Vasculitis
Vasculitis
Vasculitis
Keywords:
Vasculitis
Classication criteria
ANCA
MPA
GPA
EGPA
ANCA-associated vasculitis
Takayasus vasculitis
GCA
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
R. Waller et al. / Best Practice & Research Clinical Rheumatology 27 (2013) 317
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
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Table 2
Vasculitis terminology from 2012 CHCC used within this review [8,9].
Abbreviation
Denition
Previous terminology
GPA
EGPA
Wegeners granulomatosis
ChurgStrauss
MPA
IgA vasculitis
HenochSchonlein purpura
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
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
10
R. Waller et al. / Best Practice & Research Clinical Rheumatology 27 (2013) 317
Table 7
Revised CHCC 2012 nomenclature.
CHCC2012 Names
CHCC2012 Denitions
TAK
GCA
PAN
Kawasaki disease
MPA
GPA
EGPA
Anti-GBM disease
Cryoglobulinemic vasculitis
IgAV
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Table 7 (continued )
CHCC2012 Names
CHCC2012 Denitions
Hypocomplementemic urticarial
vasculitis (HUV) (Anti-C1q vasculitis)
Behets disease
Cogans syndrome
Lupus vasculitis
Rheumatoid vasculitis
Sarcoid vasculitis
Others
Vasculitis associated with probable aetiology
11
12
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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.
R. Waller et al. / Best Practice & Research Clinical Rheumatology 27 (2013) 317
13
Table 8
A comparison of the classication criteria or denitions used in pivotal vasculitis trials.
Study
Criteria used
Comments
CYCAZAREM [35]
CYCLOPS [36]
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
14
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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
III
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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