Rheumatol Int DOI 10.1007/s00296-014-2985-3
Original Article
Large vessel vasculitis in elderly patients: early diagnosis and steroid‑response evaluation with FDG‑PET/CT and contrast‑enhanced CT Go Muto · Hiroyuki Yamashita · Yuko Takahashi · Yoko Miyata · Miyako Morooka · Ryogo Minamimoto · Kazuo Kubota · Hiroshi Kaneko · Toshikazu Kano · Akio Mimori
Received: 22 January 2014 / Accepted: 4 March 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Large vessel vasculitis (LVV) is an oftenreported cause of inflammation of unknown origin (IUO) in elderly people. The objective of this study was to describe the usefulness of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/ CT) and contrast-enhanced CT in early diagnosis and treatment follow-up of patients with LVV presenting as elderly onset IUO. We retrospectively compared contrast-enhanced CT findings and FDG-PET/CT findings of the patients diagnosed with LVV and 11 controls; all subjects were 50 years of age or older. We evaluated maximum standardised uptake value (SUVmax) and PET score of the aortic wall for quantitative comparison of FDG-PET/CT findings. We measured the aortic wall thickness (W) and its ratio against the radius (W/R) for quantitative comparison of aortic wall thickening by contrast-enhanced CT. After steroid treatment, we compared these values with those pre-treatment. Of 124 patients
who were hospitalised due to advanced age and IUO, 88 underwent FDG-PET/CT and contrast-enhanced CT. Abnormal findings were observed on images from 78 patients. The findings were indicative of LVV in 13 patients (10.5 %), of whom more than half had only non-specific symptoms. Patients with LVV had significantly higher aortic wall SUVmax (3.85 vs. 1.95), PET scores by FDG-PET/CT, and aortic wall thicknesses by contrast-enhanced CT (3.8 vs. 2.6 mm) than controls. Significant improvement in aortic wall thickening was evidenced by reduced PET scores and by contrast-enhanced CT findings in patients who were followed up after treatment. LVV is an important cause of IUO with non-specific symptoms in elderly patients. Imaging examination comprising contrast-enhanced CT and FDG-PET/CT is useful for early diagnosis and early treatment evaluation of LVV, allowing for amelioration of reversible aortic wall thickening.
Go Muto and Hiroyuki Yamashita have contributed equally to this work.
Keywords Large vessel vasculitis · Fluorine-18 fluorodeoxyglucose positron emission tomography/ computed tomography · Contrast-enhanced CT · Inflammation of unknown origin
Electronic supplementary material The online version of this article (doi:10.1007/s00296-014-2985-3) contains supplementary material, which is available to authorized users. G. Muto (*) · H. Yamashita (*) · Y. Takahashi · H. Kaneko · T. Kano · A. Mimori Division of Rheumatic Diseases, National Center for Global Health and Medicine, 1‑21‑1 Toyama, Shinjuku‑ku, Tokyo‑to 162‑8655, Japan e-mail:
[email protected] H. Yamashita e-mail:
[email protected] Y. Miyata · M. Morooka · R. Minamimoto · K. Kubota Department of Radiology, National Center for Global Health and Medicine, Shinjuku‑ku, Tokyo‑to, Japan
Introduction Large vessel vasculitis (LVV) can be clinically diagnosed and classified according to specific criteria [1, 2]. During the Chapel Hill Conference in 1994, two forms of primary LVV were distinguished: giant cell arteritis (GCA) and Takayasu arteritis (TKA) [3]. Early diagnosis and assessment of the extent of LVV are crucial factors for adequate therapeutic management. LVV diagnosis is often difficult because of the absence of specific symptoms and signs and the limited specificity of the available biochemical tests.
13
Morphological imaging techniques such as angiography, computed tomography (CT), magnetic resonance imaging (MRI), and ultrasonography (US) cannot detect the early phase of inflammation of the vessel wall because of slight anatomical changes at this time. It is also difficult to distinguish active inflammatory lesions from the residual anatomical changes of scarring [4]. Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18FDG-PET/CT) is a functional imaging technique that has become an established tool in oncology [5]. Moreover, this imaging technique has a promising role in the field of inflammatory diseases [4, 5]. FDG, a glucose analogue, accumulates in cells with increased glycolysis, which does not occur only in neoplastic cells [6]. Even lesions with high concentrations of activated inflammatory cells show increased FDG uptake. FDG-PET/ CT may therefore be a valuable imaging technique for evaluation of the metabolic activity of the vessel wall in both the diagnosis and follow-up of patients with LVV [4, 5]. Several studies have shown the role of whole-body FDGPET/CT in patients with LVV, and a recent meta-analysis evaluated the diagnostic performance of FDG-PET/CT in patients with GCA [7]. However, no reports have described the efficacy of early treatment for patients with LVV in terms of reducing the aortic wall thickening. In this study, we retrospectively reviewed cases with inflammation of unknown origin (IUO) presenting with non-specific symptoms among elderly patients in whom contrast-enhanced CT and FDG-PET/CT were used for early diagnosis, treatment, and follow-up of LVV.
