia &
Brown, 1964
De Shazo, 1975
Gilliam & Smiley, 1976
Fauci et al., 1978
Lie, 1994

Similar to Zeek, with the addition of few subgroups

Better appreciation of the degree of overlap in size of vessels involved
between vasculitis subgroups
Kawasakis disease added to the vasculitis subtypes
Subdivisions into primary or secondary forms, as well as predominant
vessel size involvement

R. Waller et al. / Best Practice & Research Clinical Rheumatology 27 (2013) 317

Table 2
Vasculitis terminology from 2012 CHCC used within this review [8,9].
Abbreviation

Denition

Previous terminology

GPA
EGPA

Granulomatosis with polyangiitis

Eosinophilic granulomatosis with
polyangiitis
Microscopic polyangiitis
IgA vasculitis

Wegeners granulomatosis
ChurgStrauss

MPA
IgA vasculitis

HenochSchonlein purpura

Other new terminology and minor modications

Previous terminology

Anti-GBM disease
Cutaneous arteritis
Cutaneous leukocytoclastic angiitis
Hypocomplementemic urticarial vasculitis

Goodpastures disease
Cutaneous PAN

hepatitis B infection. The treatment of this group would include a short course of corticosteroids,
plasma exchange and antiretroviral therapy. Guillevin et al. attempted to dene clinical, radiological
and immunological characteristics of MPA and to separate them from PAN and EGPA [11]. Patients
presenting with microaneurysms or multiple-vessel stenosis did not have an ANCA. Skin involvement,
glomerulonephritis and the presence of ANCA were found to be signicantly more frequent in patients
with normal versus abnormal angiograms. Conversely, hypertension, renal vasculitis and hepatitis B
infection were signicantly more common in patients with abnormal angiograms. This highlighted the
potential value of ANCA as a positive predictor of MPA and a negative value predictive of PAN.
Current classication criteria
1990 American College of Rheumatology
In 1990, the ACR published a series of classication criteria for seven types of systemic vasculitis:
GCA, TAK, GPA, EGPA, PAN, IgAV and hypersensitivity vasculitis (HSV) [1218]. Rheumatologists from
48 centres submitted a total of 1020 cases. Patients with Kawasaki disease, insufcient evidence of
vasculitis and vasculitis secondary to connective-tissue disease were excluded. Patients within each of
the vasculitis subgroups were compared to the rest of the group. A total of 807 patients with vasculitis
were analysed looking for criteria to distinguish them from each other, with diagnosis made on the
basis of expert opinion. No prior denitions of vasculitis had been given to the experts. The criteria help
identify a homogeneous group for epidemiology studies and facilitate comparison between different
therapeutic strategies. The goals of the ACR committee were to provide a standard way to evaluate
patients in therapeutic and epidemiologic studies. The criteria were not intended to be used as diagnostic tools, but are often used as such. The sensitivity for the criteria ranged from 71.0% to 95.3% and
specicity 78.7%99.7%, with the most sensitive and specic criteria in EGPA, GCA and TAK. The positive predictive value of fullling any of the ACR criteria for diagnosis of vasculitis was low (1729%)
[19]. The ACR criteria were widely accepted and benecial for advancing the eld of vasculitis research.
However, they are not without their limitations (Table 3).
The ACR criteria do not include MPA or other primary vasculitides including cryoglobulinaemia,
Behets, relapsing polychondritis, primary central nervous system (CNS) vasculitis and Cogans syndrome. They were developed by determining clinical features that distinguished one form of vasculitis
over another. They therefore cannot be used to distinguish between vasculitis and other diseases. There
is considerable overlap between the criteria, meaning that patients can fall into more than one category
[19]. There is considerable heterogeneity within current groupings. They do not include information
about biochemical, pathological or radiological investigations.
The ACR classication was developed before the widespread use of ANCA testing. The different
forms of ANCA may help to differentiate between GPA, MPA and EGPA.
The sensitivity of ANCA varies according to the assay used and study design, including differences in
disease severity and treatment, with gures varying from 34% to 92%. There is also geographical

