18F-FDG-PET/CT Plays a Key Role in Formulating Treatment Strategies for Takayasu Arteritis


 Backgroud and Objective: Clinical evaluation alone cannot satisfy the prognosis of TAK. PET-CTmolecular imaging may be a useful tool to supplement the prognosis of TAK. The purpose of this study was to observe whether THE TAK patients who achieved clinical remission also achieved imaging remission with PET-CT. Pet-ct plays an important role in the prognosis of TAK patients and further formulation of treatment strategy.Results: 79% patients with TAK in remission were positive for 18F-FDG-PET /CT. The study population had a mean age of 38.8 years and was predominantly female (90%). Their mean disease duration was 3.5 years and they had a mean disease remission period of 9.4 months. Patients had a mean ESR of 37.3 mm/h and a mean CRP level of 13.5 mg/l at the first dignosis time and 4.9 mm/h/3.7 mg/l at the Courrent time point. There was a statistically significant difference between the two groups (p<0.01). All patients on initial treatment received oral glucocorticoids, 25% received methotrexate, 65% received leflumide, and 45% received cyclophosphamide. Quantitative analysis of the SUV of nineteen patients showed an increasing trend (Baseline SUVmax 2.16±0.46 vs Remission SUVmax 2.08±0.49, p=0.56; Baseline SUVmean 2.34±0.57 vs Remission SUVmean 2.42±0.81, p=0.46). The arterial SUVmax uptake was higher in 15 patients with remission than baseline (2.30 ± 0.62 vs 2.48 ± 0.91, p = 0.54). But it was not statistically significant. Most of the patients (13/19, 68%) had an SUVmax value ≥ 2.0 in visual vasculitis with positive PET/CT before treatment, and 32% ＜2.0. No correlation was found between the type of treatment used, the time that elapsed from remission, or laboratory parameters and the scintigraphic results. Conclusion: TAK's clinical remission criteria are not entirely consistent with actual vascular inflammatory activity. Patients with TAK that achieve clinical remission may not achieve imaging remission with PET-CT, and PET-CT plays an important role in the prognosis of TAK patients and further formulation of treatment strategy.


Backgroud
Takayasu Arteritis (TAK) is a Chronic, idiopathic, in ammatory disease that primary granulomatous large vessel vasculitis commonly affects the aorta and its immediate branches as well as pulmonary artery [1] .
It is the key and di cult problem in TAK diagnosis and treatment to be able to accurately judge the activity of arteritis and timely detect the recurrence of the disease. The aim of treatment in TAK is directed at suppressing the in ammatory process and establishing a state of remission. Traditional disease modifying antirheumatic drugs (DMARDs) resulted in achieving clinical remission in 30-50% of patients in various clinical settings [2] . However, the de nition of remission in TAK remains controversial. The preliminary criteria for disease activity proposed by Kerr GS et al. in 1994 that were adopted by the American College of Rheumatology (ACR) include four signs and symptoms of which two or more of the four must be satis ed were seemed as disease activity [3] . TAK is a rare disease with multiple nonspeci c clinical symptoms. It is di cult to diagnose in the early stages of the disease. A variety of biomarkers are being developed to diagnose and evaluate their activity. Imaging techniques are required to monitor the disease course and the treatment response of the drug in TAK. Increased vascular wall thickness, vascular wall edema, and wall lining enhancement are generally considered to be evidence of disease activity [4] . Studies in east Asia have shown that aortic regurgitation, pulmonary hypertension, and elevated serum nt-pro-bnp levels in TAK patients are associated with disease activity [5] . Recent studies have shown that there is a discrepancy between the clinical and laboratory parameters that indicate a state of remission and between various imaging techniques that assess vascular in ammation [6] .. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are commonly used to evaluate the activity of arteritis, but previous studies have shown that they are normal in active patients. However, ESR and CRP normal does not mean the regression of vascular wall in ammation and the cessation of lesions, and these two indicators can be elevated in many cases, which lacks speci city for the evaluation of vascular in ammation [7][8][9] . Conventional angiography,considered the 'gold standard' to assess vasculitis is invasive and associated with morbidity, radiation exposure and risk of contrast toxicity [10] . Since its usefulness in vasculitis was con rmed in 1999, 18 F-FluoroDeoxyGlucose ( 18 F-FDG) positron emission tomography (PET) has gained widespread acceptance in the diagnosis and monitoring of TAK [11] . Studies have shown that the sensitivity and speci city of 18 F-FDG-PET/CT in the diagnosis of macrovasculitis are 92% and 100%, respectively [12] .
Furthermore, 18 F-FDG-PET/CT can evaluate the e cacy of drug therapy of TAK [13,14] . Decreased vascular absorption in 18 F-FDG-PET/CT scan is associated with clinical remission. It should be noted that some patients after treatment with immunosuppressive agents, their clinical symptoms are relieved and the in ammatory markers are reduced to the normal range, but the 18 F-FDG-PET/CT scan still shows abnormal carotid artery, suggesting that the lesion may still change to a low level of activity [15] .The proposed mechanism that stands behind the idea of using 18 F-FDG-PET/CT lies in the fact that In in ammatory tissues, glucose metabolism is increased, and the uptake of radiolabelled glucose can detect its activity [9] . Even in the case of steroid therapy, 18 F-FDG-PET/CT is possible to distinguish between active and inactive patients. This theory is further strengthened by the fact that similar results of biodistribution have been achieved by using 18 F-FDG-PET/CT [13] . Nevertheless, although nuclear medicine investigations have become more speci c with the introduction of these new methods, their use is still limited due to cost and availability in various centers as compared to the use of 18 F-FDG-PET/CT.
In the present study we examined a cohort of TAK patients in clinical remission in order to nd out whether clinical and laboratory parameters are consistent with the actual in ammatory activity in the vessel assessed by 18 F-FDG-PET/CT.

Patients
Nineteen patients from a large cohort of TAK patients attending the rheumatology outpatient clinic of Xijing Hospital were randomly selected. Female(89%), Age( 37.8 ± 1.4yrs, range15-40), Disease duration (3.5 ± 0.75 yrs, range2.6-5.1). Among the 19 patients in this study, Glucocorticoid(Glu) alone accounted for 5%, and Glu + Methotrexate (MTX) + Le unomide(LEF)for 20%,Glu + Cyclophosphamide(CYS) + LEF for 25%,Glu + CYS for 20%,Glu + LEF + Tacrolimus (TAC) for 15%,Glu + LEF for 5%. Patients were included if they ful lled the following criteria:1) TAK diagnosed according to the NIH criteria [16] ; 2) Disease duration of more than 2 years; 3) No disease ares in the preceding 6 months period; 4) After the patient reached clinical remission, the treatment copy remained unchanged for at least 6 months. Exclusion criteria of the study were pregnancy, liver or renal function impairment, heart failure, respiratory failure, diabetes mellitus, psychological or neurological disorders and malignancy. All patients had to satisfy both the preliminary NIH criteria for remission. Clinical remission was de ned as the absence of new or aggravated systemic and/or local symptoms and/or signs, blood pressure stabilization, ESR and CRP reduction to normal, and no new onset or progression of existing lesions on imaging. 18

F-FDG -PET/CT acquisition of image and image analysis
All the patients received 18 F-FDG PET/CT scans on the same scanner (Biograph 40, Siemens) consistent with the standard clinical protocols [17,18] . 18 F-FDG-PET/CT was performed using a PET/CT scanner (Biograph 40,SIEMENS) 60 minutes after intravenous injection of approximately 3.7 MBq (0.1 mCi)/kg of 18 F-FDG. The blood glucose levels that were checked before FDG administration were below 200 mg/dl. PET data were reconstructed iteratively with and without attenuation correction based on CT data and reoriented in axial, sagittal, and coronal slices. Objective reference values were obtained for all patients by measuring mean standard uptake values (SUV mean) of mediastinal blood pool and liver. Vascular-wall FDG uptakes were quanti ed by drawing volume of interests (irregular and voxel) in the ascending aorta, arcus aorta, descending aorta, abdominal aorta, right brachiocephalic artery, right subclavian artery, left subclavian artery, right common carotid artery, left common carotid artery, and pulmonary arteries were not included due to their close relationship with histological intense cardiac FDG uptake. The quanti ed 18 F-FDG uptake using methods as standard uptake value (SUV). The mean SUV in the center of the inferior vena cava in all cases, and target/background ratio was calculated as max SUV in arterial wall/mean SUV in inferior vena cava in their study [19] . A max SUV cut-off was set at 2.0 for detecting active in ammation of TAK in untreated cases and a cut-off for max SUV (strong accumulation, SUV > 2.0; weak accumulation, SUV 1.2-2.0) [20] .

