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com
Heart Online First, published on November 25, 2017 as 10.1136/heartjnl-2016-310848
Cardiovascular Division,
Vanderbilt University Medical
Center, Nashville, Tennessee,
USA
Correspondence to
Dr Joshua Beckman, Vanderbilt
University Medical Center, Heart survival rate has increased from 82.9% for patients
and Vascular Institute, 1215 Ave diagnosed between 1957 and 1975 to 96.5% for those
South Medical Center East, 5th
Floor, South Tower, Nashville,
TN 37232-8802, USA; ​joshua.​a.​ arterial complications and delay to diagnosis have also
beckman@​vanderbilt.​edu
Received 25 May 2017
To cite: Kim ESH, Beckman J.
Heart Published Online
First: [please include Day
Month Year]. doi:10.1136/
heartjnl-2016-310848
Copyright Article author (or their employer) 2017. Produced by BMJ Publishing Group Ltd (& BCS) under licence.
Review
Takayasu arteritis: challenges in diagnosis
and management
Esther S H Kim, Joshua Beckman
Abstract
Takayasu arteritis (TA) is a rare disease affecting chiefly
young women, although it can affect both men and
women and persons of many different ethnicities. TA
carries a high morbidity rate, but importantly, overall
mortality has declined over time such that the 15-year
diagnosed from 1976 to 1990. Severity of presenting
decreased over the past decade owing to advances in
non-invasive diagnostic imaging and the development
of medical therapies. Despite these advances, there
still remain significant gaps in the diagnosis and
management of these complex patients. These gaps
encompass the basic, yet extremely complex, tasks of
defining a universally accepted diagnostic criterion,
accurate assessment of disease activity and development
of clinically meaningful and accurate outcome measures
to guide necessary clinical trials for the management of
these complex patients.
Introduction
Takayasu arteritis (TA) is a chronic, granulomatous,
large-vessel panarteritis with preferential involve-
ment of the aorta, its major branch arteries and
the pulmonary artery. The mean age at diagnosis
is between 25 and 30 years, and women have been
reported to comprise 75%–97% of cases.1 Although
widely considered a rare disease primarily affecting
Asian women, TA can affect persons of any ethnicity,
with prevalence of disease varying by geographical
location. In Japan, the prevalence estimates are
over 0.004%,2 while it is 4.7 cases per million in
the UK.3 Contemporary incidence estimates for the
USA are lacking but have been estimated to be 2.6
new cases per million persons per year.4
The aetiology of TA is unknown, but several
studies have demonstrated an association with
human leucocyte antigens, suggesting a genetic
predisposition for the immune-mediated process.
Granulomatous inflammation has been observed
in the media and adventitia, and mononuclear cells
(predominantly lymphocytes, natural killer cells,
macrophages and plasma cells) and giant cells are
present in the media during active inflammation.
Areas of inflammation evolve to fibrosis and dense
scarring of the artery wall leading to stenosis, while
destruction of the elastic lamina and media may
lead to aneurysm formation.
TA is a chronic, relapsing and progressive disease.
About 20% of patients will have a self-limited condi-
tion, while the majority of patients will demon-
strate a relapsing/remitting or progressive course
requiring long-term immunosuppression. Up to
20% of patients will require a surgical intervention
Kim ESH, Beckman J. Heart 2017;0:1–8. doi:10.1136/heartjnl-2016-310848
for arterial complications.5–7 The long-term prog-
nosis is related to the presence of arterial complica-
tions and progressive course. Fifteen-year survival
for those with and without TA complications was
66.3% and 96.4% and 58.3% and 92.7% for those
with and without a progressive course, respectively.7
A multicentre retrospective study of 318 patients
from the French Takayasu Network demonstrated
that the 10-year event free (ie, vascular complica-
tion, relapse and/or death) survival rate was 36.4%.
Progressive disease course and carotidynia were
associated with worse event-free survival.8
Diagnostic challenges
Diagnostic and classification criteria for TA are in
evolution
There are no gold standard imaging or laboratory
tests with adequate sensitivity or specificity for the
diagnosis of TA. Patients may have significant delays
in diagnosis due to non-specific constitutional
symptoms which may precede the onset of apparent
clinical signs. Diagnostic criteria for TA employ a
combination of physical examination, labora-
tory and imaging findings. The Fiessinger criteria
incorporate endemic country of origin and prior
tuberculosis or streptococcal infection history,9 but
the most widely adopted criteria are those proposed
by Ishikawa10 and the American College of Rheu-
matology (ACR) classification criteria.11 The Ishi-
kawa criteria include an obligatory criterion of ≤40
