Rheumatol Int (2012) 32:703–709

DOI 10.1007/s00296-010-1694-9

ORIGINAL ARTICLE

Takayasu arteritis: assessment of response to medical therapy based on clinical activity criteria and imaging techniques

Daniele Souza Freitas · Cintia Zumstein Camargo · Henrique Ataíde Mariz · Anne Elizabeth Diniz Arraes · Alexandre Wagner Silva de Souza

Received: 10 July 2010 / Accepted: 21 November 2010 / Published online: 9 December 2010© Springer-Verlag 2010

Abstract In this retrospective longitudinal cohort studywe included 52 patients with Takayasu arteritis (TA) whowere on regular follow-up at the Vasculitis Unit of Univer-sidade Federal de São Paulo between 2003 and 2009. Themean age at study was 38 years and the mean age at diag-nosis was 29 years. Patients were followed for a mean74.3 months. A relapse-remitting course was observed in41 patients (78.8%) whereas 9 (17.3%) had a monophasiccourse and only 2 (3.8%) patients were chronic-active. Dis-ease remission was achieved in 50 patients (96.2%). Angio-graphic type V was observed in 42.3% of TA patients atdiagnosis and in 61.5% during follow-up. The most aVectedarteries were the abdominal aorta (63.5%) and left subcla-vian (60.6%). Prednisone was used by 94% of TA patientsand immunosuppressive agents were prescribed for 51(98%) patients. Methotrexate was used by 82.7%, followedby cyclophosphamide (26.9%), azathioprine (25.0%), anti-TNF� agents (5.8%) and leXunomide (5.8%). Although,forty patients (76.9%) used prednisone and methotrexate asinitial treatment, 75% of them developed new vascularlesions along follow-up. Eighteen TA patients (34.6%)needed to change immunosuppressive therapy due to fail-ure or toxicity, among them 83.3% presented new lesions.Surgical treatment was performed in 34.6% of patients andrestenosis was observed in 13.5% in a median time of11 months after surgery. In conclusion besides prednisoneand methotrexate is largely used in TA, the majority ofpatients still develop new arterial lesions along time.

Keywords Vasculitides · Takayasu arteritis · Cohort studies · Immunosuppressive agents

Introduction

Takayasu arteritis (TA) is a chronic, inXammatory diseaseof unknown etiology that primarily aVects large vessels,such as the aorta and its main branches [1, 2]. VascularinXammation may lead to arterial wall thickening, stenosisand occlusion of vessel wall or to aneurysm formation [2].TA aZicts mainly women younger than 40 years and it hasbeen described in both genders and in diVerent ethnicalgroups [3–9].

Clinical features and the pattern of arterial involvementseem to be variable in diVerent genders and populations[8, 9]. Systemic features may be found in up to one-third ofcases and with disease progression angiodinia, limb claudi-cation, absent pulses, vascular bruits, new onset or severehypertension, myocardial infarction, stroke or transientischemic attack and other ischemic signs and symptomsmay occur [1, 2, 10]. Vascular imaging techniques demon-strate arterial wall abnormalities and are crucial for thediagnosis of TA. Recently serial non-invasive imagingstudies have been added as a new tool for monitoringdisease progression [1, 11].

Corticosteroids are employed to treat active disease inTA patients usually at an initial prednisolone dose of 1 mg/kg/day during at least 1 month with gradual tapering afterclinical response. Nevertheless, most of patients relapsewith dose reductions and need an additional immunosup-pressive agent such as methotrexate, azathioprine, cyclo-phosphamide or mycophenolate mofetil [1, 6, 11–15].Anti-TNF� agents, mostly inXiximab and etanercept, havebeen used for TA patients who are refractory to conventional

D. S. Freitas · C. Z. Camargo · H. A. Mariz · A. E. D. Arraes · A. W. S. de Souza (&)Rheumatology Division, Universidade Federal de São Paulo-UNIFESP, Rua Botucatu, 740, Third Floor, São Paulo, SP 04023-900, Brazile-mail: alexandre_wagner@uol.com.br

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immunosuppressive therapy with some success [16, 17].Prompt institution of medical therapy may reverse earlyvascular lesions. However, stenotic or occlusive lesionsmay require surgical treatment if hemodynamically signiW-cant. Unfortunately, restenosis is a major concern inpatients who underwent vascular surgical procedures,mainly for those with active disease at the time of the inter-vention [1, 11, 18–20]. In this study, we perform a longitu-dinal analysis of medical therapy in TA patients, comparingits eYcacy based on clinical activity criteria, developmentof new arterial lesions and modiWcation of angiographictype along follow-up. Surgical treatment, prognosis andoutcomes after surgery were also evaluated.