Methods Study design and objectives We reviewed all medical charts for patients admitted to the Division of Rheumatic Diseases of our institute between May 2006 and April 2012. Among patients who were admitted during the study period, we examined patients aged 50 years or older who were admitted with the chief complaint of IUO and who were diagnosed with LVV. The main objectives of this study were to investigate the prevalence of LVV in elderly patients with IUO and to evaluate whether a combination of contract-enhanced CT and FDG-PET/CT would allow early diagnosis of LVV and thereby lead to effective early treatment interventions. Ethics statement The study was approved by the Ethics Committee of our hospital, and informed consent was obtained from each patient.
13
Rheumatol Int
The definition of IUO Fever of unknown origin (FUO) was defined using the criteria of classical FUO by Durack and Street [8]. Similarly, we introduced and defined the term IUO as a modification to the definition of FUO. Although malignant tumours are not strictly “inflammation,” they were included in the IUO category, if the following criteria were fulfilled. That is, we retrospectively collected a series of consecutive patients with (1) an illness of more than 3 weeks’ duration; (2) diagnosis uncertain despite appropriate investigations, after at least three outpatient visits or at least 3 days in hospital; (3) at least one of the following: (a) temperature exceeding 38.3 degrees C on >3 occasions and/or (b) raised inflammatory markers (C-reactive protein >2.5 mg/dL), and those patients who satisfied the definition were summarised. Inclusion/exclusion criteria of LVV patients The diagnoses of LVV were established by consensus and were based on the 1990 American College of Rheumatology (ACR) classification criteria [1, 2]; if not fulfilled by the combination of clinical symptoms, the diagnoses were established based on the results of additional examinations such as 18FDG-PET/CT and/or contrast enhanced CT, exclusion of other diagnoses, and post-treatment outcomes. However, patients diagnosed with infectious aortitis were excluded. LVV was diagnosed in 13 patients (6 men, 7 women) hospitalised in our department between May 2006 and April 2012. The mean age of the 13 patients was 72.4 ± 9.1 years (range, 60–86 years) at the time of LVV diagnosis, and the mean time from the onset of symptoms until diagnosis was 4.4 months (range, 1–12 months). With regard to inflammatory responses, the mean C-reactive protein level was 6.56 ± 3.65 mg/dL. Control patients The imaging findings of LVV in these 13 patients were compared with control group. To form the control group, we ultimately selected 11 patients at random with a disease other than LVV who had undergone FDG-PET/CT and contrast-enhanced CT for evaluation of their primary disease activity or exclusion of malignant tumours and who were matched to the LVV group with no significant differences in age, sex, and C-reactive protein level. These 11 control patients (7 females, 4 males) consisted of active rheumatic disease or polyarthritis (rheumatoid arthritis, n = 6; systemic lupus erythematosus, n = 1; adult Still’s disease, n = 1; Behcet’s disease, n = 1; polymyositis, n = 1; RS3PE, n = 1). The diagnosis of the primary disease itself was unaffected by either the FDG-PET/CT or contrast-enhanced CT findings in all patients.
Rheumatol Int
Fig. 1 Method of evaluating aortic circumferential wall thickening. a Descending aorta on chest contrast-enhanced CT. b Enlargement of the descending aorta. For the quantitative comparison of aortic wall thickening by contrast-enhanced CT, vascular wall thickness
(W, mm) was measured and its ratio to the radius calculated (in mm) (W/R, %). The W values were measured in the 2-, 6-, and 10-o’clock directions, and the mean was used as the measurement result
FDG‑PET/CT imaging
arteries were each counted as a single vascular region; when scores differed between the right and left sides, the highest score was taken to represent that region. All LVV patients underwent FDG-PET/CT before steroid treatment. Laboratory findings were evaluated within 5 days of the PET/CT examination.
