REVIEW

CURRENT
OPINION Pediatric vasculitis
Kenan Barut, Sezgin Sahin, and Ozgur Kasapcopur

Purpose of review
The aim of this review is to define childhood vasculitis and to highlight new causative factors and treatment
modalities under the guidance of recently published studies.
Recent findings
Childhood vasculitis is difficult to diagnose because of the wide variation in the symptoms and signs. New
nomenclature and classification criteria were proposed for the diagnosis of pediatric vasculitis. Recently, progress
has been made toward understanding the genetic susceptibility to pediatric vasculitis as it was in other diseases.
Various radiological techniques provide great opportunities in establishing the diagnosis of pediatric vasculitis.
Mild central nervous system disease can accompany Henoch–Schonlein purpura and can go unnoticed.
Antineutrophilic cytoplasmic antibody-associated vasculitis is rare in children. Increased severity of the disease,
subglottic stenosis, and renal disease are described more frequently among children. Biological therapies are
used with success in children as in adults. Future studies, whose aims are to evaluate treatment responses,
prognosis and to design guidelines for activity, and damage index of vasculitis for children are required.
Summary
Henoch–Schonlein purpura and Kawasaki disease are the most frequent vasculitides of children.
Experience from adult studies for treatment and prognosis are usually used because of low incidence of
other vasculitides in children. Multicenter studies of pediatric vasculitis should be conducted to detail
treatment responses and prognosis in children.
Keywords
antineutrophilic cytoplasmic antibody–associated vasculitis, Henoch–Schonlein purpura/IgA vasculitis,
Kawasaki disease, pediatric vasculitis, Takayasu’s arteritis

INTRODUCTION However, these classification criteria are not suffi-

&

Vasculitis is a general definition that refers to the
clinical conditions and the changes in vessel wall as
a consequence of an inflammatory process. Clinical
presentation depends on severity of the disease and
size of the affected blood vessel. The symptoms of
pediatric vasculitis are highly variable. The clinical
cient for an exact diagnosis [4,5 ,6]. Preliminary
classification criteria for vasculitis were developed
by American College of Rheumatology in 1990.
Some of these criteria were also used for pediatric
patients. Subsequently, the Chapel Hill Consensus
Conference in 1994 developed a nomenclature of
&&

spectrum varies from askin eruption to that with
severe multiorgan failure. Stenosis, occlusion, and
aneurysmal dilatations can be observed as a con-
sequence of neutrophilic, lymphocytic, and eosino-
philic infiltration of affected vessels and are late
findings that develop as the disease progresses.
Henoch–Schonlein Purpura (HSP) and Kawasaki
disease (KD) are the most frequent forms of vascu-
&&
litis in childhood [1,2 ,3]. The main features of
childhood vasculitis are summarized in Table 1. This
review defines pediatric vasculitides and focuses on
recent clinical studies and developments.
CLASSIFICATION
Classification criteria for vasculitis are generally
based on clinical and laboratory findings.
vasculitis in 2012 (Table 2) [2 ]. Although the
Chapel Hill Consensus Conference nomenclature
was developed from adult data, it has also been
used for pediatric vasculitis. Final classification
criteria for pediatric vasculitis that had used a
web-based pediatric survey were developed and
validated by European Leag ue Against Rheuma-
tism/Pediatric Rheumatology INternational Trials
Department of Pediatric Rheumatology, Cerrahpasa Medical School,
Istanbul University, Istanbul, Turkey
Correspondence to Ozgur Kasapcopur, Department of Pediatric Rheu-
matology, Cerrahpasa Medical School, Istanbul University, Istanbul,
Turkey. Tel: +90 212 4143000; fax: +90 212 6036411;
e-mail: ozgurkasapcopur@hotmail.com
Curr Opin Rheumatol 2016, 28:29–38
DOI:10.1097/BOR.0000000000000236