Materials and methods

A retrospective longitudinal study was performed with 52TA patients who fulWlled the American College of Rheu-matology (ACR) 1990 Criteria [21] and were on regularfollow-up at the Vasculitis Unit in the Universidade Federalde São Paulo between 2003 and 2009. A standardized ques-tionnaire with demographic features, clinical manifesta-tions, imaging studies, medical and surgical treatment andco-morbidities was applied to TA patients. Study’s protocolwas approved by Institutional Ethics Committee.

At each visit patients were evaluated for the onset of signsand symptoms suggestive of disease activity (e.g., constitu-tional symptoms, limb claudication, carotidynea, decreasedor absence of pulses and diVerences in blood pressurebetween limbs) and with Westergren erythrocyte sedimenta-tion rate (ESR) and C-reactive protein (CRP). Vascular ultra-sound Doppler studies were performed by the sameexperienced physician within every 6 months to evaluatecarotid, subclavian, abdominal aorta, renal and iliac arteriesfor new vascular lesions. Magnetic resonance angiography(MRA) of the aorta and its primary branches was performedat least once a year. The arterial lesions evaluated in vascularimaging studies were stenosis, occlusion, vessel wall irregu-larity/thickening, dilatation and aneurism. UnscheduledMRA, computed tomography angiography and vascularultrasound would be done in case of suspected disease pro-gression. Conventional angiography was performed at diag-nosis and in speciWc cases during follow-up. Patients wereclassiWed according to the angiographic classiWcation of theInternational TA Conference in Tokyo 1994 in six diVerenttypes as follows type I (the aortic branches are involved);type IIa (the ascending aorta, arch, and its branches); type IIb(the ascending aorta, arch with its branches, and thoracicdescending aorta); type III (the thoracic descending aorta,abdominal aorta, and/or renal arteries); type IV (only theabdominal aorta and/or renal arteries); and type V (the com-bined features of type IIb and IV) [22].

Disease activity was considered if the patient presentednew lesions in vascular imaging studies or at least two ofthe following features were present (1) new onset of caroto-dynia or pain over other large arteries, (2) transient ische-mic episodes not attributed to other factors, (3) new bruit ornew asymmetry in pulses or blood pressure, (4) systemicsymptoms in the absence of infection, or (5) an increase inthe ESR. The patient’s activity proWle was classiWed asmonophasic, relapsing-remitting and chronic active [1, 16].

Patients with active disease were treated with prednisone1 mg/kg/day at least during 1 month, after achieving dis-ease control we started gradual tapering based on diseaseactivity parameters until complete withdrawal. Oral or par-enteral methotrexate was usually associated with predni-sone at a dosage of 15 mg/week which was increased to20 mg/week within 2 weeks and in some refractory cases itwas increased to 25 mg/week.

In case of failure or intolerance to methotrexate, a sec-ond immunosuppressive agent such as azathioprine (1–3mg/kg/day), mycophenolate sodium (720–2,160 mg/day) orleXunomide 20 mg/day was prescribed for patients withoutlife-threatening manifestations of the disease. However,cyclophosphamide (2 mg/kg/day) was added to corticoste-roid treatment in patients with severe manifestations of TAand it was kept until remission was achieved and thenshifted to methotrexate or azathioprine. Immunosuppres-sive therapy was continued for at least 2 years after TA wasconsidered in remission. When patients failed to two ormore immunosuppressive drugs, an anti-TNF� agent espe-cially inXiximab was prescribed.

Surgical intervention was indicated for patients withhemodynamically signiWcant lesions, mainly those with cere-brovascular disease, coronary artery disease, moderate tosevere aortic regurgitation, renovascular hypertension, limbclaudication and progressive aneurysm enlargement [19].