After a 5-h fast, blood glucose levels were measured and patients received an intravenous injection of 370 MBq of FDG. One hour after FDG injection, PET/CT imaging was performed from the vertex to the knee joints or from head to foot using a PET/CT scanner (Biograph 16; Siemens, Erlangen, Germany) with a 3-min emission scan/bed and CT attenuation correction. For the quantitative comparison of FDG-PET/CT imaging findings, we measured the maximum standardised uptake value (SUVmax) in the aortic wall. Furthermore, the spread of inflammation into major blood vessels and the primary branches of the involved vessels were evaluated using PET scores. PET scan images were scored as negative (0) or positive in seven vascular regions (thoracic aorta, abdominal aorta, subclavian arteries, axillary arteries, carotid arteries, iliac arteries, and femoral arteries). Positive results were scored semi-quantitatively as follows: (1) minimal but non-negligible FDG uptake; (2) clearly increased FDG uptake; and (3) marked FDG uptake. A total vascular score (TVS) ranging from 0 (no vascular FDG uptake in any of the seven vascular regions) to 21 (vascular FDG uptake = 3 in all seven regions) was calculated [9]. The bilateral subclavian, axillary, carotid, iliac, and femoral
Findings of aortic wall thickening in patients with LVV by contrast‑enhanced CT For the quantitative comparison of aortic wall thickening by contrast-enhanced CT, the vascular wall thickness (W) and its ratio to the radius (W/R) were measured (Fig. 1) and then compared with those of the control group. Comparison of PET scores and CT findings in patients with LVV before and after treatment We compared the FDG-PET/CT findings (seven patients) and aortic wall thickening by contrast-enhanced CT (nine patients) in patients examined after LVV treatment with the corresponding pre-treatment values. The intervals of PET/CT and contrast-enhanced CT imaging before and after treatment were 4.6 ± 3.1 and 6.3 ± 3.5 months, respectively.
13
Rheumatol Int
“others,” or “unknown,” they consisted of 61 patients with connective tissue disease, 33 patients with infection, and 18 patients with a malignancy. Of these 124 patients, 88 patients underwent FDG-PET/CT and contrast-enhanced CT, and 78 of them showed abnormal findings. Fifteen Patients showed distinct thickening around the circumference of the aortic wall on contrast-enhanced CT and distinct FDG accumulation in the corresponding site on FDG-PET/CT. Two of these patients had infectious aortitis, caused by Salmonella enterica in one patient and Aspergillus in the other. The remaining 13 patients were diagnosed as having true LVV. Clinical symptoms of LVV (Table 1)
Fig. 2 Flowchart of the retrospective study for IUO. Abbreviation IUO inflammation of unknown origin, FDG-PET/CT Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography, LVV large vessel vasculitis
Image analysis All two image modalities (PET and contrast CT) were assessed separately by four board certified radiologist (Y.M, M.M., R.M., and K.K). Statistical analyses
Table 1 lists the 13 patients with LVV. Three GCA showed positive FDG accumulation at the superficial temporal artery site. Even though massive FDG accumulation was observed in the cranium, inflammation of the temporal artery was isolated and identifiable because this artery is located outside the cranium. Most of the remaining 10 patients had neither headache nor jaw claudication and thus did not have typical GCA. Excluding polymyalgia rheumatica symptoms such as proximal muscle pain (2 of 13 patients), the most common chief complaint observed in the 13 patients was fever, including only a slight fever in seven (53.8 %), followed by no symptoms but an elevated inflammatory response alone in three, and general fatigue and weight loss in two. The seven patients with no or only non-specific symptoms accounted for 53.8 % (7/13) of the total. On the other hand, physical findings showed that three patients with LVV had posterior cervical pain or carotid artery tenderness, and all three had FDG accumulation in the vertebral and carotid arteries, suggesting an association between these accumulations and physical findings, as reported previously [10]. Only one patient was positive for antineutrophil cytoplasmic antibody (ANCA).
We used SAS 9.3 (SAS Institute Inc., Cary, NC, USA) for statistical analyses. Most values are given as means and standard deviations (SD). All p values were two-sided and considered significant at <0.05. The Mann–Whitney rank sum test was used to compare continuous variables; other analyses employed Fisher’s exact probability test. Wilcoxon’s signed-rank test was used to compare continuous variables in terms of the treatment effect.
In the LVV group, the SUVmax value (mean 3.85 ± 1.47) and PET score (mean 11.5 ± 5.1) of the aortic wall on FDG-PET/CT images were significantly higher than those in the control group (p < 0.001).
Results
Findings of aortic wall thickening in patients with LVV by contrast‑enhanced CT (Table S1)
The cause of IUO in elderly patients (Fig. 2) The number of patients who were 50 years or older and were admitted to our department due to broad-sense IUO was 124. Excluding 12 patients who were classified as “drug induced,”
13
SUVmax value and PET score in patients with LVV (Table S1)
The aortic wall in patients with LVV by contrast-enhanced CT had a mean W of 3.80 mm and W/R of 24.5 %, showing significantly more thickening than in the control group (mean W, 2.6 mm; W/R, 19.4 %) (p < 0.001 and p = 0.004, respectively) .
