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Takayasu arteritis

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Takayasu arteritis

  1. 1. Takayasu Arteritis A COMPREHENSIVE REVIEW
  2. 2. Definition An idiopathic inflammatory disease of the large elastic arteries occurring in the young and resulting in occlusive or ectatic changes mainly in the aorta and its immediate branches (aortic arch syndrome) as well as the pulmonary artery and its branches.
  3. 3. Scheme of presentation • Brief review of epidemiology and pathophysiology • Diagnosis of disease / activity status • Medical treatment • Surgical/interventional management
  4. 4. By the end of presentation we should be able to decide? • What investigations and when? • What treatment and when? • And most importantly WHAT NOT????
  5. 5. Ques1 ???? 1 month back we had a patient • 19 years male presented with CCF • RSOV aneurysm + erosion into the IVS+ severe LV dysfunction • We got him operated • ESR CRP were high • Hypertension + Carotidodynia + • Left renal artery stenosis • WAS IT TAKAYASU???? • DID WE MISS SOMETHING IN HIS DIAGNOSIS AND TREATMENT?? CAUSE OF LV DYSFUNCTION??
  6. 6. Ques2 ???? 23 yrs female • Fever +arthralgia +weight loss • Angiography s/o aortoarteritis • ESR CRP high • Left renal stenosis-critical • HOW TO TREAT???? • Steroids??? For how long???how to taper???alone or in combination??? • What to do for RAS??
  7. 7. Ques3 ???? 23 yrs female • Fever +arthralgia +weight loss NO • Angiography s/o aortoarteritis • ESR CRP high NO • Left renal stenosis-critical • HOW TO TREAT???? • Steroids??? For how long???how to taper???alone or in combination??? • What to do for RAS??
  8. 8. QUES4?? ANGIOPLASTY IN A STENOTIC LESION • DOES THE TYPE OF LESION AFFECT THE STRATEGY? • WHICH IS BETTER POBA VS STENTING VS COVERED STENT???? • SURGERY VERSUS PERCUTANEOUS INTERVENTION??
  9. 9. Why management of TA is not easy??? • First, early diagnosis is difficult and requires clinical awareness and suspicion. • lack of standard and reliable parameters reflecting disease activity. (Second, and even more important) • Low level of evidence. • Current evidence reflects the results of open studies, case series and expert opinion • Rare disease/ lack of ideal outcome measures
  10. 10. Synonyms • Takayasu’s Arteritis • Aortoarteritis • Pulseless Disease • Young female Arteritis • Occlusive thromboaortopathy • Aortic arch syndrome
  11. 11. Epidemiology • Worldwide incidence: 2.6 cases per million per year. • More frequent in Asian countries - Japan, Korea, China, India, Thailand, Singapore and Turkey. • Japanese patients with Takayasu arteritis  higher incidence of aortic arch involvement. • In contrast, series from India report higher incidences of abdominal/renal involvement. Age: • Predominantly a disease of young females: 2nd or 3rd decades.(less<40 :obligatory criteria) • Mean age: – European study - 41yrs – Japan - 29yrs – India – 24yrs Sex: • F>M (~80% women) • India – F : M = 1.6 : 1 ( panja et al 6.4:1)
  12. 12. Pathology and pathogenesis • The disease involves medium- and large-sized arteries, with a strong predilection for the aortic arch and its branches; the pulmonary artery may also be involved. • The involvement of the major branches of the aorta is much more marked at their origin than distally. • The disease is a panarteritis with inflammatory mononuclear cell infiltrates and occasionally giant cells. There are marked intimal proliferation and fibrosis, scarring and vascularization of the media, and disruption and degeneration of the elastic lamina. Narrowing of the lumen occurs with or without thrombosis. The vasa vasorum are frequently involved. Pathologic changes in various organs reflect the compromise of blood flow through the involved vessels.