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Vasculitis syndromes
KEY POINTS
 HSP is the most frequent pediatric vasculitis which is
usually a self-limiting disease, but kidney functions
should be closely monitored.
 The increased level of IL-18 helps us to differentiate
systemic juvenile idiopathic arthritis from
Kawasaki disease.
 Deficiency of Adenosine deaminase 2 should be
considered if recurrent fever, early-onset stroke, lacunar
infarcts, and pancytopenia accompany polyarteritis
nodosa-like clinical findings.
 ANCA-associated vasculitis is rarely seen in children;
however, show a more severe course by leading to
subglottic stenosis and renal disease more frequently
compared with adults.
 Unexplained neurological findings without systemic
manifestations should suggest a search for cerebral
vasculitis in children.
Organisation/ Paediatric Rheumatology European
Society in Ankara in 2008 [3]. These classification
criteria were proposed for HSP, childhood polyar-
teritis nodosa (PAN), childhood granulomatosis
with polyangiitis (GPA), and childhood Takayasu
arteritis (TA). Nevertheless, KD, one of the most
commonly seen forms of vasculitis in childhood,
is not included in these criteria. American
Heart Association recommendations are used as
&
diagnostic criteria for Kawasaki patients [3,7,8 ]
(Table 3).
HENOCH–SCHONLEIN VASCULITIS/
IMMUNOGLOBULIN A VASCULITIS
HSP is the most common form of pediatric vasculi-
tis. HSP generally follows a benign course. Although
the disease is usually seen in children, adult patients
may also be affected rarely. Because renal involve-
ment is responsible for the chronicity of disease,
renal functions should be monitored closely. Effi-
cient and aggressive treatment should be adminis-
tered promptly if there is any sign of kidney
disease [9].
Although etiopathogenesis is not well defined
some authors considered infective agents, vaccina-
tion, drugs, and insect bites to play a causative role.
HSP shows seasonal variations with most cases in
autumn and winter [10–12]. Despite HSP usually
being preceded by an upper respiratory tract infec-
tion, a clear association with a microbiologic agent
cannot be found [11].
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An et al. [10] proposed a meaningful association
between risk of HSP development and SNP7 subunit
polymorphisms of the C1GALT1 gene. Yu et al. [13]
explored an increase in chemokine levels during the
acute stage of HSP. They found an increased risk of
HSP development in children with MCP1/CCL2-
2518T polymorphisms. Also, a correlation between
disease severity and RANTES/CCL5 gene polymor-
phism together with an association between HSP
nephritis and RANTES/CCL5-403T polymorphisms
was reported.
The classical clinical presentation is the tetrad of
palpable purpura, nonerosive arthritis or arthralgia,
gastrointestinal involvement, and renal disease.
Recurrence of purpuric rashes may be associated
with severe renal involvement and seen in 25% of
disease course [14]. Familial Mediterranean fever
should be kept in mind in the differential diagnosis
of recurrent HSP attacks especially in individuals of
Mediterranean and Middle Eastern descent.
Neurologic involvement rarely occurs in HSP.
Central nervous system (CNS) injury is related
directly to vasculitis itself or occurs indirectly as a
consequence of systemic inflammation. Though
severe neurologic manifestations are rare, mild
clinical manifestations of CNS disease can go unno-
ticed. Convulsion and confusion were retrospec-
tively identified in 17/244 patients with HSP [15 ].
&
Long-term prognosis mainly depends on the
severity of renal disease. Nephritis may appear many
years later after disease onset. Hematuria is the most
frequent clinical manifestation of renal involve-
ment and generally develops in the first 4 weeks.
Range of proteinuria is quite variable. Hypertension
may be seen at disease onset or during the recovery
period [14]. Chen et al. [16] aimed to find clinically
feasible and relevant new biomarkers for renal
involvement in HSP. They found significantly elev-
ated urinary cystatin C and neutrophil gelatinase-
associated lipocalin levels in HSP patients with renal
involvement when compared with those without
renal involvement and healthy participants.
Supportive treatment is usually adequate for the
majority of the cases. Glucocorticoids promptly
relieve abdominal pain and decrease the risk of
invagination and surgery. Although some authors
proposed that glucocorticoids could decrease the
development of renal disease, this hypothesis could
not be verified by randomized, controlled clinical
trials [14,17]. Prognosis of HSP is pretty good
because it is a self-limiting disease that symptoms
and signs can resolve spontaneously. Recurrence
usually occurs in the first 4 months and may be
seen in one third of the cases [14]. Abdominal pain,
fever, C-Reactive Protein greater than 45 mg/dl and
patient age more than 6 years were accepted as
Volume 28  Number 1  January 2016
 Table 1. A brief summarization of childhood vasculitis