Rheumatol Int Table 1 Basic characteristics of participants Patient number
Age/sex
Disease activity
CRP (mg/dl)
Duration to diagnosisa
SUV max of the aorta
PET score
Wall thickness of the aorta on enhanced CT (mm)b
W/R (%)c
Large vessel vasculitis with cranial lesion
1
60/M
Active
3.54
5 months
3.13
6
4.1
24.8
No
2
60/F
Active
2.67
6 months
3.09
13
2.9
19.1
No
3
80/M
Active
8.46
8 months
2.68
9
3.7
21.3
No
4
69/F
Active
6.87
2 months
5.58
15
4.6
25.6
No
5
74/F
Active
9.61
3 months
4.65
18
3.3
18.6
No
6
69/M
Active
4.60
12 months
3.50
12
5.0
31.3
No
7
60/M
Active
3.55
12 months
2.86
4
5.3
32.9
No
8
80/F
Active
8.70
1 month
2.72
3
4.1
20.9
No
9
65/F
Active
2.88
3 months
3.73
14
3.4
24.9
No
10
80/M
Active
13.3
1 month
3.14
9
3.2
21.4
No
11
78/M
Active
4.37
2 months
2.90
14
3.2
20.4
Yes
12
86/F
Active
12.5
1 month
4.25
12
2.8
31.2
Yes
13
80/F
Active
4.18
1 month
7.84
20
3.7
26.7
Yes
Control group
68.1 ± 9.0 (8 M, 3F)
All active
7.83 ± 4.00
No data
1.95 ± 0.32
0.3 ± 0.5
2.6 ± 0.3
19.4 ± 1.4
No
M male, F female, CRP C-reactive protein, SUV standardised uptake value, PET positron emission tomography, CT computed tomography a
Period from symptom onset until definitive diagnosis
b
Wall thickness was calculated as the average of the thicknesses of three selected points (In the 2, 6, and10 o’clock directions) in the aorta on an enhanced CT image. CT images were taken when large vessel vasculitis was diagnosed c
W/R = the percentage of aortic wall thickness divided by the radius of the aorta on an enhanced CT image. CT images were taken when large vessel vasculitis was diagnosed
Comparison of PET scores and CT findings in patients with LVV before and after treatment (Table 2) LVV was treated with prednisolone at 20–60 mg/day, which resulted in the disappearance of symptoms and reduced the CRP values in all patients (mean CRP decreased from 6.56 ± 3.65 to 0.14 ± 0.27 mg/dL) (p = 0.001). With regard to imaging findings, the PET scores improved in all seven patients who underwent follow-up FDG-PET/ CT (mean score decreased from 11.9 ± 5.1 to 5.6 ± 4.0) (p = 0.004) (Fig. 3), while all nine patients who underwent follow-up contrast-enhanced CT showed significant improvement in aortic wall thickening with the mean W being reduced from 3.6 ± 0.6 to 2.6 ± 0.6 mm (p = 0.008) and the mean W/R from 23.0 ± 4.0 to 17.5 ± 4.7 % (p = 0.008) (Fig. 4). The steroid dose could be reduced in all 13 patients, although the maintenance doses varied among patients within the range of 0–10 mg/day.
Discussion Several diagnostic methods are recommended for the evaluation of FUO [11]. Nuclear imaging detects functional and metabolic changes even before a morphological
correlate develops. FDG has been shown to be a useful tracer because it accumulates in both malignant and inflammatory cells, covering more than 50 % of possible causes of FUO, including vasculitis [12]. Similar to past studies [9, 13], SUVmax values and PET scores for the aortic wall by FDG-PET/CT improved after steroid treatment along with improvements in clinical symptoms and inflammatory responses, demonstrating that FDG-PET/CT is effective for assessing treatment responses. In contrast, Treglia’s systematic review about PET/CT and LVV concluded that the correlation between FDG-PET findings and serological levels of inflammatory markers, as well as the usefulness of FDG-PET/CT in evaluating treatment response, remains unclear [14]. On the other hand, Fuchs et al. [15] examined whether the availability of PET findings affected diagnosis or therapeutic strategies in patients suspected to have LVV, showing that the clinical diagnostic accuracy for LVV was significantly increased from 54.1 to 70.5 % by additionally performing PET and that diagnostic accuracy was significantly higher in patients not receiving immunosuppressive treatment (93.3 %) than in those receiving it (64.5 %). Furthermore, there were rather more patients indicated for biopsy among those who underwent PET. It was revealed that while PET does not always substitute for biopsy, it does influence therapeutic strategies. As described above,
13
13
Steroid pulse and PSL 60 mg/day PSL 20 mg/day PSL 20 mg/day and tacrolimus 3 mg PSL 20 mg/day PSL 20 mg/day PSL 30 mg/day
PSL 20 mg/day PSL 30 mg/day PSL 20 mg/day PSL 25 mg/day PSL 30 mg/day PSL 30 mg/day PSL 30 mg/day PSL 27.3 ± 10.9 mg/day
1
7 8 9 10 11 12 13 Mean ± SD p = 0.001*
3.55 8.70 2.88 13.3 4.37 12.5 4.18 6.56 ± 3.65
6.87 9.61 4.60
2.67 8.46
3.54
CRP before treatment
0.00 0.00 0.00 1.00 0.02 0.06 0.00 0.14 ± 0.27
0.26 0.07 0.18
0.13 0.00
0.09
CRP after treatment
p = 0.008*
5.3 4.1 3.4 3.2 3.2 2.8 3.7 3.6 ± 0.6
4.6 3.3 5.0
2.9 3.7
4.1
Wall thickness of the aorta on enhanced CT (mm) before treatmenta
No data 2.5 2.8 No data 1.9 2.0 No data 2.6 ± 0.6
3.7 2.3 No data
2.5 2.2
3.2