  13. 13. 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 Distribution of lesion in the Aorta Localized: 37.5% - Adults:- Abdominal Aorta Children:-Thoracic+Abdominal Diffuse: 62.5% -thoraco-abdominal Descending thoracic Aorta is maximally affected area Aortic Arch: Distal involvement more than proximal. Dilatation of Ascending Aorta seen in portion proximal to obstructive lesion. Aneurysm may occur without any obstructive lesion.
  14. 14. FOUR Types of luminal changes: 1.Irregular lumen 2.Ectasia 3.Obstructive lesion-”stenosis” (hallmark of disease) 4.Aneurysms-saccular & fusiform
  15. 15. Relative involvement of branch arteries: (%)(Panja et al) ARTERY % RENAL 63.75 LEFT SUBCLAVIAN 40 SUPERIOR MESENTRIC 16.75 CORONARY 16.75 RIGHT SUBCLAVIAN 13.75 RT.CCA 11.25 LT.CCA 7.5 INNOMINATE 7.5 COELIAC 3.75 Commenest lesion in branches is ostial stenosis. BL Renal A Stenosis > UL (2.5 times)
  16. 16. Frequency of Arteriographic Abnormalities and Potential Clinical Manifestations of Arterial Involvement in Takayasu's Arteritis Kerr, G. S. et. al. Ann Intern Med 1994;120:919-929
  17. 17. DIAGNOSTIC CRITERIA • ISHIKAWA CRITERIA (1988) • ACR CRITERIA (1990) • SURI & SHARMA et. al CRITERIA (1995)
  18. 18. 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
  19. 19. 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.
  20. 20.  Left mid common 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
  21. 21. Obligatory criteria + 2 Major criteria or 1 Major and ≥ 2 Minor criteria or ≥4 Minor criteria High probability of Takayasu’s disease ( sensitivity:84%)
  22. 22. 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 ( sensitivity 90.5%, specificity 97.8%)
  23. 23. 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.
  24. 24. 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
  25. 25. • Sensitivity of 92.5% and specificity of 95% that was higher than that of Ishikawa's 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.
  26. 26. Clinical Features Disease 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 diagnosis 2. Pulseless Phase (Ischemic): (sequel of occlusion of arch of aorta) HTN,  / No Pulse, Bruit,, HF, Abnormal Fundi.
  27. 27. Frequency of Arteriographic Abnormalities and Potential Clinical Manifestations of Arterial Involvement in Takayasu's Arteritis Kerr, G. S. et. al. Ann Intern Med 1994;120:919-929
  28. 28. Kerr, G. S. et. al. Ann Intern Med 1994;120:919-929 Frequency of clinical features of Takayasu arteritis at presentation and during the course of disease
  29. 29. Evaluation Of Takayasu’s Arteritis • Hematology: Mild Anaemia Leucocytosis • Markers of disease activity : E S R >40mm 50% cases progress with N ESR C R P 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. • Echocardiogram • fundus
  30. 30. 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 aneurysm formation stage 3 : wreath like AV anastamosis formation surrounding optic papillae stage 4 : cataract ,secondary glacoma ,rubeosis, neo vascularisation, proliferative retinopathy, vitreous hemorrhage.
  31. 31. Histologic Findings • The early stage: continuous or patchy granulomatous inflammatory reaction involving macrophages, lymphocytes, and multinucleated giant cells. • Inflammation initially occurs in the vasa vasorum  artery wall becomes irregularly thickened and the lumen becoming narrowed. • Takayasu arteritis progresses to a sclerotic stage, with intimal and adventitial fibrosis and scarring of the media. • Lesions are initially inflammatory and later become occlusive. • Inflammatory cells—predominantly CD4 and CD8 lymphocytes, macrophages, plasma cells, histiocytes, and giant cells—invade the adventitia and media but not the intima.
  32. 32. HOW TO ASSESS DISEASE ACTIVITY??
