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PET-CT spectrum of large vessel vasculitis (LVV) in a tertiary center: differences in FDG uptake between LVV with predominant cranial and extracranial giant cell arteritis phenotypes

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07 September 2023

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11 September 2023

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Abstract
Objective: To assess the spectrum of PET-CT-related large vessel vasculitis (LVV) in a Spanish tertiary center and to determine whether FDG uptake by PET-CT differs between giant cell arteritis (GCA) with predominant cranial or extracranial phenotypes. Methods: The spectrum of patients diagnosed with LVV by PET-CT in a tertiary referral hospital that cares for 450,000 people over a period of two years was reviewed. Moreover, differences in FDG uptake between LVV-GCA with predominantly cranial and extracranial phenotype were analyzed. Results: Eighty patients were diagnosed with LVV by PET-CT. Most were due to systemic vasculitis (n=64; 80%), especially GCA (n=54; 67.5%). Other conditions included the presence of rheumatic diseases (n=4; 3.2%), tumors (n=9; 7.2%), and infections (n=3; 2.4%). LVV-GCA patients with predominant extracranial GCA phenotype were younger (mean ± SD: 68.07 ± 9.91 versus 75.46 ± 7.64 years; p= 0.017) and had a longer delay to the diagnosis (median [interquartile range] 12 [4-18] versus 4 [3-8]; p=0.006), but had PMR symptoms more frequently than those with predominantly cranial GCA phenotype (46.3% versus 15.4%, p= 0.057). When FDG uptake was compared according to the two different disease patterns, no statistically significant differences were observed. However, patients with extracranial LVV-GCA showed a non-significantly higher frequency of vasculitic involvement of lower extremity arteries. Conclusion: Regardless of the predominant phenotype, LVV identified by PET-CT is more commonly due to GCA in the Spanish population. In these GCA patients, younger age, PMR and a higher frequency of lower extremity artery vasculitis suggest the presence of LVV.
Keywords: 
Subject: Medicine and Pharmacology  -   Internal Medicine

1. Introduction

Large vessel vasculitis (LVV) in adults covers a wide spectrum of conditions with giant cell arteritis (GCA) being the most common entity [1]. Although GCA was classically considered to be a disease affecting the cranial arteries [2], imaging techniques have made it possible to identify GCA patients with a predominantly extracranial pattern of the disease. These patients may have few or no cranial ischemic manifestations [3]. They may present with non-specific manifestations such as constitutional syndrome, fever of unknown origin or as polymyalgia rheumatica (PMR), which in some cases may have atypical manifestations such as predominantly affecting the lower extremities and pelvic girdle or be refractory to conventional therapy [3,4]. These patients may more frequently present with extracranial ischemic manifestations affecting the upper or lower extremities. In this sense, experts from the European League Against Rheumatism (EULAR) have recommended the use of imaging techniques in patients with suspected LVV [5].
Positron emission computed tomography (PET-CT) with 18F-fluorodeoxyglucose (FDG) is one of the imaging techniques that has been shown to be useful in identifying patients who present with a predominantly extracranial pattern of GCA [6]. 18F-FDG-PET combined with CT is a functional imaging technique that has demonstrated usefulness for LVV diagnosis due to its ability to detect glucose uptake from the high activity of inflammatory cells in the vessel walls. PET-CT yields a great overview of the extension of vascular inflammation. Moreover, it is useful to exclude other entities such as infection or malignancy [7,8]. Increased FDG uptake is seen after PET imaging in more than 80% of patients with GCA. This is especially true in the case of involvement of the thoracic and abdominal aorta. Additionally, this imaging technique can identify vascular inflammation affecting lower extremity arteries in patients with GCA [9].
PET-CT is an expensive technique and this fact constitutes a limitation for its use in typical cases of GCA associated with cranial ischemic manifestation. In these patients presenting with headache or other cranial ischemic manifestations, Doppler ultrasonography (US) and/or biopsy of the temporal arteries are the most commonly used tools for making a diagnosis of GCA. For this reason, in clinical practice PET-CT is performed when GCA is suspected and cranial ischemic manifestations are not relevant.
Taking into account these considerations, the purpose of the present study was to assess the spectrum of PET-CT-related LVV in a Spanish tertiary center and to determine whether FDG uptake by PET-CT differs between GCA with a predominant cranial or extracranial phenotype.

2. Patients and Methods

2.1. Study Design and Patient Recruitment

This is a retrospective study conducted at the Fundación Jiménez Díaz University Hospital (Madrid, Spain). Patients who underwent FDG-PET-CT between April 2001 and March 2023 were evaluated. Those with LVV were assessed.
The study procedures acted in accordance with the Helsinki Declaration of 1975, as revised in 2000. Although it was a retrospective study, ethical committee approval was obtained (PIC034-23).
First, we analyzed the spectrum of LVV. In a second step we evaluated the differences of FDG-PET-CT between GCA patients according to the predominant disease pattern, that is; predominantly cranial or extracranial LVV phenotype.

2.2. Study Protocol

2.2.1. Patient Disease Assessment

Fundación Jiménez Díaz University Hospital provides medical care to 450,000 people. During the study period, 1,302 patients underwent a PET-CT.
The Big Data Department of the Jiménez Díaz Foundation Hospital was asked to carry out an exhaustive search of the patients who underwent PET-CT during the two years of the study. Then PET-CT of patients that included any of the following keywords: “vasculitis”, “large vessels”, “medium vessels”, “vascular wall”, “vascular”, “aortitis”, “vessel inflammation”, “ increased FDG vessel uptake”, “polymyalgia rheumatica”, “giant cell arteritis”, “Takayasu arteritis” were reviewed by members of the Divisions of Rheumatology and Nuclear Medicine. Those patients in whom agreement on the presence of LVV was confirmed were included in the study. Subsequently, clinical information was obtained by reviewing medical records. Additionally, rheumatologists evaluated disease diagnosis, demographic and clinical characteristics, as well as laboratory data.

2.2.2. FDG-PET-CT Equipment, Protocol and Interpretation

PET-CT examinations were performed on an integrated digital PET-CT system (GE Discovery MI3R, with NEMA sensitivity of 7.5 cps/kbq, 3 rings and 15 cm axial field of view). Patients were administered 175-350 mbq (2.5-5.0 MBq/kg) of 18F-FDG after at least a 4-hour fast. The postinjection rest time was 60min. PET-CT was performed in the supine position, with arms stretched above the head, and scans were acquired from the base of the skull to the femur.
Low-dose CT was performed for PET co-registration (140 kv, 380 ma) followed by PET imaging (1.45 min per bed). Blood glucose levels before tracer injection were <200 mg/ml in all cases.
All PET-CT scans were reviewed by a nuclear medicine physician with experience in LVV. The nuclear medicine physician visually evaluated the characteristics of the distribution of the radiopharmaceutical in four segments of the aorta (ascending, arch, descending thoracic and abdominal) and in five arterial branches (carotids, brachiocephalic trunk, subclavian arteries) and used a visual uptake classification scale. Additionally, information on involvement of the axillary, vertebral, humeral, iliac, and femoral arteries was evaluated. The standardized grading system from 0 to 3 (vascular to hepatic uptake): 0 = no uptake (≤mediastinum); 1 = low-grade uptake (<liver); 2 = intermediate-grade uptake (=liver), 3 = high-grade uptake (>liver), with grade 2 indicative and grade 3 considered strongly positive for LVV.

2.3. