Takayasu arteritis (TA) is a rare nonspecific inflammatory disease of unknown cause, predominantly affecting the aorta and its main branches, coronary arteries, and pulmonary arteries of young females. It induces a variety of nonspecific inflammatory symptoms and ischemic symptoms due to stenotic lesions. Further progression of TA causes destruction of the arterial wall media, leading to aortic regurgitation and aneurysms or rupture of the involved arteries. Although serological tests specific for TA are not available, new better biomarkers are emerging such as pentraxin3 and matrix metalloproteinases. Recent advances in imaging modalities including magnetic resonance angiography, computed tomography (CT), sonography, and fluorodeoxy glucose positron emission tomography/CT (FDG-PET/CT) allow earlier and accurate diagnosis of TA. Duration between onset of the disease and diagnosis has become much shorter during the last decade. Medical treatment for TA is also changing. In addition to the traditional glucocorticoids and immunosuppressants, many new biological agents are being applied to patients with TA refractory to conventional treatment with favorable results. As for treatment for vascular complications, efficacy of endovascular treatment is still a matter of controversy because of the high rate of restenosis at an early stage after the procedure. Based on these advances, the prognosis and quality of life of TA patients have improved to a great deal. However, there are many issues that remain to be solved in the management of TA.

1. Takayasu arteritis : CurrentTakayasu arteritis : Current
diagnosis and treatmentdiagnosis and treatment
RamachandraRamachandra

2. Bird’s eye viewBird’s eye view
Takayasu arteritis (TA) is a rare nonspecificTakayasu arteritis (TA) is a rare nonspecific
inflammatory disease of unknown cause,inflammatory disease of unknown cause,
predominantly affecting the aorta and its mainpredominantly affecting the aorta and its main
branches, coronary arteries, and pulmonarybranches, coronary arteries, and pulmonary
arteries of young females. It induces a varietyarteries of young females. It induces a variety
of nonspecific inflammatory symptoms andof nonspecific inflammatory symptoms and
ischemic symptoms due to stenotic Althoughischemic symptoms due to stenotic Although
serological tests specific for TA are notserological tests specific for TA are not
available, new better biomarkers are emergingavailable, new better biomarkers are emerging
such as pentraxin3 and matrixsuch as pentraxin3 and matrix
metalloproteinases.metalloproteinases.

3. Bird’s eye viewBird’s eye view
Recent advances in imaging modalities includingRecent advances in imaging modalities including
magneticresonance angiography, computed tomography (CT),magneticresonance angiography, computed tomography (CT),
sonography, and fluorodeoxy glucose positron emissionsonography, and fluorodeoxy glucose positron emission
tomography/CT (FDG-PET/CT) allow earlier and accuratetomography/CT (FDG-PET/CT) allow earlier and accurate
diagnosis of TA. Duration between onset of the disease anddiagnosis of TA. Duration between onset of the disease and
diagnosis has become much shorter during the lastdiagnosis has become much shorter during the last
decade.Glucocorticoids ,immunosuppressants and newdecade.Glucocorticoids ,immunosuppressants and new
biological agents are being applied to patients with TAbiological agents are being applied to patients with TA
refractory to conventional treatment with favourable results. Asrefractory to conventional treatment with favourable results. As
for treatment for vascular complications, efficacy offor treatment for vascular complications, efficacy of
endovascular treatment is still a matter of controversy becauseendovascular treatment is still a matter of controversy because
of the high rate of restenosis at an early stage after theof the high rate of restenosis at an early stage after the
procedure. However, there are many issues that remain to beprocedure. However, there are many issues that remain to be
solved in the management of TA.solved in the management of TA.

4. IntroductionIntroduction

5. EpidemiologyEpidemiology
1. In Japan, all cases of TA are registered by the Government. More than1. In Japan, all cases of TA are registered by the Government. More than
5000 cases are registered and the number of patients increases by 200 to5000 cases are registered and the number of patients increases by 200 to
400 every 3 years. However, the annual rate of increase has become400 every 3 years. However, the annual rate of increase has become
blunted in recent years.blunted in recent years.
2. Peak age of onset is the latter half of teens and early twenties in female2. Peak age of onset is the latter half of teens and early twenties in female
patients. No such peak exists in male patients.patients. No such peak exists in male patients.
3. A world-wide survey of TA revealed that cases are prevalent in Asia3. A world-wide survey of TA revealed that cases are prevalent in Asia
and Middle Eastern countries. 4.Male-to-female ratio is unique to eachand Middle Eastern countries. 4.Male-to-female ratio is unique to each
country.country.
5. vascular involvement differs in each area.5. vascular involvement differs in each area.
6. In Japan and South America, cervical and thoracic arterial lesions are6. In Japan and South America, cervical and thoracic arterial lesions are
more prevalent, but in Israel and other Asian countries, abdominalmore prevalent, but in Israel and other Asian countries, abdominal
lesions are more frequent. The reasons for these differenceslesions are more frequent. The reasons for these differences
accompanying ethnicity are not known. However, differences inaccompanying ethnicity are not known. However, differences in
genetic background may partly account for them, since different HLAgenetic background may partly account for them, since different HLA
risk alleles for TA are reported in each country .risk alleles for TA are reported in each country .

6. PathologyPathology
Pan-arteritis mainlyaffecting the aorta, pulmonary artery and theirmajor branches.Pan-arteritis mainlyaffecting the aorta, pulmonary artery and theirmajor branches.
The etiologyof this disease is still unknown, although, it is generally accepted that a TThe etiologyof this disease is still unknown, although, it is generally accepted that a T
cell-mediated autoimmune reaction against components of the vesselwalls, especiallycell-mediated autoimmune reaction against components of the vesselwalls, especially
the vasa vasorum, causes the chronic inflammation of large vessels .The first step ofthe vasa vasorum, causes the chronic inflammation of large vessels .The first step of
the pathological change in TA is granulomatous inflammation of vascular adventitiathe pathological change in TA is granulomatous inflammation of vascular adventitia
and outer part of the media .Severe inflammation of the vasa vasorum is a typicaland outer part of the media .Severe inflammation of the vasa vasorum is a typical
feature of TA. Pathologically, TA has an aspect of vasa vasoritis. Infiltrating cells arefeature of TA. Pathologically, TA has an aspect of vasa vasoritis. Infiltrating cells are
comprised of γδ T lymphocytes, natural killer cells,macrophages, cytotoxic Tcomprised of γδ T lymphocytes, natural killer cells,macrophages, cytotoxic T
lymphocytes and T helper cells and occasional giant cells in the media. Heat shocklymphocytes and T helper cells and occasional giant cells in the media. Heat shock
protein 65, which responds to γδT lymphocytes, is strongly induced in the media andprotein 65, which responds to γδT lymphocytes, is strongly induced in the media and
vasa vasorum in contrast to atherosclerosis, in which γδT lymphocytes and heartvasa vasorum in contrast to atherosclerosis, in which γδT lymphocytes and heart
shock protein 65 are not observed. This suggests participation of γδT lymphocytes inshock protein 65 are not observed. This suggests participation of γδT lymphocytes in
the pathogenesis of TA. The inflammation eventually extends to all layers of thethe pathogenesis of TA. The inflammation eventually extends to all layers of the
aortic wall. Strong calcification of the intima is another feature of TA in the chronicaortic wall. Strong calcification of the intima is another feature of TA in the chronic
stage .Distribution of affected vessels varies from case to case as well as having trendsstage .Distribution of affected vessels varies from case to case as well as having trends
based on race as mentioned above. Numano proposed a typing of TA depending onbased on race as mentioned above. Numano proposed a typing of TA depending on
the distribution of affected vessels .the distribution of affected vessels .

7. Genetic backgroundGenetic background
This disease is apparently not a genetic disorder. However, epidemiology of TAThis disease is apparently not a genetic disorder. However, epidemiology of TA
revealed its genetic background. There are risk alleles in HLA. About a half ofrevealed its genetic background. There are risk alleles in HLA. About a half of
Japanese patients with TA have the HLA B52 allele. Also, it is obvious that some, butJapanese patients with TA have the HLA B52 allele. Also, it is obvious that some, but
not many, patients show familial history of the same disease among siblings ornot many, patients show familial history of the same disease among siblings or
between mother and daughter. The genetic background is currently underbetween mother and daughter. The genetic background is currently under
investigation, but it may be that it is the susceptibility to this disease that isinvestigation, but it may be that it is the susceptibility to this disease that is
genetically transmitted. We analyzed HLA alleles in two cases of familial TA. Onegenetically transmitted. We analyzed HLA alleles in two cases of familial TA. One
case was mother and daughter, the other case was sisters. As shown in Table 1, HLA-case was mother and daughter, the other case was sisters. As shown in Table 1, HLA-
B52 was found in all patients.HLA typing provides important clinical information forB52 was found in all patients.HLA typing provides important clinical information for
diagnosis. We investigated HLA typing in a series of 96 patients . We confirmed thatdiagnosis. We investigated HLA typing in a series of 96 patients . We confirmed that
B52 was a risk allele for TA. However, cases of B39 were not frequent and we couldB52 was a risk allele for TA. However, cases of B39 were not frequent and we could
not find any difference of statistical significance in prevalence of the B39 allelenot find any difference of statistical significance in prevalence of the B39 allele
between TA patients and normal Japanese. In this series of analysis, we identified abetween TA patients and normal Japanese. In this series of analysis, we identified a
novel risk allele in other HLA molecules, B67 showed a higher odds ratio asnovel risk allele in other HLA molecules, B67 showed a higher odds ratio as
compared to B52. We found that patients with HLA-B52 were resistant to steroid andcompared to B52. We found that patients with HLA-B52 were resistant to steroid and
immunosuppressive treatment, although differences in severity of complicationsimmunosuppressive treatment, although differences in severity of complications
between patients positive for specific HLA alleles and those without could not bebetween patients positive for specific HLA alleles and those without could not be
found, contrary to previous reports.found, contrary to previous reports.

8. Clinical manifestationClinical manifestation
Clinical signs and symptoms originate from both the systemic inflammation and fromClinical signs and symptoms originate from both the systemic inflammation and from
local vascular complications. Serious complications such as visual loss, severelocal vascular complications. Serious complications such as visual loss, severe
hypertension, end-stage renal disease,and strokes are becoming less frequent,hypertension, end-stage renal disease,and strokes are becoming less frequent,
probably because of recent advances in imaging tests which allow relatively earlyprobably because of recent advances in imaging tests which allow relatively early
diagnosis. The most frequently observed systemic inflammatory symptoms are low ordiagnosis. The most frequently observed systemic inflammatory symptoms are low or
high grade fever, and general fatigue. These systemic symptoms could be insidioushigh grade fever, and general fatigue. These systemic symptoms could be insidious
and therefore be missed. Focal symptoms and signs are different depending on theand therefore be missed. Focal symptoms and signs are different depending on the
location of affected arteries. Pain in the upper body such as of the neck, jaw, arm,location of affected arteries. Pain in the upper body such as of the neck, jaw, arm,
shoulder,back, upper chest, and numbness of unilateral or both arms is a commonshoulder,back, upper chest, and numbness of unilateral or both arms is a common
complaint, since the aortic arch and its branches are the most commonly affectedcomplaint, since the aortic arch and its branches are the most commonly affected
lesions in this disease. Faintness or light headedness, especially upon gazinglesions in this disease. Faintness or light headedness, especially upon gazing
upwards, looking back, or using arms, is a frequently observed complaint. Lesions inupwards, looking back, or using arms, is a frequently observed complaint. Lesions in
the abdominal aorta cause hypertension, intermittent claudication, abdominal andthe abdominal aorta cause hypertension, intermittent claudication, abdominal and
low back pain.Physical examination is crucially important for being alerted to thelow back pain.Physical examination is crucially important for being alerted to the
presence of this disease. Pulselessness of unilateral or both radial arteries,andpresence of this disease. Pulselessness of unilateral or both radial arteries,and
vascular bruit are noticed in the neck, chest, back and abdomen.Visual as well asvascular bruit are noticed in the neck, chest, back and abdomen.Visual as well as
hearing disturbance are observed but can be temporal.Since the inflammatory lesionshearing disturbance are observed but can be temporal.Since the inflammatory lesions
usually extend longitudinally and are continuous in the aorta, we should be veryusually extend longitudinally and are continuous in the aorta, we should be very
careful to manage the whole aorta and its major branches even if there are nocareful to manage the whole aorta and its major branches even if there are no
apparent signs of arterial stenosis or dilationapparent signs of arterial stenosis or dilation

9. Differential DiagnosisDifferential Diagnosis
 Behcet's diseaseBehcet's disease
 giant cell arteritis such as temporalgiant cell arteritis such as temporal
arteritisarteritis
infective aortitis.infective aortitis.

10. DiagnosisDiagnosis
Blood testBlood test
 No blood tests specificNo blood tests specific
 The most useful markers :CRP,ESR.The most useful markers :CRP,ESR.
 Conventional inflammatory markers : fibrinogen, WBC, C3, C4, CH50 andConventional inflammatory markers : fibrinogen, WBC, C3, C4, CH50 and
immunoglobulin G. CRP is useful for following patients up after steroidimmunoglobulin G. CRP is useful for following patients up after steroid
treatment.treatment.
 Active disease :Matrix metalloproteinases (MMPs), interleukin (IL)-6 , IL18 ,Active disease :Matrix metalloproteinases (MMPs), interleukin (IL)-6 , IL18 ,
soluble receptor for advanced glycation end products (sRAGE) , serum amyloidsoluble receptor for advanced glycation end products (sRAGE) , serum amyloid
A , and soluble ICAM-1 .A , and soluble ICAM-1 .
 It is difficult to distinguish active from inactive disease using these markers.It is difficult to distinguish active from inactive disease using these markers.
MMP2 value was useful for the diagnosis of TA, and that MMP-3 and MMP-9MMP2 value was useful for the diagnosis of TA, and that MMP-3 and MMP-9
could be good markers for activity of TA inflammation.could be good markers for activity of TA inflammation.
 Pentraxins are a superfamily of conserved proteins characterized by thePentraxins are a superfamily of conserved proteins characterized by the
pentraxin domain. CRP and serum amyloid P are recognized as classical shortpentraxin domain. CRP and serum amyloid P are recognized as classical short
pentraxins, whereas pentraxin3 (PTX3) belongs to the long pentraxins. CRP andpentraxins, whereas pentraxin3 (PTX3) belongs to the long pentraxins. CRP and
serum amyloid P are produced in the liver in response to IL-6 and released intoserum amyloid P are produced in the liver in response to IL-6 and released into
the blood. In contrast,PTX3 can be produced locally by a variety of tissues andthe blood. In contrast,PTX3 can be produced locally by a variety of tissues and
cells, such as vascular endothelial cells, macrophages and neutrophils,cells, such as vascular endothelial cells, macrophages and neutrophils,
predominantly in response to proinflammatory signals]. PTX3 is the best singlepredominantly in response to proinflammatory signals]. PTX3 is the best single
biomarker, which is not affected by prednisolone dose.biomarker, which is not affected by prednisolone dose.

11. ImmagingImmaging
MRIMRI
CTCT
18FDG-PET/CT18FDG-PET/CT
Carotid sonography: Homogenous, bright,Carotid sonography: Homogenous, bright,
and concentric thickening of intima of theand concentric thickening of intima of the
internal and/or common carotid arteries,internal and/or common carotid arteries,
sometimes called as the “sometimes called as the “macaroni sign”macaroni sign”

12.  MedicalMedical
Induction:Induction:
immunosuppression=Steroid,methotrexate azathioprine ,immunosuppression=Steroid,methotrexate azathioprine ,
cyclophophamidecyclophophamide
mycophenolate mofetil tacrolimusmycophenolate mofetil tacrolimus
maintenance:maintenance:
steroidsteroid
 Suurgical /InterventionSuurgical /Intervention
management of arterial complications.management of arterial complications.
Remission :disappearance of symptomsRemission :disappearance of symptoms
and normalization of inflammatoryand normalization of inflammatory
biomarkers.biomarkers.

13. Newer ImmunosuppressantsNewer Immunosuppressants
 TNF- α receptor antagonistsTNF- α receptor antagonists
Etanercept,Adalimumab andEtanercept,Adalimumab and
Infliximab are not effectiveInfliximab are not effective
anti-IL-6 receptor antagonistsanti-IL-6 receptor antagonists
Tocilizumab is effectiveTocilizumab is effective

14. Disease monitoringDisease monitoring
Biomarkers that allow monitoring of diseaseBiomarkers that allow monitoring of disease
activity especially during immunosuppressiveactivity especially during immunosuppressive
treatment are desirable. Some patients withtreatment are desirable. Some patients with
recurrence during steroid treatmentrecurrence during steroid treatment
 CRP of no useCRP of no use
 TX3 could reflect disease activity even underTX3 could reflect disease activity even under
immunosuppression .shows a typical case treatedimmunosuppression .shows a typical case treated
with such agents. In particular, tocilizumab iswith such agents. In particular, tocilizumab is
reported to suppress intractable inflammation ofreported to suppress intractable inflammation of
TA, but at the same time this new agent inhibitsTA, but at the same time this new agent inhibits
CRP production by suppressing IL-6 activity.CRP production by suppressing IL-6 activity.

15. ConclusionConclusion
TA is a rare disease accompanied by a variety of nonspecific clinical symptoms thatTA is a rare disease accompanied by a variety of nonspecific clinical symptoms that
may sometimes make it difficult to diagnose in its early stages. Multiple biomarkersmay sometimes make it difficult to diagnose in its early stages. Multiple biomarkers
for its diagnosis and evaluation of activity are being developed but more specificfor its diagnosis and evaluation of activity are being developed but more specific
markers are desirable. Although PTX-3 and MMPs have been proposed, their role inmarkers are desirable. Although PTX-3 and MMPs have been proposed, their role in
the assessment of TA is still a matter of investigation. However, recent advances inthe assessment of TA is still a matter of investigation. However, recent advances in
imaging modalities have resulted in earlier diagnosis and accordingly earlierimaging modalities have resulted in earlier diagnosis and accordingly earlier
treatment. These advances may lead to improvement of vascular complications.treatment. These advances may lead to improvement of vascular complications.
Medical treatment includes high dose steroids and new immunosuppressive drugs.Medical treatment includes high dose steroids and new immunosuppressive drugs.
Among them, anti-TNF agents are showing promise in suppressing inflammation,Among them, anti-TNF agents are showing promise in suppressing inflammation,
even in cases resistant to steroids. However, since the number of cases reported haseven in cases resistant to steroids. However, since the number of cases reported has
been limited, safety and long-term efficacy of these new agents for TA are still abeen limited, safety and long-term efficacy of these new agents for TA are still a
matter of further investigation. Surgical treatment of arterial stenosis provides reliefmatter of further investigation. Surgical treatment of arterial stenosis provides relief
of ischemic symptoms. Although the long-term safety of bypass surgery is generallyof ischemic symptoms. Although the long-term safety of bypass surgery is generally
accepted, the operation should be performed after the control of inflammation. As foraccepted, the operation should be performed after the control of inflammation. As for
endovascular stent implantation, many investigators report a high incidence of short-endovascular stent implantation, many investigators report a high incidence of short-
term restenosis, especially procedures conducted during uncontrolled inflammation.term restenosis, especially procedures conducted during uncontrolled inflammation.
Careful consideration is necessary for indication for surgery. Overall, advances in theCareful consideration is necessary for indication for surgery. Overall, advances in the
management of TA are supported by advances in technologies for biomarkers,management of TA are supported by advances in technologies for biomarkers,
imaging tests, immunosuppressant and surgical treatmentimaging tests, immunosuppressant and surgical treatment

16. Thanks to end.Thanks to end.