18F-FDG PET/CT in Late Acquisition Identifies Sites of Active Disease in Treated Takayasu Arteritis

Takayasu arteritis (TA) is a vasculitis of large vessels defined as inflammation in the aorta and its main branches.1 Evaluation of disease activity in large vessel vasculitis (LVV) is still a challenge with a direct impact on the therapeutic decision and prevention of severe ischemic complications. Patients in apparent clinical remission often show progression of the disease even in the course of treatment and with evidence of normal values of inflammatory activity markers.2,3

18F-Fluorodeoxyglucose positron emission tomography (18F-FDG PET) is based on the identification of areas of increased glucose metabolism in inflammatory cells, showing hypermetabolic areas in neoplastic, infectious, and inflammatory processes. Several studies have documented the usefulness of 18F-FDG PET in granulomatous inflammation such as sarcoidosis, granulomatosis with polyangiitis, giant cell arteritis, and TA, as well as to evaluate the extent of vascular involvement in inflammatory diseases.4,5 The use of 18F-FDG PET associated with computed tomography (CT) increases the accuracy of the anatomic location of radiopharmaceutical accumulation on the vessel wall in rheumatic diseases.6 To date, the use of 18F-FDG PET has become a valuable complement in assessing activity in TA. The increase in FDG uptake in the arterial wall may precede clinical relapses in clinical remission patients and future structural changes detected by other imaging modalities.7,8

Glucocorticoids, immunosuppressants, and immunobiological agents inhibit the release of cytokines and inflammatory mediators, which may alter the assessment of disease activity.9

Many studies that described a correlation between vascular uptake by 18F-FDG PET/CT and disease activity include other LVV and different imaging techniques, either by visual or semiquantitative analysis.8,10,11 During examination, image acquisition generally occurs 60 minutes after the radiopharmaceutical injection.11 Image acquisition time differs among studies of LVV patients. Images were acquired early (40 and 60 minutes) in previous TA studies using 18F-FDG PET/CT.10,12–15 Martínez-Rodríguez et al16 showed that late imaging (180 minutes) resulted in increased FDG uptake in the arterial wall, increasing the possibility that PET/CT could be interpreted as active vasculitis. A more recent study demonstrated that image acquisition after 2 hours of tracer injection was better than conventional imaging after 1 hour to detect vascular activity inflammation in LVV, increasing PET sensitivity from 56% to 77%.17

To date, there are few reports that use late 18F-FDG PET/CT image acquisition to study LVV. The objective of this study is to evaluate the utility of 18F-FDG PET/CT in monitor sites of active disease in TA patients under full treatment, 120 minutes after the radiopharmaceutical infusion.

METHODS Study Design and Settings

This is a cross-sectional study conducted at the Rheumatology Unit of the State University of Campinas, São Paulo, Brazil.

Ethics and Informed Consent

This study was performed in accordance with the Declaration of Helsinki and was approved by the ethics committee of the Faculty of Medical Sciences of the University of Campinas–Unicamp (CAAE-51793915.5.0000.5404). All subjects provided a written informed consent before study.

Subjects

Between July 2017 and January 2018, 25 consecutive patients with a diagnosis of TA were selected for the study. Inclusion criteria were the fulfillment the American College of Rheumatology classification criteria for TA,18 aged older than 18 years, and regular follow-up. The exclusion criteria included history of iodine allergy, renal insufficiency, heart failure, asthma, pregnancy, and sickle cell anemia.

Assessment Measurements for Disease Activity

All patients had their clinical history registered and underwent detailed physical examination and laboratory tests on the day of the 18F-FDG PET/CT examination. Disease activity was assessed according to the criteria proposed by the National Institutes of Health (NIH), which consists of a worsening of 2 or more of the following criteria: (1) systemic complaints with no other identified cause (fever, arthralgia, myalgia, weight loss, and asthenia); (2) increased erythrocyte sedimentation rate (ESR); (3) ischemia (claudication, heart murmur, decreased or absent murmur, blood pressure asymmetry, pain in vessel pathways); and (4) new arteriographic changes.19

Disease duration was defined as less than 3 years, between 3 and 6 years, and more than 6 years.

The ESR and C-reactive protein (CRP) tests were used to assess disease activity, with normal values below 20 mm/h for ESR and 0.3 mg/dL for CRP.

All patients were on immunosuppressive and/or immunobiological treatment. Patients considered in disease remission stage were treated with prednisone at doses below 20 mg daily.