Wall thickness of the aorta on enhanced CT (mm) after treatmenta
p = 0.008*
32.9 20.9 24.9 21.4 20.4 31.2 26.7 23.0 ± 4.0
25.6 18.6 31.3
19.1 21.3
24.8
W/R (%) before treatmentb
No data 13 21 No data 13.1 25.1 No data 17.5 ± 4.7
21.7 13.2 No data
16.4 13.5
20.8
W/R (%) after treatmentb
p = 0.004*
4 3 14 9 14 12 20 11.9 ± 5.1
15 18 12
13 9
6
PET score before treatment
No data No data No data No data 6 3 13 5.6 ± 4.0
6 4 No data
7 No data
0
PET score after treatment
W/R wall thickness divided by the radius of the aorta
b
a Wall thickness was calculated as the average of the thicknesses of three selected points (In the 2, 6, and 10 o’clock directions) in the aorta on an enhanced CT image. CT images were taken when large vessel vasculitis was diagnosed
* Significant difference (p < 0.05) between groups according to the Wilcoxon signed-rank test
CRP C-reactive protein, PET positron emission tomography, CT computed tomography, PSL prednisolone, SD standard deviations
p value
4 5 6
2 3
Initial treatment
Patient number
Table 2 Change of measurements of patients after treatment
Rheumatol Int
Rheumatol Int
Fig. 3 FDG-PET/CT images at diagnosis and after steroid treatment in a 69-year-old patient. A female patient with LVV (Patient 4). FDGPET/CT at diagnosis (a) showed aortitis in the thoracic and abdomi-
nal aorta and subclavian and axillary arteritis bilaterally. There was strong uptake in the walls of the aorta and arteries, which decreased markedly during steroid treatment (b)
it is important to recognise that diagnosing LVV with PET before treatment increases diagnostic accuracy and that PET findings impact therapeutic strategies. According to other studies, LVV represents ~17 % of all cases of FUO among patients over 50 years of age [16]. There is also a report describing the prospective and retrospective use of PET/CT in patients aged 50 years and older with IUO who had only non-specific symptoms, showing that 19 of all 88 patients (21.6 %) had LVV [17]. We reconfirmed that the rate of LVV as the cause of IUO in patients aged 50 years and older is relatively high, at 10.5 % in this study. Meanwhile, the percentage of patients with LVV who had no or only non-specific symptoms was 53.8 %, indicating that it is important to differentiate LVV as the cause of inflammation when elderly people have IUO but no specific symptoms. Temporal artery biopsy is considered to be the cornerstone of the diagnosis of GCA; however, it is invasive and has a false-negative rate of 15–70 %, which may delay the diagnosis [18, 19]. LVV may often remain undiagnosed when using conventional diagnostic methods [20, 21]. The ACR defined specific criteria for LVV, for both GCA and Takayasu arteritis (TKA) [1, 2]. However, these criteria are based on the diagnosis of advanced cases, resulting in a
possible delayed diagnosis [22, 23]. FDG-PET/CT is also useful for early diagnosis of GCA. LVV in elderly patients frequently accompanies the clinical syndrome of GCA [15]. However, isolated LVV is increasingly recognised as a specific phenotype of GCA. The non-specific presentation of this type of LVV, which is referred to as “occult” or “silent” GCA, may cause a diagnostic delay [24, 25]. Furthermore, aortic pathology and large artery obstruction are not rare in these patients [26]. FDG-PET/CT has contributed to the detection of early signs of LVV because the aorta and its proximal branches are often affected without symptomatic involvement of the temporal arteries. In this study, two patients with LVV were asymptomatic, with only an increased inflammatory response. One showed FDG accumulation in the temporal artery and major blood vessels and was given a diagnosis of GCA based on temporal artery biopsy [27]. A very early diagnosis of GCA can be achieved by conducting FDGPET/CT in patients with IUO alone, and early treatment can prevent complications such as ophthalmic symptoms. In the study by Liang et al., the patients with histological evidence of active non-infectious aortitis who underwent ascending aortic aneurysm resection were identified [28]. By vascular imaging such as CTA and MRA, additional
13
Rheumatol Int
Fig. 4 Comparison of LVV on contrast-enhanced CT before and after treatment. Changes in vascular wall thickening in the abdominal aorta (a), ascending aorta (b), and descending aorta (c) before and after steroid treatment. The patient was a 56-year-old female (Patient
5). She was diagnosed with LVV, and treatment was initiated with prednisolone at 20 mg/day, which reduced the vascular wall thickness from 3.3 to 2.3 mm. The image clearly shows vascular wall thickening before treatment