Affected Male-to- Common mean

Type of vasculitis vessel size Incidenceb female ratio age at onset Histopathological finding Main clinical findings Treatment options

Henoch–Schonlein
purpura
Kawasaki disease Medium
Polyarteritis nodosa Medium
Takayasu arteritis
Small 9–86 1.5/1 3–15 IgA dominant immune deposits Purpura, arthralgia/arthritis, Supportive, glucocorticoids
abdominal pain,
gastrointestinal bleeding,
renal involvement,
subcutaneous edema, and
orchitis
5.5–239.6 1.62/1 <5 years Necrotizing vasculitis with Fever, conjunctivitis, cracked Aspirin, intravenous
fibrinoid necrosis of the the lips with erythematosus immunoglobulin
coronary arteries oropharynx, rash,
lymphadenopathy, erythema
of palms, and soles
0.2–0.9 1/1 7–12 Fibrinoid vascular necrosis of Fever, myalgia, livedo Glucocorticoids,
the vessel wall with a mixed reticularis and subcutaneous cyclophosphamide
infiltrate consisting of nodules, arthralgia/arthritis,
various combinations of renal involvement, and
leukocytes and lymphocytes neurologic involvement
Large 0.12–0.26 1/1.3–1/9 10–30 Nonnecrotizing granulomatous Decreased peripheral artery Glucocorticoids,
inflammatory infiltrate pulse, blood pressure cyclophosphamide, and
difference between limbs of tocilizumab
>10 mmHg, bruits over
aorta and major branches,

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and hypertension
Granulomatosis with Small 0.02–0.06 1/3 10–20 Necrotizing or granulomatous Pulmonary and renal Glucocorticoids,
polyangiitis vasculitis involvement with ear-nose- cyclophosphamide, and
throat involvement rituximab
Eosinophilic Small Very rare 1/3 12 Vasculitis with/without Asthma, allergic rhinitis, and Glucocorticoids,
granulomatosis with granulomas and pulmonary infiltrations cyclophosphamide
polyangiitis extravascular necrotizing
granulomas usually with
eosinophilic infiltrates
Microscopic Small 0.36 1/2.3 9–12 Pauci-immune necrotizing Fever, myalgia, arthralgia, Glucocorticoids,
polyarteritis vasculitis andpulmonary and renal cyclophosphamide
involvement
a c c
Central nervous 7.2 Nongranulomatous, Focal deficits, cognitive Glucocorticoids,
systemvasculitis lymphocytic infiltration of dysfunction, and seizures cyclophosphamide
small vessels

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a
Classified in single organ vasculitides.
b
Incidence rate was expressed as per 100 000 children per year.
c

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There are no epidemiological data.
Pediatric vasculitis Barut et al.