R. Waller et al. / Best Practice & Research Clinical Rheumatology 27 (2013) 317

Table 3
Summary of ACR criteria and their limitations [1218].
Type of Vasculitis

Sensitivity

Specicity

GCA

93.5%

91.2%

TAK

90.5%

97.8%

GPA

88.2%

EGPA

85%

92%
99.7%

PAN

82.2%

86.6%

IgAV

87.1%

87.7%

Hypersensitivity vasculitis
Microscopic polyangiitis

71%

83.9%

Limitations
Temporal artery biopsy is an important diagnostic
tool but is not an obligatory criterion.
Newer imaging modalities, such as CT PET maybe
useful, but are not included
No clear discrimination between GPA and MPA, or
other mimics of GPA. Does not incorporate ANCA test.
No inclusion of common features such as cardiac
manifestations and rash. Does not incorporate ANCA test.
No absolute requirement for arteriography, or biopsy
ndings. No clear discrimination between PAN and MPA.
Do not distinguish between IgAV from allergic reactions,
or infectious related purpura. Common features; arthritis
and nephritis are excluded. Age set as important criteria,
but almost 30% of patients were above the age of 20.
Difcult to distinguish from IgAV
Not recognized by ACR

variation in sensitivity. Optimal results for ANCA testing are from combined use of indirect immunouorescence and enzyme linked immunosorbent assay (ELISA). A meta-analysis of seven studies using
these techniques gave a weighted pooled sensitivity of 85.5% for myeloperoxidase antibodies on
ethanol-xed neutrophils (MPO-pANCA) and 98.6% for c-ANCA antigen specic for proteinase 3 (PR3cANCA) [20]. Specicity seems to be more consistent between studies. The absence of ANCA is also
useful diagnostically, particularly in differentiating PAN from MPA.
Radiological techniques have also advanced signicantly in the time since the ACR criteria were
developed. CT angiography (CTA) and magnetic resonance angiography (MRA) are less invasive than
conventional angiography and have similar sensitivity (95% and 100%, respectively) and specicity
levels (100%) when assessing for TAK [21,22]. Ultrasonography (US) may have a role in detecting mural
changes, particularly in early disease where CTA does not perform as well. US may also have an
important role in GCA, where the abnormal halo sign around arteries increases the likelihood of
disease and will therefore affect the pre-test probability of a temporal artery biopsy. Compared with
biopsy, it has a sensitivity of 69% and specicity of 82% [23,24]. The role of US is being further assessed
in a multicentre study, aiming to recruit 400 patients (TABUL (The Temporal Artery Biopsy vs. Ultrasound in diagnosis of Giant Cell Arteritis) study). Positron emission tomography scanning (PET) may
also prove useful in the diagnosis of large-vessel vasculitis, although its radiation dose is large, particularly when combined with CT.
Further examples of where imaging may have a role in diagnosis include PAN, where CTA and MRA
may detect medium-vessel aneurysms. Imaging can also be useful to guide biopsies and therefore
increase diagnostic yield, such as CT and MRI in GPA to visualise sinus inammation and destruction.
However, there is no consensus regarding the role of radiology in the diagnosis and management of
vasculitis and no widely acknowledged gold standard [25].
Paediatric vasculitis
In 2006, EULAR and the Paediatric Rheumatology European Society (PReS) produced consensus
criteria for the classication of childhood vasculitis [26]. Prior to the publication of these criteria, there
were no widely accepted paediatric vasculitis criteria, and paediatricians used adult guidelines. The
authors of the criteria acknowledged that there were forms of vasculitis such as Kawasaki that occurred
exclusively in childhood, other forms such as GCA that did not occur at all and others such as PAN and
GPA that had very different clinical features in children compared with adults. The guidelines were
intended to be used to aid research and the aim was that they would be easily applied and widely
accepted. The criteria are intended to classify those children in whom the diagnosis of primary vasculitis had already been made and not to differentiate vasculitis from mimicking conditions.

