Best Practice & Research Clinical Rheumatology: Richard A. Watts, Joanna Robson

Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
Contents lists available at ScienceDirect
Best Practice & Research Clinical

Rheumatology
journal homepage: www.elsevierhealth.com/berh
Introduction, epidemiology and classification of

vasculitis
Richard A. Watts a, b, *, Joanna Robson c
a
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford,
Oxford, UK
b
Norwich Medical School, University of East Anglia, Norwich, UK
c
Faculty of Health and Applied Sciences, University of the West of England, University Hospitals Bristol NHS
Trust, Bristol, UK
a b s t r a c t
Keywords:
Vasculitis Classification of the vasculitides has been traditionally based on
Epidemiology vessel size. The American College of Rheumatology (ACR) criteria
Classification criteria were developed in the 1980s and published in 1990 before the
Diagnostic criteria development of ANCA testing and modern imaging techniques
ANCA such as MRI and PET scanning, and therefore, these criteria are not
fit for use in 2010s. The Chapel Hill Consensus Conference pro-
vided a framework for defining various types of vasculitis. In the
next two years, new classification criteria will be published from
the DCVAS study, which will provide a modern system for the
classification of vasculitis for clinical studies.
The epidemiology of vasculitides is increasingly well studied;
however, there remain gaps in our knowledge of the occurrence of
vasculitis in many populations, especially from the third world or
those with health care systems that do not permit ready collection
of accurate epidemiological data. Giant cell arteritis presents in the
elderly and those of Northern European ancestry; ANCA-associated
vasculitis appears to have a consistent overall occurrence, but
there are differences in the occurrence of MPO and PR3 vasculitis
between populations. Kawasaki disease occurs most commonly in
Asian populations, especially Japanese, and in those aged less than
5 years. It is currently the most common cause of acquired cardiac
disease in those populations.
© 2018 Elsevier Ltd. All rights reserved.
* Corresponding author. Norwich Medical School, University of East Anglia, Norwich, UK.
E-mail addresses: Richard.watts@ipswichhospital.nhs.uk (R.A. Watts), jo.robson@uwe.ac.uk (J. Robson).
https://doi.org/10.1016/j.berh.2018.10.003
1521-6942/© 2018 Elsevier Ltd. All rights reserved.
Please cite this article as: Watts RA, Robson J, Introduction, epidemiology and classification of vasculitis,
Best Practice & Research Clinical Rheumatology, https://doi.org/10.1016/j.berh.2018.10.003
2 R.A. Watts, J. Robson / Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx
Abbreviations
ACR American College of Rheumatology

ANCA Anti-neutrophil Cytoplasmic Antibody
BD Behçet's Disease
CHCC Chapel Hill Consensus Conference
CPRD Clinical Practice Research Datalink
DCVAS Diagnostic and Classification Criteria in Vasculitis study
EGPA Eosinophilic granulomatosis with polyangiitis
EULAR European League Against Rheumatism
FVSG French Vasculitis Study Group
GCA Giant Cell Arteritis
GPA Granulomatosis with polyangiitis
GWAS Genome-wide association study
LVV Large Vessel Vasculitis
MPA Microscopic Polyangiitis
MPO Myeloperoxidase
MRI Magnetic Resonance Imaging
PAN Polyarteritis Nodosa
PET Positron Emission Tomography
PRES Paediatric Rheumatology European Society
PRINTO Paediatric Rheumatology International Trials Organization
PR3 Proteinase 3
SOV Single-organ vasculitis
TAK Takayasu Arteritis
VCRC Vasculitis Clinical Research Consortium
Introduction
Systemic vasculitides are multi-system disorders of blood vessels, defined by the size of the vessel
they predominantly affect, namely, small, medium or large, or variable vessel size (Table 1). The Chapel
Hill International Consensus Conference (CHCC) of 1994 and 2012 defined and standardised the
nomenclature of systemic vasculitides [1,2]. Disease definitions have also been clarified, for example,
the distinction between polyarteritis nodosa (PAN) and microscopic polyangiitis (MPA) based on vessel
size involvement; MPA is characterised by vasculitis of small-sized arteries, for example, in the kidneys,
thus causing rapidly progressive glomerulonephritis, whereas PAN typically has medium-vessel
involvement of the kidney, thereby resulting in renal infarcts. There has also been a shift to the use
of pathophysiological descriptions rather than eponyms, for example, granulomatosis with polyangiitis
(GPA) rather than Wegener's granulomatosis [1,2].
In defining vessel size, the term ‘large vessel’ relates to the aorta and its major branches, ‘medium
vessel’ refers to the main visceral arteries and veins and their initial branches and ‘small vessel’ refers to
arterioles, capillaries, intraparenchymal arteries, venules and some veins. There is, however, some
overlap, and artery of any size can potentially be involved in any case of the three main categories of
dominant vessel pattern involvement [2]. In addition to the multi-organ systemic vasculitides, other
forms of vasculitis have also been defined, including single-organ vasculitis (SOV) (including cutaneous
arteritis, primary central nervous system vasculitis and isolated aortitis); vasculitis associated with
systemic disease (including rheumatoid vasculitis, lupus vasculitis and sarcoid vasculitis) and vasculitis
associated with an underlying cause (including Hepatitis B, Hepatitis C-associated cryoglobulinaemia,
cancer, and drug related) [2]. In addition to providing a standardised system of nomenclature, the CHCC
also agreed definitions for different forms of vasculitis, including detailed pathophysiological de-
scriptions for each type of systemic vasculitis [2]. The CHCC is, however, a nomenclature system rather
than a classification system and represents expert consensus rather than being data driven [2]. An
R.A. Watts, J. Robson / Best Practice & Research Clinical Rheumatology xxx (xxxx) xxx 3
Table 1
Nomenclature of the Systemic Vasculitides defined during the 2012 International Chapel Hill Consensus Conference [1].
Systemic Vasculitides
Small-vessel vasculitis (SVV)