vascular abnormalities other than ascending aortic aneurysm were found in 72 % of patients. It has been suggested that isolated aortitis may be potentially cured by surgical resection alone; the value of corticosteroid or other immunosuppressive treatment is uncertain [29–32]. Meanwhile, early treatment intervention significantly improved the aortic wall thickening in this study; as it may have been possible to prevent anatomical changes, long-term follow-up will be required for further validation. Co-registration of 18F-FDG-PET images with enhanced CT images has been described to provide good anatomical localisation of functional data [33, 34]. Visual side-by-side analysis of nuclear medicine and CT studies is of value in characterising large, single lesions [35, 36]. Although 18F-FDG-PET is superior to CT for the detection of inflammation in LVV and is useful for evaluating the distribution of inflammation, this imaging technique has the disadvantage that the degree of aortic wall thickening cannot be assessed. On the other hand, contrast-enhanced CT is inferior to PET in sensitivity for the detection of inflammation, and radiologist expertise is thus still needed for detecting inflammation. However, contrast-enhanced CT has the advantage that it can specifically demonstrate the degree of wall thickening. For example, it is possible to perform the
procedures as follows: first, perform FDG-PET as a screening examination for FUO/IUO, and if FDG accumulation is recognised in the aortic wall, consider a diagnosis of active LVV. Next, perform contrast-enhanced CT before and after the steroid treatment and evaluate the extent of the anatomical improvement in aortic wall thickening. Our study shows that co-registration of 18F-FDG-PET and enhanced CT may facilitate the diagnosis and treatment evaluation of LVV. To our knowledge, no prior study has specifically reported that early diagnosis of LVV by FDG-PET/CT allows for early treatment intervention that ameliorates blood vessel thickening. De Leeuw et al. [37] underlined that FDG-PET/CT and morphological imaging might complement each other because some discrepancies between these methods were found; in fact, FDG-PET/CT may show inflammatory changes while morphological imaging findings remain normal. Conversely, after progression to the late phase of the disease with stenoses and occlusions, inflammation may disappear, and FDG-PET/CT might not show the irreversible anatomical changes seen on morphological imaging. In other words, this study demonstrated that FDG-PET/CT captures positive images at an early disease stage prior to the complete stenosis of blood vessels
13
Rheumatol Int
and disappearance of inflammation. At such an early stage, treatment can prevent irreversible anatomical changes. Because approximately 4.4 months on average elapsed from the initial tentative diagnosis until definitive diagnosis, whether early treatment had been performed might be questionable. However, because amelioration of reversible aortic wall thickening was achieved before irreversible anatomical changes occurred, we suspect that treatment interventions were probably performed relatively early. As for the steroid dosage in treating LVV discovered incidentally in the work-up for IUO, Table 2 shows that all LVV patients, except Patient 1, were treated with only PSL (20– 30 mg/day). This may suggest that even moderate doses of steroids may be effective in treating these LVV, although the adequate steroid dose is controversial [28] and has not been systematically studied in detail. This study included patients with findings of posterior cervical pain or carotid artery tenderness along with FDG accumulation in the vertebral artery or carotid artery. Carotid artery tenderness is a physical finding that reflects inflammation of the carotid arteries and is found in 29 % of patients with LVV [38]. The carotid artery tenderness may occur before stenosis develops because it rather indicates that the carotid arteries are involved in an inflammatory process [10, 39]. Thus, it is considered important to pay attention to physical symptoms, which should raise the suspicion for LVV, prompting the performance of imaging examinations including FDG-PET/CT. Our study had several limitations. Because it was retrospective, it may have weaknesses such as a selection bias and incomplete or suboptimal data collection. However, our series comprised consecutive patients who agreed to undergo a PET scan. Prospective confirmation of our findings would be valuable. Second, we were not able to perform follow-up FDG-PET scans in all patients. Followup FDG-PET scans were performed only in patients who agreed to undergo follow-up imaging. Another important limitation of this study was the small sample size. A largerscale and longer-term study is required to determine the extent to which vascular stenosis and obstruction can be prevented by early treatment based on early diagnosis by FDG-PET/CT.