years of age at time of diagnosis or onset of charac-
teristic signs and symptoms. The Ishikawa criteria
had a sensitivity of 84% when applied to a cohort
of 96 Japanese patients.10 The ACR criteria (table 1)
were developed to distinguish TA from other vascu-
litides for the purpose of research, rather than as
diagnostic criteria, and were developed using other
vasculitides as controls.11 The gold standard used
to test these criteria was a TA diagnosis adjudicated
by vasculitis experts. When three of six criteria are
present, the ACR criteria have a 90.5% sensitivity
and 97.8% specificity for the correct classification
of TA.
Major criticisms of the Ishikawa and ACR criteria
were their potential to underdiagnose patients
with late-onset TA and those with predominantly
abdominal aortic involvement. Vascular distribu-
tion of TA may vary geographically with higher
incidence of aortic arch involvement in Japanese
patients compared with higher incidence of thora-
coabdominal and renal disease seen in Indian
and Southeast Asian patients.12 Modifications
were proposed which removed the obligatory age
requirement and included the addition of coronary
artery lesions in patients <30 years of age in the
absence of atherosclerotic risk factors (table 2).
  1
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Review
Table 1  The 1990 American College of Rheumatology Classification
criteria for Takayasu arteritis
Criteria Definition
Age at disease Development of symptoms or findings related to TA
onset ≤40 years age ≤40 years
Claudication of extremities Development and worsening of fatigue and discomfort
while in use, especially the upper extremities
Decreased brachial artery Decreased pulsation of one or both brachial arteries
pulse
Blood pressure difference Difference of >10 mm Hg in systolic blood pressure
>10 mm Hg between arms
Bruit over subclavian Bruit audible on auscultation over one or both
arteries or aorta subclavian arteries or abdominal aorta
Arteriogram abnormality Arteriographic narrowing or occlusion of the entire
aorta, its primary branches or large arteries in the
proximal upper or lower extremities, not due to
arteriosclerosis, fibromuscular dysplasia or similar
causes; changes usually focal or segmental
For classification purposes, a patient is said to have Takayasu arteritis if at least
three of the six criteria are present. Reproduced with permission from Arend et al.11
These modifications resulted in a sensitivity of 92.5% and spec-
ificity of 95.0% for the diagnosis of TA in a population of 106
Indian patients with angiographically proven TA.12
Importantly, TA must be differentiated from giant cell arte-
ritis (GCA), another major cause of inflammatory aortitis also
thought to be an antigen-driven, cell-mediated autoimmune
process.1 TA and GCA may involve common arterial sites;
however, presenting symptoms differ such that patients with
GCA have greater prevalence of jaw claudication, visual symp-
toms and blindness. The major distinguishing feature between
TA and GCA is the age of onset; GCA affects an older cohort
with mean age at time of diagnosis of 75 years13. For this reason,
the ACR criteria for GCA includes an age of disease onset ≥50
years in addition to the criteria of new headache, temporal artery
abnormality, elevated erythrocyte sedimentation rate (ESR) and
abnormal artery biopsy.14 Multicentre, internationally collab-
orative work is ongoing to develop diagnostic criteria able to
differentiate the vasculitides, including TA, from its mimics and
to discriminate systemic vasculitides from each other.15
Clinical presentation is highly variable
Clinical presentations vary from non-specific constitutional
symptoms without clinical or radiographical evidence of arte-
rial occlusive disease (pre-pulseless stage) to symptoms attrib-
utable to arterial stenosis, aneurysm and occlusion (pulseless
stage) (table 3).16 Ascending aortic involvement can result
in aortic root dilatation and aneurysm with aortic regurgita-
tion. Abdominal aortic involvement may cause middle aortic
syndromes with resultant renovascular hypertension,17 while
distal aortic involvement can produce lower extremity clau-
dication symptoms (figure 1). The pulseless stage reflects the
advanced stages of disease, and diagnostic criteria and labora-
tory/imaging modalities able to detect TA in the early stages
disease are highly desirable.
Available biomarker findings are not specific
No blood tests are specific for TA. Autoantibodies (eg, antinuclear
antibody, antinuclear cytoplasmic antibody (ANCA), anti-DNA
antibody, anti-Ro antibody, circulating immune complexes18)
associated with other vasculitides are not useful for the diagnosis
of TA. Acute phase reactants (APRs) such as C reactive protein
(CRP) and ESR are non-specific. Active inflammation may also
be noted in elevated white blood cell counts, complement (C3,
C4, CH50) levels, fibrinogen and immunoglobulin G.5