Anti-neutrophil cytoplasmic antibody (ANCA)eassociated vasculitis (AAV)
Microscopic polyangiitis (MPA)
Granulomatosis with polyangiitis (Wegener's) (GPA)
Eosinophilic granulomatosis with polyangiitis (ChurgeStrauss) (EGPA)
Immune complex SVV
Anti-glomerular basement membrane (anti-GBM) disease
Cryoglobulinaemic vasculitis (CV)
IgA vasculitis (HenocheSchonlein) (IgAV)
Hypocomplementaemic urticarial vasculitis (HUV) (anti-C1q vasculitis)
Medium-vessel vasculitis (MVV)
Polyarteritis nodosa (PAN)
Kawasaki disease (KD)
Large-vessel vasculitis
Takayasu arteritis (TA)
Giant cell arteritis (GCA)
Variable vessel vasculitis (VVV)
Behçet's disease (BD)
Cogan's syndrome (CS)
extension to the CHCC covering dermatological vasculitides has been developed covering both cuta-
neous manifestations of systemic disease and conditions localised to the skin [3].
Classification criteria
Classification criteria are designed to distinguish patients with a specific condition (for example,
GPA) from a group of patients with similar conditions (for example, other types of SVV) to ensure a
homogeneous population for clinical studies [4]. Diagnostic criteria are used to identify patients with a
specific condition (for example, GPA) from patients presenting in a similar way but with different
underlying conditions (in this example, patients presenting with cough, lung infiltrates and a rash who
are found to have an underlying infection or malignancy rather than GPA) [4]. Patients who present in a
way similar to systemic vasculitides are termed vasculitis mimics, examples of which are shown in
Table 2. It is important to exclude these causes clinically before any classification criteria are applied.
Classification criteria for systemic vasculitides in adults, including giant cell arteritis (GCA) [5],
Takayasu arteritis [6] (TAK), eosinophilic granulomatosis with polyangiitis (EGPA; ChurgeStrauss) [7],
GPA (Wegener's) [8], PAN [9] and IgA vasculitis (IgAV; HenocheScho €nlein) [10], were last published in
1990 by the American College of Rheumatology (ACR) [11]. The methodology used was to compare
patients who had the subtype of vasculitis under study (for example, GPA) with those who had all other
types of vasculitis including those with different-sized vessel involvement [12]. Each final criterion
includes clinical, laboratory and histological items, and a minimum number of criteria need to be
present to classify a patient with each type of vasculitis [12]. Performance characteristics are shown in
Table 3. The 1990 criteria have proven to be effective and widely accepted and have facilitated a co-
ordinated approach to randomised controlled trials and epidemiological studies by the European
Vasculitis Study Group (EUVAS), French Vasculitis Study Group (FVSG), Vasculitis Clinical Research
Consortium (VCRC) and other collaborative networks working within vasculitis research [13e15].
A consensus meeting at the European Medicines Agency in September 2004 and January 2006
created and validated a common method for applying the ACR criteria for ANCA-associated vasculitis
(AAV) and PAN, the CHCC definitions and ANCA results to systematically classify all patients with AAV
for use in epidemiological studies and trials [16] (Fig. 1). The algorithm uses a hierarchical approach
starting with EGPA. EGPA was considered as the starting point because the ACR (1990) criteria have a
high specificity and sensitivity. Next, GPA was considered, followed by MPA and finally PAN. The aim
was to have a minimum number of unclassifiable patients. Although ANCA was included, the specificity
was not associated with a particular type of vasculitis. The algorithm was validated in both paper
Table 2
Vasculitis mimics.
Mimics of vasculitis
Infectious causes Infective endocarditis, Mycotic aneurysms associated with septicaemia, Tuberculosis,
syphilis, leprosy
HIV, HBV, HCV, Herpes viruses
Malignancy Lymphoma, Leukaemia
Atherosclerosis Stroke, Myocardial infarction
Congenital causes Coarctation of the aorta, Middle aortic syndrome
Hereditary disorders EhlerseDanlos syndrome (types IV and VI), Marfan syndrome, Neurofibromatosis,
Pseudoxanthoma elasticum, LoeyseDietz syndrome, Grange syndrome
Fibromuscular dysplasia
Iatrogenic Post-radiation therapy or surgery
Drug induced Cocaine-induced midline destructive lesions, Levamisole
, sulfasalazine, D-penicillamine
Propylthiouracil, hydralazine, anti-tumour necrosis factor-a
and minocycline.
Hypercoagulable states Thrombotic thrombocytopenic purpura, antiphospholipid syndrome
Other multi-system Sarcoidosis, Susac's syndrome, systemic lupus erythematosus, mixed connective tissue
inflammatory conditions disease, scleroderma.
Vasospastic disorders Reversible cerebral vasoconstrictive syndrome
Stroke-like syndromes CADASIL, Sneddon's syndrome, Mitochondrial diseases, Sickle cell disease, Fabry disease
Leukoencephalopathies Progressive multifocal leukoencephalopathy, Reversible posterior leukoencephalopathy
syndrome
Table 3
Performance characteristics of classification criteria derived for adults and children with systemic vasculitis.
Sensitivity Specificity
ACR 1990 (Adults)

