Takayasu arteritis – current issues P.Nagaraj kumar
DefinitionAn idiopathic inflammatory disease of thelarge elastic arteries occurring in theyoung and resulting in occlusive or ectaticchanges mainly in the aorta and itsimmediate branches as well as thepulmonary artery and its branches.
History• 1761- Morgagni- Reported first Case• 1856- Savory - reported a case• 1908- Takayasu, professor of ophthalmology - 21 yrs woman with characteristic fundal arterio- venous anastomoses and absent radial pulse• 1921- SHIKARE- first case report in india• 1951- Shimizu and Sano- Pulseless Disease• 1962 & 1971 –Sen – Middle Aortic Syndrome and association with TB in 101cases.• 1993- Chappel Hill - Takayasu Arteritis as granulomatous inflammations of Aorta
EPIDEMIOLOGY• Predominantly a disease of young females in their 2 nd or 3rd decades. Less than 40 yrs – obligatory crtiteria Childhood onset is not rare. Mean age European study- 41yrs, Japan-29yrs India –age of onset mean -24yrs, Age at Δ -28 yrs• Sex: F>M• Geographical variation : Japan - 8:1, Israel - 1.2:1, Mexico - 5:1, India - 4 : 1 (recently,panja et al - 6.4:1)• Geographical variation :Japan-proximal Aorta (Aortic Site) SE Asia-Middle Aortic syndrome North Europeans: patchy .,assoc. RArthritis,SLE• Incidence & prevalence : most commonly seen in Japan, South East Asia, India, and Mexico. Hospital based studies- 0.8 -2.6per million.
ETIOPATHOGENESISGenetic: India HLA B5, B21 (kumar et al) USA HLADR4, MB3 Japan HLADR2, MB1, Bw52, DW2, DQW1 HLA Bw52-IHD,AR,Pul involvement HLA B39-Renal artery stenosisAutoimmunity: immune reaction against elastin circulating gammaglobulins (alpha1& globulins,IgG, IgA, IgM, CMI, ANA, Anti - Aorta Ab (AA), Anti - endothelial cell Ab) , raised ESR, leucocytosis, arthralgia and high titers of anti-aorta antibodies Cell mediated immunity
Rheumatic : (Upmark 1954) some pts had raised ASO titreFemale predilection : Urinary estrogens elevated. Estradiol and progesterone, but not testosterones, enhance leucocyte adhesion to endothelial cells in the presence of TNF.?Infection: hypersensitivity to Mycobacterium tuberculosis
Tuberculosis and TA• Lupi-Herrera et al. previous tuberculosis in 48% of Japanese patients• Sen et al. tuberculosis in 71% patients in India• Pantell and Goodman 1961 to 1981 tuberculin test positive in 73.3% – 100% of cases active tuberculosis in 0.26% – 4.2% of the cases.• Heightened response to tubercular antigens especially the 65 kDa HSP• Tubercular aortitis lesions- discrete, aneurysm formation, nonobstructive.• Granulomas -caseating in nature in TB. In TA - proliferative without caseation.• No evidence for causation• ?Viral etiology
Pathology - Lesions in the AORTA• Localised involvement of a segment of Aorta varying in size 2-7 cms.• Multiple short segments with normal “skipped areas” in between.• Diffuse involvement of large portion of aorta with a stretch of normal aorta in between.• Proximally,lesion may start at aortic valve
• Variable amount of adventitial or periadventitial fibrous thickening over involved part of aorta.• Dilatation of Ascending Aorta seen in portion proximal to obstructive lesion.• Aneurysm may occur without any obstructive lesion.• FOUR Types of luminal changes: 1. Irregular lumen 2. Ectasia 3. Obstructive lesion-”stenosis” (hallmark of disease) 4. Aneurysms-saccular & fusiform
Distribution of lesion in the AortaLocalized: 37.5% - Adults:- Abdominal Aorta Children:-Thoracic+AbdominalDiffuse: 62.5% -thoraco-abdominalDescending thoracic Aorta is maximally affected areaAortic Arch: Distal involvement more than proximal.Relative involvement of branch arteries: (%)(Panja et al)Coronaries 16.75 Lt.CCA 7.5Innominate 7.5 Coeliac A 3.75Rt.SCA 13.75 Sup.Mesentric A 16.75Lt.SCA 40 Renal A 63.75Rt.CCA 11.25Commenest lesion in branches is ostial stenosis.BL Renal A Stenosis > UL(2.5 times)