Classification of obesity followed the recommendations of the World Health Organization,20 and dyslipidemia followed the recommendations of the V Brazilian Guidelines on Dyslipidemias and Prevention of Atherosclerosis.21

Examination Protocol

Capillary glycemia was measured after an 8-hour fast. Fluorodeoxyglucose 4.44 GBq/kg (0.12 mCi/kg) was administered 120 minutes before examination in a Biograph Truepoint PET/CT model mCT (Siemens USA). All images were acquired after a 35-mA topogram from the head to the root of the thighs, followed by a whole-body CT with kV and mA modulated by the topogram, and finally a PET with a duration of 90 seconds per bed position every 20 cm. The acquisitions of the images were performed at 120 minutes to increase the sensitivity of the method.

Interpretation of Findings

The examinations were interpreted by 2 experienced nuclear physicians without knowing the patients' identities and clinical histories. Divergent cases were discussed in a consensus meeting.

The anatomic locations selected for analysis included the aortic arch, brachiocephalic trunk, right and left subclavian arteries, right and left carotid arteries, ascending aorta, descending aorta, abdominal aorta, and renal arteries. 18F-FDG uptake was measured according to visual and quantitative analysis.

Quantification was performed using standardized uptake value (SUV). The area of greatest vascular uptake of 18F-FDG was considered for calculating maximum SUV (SUVmax).

Visual analysis was performed following the technique proposed by Meller et al.22 The vascular uptake was compared with liver uptake: degree 0 (no uptake), degree 1 (lower uptake than liver), degree 2 (same uptake as liver), and degree 3 (greater uptake than liver). Equivocal cases (when deciding between grades 1 and 2 or between 2 and 3) were defined using SUV quantification. In these cases, liver mean SUV (SUVmean) measurements were taken from normal-appearing right lobe of the liver. Grade 2 was considered when lesion uptake was equal to liver SUVmean ± 2 standard deviations.

Disease activity was considered when the degree was ≥2 in one of the analyzed arterial locations.

Statistical Analysis

The data were processed in the SAS System for Windows (Statistical Analysis System, version 9.4; SAS Institute Inc, 2002–2012, Cary, NC).

To describe the profile of the sample under study, the frequency of categorical variables were described in absolute (n) and percentage (%) frequency values, and for quantitative variables, descriptive measures (mean, standard deviation, minimum, median, and maximum) were obtained.

Fisher test was used to assess the association of PET/CT with the use of immunosuppressants, the duration of the disease, CRP level >0.3, and disease activity according to the criteria proposed by the NIH. In the quantitative assessment of the SUV, the values were grouped using the mean of each vascular site as the cutoff point.

The level of significance adopted for the study was 5%.

RESULTS

Twenty-five patients were initially selected for the study, 4 of whom were excluded due to renal failure and one due to acute myocardial infarction. This study included 20 patients, and 18 (90%) were women. The mean age at the time of examination was 43.6 years (±11.58), and the mean age at diagnosis was 36.6 years (±9.69). Most patients had more than 6 years of illness (45%), 6 patients between 3 and 6 years (30%), and 5 patients less than 3 years (25%). There was a predominance of patients who were overweight (40%) and with obesity (35%). Low-density lipoprotein cholesterol levels above 70 mg/dL were present in 18 participants (90%). All patients involved in the study were currently using immunosuppressive agents (methotrexate or leflunomide), and only one (5%) under immunobiological treatment at the time of the 18F-FDG PET/CT. Sixteen patients (80%) were taking prednisone, 10 of them (62.5%) with a dose above 20 mg/d. Erythrocyte sedimentation rate values were above 20 mm/h in 14 patients (70%), and CRP values were above 0.3 mg/dL in 13 patients (65%). According to the NIH criteria, 13 participants (65%) experienced inflammatory activity, and there was no significant association between disease activity and CRP (p = 0.1736). The baseline characteristics of the patients are presented in Table 1.

TABLE 1 - Baseline characteristics of AT patients Variable Total (N = 20) Age, mean (range), y 43.6 (23–71) Age at diagnosis, mean (± SD), y 36.6 (19–55) Sex, n (% female) 18 (90) Race, n (%)  White 16 (80)  Asian 1 (5)  African descendants 3 (15) Obesity, n (%) 7 (35) Overweight, n (%) 8 (40) Dyslipidemia, n (%) 18 (90) Immunosuppression, n (%) 16 (80) Immunobiological, n (%) 1 (5) Prednisone >20 mg/d, n (%) 10 (62.5) ESR >20 mm/h, n (%) 14 (70) CPR >0.3 mg/dL, n (%) 13 (65) Active disease (NIH criteria), n (%) 13 (65)

In visual analysis, 19 participants (95%) presented at least 1 vascular site with active inflammation. In decreasing order of frequency, active disease (visual grade 2 or 3) was found in the following sites: aortic arch, descending aorta, ascending aorta, carotid arteries, abdominal aorta, subclavian arteries, and brachiocephalic trunk. The visual grade ≥2 was found in 12 (92%) of the 13 patients with clinical disease activity, 11 with uptake grade 3 uptake. Between patients without clinical activity of the disease, all presented vascular activity on PET/CT images, 4 with grade 3 uptake.