  33. 33. Kerr, G. S. et. al. Ann Intern Med 1994;120:919-929 Criteria for Active Disease in Patients with Takayasu Arteritis*
  34. 34. • Systemic inflammatory response does not always show a positive correlation with inflammatory activity in the vessel wall. • Therefore TA may be active despite a normal ESR and serum CRP level, and vice versa. In patients with apparent clinical and laboratory remission, arterial specimens may show histological signs of vasculitis • The absence of systemic clinical features does not exclude ongoing vascular inflammation nor does the presence of ischemic symptoms always suggest active inflammation. • As many as 44% of clinically inactive patients were found to have active vasculitis when tissue samples were taken from vessels at surgery performed for obstructive lesions. Hoffman GS. Takayasu arteritis: lessons from the American National Institutes of Health experience. Int J Cardiol 1996; 54 Absence of constitutional symptoms and normal ESR/CRP , does not rule out active disease
  35. 35. Imaging – Conventional angiography • Advantage: – Gold standards for determining anatomy – Serial evaluation good indicator of progression • Limitations – Invasive – Contrast required – Inability to evaluate arterial wall changes, so may not detect activity early 41
  36. 36. • NON-INVASIVE MODALITIES – magnetic resonance angiography (MRA), – colour Doppler ultrasound (CDU), – computerized tomography angiography (CTA) – PET SCAN • can visualize the characteristic, homogeneously thickened vessel walls and luminal changes of large arteries. • can demonstrate early inflammatory signs (vessel wall thickening and mural inflammation) as well as late complications (stenosis and aneurysms). •
  37. 37. NON INVASIVE MODALITIES • Non-invasive imaging methods are essential for monitoring disease activity and response to treatment in TA. • Increased vessel wall thickness, vessel wall oedema and mural contrast enhancement are usually considered evidence of active disease . Vessel wall oedema, mural contrast enhancement or 18F-FDG uptake may decrease with successful immunosuppression. • A decrease in wall thickness provides information about whether the disease has been well controlled over months or years. However, these findings are not always reliable . • Using echocardiography, the heart should also be monitored for the presence or progression of aortic regurgitation or left ventricular hypertrophy due to hypertension in TA Absence of constitutional symptoms and normal ESR/CRP , does not rule out active disease So in such a scenario- go for NONINVASIVE MODALITIES
  38. 38. Imaging – MR angiogram • Non invasive • Useful for detecting – Mural thickening – Luminal changes – Aneurysmal dilation • Delayed contrast enhanced MRI esp useful for arterial wall inflammation 44
  39. 39. Three dimensional MRA • N= 30 TA patients • Direct comparison of angiography and MRA • 90% agreement in identification of normal & abnormal vessels Yamada I et al. J Magn Reson Imaging 2000;11:481–7 Kumar S et al. Eur Radiol 1997;7:44–50 45
  40. 40. CMC Vellore study • Aortic wall thickness > 4mm was sensivite (90%) • Limitations: – Over sensitive – Post endovascular stent procedure – no clear correlation of vessel edema with disease activity or progression* *Tso E. Arthritis Rheum 2002;46:1634–42 46
  41. 41. High-resolution Doppler ultrasound 47 Activity common carotid arterial wall thickness vessel diameter Active lesions 2.5–5.0mm 10mm Inactive lesions 1.1–2.0mm <7mm Good for common carotids and vertebral arteries Non Invasive Operator dependent Correlates closely with angiography and MRA (> 95% agreement)* Cantu C. Stroke 2000;31:2197–202
  42. 42. conclusions • monitoring disease activity in TA may be accomplished by the integrated use of non-invasive imaging methods, patient symptoms, clinical findings and acute phase reactants. • There is no single imaging modality that can provide all the information required and each method has distinct and complementary roles in monitoring. • The use of non-invasive procedures providing a good overview of the involved vessels without radiation exposure, such as MRA, is recommended if available