31
Vasculitis syndromes

Table 2. Vasculitis nomenclature in Chapel Hill Consensus in treatment, or inadequate treatment may lead to
Conference severe complications. The leading cause of acquired
heart disease during childhood is KD. Incidence of
Large vessel vasculitis
KD is highest in Asian countries especially in Japan.
Takayasu arteritis
Annual incidence rate of KD in children under
Giant cell arteritis
5 years of age was reported as 239.6 per 100 000
Medium vessel vasculitis individuals at 2010 in Japan [7,19].
Polyarteritis nodosa As there is seasonal clustering, it is suggested
Kawasaki disease that some viral infections may lead to KD [20].
SVV Globally, KD incidence per 100 000 children were
ANCA-associated vasculitis reported as 2648 cases in Japan, 1344 cases in Korea,
Microscopic polyangiitis 827 in Taiwan, 514 in Singapore, 219 in Canada, 181
Granulomatosis with polyangiitis (Wegener’s) in the United States, 152 in Ireland, 9 in France, 72
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) in Finland, 64 in Israel, and 454 in India [21].
Immune complex SVV
Mortazavi et al. [22] proposed a novel anti-
inflammatory mechanism why intravenous immu-
Antiglomerular basement membrane disease
noglobulin (IVIG) therapy is beneficial. After
Cryoglobulinemic vasculitis
administration of IVIG, they observed and found
IgA vasculitis (Henoch–Schönlein)
significant decline in the levels of inflammatory
Hypocomplementemic urticarial vasculitis (anti-C1q vasculitis) molecules such as Toll-like receptors (TLRs) 2, 3,
Variable vessel vasculitis and 9 as well as their corresponding signaling
Behçet’s disease mediators like myeloid differentiation primary
Cogan’s syndrome response gene and Toll/interleukin-1 receptor-
Single-organ vasculitis domain-containing adapter-inducing interferon-b,
Cutaneous leukocytoclastic angiitis downstream of TLR3. They concluded that TLR
Cutaneous arteritis signaling pathway could have a potential role in
Primary central nervous system vasculitis disease pathogenesis.
Isolated aortitis
Functional single-nucleotide polymorphisms of
ITPKC, CASP3, the transforming growth factor-b
Others
signaling pathway, B lymphoid tyrosine kinase,
Vasculitis associated with systemic disease
FCGR2A, KCNN2 genes together with an imbalance
Lupus vasculitis
of Th17/Treg were identified as potential suscepti-
Rheumatoid vasculitis bility genes to development of KD in a recently
Sarcoid vasculitis published review. However, there are conflicting
Others results about which genes are associated with cor-
Vasculitis associated with probable etiology onary artery aneurysm (CAA) development and
Hepatitis C virus-associated cryoglobulinemic vasculitis IVIG resistance and personalized therapeutic modal-
Hepatitis B virus–associated vasculitis ities may need to be developed for use in patients at
Syphilis-associated aortitis increased risk of CAA [23].
Drug-associated immune complex vasculitis KD often begins with high fever and other clinical
Drug-associated ANCA-associated vasculitis
findingsgenerallyaccompanythissymptom(Table3).
In addition to fever, the five fundamental clinical
Cancer-associated vasculitis
manifestations of KD are: mostly bilateral nonexuda-
Others
tive conjunctival hyperemia; erythema of the oral
ANCA, antineutrophilic cytoplasmic antibody; SVV, small vessel vasculitis. cavity, lips, and pharyngeal mucosa that red, hemor-
&&
Adapted with permission from [2 ]. rhagic, cracked lips – the most unique clinical criteria;
edemaand erythemaofthehandsand feetfollowedby
periungaldesquamationofthefingersandtoes;gener-
major determinants of length of hospitalization by ally scarlatiniform maculopapular rash; and a non-
Cohen et al. [18]. suppurative cervical lymphadenopathy [7].
Symptoms and signs other than the clinical
criteria are also common. Rezai and Shahmohammadi
KAWASAKI DISEASE [24] reviewed the literature to evaluate the usefuln
KD is an acute febrile clinical condition of early ess of erythema at the Bacille Calmette-Guérin
childhood and is the second most common inoculation site as diagnostic criteria for early
pediatric vasculitis after HSP. Late diagnosis, delay diagnosis of KD. They noticed that this reaction was

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 Pediatric vasculitis Barut et al.