R. Waller et al. / Best Practice & Research Clinical Rheumatology 27 (2013) 317

The EULAR/PReS guidelines use vessel size to categorise vasculitis based on the CHCC denitions
(Table 4). The existing ACR criteria for different forms of adult vasculitis were then modied and are
outlined in Table 5.
The criteria have been validated using a retrospective and prospective web-based database of
children with primary vasculitis rst diagnosed before the age of 18 [27,28]. A total of 1398 children
were enrolled. An expert consensus panel, who were blinded to the primary physician diagnosis,
classied a representative sample of 280 of the cases. Sensitivity ranges from 89.6%to 100% and specicity ranges from 87% to 99.9% for the classication of vasculitis (Table 6).
Current denitions of the vasculitides
Chapel Hill Consensus Conference CHCC Nomenclature (1994)
In 1994, a group of experts convened at the CHCC with the goal of determining names and denitions for
the common systemic vasculitides, with efforts made to use already widely accepted terms [1]. The proposed nomenclature aimed to standardise the naming and denitions of the subtypes of primary vasculitides. This was as a reection of the ACR criteria, where the categorisation of patients had been determined
by physician judgement; however, the clinicians giving their judgement had not been provided with a strict
uniform denition for each vasculitis subtype. The panel of multidisciplinary experts emphasised that their
objectives were not to determine the classication of vasculitis, nor to provide diagnostic criteria.
Ten vasculitis syndromes were dened using clinical and histological criteria and these were
grouped according to vessel size. The large-vessel vasculitis group was composed of GCA and TAK. The
CHCC group recognised that age was a useful differentiating feature between the two.
The CHCC, unlike the ACR criteria, recognised MPA as a distinct entity. The CHCC denitions, in
particular, addressed the differences between classical PAN and MPA. The distinguishing features
suggested were the absence of a vasculitis affecting arterioles, venules or capillaries and glomerulonephritis in PAN but small- and medium-vessel involvement with necrotising glomerulonephritis
in MPA. Furthermore, MPA was also dened as a distinguishable disease to GPA.
The CHCC incorporated ANCA testing into their denitions in contrast to the ACR criteria. However,
there is now a better understanding of the role of ANCA in aetiology, pathogenesis and disease prognosis,
even within the ANCA-associated vasculitis subgroups. This is not clearly appreciable in CHCC, where
ANCA is only used as a distinguishing feature between these diseases and other forms of vasculitis.

Table 4
EULAR/Pres classication of childhood vasculitis.
Vessel size

Vasculitis subtypes

Large
Medium

TAK
Childhood PAN
Cutaneous Polyarteritis
Kawasaki disease
Granulomatous
GPA
EGPA
Non-granulomatous
MPA
IgA vasculitis
Isolated cutaneous leucocytoclastic vasculitis
Hypocomplementaemic urticarial vasculitis
Behcets disease
Secondary vasculitis
Vasculitis associated with connective tissue diseases
Isolated vasculitis of the central nervous system
Cogan syndrome
Unclassied

Small

Other

Reproduced from [Ann Rheum Dis, Ozen S, Ruperto N, Dillon et al., 65, 936941, 2006] with
permission from BMJ Publishing Group Ltd.

R. Waller et al. / Best Practice & Research Clinical Rheumatology 27 (2013) 317

Table 5
Classication criteria for childhood vasculitis.
Class of vasculitis

Classication criteria

IgAV

Palpable purpura mandatory plus 1 of:

 Diffuse abdominal pain
 Biopsy showing predominant IgA deposition
 Arthritis or arthralgia
 Renal involvement (proteinuria or haematuria)
Fever for ve days mandatory plus 4 of:
 Changes in peripheries or perineal area
 Polymorphous exanthema
 Bilateral conjunctival injection
 Injection of oral and pharyngeal mucosa
 Cervical lymphadenopathy
Systemic illness with a biopsy showing small and medium-vessel
necrotising vasculitis or angiographic evidence of aneurysms or
occlusions mandatory plus 2 of:
 Skin involvement (livedo
reticularis, tender subcutaneous
nodules, other vasculitic lesions)
 Myalgia or muscle tenderness
 Systemic hypertension
 Mono- or polyneuropathy
 Abnormal urinalysis or GFR less than 50% normal
 Testicular pain or tenderness
 Signs or symptoms of vasculitis in another major organ
(GI, cardiac, pulmonary or CNS)
 Cutaneous Polyarteritis as outlined above
 No systemic involvement (except myalgia, arthralgia
and non erosive arthritis)
 Skin biopsy showing necrotising non-granulomatous vasculitis
 Negative ANCA
 Evidence of streptococcal infection
3 from:
 Haematuria or proteinuria
 Granulomatous inammation on biopsy
 Nasal sinus inammation
 Subglottic, tracheal or endobronchial stenosis
 Abnormal chest XR or CT
 PR3 ANCA or c-ANCA staining
Angiographic abnormalities of aorta or its main branches
mandatory plus 1 of:
 Decreased peripheral artery
pulses or claudication of extremities
 Blood pressure difference of >10 mmHg
 Bruits over aorta or its major branches
 Hypertension

Kawasaki disease

Childhood PAN

Cutaneous polyarteritis

GPA

TAK

Reproduced from [Ann Rheum Dis, Ozen S, Ruperto N, Dillon et al., 65, 936941, 2006] with permission from BMJ Publishing
Group Ltd.