  43. 43. 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. Matrix Metalloproteinases as Novel Disease Markers in Takayasu Arteritis
  44. 44. Potential Biomarkers • Pentraxin-3 • MMP-9 • IL-18 51
  45. 45. ITAS2010 – IndianTaka yasu’s Arteritis Activity Score Tick Box only if abnormality is present and new or worse within the past 3/12. Tick box only if abnormality is ascribed to current, active vasculitis
  46. 46. MANAGEMENT
  47. 47. General principles of Management • Patient education – Nature of Disease – Disease Course – Medical Management Options- First and Second lines – Side effects and Compliance – Surgical Management
  48. 48. Supportive measures • Diet, low salt intake, calcium, vitamin D corection and regular exercise • Monitoring and control of blood pressure – BP measurements should be made in the unaffected extremities – If unreliable measurements, presence of hypertensive retinopathy may be a warning sign – In treatment-resistant HTN, the possibility of reno-vascular HTN should be considered
  49. 49. • Atherosclerosis risk is increased in TA • Antiplatelet agents have a protective effect against ischemic events in TA (hazard ratio =0.055, 95% confidence interval: 0.06-0.514; P=0.011) Seyahi E, Ugurlu S, Cumali R et al. Atherosclerosis in Takayasu arteritis. Ann Rheum Dis 2006;65:12027. de Souza AWS, Machado NP, Pereira VM et al. Antiplatelet therapy for the prevention of arterial ischemic events in Takayasu arteritis. Circ J 2010;74: 123641.
  50. 50. Atherosclerosis risk is increased in TA • Systemic vasculitides, such as giant cell arteritis, Takayasu arteritis, polyarteritis nodosa, and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, are immune-mediated rheumatological diseases characterized by inflammation of the vasculature that results in accelerated atherosclerosis. • In patients with vasculitis, the intima of affected blood vessels becomes activated, leading to endothelial cell activation and damage, and an ensuing immune response—factors that can all promote atherosclerosis. • After activation, endothelial cells can expose adhesion molecules and secrete cytokines. This increase in secretion of mediators of inflammation promotes enhanced adhesion between the endothelial cells and monocytes, and serves as a proatherogenic substrate by promoting plaque formation.
  51. 51. Atherosclerosis risk is increased in TA • In addition to inflammatory reactions that can lead to atherosclerosis, vasculitis might also promote increased expression of autoantigens (such as heat shock proteins) on activated endothelial cells. Furthermore, accumulation of oxLDL can promote activation of endothelial cells, monocytes, and macrophages, as well as formation of foam cells. • Importantly, patients with vasculitis have generalized endothelial dysfunction characterized by impaired endothelium-dependent vasodilatation.
  52. 52. Antiplatelets in takayasu arteritis • Similar to other inflammatory diseases, atherosclerosis risk is also increased in TA, and preventive measures should be considered . • There are some basic studies favouring the use of antiplatelet agents in TA. • In the limb affected by arterial stenosis, more platelet aggregation and higher levels of thromboxane were reported, and these findings were shown to improve after 80 mg/ day aspirin treatment. • A recent retrospective observational study suggested that antiplatelet therapy was associated with a lower frequency of ischaemic events in patients with TA . • However, the relative efficacy of this treatment between different angiographic stages of TA is not known .
  53. 53. Anti-platelet Agents To decrease the occurrence of restenosis, antiplatelet treatment should be used before and after endovascular interventions in TA Visona` A, Tonello D, Zalunardo B et al. Antithrombotic treatment before and after peripheral artery percutaneous angioplasty. Blood Transfus 2009;7:1823. STRICT CONTROL of dyslipidemia, hypertension, and lifestyle factors that increase the risk of cardiovascular disease. These complications are the major cause of death in Takayasu arteritis.