GPA 88.2 92.0
MPA No criteria
EGPA 85.0 99.7
GCA 93.5 91.2
TAK 90.5 97.8
IgA 87.1 87.7
PAN 82.2 86.6
EULAR/PRINTO/PRES 2010 (Paediatric)
HSP 100 87
c-PAN 89.6 99.6
c-WG 93.3 99.2
c-TAK 100 99.9
Behçet's diseasea 94.8 94.5
Cryoglobulinaemic vasculitisb 89.9 93.5
cPAN: childhood polyarteritis nodosa. C-WG: C-Wegener granulomatosis; c-TAK: c-Takayasu arteritis.
a
Davetchi et al., 2013.
b
Quartuccio et al., 2014.
patients and a cohort of patients from a single centre. It has subsequently been validated in cohorts of
patients of non-European ancestry and children. It has also been revalidated using the revised CHCC
2012 definitions [17e20].
In 2010, a European League Against Rheumatism (EULAR) panel reported a number of ‘points to
consider’ in relation to developing new classification criteria [21] including incorporating newer
diagnostic tools such as ultrasound, magnetic resonance imaging, and computerised tomography and
anti-neutrophil cytoplasm antibody testing, all of which are currently in routine practice. The absence
of MPA as a distinct entity from PAN was also highlighted. There have been methodological advances in
the derivation of classification criteria in other diseases, moving away from the ‘number of criteria’ rule
[12], towards weighted criteria with threshold scores, which can improve performance characteristics.
There has also been a decline in the sensitivity of the 1990 ACR classification criteria for vasculitis,
particularly for the AAVs [22]. In a single-centre study of 124 adults with IgAV, according to CHCC 2012
Fig. 1. European Medicines Agency algorithm for classification of vasculitis. (reproduced with permission from Watts et al, 2007).
definitions, the EULAR/PRINTO/PRES IgAV classification criteria had a higher sensitivity and specificity
than the ACR criteria [23].
The aim of the Diagnostic and Classification Criteria in Vasculitis study (DCVAS) is to develop data
driven classification criteria, which also incorporate expert consensus for the systemic vasculitides
[24]. Provisional criteria have been presented in abstract form only and will need further testing before
potential endorsement by the ACR and the EULAR [25].
Current discussion around the classification of the systemic vasculitides
Patients with positive proteinase 3 (PR3), versus positive myeloperoxidase (MPO) serology have
been shown to have different outcomes [26e29]. Disease phenotype (as opposed to ANCA status) also
independently determines outcome [30], and 30% of cases of patients with limited GPA are ANCA
negative [31]. Classification by ANCA subtype alone is not currently recommended for clinical trials in
the AAVs, but ANCA serology is usually included as one of the eligibility criteria [32].
Within the large vessel vasculitis (LVVs), there are ongoing questions about whether TAK and GCA
are on different ends of the spectrum of the same underlying disease or represent completely separate
conditions [33]. Inclusion of patients with LVV involvement who did not have cranial GCA within a
recent large clinical trial of GCA has been a recent paradigm shift [34]. Expert opinion suggests that a
common approach to disease assessment in both diseases may be appropriate, but additional disease-
specific assessment tools may be needed for GCA and TAK [35]. The discussion on whether to develop
combined classification criteria for the LVVs for use in clinical trials is still ongoing, but it is likely at
present that both diseases will have separate criteria within the DCVAS study [36].
Diagnostic criteria
The ACR have highlighted several methodological issues with the production and use of diagnostic
criteria, primarily because diagnosis is a complex cognitive process performed by a physician working
within a specific population, and this is difficult to replace with a single set of criteria which work in all
cases [4]. To ensure patient safety, both sensitivity and specificity should be approaching 100% for
diagnostic criteria, and this is particularly difficult for diseases without a gold standard that present in a
heterogeneous way, as is the case in systemic vasculitis [4].
Behçet's disease (BD)
In 1990, an International Study Group (ISG) developed internationally agreed diagnostic/classifi-

