Patient Characteristics
Nineteen patients with TA were selected for the study. Demographic, clinical, laboratory, and treatment data are detailed in Table 1.
Table 1
Demographic, clinical, and treatment characteristics of the Takayasu's arteritis patients.
Variables | n (%) | Mean (SD) | Median (95%CI) |
|---|
Demographic | | | |
| | Age (years) | | 38 (8.3) | |
| | Age at diagnosis of TA (years) | | 27 (8.7) | |
| | Female sex | 18 (95.0) | | |
| | White | 12 (63.2) | | |
| | Non-white | 7 (36.8) | | |
Clinical | | | Mean (SD) |
| | Disease duration (years) | | 11.5 (6.1) | |
| | Clinical /laboratory disease activity | 11 (57,9) | | |
| | Disease in remission | 8 (42.1) | | |
Laboratory | | | Median (min-max) |
| | ESR (mm/hora) | | | 12.0 (2–56) |
| | CRP (mg/L) | | | 9.0 (2–86) |
| | TADS damage score# | | | 4.0 (1–4) |
| | Prednisone | 13 (68.4) | | |
| | Daily dose of prednisone (mg) | | | 10.0 (0–80) |
Synthetic immunosuppressant | | | |
| | Methotrexate | 9 (47.4) | | |
| | Leflunomide | 1 (5.3) | | |
| | Azathioprine | 2 (10.5) | | |
| | Infliximab | 1 (5.3) | | |
| | Tocilizumab | 2 (10.5) | | |
| | ASA | 19 (100.0) | | |
| Note: TA: Takayasu arteritis; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; AAS: acetyl salicylic acid; #: Takayasu Arteritis Damage Score; n: sample size; SD: Standard Deviation; 95% CI: 95% confidence interval. |
At the time of data collection, 5 (26.3%) patients were classified as having clinical activity, 7 (36.8%) were in remission, and 7 (36.8%) presented with only laboratory abnormalities. Regarding the extent of disease, the majority of patients exhibited vascular involvement type V (8; 42.1%), followed by type IIa (6; 31.6%) and type IIb (3; 15.8%). During the period between the diagnosis of Takayasu arteritis and the date of inclusion in the study, 10 (52.6%) patients experienced disease relapses.
CRP values [median, min. and max. 12.2 (5–86) mg/L vs. 5 (2–9) mg/L, p = 0.04] were significantly higher in patients with clinical activity compared to patients in remission, after excluding patients with exclusively laboratory abnormalities. No significant difference was observed in ESR values [median, min. and max. 20 (3–52) mm/h vs. 10 (2–12) mm/h, p = 0.06] between patients with clinical activity and those in remission.
Data pertaining to disease activity, laboratory values, and imaging tests of the study population are presented suplementary material.(Supplement 1)
Angiotomography
Eighteen patients (94.7%) exhibited alterations indicative of vascular activity on CTA, characterized by thickening of the vessel wall and/or the double halo sign, primarily affecting the ascending aorta, aortic arch, and descending aorta.
CTA examinations revealed vessel wall thickening in five (100%) patients with clinical activity. Of the total of 7 patients in remission, all demonstrated vessel wall thickening on CTA.
Patients with clinical activity showed greater aortic wall thickening (ascending, aortic arch, descending, and abdominal) compared to patients in remission [median, min. and max. 2.9 (0–6) mm vs. 0 (0-5.5) mm, p = 0.02]. In the analysis of aortic branches, no significant difference was found in vessel wall thickening between patients with clinical activity and those in remission [median, min. and max. 0 (0–3) mm vs. 0 (0–5) mm, p = 0.98] (Fig. 1 A and B).
The double ring sign was identified in one (20%) of the 5 patients with clinical activity and was not observed in 5 (71.4%) of the 7 patients in remission. Patients exhibiting the double ring sign on CTA had a shorter disease duration compared to those without this vascular alteration [median, 7.5 (range, 2–22) years vs. 13.4 (range, 5–19) years, p = 0.04].