Table 2  Modified Ishikawa diagnostic criteria for Takayasu arteritis

Three major criteria:
 1. Left mid subclavian artery lesion The most severe stenosis or occlusion present in the mid portion from the point 1 cm proximal to the vertebral artery orifice
up to that 3 cm distal to the orifice determined by angiography
 2. Right mid subclavian artery lesion The most severe stenosis or occlusion present in the mid portion from the right vertebral artery orifice to the point 3 cm
distal to orifice determined by angiography
 3. Characteristic signs and symptoms of at least These include limb claudication, pulselessness or pulse differences in limbs, an unobtainable or significant blood pressure
1-month duration difference (>10 mm Hg systolic blood pressure difference in limb), fever, neck pain, transient amaurosis, blurred vision,
syncope, dyspnoea or palpitations
Ten minor criteria:
 1. High ESR Unexplained persistent high ESR >20 mm/h (Westergren) at diagnosis or presence of the evidence in patients history
 2. Carotid artery tenderness Unilateral or bilateral tenderness of common arteries on palpation. Neck muscle tenderness is unacceptable.
 3. Hypertension Persistent blood pressure >140/90 mm Hg brachial or >160/90 mm Hg popliteal
 4. Aortic regurgitation By auscultation or Doppler echocardiography or angiography.
or annuloaortic ectasia By angiography or two-dimensional echocardiography
 5. Pulmonary artery lesion Lobar or segmental arterial occlusion or equivalent determined by angiography or perfusion scintigraphy, or presence
of stenosis, aneurysm, luminal irregularity or any combination in pulmonary trunk or in unilateral or bilateral pulmonary
arteries determined by angiography
 6. Left mid common carotid lesion Presence of the most severe stenosis or occlusion in the mid portion of 5 cm in length from the point 2 cm distal to its
orifice determined by angiography
 7. Distal brachiocephalic trunk lesion Presence of the most severe stenosis or occlusion in the distal third determined by angiography
 8. Descending thoracic aorta lesion Narrowing, dilation or aneurysm, luminal irregularity or any combination determined by angiography: tortuosity alone is
unacceptable
 9. Abdominal aorta lesion Narrowing, dilation or aneurysm, luminal irregularity or aneurysm combination.
 10. Coronary artery lesion Documented on angiography below the age of 30 years in the absence of risk factors like hyperlipidaemia or diabetes
mellitus
Presence of two major or one major and two minor criteria or four minor criteria suggests a high probability of Takayasu arteritis. The table is from Sharma et al,12 reproduced
with permission.
ESR, erythrocyte sedimentation rate.