  54. 54. IMMUNOSUPPRESSION
  55. 55. Outline Evidence for – Efficacy of steroids – Efficacy of additional Immunosuppressant – Biological agents – Conclusion 62
  56. 56. Biological basis Takayasu arteritis is a chronic relapsing autoimmune large vessel vasculitis 63 Schmidt J et al. Mayo Clin Proc. 2013;nn(n):1-9 No. of relapses correlates with likelihood of disability (p< 0.0001) Maksimowicz-Mc Kinnon etal. A& R 2007; 56 (3); 1000-1009 (Cleveland Clinics)
  57. 57. Treat to target • Inducing stable disease state • Sustaining stable disease • Prevent progression of damage • Attain regression of disease 64
  58. 58. • In the presence of active disease, standard initial treatment of TA is high-dose (1 mg/kg/day) prednisolone or its equivalents. • The response to high dose prednisolone is generally favourable, but relapses may occur while gradually tapering the dose and adverse effects of long-term treatment can cause problems. STEROIDS
  59. 59. Radial pulse became palpable in 5 patients with steroids N= 84 Korean patients Nakao et al. Circulation 1967; 35: 1141-1155 Steroids works in 62% of TA 66 The first data on efficacy of steroids in TA dates to 1967 when Nakao etal from Japan showed fair to remarkable imrpovement in clinical status in 18/29 pts on steroids . In fact they showed reversiblity of radial pulseloss in 5 of their pts with steriods
  60. 60. 67
  61. 61. Ques1 ???? 1 month back we had a patient • 19 years male presented with CCF • RSOV aneurysm + erosion into the IVS+ severe LV dysfunction • We got him operated • ESR CRP were high • Hypertension + Carotidodynia + • Left renal artery stenosis • WAS IT TAKAYASU???? • DID WE MISS SOMETHING IN HIS DIAGNOSIS AND TREATMENT?? CAUSE OF LV DYSFUNCTION??
  62. 62. 100% improvement in aorto-arteritis associated myocarditis with immunosuppression N= 13 non-specific aortoarteritis and myocarditis in EM biopsy on prednisolone & CYC At 12, 24, 52 weeks 70 Clinical Improvement 100% ESR drop 48 +/- 12 mm/1st h to 31 +/- 12 mm/1st h, p < 0.05 Resolution of EM biopsy changes 100% Arterial lesions static, no new lesions Talwar KK etal. Int J Cardiol. 1993 Apr;39(1):79-84
  63. 63. No. 106 Steroids : 17 Remission: 5 Mortality : 17% No. = 107 Steroids : 8 Remission : 1 Mortality : 15% Lupi-Herrera E etal. Am Heart J 1977;93:94–103 Jain etal. Int J Cardiol 1996;54 Suppl:S111–6 Pre-steroid era 71
  64. 64. Success rate of steroids : 20% - 100% No. 106 Steroids : 17 Remission: 5 Mortality : 17% No. = 107 Steroids : 8 Remission : 1 Mortality : 15% Kerr GS et al. Ann Surg 1987; 205: 157–166 Lupi-Herrera E etal. Am Heart J 1977;93:94–103 No. 60 Steroids : 28 Remission: 60% Sustained Remission :40% No response : 23% Mortality : 3% No. 118 Steroids : 78 Remission: 75% Angio regression : 10% Steroids stopped : 26% Ishikawa K. Am J Cardiol 1991; 68: 410–413 Jain etal. Int J Cardiol 1996;54 Suppl:S111–6 72 POST STEROID ERA THESE RESULTS MAKE STEROIDS THE FIRST LINE IMMUNOSUPPRESSANTS IN TA
  65. 65. Treatment with glucocorticoids- an independent predictor for remission • Independent predictors for Remission – Low ESR at diagnosis & – Treatment with glucocorticoids Park MC etal. Scand J Rheumatol. 2005 Jul-Aug;34(4):284-92 73
  66. 66. Outline Evidence for – Efficacy of steroids – Efficacy of additional Immunosuppressants – Biological agents – Conclusion 74