Table 3. The classification and diagnostic criteria for pediatric vasculitis

Henoch–Schonlein purpura/IgA vasculitis classification criteria
Purpura or petechia (mandatory) with lower limb predominance plus one of four:
Abdominal pain
Histopathology (IgA deposit in a biopsy)
Arthritis or arthralgia
Renal involvement
Kawasaki disease diagnostic criteria
Fever (must be present), plus four of five
Conjunctivitis
Mucosal changes
Cervical lymphadenopathy
Polymorphous rash
Extremity changes
Takayasu arteritis classification criteria
Angiographic abnormalities of the aorta or its major branches and pulmonary arteries showing aneurysm/dilatation (mandatory) plus one of
five:
Pulse deficit or claudication
Four limbs blood pressure discrepancy
Bruits
Hypertension
Elevated acute–phase reactants
Polyarteritis nodosa classification criteria
Histopathology or angiographic abnormalities (mandatory) plus one of five:
Skin involvement
Myalgia/muscle tenderness
Hypertension
Peripheral neuropathy
Renal involvement
Granulomatosis of polyangiitisclassification criteria (at least three of six)
Histopathology (granulomatous inflammation)
Upper airway involvement
Laryngo-tracheo-bronchial stenosis
Pulmonary involvement
Antineutrophilic cytoplasmic antibody positivity
Renal involvement
Primary angiitis of the central nervous system classification criteria
The presence of an acquired otherwise unexplained neurological or psychiatric deficit
The presence of either classic angiographic or histopathological features of angiitis within the central nervous system
No evidence of systemic vasculitis or any disorder that could cause or mimic the angiographic or pathological features of the disease

&
Adapted with permission from [3,7,8 ].

more prevalent than the classical diagnostic criteria
of KD-like cervical lymphadenopathy and rash.
Other less frequent clinical findings include marked
irritability, diarrhea, hepatitis, hydrops of the gall-
bladder, jaundice, pancreatitis, aseptic meningitis,
anterior uveitis, urethritis and meatitis with sterile
pyuria, and arthralgia/arthritis, respiratory symp-
toms, otitis media or tympanitis and facial nerve
palsy [25].
Cardiovascular involvement during the suba-
cute stage is responsible for the morbidity and
mortality. CAA is the most serious complication
of KD which may result in myocardial infarction.
Other less frequent complications include myo-
carditis and pericarditis. Although the involvement
of coronary arteries is classically defined as aneur-
ysms, our experience suggests coronary artery dila-
tation might also be common. Early diagnosis