Table 6
Sensitivity and specicity of the EULAR/PRINTO/PRES vasculitis criteria for paediatric vasculitis.
Vasculitis type

Sensitivity%

Specicity%

Area under
curve%

IgAV
PAN
GPA
TAK

100
89.6
93.3
100

87
99.6
99.2
99.9

93.5
94.6
96.3
99.9

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A limitation of the CHCC criteria is that the denitions are based on histological criteria. In practice,
gaining histology may not be feasible and the diagnostic yield is highly variable depending on the site
of biopsy and phase of disease. For example, in GPA nasal and sinus biopsies are easily obtainable, but
only 20% and 50% respectively contribute to the diagnosis [29,30]. These ear, nose, throat (ENT) biopsies
are often more useful to exclude malignancy and chronic infection. In contrast, renal biopsy in GPA has
better yield and can be prognostically benecial. Furthermore, there is a degree of overlap in the
histological features. EGPA is dened as an eosinophil-rich and granulomatous inammation involving
the respiratory tract; however, eosinophils may be present in GPA and MPA. It is now better appreciated that early diagnosis and treatment of vasculitis is essential to reduce mortality and morbidity,
and therefore with more convenient, less invasive tests available, such as ANCA and imaging modalities, histology is not always necessary to make a diagnosis.
There have been efforts to use the CHCC nomenclature system as a diagnostic criterion by some [31].
The CHCC denitions with additional surrogate clinical, radiological or biological markers where
histology was unavailable were used to re-dene the diagnosis in 97 patients with an established
primary vasculitis. However, this system failed to differentiate between GPA and MPA in particular,
with only 8 out of 27 patients diagnosed as GPA and 3 out of 12 as MPA.
Updated CHCC 2012 nomenclature
Recently the International CHCC convened again to improve upon the 1994 nomenclature. The goals
were to update names and denitions as appropriate and justied and to add categories of vasculitis
previously not included [8]. The authors re-emphasised that the denitions were not classication or
diagnostic criteria but should provide a framework for validating such criteria. The updated denitions
utilise the improved understanding of the aetiology, pathogenesis, demographics and clinical features
of subtypes (Table 7).
A notable difference within this update is with regard to the denition of PAN, which now includes
a negative ANCA in its denition, helping to clearly distinguish it from MPA. The greatest change in
nomenclature has been within the predominant small-vessel vasculitides group, with subdivision into
those with a paucity of vessel-wall immunoglobulin (ANCA-associated vasculitides), and those with
prominent vessel-wall immunoglobulin (immune complex small-vessel vasculitides). Additionally
anti-glomerular basement membrane disease and hypocomplementaemic urticarial vasculitis have
now been incorporated.
The denitions for the three ANCA-associated vasculitides for the most part remain similar to the
1994 CHCC. The denition of MPA has been rened with the addition of the statement granulomatous
inammation is absent, presumably to help differentiate the respiratory tract involvement in MPA
compared with GPA. Limited GPA has been recognised in the updated CHCC 2012, and it is suggested that
where there is good evidence of clinical and pathological features of GPA conned to the respiratory
tract, especially if associated with a positive ANCA result, they should be dened within this category.
The 2012 CHCC has incorporated other vasculitides now well recognised and includes denitions
for Behets disease and Cogans syndrome. Furthermore, there has been effort made towards incorporating and recognising other single-organ disease and secondary vasculitides, which are incorporated under the denitions of vasculitis associated with systemic disease and vasculitis associated
with probable aetiology.
Application of current classication criteria and denitions
Watts et al. [32] developed an algorithm for the purpose of categorising patients with GPA, MPA,
EGPA and PAN for epidemiological studies in 2006. It was intended for use in patients in whom the
primary diagnosis of vasculitis had already been made and not to diagnose or classify individual patients. The algorithm combined the ACR and 1994 CHCC tools, included ANCA testing and other surrogate markers such as radiographic evidence of xed pulmonary inltrates, nodules or cavitations
present for more than 1 month as symptoms suggestive of granulomatous disease. It also incorporates
Lanhams criteria for EGPA. These criteria were developed from a case series of 16 patients combined
with a literature review [33]. The authors suggested that typical clinical features could be used to

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Table 7
Revised CHCC 2012 nomenclature.
CHCC2012 Names

CHCC2012 Denitions

Large vessel vasculitis (LVV)

Vasculitis affecting large arteries more often than other vasculitides.