Conclusion LVV is an important cause of IUO with non-specific symptoms in elderly patients. Imaging examinations combining contrast-enhanced CT and FDG-PET/CT are useful for early diagnosis of LVV, which allows not only early treatment with improvement in non-specific symptoms, but also improvement in reversible vascular wall thickening. In future studies, a randomised controlled trial will be
required to determine the appropriate dose of steroids for LVV treatment. Acknowledgments This study was supported by Grants-in-Aid for Research on Intractable Diseases from the Ministry of Health, Labor, and Welfare of Japan. We thank R.K. for statistical assistance; and J.K., T.U., and Y.M. for critical suggestions. Conflict of interest The authors have no conflict of interests to declare.
References 1. Arend WP, Michel BA, Bloch DA, Hunder GG, Calabrese LH, Edworthy SM et al (1990) The American College of Rheumatology 1990 criteria for the classification of Takayasu arteritis. Arthritis Rheum 33:1129–1134 2. Hunder GG, Bloch DA, Michel BA, Stevens MB, Arend WP, Calabrese LH et al (1990) The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum 33:1122–1128 3. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL et al (1994) Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 37:187–192 4. Gotthardt M, Bleeker-Rovers CP, Boerman OC, Oyen WJ (2010) Imaging of inflammation by PET, conventional scintigraphy, and other imaging techniques. J Nucl Med 51:1937–1949 5. Treglia G, Cason E, Fagioli G (2010) Recent applications of nuclear medicine in diagnostics—first part. Ital J Med 4:84–91 6. Kubota R, Yamada S, Kubota K, Ishiwata K, Tamahashi N, Ido T (1992) Intratumoral distribution of fluorine-18-fluorodeosxyglucose in vivo: high accumulation in macrophages and granulation tissues studied by microautoradiography. J Nucl Med 33:1972–1980 7. Besson FL, Parienti JJ, Bienvenu B, Prior JO, Costo S, Bouvard G et al (2011) Diagnostic performance of (18)F-fluorodeoxyglucose positron emission tomography in giant cell arteritis: a systematic review and meta-analysis. Eur J Nucl Med Mol Imaging 38:1764–1772 8. Durack DT, Street AC (1991) Fever of unknown origin—reexamined and redefined. Curr Clin Top Infect Dis 11:35–51 9. Blockmans D, De Ceuninck L, Vanderschueren S et al (2006) Repetitive 18-fluorodeoxyglucose positron emission tomography in giant cell arteritis: a prospective study in 35 patients. Arthritis Rheum 55:131 10. Hayakawa I, Kunimatsu J, Watanabe R, Kubota K, Yoshizawwa A (2012) Value of carotid artery tenderness for the early diagnosis of Takayasu Arteritis. Intern Med 51:3431–3434 11. Kubota K, Nakamoto Y, Tamaki N, Kanegae K, Fukuda H, Kaneda T et al (2011) FDG-PET for the diagnosis of fever of unknown origin: a Japanese muti-center study. Ann Nucl Med 25:355–364 12. Ferda J, Ferdova′ E, Za′hlava J, Matejovic M, Kreuzberg B (2010) Fever of unknown origin: a value of (18)F-FDG-PET/CT with integrated full diagnostic isotropic CT imaging. Eur J Radiol 73:518–525 13. Brodmann M, Lipp RW, Passath A, Seinost G, Pabst E, Pilger E (2004) The role of 2–18F-fluoro-2-deoxy-d-glucose positron emission tomography in the diagnosis of giant cell arteritis of the temporal arteries. Rheumatology 43:241–242 14. Treglia G, Mattoli MV, Leccisotti L, Ferraccioli G, Giordano A (2011) Usefulness of whole-body fluorine-18-fluorodeoxyglucose
13
positron emission tomography in patients with large-vessel vasculitis: a systematic review. Clin Rheumatol 30:1265–1275 15. Fuchs M, Briel M, Daikeler T, Walker UA, Rasch H, Berg S et al (2012) The impact of 18F-FDG PET on the management of patients with suspected large vessel vasculitis. Eur J Nucl Med Mol Imaging 39:344–345 16. Vanderschueren S, Knockaert D, Adriaenssens T, Demey W, Durnez A, Blockmans D et al (2003) From prolonged febrile illness to fever of unknown origin: the challenge continues. Arch Intern Med 163:1033–1041 17. Lensen KJ, Voskuyl AE, van der Laken CJ, Comans EF, van