In quantitative analysis, considering the values at each vascular site, the highest SUVmax were 6.2, 5.0, and 4.5 in the aortic arch, ascendant aorta, and descendent aorta, respectively. Seven (35%) of the 20 patients had maximum SUVmax equal to or above liver SUVs, independent of the evaluation of the disease activity according to the criteria suggested by the NIH. The mean values of SUVmax founded in the evaluated arteries are described in Table 2.

TABLE 2 - Values of SUVs at Each Vascular Site Evaluated Location Mean Median Standard Deviation Minimum Maximum p value AoA Total group (n = 20) 3.0 2.8 1.0 1.5 6.2 Active NIH (n = 13) 3.1 2.7 1.1 2.0 6.2 Inactive NIH (n = 7) 2.7 2.8 0.9 1.5 4.3 0.6060 AbA Total group (n = 20) 2.9 2.8 0.6 1.8 4.2 Active NIH (n = 13) 3.1 3.1 0.7 1.8 4.2 Inactive NIH (n = 7) 2.6 2.6 0.3 2.2 3.1 0.0677 DA Total group (n = 20) 2.9 2.8 0.8 1.8 4.5 Active NIH (n = 13) 2.8 2.8 0.6 1.9 3.8 Inactive NIH (n = 7) 3.0 2.8 1.1 1.8 4.5 0.8736 AsA Total group (n = 20) 2.8 2.7 0.8 1.7 5.0 Active NIH (n = 13) 3.0 2.9 0.9 1.7 5.0 Inactive NIH (n = 7) 2.5 2.5 0.3 2.0 3.1 0.2332 BB Total group (n = 20) 2.3 2.1 0.6 1.4 3.3 Active NIH (n = 13) 2.1 2.0 0.4 1.4 3.1 Inactive NIH (n = 7) 2.5 2.8 0.7 1.7 3.3 0.3179 LC Total group 2.3 2.5 0.6 1.2 3.2 Active NIH 2.4 2.5 0.5 1.6 3.2 Inactive NIH 2.1 2.4 0.6 1.2 2.8 0.2321 RS Total group 2.1 2.2 0.5 1.2 3.2 Active NIH 2.1 2.1 0.5 1.4 3.2 Inactive NIH 2.0 2.2 0.7 1.2 2.9 1.0000 RC Total group 2.1 2.0 0.5 1.1 3.4 Active NIH 2.1 2.0 0.5 1.4 3.4 Inactive NIH 1.9 1.9 0.6 1.1 2.7 0.5508 LS Total group 1.9 2.0 0.5 1.0 2.9 Active NIH 1.8 1.8 0.5 1.0 2.9 Inactive NIH 2.1 2.2 0.4 1.5 2.5 0.1733

AoA, aortic arch; AbA, abdominal aorta; DA, descending aorta; AsA, ascending aorta; BB, brachiocephalic branch; LC, left carotid; LS, left subclavian; RC, right carotid; RS, right subclavian.

There was no significant difference between the means or medians of the SUV values at each vascular site evaluated among the patients with and without disease activity according to NIH criteria.

The mean SUVmax did not differ between clinical active and inactive results, with values of 3.53 and 3.21, respectively.

There was no correlation between disease duration and mean SUVmax values at each vascular site.

In both visual and quantitative analysis, prednisone doses and immunosuppressive therapy had no influence on radiopharmaceutical uptake among patients considered active and inactive at each vascular site.

Only in abdominal aorta, a significant association was found between CRP greater than 0.3 mg/dL and 18F-FDG uptake greater than the mean of all abdominal aorta SUV measurements (p = 0.008).

Table 3 shows the characteristics, laboratory results, and visual scale results of 18F-FDG PET/CT of each patient.

