|Year : 2016 | Volume
| Issue : 1 | Page : 164-169
|Evaluation and therapy in four patients with Takayasu's arteritis
S Conkar1, S Mir1, B Sözeri1, Kaplan Bulut1, C Çınar2
1 Department of Pediatric Nephrology, Ege University, Faculty of Medicine, Izmir, Turkey
2 Department of Interventional Radiology, Ege University, Faculty of Medicine, Izmir, Turkey
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|Date of Web Publication||15-Jan-2016|
| Abstract|| |
Takayasu's arteritis (TA) is a large-vessel vasculitis primarily affecting the aorta and its branches. It ranks third among other types of childhood vasculitis, while it is the most common large vessel vasculitis observed in childhood. The diagnosis of TA should be made on the basis of clinical criteria and supported with laboratory findings, while confirming it with the imaging methods. Angioplasty, stent and bypass grafts may be necessary in the case of an irreversible arterial stenosis. Small-vessel involvement in TA and acute phase reactants should be taken into account for the diagnosis of an attack. In this report, treatment choices for four patients with the diagnosis of pediatric TA, their clinical and laboratory findings and their responses to treatment will be discussed.
|How to cite this article:|
Conkar S, Mir S, Sözeri B, Bulut K, Çınar C. Evaluation and therapy in four patients with Takayasu's arteritis. Saudi J Kidney Dis Transpl 2016;27:164-9
|How to cite this URL:|
Conkar S, Mir S, Sözeri B, Bulut K, Çınar C. Evaluation and therapy in four patients with Takayasu's arteritis. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2021 Aug 2];27:164-9. Available from: https://www.sjkdt.org/text.asp?2016/27/1/164/174205
| Introduction|| |
Takayasu's arteritis (TA) is a large-vessel vasculitis primarily affecting the aorta and its branches. It ranks third among other types of childhood vasculitis, while it is the most common large vessel vasculitis observed in childhood. The prevalence of the disease in childhood is 2.6/1.000.000. In etiology of TA, cellmediated autoimmunity and granulomatous inflammation are responsible for the vascular impairment.  The thoracic aorta and its branches and the abdominal aorta and its branches are often affected. In the beginning, plasma cells, lymphocytes and giant cell infiltration are observed in the vessel wall, and the incidence of ischemic symptoms related to the organ supplied by the affected vessel resulted from luminal stenosis, which is caused by fibrosis of the vessel wall, are observed in the next stages.
Diagnosis of the disease may be quite challenging and delayed by reasons of the nonspecific symptoms that occur in the onset of the disease, such as, malaise, fever and weight loss.  Claudication may be observed due to the affected vessels that supply extremities.  The vessel wall inflammation leads to wall thickening, fibrosis and the formation of thrombus. Occlusion or aneurysm may develop in the affected vessel. Also, occurrence of renal stenosis and stroke may be observed. ,, TA diagnosis is made on the basis of the clinical criteria, as biopsy of the large vessels is usually not possible. The EULAR/PRINTO/PRES diagnostic criteria, published in 2010, are used for the diagnosis of TA. Diagnosis of TA still continues to be a challenge for clinicians. 
The patients who meet at least three of the six criteria are considered as TA. Glucocorticoids are frequently used during the treatment as well as other immunosuppressives in case of no response to steroids.
Angioplasty, stent and bypass grafts may be necessary in the case of an irreversible arterial stenosis.
Here, we report the clinical and laboratory findings and treatment choices for four patients with the diagnosis of pediatric TA.
| Case Reports|| |
A 14-year-old girl was admitted to the hospital because of pain in the lower limbs and intermittent fever that was ongoing for a month. The left radial artery pulse was absent on physical examination. The right and left arm blood pressure were measured as 120/80 mm Hg (prehypertension) and 60/35 mm Hg (<90 p), respectively. Laboratory investigations were unremarkable, except erythrocyte sedimentation rate (ESR) 110 mm/h, C-reactive protein (CRP) 9.8 (<0.3) mg/dL and serum amyloid A (SAA): 706 (0-6) mg/L.