2 Kim ESH, Beckman J. Heart 2017;0:1–8. doi:10.1136/heartjnl-2016-310848

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Table 3  Clinical presentations of Takayasu arteritis by affected
vascular territory
Sign/symptom
Constitutional Fatigue, weight loss, low-grade fevers, night
sweats
Musculoskeletal Arthralgias, myalgias, synovitis
Dermatologic Erythema nodosum, pyoderma
gangrenosum
Vascular Diminished or absent pulses, vascular bruits
 Aorta Aneurysm
Aortic regurgitation due to aortic dilatation
Aorta stenosis
 Common carotid arteries Stroke/TIA, syncope, orthostasis, headaches,
seizures, carotidynia, visual loss,
lightheadedness
 Vertebral arteries Subclavian steal syndrome, vertigo
 Subclavian arteries Upper extremity claudication, digital
ischaemia/gangrene, interarm blood
pressure discrepancy >10 mm Hg
 Coronary arteries (rare, lesions often Angina, heart failure, myocardial infarction
ostial in location)
 Pulmonary arteries Chest pain, dyspnoea, hemoptysis,
pulmonary hypertension
 Mesenteric arteries Abdominal pain, anorexia, diarrhoea,
gastrointestinal haemorrhage
 Renal arteries Renovascular hypertension (either from
renal artery stenosis or suprarenal aortic
stenosis)
 Iliac arteries Lower extremity claudication
16
 Small vessel Raynaud’s phenomenon (uncommon)
TIA, transient ischaemic attack.
Laboratory findings are not reliable indicators of disease
activity
Elevations in APRs are not consistently associated with disease
activity.19 ESR is elevated in >50% of patients considered to
be in remission.19 Biomarkers including interleukin (IL) 6, IL-8,
Review
IL-18, matrix metallopeptidase 9, vascular endothelial growth
factor, anti-endothelial cell antibodies and circulating endothe-
lial progenitor cells have been proposed as potential surrogates
for disease activity; however, investigations have yielded incon-
clusive results.20 One promising biomarker, pentraxin-3 (PTX3),
is part of a superfamily of proteins which behave as APRs.
PTX3 is produced by immune and vascular cells in response
to proinflammatory signals and plays a role in the recognition
of certain pathogens, activates the complement system and is
synthesised locally at sites of inflammation. Levels of PTX3 have
been observed to be higher in TA patients with active disease
(median >2.14 ng/mL) versus inactive disease (median 0.63 ng/
mL), healthy patients (median 0.11 ng/mL) and patients with
active infection (median 0.26 ng/mL). Levels of PTX3 have also
been shown to have higher area under the receiver operating
characteristic curve than ESR or CRP (0.92 (95% CI 0.847 to
0.991) versus 0.75 (95% CI 0.623 to 0.876) versus 0.68 (95%
CI 0.582 to 0.850), respectively).21 A PTX3 level of 5.37 ng/mL
has been shown to have a sensitivity of 82.6% and specificity
of 77.8% and area under the curve of 0.914 for the detection
of active disease, and PTX3 levels have been shown to be inde-
pendent of prednisolone dose.22 Small validation studies have
shown mixed results, and larger confirmatory studies are neces-
sary prior to the adoption of PTX3 as an accepted clinical deter-
minant of disease activity.
Lack of a ‘gold standard’ imaging modality
Physical examination for the detection of arterial lesions has
low sensitivity (range 14%–50%) but good specificity (range
71%–98%) when compared with angiography. Thus, the
majority of diagnostic criteria for TA are dependent on lesion
location as determined by imaging studies. The relative advan-
tages and limitations of the imaging studies used to establish the
diagnosis of TA are listed in table 4.5 23–26 Lack of specificity for
disease activity in available imaging tests highlights the comple-
mentary role of imaging to clinical assessment of disease activity.
TA lesions are generally smoothly tapered, circumferential
areas of luminal narrowing typically found close to the origin
of the primary branches of the aorta (figure 2). Copious collat-
eral vessels may be present and are indicative of the chronicity
of stenotic lesions. Additionally, TA lesions have been observed
to demonstrate ‘vascular symmetry’ whereby stenotic lesions
develop in paired vascular territories with contiguous disease
extension in the aorta.27 An angiographic classification has
been developed that categorises lesions based on their region
of involvement: type I (branches of the aortic arch), type IIa
(ascending aorta, aortic arch and its branches), type IIb (type
IIa lesions plus thoracic descending aorta), type III (thoracic
descending aorta, abdominal aorta, renal arteries or a combina-
tion), type IV (abdominal aorta, renal arteries or both) and type
V (entire aorta and its branches).28