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Vasculitis syndromes
during acute stage and prompt administration of
IVIG decrease the development of CAA formation
[7,25].
Giacchi et al. [26] enrolled 31 children with KD
and compared them with healthy controls. Signifi-
cant coronary artery intima thickness was noticed in
children with KD compared with the healthy con-
trols. In addition, coronary vessel wall thickness was
also increased in KD even in the absence of coronary
involvement in acute stage. Higher cardiovascular
disease risk was noted among children who had
increased coronary vessel wall thickness in this
study.
Typical changes of the mucosal surfaces and
lymph nodes usually do not present in the first
6 months of life. The diagnosis of atypical KD should
be considered and echocardiography should be per-
formed if the infant does not meet the diagnostic
criteria but shows signs of systemic inflammation.
Especially infants may have an incomplete presen-
tation. As risk of coronary artery abnormalities is
higher in infants, treatment should be initiated
immediately to prevent CAA if there is a suspicion
of KD [27].
Rarely, CAAs may also develop in other rheu-
matological diseases like PAN, GPA, microscopic
polyangiitis, and systemic onset juvenile idiopathic
arthritis (SoJIA). There are reported cases of SoJIA in
literature that presented with KD-like symptoms
and were treated initially as KD [28]. Serum IL-18
levels were proposed as the most efficient data in
differential diagnosis of SoJIA and KD by Takahara
&
et al. [29 ].
IVIG significantly improves the short and long-
term natural history of disease, as fever and other
systemic clinical findings of first stage typically
resolve in a short time(less than 7 days). Approxi-
mately 10–20% of the children do not respond to
the initial infusion of IVIG. If fever and clinical
findings do not resolve within 36 h, IVIG may be
readministered. In persisting IVIG resistance, in 3–
4% of the cases, pulse steroids are administered as
30 mg/kg/day dose. Alternative treatment modal-
ities in unresponsive cases include anti-TNFa agen
ts (infliximab), calcineurin inhibitors, plasma
exchange, rituximab, and anakinra [7,30].
TAKAYASU ARTERITIS
TA is a chronic granulomatous large vessel vasculitis
typically involving aorta and its main branches. It is
typically seen among young women. Although
rather rare in patients younger than 16 years, TA
is the third most common cause of vasculitis in the
pediatric population after KD and HSP. In children,
disease is characterized with nonspecific features
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including fever, fatigue, myalgia, arthralgia,
abdominal pain, hypertension, hypertensive retin-
opathy, cardiac insufficiency, headache, and con-
vulsion. In the ischemic phase of the disease, loss of
pulses and bruits over involved arteries could be
noticed. The main presenting clinical feature is
hypertension. Bruits and loss of pulses share the
second place among clinical features. Therefore,
detailed physical examination including ausculta-
tion for bruits in children with hypertension and
nonspecific conditional symptoms is of high
importance for early diagnosis of TA [31–35].
The cause of the disease remains unclear. Gran-
ulomas and Langhan’s giant cells resembling tuber-
culosis lesions indicate a possible role of tuberculosis
in etiopathogenesis of the disease. The incidence of
positive Purified protein derivative test is reported to
be high [35].
The assessment of disease activity in TA patients
is difficult, especially in the pediatric population.
Main reasons are the deficient sensitivity of acute-
phase reactants, nonspecific clinical features, and
insidious clinical course of the disease. Active vas-
culitis could be seen even in patients with normal
acute-phase markers and those without pathological
findings on Florine 18 (F18) fluorodeoxyglucose,
Positron emission tomography-computerized tom-
ography scan [35,36]. The use of circulating
biomarkers (e.g. pentraxin 3) still needs clinical
validation [37].
Because of nonspecific features mimicking
different diseases, the diagnosis of TA in children
is usually delayed. This leads to disease progression
and secondary organ damage. Aggressive immuno-
suppressive therapy and timely endovascular inter-
vention could possible abort the progression of the
disease and consequently decrease the frequency of
surgical interventions and rate of mortality [31–
34]. Evidence based data about therapy in child-
hood TA are lacking; aggressive and timely treat-
ments are thought to be of high significance in
decreasing the morbidity and mortality of the dis-
ease [34].
There is no control clinical study about in child-
hood TA therapy. Although the course of the disease
is variable, the use of corticosteroids is shown to
reduce the lesions’ progression. Immunosuppressive
therapy is responsible for better disease control and
prevention from restenosis. Angioplasty techniques
are effective in TA therapy, increasing 5-year sur-
vival to 80–95% [38]. Tocilizumab has been
reported to be effectively used in just a few pediatric
TA cases despite its common usage in adults. A 3-
year-old TA patient nonresponsive to classical
therapy showed a good response to tocilizumab
[38,39].
Volume 28  Number 1  January 2016