  67. 67. Data from recent studies • N= 75 ; 30 followed up 3 yrs (4 months-10 years) • All patients who followed up were treated with steroids • 73% required adjunctive immunosuppressive agents 75 Remission with additional IS 93% (28/30) Remission with steroid monotherapy 20 % (6/30) Sustained remission (≥6 months on <10mg/kg) 28% (8/28) Sustained remission till last follow up 18% (5/28) Persistent active disease 2 No. of relapses correlated with likelihood of disability (p< 0.0001) Maksimowicz-Mc Kinnon etal. A& R 2007; 56 (3); 1000-1009 (Cleveland Clinics)
  68. 68. Steroids in pediatric TA(CMC Vellore) • N= 40; follow up = 34 pts for 21.5 (IQR 8.7- 37.2) • Relapse in 15 children at a median duration of 16.5 (9.5- 47 months) • Median steroid dose at relapse – 5 (IQR -0-15)mg/day 76 Steroids with 2nd line agents 34 (85%) Remission 30/ 34 Sustained remission till last follow up 15/ 34 Persistent active disease 4 Goel R, Kumar TS, Danda D, Joseph G, Bacon P, Jayaseelan V [unpublished data] Higher disease progression was observed in patients with persistent active/ relapsing disease
  69. 69. 78 Treatment of Glucocorticoid-resistant or relapsing Takayasu Arteritis with Methotrexate Gary S. Hoffman etal. Arthritis & Rheumatism 1994;37(4) : 578-582 Methotrexate : sustained remission for 18 months in 50% patients
  70. 70. Steroids with Azathioprine : arrested disease progression in 100% • N= 65 new patients (1996 -2001) • 15 had active disease, treated with azathioprine + prednisolone • At 3 months : – Clinical improvement : 100% • At 1 year: – Clinical Improvement sustained – Angiogram showed no progression / new lesions in any patient 79 Valsakumar AK, Valappil UC, Jorapur V, Garg N, Nityanand S, Sinha N . J Rheumatol. 2003;30(8):1793-8
  71. 71. Mycophenolate & Azathioprine probably better than Methotrexate (Indirect evidence) 80 0 5 10 15 20 25 30 35 40 45 MTX sustained remission improvement 43 28 CCF cohort (MTX based) No.ofpatients(%) Maksimowicz-Mc Kinnon etal. A& R 2007; 56 (3); 1000-1009
  72. 72. Mycophenolate & Azathioprine probably better than Methotrexate (Indirect evidence) 81 0 10 20 30 40 50 60 70 80 90 100 NO OF PTS sustained remission improvement 43 28 23 100 100 Methotrexate based Azathioprine based No.ofpatients(%) Maksimowicz-Mc Kinnon etal. A& R 2007; 56 (3); 1000-1009 Valsakumar AK etal. J Rheumatol. 2003;30(8):1793-8
  73. 73. Mycophenolate & Azathioprine probably better than Methotrexate (Indirect evidence) 82 0 10 20 30 40 50 60 70 80 90 100 Mtx/Aza/ MMf used sustained remission improvement 43 28 23 100 100 19 50 15 96 methotrexate based* azathioprine based ** (n= 15/65) at 1yr follow up mycophenolate based$ (n=19/40) Adult TA (MMf)% (n=21/21) No.ofpatients(%) Maksimowicz-Mc Kinnon etal. A& R 2007; 56 (3); 1000-1009 Valsakumar AK etal. J Rheumatol. 2003;30(8):1793-8 Goel R, Kumar TS, Danda D, Joseph G, Jayaseelan V. [unpublished] Goel R, Danda D, Mathew J, Edwin N. Clin Rheumatol (2010) 29:329–332
  74. 74. TURKISH TA STUDY GROUP DEFINITION OF REFRACTORY DISEASE IN TA • Angiographic or clinical progression despite treatment • Presence of any of the following – prednisolone dose >7.5 mg /day after 6 months of treatment, despite administration of conventional immunosuppresive agents – need for new surgery due to persistent disease activity – frequent flares (>3/year) – death associated with disease activity Saruhan-Direskeneli G, Hughes T, Aksu K, et al. Identification of multiple genetic susceptibility loci in Takayasu arteritis. Am J Hum Genet. 2013;93:298-305. Biologic agents IS THE SOLUTION