Statistical analysis was carried out with the softwareSPSS 15.0 for Windows, Chicago, USA. Numerical datawas presented as mean, median, standard deviation (SD),and in some instances by 95% conWdence interval (95%CI). Categorical data was presented as total number andpercentage of cases. Comparisons between groups wereperformed using Mann–Whitney test and Student’s t testfor continuous variables and with Chi-square or Fisher’sexact test for categorical variables. The signiWcance levelaccepted was 5% (P < 0.05).

Results

Demographic features

Fifty-two TA patients were followed for a mean 74.3 months(95% CI 55.6–93.1 months). The mean age at study was

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38 years (SD 12.2 years) and the mean age at TA diagnosiswas 29.0 years (SD 9.7 years). The median disease durationwas 109.0 months (95% CI 85.2–132.8 months). About20.0% of patients were older than 40 years at TA diagnosis.Female gender comprised for 92% of TA patients and mostof them were Caucasian (58.0%), followed by mestizos(31.0%), blacks (8.0%) and Asian descendents (4.0%).

Angiographic features of TA patients

The most aVected arteries were the abdominal aorta (63.5%),left subclavian (60.6%) and left common carotid artery(57.3%) (Table 1). Stenosis was the most frequent arteriallesion found in 43 (82.7%) patients, followed by vascularocclusions in 28 (53.8%) and aneurysms in 9 (17.3%)patients while vessel wall thickening was observed in 22(42.3%) and dilatation in 16 (30.8%) patients. Angiographictype V was the most common type at diagnosis and tenpatients evolved to type V during follow-up. At diagnosis,angiographic type I was observed in 16 (30.8%), type IIa andIIb in 1 (1.9%) patient each, type III in 4 (7.7%), type IV in 8(15.4%) and type V in 22 (42.3%) patients. At study end,angiographic type I was observed in 10 (19.2%) patients,each type IIa and IIb remained in one patient (1.9%), type IIIin 3 (5.8%), type IV in 5 (9.6%) and type V in 32 (61.5%).

Disease activity

A relapse-remitting course was observed in 41 patients(78.8%) whereas 9 (17.3%) had a monophasic course and

only 2 (3.8%) patients were considered chronic-active. Dis-ease remission of any duration was achieved in 50 patients(96.2%). Along follow-up, new arterial lesions wereobserved in 37 patients (71.2%) while the evolution to adiVerent angiographic type was observed in 10 patients(19.2%). The majority of patients with a relapse-remittingcourse (80.5%) developed new arterial lesions whencompared to patients with other disease activity proWles(36.4%), P = 0.004. Although being considered in pro-longed remission, three out of nine patients with a mono-phasic disease course developed new arterial lesions alongfollow-up.

Evaluation of TA management

Prednisone was ever used by 94% of TA patients and it wasthe sole medication prescribed at diagnosis in six (11.5%)patients. The mean time of prednisone intake was75.4 months, ranging from 40.0 to 105.8 months. Immuno-suppressive agents were prescribed for 51 (98%) TApatients. Methotrexate was used in association with predni-sone in 76.9% of patients at TA diagnosis and eventuallyby 82.7% of patients for an average of 26.5 months. Cyclo-phosphamide, azathioprine, anti-TNF� agents and leXuno-mide were used by 26.9, 25.0, 5.8 and 5.8% of TA patients,respectively (Table 2). Only one patient (1.9%) usedsodium mycophenolate during the follow-up period. InXix-imabe was the drug of choice in all patients on anti-TNF�therapy agents. However, it was changed to adalimumab inone of them due to a serious allergic reaction to inXiximab.

Table 1 Distribution of diVerent vascular lesions in TA patients

Arteries Any lesion (%)

Stenosis (%)

Oclusion (%)

Aneurysms (%)

Dilatation (%)

Irregularity/thickening (%)