Doppler ultrasonography did not detect a significant stenosis in the renal arteries. However, the computed tomography (CT) angiography detected stenosis in the brachiocephalic arteries, the aorta and the proximal superior mesenteric artery (SMA). No hypertension was observed in the patient with ambulatory blood pressure monitoring (ABPM). The patient was diagnosed to have TA due to age under 40 years, difference in blood pressure between both arms, absence of the left radial pulse in addition to the angiographic findings and presence of the three criteria according to the American College of Rheumatology (ACR). Prednisolone 2 mg/kg/ day dose (max 60 mg/day) and acetylsalicylic acid at a dose of antiagregant were administered. It was observed that her ESR decreased to the level of 5 mm/h during the control examinations performed at the end of the first month. Brachial and radial artery pulses started to be detected. Blood pressure in the right and left arm were measured as 110/70 and 105/67 mm Hg, respectively. Steroids were tapered to 0.5 mg/kg/ steroids and the patient has been stable for one year.
A 13-year-old female patient was admitted to the hospital with complaints of malaise that were ongoing for one month and numbness in the feet for one week. Body weight and height were 31.5 kg (<3p) and 145 cm (3 p), respectively. The pulses of all arteries could not be palpated except those of the right radial artery. Blood pressure of the right arm was measured as 154/101 mm Hg; however, the blood pressure of the left arm, left leg and right leg could not be measured. Abdominal murmur was detected. Laboratory investigations revealed ESR 120 mm/h, CRP 13.96 mg/dL, high-sensitive CRP (hsCRP) >2 mg/dL and SAA 384 mg/L.
Renal Doppler ultrasonography revealed that where the renal arteries branched from the abdominal aorta, a thickening that obstructed the right renal artery was present. The peripheral renin levels were normal.
ABPM, daytime systolic and diastolic load and nocturnal systolic and diastolic load were detected as 1.4%, 0%, 35% and 49%, respectively, and the patient was considered as nocturnal non-dipper hypertensive with the findings of systolic and diastolic dips, which were 5% and 2.6%, respectively.
In echocardiography, aneurysmal dilatation was observed in the right aortic coroner artery; however, obstruction was not observed in the branches of the aortic arch. In CT angiography, wall thickening secondary to aortitis was observed in addition to the stenosis in the left subclavian long segment, the midaortic segment of the abdominal aorta, both the renal arteries, and the superior mesenteric artery (SMA).
In the magnetic resonance angiography (MRA) examination, stenosis was observed in the right brachycephaly truncus, in the proximal part of the right subclavian, in the left common carotid and in the area where the left subclavian branches from the aorta; both subclavian arteries had collaterals. In the abdominal MRA examination, stonosis and significant contour irregularities were observed in the abdominal aorta, output of celiac and mesenteric arteries and output of the SMA. In addition, both renal arteries were detected as being quite thin. The radiological findings were compatible with TA. Steroids and acetylsalicylic acid were administered to the patient.
The patient's complaints of weakness and malaise and numbness of the limbs during exercise diminished. The high fever disappeared and appetite improved. On physical examination, the distal pulses started to become palpable. Laboratory investigations on Day 15 of the steroid therapy revealed a decrease of ESR from 120 to 12 mm/h, CRP from 13.9 to 0.5 mg/dL and SAA from 384 to 22.3 mg/L.
In the fourth month of follow-up, prednisone 1 mg/kg/on alternate days was continued and the patient remained clinically and chemically stable. In the renal artery Doppler ultrasonography, the right artery blood flow velocity is decreased from 300 cm/s to 234 cm/s and the left renal artery flow velocity is decreased from 288 cm/s to 211 cm/s. The decrease in pretreatment renal artery flow velocity suggested that stenosis regressed.
The patient was followed-up for six months without any problem and received prednisone 0.5 mg/kg/alternate days.
A 15-year-old female patient was admitted to the hospital with complaints of respiratory distress and cough and she had a history of syncope 1.5 years and 6 months prior to the admission. Findings on physical examination of the patient included body weight 62 kg (50-75 p), height 169 cm (75-90 p), heart rate 125/min and respiratory rate 32/min. The blood pressure as measured in the right arm was 154/101 mm Hg, in the left arm was 134/87 mm Hg, in the right leg was 134/90 mm Hg and in the left leg was 136/89 mm Hg. All peripheral pulses were palpable. Other systemic examinations were normal.
Laboratory investigations included normal renal function, but ESR was 63 mm/h, CRP was 7 mg/dL and SAA was 153 mg/L.