cation criteria for Behçet's disease [37], which were then validated by a comparison of clinical features
between 914 patients and 308 disease-mimic controls. These criteria perform well in the clinical
context to aid in diagnosis. The ISG criteria were found to have lower sensitivity than other classifi-
cation criteria. The ISG criteria also did not allow for variations in the symptoms of BD because the
presence of oral aphthous ulceration was considered an obligatory manifestation for BD diagnosis. In
2014, the new International Criteria for Behçet's disease (ICBD) were described, including vascular and
neurological manifestations, and has been reported as having improved sensitivity whilst maintaining
specificity. These criteria were validated in 2556 patients and 1163 controls [38] and found to have
satisfactory sensitivity and specificity (Table 2).
Cryoglobulinaemic vasculitis (CV)
Classification criteria for cryoglobulinaemic vasculitis were developed through expert consensus,
including patient questions related to symptoms (e.g. skin symptoms), the pattern of organ
involvement and results of laboratory tests. Positivity of serum cryoglobulins was defined as
essential for a classification of cryoglobulinaemic vasculitis. Validation of these classification criteria
was completed in 2014 in a large international study and demonstrated desirable sensitivity and
specificity [39,40] (Table 2).
Hypocomplementaemic urticarial vasculitis
Preliminary diagnostic criteria include two major criteria: recurrent urticarial lesions and hypo-
complementaemia, together with at least two minor criteria from the following: leucocytoclastic
vasculitis, arthralgias or arthritis, ocular inflammation, glomerulonephritis, abdominal pain and/or
anti-C1Q antibody positivity [41]. The relationship between HUV and normocomplementaemic urti-
carial vasculitis is controversial but could reflect a continuum of disease ranging from isolated urticaria
to systemic illness with vasculitis and hypocomplementaemia.
Paediatric classification criteria
The 1990 ACR classification criteria for systemic vasculitides did not include children or adolescents
[12]. Despite some overlapping clinical features with adults, it was decided that classification criteria
should be developed based on cases of children with vasculitis [42]. In 2010, a collaboration between
EULAR, the Paediatric Rheumatology International Trials Organization (PRINTO) and the Paediatric
Rheumatology European Society (PRES) published classification for HenocheSchonlein purpura,
childhood PAN, childhood GPA and childhood TAK [43]. Performance characteristics for all subtypes of
childhood vasculitis demonstrate excellent sensitivity and specificity and are shown in Table 3.
Epidemiology
The epidemiology of systemic vasculitis has been increasingly well described during the past 30
years; however, there are still formidable challenges and gaps in our knowledge.
Obtaining accurate epidemiological data is important for several reasons. Knowledge of the
occurrence and pattern of disease in a given population is important for planning health services, and
identification of patterns of occurrence such as epidemics or seasonality may provide clues to the
causes of disease, both infectious and environmental. Comparison of disease occurrence between
populations may provide clues as to causation and possibly permit assessment of genetic risk factors.
The challenges fundamentally relate to the difficulty in conducting high-quality epidemiology
research in rare diseases. Accurate epidemiology requires a well-defined population from within a
well-defined geographical boundary. Universal health care systems with registration of patients at
both inpatient and ambulatory care are ideal for this type of research; however, in some parts of the
world, such universal health care systems do not exist, and it is therefore much more difficult, if not
impossible, to obtain reliable data. To collect information about a sufficiently large number of patients
with a rare disease either takes a long time or requires a large population, both of which make it more
difficult to conduct good-quality epidemiology research. A further requirement is a reliable classifi-
cation system. For the reasons described above, the current classification for many types of vasculitis is
outdated and not in line with current clinical practice, and this has hindered epidemiological research
in the field. With increasing interest in the occurrence of disease in different populations, accurate
determination of ancestry is important. The ideal determination of ancestry is the determination of the
place of birth of all four of a person's grandparents. This is often not possible, especially in studies based
on administrative databases. There is then a reliance on self-reported ethnicity or ancestry. Compar-
ative population studies can be conducted either in a single population of multi-ancestry or by direct
comparison of population in geographically dispersed areas, e.g. UK vs Japan. When comparing pop-
ulations from different ancestries, it is important to ensure that the age structure of the studied
population is the same. This is particularly important for many types of vasculitis, e.g. Kawasaki disease
(KD) and GCA, which show a marked age tropism.
Two main approaches have been used in studying the epidemiology of the vasculitides: i) devel-
opment of a complete cohort from a well-defined geographical area often based around a single
referral centre (e.g. [44,45]) or ii) using administrative databases (e.g. [46]). The former has the major
advantage that it is often possible to examine the individual patient case records to confirm the
diagnosis and formally classify the individual patient. Because of the difficulties of collecting a com-
plete cohort, these studies tend to have relatively small denominator populations and numbers of
patients. The use of administrative databases has the advantage of automatic data collection, large
populations and hence large numbers of patients. The disadvantage is that it is usually impossible or
impracticable to confirm the ancestry, diagnosis and classification of any individual patient. Surrogate
or algorithmic means of confirming the diagnosis then need to be developed [47].
Large-vessel vasculitis
TAK is a rare large-vessel vasculitis that was originally described in Japan. TAK has long been
considered to be most common in the population of Asian ancestry. To date, the highest prevalence
reported is 40 per million from Japan [48], although a study from a multi-ethnic population in Norway
reported a higher prevalence in very small populations of Asian (71 per million) or African (108 per
million) ancestry [49]. The annual incidence in most European populations is approximately 1e2 per
million; higher figures (6.4/million and 13.1/million respectively) were reported in Asian and African
populations in Norway. TAK is more common in women than in men [49]. The mean age of disease
onset is in the fourth decade [49], but classification criteria include an age cutoff at 40 years, which
means that older patients are probably not considered to have TAK.
The strongest genetic susceptibility locus for the disease is the classical HLA allele, HLA-B*52,
which has been confirmed in several ethnicities. The genetic susceptibility with HLA-B*52, as well
as additional classical alleles and loci, implicate both HLA class I and class II involvement in TAK. Non-
HLA susceptibility loci that have been recently established for TAK with a genome-wide level of
significance include FCGR2A/FCGR3A, IL12B, IL6, RPS9/LILRB3, and a locus on chromosome 21 near
PSMG1 [50].
Long-term follow-up studies suggest that relapse is common; after a median follow-up of 318 cases
for 6.1 years, relapses were observed in 43%, vascular complications in 38% and death in 5%. A pro-
gressive clinical course was observed in 45%, carotidynia in 10% and retinopathy in 4%. The 5- and 10-
year event-free survival rates were 48.2% and 36.4%, respectively, whilst relapse-free survival rates
were 58.6% and 47.4%, respectively. The 5- and 10-year complication survival rates were 69.9% and
53.7%, respectively [51].
Giant cell arteritis