Abdominal aorta 63.5 26.9 1.9 7.7 11.5 15.4

Left subclavian 60.6 25.0 25.0 1.9 0.0 7.7

Left common carotid 57.3 30.8 9.6 5.8 1.9 9.6

Right subclavian 40.4 26.9 5.8 1.9 5.8 0.0

Right common carotid 40.4 23.1 9.6 1.9 0.0 5.8

Right renal 36.5 25.0 3.8 0.0 0.0 7.7

Left renal 34.6 15.4 9.6 0.0 0.0 9.6

Descending aorta 34.6 9.6 0.0 3.8 9.6 11.5

Ascending aorta 30.8 1.9 0.0 3.8 19.2 5.8

Superior mesenteric 28.8 15.4 11.5 0.0 0.0 1.9

Left vertebral 25.0 13.5 3.8 0.0 1.9 5.8

Innominate 25.0 11.5 1.9 1.9 7.7 1.9

Right iliac 23.1 9.6 5.8 0.0 0.0 7.7

Left iliac 23.1 11.5 5.8 0.0 0.0 5.8

Aortic arch 19.2 1.9 0.0 1.9 9.6 5.8

Celiac 15.4 11.5 3.8 0.0 0.0 0.0

Right vertebral 11.5 5.8 5.8 0.0 0.0 0.0

Inferior mesenteric 3.8 3.8 0.0 0.0 0.0 0.0

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Shift for another immunosuppressive drug or anti-TNF�agent due to treatment failure occurred in 34.6% of TApatients.

Among patients on methotrexate 41.9% had to changetherapy due to drug failure or toxicity and the developmentof new vascular lesions occurred in 75.0% of patients whostarted prednisone and methotrexate at diagnosis and in76.7% of patients who used methotrexate ever. Patientswho needed to change their immunosuppressive therapydue to treatment failure had similar rates of development ofnew vascular lesions when compared to those who usedonly one immunosuppressive drug (83.3% vs. 64.7%,P = 0.158).

Surgical treatment was performed in 18 (34.6%)patients. Bypass and vascular grafts were made in 7(13.5%) patients whereas endovascular procedure wasperformed only in two patients. Balloon angioplasty andstenting were performed in 5 (9.6%) cases each. Aorticmechanical valve replacement was done in 6 (11.5%)patients due to dilation of aortic root and regurgitation. Thisprocedure was associated with aortic vascular graft in fourof them and with renal artery angioplasty with stentingin one patient. The median time from diagnosis of TA tothe surgical procedure was 7 months, ranging from 1 to36 months. Restenosis was observed in 7 patients (13.5%)including 4 patients who underwent angioplasty, 2 with

bypass surgery and 1 who had a previous stenting proce-dure. Restenosis occurred in a median time of 11 monthsafter surgery, ranging from 1 to 60 months. One patientwho underwent aortic bypass developed anastomotic aneu-rysm. No diVerence was found concerning surgical treat-ment and development of new angiographic lesions, changein angiographic type, use of prednisone and methotrexate asWrst line of treatment or failure to methotrexate.

Survival rate

The survival rate of TA patients in 6 years of follow-up was92.3%. Four deaths occurred during the study period; oneof them was due to pyelonephritis and sepsis, another dueto a massive stroke and in two patients the death was due toacute myocardial infarction.

Discussion

In this study, we describe demographic features, distribu-tion of vascular lesions, patterns of disease activity andmanagement of patients with TA longitudinally in a six-year duration cohort study. We highlight the Wndings of arelapse-remitting course in the majority of patients with TA(78.8%) and the development of new vascular lesions in76.7% of patients despite the long term use of methotrexate(mean 26.5 months). Even one-third of those patientsthought to be on sustained clinical remission of diseaseactivity developed new vascular lesions. These results reas-sure the chronic and relapsing nature of TA.

Patients with TA usually have the onset of symptoms inthe third decade of life [1, 4–6, 11, 23, 24]. In this study, themedian age at TA diagnosis was 26.5 years which is similarto that described by literature and by previous publicationsfrom our center [3, 25]. In one decade we have observed anincrease in the rate of female patients with TA from 80 to84% to 92% and a decrease in the frequency of Caucasiansfrom 68.5 to 73.0% to 58.0% while mestizos, blacks andAsians have been more represented [3, 25]. TA aVects pre-dominantly women in most cohort studies, except for anIndian cohort study in which the frequency of femalepatients was almost similar to males with TA [26].