Validated composite measures of disease activity for TA are

Figure 1  Magnetic resonance angiography demonstrating distal
aortic occlusion in a patient with Takayasu arteritis and bilateral lower
extremity claudication.
Kim ESH, Beckman J. Heart 2017;0:1–8. doi:10.1136/heartjnl-2016-310848
lacking
Therapy decisions in Takayasu arteritis depend on an accurate
assessment of disease activity. Major barriers include the lack
of a widely accepted TA-specific disease activity scoring system,
lack of a sensitive and specific biomarker which tracks with
disease activity, and lack of a gold-standard imaging modality
which can provide early recognition of active disease prior to
arterial stenosis and provide adequate differentiation within
stenotic lesions between active inflammation and scarring from
prior disease activity. In practice, disease activity is defined by a
3
4
Table 4  Imaging modalities for the evaluation of Takayasu arteritis
Catheter-based (digital subtraction)
angiography
CT angiography (CTA)
Magnetic resonance angiography (MRA)
18
F-fluorodeoxyglucose positron  ►► May be able to localise active vessel inflammation and provide data on
emission tomography (FDG-PET)
Duplex ultrasound
Transthoracic and transesophageal
echocardiography
Kim ESH, Beckman J. Heart 2017;0:1–8. doi:10.1136/heartjnl-2016-310848
Review
Advantages Limitations Assessment of disease activity
►► Precise evaluation of severity of stenotic arterial lesions ►► Invasive ►► None
►► Allows central aortic pressure measurements ►► Iodinated contrast
►► Concomitant therapeutic intervention as necessary ►► Radiation
►► No assessment of arterial wall thickness
►► Not a practical means for surveillance imaging
►► Ability to evaluate stenotic and aneurysmal lesions ►► Iodinated contrast ►► ‘Double ring’ pattern (circumferentially thickened aortic
►► ‘Roadmap’/relational imaging of vascular lesions ►► Radiation wall surrounding a concentric, low-attenuation ring inside
►► Ability to measure arterial wall thickness the aorta) on delayed-phase imaging described in small
►► When used in patients at high suspicion for TA, CTA has a sensitivity of studies
95% and specificity of 100%, using catheter-based angiography as the
gold standard.23
►► Ability to evaluate stenotic and aneurysmal lesions ►► Decreased sensitivity for smaller branch involvement ►► Delayed enhancement imaging has been poorly correlated
►► ‘Roadmap’/relational imaging of vascular lesions ►► Overestimate degrees of severe stenosis or occlusion with disease activity5 25
►► Vessel wall evaluation (thickening, oedema, degeneration)
►► Improved soft tissue discrimination vs CTA with ability to assess mural
oedema and vascularity
►► No radiation exposure
►► Sensitivity and specificity of 100% vs catheter-based angiography24
►► Not an angiographic study modality ►► Possible; moderate diagnostic value, studies with mixed
intensity of inflammation results
►► Sensitivity and specificity 70.1% and 77.2% for evaluation of disease
activity26
►► Ability to evaluate localised areas of stenosis and aneurysm ►► Unable to provide a ‘roadmap’ of vascular lesions ►► Possible; regression of carotid intima media interface with
►► Vessel wall evaluation ►► Unable to perform complete imaging of the aortic treatment reported
►► Non-invasive, no radiation exposure, does not require iodinated contrast arch and descending aorta ►► Pilot studies on the use of contrast-enhanced ultrasound
►► Operator dependent for disease assessment
►► Non-invasive, ability for concomitant assessment of aortic root and aortic ►► Unable to provide a ‘roadmap’ of vascular lesions ►► None
valve for insufficiency ►► Unable to differentiate among pathologies causing
►► May be used to demonstrate circumferential aortic wall mural thickening hypoechoic aortic wall mural thickening
►► May be used for surveillance of known ascending aortic dilatation or ►► Operator dependent
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aneurysm
►► May be used for the detection of pulmonary hypertension and emerging
use for the detection of pulmonary artery involvement
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Figure 2  Power Doppler image of the right common carotid
artery in a patient with Takayasu arteritis. There is a long segment of
hypoechoic, smooth, concentric arterial wall thickening (Macaroni sign)
characteristic of vasculitis.
combination of clinical signs and symptoms, laboratory assess-
ment and vascular imaging. Unfortunately, arterial specimens
have shown active inflammation in patients with apparent clin-
ical and laboratory remission.19
There are no validated disease activity criteria for large-vessel
vasculitis, including TA. The most commonly used measure is
known as the US National Institutes of Health (NIH) criteria
where active disease is defined as any two or more of the following:
(1) signs or symptoms of vascular ischaemia or inflammation,
(2) increase in sedimentation rate, (3) angiographic features and
(4) systemic symptoms not attributable to another disease.19
Review
Other disease activity assessment tools include the Birmingham
Vasculitis Activity Score (BVAS), but this scoring system has been
validated only and used primarily for the assessment of disease
activity in small-sized and medium-sized vasculitides (granulo-
matosis with polyangiitis and microscopic polyangiitis). Because
common manifestations of small-vessel disease are rare in TA,
some argue that the use of the BVAS may lead to unnecessary
organ evaluation and incomplete investigation of cardiovascular
findings.20 29 The Disease Extent Index for Takayasu’s Arteritis
(DEI.Tak) was developed to record disease extent and, while
based on the BVAS, assigned heavier weights to items related to
larger arterial disease. Unlike the NIH criteria, the DEI.Tak did
not include imaging or laboratory findings and, while was simple
to use, had only modest agreement with the physician’s global
assessment (PGA) (68%).30 The Indian Takayasu Clinical Activity
Score (ITAS2010) was subsequently developed as quantitative
score of new active disease by evaluating clinical features newly
present in the prior 3 months31. Elevated ESR and CRP were
added to the ITAS2010 (ITAS2010-A), and while these scoring
systems had good inter-rater agreement with the BVAS and PGA,
the ITAS2010-A scores did not decrease accordingly in patients
considered to have inactive disease by PGA after therapy.
Disease assessment methods for TA and their advantages and
disadvantages are summarised in table 520
Recognising the lack of widely accepted outcome measures
in TA, the goal of the Large Vessel Vasculitis task force, initi-
ated by the Outcome Measures in Rheumatology (OMERACT)
vasculitis working group in 2009, is to develop a core set of
data-driven, validated outcome tools for clinical trials in large
vessel vasculitis, including TA.20 In addition to incorporation of
physicians’ perspectives for important elements for assessment
of disease activity, patient-reported outcomes are also strongly