Results
Demographic and clinical features A total of 19 TAK patients who satis ed the preliminary NIH criteria for remission were studied. The demographic and clinical features of the study group are presented in Table 1. The study population had a mean age of 38.8 years and was predominantly female (90%). Their mean disease duration was 3.5 years and they had a mean disease remission period of 9.4 months.
Patients had a mean ESR of 37.3 mm/h and a mean CRP level of 13.5 mg/l at the rst dignosis time and 4.9 mm/h/3.7 mg/l at the current time point. There was a statistically signi cant difference between the two groups (p < 0.01). All patients on initial treatment received oral glucocorticoids, 25% received methotrexate, 65% received le umide, and 45% received cyclophosphamide. Most patients received a combination of glucocorticoids and DMARDs.

Discussion
TAK is a chronic, idiopathic, in ammatory disease that primarily affects the great vessels [21] . Due to its non-speci c clinical manifestations, lack of speci c biomarkers, characteristic imaging changes, and lack of a uni ed treatment regimen. Therefore, there are still some di culties in the diagnosis and treatment of TAK. Especially, it is di cult to diagnose, assess the activity, evaluate the curative effect and evaluate the prognosis of atypical arteritis. In a subset of patients with signs and symptoms of active disease, serum reactant levels did not increase during the acute phase.In other patients who appear to have no disease, there is laboratory or radiological evidence [16] . Although the NIH criteria all use in ammatory markers such as ESR and CRP as part of the assessment, the methods used to assess disease activity or remission status are not su cient and sensitive enough to detect low levels of vascular in ammation. 18 F-FDG PET/CT combines the functional information of PET with the anatomical information of CT [22] .This is a new diagnostic tool that can show vascular in ammation before any structural changes. 18 F-FDG PET/CT is a non-invasive imaging method that measures the accumulation of 18 F-FDG in the highly metabolized and activated in ammatory cell in ltration vessels [23] . In in ammatory tissue, glucose metabolism is increased, and its activity can be measured by the uptake of radio-labeled glucose [24] . Even when treated with steroids, it is possible to distinguish between active and inactive patients [24] . In our study, TAK patients also met NIH remission criteria by using PET/CT technology, while active subclinical vascular in ammation was still present. The PET/CT method we used is only functional and only related to the activity of vascular in ammation. Similar to the studies of Grayson et al., PET/CT can predict the recurrence and mitigate the risk [25] .
In addition, we found no association between the type of drugs used by patients (including hormones, anti-tnf therapy, and immunosuppressants) and the outcome of the in ammatory process. However, due to the limited number of reported cases, the safety and long-term e cacy of these drugs in TAK-CAD remains to be further investigated. The Ishikawa and Maetani study showed that among 120 TA patients, the 15-year survival rate was 93% for those with prolonged remission, the 15-year survival rate for people with persistent active disease was 68 percent. Those with both persistent and severe vascular disease had a 15-year survival rate of just 40 percent. The reported mortality rate of patients with ta-cad was between 3% and 21.0% [26] . These large differences are due to different study methods, different follow-up times, and different demographic/clinical and therapeutic differences. However, our study makes us realize that some limitations may lead us to bias in interpreting the data. The number of patients in remission in this study was too small, so it is necessary to further expand the sample size and continue to observe the prognosis of such patients.Whether patients and doctors should continue treatment after TAK clinical remission and accurately assess patients' disease activity is a challenging clinical issue at present. It is of great signi cance to nd appropriate clinical assessment methods and guide clinical treatment to prolong patients' survival and reduce mortality.Our results suggest that vascular in ammation and injury in TAK patients in clinical remission is still progressing, providing evidence for further enhancement of treatment. Therefore, angiography alone seems to be inadequate as a means of assessing TAK structural damage. Other models, such as power doppler ultrasound, MRI, and PET/CT, should be used to comprehensively assess disease activity. These results may also prompt researchers to modify the current criteria for TAK mitigation to meet modern standards, including clinical, laboratory and imaging parameters.   Figure 1 shows the changes in SUVmax (-0.09±0.63) and SUVmean (-0.08±0.46) between baseline and remission in TAK patients. There was no statistical signi cance in the remission stage of nineteen TAK patients compared with the baseline stage. Only 4 TAK patients were in non-disease activity in remission stage, and 79% TAK patients were still in imaging disease activity in remission stage.

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