In her ABPM, the patient was found to have all-day severe non-dipper hypertension with the findings of daytime systolic diastolic load and nocturnal systolic and diastolic load, which were detected as 96%, 70%, 100% and 100%, respectively. HsCRP, augmentation index (AIX) and pulse wave velocity (PWV) were detected as >2 mg/dL (<0.3 mg/dL), 19% (normal <10%) and 7.5 m/s (normal <5.6), respectively.
Dilated cardiomyopathy, ejection fraction (50%), mild mitral regurgitation and first-degree aortic insufficiency were detected by echocardiography.
In the renal artery Doppler ultrasonography, >200 cm/s flow rate was measured in the renal arteries. Bilateral renal artery stenosis was detected with ongoing stenosis up to 1.5-2 cm after branching from the abdominal aorta. Stenosis and irregularities in both of the proximal renal arteries and post-stenotic expansion were detected in the renal MRA.
Doses of 2 mg/kg/day prednisolone and 3 mg/kg acetylsalicylic acid and amlodipine were prescribed to the patient. Generalized tonicclonic seizures were observed twice during the follow-up. During the event, blood pressure was measured as 200/110 mm Hg. The patient diagnosed as hypertensive encephalopathy was treated with esmolol and sodium nitroprusside under intensive care conditions. At the end of 24 h, the blood pressure regressed to 138/89 mm Hg.
Endovascular intervention for renal artery was contemplated due to the presence of hypertension, which could not be controlled with medical therapy. In the control angiograms, a 5 mm × 19 mm diameter stent was inserted into the area where stenosis was observed. It was detected that the bilateral renal arteries achieved sufficient flow in the control angiograms. The operation was terminated without any complication.
The laboratory investigations on the 15 th day of steroid therapy revealed that the sedimentation rate decreased from 63 to 12 mm/h, CRP from 7 to 0.5 mg/dL and SAA from 153 to 22.3 mg/L. In the second month of steroid therapy, the blood pressure of the right and left arms was measured as 138/81 and 123/75 mm Hg, respectively. However, the activation markers of the disease increased, including sedimentation rate from 12 mm/h to 70 mm/h, CRP from 0.5 mg/dL to 8.2 mg/dL and SAA from 153 mg/L to 198 mg/L (normal: 0-6). In her ABPM, she was normotensive all day. HsCRP, augmentation index and PWV were >2 mg/dL (normal <0.3 mg/dL), 21% and 7.5 m/s, respectively, denoting small-vessel functional impairment. Accordingly, cyclophosphamide 3 mg/kg/day was added.
In the 3 rd month of the treatment, the parameters continued to be abnormal, including sedimentation rate, CRP, renal Doppler ultrasound parameters and ABPM parameters. Hypertensive encephalopathy developed and bilateral percutaneous transluminal angioplasty (PTA) was performed on the renal arteries by interventional radiology for the second time. There was a reduction of renal artery blood flow velocity and an increase in RI values after PTA that denoted regression of the renal artery stenosis.
In the 4 th month, 0.5 mg/kg/day steroid therapy on alternate days was increased to 2 mg/kg/day, whereby the acute phase reactants were seen to be increased in the 3 rd week of the cyclophosphamide and steroid treatment. Azathioprine 2 mg/kg/day, methotrexate 12.5 mg/ m 2 /week and folic acid were added to the regimen. The patient has been followed-up for six months. The patient was planned to receive a 3 mg/kg dose of anti-tumor necrosis factor (TNF) every eight weeks because of the diagnosis of TA resistant to treatment.
A 16-year-old female was admitted with the complaints of intermittent fever and weight loss for the last two months. Her physical examination disclosed a body weight of 43.6 kg (3-10 p), height of 161 cm (25-50 p), pallor and murmur on the bilateral carotid artery and 1/6 systolic murmur on the mesocardiac area. Peripheral pulses were bilaterally palpable, but the left radial pulse was weaker than the right radial pulse. Blood pressure measurements on the right and left arms and right and left legs were 129/68 (stage 1) mm Hg, 90/62 (<90 p) mm Hg, 102/61 (<90 p) mm Hg and 100/59 (<90 p) mm Hg, respectively. Laboratory investigations revealed elevated acute phase reactants like the other cases in our report.