Table 5  Disease assessment methods for Takayasu arteritis

Outcome Advantages Disadvantages
TAK-related outcomes
 PGA Feasible, gold standard Not sufficiently discriminative for activity assessment, not
validated
 Flare Feasible Not sufficiently discriminative for activity assessment
 Remission Feasible Not sufficiently discriminative for activity assessment
 TAK disease activity scale (DEI.Tak/ Feasible Not in good concordance with PGA
ITAS2010)
 BVAS Feasible Missing aspects of disease
Consistent with other vasculitides Poorly accepted by investigators and not well validated for
Takayasu’s
 Vascular interventions (angioplasty, Major outcome—possibly well associated with long-term Not sufficiently sensitive for activity/damage assessment
stents, surgery) prognosis
 Catheter-based angiography Accurate assessment of vessel changes Not feasible for routine follow-up
 CTA or MRA Accurate assessment of vessel changes Expensive
Not validated
 PET Whole-body imaging Expensive
Potential for quantification of disease activity Not validated
 Damage index (VDI, TADS) Feasible, possibly associated with prognosis Hard to discriminate disease vs treatment effects
Laboratory testing outcomes
 APRs (ESR, CRP), PTX3 Feasible Not specific
Not validated
Other outcomes
 Mortality Feasible Not sufficiently discriminative as a study endpoint
 Patient-reported assessments Feasible Not validated
Disease-specific outcomes not yet developed
APR, acute phase reactant; BVAS, Birmingham Vasculitis Activity; CRP, C reactive protein; CTA, CT angiography; ESR, erythrocyte sedimentation rate; MRA, magnetic resonance
angiography; PGA, Physician’s Global Assessment; PTX3, pentraxin-3; TADS, Takayasu arteritis score; TAK, Takayasu’s arteritis; VDI, vasculitis damage index. The table is from
Aydin et al,20 reproduced with permission.