The Wnding of angiographic type V in 42% of ourpatients already at diagnosis is somewhat higher than the33.3% found by Park et al. [6]. It might indicate a delay indiagnosis of TA in our patients leading to extensive vascu-lar lesions even before the beginning of therapy. A previousstudy showed a median delay of 24 months in diagnosis ofTA (range 2–348 months) in our center [25] which ishigher than the range of 6.1–15.5 months described byother studies [1, 4, 6, 24] and lower than the delay of34.2 months observed by the Turkish cohort study [23].

Table 2 Features of corticosteroid and immunosuppressive therapy in52 TA patients

SD standard deviation, n number of patients

TA treatment Results

Only prednisone as Wrst line, n (%) 6 (11.5)

Prednisone ever, n (%) 49 (94.2)

Duration of prednisone use in months, mean § SD

75.43 § 32.90

Methotrexate as Wrst line, n (%) 40 (76.9)

Methotrexate ever, n (%) 43 (82.7)

Duration of methotrexate use in months, mean § SD

26.50 § 34.65

Azathioprine as Wrst line, n (%) 2 (3.8)

Azathioprine ever, n (%) 13 (25.0)

Duration of azathioprine use in months, mean § SD

20.00 § 19.45

Cyclophosphamide ever, n (%) 14 (26.9)

Cyclophosphamide as Wrst line, n (%) 3 (5.8)

Duration of cyclophosphamide use in months, mean § SD

13.29 § 14.92

LeXunomide, n (%) 3 (5.8)

Sodium mycophenolate, n (%) 2 (3.8)

Anti-TNF� agents, n (%) 3 (5.8)

Duration of anti-TNF� agents use in months, mean § SD

18.50 § 21.92

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The median delay in diagnosis seems to be higher in pediat-ric patients with TA and the age of onset <15 years is asso-ciated with a delay ¸2 years [1, 4, 24]. In an older study,Ueda et al. showed that in the 1960�s the average periodsince the onset of symptoms up to admission 6.1 years [27].

In our cohort study, the pattern of distribution of arteriallesions was slightly diVerent from other cohort studiesincluding Western patients with TA in which the subcla-vian and carotid arteries were more frequently involved [1,4, 5]. Although the abdominal aorta was the most aVectedartery in Korean and Indian patients with TA, unexpectedlywe found the abdominal aorta as the most aVected artery inBrazilian patients with TA [6, 26]. Nevertheless, in accor-dance with other cohort studies with Caucasian predomi-nance, the frequency of subclavian, carotid and renalarteries involvement was also high in our patients [1, 4–6,11, 23, 26]. Along follow-up most of our patients (61.5%)presented angiographic type V which is the most frequentangiographic type in patients with TA from diVerent popu-lation backgrounds [3, 5, 6, 23–26].

Longitudinal studies from the Cleveland Clinic and theNational Institutes of Health have demonstrated that manypatients with TA develop new vascular lesions over timeeven being free of symptoms attributed to TA [1, 11]. Con-sidering the relapsing and progressive nature of TA, weusually add associate corticosteroid and methotrexate whenstarting therapy. Therefore, we had the highest rate of pre-scription of immunosuppressive agents (98%) when com-paring to 40–84% in other cohort studies that evaluatedtherapy in TA patients [1, 4–6, 11, 23, 24, 28].

The combination of steroid and methotrexate with amean stable dose of 17.1 mg/week was eVective in 16patients with steroid resistant TA. Remission was achievedin 81% of TA patients [12]. Methotrexate is usually the Wrstimmunosuppressive agent used in the management ofpatients with TA when there is not enough disease controlwith corticosteroids [11, 24]. The frequency of methotrex-ate use in TA is variable in diVerent studies. No referenceto methotrexate use is given in the Indian cohort studywhereas it is added to corticosteroid treatment in 16.3% ofMexican patients, in 20.3% of Korean patients and in25.6% of French patients with TA [5, 6, 24, 26]. The fre-quency of methotrexate use in TA is higher in the US(43%) and Turkish (63%) cohort studies [11, 23]. In theformer study, the majority of the relapses (63%) occurredwhile patients were on immunosuppressive therapy andamong them methotrexate and prednisone were used by38% and methotrexate alone in 12% of the relapses.Median dosages of prednisone and methotrexate at relapsewere 10 mg/day and 17.5 mg/week, respectively [11].