Large arteries are the aorta and its major branches. Any size
artery may be affected.
Arteritis, often granulomatous, predominantly affecting the aorta
and/or its major branches. Onset usually in patients younger
than 50.
Arteritis, often granulomatous, usually affecting the aorta and/or
its major branches of the carotid and vertebral arteries. Often
involves the temporal artery. Onset usually in patients older
than 50 and often associated with polymyalgia rheumatic.
Vasculitis predominantly affecting medium arteries dened as
the main visceral arteries and their branches. Any size artery may
be affected. Inammatory aneurysms and stenoses are common
Necrotizing arteritis of medium or small arteries without
glomerulonephritis or vasculitis in arterioles, capillaries, or
venules; and not associated with ANCA
Arteritis associated with the mucocutaneous lymph node
syndrome and predominantly affecting medium and small arteries.
Coronary arteries are often involved. Aorta and large arteries
may be involved. Usually occurs in infants and young children
Vasculitis predominantly affecting small vessels, dened as small
intraparencyhmal arteries, arterioles, capillaries and venules.
Medium arteries and veins may be affected
Necrotizing vasculitis, with few or no immune deposits,
predominantly affecting small vessels (i.e. capillaries, venules,
arterioles and small arteries), associated with MPO-ANCA or
PR3-ANCA. Not all patients have ANCA. Add a prex indicating
ANCA reactivity, e.g. PR3-ANCA, MPO-ANCA, ANCA negative
Necrotizing vasculitis, with few or no immune deposits,
predominantly affecting small vessels i.e. capillaries, venules, or
arterioles). Necrotizing arteritis involving small and medium
arteries may be present. Necrotizing glomerulonephritis is very
common. Pulmonary capillaritis often occurs. Granulomatous
inammation is absent.
Necrotizing granulomatous inammation usually involving the
upper and lower respiratory tract, and necrotizing vasculitis
affecting predominantly small to medium vessels (e.g., capillaries,
venules, arterioles, arteries and veins). Necrotizing
glomerulonephritis is common.
Eosinophil-rich and necrotizing granulomatous inammation
often involving the respiratory tract, and necrotizing vasculitis
predominantly affecting small to medium vessels, and associated
with asthma and eosinophilia. ANCA is more frequent when
glomerulonephritis is present.
Vasculitis with moderate to marked vessel wall deposits of
immunoglobulin and/or complement components predominantly
affecting small vessels (i.e., capillaries, venules, arterioles and
small arteries). Glomerulonephritis is frequent.
Vasculitis affecting glomerular capillaries, pulmonary capillaries,
or both, with basement membrane deposition of anti-basement
membrane autoantibodies. Lung involvement causes pulmonary
haemorrhage, and renal involvement causes glomerulonephritis
with necrosis and crescents.
Vasculitis with cryoglobulin immune deposits affecting small
vessels (predominantly capillaries, venules, or arterioles) and
associated with cryoglobulins in serum. Skin, glomeruli and
peripheral nerves are often involved.
Vasculitis, with IgA1-dominant immune deposits, affecting small
vessels (predominantly capillaries, venules, or arterioles). Often
involves skin and gastrointestinal tract, and frequently causes
arthritis. Glomerulonephritis indistinguishable from IgA
nephropathy may occur.

TAK

GCA

Medium vessel vasculitis (MVV)

PAN

Kawasaki disease

Small vessel vasculitis (SVV)

ANCA associated vasculitis

MPA

GPA

EGPA

Immune complex vasculitis

Anti-GBM disease

Cryoglobulinemic vasculitis

IgAV

R. Waller et al. / Best Practice & Research Clinical Rheumatology 27 (2013) 317
Table 7 (continued )
CHCC2012 Names

CHCC2012 Denitions

Hypocomplementemic urticarial
vasculitis (HUV) (Anti-C1q vasculitis)