  75. 75. TNF alpha blocker : works in refractory cases • N= 11 refractory pts with TA initiated on anti-TNF agents • 10 pts had a durable response • Median duration in remission was 26 months (range : 3 months to 6 yrs) • 6 pts had achieved sustained remission without requiring glucocorticoids Hoffman GS et al. Arthritis & Rheumatism 2004;50: 2296-304 85
  76. 76. TNF alpha blocker : works in refractory cases • Recent review • N= 84 treated with TNF-𝛼 antagonists – complete remission in 37% – partial remission in 53.5% – Non responders 9.5% C Comarmond. Autoimmunity Reviews, vol. 11, no. 9, pp. 678–684, 2012 86
  77. 77. Tocilizumab (anti IL-6) as a stop gap measure N= 10 active TA patients (disease duration 25.5 (1.5-60) months 87 Response No. of patients (n= 10) Sustained remission (during 6 doses) 6 Reduction in steroids to <10mg/day 7 Sustained remission post TCZ withdrawal 2 Major adverse events 0 Mean steroid dose reduction : 24 ± 15 to 5.4 ± 4.9 mg/day Goel R, Danda D, Kumar S, Joseph G. Int J Rheum Dis. 2013 Dec;16(6):754–61
  78. 78. Circulation november 2015
  79. 79. Outline Evidence for – Efficacy of steroids – Efficacy of additional Immunosuppressants – Biological agents – Conclusion 90
  80. 80. Summary-IMMUNOSUPPRESSANTS IN TA •Inducing stable disease state √ (60%=93%) •Sustaining stable disease √ (20-50%) •Prevent progression of damage √ (upto 100%) •Attain regression of disease +/- (few studies) 91
  81. 81. Ques2 ???? 23 yrs female • Fever +arthralgia +weight loss • Angiography s/o aortoarteritis • ESR CRP high • Left renal stenosis-critical • HOW TO TREAT???? • Steroids??? For how long???how to taper???alone or in combination??? • What to do for RAS??
  82. 82. Ques3 ???? 23 yrs female • Fever +arthralgia +weight loss NO • Angiography s/o aortoarteritis • ESR CRP high NO • Left renal stenosis-critical • HOW TO TREAT???? • Steroids??? For how long???how to taper???alone or in combination??? • What to do for RAS??
  83. 83. ENDOVASCULAR AND SURGICAL INTERVENTIONS
  84. 84. NO INTERVENTION IN ACTIVE DISEASE Surgery Endovascular interventions Balloon angioplasty Stent Stent graft replacement Should be tried only after inflammation in the vessel wall has been controlled Post-interventional Immunosuppression is also recommended Park MC, Lee SW, Park YB et al. Postinterventional immunosuppressivetreatment and vascular restenosis in Takayasu’sarteritis. Rheumatology 2006;45: 6005.
  85. 85. Biological inflammation at the time of vascular procedure independently associated with procedure Saadoun D et al. Circulation 2012;125:813-819 Copyright © American Heart Association 166 Vascular Procedures in 79 Patients With TA 100
  86. 86. Critical Arterial Stenosis Short-segment Balloon angioplasty or Stent graft replacement Long-segment stenosis with extensive peri-arterial fibrosis or occlusion Surgical bypass of the affected segment
  87. 87. Indian heart jnl 2014
  88. 88. POBA vs STENTING
  89. 89. Advantages and Disadavantages of Endovascular Procedures Percutaneous Transluminal Angioplasty Stent GRAFTS Less invasive and safe More invasive Cheaper Costlier Restenosis rate ̴ 77.3% Restenosis rate ̴17% Less Cost Effective More Cost effective Qureshi MA, Martin Z, Greenberg RK. Endovascular management of patients with Takayasu arteritis: stents versus stent Grafts. Semin Vasc Surg 2011;24: 4452.