Schaardenburg D, Arntzenius AB et al (2013) 18F-fluorodeoxyglucose positron emission tomography in elderly patients with an elevated erythrocyte sedimentation rate of unknown origin. PLoS ONE 8:e58917 18. Blockmans D, Stroobants S, Maes A, Mortelmans L (2000) Positron emission tomography in giant cell arteritis and polymyalgia rheumatica: evidence for inflammation of the aortic arch. Am J Med 108:246–249 19. Gonzalez-Gay MA, Garcia-Porrua C, Llorca J, Gonzalez-Louzao C, Rodriguez-Ledo P (2001) Biopsy-negative giant cell arteritis: clinical spectrum and predictive factors for positive temporal artery biopsy. Semin Arthritis Rheum 30:249–256 20. Ezeonyeji AN, Borg FA, Dasgupta B (2011) Delays in recognition and management of giant cell arteritis: results from a retrospective audit. Clin Rheumatol 30:259–262 21. Mukhtyar C, Guillevin L, Cid MC et al (2009) EULAR recommendations for the management of large vessel vasculitis. Ann Rheum Dis 68:318–323 22. Schmidt WA, Seifert A, Gromnica-Ihle E, Krause A, Natusch A (2008) Ultrasound of proximal upper extremity arteries to increase the diagnostic yield in large-vessel giant cell arteritis. Rheumatology (Oxford) 47:96–101 23. Zerizer I, Tan K, Khan S et al (2010) Role of FDG-PET and PET/ CT in the diagnosis and management of vasculitis. Eur J Radiol 73:504–509 24. Gerber NJ (1984) Giant cell arteritis and its variants. Eur Neurol 23:410–420 25. Brack A, Martinez-Taboada V, Stanson A, Goronzy JJ, Weyand CM (1999) Disease pattern in cranial and large-vessel giant cell arteritis. Arthritis Rheum 42:311–317 26. Nuenninghoff DM, Hunder GG, Christianson TJ, McClelland RL, Matteson EL (2003) Incidence and predictors of large-artery
13
Rheumatol Int complication (aortic aneurysm, aortic dissection, and/or largeartery stenosis) in patients with giant cell arteritis: a populationbased study over 50 years. Arthritis Rheum 48:3522–3531 27. Yamashita H, Inoue M, Takahashi Y, Kano T, Mimori A (2012) The natural history of asymptomatic positron emission tomography: positive giant cell arteritis after a case of self-limiting polymyalgia rheumatica. Mod Rheumatol 22:942–946 28. Liang KP, Chowdhary VR, Michet CJ, Miller DV, Sundt TM, Connolly HM et al (2009) Noninfectious ascending aortitis: a case series of 64 patients. J Rheumatol 36:2290–2297 29. Hernandez-Rodriguez J, Molloy ES, Hoffman GS (2008) Singleorgan vasculitis. Curr Opin Rheumatol 20:40–46 30. Miller DV, Isotalo PA, Weyand CM, Edwards WD, Aubry MC, Tazelaar HD (2006) Surgical pathology of noninfectious ascending aortitis: a study of 45 cases with emphasis on an isolated variant. Am J Surg Pathol 30:1150–1158 31. Rojo-Leyva F, Ratliff NB, Cosgrove DM 3rd, Hoffman GS (2000) Study of 52 patients with idiopathic aortitis from a cohort of 1,204 surgical cases. Arthritis Rheum 43:901–907 32. Kerr LD, Chang YJ, Spiera H, Fallon JT (2000) Occult active giant cell aortitis necessitating surgical repair. J Thorac Cardiovasc Surg 120:813–815 33. Weber DA, Ivanovic M (1994) Correlative image registration. Semin Nucl Med 24:311–323 34. Wahl RL, Quint LE, Cieslak RD, Aisen AM, Koeppe RA, Meyer CR (1993) “Anatometabolic” tumor imaging: fusion of FDG PET with CT or MRI to localize foci of increased activity. J Nucl Med 34:1190–1197 35. Correia JA (1990) Registration of nuclear medicine images. J Nucl Med 31:1227–1229 36. Shreve PD (2000) Adding structure to function. J Nucl Med 41:1380–1382 37. de Leeuw K, Bijl M, Jager PL (2004) Additional value of positron emission tomography in diagnosis and follow-up of patients with large vessel vasculitides. Clin Exp Rheumatol 22(6 Suppl 36):S21–S26 38. Kerr GS, Hallahan CW, Giordano J, Leavitt RY, Fauci AS, Rottem M et al (1994) Takayasu arteritis. Ann Intern Med 120:919–929 39. Kawashima M, Koike R, Nishio J, Nanki T, Kohsaka H, Kubota T et al (1999) A case of Takayasu’s arteritis with ulcerative colitis diagnosed by carotodynia and MRI findings. Nihon Rinsho Meneki Gakkai Kaishi 22:317–323