GCA remains the commonest form of systemic vasculitis in those aged >50 years. GCA is usually
classified for epidemiology studies using the ACR 1990 criteria. Not all studies required a temporal
artery biopsy to confirm the diagnosis, and this can make it difficult to compare studies. The incidence
is highest in populations of Northern European, especially in Scandinavian populations. The available
data are presented in Fig. 2. There is also a high incidence in Olmsted County, Minnesota USA, a
population that is predominantly of Scandinavian ancestry [52].
Some studies have suggested an increasing incidence with time, but it is not always clear that this
does not reflect better case identification, changing rates of temporal artery biopsy and awareness of
the disease. A recent Scandinavian study described an increase in reported incidence from 1972 to 1992
but no further increase up to 2012 [53]. GCA is much less common in populations of non-European
ancestry, especially from Asia. The prevalence in Japan appears to be 100-fold less than that in
Olmsted County [54]. GCA is rarely observed in African ancestry populations [53].
Environmental factors have long been thought to be important in the aetiopathogenesis of GCA.
There is an inconsistent relationship with season of onset. Infection has also been suspected, but no
clear link has emerged.
Genetic epidemiology studies have shown that HLA-DRB1*04 is the strongest risk factor for GCA,
and it has been suggested that variation in HLA-DRB1*04 frequency in populations may partly explain
variations in GCA incidence [55]. PTPN22, PLG and P4HA2 were identified as GCA risk genes at the
genome-wide level of significance [57]. A recent theory is that the development of GCA represents a
breach of the immune privilege of the aorta as a consequence of checkpoint inhibition failure [58].
Outcome of giant cell arteritis

