Takayasu arteritis : Takayasu arteritis : Current diagnosis and Current diagnosis and

treatmenttreatmentRamachandraRamachandra

Bird’s eye viewBird’s eye view

Takayasu arteritis (TA) is a rare Takayasu arteritis (TA) is a rare nonspecific inflammatory disease of nonspecific inflammatory disease of unknown cause, predominantly affecting unknown cause, predominantly affecting the aorta and its main branches, the aorta and its main branches, coronary arteries, and pulmonary arteries coronary arteries, and pulmonary arteries of young females. It induces a variety of of young females. It induces a variety of nonspecific inflammatory symptoms and nonspecific inflammatory symptoms and ischemic symptoms due to stenotic ischemic symptoms due to stenotic Although serological tests specific for TA Although serological tests specific for TA are not available, new better biomarkers are not available, new better biomarkers are emerging such as pentraxin3 and are emerging such as pentraxin3 and matrix metalloproteinases. matrix metalloproteinases.

Bird’s eye viewBird’s eye view

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

IntroductionIntroduction

EpidemiologyEpidemiology

1. In Japan, all cases of TA are registered by the Government. 1. In Japan, all cases of TA are registered by the Government. More than 5000 cases are registered and the number of More than 5000 cases are registered and the number of patients increases by 200 to 400 every 3 years. However, the patients increases by 200 to 400 every 3 years. However, the annual rate of increase has become blunted in recent years.annual rate of increase has become blunted in recent years.

2. Peak age of onset is the latter half of teens and early twenties 2. Peak age of onset is the latter half of teens and early twenties in female patients. No such peak exists in male patients.in female patients. No such peak exists in male patients.

3. A world-wide survey of TA revealed that cases are prevalent in 3. A world-wide survey of TA revealed that cases are prevalent in Asia and Middle Eastern countries. 4.Male-to-female ratio is Asia and Middle Eastern countries. 4.Male-to-female ratio is unique to each country. unique to each 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 6. In Japan and South America, cervical and thoracic arterial

lesions are more prevalent, but in Israel and other Asian lesions are more prevalent, but in Israel and other Asian countries, abdominal lesions are more frequent. The reasons countries, abdominal lesions are more frequent. The reasons for these differences accompanying ethnicity are not known. for these differences accompanying ethnicity are not known. However, differences in genetic background may partly However, differences in genetic background may partly account for them, since different HLA risk alleles for TA are account for them, since different HLA risk alleles for TA are reported in each country .reported in each country .

PathologyPathology

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

Genetic backgroundGenetic background This disease is apparently not a genetic disorder. However, epidemiology of This disease is apparently not a genetic disorder. However, epidemiology of

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

  

Clinical manifestationClinical manifestation Clinical signs and symptoms originate from both the systemic Clinical signs and symptoms originate from both the systemic

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

Differential DiagnosisDifferential Diagnosis

Behcet's diseaseBehcet's disease giant cell arteritis such as giant cell arteritis such as

temporal arteritistemporal arteritisinfective aortitis.infective aortitis.

DiagnosisDiagnosisBlood testBlood test

No blood tests specific No blood tests specific The most useful markers :CRP,ESR.The most useful markers :CRP,ESR. Conventional inflammatory markers : fibrinogen, WBC, C3, C4, CH50 Conventional inflammatory markers : fibrinogen, WBC, C3, C4, CH50

and immunoglobulin G. CRP is useful for following patients up after and immunoglobulin G. CRP is useful for following patients up after steroid treatment. steroid treatment.

Active disease :Matrix metalloproteinases (MMPs), interleukin (IL)-6 , Active disease :Matrix metalloproteinases (MMPs), interleukin (IL)-6 , IL18 , soluble receptor for advanced glycation end products (sRAGE) , IL18 , soluble receptor for advanced glycation end products (sRAGE) , serum amyloid A , and soluble ICAM-1 .serum amyloid A , and soluble ICAM-1 .

It is difficult to distinguish active from inactive disease using these It is difficult to distinguish active from inactive disease using these markers. MMP2 value was useful for the diagnosis of TA, and that MMP-markers. MMP2 value was useful for the diagnosis of TA, and that MMP-3 and MMP-9 could be good markers for activity of TA inflammation. 3 and MMP-9 could be good markers for activity of TA inflammation.

Pentraxins are a superfamily of conserved proteins characterized by Pentraxins are a superfamily of conserved proteins characterized by the pentraxin domain. CRP and serum amyloid P are recognized as the pentraxin domain. CRP and serum amyloid P are recognized as classical short pentraxins, whereas pentraxin3 (PTX3) belongs to the classical short pentraxins, whereas pentraxin3 (PTX3) belongs to the long pentraxins. CRP and serum amyloid P are produced in the liver in long pentraxins. CRP and serum amyloid P are produced in the liver in response to IL-6 and released into the blood. In contrast,PTX3 can be response to IL-6 and released into the blood. In contrast,PTX3 can be produced locally by a variety of tissues and cells, such as vascular produced locally by a variety of tissues and cells, such as vascular endothelial cells, macrophages and neutrophils, predominantly in endothelial cells, macrophages and neutrophils, predominantly in response to proinflammatory signals]. PTX3 is the best single 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.

ImmagingImmaging

MRIMRICTCT18FDG-PET/CT18FDG-PET/CTCarotid sonography: Homogenous, Carotid sonography: Homogenous,

bright,bright,

and concentric thickening of intima of the and 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 macaroni sign”sign”

MedicalMedical Induction:Induction: immunosuppression=Steroid,methotrexate azathioprine , immunosuppression=Steroid,methotrexate azathioprine ,

cyclophophamide cyclophophamide mycophenolate mofetil tacrolimus mycophenolate mofetil tacrolimus maintenance:maintenance: steroidsteroid Suurgical /InterventionSuurgical /Intervention management of arterial complications.management of arterial complications.

Remission :disappearance of Remission :disappearance of symptoms and normalization of symptoms and normalization of inflammatory biomarkers.inflammatory biomarkers.

Newer Newer ImmunosuppressantsImmunosuppressants

TNF- α receptor antagonists TNF- α receptor antagonists Etanercept,Adalimumab and Etanercept,Adalimumab and Infliximab are not effectiveInfliximab are not effective

anti-IL-6 receptor antagonistsanti-IL-6 receptor antagonists

Tocilizumab is effectiveTocilizumab is effective

Disease monitoringDisease monitoring

Biomarkers that allow monitoring of diseaseBiomarkers that allow monitoring of disease activity especially during immunosuppressive activity especially during immunosuppressive

treatment are desirable. Some patients with treatment 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 under TX3 could reflect disease activity even under

immunosuppression .shows a typical case immunosuppression .shows a typical case treated with such agents. In particular, treated with such agents. In particular, tocilizumab is reported to suppress tocilizumab is reported to suppress intractable inflammation of TA, but at the intractable inflammation of TA, but at the same time this new agent inhibits CRP same time this new agent inhibits CRP production by suppressing IL-6 activity.production by suppressing IL-6 activity.

ConclusionConclusion TA is a rare disease accompanied by a variety of nonspecific clinical TA is a rare disease accompanied by a variety of nonspecific clinical

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

Thanks to end.Thanks to end.