Vasculitis accompanied by urticaria and hypocomplementemia

affecting small vessels (i.e., capillaries, venules, or arterioles),
and associated with anti-C1q antibodies. Glomerulonephritis,
arthritis, obstructive pulmonary disease, and ocular
inammation are common.
Vasculitis with no predominant type of vessel involved that can
affect vessels of any size (small, medium, and large) and type
(arteries, veins, and capillaries).
Vasculitis occurring in patients with Behets disease that can
affect arteries or veins. Behets disease is characterized by
recurrent oral and/or genital aphthous ulcers accompanied by
cutaneous, ocular, articular, gastrointestinal, and/or central
nervous system inammatory lesions. Small vessel vasculitis,
thromboangiitis, thrombosis, arteritis and arterial aneurysms
may occur.
Vasculitis occurring in patients with Cogans syndrome. Cogans
syndrome is characterized by ocular inammatory lesions,
including interstitial keratitis, uveitis, and episcleritis, and inner
ear disease, including sensorineural hearing loss and vestibular
dysfunction. Vasculitic manifestations may include arteritis
(affecting small, medium or large arteries), aortitis, aortic
aneurysms, and aortic and mitral valvulitis.
Vasculitis in arteries or veins of any size in a single organ that
has no features that indicate that it is a limited expression of a
systemic vasculitis. The involved organ and vessel type should
be included in the name (e.g. cutaneous small vessel vasculitis,
testicular arteritis, central nervous system vasculitis). Vasculitis
distribution may be unifocal or multifocal (diffuse) within an
organ. Some patients originally diagnosed with SOV will develop
additional disease manifestations that warrant re-dening the
case as one of the systemic vasculitides (e.g. cutaneous arteritis
later becoming systemic polyarteritis nodosa, etc.).

Variable vessel vasculitis (VVV)

Behets disease

Cogans syndrome

Single organ vasculitis (SOV)

Cutaneous leukocyotoclastic angiitis

Cutaneous arteritis
Primary CNS vasculitis
Isolated aortitis
Others
Vasculitis associated with systemic disease

Lupus vasculitis
Rheumatoid vasculitis
Sarcoid vasculitis
Others
Vasculitis associated with probable aetiology

Hepatitis C virus-associated cryoglobulinemic

vasculitis
Hepatitis B virus-associated vasculitis
Syphilis associated aortitis
Drug induced immune complex vasculitis
Drug associated ANCA associated vasculitis
Cancer associated vasculitis
Other

Vasculitis that is associated with and may be secondary to

(caused by) a systemic disease. The name (diagnosis) should have
a prex term specifying the systemic disease (e.g. rheumatoid
vasculitis, lupus vasculitis, etc.).

Vasculitis that is associated with a probable specic aetiology.

The name (diagnosis) should have a prex term specifying the
association (e.g. hydralazine-associated microscopic polyangiitis,
hepatitis B virus-associated vasculitis, hepatitis C virus-associated
cryoglobulinemic vasculitis, etc.).

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dene EGPA more usefully than pathological features, which were often not fully present and may
therefore result in the under-recognition of EGPA. The clinical criteria were asthma, peak peripheral
blood eosinophil count >1.5  106/cc and systemic vasculitis involving two or more extrapulmonary
organs.
Watts et al. used consensus methodology to draw up the algorithm and a stepwise classication tool
was developed. The patients included already had a clinical diagnosis of ANCA-associated vasculitis or
PAN made with other alternative causes excluded. They were then assessed using the algorithm as
outlined in Fig. 1. The algorithm was validated using a three-step process. It was initially tested on 99
patients from a single centre who had been previously been well dened. It was then trialled by each
author on 20 of their own patients, with minor modications. The modied algorithm was tested on 80
paper cases. The two lead authors classied each of the paper cases and this was the comparator
diagnosis used. There was overall a 91.5% agreement between the assessors and the comparator
diagnosis.
Linder et al. [34] compared ACR, CHCC and Srensen denitions for GPA and MPA with an articial
neural network (ANN). A software tool is used to input data and the output variables are GPA or MPA.
The outcomes are learned during the training of the network. The system attempts to minimise errors
by adjusting the input weighting according to a learning algorithm. The ANN achieved an accuracy of
94.3% based on four measurements: involvement of nose, sinus, ear and pulmonary nodules to distinguish between GPA and MPA based solely on these clinical data. The ANN is a promising tool used to
estimate prognosis and survival and may offer exciting prospects in the classication of vasculitides in
the future.

Fig. 1. Watts et al. classication algorithm. Reproduced from [Annals Rheumatic Diseases, Watts R, Lane S, Hanslik T et al., 66, 222
227, 2007] with permission from BMJ Publishing Group Ltd.