The mortality of patients with GCA is increased compared with unaffected adults. A recent study
from Sweden suggested that mortality was significantly increased during the first 2 years after GCA
diagnosis (SMR 1.52 (95% CI 1.20 to 1.85)), but after that time, the mortality risk returned to normal. The
Fig. 2. Annual incidence of giant cell arteritis.
estimated excess mortality was greater in women and patients aged 70 years at diagnosis [45]. This
suggests that with long-term follow-up, GCA has less impact on the survival of elderly patients. The
major morbidity of GCA is blindness, with visual loss occurring in up to 20% of patients before the
prescription of glucocorticoids [59]. Estimates of the overall rate of visual loss of up to 66% have been
reported, thus reflecting varying definitions of disease and visual impairment [60]. Using data from the
DCVAS study from 26 countries, blindness in at least one eye at 6 months was reported in 7.9% of 433
patients with GCA. Risk factors identified at presentation for blindness at 6 months included prevalent
stroke (OR ¼ 4.47) and peripheral vascular disease (OR ¼ 10.44) [61]. Cerebrovascular accidents, stroke
and TIAs occur in 1.5e7% of patients with GCA [59].
Medium-vessel vasculitis
Kawasaki disease
KD is a medium-sized vasculitis that affects children aged <5 years, and is the predominant cause of
childhood-acquired heart disease in the developed world [62]. It was originally described by Kawasaki
in Japan in the 1960s but has been recognised as occurring in most populations; there are, however,
marked differences in occurrence between populations. Populations of Asian ancestry have the highest
incidence of KD. The incidence of KD continues to increase in Japan; in 2012, the annual incidence rates
were 243.1 per 100,000 population aged 0e4 years in 2011 and 264.8 in 2012 [63]. In Japan, the cu-
mulative incidence means that 1.5/100 boys and 1.2/100 girls of age 10 years have been affected by KD
[64]. The current epidemiological data are summarised in Fig. 3. Most studies suggest that it is more
common in boys than in girls; this finding is in contrast to most other rheumatic diseases, which are
more common in females than in males.
In Europe, USA and Australia, the previously observed increase in the incidence of KD appears to
have plateaued, whereas in North-East Asian countries (e.g. Japan and Korea), the reported incidence is
10e20 times higher than that in the USA and Europe, and the incidence is continuing to increase. The
current incidence in Japan is 265/100,000 children aged <5 years. In China and Indiadthe two most
populous countriesdthe incidence also appears to be increasing, thus mirroring rapid industrialisation
and economic growth. Further epidemiological data are needed from these countries to examine this
pattern further.
An infectious aetiology has long been suspected, especially in Japan, where there have been several
epidemics of KD but none since 1986. Several countries have reported distinct seasonality in KD, but
Fig. 3. Annual incidence of Kawasaki disease.
there is no overall pattern even allowing for differences in latitude and longitude. Japan reports two
seasonal peaks of KD incidence in January and July, with a nadir in October [63]. Korea, located at
approximately the same latitude, has similar peaks in June/July and December/January [65]. Taiwan has
peaks in May/June, and the lowest incidence is reported from November to January. Seasonality data
from China are more variable. In Chandigarh (India), a consistent peak is observed in October with a
nadir in February. KD has been reported to occur more commonly in the winter months in Mainland
USA, Canada and Europe and in the more temperate regions of Australia.
The recurrence rate is very low. In Japan, the recurrence rate in patients with KD is 6.51/1000 years
of patient follow-up. Risk factors for recurrence are male sex, young age and initial resistance to
immunoglobulin therapy. The presence of cardiac sequelae during the initial episode does not affect
the recurrence risk [66].
Coronary artery abnormalities are the most significant long-term sequelae of KD; these include
coronary artery dilatation, aneurysms and giant aneurysm formation. The frequency at which these
abnormalities occur has decreased since the 1990s In Japan, the prevalence of coronary artery dila-
tation, aneurysm and giant aneurysm (lumen size 8 mm) within 30 days after KD onset were 8.54%,
1.21% and 0.25%, respectively, during the 2008e2009 study period. Patients who are male, aged <1 or
>5 years or resistant to initial IVIG treatment have a higher risk of developing CAAs [67].
Polyarteritis nodosa
PAN is a rare vasculitis of medium vessels associated with the development of aneurysms. It should
be remembered that up to the 1990s, the term PAN was used to cover several types of vasculitis that
would currently be considered AAV. PAN is one of the few types of vasculitis for which a clear infectious
cause has been recognised, PAN in many cases follows hepatitis B (HBV) infection. Following the
introduction of modern classification systems and possibly the fall in incidence in Hepatitis B, it has
become less common.
The annual incidence of PAN currently ranges from 0 to 1.6 cases/million inhabitants in European
countries with a prevalence of 31 cases/million [68e70]. The typical age of occurrence is between the
ages of 40 and 60 years; it rarely affects children, and there is a 1.5:1 male preponderance.
PAN associated with HBV infection has become very uncommon since the introduction of vacci-
nation programmes and effective screening of blood products.
The outcome of PAN remains relatively poor; in large French series, the 5-year relapse-free survival
rate for non-HBV-related PAN was 59.4% compared with that of 67.0% for HBV-related PAN. Risk factors
for mortality are age >65 years, hypertension and gastrointestinal manifestations requiring surgery;
the risk of relapse was associated with the presence of cutaneous disease and non-HBV status [71].
Small-vessel vasculitis
ANCA-associated vasculitis
The AAV comprise GPA, MPA and EGPA. Most epidemiological studies on AAV are from Europe, but
there are increasing data from populations of other ancestry. In populations of European ancestry, the
overall annual incidence of all forms of AAV combined is approximately 20 per million. EGPA is the least
common of the three subtypes. There is, however, variation in the relative occurrence of the three
subtypes in different geographical areas. Data from the 1990s suggested that GPA was more common
than MPA in northern European populations, whilst in southern European populations, the reverse was
observed [72]. Recent studies have suggested that this may not be quite clearcut as previously sug-
gested. Recent data from the UK suggested that MPA was more common than GPA in an urban area
(13.3 per million and 8.2 per million, respectively), in contrast to results from previous studies from a
more rural area (11.3 per million and 5.9 per million, respectively) [44,73]. In Olmsted County, USA, in a
population of Northern European ancestry, the occurrence of GPA and MPA was similar (13 per million
and 16 per million, respectively) [74].
The incidence rates of AAV are similar in most Caucasian populations; the populations studied in the
Western USA, Australia and New Zealand are predominately white Caucasian populations of northern
European descent (Fig. 4). Recent studies conducted in non-European ancestry populations suggest a
lower incidence. A prevalence study from an urban area of France reported that the overall prevalence
of PAN, GPA, EGPAS and MPA in the European ancestry population was twice as that in the non-
European ancestry population [69]. In New Zealand, GPA is twice as common in Europeans than
amongst Maoris or Asians [75]. Large case series from China suggest that MPA is more common than
GPA [17]. In a multi-ethnic series from Chapel Hill in the USA, GPA is relatively uncommon in African
Americans compared to that in white Caucasians [76]. A comparative study between the United
Kingdom (UK) and Japan regions observed that the overall incidence of AAV was similar (22.6 per
million and 21.8 per million, respectively). In Japan, GPA was much less common (2.1 per million) than
MPA (18.2 per million) [77], and cANCA-associated disease is 10-fold less frequent than pANCA-
associated disease [77]. A recent study from a multi-ethnic population in the UK showed no differ-
ence in the incidence between Northern Europeans and a mixed black ethnic minority ancestry
population. In this study, a difference was noted in a crude analysis but not when corrected for sex and
age, thus highlighting the importance of controlling for age [73].
Fig. 4. Annual incidence of ANCA-associated vasculitis.
The environmental factors important in the aetiology of AAV are in general unknown. Environmental
dust has been suggested as a factor, and there is an association with silica [78]. Studies in Japan after two
large earthquakes suggested an increased incidence in the years immediately after earthquake [79,80].
However, an increased incidence was not seen after the Twin Towers attack in New York. Infectious
triggers have long been sought [81]. A recent study from the UK Clinical Practice Research Datalink (CPRD)
has shown an association between GPA and bronchiectasis and also with the occurrence of other auto-
immune diseases, especially type 1 diabetes, inflammatory bowel disease and rheumatoid arthritis [82].
The genetic associations of AAV have been investigated by genome-wide association study (GWAS)
methods. In European Caucasian patients, the strongest genetic associations were with the antigenic
specificity of ANCA rather than with the clinical syndrome [83]. Anti-proteinase 3 (PR3) ANCA was
associated with HLA-DP, SERPINA1 and PRTN3 (PRTN3 encodes proteinase 3). HLA-DPB1*0401 is a GPA
susceptibility allele, and HLA-DPB1*0401 population allele frequencies may help explain variations in
GPA incidence [84]. Detailed HLA data are not yet available for the other types of AAV, but the HLA
associations of MPA and EGPA are different from those of GPA.
Outcome of ANCA-vasculitis
The long-term outcome of the AAV remains suboptimal. Before the introduction of cyclophospha-
mide, the 1-year mortality rate of GPA was approximately 90%. A recent meta-analysis of observational
studies in AAV suggests that there is an overall 2.7-fold increase in mortality compared with that in the
general population. For GPA alone, the risk was 2.63 [85]. With current treatment protocols, the 1-year
survival rate for AAV is approximately 90%, with a 5-year survival rate of 75%. Relapse is more common
in patients with GPA who are PR3 positive and have better initial renal function [86]. The main causes of
mortality in AAV are uncontrolled active disease, adverse events, infection and cardiovascular disease.
Adverse events from therapy (including infection) are most likely to occur in the first year after diag-
nosis. AAV carries a relative risk of 1.65 (95% CI: 1.23, 2.22) for all cardiovascular events, 1.60 (95% CI:
1.39, 1.84) for ischaemic heart disease and 1.20 (95% CI: 0.98, 1.48) for cerebrovascular accidents [87].
Immune complex small-vessel vasculitis
Anti-glomerular basement membrane disease