DIAGNOSTIC CRITERIA• ISHIKAWA CRITERIA (1988)• ACR CRITERIA (1990)• SURI & SHARMA et. al CRITERIA (1995)
Diagnostic Criteria ISHIKAWA’S• Obligatory: Age< 40yrs ; at the time of diagnosis, at onset of characteristic symptoms & signs of 1 month duration• Major : • Left Mid Subclavian Artery Lesion • Right Mid Subclavian Artery Lesion *Most severe obstruction occurs in mid portion 1cm proximal to lt vertebral to 3cm distal
MINOR CRITERIA High ESR : unexplained high ESR > 20mm at diagnosis or presence of evidence in history. CAROTID ARETRY TENDERNESS : unilateral or bilateral tenderness on carotid palpation. HYPERTENSION : persistent BP brachial > 140/90 or popliteal >160/90 at age < 40 yrs or history at age <40 yrs AR or annuloaortic ectasia : by auscultation or doppler echo or angiography Pulmonary artery lesion : lobar or segmental artery occlusion or equivalent (by angio or perfusion scintigraphy )or stenosis, aneurysm, luminal irregularity or any combination in pulmonary trunk or in unilateral or bilateral pulmonary arteries.
Left mid comon carotid lesion : presence of most severe occlusion in mid portion of 5cm in length from the point 2cm distal to its orifice determined by angiography Distal brachiocephalic lesion : presence of severe stenosis or occlusion in distal third in angiography Descending thoracic aorta lesion : narrowing dilatation , aneurysm or luminal irruegularity or any combination determined by angiography . Tortuosity alone is unacceptable Abdominal aorta lesion : narrowing dilatation , aneurysm or luminal irruegularity or any combination and absence of lesion in aortoiliac region consisting of 2cm of terminal aorta and bilateral common iliac arteries determined by angiography . Tortuosity alone is unacceptable
Obligatory criteria + 2 Major criteria or 1 Major and ≥ 2 Minor criteria or ≥4 Minor criteriaHigh probability of Takayasu’s disease ( sensitivity:84%)
American College Of Rheumatology (ACR)criteria• Age at disease onset ≤ 40 yrs• Claudication of extremities.∀ ↓ Brachial Artery pulse• Systolic BP difference of > 10 mm Hg between arms• Bruit over Subclavian Artery or Aorta.• Aortogram abnormality. ≥ 3 criteria — TA
Suri & Sharma et. al Criteria (PGI)The proposed modifications include: Removal of the obligatory criteria of age less than 40 years. Inclusion of characteristic signs and symptoms as a major criteria. Removal of age in defining hypertension. Deletion of the absence of aorto-iliac lesion, in defining abdominal aortic lesion and. An addition of coronary artery lesion in absence of risk factors.
The criteria proposed consists of three major criteria:• left and right mid subclavian artery lesions and• characteristic signs and symptoms of at least one month duration and• Ten minor criteria: • High ESR • Hypertension • Carotid artery tenderness • Aortic regurgitation or Annuloaortic ectasia • Left mid common carotid lesion • Distal brachiocephalic trunk lesion • Descending thoracic aorta lesion • Abdominal aorta lesion • Coronary artery lesion. • Pulmonary artery lesion Presence of two major or one major and two minor criteria or four minor criteria suggests a high probability of TA
• Sensitivity of 92.5% and specificity of 95% that was higher than that of Ishikawas criteria (sensitivity 60.4%, specificity 95%) and American college of Rheumatology criteria (sensitivity 77.4%, specificity 95%).• Similarly, this criteria had a 96% sensitivity and specificity when applied to 79 Japanese patients of TA and 79 control subjects.• Adoption of these criteria is expected to prevent the possibility of an under diagnosis of TA.