POLYARTERITIS NODOSA
PAN is a clinical syndrome that has a variety of
different combinations of clinical presentations
and is characterized by fibrinoid necrosis of small
and/or medium-sized arteries. The decrease in the
prevalence of hepatitis B has resulted in a significant
decrease in PAN frequency. Therefore, infectious
triggers in the disease pathogenesis have been pro-
&& &
posed [1,40 ,41,42 ].
Both PAN and ANCA-associated vasculitis (AAV)
are necrotizing vasculitis of small to medium-sized
blood vessels and discrimination based on clinical
and pathological findings between these two enti-
ties is quite difficult.
&&
Iudici et al. [40 ] recently reported 35 children
with AAV, together with 21 children with PAN and
found no clear difference between the relapse rates.
This study is remarkable for its follow-up period
with a mean period of 9.5 years.
The authors, the French Vasculitis Study Group,
compared the most frequent seen symptoms and
signs from 56 cases of systemic necrotizing vasculi-
tis. Constitutional, ear-nose-throat (ENT) and respir-
atory symptoms and signs were the most frequent
clinical findings of GPA, whereas mucocutaneous
and musculoskeletal symptoms were more pro-
nounced in PAN. There were no lung, ear-nose-
throat and eye involvement in this PAN cohort.
Relapses occurred in three quarters of children,
but most of them were minor flares and the overall
&&
mortality rate was 10% [40 ].
A retrospective study of 69 children with child-
hood PAN who had been followed over a 32-year
period reported by Eleftheriou et al. [41] has also
been available. Cutaneous involvement, fever,
myalgia, arthritis/arthralgia, weight loss, and fatigue
were the most frequent symptoms of onset. Hyper-
tension, renal disease, gastrointestinal, and neuro-
logic involvement were less frequent. Skin biopsies
revealed necrotizing vasculitis in 40 of 50 cases and
selective visceral angiography results were consist-
ent with PAN of the 96% of the patients. Cyclo-
phosphamide and corticosteroids were the most
frequent agents used. The relapse and the mortality
rates were reported as 35 and 4%, respectively.
There is still some controversy among rheuma-
tologists about whether cutaneous PAN should be
&
accepted in the spectrum of PAN. Merlin et al. [42 ]
have recently underlined no differences in patient
outcome between visceral PAN, cutaneous PAN,
and a moderate form of cutaneous PAN with sig-
nificant extra-cutaneous features in his retrospec-
tive survey of 29 patients diagnosed with
childhood-onset PAN.
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Pediatric vasculitis Barut et al.
Deficiency in adenosine deaminase 2
Deficiency in adenosine deaminase2 (DADA2)
represents a condition with variable clinical presen-
tations ranging from a silent disease limited to skin
to a fatal form of vasculopathy. Early-onset stroke,
childhood PAN, fever, livedo reticularis, lacunar
infarctions, hepatomegaly accompanying portal hy-
pertension, Sneddon syndrome, and humoral
immune deficiency are the most common clinical
& & &
presentations of the DADA2 [43 ,44 ]. A study [43 ]
of five different Georgian Jewish families where the
19 individuals were recognized to have PAN indi-
cated a possible autosomal recessive inheritance and
monogenic form of the disease. Exome sequencing
was performed in 16 patients. All 16 patients were
found to have a CECR1 gene mutation associated
with DADA2. We reported a patient of fatal vascul-
opathy with early-onset stroke and clinical features
mimicking autoinflammatory diseases [45]. A vari-
able dermatological lesions (e.g. livedo reticularis,
nodules) and histopathological findings of nongra-
nulomatous necrotizing arteritis have also been
described [46]. Although there is still no consensus
on how to treat DADA2, plasma infusions and eta-
& &
nercept have been recommended [43 ,44 ].
ANTINEUTROPHILIC CYTOPLASMIC
ANTIBODY-ASSOCIATED VASCULITIS
Systemic necrotizing vasculitis accounts for 3% of
all cases being referred to pediatric rheumatology
&&
clinics [40 ]. GPA, eosinophilic granulomatosis
with polyangiitis, and microscopic polyangiitis
represent the main entities of the AAV. An annual
incidence of GPA is reported to be from 0.2 to 1.2 per
100 000 (Table 1). The most common age of onset is
between 40 and 60 years. In the pediatric popu-
lation, the peak of the disease is thought to be in
the second decade of life with a higher prevalence
among female patients [47].
The GPA is characterized by its triad of inflam-
mation in the upper and lower respiratory tracts
&
accompanied by renal involvement [48,49 ]. In
the A Registry for Children with Vasculitis: e-entry
study of 65 cases, the most prominent consti-
tutional complaints were fatigue, weight loss, fever,
and malaise. ENT, pulmonary and renal findings
were the most common findings in the physical
examination [48]. In the study by Bohm et al.
&
[49 ] nasal septum perforation, saddle nose, ear
chondritis, subglottic stenosis, coarsening, and stri-
dor were the most frequent ENT findings. Wheez-
ing, expiratory dyspnea, pulmonary nodule, and
cavity were the most frequent pulmonary findings.
www.co-rheumatology.com 35
Vasculitis syndromes

