Clinical Characteristics And Disease Activity Screening Of Takayasu's Arteritis

ObjectiveTakayasu's arteritis?TA?is a chronic and granulomatous large-vessel vasculitis characterized by inflammation of the aorta and its major branches.TA primarily affects young females in the majority of series.TA has a long disease course with alternating remission and attack.Chronic vasculitis eventually results in vascular wall thickening,fibrosis,lumen stenosis,occlusion,dilation or aneurysm formation.TA patients have various severe complications and high disability rate.Clinical manifestations of TA are varied from an asymptomatic condition suspected owing to impalpable pulses or arterial murmurs,to life–threatening neurological manifestations.According to the imaging results,TA disease process can be divided into an early active inflammatory phase and a late chronic phase.The early active inflammatory phase is characterized by generalized,non–specific symptoms which include discomfort,fever,night sweat,joint pain,headaches,and weight loss,etc.Anemia and elevated erythrocyte sedimentation rate?ESR?are often detected at this stage.These non-specific symptoms spontaneously alleviate in three months or TA patients enter a chronic phase within months to years.The late chronic phase was accompanied by the symptoms of limp,ischemia,pulselessness and hypertension and terminal organ dysfunction.However,up to 50%of TA patients cannot be identified in the active inflammatory phase,which has delayed the diagnosis and treatment of TA^[1].Accurate estimation of disease activity during TA diagnosis and follow-up,which affects disease prognosis and treatment,is the key and difficult problem in TA clinical management.The symptoms of local ischemia in TA patients are related to the degree of vessel wall injury and stenosis,but not necessarily consistent with the active inflammation of vessel wall.In about 50%of TA patients,clinical features are not related to inflammatory markers such as ESR and C-reactive protein?CRP?,and active vascular lesions may persist in patients with normal ESR and CRP^[2].Kerr criteria and the Indian Takayasu clinical activity score?ITAS2010?are usually used for clinical evaluation.Currently,imaging techniques can be used to evaluate and manage TA patients,which include computed tomography angiography?CTA?,ultrasonography?US?,positron emission tomography?PET/CT?,magnetic resonance angiography?MRA?,and so on.Especially in the 2018 EULRA Guidelines for Imaging of Vasculitis,MRA is recommended as the first choice to assess wall inflammation and/or changes of diameter.However,these imaging methods have some shortcomings,including radiation,time-consuming,expensive,high technical requirements,possible renal toxicity and economic considerations caused by the use of iodine contrast agents,which limit their clinical application.Therefore,an effective and repeatable imaging method is needed to evaluate disease activity.Accurate assessment of disease activity is the key to effective treatment of TA patients.US is often used to diagnose TA and/or to detect vessel changes before stenosis.Concentric thickening of arterial wall can be seen in US examination of TA patients,which may indicate inflammation and edema of arterial wall.However,whether wall thickening represents arterial inflammation remains unclear.In recent years,clinicians began to use contrast-enhanced ultrasound?CEUS?for carotid artery angiography,which can enhance the visualization of the vascular lumen and the formation of new blood vessels.CEUS can help quantify the vascularization of vascular wall and gradually become a hot spot of clinical research.There are only case reports and no large cohort of literature reports about the relationship between carotid CEUS and TA disease activity.Although CEUS may be used to monitor disease activity in TA patients,its operation needs more professional doctors and it is not conducive to repeated operation in a short time.Therefore,it is also very important to find sensitive serological indicators for evaluating disease activity.Vascular endothelial growth factor?VEGF?is one of the most important angiogenic cytokines,which can lead to angiogenesis and increase vascular permeability.It has been reported that the level of VEGF increases in patients with TA,but the correlation between VEGF and neovascularization has not been reported.It is difficult to differentiate acute vascular inflammatory injury from permanent vascular fibrosis stenosis in clinical practice^[3].Therefore,it is necessary to further search reliable serum markers for progressive angiopathy.Recent studies have shown that serum interleukin?IL?-6,tumor necrosis factor alpha?TNF-??,IL-8,IL-9,IL-18,interferon gamma?IFN-??,IL-17A,vascular endothelial adhesion molecule?VCAM?and penetrating hormone?PTX?-3 in patients with TA are elevated.In particular,PTX-3 is produced in the inflammation site.In contrast,CRP responses to IL-6 secretion and indicates systemic inflammation.Under the action of local pro-inflammatory factors,PTX-3 is mainly produced by vascular endothelial cells,macrophages and DC,and plays a local role.PTX-3 may be a useful marker of local inflammation and vasculitis.Currently,there are few reports on qualitative studies of cytokine in TA patients,and the results of different studies are inconsistent.Therefore,to better identify,diagnose,treat and manage TA patients at early stage,our study carried out the following three aspects.1)The clinical and epidemiological characteristics,complications and recurrence rate of TA patients in our center were systematically reviewed,and the risk factors of complications and the causes of disease relapse were analyzed.2)To evaluate the active lesions in carotid CEUS of TA patients,and to analyze the correlation with ITAS 2010 and Kerr criteria.The sensitivity and specificity of CEUS were analyzed according to the gold standard of carotid PET/CT examination.3)To explore serum levels of cytokines?IFN-?,TNF-?,IL-6,IL-8,IL-9,IL-17A,IL-18,PTX-3,and VEGF?in different T helper?Th?cells pathways.To evaluate their relationship between these cytokines and inflammatory markers?ESR and CRP?or carotid CEUS results and to estimate the value of these serum factors for disease activities.Thus,it provides experimental basis for TA diagnosis,accurate disease assessment,and then therapy adjustment.MethodsWe evaluated Xijing hospital records of 341 consecutive TA patients,who accessed the department of Clinical Immunology over 11 consecutive years?2008–2018?.The diagnosis of TA was established based on the 1990 ACR criteria.We investigated the clinical manifestations,signs,radiological features,vascular complications,treatment and the relapse rate of TA patients.Logic regression was used to analyze the risk factors of vascular complications and disease recurrence.This was a retrospective analysis of 71 patients with TA who had undergone carotid CEUS.Twenty-two of 71 patients underwent ¹⁸FDG-PET after CEUS.We investigated the association between carotid vascularization as determined with CEUS and clinical data.The consistency of CEUS and PET in assessing carotid inflammation was compared with receiver operating characteristic curve?ROC?.Serum levels of PTX3,TNF-?,IL-6,IL-8,IL-9,IL-17A,IFN-?and VEGF were measured in 49 patients with TA by luminex kits.49 TA patients were divided into active group and inactive group according to Kerr criteria.Statistical analyses and charts were performed using SPSS software?version19.0?.P<0.05 was considered statistically significant.Results1.We evaluated hospital records of 341 consecutive TA patients,who accessed the Clinical Immunology Department of our institution over 11 consecutive years?2008–2018?.The median age at diagnosis was 36 years.The ratio of male to female was1:4.8.The most common type of TA was type V?59.9%?and the second is type I.The common symptoms were dizziness?56%?,limb weakness?44.3%?and so on.The most common signs were the blood pressure difference between upper and lower limbs>20mmHg?80.1%?,carotid murmur?66.7%?,weakened or untouchable pulse?65.2%?and hypertension?45.3%?.The incidence rates of vascular stenosis and aneurysm were 91.2%and 19.6%respectively.The sites of vascular involvement were common carotid artery83.6%,subclavian artery 76%,thoracic aorta 58.9%,aortic arch 51.2%,anonymous artery43.7%,abdominal aorta 41.4%,renal artery 30.1%,mesenteric artery 27%,pulmonary artery 25.6%,etc.The common complications of TA patients were stroke 8.5%,pulmonary hypertension 10.7%,aortic regurgitation 27.3%,aortic valve insufficiency8.8%,and cardiac insufficiency 9.7%and so forth.The drug treatments of TA includes glucocorticoids?GCs?and immunosuppressants,such as GCs 89.4%,cyclophosphamide?CTX?40.5%,methotrexate?MTX?33.1%,Tocilizumab?TCZ?6.7%,etc.Surgical intervention accounted for 12.0%in patients with TA.Renal artery and upper extremity angioplasty were the most common intravascular interventions,accounting for 50%and22.2%respectively.The incidence of vascular complications was 45.2%.The risk factors of vascular complications were age??35 years old,2.0 times?,progressive course of disease?1.7 times?and hypertension??2 grade,1.89 times?.Under the condition of combined treatment of GCs and immunosuppressants,there was still the recurrence rate of35.2%in TA patients.The risk factors of recurrence were 2.6 times in males,1.67 times in CRP and 1.99 times in cervical pain.There are three kinds of drug withdrawal in TA patients with relapse,including 13.3%by themselves,53.3%according to ESR/CRP level,and 33.4%under the guidance of inflammatory index and imaging.The average diagnostic time of TA patients was 2.94±4.77 years.234 cases?68.6%?were delayed in diagnosis,including patient cause?38.5%?and iatrogenic factors?61.5%?.2.There was a statistically significant association between the results of CEUS assessment and ITAS 2010?P=0.01?or Kerr's criteria?P=0.000?.Among 71 TA patients,there were 34 with clinically inactive disease,according to ITAS 2010 criteria.Assessment of 34 TA patients with clinically inactive disease yielded 11 CEUS scans that showed active lesions?visual grade?2?in the region of the right or left carotid artery.In 22 TA patients who underwent CEUS and ¹⁸F-FDG/PET,right?or left?carotid CEUS vascularization grade positively correlated with vascular ¹⁸F-FDG uptake?all P=0.000?.When vascular inflammation was defined as ¹⁸F-FDG uptake with visual grade?2,carotid CEUS showed sensitivity of 100%and specificity of 80%.3.According to Kerr criteria,49 TA patients?Average age:31.4±9.39 years,female/male:43/6?were divided into active group?n=29?and inactive group?n=20?.Serum PTX-3 level was higher in the active group than that of inactive group?P<0.05?.While other cytokines were higher in the active group than that in the inactive group,but there were no statistical discrepancies.The serum level of ESR was positively correlated with the levels of CRP?r=0.615,P=0.000?and PTX-3?r=0.3,P=0.036?.The serum level of IFN-?was negatively correlated with the levels of ESR?r=-0.305,P=0.033?and PTX-3?r=-0.357,P=0.012?.The levels of TNF-?,IL-6 and IFN-?were positively correlated each other?P<0.05?.The serum level of VEGF was positively correlated with the levels of TNF-??P<0.05?and IL-6?P<0.01?.Serum VEGF level was correlated with bilateral carotid CEUS findings?r=0.522,P=0.032?.When disease activity was defined as Kerr criteria?2,a PTX-3 level of 2.9ng/ml was the predictive cutoff value for TA?sensitivity 82.8%,specificity 50%,AUC=0.67?.In 23TA patients with normal ESR and CRP,the level of PTX-3 was higher than the predictive cutoff value in 10 patients?43.4%?,6 patients of which?60%?had active carotid CEUS lesions?left and/or right grade?2?.ConclusionTA patients of our center are mostly females and V type is the most common.These patients have a wide range of involved arteries.The aortic arch and its branches,especially carotid artery,were most often involved.Hypertension,stroke,pulmonary hypertension and vascular complications are common,and the recurrence rate of diseases is high.Male,elevated CRP and neck pain are its risk factors for disease recurrence.After drug reduction according to current serological and imaging indicators,TA patients still have a high recurrence rate and vascular progress.The lack of effective disease surveillance indicators for TA causes these adverse consequences.For TA patients with clinically inactive disease,CEUS could help clinicians to identify active lesions in the carotid vascular region.Carotid CEUS may be a rapid and cost-effective substitute tool for angiography in the follow-up of patients with TA.PTX-3 may be a potential biomarker for evaluating disease activity.Serum VEGF level may be associated with local angiogenesis.