Results of imaging tests and renal Doppler ultrasound did not reveal a significant renal flow velocity increase. The abdominal MRA showed contour irregularities in the suprarenal segment of the abdominal aorta, including the descending aorta, localized luminal stenosis and wall thickening. Thoraco-abdominal CT angiography showed diffuse wall thickening through the arcus aorta, thoracic descending aorta and abdominal aorta as well as saccular aneurysmal dilatation in the thoracic segment with a diameter reaching 2-3 cm. All these findings were compatible with aortitis. Furthermore, wall thickening in the common carotid artery and the left subclavian artery and aneurysmal dilatation in the left subclavian artery were detected.
The patient was found to have nocturnal systolodiastolic non-dipper hypertension by using the AMBP monitoring. In echocardiography, left ventricular mass index was within normal limits. No hypertensive retinopathy was detected in fundoscopy.
The patient was started on prednisolone 2 mg/kg/day and acetylsalicylic acid 3 mg/kg for the treatment of TA. Cyclophosphamide 3 mg/kg was added to the regimen because of the partial response of the patient to the steroid therapy after one month of therapy.
In the 3 rd month of follow-up, the active phase reactants remained elevated. Therefore, the patient was planned to be initiated on anti-TNF with a dose of 3 mg/kg every eight weeks.
| Discussion|| |
In TA, diagnosis is often delayed due to nonspecific systemic symptoms of the early stage, which are not specific to the disease. The most important findings on physical examination include pain and limitation of movement observed during the phase of vascular inflammation in the extremities, vascular ischemic symptoms such as reduction or absence in pulses, vascular murmur and difference >10 mm Hg in systolic blood pressure between both arms.  In the literature, diagnosis for pediatric patients ranged from one month to five years after the onset of symptoms.  The time between the onset of symptoms and the diagnosis was detected as one month for our first and second patients, 1.5 years for the third patient and two months for the fourth patient. The diagnosis was delayed only in the third patient. In our patients, except for the acute phase reactants, the laboratory investigations were normal.
Vascular changes in TA include mostly stenosis and, rarely, aneurysms,  located usually in the ascending aorta, aortic arch and its branches, the descending thoracic and abdominal aorta and the renal arteries.  The most common involvement in our cases was encountered in the ascending aorta, comparable to that in the literature.
One of the most important problems in the treatment of TA is how to determine the activity of the disease, which is usually based on clinical and laboratory findings. The presence of vascular ischemic changes and high acute phase response such as ESR, serum CRP and low hemoglobin values are the usual parameters for follow-up of activity of the disease; however, none of them is reliable enough. The DEITak (Disease Extent Index-Takayasu's) criteria can be used to determine the activity of the disease.  ABPM, AIX and PWV values usually correlate with the angiographic findings in case of small-vessel involvement and can help determine the activity of the disease.
The mainstay of medical treatment of TA includes corticosteroids and classical immunosuppressive agents. We achieved improvement in the first and second patients with steroid therapy, but immunosuppressive drugs were required in the other two cases. However, the efficacy of these drugs is still not confirmed in patients with TA. 
Infliximab, etanercept and adalimumab and tumor necrosis factor-α blocking (anti-TNF) agents can be used for cases in which the cyclosporine dose cannot be reduced and one or more immunosuppressive agents are ineffective. TA is a granulomatous disease and TNF-α is an important cytokine for granuloma formation and its maintenance.  In the literature, there are many case reports or series reflecting the experiences of the use of infliximab, etanercept and adalimumab in TA treatment. ,,,, We also planned to use anti-TNF agent in two of our cases.
Surgical interventions such as arterial by-pass are required in patients with TA in case of failure of transluminal angioplasty, severe or long vascular stenosis non-responsive to medical treatment or a sudden thrombosis. Performing these types of interventions after the onset of wall inflammation with good medical treatment increases the chances of success of the intervention. ,, However, early endovascular intervention had to be performed in one case while the disease was still active due to the uncontrolled high blood pressure.
Surgical bypass operations in TA are decreasing because of the more successful combination of angioplasty and immunosuppressive therapy. 
Because TA is a rare vasculitis, there are no placebo-controlled, randomized clinical trials in the literature about it. The few existing studies were conducted on a limited number of patients. Accordingly, there is no consensus on a treatment protocol.
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Department of Pediatric Nephrology, Ege University, Faculty of Medicine, Izmir
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