Classification Proposed by Ueno et al, modified by Lupi Herrera• Type I - involvement of aortic arch and its branches (16%)• Type II -Thoraco abdominal aorta,but spares arch (8%)• Type III-Features of I &II (76%)• Type IV-Pulmonary artery involvement (Lupi herrera et al) (36%)• Type V-Coronary artery involvement (Panja et al) (10%)
Clinical FeaturesDisease Basically evolves through 1. Early Pre-pulseless (50%): Active phase Nonspecific symptoms & signs: Fever, Wt loss, Fatigue, Headache, Arthralgias, Splenomegaly, LNpathy etc. - challenge in the early diagnosis2. Pulseless Phase (Ischemic): (sequel of occlusion of arch of aorta) HTN, ↓↓ / No Pulse, Bruit,, HF, Abnormal Fundi.
Early phaseNon specific systemic symptoms : fever, loss of weight, head ache, fatigue, gen weakness, night sweats, anoreia, arthralgia, skin rash, splenomegaly, cervical lymphadenopathy, pleurisy, myocarditis, pericarditis, CVA.Lab abnormalities : ↑ESR, mild leukocytosis, anemia, CRP, IGs, RA factor, ANF, ANCA, mild proteinuria, albuminuria.
Criteria for Active Disease in Patients with Takayasu Arteritis* Kerr, G. S. et. al. Ann Intern Med 1994;120:919-929
Late phase Diminished or absent pulses 96% Bruits 94% HTN 72% Heart failure 28%
Hypertension• 33–83% of patients, more among Indians• renal artery stenosis in 28–75%Aortic regurgitation -20-24%• dilatation of the ascending aorta• separation of the valve leaflets• Valve thickening (Chhetri et al)Congestive cardiac failure• hypertension• aortic regurgitation• myocarditis.
Pulmonary involvement• 70% angiographic studies (36% - Panja et al)• segmental and subsegmental branches, more in the upper lobes• haemoptysis, chest pain, disproportionate PAH abnormal ventilation-perfusion scanCoronary involvement• in 10%• usually ostial and proximal• diffuse lesions or arteritis and aneurysm rarely occur.Neurological• Secondary to hypertension or ischaemia.
OCULAR :• Amaurosis fugax• Hypertensive retinopathy [keith-wagner] arteriolar narrowing, av crossing changes silver wiring, exudates, papilloedema.• Ischemic retinopathy [ Uyama and Asayama] Stage 1 : dilatation of small vessels stage 2 : micro aneurism formation stage 3 : wreath like AV anastamosis formation surrounding optic papillae stage 4 : cataract ,secondary glacoma ,rubeosis, neo vascularisation, proliferative retinopathy, vitreous hemorrhage.
Frequency of clinical features of Takayasu arteritis at presentation and during the course of disease Kerr, G. S. et. al. Ann Intern Med 1994;120:919-929
Takayasu’s Disease in Children• Not as frequent as in adults• Clinical profile same• Manifestations may be more severe• Most common cause for renovascular HTN• Presenting features: HTN, CCF• An association with TB has been hypothesized , never proven
PREGNANCY• Pregnancy per se does not exacerbate the disease• Management of hypertension is essential.• Maternal complications: superimposed pre- eclampsia, congestive cardiac failure, progressive renal impairment.• Abdominal aortic involvement and a delay in seeking medical attention predicted a poor perinatal outcome.
Natural history• Subramanyam et al- cumulative survival at 5 years-91%,10 yrs-84%. Event free survival- 75%• Ishikawa-Survival rate: 83.1 at 5 years after diagnosis.• Cardiac failure - most common cause of death.• Spontaneous improvement can occur in young patients.• Childhood-onset particularly when associated with a DCM like picture carries ominous prognosis.• Failed angioplasty implicates high mortality.