TABLE 3 - Association Between Disease Activity at Each Vascular Site Evaluated and Time of Disease, in Visual Analysis Compared With Liver Uptake <3 y, n = 5 (%) 3–6 y, n = 6 (%) >6 y, n = 9 (%) Total, n = 20 (%) p value AsA 1.000  Active disease 4 (80) 5 (56) 7 (78) 16 (80)  Inactive disease 1 (20) 1 (44) 2 (22) 4 (20) AoA 0.047  Active disease 4 (80) 3 (50) 7 (78) 14 (70)  Inactive disease 1 (20) 3 (50) 2 (22) 6 (30) DA 0.625  Active disease 2 (40) 3 (50) 6 (67) 11 (55)  Inactive disease 3 (60) 3 (50) 3 (33) 9 (45) AbA 0.310  Active disease 1 (20) 0 3 (33) 4 (20)  Inactive disease 4 (80) 6 (100) 6 (67) 16 (80) BB 1.000  Active disease 3 (60) 3 (50) 5 (56) 11 (55)  Inactive disease 2 (40) 3 (50) 4 (44) 9 (45) RC 0.728  Active disease 3 (60) 0 2 (22) 5 (25)  Inactive disease 2 (40) 6 (100) 7 (78) 15 (75) LC 0.319  Active disease 3 (60) 1 (44) 5 (56) 9 (45)  Inactive disease 2 (40) 5 (56) 4 (44) 11 (55) RS —  Active disease 0 0 2 (22) 2 (10)  Inactive disease 5 (100) 6 (100) 7 (78) 18 (90) LS 0.415  Active disease 0 1 (44) 3 (33) 4 (20)  Inactive disease 5 (100) 5 (56) 6 (67) 16 (80)

AsA indicates ascending aorta; AoA, aortic arch; DA, descending aorta; AbA, abdominal aorta; BB, brachiocephalic branch; RC, right carotid; LC, left carotid; RS, right subclavian; LS, left subclavian.

Figure shows the 18F-FDG PET/CT images of a patient with clinical active disease.

FIGUREFIGURE: Coronal (A), sagittal (B), and transaxial (C) 18F-FDG PET images, and transaxial fusion PET/CT images (D), of a male patient, aged 38 years, under treatment for TA for 5 years. At the time of the PET images, the patient was on treatment with prednisone (15 mg/d) and methotrexate (15 mg/wk), presenting malaise, fever, myalgia, worsening of lameness, and pain in the upper limbs. Erythrocyte sedimentation rate was 61 mm/h, and CPR level was 0.95 mg/dL, and he was considered to have active disease according to NIH criteria. Note the increased 18F-FDG uptake in the ascending (blue arrows) and descending aorta (red arrows) as well as in the aortic arch (green arrows) with an SUVmax of 3.4 and grade 3 on the visual scale. Color online-figure is available at http://www.jclinrheum.com.DISCUSSION

Nuclear imaging has gained importance as a noninvasive method for diagnosis and monitoring of inflammatory diseases.4–6 In TA, even with the improvement of imaging techniques, assessing disease activity is still a challenge. This study showed that 18F-FDG PET/CT in late acquisition is an effective imaging method to assess TA activity even in full treatment patients.

The activity criterion proposed by Kerr et al19 was most widely used in clinical practice, although clinical characteristics do not correlate with inflammatory evidence in approximately 50% of cases. In this study, CRP was correlated with 18F-FDG uptake only in abdominal aorta in quantitative analysis. At other sites, ESR and CRP levels were not related to intensity of uptake in 18F-FDG PET/CT, neither in visual nor in quantitative analysis.

Corticosteroids, immunosuppressants, and immunobiological agents are known to reduce FDG uptake.23–26 Nevertheless, in the present study, all patients were under immunosuppression and most presented activity at the image examination, both by visual and quantitative analyses, regardless of the presence of clinical activity according to the criteria proposed by Kerr et al.19 Furthermore, even those patients who used more than 20 mg/d of prednisone had disease activity in PET evaluation. When the visual analysis was considered, 95% of patients presented upgrade 2 or 3 in at least 1 anatomic location, also independently of clinical activity (Table 4). Recent evidence demonstrates that immunobiological therapy (infliximab and tocilizumab) results in fewer relapses than the disease-modifying antirheumatic drugs (DMARDS).27,28 Gudbrandsson et al27 reports the appearance of new arterial lesions in 40% of patients treated with DMARDS, whereas this occurs in only 10% in those patients treated with immunobiological therapy. These findings also support our results that even in patients under immunosuppression with DMARDS, 18F-FDG PET/CT can identify inflammatory activity on the vessel wall, probably due to smoldering inflammatory vessel activity and might be a predictor of clinical recurrence.

TABLE 4 - TA Patients Who Underwent an 18F-FDG PET CT Examination—Visual Analysis Sex Age, y Stage of Disease ESR CRP Visual Scalea 1 M 38 Active 61 0.95 3 2 F 36 Active 57 1.62 1 3 F 51 Active 49 1.18 3 4 F 46 Inactive 46 1.5 3 5 F 32 Active 43 0.56 3 6 F 51 Active 39 1.07 3 7 F 32 Active 38 1.49 3 8

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