  90. 90. Anti-platelet Agents To decrease the occurrence of restenosis, antiplatelet treatment should be used before and after endovascular interventions in TA Visona` A, Tonello D, Zalunardo B et al. Antithrombotic treatment before and after peripheral artery percutaneous angioplasty. Blood Transfus 2009;7:1823.
  91. 91. Indications for surgery in TA • Critical cerebrovascular ischemia • Coronary artery ischemia • Extremity claudication • Severe renal artery stenosis • Progressive aneurysm enlargement with a tendency for dissection or rupture • Severe aortic regurgitation and aortic coarctation Giordano JM. Surgical treatment of Takayasu’s arteritis. Int J Cardiol 2000;75(Suppl 1):S1238.
  92. 92. Outcomes of 79 consecutive patients with TA who underwent 104 surgical and 62 endovascular procedures, the frequencies of complications were 37.5% and 50%, respectively, after a follow-up of 6.5 years
  93. 93. QUES4?? ANGIOPLASTY IN A STENOTIC LESION • DOES THE TYPE OF LESION AFFECT THE STRATEGY? • WHICH IS BETTER POBA VS STENTING VS COVERED STENT???? • SURGERY VERSUS PERCUTANEOUS INTERVENTION??
  94. 94. Post interventional immunosuppressants
  95. 95. Prognosis • Substantial morbidity and mortality. • Approximately 20% of patients have a monophasic and self-limited disease. • A National Institutes of Health (NIH) study of 60 patients with Takayasu arteritis: – 20% of patients had a monophasic illness, self-limiting illness and therefore did not require immunosuppressive treatment. – Remaining 80% of patients, who did not have a monophasic illness and who experienced 1 exacerbation, immunosuppressive therapy resulted in remission in 60%. – Of these, one half experienced relapse after immunosuppressive therapy was stopped.
  96. 96.  Complications • Stroke • Intracranial haemorrhage • Seizures • Graft stenosis and/or occlusion • Ischemia • Organ failure • Complications of hypertension • Foetal injury • Valvular heart disease • Retinopathy • Renovascular hypertension • Long-term use of corticosteroids: infection, adrenal suppression, cataracts, hyperglycemia, hypertension (which complicates blood pressure control), osteoporosis, and aseptic necrosis.
  97. 97. 5 yr Survival And Event Free Survival rate
  98. 98.  Morbidity and mortality • Overall 10-year survival rate is approximately 90%. • Rate is reduced in the presence of major complications. • 5- and 10-year survival rates are approximately 69% and 36%, respectively, in patients with 2 or more complications. • 5- and 10-year survival rates associated with 1 or fewer complications are 100% and 96%, respectively. • Most common causes of death= CCF/CVA/MI/ANEURYSMAL RUPTURE/RENAL FAILURE Disease remission is the only factor that positively influences physical and mental quality of life.
  99. 99. Take home messages  The diagnosis of TA should preferably be made before a critical stenosis or occlusion occurs in the involved arteries.=> HIGH INDEX OF SUSPICION WARRANTED FOR THIS TO HAPPEN  As acute phase responses are not always reliable, non- invasive imaging methods are used to monitor disease activity.=> MRA suitable for this  As a rule, the information obtained from non-invasive imaging methods should be integrated with patient symptoms, clinical findings and acute phase reactants to adjust the dose of IS agents and the duration of treatment.
  100. 100. Take home messages  Biologics should be tried in treatment-resistant Takayasu arteritis patients.  Revascularization procedures may be performed during the inactive phase of Takayasu arteritis.  Low dose aspirin has been found to be protective against ischemic events in TA patients  Placebo-controlled,Large scale, randomized clinical trials, are required to ascertain the treatment strategies and outcome scores for this rare but important disease entity
  101. 101. THANKYOU!!!
  102. 102. ROUTINE STENTS VS STENT GRAFTS

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