Evaluation Of Takayasu’s Arteritis• Hematology: Mild Anaemia Leucocytosis• Markers of disease activity : E S R >40mm 50% cases progress with N ESR CRP ASO titre – increased in 50% cases but not correlated with activity RA factor, ANA, fibrinogen , p-ANCA• CXR: Aortic knob widening Thoracic Aorta irregularity ↓ Pulm. Vascularity Aortic calcification Cardiomegaly. Notching of upper ribs prox. Subclavian block lower ribs Abd. Aortic stenosis• X-ray Abdomen: Abd. Aorta calcification.
Matrix Metalloproteinases as Novel Disease Markers inTakayasu Arteritis In conclusion, the present results suggest that monitoring of circulating levels of MMP-2 as a helpful marker in diagnosing TA and those of MMP-3 and MMP-9 as disease activity markers might help provide adequate evaluation of treatment and guide therapeutic decision making for individual patients with TA. These measurements can be part of routine hospital laboratory examinations that are easy to perform at low cost. Furthermore, the noninvasive nature of such measurements is attractive, because patients can be spared from invasive angiographic examination.
Non –invasive imaging modalities• USG: Duplex Scanning• 2DECHO: Assessment of LV Dysfunction, Valvular involvement.• CT Angiography: Aorta & Pulmonary Artery• MRI : Mural involvement ;dilatation of vasavasorum• Flouroscein Angiogram of retinal vessels Ophthalmodynamometry .
Ultrasound scan of the internal carotid arterydemonstrating marked thickening of the arterial walls
Fluorescein Angiogram Filling defect: A filling defect may be present in either the retinal or choroidal circulation which may be produced by emboli seen in Takayasus disease.
A B Magnetic resonance imaging of the aorta and its major proximal branches. There is thickening of the aortic arch that extends into both common carotid arteries (A), with almost complete obliteration of the right carotid artery and both subclavian arteries (B).
Catheterization and Angiography• Pan-aortography, preferably with intrarterial digital subtraction angiography most important diagnostic investigation helps in planning management Visualisation of entire Aorta& its major branches special attention to innominate, subclavian& extracranial portions of carotid arteries.• Coronary Angiography• Pulmonary Angiography
Rt CCA Long Stenosis Lt SCA Not SeenRt SCA Narrowing
Diagnosis of systemic arterial diseases with whole body 3D contrast-enhanced magnetic resonance angiography Chin Med J 2006; Fig. 1. A 45-year-old patient with polyarteritis nodosa. Whole-body MRA reveals multiple aneurysms of different size in bilateral lower extremity arteries (arrows). Fig. 2. A 70-year-old man with clinically documented abdominal aorta aneurysm. A: Whole-body MRA demonstrates multiple aortic aneurysms and concomitant PAOD (arrows). B:Oblique sub-volume maximum- intensity-projection shows the aneurysm at the aortic arch (arrow). C:Sub-volume maximum-intensity-projection shows multiple aneurysms in the thoraco-abdominal, abdominal aorta and iliac arteries (arrows).
Management of TA• Depend on : Clinical presentation Disease activity• One of the challenges in the management of TA is determining disease activity. Kerr et al define active disease as any two or more of the following1. New or worsening:Signs or symptoms of vascular ischemia or inflammation2. Increase in sedimentation rate3. Angiographic features4. Systemic symptoms not attributable to another disease
Therapeutic Strategies• Medical Therapy: • Active or Early Lesions, • Not In Need of Interventions. • Co-Morbid Conditions. • Refuse Interventions. Steroids Antihypertensives Decongestants Cytotoxic Drugs Oral Anticoagulants
MEDICAL MANAGEMENT1. Immunosuppressive therapy2. decongestive therapy anti hypertensive therapy
• Decongestive therapy• Anti hypertensive therapy• Treatment of renal failure• Antiplatelet therapy• Anti tuberculous therapy caution: ????? Steroids in aneurismal dilation of vessels
Minocycline for the Treatment of TakayasuArteritis Annals of Internal MedicineActions of minocycline in these diseases arethought to be independent of antimicrobialactivity and are related to pleiotropic effects,including inhibition of MMP activitiesMinocycline may be a valuable additive tosteroids or an alternative to immunosuppressiveagents for patients with Takayasu arteritis andshould be tested in randomized, controlled trials.