Anti-glomerular basement membrane (GBM) disease (Goodpasture syndrome) is a vasculitis that
affects glomerular capillaries, thereby causing rapidly progressive renal failure, often in association
with a pulmonary capillaritis causing lung haemorrhage, with basement membrane deposition of anti-
basement membrane autoantibodies. Some patients also have ANCA present, which leads to the
suggestion of an overlap with AAV. There is a debate as to whether it is a true vasculitis or a vascul-
opathy. An Irish study calculated the national incidence at 1.64 per million population per year during
an 11-year period (2003e2014) [88].
Cryoglobulinaemic vasculitis
Cryoglobulinaemic vasculitis is a rare form of immune complex vasculitis in which circulating
cryoglobulins can be demonstrated in the serum or tissue. There is an association with myeloprolif-
erative disorders, connective tissue diseases and, in particular, hepatitis C infection. The incidence and
prevalence of cryoglobulinaemic vasculitis is unknown. The outcome is dependent on the underlying
condition. Modern antiviral therapies for hepatitis C are very effective at curing the infection, and the
outlook is consequently very good.
IgA vasculitis
IgAV (formerly known as HenocheScho € nlein purpura) is an immune complex vasculitis predomi-
nantly affecting small vessels [2]. IgAV is a common childhood systemic vasculitis with clinical charac-
teristics of cutaneous palpable purpura, arthralgia/arthritis, bowel angina and haematuria/proteinuria.
The annual incidence in children ranges from 3.5 to 27.6 per 100,000 and is highest between the ages of 4
and 6 years (70 per 100,000) [89]. A recent study from a suburban area of Paris described an annual
incidence of 18.6/100,000 children. The annual distribution of diagnoses consistently showed a trough in
summer months: 72% of children had infectious symptoms (mainly upper respiratory tract) a few days
before the onset of IgAV and 23% had a North African background [90]. The outcome of IgAV in children is
generally desirable with a low rate of development of renal failure.
IgAV is much less common in adults. Recent studies from Finland and Spain suggest the incidence is
approximately 1.4e1.5 million adults, whereas earlier studies from the UK and Spain suggested that the
incidence could be 10-fold higher than that. It is not certain whether this represents different case
capture approaches or classification. Adult-onset IgAV is more common in males than in females (63%)
and has a mean age of onset of 50 years [91].
Hypocomplementaemic urticarial vasculitis