(a) (d)

(e)

(b)

(f)

(c)

FIGURE 1. Radiological images in different childhood vasculitis. (a) Giant coronary artery involvement in Kawasaki disease.
(b) Aortic involvement in Takayasu arteritis. (c) Renal artery aneurysms in polyarteritis nodosa. (d) Intracranial hemorrhages
and cerebral vasculitis in deficiency of adenosine deaminase 2. (e) Lung involvement in granulomatosis with polyangiitis.
(f) Central nervous system vasculitis.

The features of eye involvement are conjunctivitis,
keratitis, and blepharitis.
&
Bohm et al. [49 ] reported 67 and 26% of patients
with PR3 and MPO positivity, respectively. The dis-
ease activity index and damage scoring system com-
monly used among adult patients were found to be
inappropriate for childhood AAV and there are
only a few related pediatric studies in this area.
Morishita et al. [50] found the Birmingham Vascu-
litis Activity Score was unsatisfactory in children
with a weak relation between treatment decision
and Erythrocyte sedimentation rate, whereas Dole-
zalova et al. [51] proposed apediatric vasculitis
activity score for clinical trials.
As no reliable study on treatment of childhood
AAV is available, the therapy modality is generally
&
basedontheadultexperience.Alargestudy[52 ]about
the treatment of pediatric vasculitis has recen tly
&
been published [52 ]. The majority of pediatric rheu-
matologists agree with effective and aggressive treat-
ment. The recommended first-line treatment regime
includes glucocorticoids and cyclophosphamide.

36 www.co-rheumatology.com Volume 28  Number 1  January 2016

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


CENTRAL NERVOUS SYSTEM VASCULITIS
CNS vasculitis represents a type of vasculitis charac-
terized by isolated CNS clinical features, without
other constitutional symptoms. Radiological exam-
inations reveal infarctions and/or ischemic finding
in CNS. A diagnosis is confirmed by angiography or
brain biopsies. The clinical course of the disease is
variable, mainly influenced by the presence of
systemic symptoms. Also known as primary angiitis
of the CNS (cPACNS), childhood CNS vasculitis is
the most common cause of acquired neurological
& consensus conference nomenclature of vasculitides. Arthritis Rheum 2013;
deficits in previously healthy children [8 ].
Calabrese CNS vasculitis criteria are used as
classification criteria of childhood CNS vasculitis.
There are three different subtype of the disease:
(1) Nonprogressive medium-large vessel cPACNS
(angiography positive),
(2) Progressive medium-large vessel cPACNS
(angiography positive),
(3) Small vessel cPACNS (angiography negative,
biopsy positive).
A study provided by Celucci et al. [53] revealed
that the Von Willebrand factor antigen might help
clinicians to identify changes in disease activity
during follow-up and predict the response to treat-
ment. A decrease in vWF level correlates with
reduction of disease activity in children with
primary CNS vasculitis.
CONCLUSION
Pediatric vasculitis often present with nonspecific
symptoms and signs like fever rash, malaise, and
fatigue which can present diagnosis challenges. In
the case of vasculitis these manifestations persist or
recurrence and significant increase in acute-phase
reactants usually accompany them. Specific labora-
tory examinations, imaging techniques (Fig. 1) and
biopsies of the skin and involved organs are usually
needed to confirm the diagnosis. Most pediatric
rheumatologists have an approach to administer
an immediate aggressive treatment strategy because
of lack of case-control studies providing prognostic
and treatment data in pediatric vasculitis. As
pediatric vasculitis is rare, large and long-term mul-
ticenter studies should be designated.
Acknowledgements
We would like to thank Amra Adrovic and Ayse Cigdem
Aktuglu Zeybek for their assistance with the study.
Financial support and sponsorship
None.
1040-8711 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pediatric vasculitis Barut et al.
Conflicts of interest
There are no conflicts of interest.
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Volume 28  Number 1  January 2016