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13

The need for updated criteria

Without treatment, several forms of primary vasculitis can be rapidly fatal. Early and accurate
diagnosis is important, both in terms of distinguishing vasculitis from conditions with similar presentations and in terms of subtyping the vasculitis. Given the relative rarity of primary vasculitis and
the often non-specic initial symptoms, early diagnosis can prove difcult. These difculties are
compounded by the lack of an agreed gold standard diagnostic test. The current classication criteria
were not intended to be used as diagnostic tools but were designed to produce homogeneous patient
sets for research. Redeveloping classication and forthcoming diagnostic criteria would aid early
diagnosis and facilitate the multicentre collaborative research approach that is necessary for uncommon conditions such as vasculitis.
Review of recent trials in vasculitis illustrates some of the issues with current criteria. These trials
have largely classied ANCA-associated vasculitis as one group [3541]. These different diseases have
variable pathologies, organ involvement, treatment options and prognosis. In addition, the different
diagnostic, disease denition and eligibility criteria used in each trial make direct comparison of these
studies difcult (Table 8). For example, in the WGET (Wegeners Granulomatosis Etanercept Trial) trial,
only GPA was studied and the ACR criteria were applied [42]. This is in contrast to the majority of the
European Vasculitis Study Group (EUVAS) trials, which used CHCC denitions and patients with all
three subtypes of ANCA-associated vasculitides. The CYCAZAREM group reported a 15% relapse rate
compared to 57% in the WGET trial [35]. Thirty-nine percent of the patients had MPA in the CYCAZAREM study compared with none in the WGET trial and MPA is less likely to relapse than GPA. It is
difcult to therefore interpret whether it was the differences in study population demographics or
differences in treatment regimes that explain the differing relapse rates.
An international multidisciplinary working group discussed the issues and shortcomings of the current
criteria [25]. It was agreed that new criteria required development to take account of our improved understanding of aetiology and pathology, ANCA testing, newer biomarkers and improved imaging. A total of
17 points for consideration were generated by this working group for use in developing updated criteria
(Table 9). They concluded that there was a clear need to update the current classication criteria and that
their points for consideration should be used as a starting point for this update.
Future aspirations for the classication and diagnosis of vasculitis
Diagnosis and classication of vasculitis study
Diagnosis and Classication of Vasculitis (DCVAS) is a multicentre international collaboration aiming
to develop a single classication and diagnostic criteria using data-driven methods [43,44]. A total of 75
international centres are aiming to recruit 2000 patients with vasculitis and 1500 patients with vasculitis
mimics. The clinical, serological, pathological and radiological features of each patient that were used to

Table 8
A comparison of the classication criteria or denitions used in pivotal vasculitis trials.
Study

Criteria used

Comments

CYCAZAREM [35]

Adapted from CHCC 1994

CYCLOPS [36]

Adapted from CHCC 1994

IMPROVE [37]
MEPEX [38]
NORAM [39]
RAVE [40]
RITUXVAS [41]

CHCC 1994
Adapted from CHCC 1994
CHCC 1994
CHCC 1994
Adapted from CHCC 1994

WGET [42]

Modied ACR

Patients had a diagnosis of MPA, GPA or

renal-limited vasculitis
Patients had a diagnosis of MPA, GPA or
renal-limited microscopic polyangiitis
Patients had a diagnosis of MPA or GPA
Patients had a diagnosis of MPA or GPA
Patients had a diagnosis of MPA or GPA
Patients had a diagnosis of MPA or GPA
New diagnosis of GPA, MPA or renal
limited vasculitis and positive renal biopsy/red
cell casts on urine microscopy and ANCA positivity
GPA patients only

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Table 9
Points to consider in the development of classication criteria and denitions in the systemic vasculitides.

Biopsy

Laboratory testing

Diagnostic radiology

Nosology

Denitions
Research agenda

Statement

Level of
evidence

Although histology is fundamental to the diagnosis of vasculitis and

exclusion of its mimics, biopsy of affected organs is not always possible
and yields vary signicantly according to conditions and target organs
TAB is an important tool in the diagnosis of GCA
Cases of IgA vasculitis usually have Ig A deposits present on biopsy
ANCA testing plays an important role in suspected small vessel vasculitis
In suspected PAN, the absence of ANCA has diagnostic value
The role of clinical features and additional surrogate biomarkers for
vasculitis is likely to have an important role in the development of
future diagnostic criteria
CT and MRA techniques can replace standard angiography in the
diagnosis of TAK
Ultrasound and high resolution MRI may have a role in the diagnosis of GCA