Mycophenolate Mofetil for theTreatment of Takayasu Arteritismycophenolate mofetil could represent a valid alternative to conventional therapy in patients with Takayasu arteritis. Although the rareness of the disease is an obstacle to designing prospective, controlled clinical trials, this first description of mycophenolate mofetil therapy in patients with Takayasu arteritis is encouraging.
Infliximab is Effective for Takayasu Arteritis Refractory to Glucocorticoid and MethotrexateThe pathogenesis of TA includes vessel injury due to products from activated Tcells, natural killer cells, γ/δ T cells and macrophages. One of the importanthumoral factors is TNF-α, the molecular target for human autoimmune diseasesGlucocorticoid therapy is usually introduced for TA, but glucocorticoid alone issometimes not efficient; Kerr et al reported that about half of active TA patientsdid not respond well to glucocorticoid alone (6). In addition to glucocorticoid, animmunosuppressive regime such as cyclophosphomide, methotrexate andazathioprine has been used to treat TA (6-8); however, some patients arerefractory to both glucocorticoid and immunosuppressants. Hoffman et al haverecently reported the efficacy of TNF blockers toward TA refractory toconventional glucocorticoid therapy and immunosuppressants Patient selectioncriteria described by Hoffman et al include:1] required toxic doses ofglucocorticoids to maintain remission, and 2] either experienced multiplerelapses while receiving conventional and experimental therapy or refused re-treatment with glucocorticoids following relapses
Therapeutic Strategies (Cont)• Surgical Therapy: (Definitive Treatment for occlusive disease & Aneurysm) • Stenosis • Hypertension • End organ Damage • Bypass Grafting, Endarterectomy, Patch Aortoplasty, Resection of Narrow Segment, Excision of Saccular Aneurysms and AVR
Surgical treatment Indications• Hypertension with critical renal artery stenosis• Extremity claudication limiting activities of daily living,• Cerebrovascular ischaemia or critical stenoses of three or more cerebral vessels• Moderate or severe aortic regurgitation• Cardiac ischaemia with confirmed coronary artery involvement.• Thoracic aneurysms> 6 cm;abd aortic aneurysms> 5 cm.• Surgery is recommended at a time of quiescent disease to avoid complications like restenosis, anastamotic failure, thrombosis, haemorrhage, and infection.
Fig.5. The onset segments of the celiac trunk, superior mesenteric artery andinferior mesenteric artery are occlusive completely but the vessel wall of the distalextremity has no hyperplasia lesion and the true lumen still exists.Fig.6. The infra-diaphragm aortic artery has no stenosis.Fig.7. The Aorto-SMA grafting by-pass.Fig.8. End to side anastomosis, 6-mm e-PTFE graft without outer rings, Gore.
AngioplastyBalloon Angioplasty ± Stenting of theinvolved segment.• For discrete aortic lesions• low rates of restenosis (0%–19%)• Renal angioplasty successful in 95%• Stent-supported angioplasty for subclavian and carotid artery obstructions with good success rates (86%) and moderate rates of restenosis
Sirolimus-Eluting Stent for In-Stent Restenosis of Left Main Coronary Artery in Takayasu Arteritis Circ J 2005; 69: 752 –755 In conclusion, Takayasu arteritis with LMCA in-stent restenosis was successfully treated by a SES. Because of its immunosuppressive effects in the inflamed arterial walls, the SES shows promise for the treatment of stenotic lesions in patients with Takayasu arteritis.