18F-FDG PET/CT
Based on the visual scale, two (10.5%) patients were classified as grade one, 11 (57.9%) as grade two, and six (31.6%) as grade three. The median of the highest SUVmax value in the studied population was 5.6, with a range of 4.5 to 8.3. 18F-FDG PET/CT demonstrated significant uptake in 1 (20%) of the 5 patients with clinical activity and was negative in 5 (71.4%) of the 7 patients in remission. There was no statistically significant difference in SUVmax values [median, 3.8 (range, 1.2–7.3) vs. 3.7 (range, 1.9–8.3), p = 0.45] and PETVAS score [median, 0 (range, 0–3) vs. 1 (range, 0–3), p = 0.67] between patients with clinical activity and those in remission (Fig. 2 A and B)
Comparative analysis of CTA and 18F-FDG PET/CT images
Based on the visual scale, 18F-FDG PET/CT identified 17 (94.4%) of the 18 patients with thickening on the CTA and did not show uptake in the one patient (100%) without this vascular alteration. 18F-FDG PET/CT presented significant uptake in 5 (83.3%) of the 6 patients who had a double ring sign on the CTA. There was a weak correlation between the medians of the vessel wall thickening values on the CTA and SUVmax in 18F-FDG PET/CT (Fig. 3)
There was no difference in the SUVmax values [median, 5.9 (range, 4.74–7.74) vs. 5.2 (range, 4.56–8.3), p = 0.63] among patients with and without the double ring sign on the CTA.
Vessel wall thickening values on CTA [median, min. and max. 1.8 (0–6) mm vs. 0 (0-5.3) mm, p = 0.013] were significantly higher in patients with an 18F-FDG PET/CT uptake score ≥ 2 compared to those with an uptake score < 2 (Fig. 4).
Aortic wall thickening greater than or equal to 3.3 mm showed a sensitivity of 45% and specificity of 86% (the area under the ROC curve was 0.67, with 95% CI 0,51 − 0,82, p = 0.04) to predict disease activity considering the clinical criteria as a reference (Fig. 5).
There was no association between image exams (CTA and 18 FDGPET/CT) and the various treatments of the studied population ( data not shown).
In the present study, which primarily included patients with extensive vascular involvement and long-standing disease, 26.3% were classified as having clinically active disease and 36.8% had only laboratory abnormalities. Vascular alterations, such as vessel wall thickening observed on CTA, were effective in identifying disease activity in the aorta but proved inadequate for assessing its branches. An aortic wall thickness ≥ 3.3 mm demonstrated low sensitivity (45%) but good specificity (86%) for predicting clinical activity. No significant differences were observed in SUVmax values or PETVAS scores between patients with clinically active disease and those in remission. Vessel wall thickening on CTA showed only a weak correlation with vascular activity as assessed by 18F-FDG PET/CT.
To date, no clinical criterion has been described in the literature to evaluate disease activity in TA in a standardized manner and with adequate accuracy. Several studies have classified disease activity in TA based on NIH classification criteria (4, 5, 10). More recent studies (6, 7, 9, 11) defined diseaseactivity without considering image evaluation and with variation in the inclusion of subjective systemic symptoms. Nakaoka et al. (20) included assessing subjective systemic symptoms, while Grayson et al. (12) considered only objective systemic symptoms. Due to the lack of definition of a method for assessing TA activity and the heterogeneity of the studies, we chose to define patients as having disease activity with clinical symptoms associated with vasculitis, without considering chronic fatigue. In the study of Arnaud et al. (13) who evaluated clinical and laboratory criteria separately, 32% of patients presented clinical activity and 34% laboratory activity. In the study of Lee et al. (21, 22), 63% of patients had disease activity based on the NIH classification criteria, with 29% due to symptoms of ischemia or inflammation. We found similar results in our study (26.3% active, 36.8% laboratory abnormalities and 36.8% inactive).
Early detection of inflammation in the vessel wall in TA is essential before irreversible structural alterations occur (2, 3). To date, no single imaging technique is sufficiently accurate to determine activity in the vessel wall. Some vascular alterations identified as disease activity may represent fibrotic remodeling (5, 6). A recent recommendation from the European League Against Rheumatism (EULAR) (23) for the use of images in vasculitis of large vessels indicated MRI as the first choice for investigating mural inflammation and/or luminal alterations in patients with suspected TA, considering the high experience and availability of the technique. 18F-FDG PET/CT, CTA, and ultrasound were indicated as alternative imaging modalities. Regarding MRI, some studies have shown an association between edema of the vascular wall and enhancement by contrast with disease activity in TA (7, 8). In contrast, other studies did not identify differences in MRI alterations in the activity and remission phases of the disease (4, 5). The MRI with gadolinium also showed low agreement with the development of new lesions in a longitudinal study since edema in the vessel wall, which can indicate activity, may also be present in the remodeling phase of the vascular wall (4–6). CTA, in addition to assessing arterial lesions such as stenosis and aneurysm, also assesses the thickening of the vessel wall, a sign of activity. However, few studies have investigated this method in TA, and all of them included a small sample (9, 10, 11, 21). In the study by Chen et al. (10), all patients with TA exhibited vessel wall thickening on CTA; however, the degree of thickening was greater in patients with active disease compared to those with inactive disease. Similarly, in the present study, patients with clinical activity demonstrated increased aortic wall thickening compared to those in remission. In contrast, no significant difference in vessel wall thickening was observed in the aortic branches between patients with and without clinical activity. These findings suggest that CTA is more effective in detecting disease activity in the aortic wall than in its branches.