Kim ESH, Beckman J. Heart 2017;0:1–8. doi:10.1136/heartjnl-2016-310848 5

6
Table 6  Prospective studies of disease-modifying anti-rheumatic drugs for Takayasu arteritis
Review

Drug Study type n Patient population Outcome

Methotrexate (MTX)33
Leflunomide (LEF)35 36
AZA37
MMF38
Etanercept/inflixibmab39
Tocilizumab (TCZ)40
TCZ41
Open-label 18 ►► Mean disease duration 5.2 years ►► 81% (n=13) of patients achieved remission; 44% (n=7) relapse when steroids
►► Angiographically proven disease, failed steroids tapered, 23% (n=3) could stop steroids
►► Mean MTX dose 17.1 mg weekly added to steroids ►► 50% (n=8) attained remission for mean 14.2 months without steroids; 25% (n=4)
►► 16 patients followed for mean 2.8 years (two withdrew) could be taken off MTX
►► 18.8% (n=3) progressed despite treatment
Open-label 15 ►► Median disease duration 38 months ►► 80% (n=12) attained remission with reductions in steroid dose, ESR and CRP
►► Failed steroids, failed/intolerant to azathioprine (AZA), CYC, mycophenolate ►► 13.3% (n=2) new vascular lesions
mofetil (MMF), anti-tumour necrosis factor agents ►► 13.3% (n=2) improvement in prior lesions
►► Oral LEF 20 mg/day ►► In extended follow-up of 43 months in 12 of the 15 original cohort, 58% (n=7)
►► Median follow-up 9.1 months switched to other medications due to relapse (n=6) or GI side effects (n=1). No
patients who continued LEF had new vascular lesions
Open-label 15 ►► Newly diagnosed, angio-proven, active TA ►► 100% attained remission, reduction in ESR and CRP, no new angiographic lesions;
►► AZA 2 mg/kg daily added to steroids 50% arteries no progression, 31% improvement of stenosis, 15% worsening stenosis
►► 1-year follow-up ►► No side effects requiring discontinuation
Open-label 10 ►► Mean disease duration 4.8 years ►► 90% sustained clinical remission, significant reduction ESR and CRP
►► Active disease, failed steroids ►► 50% able to discontinue steroids, remaining 50% able to reduce steroid dose by 76%
►► MMF 2 g/day ►► No angio assessment of disease progression
►► Mean follow-up 23.3 months
Open-label 15 ►► Median disease duration 6 years ►► Seven patients received etanercept (three later switched to infliximab), eight received
►► Active, relapsing TA, failed steroids infliximab
►► Etanercept 25 mg twice weekly ►► 66.7% (n=10) achieved remission off steroids, 26.7% (n=4) partial remission
►► Infliximab 3–5 mg/kg 2 and 6 weeks after first dose, then every 4–8 weeks with>50% reduction in steroid dose.
after ►► 64.3% of responders required increase in dosage to sustain remission
►► Median follow-up 12 months
Open-label 2 ►► TCZ 8 mg/kg monthly×6 months ►► Patient one able to taper off steroids after prior failure of MTX, ESR and CRP
normalised. Asymptomatic at 7-month follow-up
►► Patient 2, TCZ monotherapy normalised ESR and CRP after first TCZ infusion,
asymptomatic at 10-month follow-up
►► PET/CT marked decrease in vascular FDG uptake after six TCZ infusions in both
patients
Open-label 16 ►► Newly diagnosed (1) or relapsed active disease; median three prior ►► Three withdrawal for severe neck pain after 1st dose
immunosuppressants ►► No withdrawals due to lack of efficacy
►► TCZ 4/mg/kg in seven patients, TCZ 8 mg/kg in nine patients for first dose, ►► One patient able to stop steroids; >50% reduction in steroid dose in seven patients.
then 8 mg/kg subsequent doses ►► Significant decreases in ESR, hsCRP, common carotid and subclavian artery wall
►► Median 10 doses in 13 months thickness by duplex ultrasound
►► Follow-up range 8–20 months
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TCZ42
(abstract form only)
Abatacept (CTLA-4lg)43
CRP, C reactive protein; ESR, erythrocyte sedimentation rate; FDG, fluorodeoxyglucose; GI, gastrointestinal; hsCRP, high-sensitivity C reactive protein; PET, positron emission tomography; TA, Takayasu arteritis.
Randomised, Double-blind,
phase III trial
Randomised, double-blind trial 34
18 ►► TA patients ≥12 years old who had relapsed ≤12 weeks before enrolment ►► Relapse-free rates at week 24: 50.6% TCZ, 22.9% placebo, no difference in time to
►► ≥2× steroid dose at relapse and in remission for 1 week prior to first relapse (HR 0.41 (95.41% CI 0.15 to 1.10), P=0.0596)
randomisation
►► TCZ 162 mg vs placebo weekly
►► Steroids tapered by 10 %/week
►► Newly diagnosed or relapsing TA patients treated with prednisone and ►► Relapse-free survival at 12 months
abatacept 10 mg/kg intravenous who achieved remission at 12 weeks were ►► 22% abatacept vs 40% placebo (P=0.853)
randomised to abatacept or placebo ►► Median duration of remission
►► 5.5 months abatacept vs 5.7 months placebo (P=0.125)