Coronary and pulmonary angiographic findings during the first hospitalization for angina. (A) Leftcoronary selective injection revealed 90% stenosis in the ostium of the left main coronary artery (LMCA).(B) Intact right coronary artery. (C) Totally occluded left pulmonary artery. (D) Left coronary angiographyafter percutaneous coronary stenting. The 90% stenosis of the LMCA was successfully dilated to 0%.
Multiple stenting in a patientFig. 2 - Preinterventional angiography: A and B: left and right coronary arteries, respectively, with noobstructive lesions; C: left common carotid artery with severe obstruction; D: right common carotidartery with mild obstruction; E: left subclavian artery with occlusion in the proximal third; F and G: rightand left renal arteries with moderate and severe lesions, respectively; H: left iliac artery with occlusionin the proximal third; I: left ventricle with diffuse hypokinesia; J: aortic valve regurgitation and ectasiaof the ascending aorta.
Fig. 3 - Herculink stent implantation in renal artery lesion; pre andpostintervention.
Smart stent implantation in carotid artery lesion; pre andpostintervention.
Fig. 5 - Successful previous interventions remainedunchanged. Lesion in the right common carotid artery.
Fig. 6 - Herculink stent implantation in carotid artery lesion;pre and postintervention.
Balloon aortoplasty of aorta in TAAuthor No: Balloon Results : aorta at Major Follow up of diamet stenosis complications pts. er Befor After Dilated % Durat reste e ion(m nosis onths )Gu et al 16 10-20 4.6m 10.2m 14(87.5%) Dissection-1 19.1 Nil– 1991 m mRao et 16 All(100%) Cerebral 21.4 19%al – infarct-11993 Axillary artery stenosis-1 Dissection-2Sharma 10 5-12 80.5 14% 8(80) Dissection-2 17.8 Nil- 1994 %Tyagi – 146 7-20 4.2m 9.9mm 120(82.2) Long 54.4 8.2%1992 & m 141(96.5) dissection-41999 with Retro stent peritoneal
Percutaneous transluminal renal angioplasty in TAAuthor No: Initial results Complicat Follow up of ions Duration results lesion sDong et al- 32 D↑from 1.8 to 16.7 % 25.5 Htn ↓ 87%1987 4.8mmGu et al- 6 No stenosis-1 - - Htn ↓1988 Partial stenosis-5Park et al- 9 All dilated Nil 4 Restenosis 22%1989Kumar et 9 6/9 dilated 33.3% -al 1989Fava et al- 12 83% success - - 5 yr patency1993Sharma et 66 Success 91/96(95%) 6(9.1%) 22±17 Restenosis 16%al-1998 (96)Tyagi et al 148 Ptra success – 85.6% 7(3.4%) 47±38.5 Restenosis -17%
A follow-up study of balloon angioplasty and de-novo stenting in Takayasu arteritis. Sharma BK, Jain S, Bali HK, Jain A, Kumari S (PGIMER) Int J Cardiol. 2000 Aug 31;75 Suppl 1:S147-52• Percutaneous balloon angioplasty(PTBA) was done in 20 pts with TA.• All pts received steroids, aspirin and ticlodipine (for stenting) prior to procedure.• Angioplasty was carried in pts with symptomatic stenotic vessel of more than 70% of N. D or a peak systolic gradient of more than 50 mm across stenotic aortic lesion.• Stenting was performed for ostial lesion, long segment lesion or incomplete relief of stenosis and dissection following angioplasty.• Carotid angioplasty and stenting was performed in 5 patients,• aortic angioplasty in 9 pts, aortic angioplasty and stenting in 4 pts,• renal angioplasty in 3 pts, renal angioplasty and stenting in 2 pts and• subclavian angioplasty in 2pts,subclavian angioplasty & stenting in 3pts &• coronary angioplasty and stent placement in 1 patient.• The procedure was successful in all but 1 patient.• On following up, 2 patients with carotid stent placement had restenosis. A saccular aneurysm developed at the lower end of stent in 1 patient with aortic stenting.• The PTBA with or without stent placement is a safe and effective method for relief of stenotic lesion in patients with TA.