III

The role of abdominal angiography in the diagnosis of adult PAN is unclear

CT and MRI may be useful in diagnosing ENT involvement associated
with GPA/EGPA
The role of radiology in the diagnosis of CNS vasculitis is unclear
The nomenclature in use for distinguishing between disease denitions,
classication and diagnostic criteria is confusing and should be claried
wherever possible.
Nosology of different forms of vasculitis should be a reection of the
aetiopathogenesis wherever this has been determined. In the absence of
this, denitions must rely on a clear accurate description of the salient
features of the condition.
The use of eponyms should be reviewed if a more rational approach to
nomenclature can be developed, based on aetiopathogenesis, but their
retention is necessary at present to avoid confusion
Age is worthy of inclusion in the denitions of some forms of vasculitis,
but its role should not be overstated
Future criteria initiatives should include all forms of vasculitis, providing
denitions of less common syndromes not covered by CHCC
The development of a classication tree will provide the foundations to
future criteria

Ia
IIb
Ia
IIa
IV

IIa
US Ia/
MRI IIa
III
III
III
IV

IV

IV

III
IV
IV

Reproduced from [Annals Rheum Dis, Basu N, Watts R, Bajema I, 69, 17441740, 2010] with permission from BMJ Publishing
Group Ltd.

make the diagnosis of vasculitis will undergo multivariate analysis to determine which features are key
both in discriminating vasculitis from similar conditions and also in discriminating between different
subtypes of vasculitis. An expert consensus group will categorise the cases collected and determine the
important components of each disease entity. To date, over 1600 patients have been recruited.
Genome-wide association study
Lyons et al. [45] performed a genome-wide association study (GWAS) in patients with ANCAassociated vasculitis. Major histocompatibility complex (MHC) and non-MHC associations were
associated with GPA and MPA to suggest distinct genetic entities. Anti-PR3 ANCA was associated with
human leucocyte antigen-DP (HLA-DP) and the genes encoding a1 antitrypsin (SERPINA1) and proteinase 3 (PRTN3). Anti-MPO ANCA was associated with HLA-DQ. The genetic associations were aligned
with ANCA specicity rather than clinically dened syndrome GPA or MPA. These genetic markers may
provide a rationale in the future for devising antigen-specic therapeutic strategies.
Predictive markers
A recent study by McKinney et al. [46] demonstrated that in patients with ANCA-associated vasculitis, genes in the interleukin 17 receptor pathway, T cell receptor signalling and genes expressed by

R. Waller et al. / Best Practice & Research Clinical Rheumatology 27 (2013) 317

15

memory T cells correlate with increased relapse rates. These ndings suggest markers such as these,
which are predictive of subsequent relapses, may allow us in the future to identify patients who are
likely to have poorer prognosis at the outset, and so enable individualised therapy. These data are still
preliminary, but efforts such as these may result in discovery of an array of biomarkers that will not
only allow us to diagnose vasculitis earlier, but may even allow us to prevent future disease.
Conclusion
This review has outlined the classication criteria and denitions currently used in the assessment
of vasculitis. These are used to both differentiate between primary vasculitis and other inammatory
conditions and to further categorise patients with vasculitis, although none were developed to be used
as such. We have highlighted the need for these criteria to be updated in light of developments in our
understanding of the pathogenesis of vasculitis and improved diagnostic techniques. In view of
increased treatment options that are improving morbidity and mortality outcomes, it is essential that
tools are developed to enable accurate and early diagnosis of these potentially fatal diseases. Future
studies, as well as further development of genetic testing and recognition of biomarkers, will hopefully
enable accurate and unied classication criteria in vasculitis to be developed.

Practice points
 Classication criteria are intended to create homogeneous patient groups for research and
not to diagnose individual patients.
 Classication criteria continue to be misused as diagnostic criteria both in practice and in
publications, thereby further adding to the confusion.
 Separating large-, medium- and small-vessel vasculitis does provide more homogeneous
groups for clinical studies and is increasingly important as we develop more potent but more
focussed therapy.
 The ACR classication criteria are currently most widely used but do not recognise MPA.
 Improved diagnostics including ANCA testing and imaging would argue in favour of an
updating of existing classication criteria.
 The CHCC denitions are based largely on pathological features. They have been recently
updated to include new denitions and exclude eponymous terms.

Research agenda
 Dening subtypes within each form of vasculitis according to likely severity and treatment
requirement.
 Studies are currently underway to develop diagnostic criteria that are able to differentiate
vasculitis from its mimics and to discriminate one form of vasculitis from another.
 Improved knowledge provided by GWAS and other genetic and genomic studies to further
characterise the clinical subgroups of vasculitis.

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