Previous studies have shown that vessel wall thickening ≥ 2 mm in large vessels and/or ≥ 1 mm in their branches on CTA is associated with vascular activity (9–11). In a Chinese study, consistent with our findings, a maximal wall thickness ≥ 3.3 mm demonstrated a sensitivity of 83.1% and a specificity of 89.7% for identifying disease activity in patients with TA. These results suggest that a cutoff value of ≥ 3.3 mm for wall thickness on CTA may serve as a more reliable predictor of vascular activity in patients with TA (10).
The majority of patients with the double halo sign in the study had less than five years of illness, possibly indicating this find as an early change. It is essential to carry out studies with larger samples, which allow separate analysis and comparison of CTA performance between patients with recent-onset TA and those with established disease.
In the present study, 89.5% of patients presented vascular uptake on the 18F-FDG PET/CT, classified as vasculitis activity, including 2 of the 7 patients considered to be in remission. High SUVmax values could be a warning for persistent activity and greater difficulty in controlling the disease. This is consistent with recent studies demonstrating that 18F-FDG PET/CT can predict future clinical relapses and is associated with a significantly higher risk of developing new angiographic changes compared to individuals without 18F-FDG PET/CT activity (24–28).
No significant differences in SUVmax values and PETVAS scores were observed between patients with active disease and those in remission. In the study of Arnaud et al. (13), there was also no association between 18F-FDG PET/CT uptake and clinical activity. A similar result was described by Grayson et al. (12), in which 41 of 71 patients with large vessel vasculitis in remission also presented uptake interpreted as active vasculitis. A recent metanalysis, with great heterogeneity between the studies, described sensitivity of 87% and specificity of 73% of 18F-FDG PET/CT to predict disease activity in TA, considering the NIH activity criteria as a reference. A considerable number of patients in remission presented moderate uptake on the 18F-FDG PET/CT (29–30). Is the low performance of the 18F-FDG PET/CT to evaluate activity in vasculitis of large vessels related to the low sensitivity of the disease activity reference criteria used to date? Does the 18F-FDG PET/CT identify subclinical vascular activity or also present uptake of areas of remodeling in vascular segments without inflammation? The 18F-FDG also accumulates in atherosclerotic vascular lesions, a condition that should be considered mainly in patients with long-term disease, as in the present study (21, 22, 31). Another problem related to 18F-FDG PET/CT is the lack of adequate standardization of the criteria for defining vascular activity. The majority of the studies used the visual uptake intensity scale to evaluate activity (9, 11, 14, 18). Other studies used the SUVmax and uptake intensity (vascular SUVmax/hepatic SUVmean ratio) or vascular SUVmax/inferior vena cava SUVmean. Recently, the PETVAS score has been used more frequently, making studies more homogeneous in image analyses.
Comparing 18F-FDG PET/CT with CTA in this study, 94.4% of patients with thickening and 83.3% of patients with double halo presented abnormal uptake by the 18F-FDG PET/CT visual scale. Vessel wall thickening values on CTA were higher in patients with 18F-FDG PET/CT uptake. Still, there was a weak correlation between the values of the vessel wall thickening and SUVmax of the vessels studied. According to Kobayashi et al. (32), the accumulation of 18F-FDG does not always coincide with the thickening of the vascular wall because it may represent areas of inflammation that have not yet progressed to the development of vascular thickening. The uptake on the 18F-FDG PET/CT can be an earlier process than the vascular alterations on the CTA. Recently, a study showed the possibility of 18F-FDG PET/CT identifying vasculature lesions early, before clinical, laboratory presentation or image changes on CTA or MRI (31). There are still not enough prospective studies to confirm whether early 18F-FDG PET/CT uptake could suggest activity and whether it would progress to some vascular damage (30–35).
The small sample size, cross-sectional design, and lack of a sensitive and standardized disease activity criterion to assess TA were the main limitations of this study. The majority of studies that evaluate 18F-FDG PET/CT are retrospective analyses of medical records (32, 33, 34). In the current study, all patients underwent imaging tests, with clinical, laboratorial evaluation and imaging tests at the same moment.