There are very little data on the epidemiology of hypocomplementaemic urticarial vasculitis
(HUVS). A study from Sweden reported on 16 patients (14 females), all of whom were positive for anti-
C1Q antibody seen between 2000 and 2015 from a well-defined population of 1,474,105 individuals.
The annual incidence was 0.7 per million, with a point prevalence on 31 December 2015 of 9.5 per
million. There was no detectable age variation. The median age of onset was 51 years. The 5-year
survival rate was 92%, with a 10-year survival rate of 83% [92].
Variable vessel vasculitis
Behçet's disease
The occurrence of Behçet's disease has been studied in many disparate populations and is perhaps
therefore one of the best documented of the vasculitides. There is a striking variation in prevalence
between populations, with the highest rates in countries in the region between the Eastern Mediter-
ranean and China. This has led to the hypothesis that an environmental or genetic factor was
disseminated through the historical Silk Road along these ancient trade routes when people migrated
between the Mediterranean and Northern China [93].
A recent meta-analysis has confirmed the geographical variation in the prevalence of Behçet's
disease. The global overall prevalence was 10.3/100,000 inhabitants. In Turkey the pooled prevalence
was 119.8/100,000 inhabitants, 31.8/100,000 inhabitants in the Middle East, 4.5/100,000 in Asia and
3.3/100,000 inhabitants in Europe [94]. In Europe, the prevalence is greater in southern Europe, thus
suggesting that Behçet's disease is rare amongst populations of northern European ancestry.
The genetic background of Behçet's disease has been investigated, and the strongest association is
found with HLA-B*51. Expression of HA-B*51 is related to the occurrence of Behçet's disease, with
prevalence being highest in Europe and the Middle and Far East, where HLA-B*51 is found in >15% of
persons, and lowest in Africa, Oceania and South America (reviewed in [95]).
Single-organ vasculitis
There are no data on the occurrence of SOV apart from isolated cutaneous vasculitis.
Vasculitis associated with systemic disease
In general, there are little epidemiological data on the occurrence of vasculitis in association with
systemic disease. The exception is rheumatoid vasculitis.
Systemic rheumatoid vasculitis
Vasculitis occurring in association with rheumatoid arthritis has been recognised for more than 100
years. Between 1970 and the 1990s, the incidence in the UK and Spain was 6 and 6.4 per million,
respectively. In the UK, there was significant decline in annual incidence between 1998 and 2000 and
the period 2001e2010 from 9.1 per million to 3.9 per million [96]. The decline was predominantly
during the late 1990s. Several studies from the USA have supported this decline in systemic rheumatoid
vasculitis (SRV); a population-based study of the incidence of extra-articular RA reported a reduction in
the 10-year cumulative incidence of SRV from 3.6% in 1985e1994 to 0.6% in 1995e2007 [97].
The reasons for this gradual decline in SRV are unclear. Rheumatoid arthritis in general has become
less severe, with extra-articular disease becoming much less common; the need for surgery such as
hand surgery, foot surgery, cervical spine stabilisation and splenectomy for Felty's syndrome, both of
which may be considered to be surrogate markers of disease severity, has declined [98]. During the past
two decades, there have been major changes in the treatment of RA, with increased focus on the tight
control of inflammation through the introduction of treat-to-target initiatives. To achieve this, there
has been much wider and earlier use of methotrexate, and in the UK, this seems to be associated
temporally with the decrease in SRV [96,99].
Mortality in SRV remains high; in a single-centre cohort, the mortality at 5 years was 57% with a 20%
1-year mortality, an overall mortality that is worse than that for AAV [96].
Childhood vasculitis
The two commonest types of paediatric vasculitis are IgAV and KD; their epidemiology is described
above. TAK occurs in younger people but is rare in the paediatric age group. Other types of vasculitis
including the AAV are much rarer in children than in adults. A recent study from Sweden reported in
children aged <17 years that the incidence was 200 per million for all primary systemic vasculitides,
175.5 per million for IgAV, 201 per million for KD, 1.4 per million for GPA and MPA, 0.7 per million for
PAN and 0.4 per million for EGPA and TAK. Among children aged <10 years, 99.5% of cases were IgAV or
KD [100].
Summary
The CHCC has produced agreed definitions covering most types of vasculitis, which have been
widely adopted. The classification of vasculitis is a field that is progressing; the DCVAS project will
produce new criteria for AAV, PAN and LVV, which have been developed using a robust methodology
and incorporating modern investigation including ANCA and imaging.
Considerable knowledge on the occurrence of the vasculitides has been reported during the past
few years; however, there are still gaps in our knowledge particularly for the rarer forms of vasculitides.
Much of the available data come from populations of European ancestry, and it may not be appropriate
to extrapolate to different populations who may have alternative genetic and environmental back-
grounds. Overall, the vasculitides occur at the ends of the age spectrum: IgAV and KD are diseases of
childhood whilst GCA is much more common in those aged greater than 60 years. The AAV are similarly
seen more frequently with increasing age. Behçet's disease shows striking geographical variation, being
much more frequent in the region between the Mediterranean and China than elsewhere in the world.
Future research studies within non-European populations are therefore warranted.
Funding statement
No specific funding was received for the writing of this review.
Conflicts of interest statement
The authors have no conflicts of interest to declare.
Practice points
Current classification criteria are outdated.

Classification criteria should not be used as diagnostic criteria.
It is important to use populations of homogeneous cases with a specific condition within
clinical studies.
Research agenda
New classification criteria incorporating ANCA and current imaging methods.

Development of diagnostic criteria.
Descriptive epidemiology from non-European ancestry populations.
Exploration of subsets within diseases, for example, large-vessel disease versus cranial
disease in GCA
Exploration of genetics to aid diagnosis
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Best Practice & Research Clinical Rheumatology: Richard A. Watts, Joanna Robson

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Contents lists available at ScienceDirect

Best Practice & Research Clinical

Introduction, epidemiology and classiﬁcation of

ACR American College of Rheumatology

Small-vessel vasculitis (SVV)

ACR 1990 (Adults)

Current discussion around the classiﬁcation of the systemic vasculitides

Behçet's disease (BD)

In 1990, an International Study Group (ISG) developed internationally agreed diagnostic/classiﬁ-

Cryoglobulinaemic vasculitis (CV)

Hypocomplementaemic urticarial vasculitis

Paediatric classiﬁcation criteria

Giant cell arteritis

Outcome of giant cell arteritis

Fig. 2. Annual incidence of giant cell arteritis.

Fig. 3. Annual incidence of Kawasaki disease.

Fig. 4. Annual incidence of ANCA-associated vasculitis.

Immune complex small-vessel vasculitis

Anti-glomerular basement membrane disease

Hypocomplementaemic urticarial vasculitis

Variable vessel vasculitis

Vasculitis associated with systemic disease

Systemic rheumatoid vasculitis

No speciﬁc funding was received for the writing of this review.

Conﬂicts of interest statement

The authors have no conﬂicts of interest to declare.

Current classification criteria are outdated.

New classification criteria incorporating ANCA and current imaging methods.

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