Kim ESH, Beckman J. Heart 2017;0:1–8. doi:10.1136/heartjnl-2016-310848

 Downloaded from http://heart.bmj.com/ on March 7, 2018 - Published by group.bmj.com
considered in the formation of these core outcome measures as it
has been recognised that disease manifestations of high priority
for patients with various forms of vasculitis are not routinely
collected by physician-based measures, although they have been
shown to have discriminatory capability among different disease
states in ANCA-associated vasculitis.32
Management challenges
Lack of large prospective clinical studies of medical therapy
Corticosteroids comprise the mainstay of therapy for TA.
Induction therapy with oral corticosteroids (1 mg/kg once
daily or divided into twice daily doses) is followed by
gradual tapering over weeks to months depending on the
rate of symptom and biomarker improvement. They can be
discontinued on remission; however, approximately half
of patients are not able to attain sustained remission with
glucocorticoid therapy alone. 33 Maintenance therapy with
disease-modifying antirheumatic drugs (DMARDs) such as
methotrexate, mycophenolate mofetil or azathioprine and
cytotoxic drugs such as cyclophosphamide may be neces-
sary. Patients unable to achieve remission with DMARDs are
treated with biological agents such as anti-tumour necrosis
factor alpha agents (infliximab, etanercept, adalimumab,
golimumab), tocilizumab, abatacept and rituximab,34 but
studies demonstrating improvement in disease status are
limited to small open-label studies composed of <20 patients
(summarised in table 6).33 35–43
The first and only randomised controlled trial of therapy
for TA enrolled 34 patients from 11 academic medical
centres and required a period of nearly 5 years. This was a
negative trial which did not show any difference in relapse-
free survival among patients randomised to abatacept or
placebo after having achieved remission with prednisone
and abatacept.43 Despite the negative results, this trial high-
lights important elements necessary to run a successful trial
of a rare vasculitis: a multicentre, collaborative approach, a
predetermined definition of disease activity, blinded assess-
ment of relapse, protocol-driven imaging schedule to assess
for asymptomatic progression of arterial disease.43 In 2009,
the European League Against Rheumatism34 developed
recommendations for the management of large-vessel vascu-
litis to include the following: early initiation of corticosteroid
therapy for induction of remission, use of immunosuppres-
sive agents as adjunctive therapy, clinical monitoring of
therapy with inflammatory markers as supportive data and
revascularisation to be performed in expert centres during
the quiescent phase of disease.34
Patency after revascularisation depends on disease activity
In the late and chronic stages of TA, revascularisation of
severely stenotic lesions may be required. No controlled
trials have been performed comparing open versus endovas-
cular revascularisation, and choice of therapy depends on
lesion characteristics. Success rates for percutaneous translu-
minal angioplasty used for short-segment stenosis have been
reported to range from 81% to 100%; however, restenosis
rates with or without stents vary widely but are reported
to be as high as 71.4% over 1.3 years44.45 A small single-
centre experience suggested that the use of stent grafts may
improve patency rates 45 due to deprivation of blood flow to
the inner layers of the vessel.
Open bypass is superior to endovascular therapy for
long-segment stenosis or occlusion, but results are worse when
Kim ESH, Beckman J. Heart 2017;0:1–8. doi:10.1136/heartjnl-2016-310848
Review
compared with those for bypass performed for atherosclerotic
disease. The reasons are several: longer lesion length, more
fibrotic vessels and persistence of vessel wall inflammation
despite clinical or laboratory evidence of quiescent disease.44
Around 20% of patients with TA will require surgical treat-
ment for vascular complications, primarily for stenotic
lesions.5 6 Bypass surgery is associated with low morbidity
and mortality and occlusion or restenosis after bypass grafting
occurs in 8%–31% of causes during a follow-up of 3–6 years45.
Patients with active disease are more likely to require surgical
revision or develop restenosis, and thus, when possible, revas-
cularisation is usually delayed until the disease is not active.46 A
retrospective multicentre review of 79 consecutive patients with
TA who underwent 166 vascular procedures (62.7% surgery,
37.3% endovascular repair) found a 37.5% complication rate for
those who underwent surgery compared with 50% for those who
underwent endovascular repair. The overall 5-year complication
rate for all procedures was 44%, and in multivariate analysis,
biological inflammation was independently associated with the
occurrence of complications (OR 7.48, 95% CI 1.42 to 39.39;
P=0.04).46 A single-centre registry of 42 patients with TA who
underwent surgical revascularisation showed that patients with
quiescent disease on no steroids had freedom from graft revision
at 5 and 10 years of 100% compared with 57% in those with
active disease on steroids and 33% in those with active disease
not on long-term steroids.6 In a study of 25 patients who under-
went 58 endovascular procedures, with or without stenting, only
after patients were treated with immunosuppressive therapy, and
after the ESR had normalised, there was a 17% restenosis rate
over a mean of 23.7 months47. Other studies have demonstrated
restenosis rates are lower when interventions are performed in
the stable stage of disease and when immunosuppressive therapy
postintervention is used.48
Conclusions
Several advances in the diagnosis and management of
patients with TA have led to significant improvement in
survival and decrease in morbidity. Significant gaps remain
in the diagnosis and management of these complex patients,
and given the rarity of the disease, bridging these knowledge
gaps will be the work of collaborative networks such as the
Vasculitis Clinical Research Consortium (www.​ rarediseas-
esnetwork.​org/​c ms/​v crc) and international efforts of organ-
ised networks such as OMERACT.49 The evidence base in the
study of TA also requires a move beyond expert opinion and
descriptive studies to adequately powered clinical trials in
order to provide the most optimal patient outcomes.
Competing interests  None declared.
Provenance and peer review  Commissioned; externally peer reviewed.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
article) 2017. All rights reserved. No commercial use is permitted unless otherwise
expressly granted.
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Takayasu arteritis: challenges in diagnosis

and management
Esther S H Kim and Joshua Beckman

Heart published online November 25, 2017

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