Methotrexate is widely used to treat TA in the VasculitisUnit of Universidade Federal de São Paulo. It was pre-scribed for 76.9% of patients at diagnosis and for 82.7%

along follow-up. This is the highest frequency of metho-trexate use among observational studies with TA patients.Furthermore, there has been a trend to use higher dosesof methotrexate during the last few years when its meandosage shifted from 8.8 mg/week (range 5–15 mg/week)described by a previous publication from our center [25] to20 mg/week (range 15–25 mg/week). Nonetheless, the rateof methotrexate discontinuation in our study was 41.9%and it was mainly due to ineYcacy based on clinical criteriafor disease activity [11].

Neither the use of prednisone and methotrexate as theinitial therapy nor the sustained use of methotrexate for amean period of 26.5 months seemed to halt the disease pro-gression. Despite the high rate of methotrexate use we stillobserved the development of new vascular lesions in 76.7%of patients using longitudinal evaluation with non-invasivestudies. This Wgure is higher than the overall rate of 53% ofnew vascular lesions in TA patients observed longitudinallyby Maksimowicz-McKinnon [11] and much higher than theonly 3 patients out 16 in whom disease progressed in spiteof methotrexate use [12]. One of the reasons for this higherrate of new lesions might have been the inclusion of dilata-tion and vessel wall thickening/irregularity as criteria fornew vascular lesion in MRA evaluation in our studybesides stenosis, occlusions and aneurysms.

Taken together those Wndings indicate that althoughgood results were found in an older study evaluating meth-otrexate in TA [12], a signiWcant proportion of TA patientsmay not respond adequately to methotrexate therapyregarding the prevention of relapses and the developmentof new vascular lesions. Therefore, regular monitoring fordisease activity based on clinical criteria and vascularimaging studies may help the attending physician toobserve the failure of medical treatment and change immu-nosuppressive therapy in order to prevent the developmentof new vascular lesions and avoid further complications[29].

Other immunosuppressive agents such as azathioprine,cyclophosphamide, mycophenolate mofetil and leXuno-mide have also been used as an alternative to methotrexatein case of failure to control disease activity or intolerance[13–15, 23, 26, 30]. Moreover, anti-TNF� agents especiallyinXiximab and etanercept have been used to treat TArefractory to immunosuppressive drugs with good results[16, 17].

Surgical treatment was performed in 34.6% of ourpatients. Despite angioplasty was the most performed pro-cedure, restenosis was observed in 4 out of 5 patients whounderwent this procedure whereas it occurred in only 2patients after bypass surgery and in 1 after angioplasty withstent. In diVerent studies the long-term patency is usuallyhigher for surgical bypass when compared to angioplastywith balloon dilatation without stenting [1, 11, 19]. Regardless

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of the procedure, it is advisable that vascular interventionsin TA should be done in the quiescent phase of the disease.It has been shown that the rate of restenosis is higher whenthe surgery is performed during the active phase of thedisease when compared to those with stable disease. More-over, post-procedure therapy also plays an important rolefor the prevention of restenosis and the combination of ste-roids with immunosuppressive agents being more eVectivethan steroids alone or no therapy [31].

The survival rate of 92.3% during the 6 years of follow-up in this study is rather similar to the 5-year survival rateof 90–96% observed by diVerent studies [1, 6, 11, 24, 32].Although cardiac failure is the leading cause of death in TA[20], ischemic events such as acute myocardial infarctionand massive stroke were the commonest causes of death inour study.

In conclusion, although this was the cohort study with thehighest frequency of immunosuppressive agents prescriptionfor TA, the rate of development of new arterial lesions wasstill high, even with long term use of methotrexate which isthe most widely used medical therapy for TA besides corti-costeroids. The rate of methotrexate discontinuation due tolack of eYcacy based on clinical parameters for diseaseactivity was lower than the rate of disease progression dem-onstrated by serial imaging studies indicating the low sensi-tivity of clinical parameters to detect disease activity. Thecombination of clinical assessment with non-invasive longi-tudinal imaging studies seems to be more appropriate toevaluate response to medical therapy for TA.

Acknowledgments The authors thank Raissa Maria Sampaio Nevesand Kathia Regina Bezerra de Oliveira for their contribution for thedevelopment of this study.

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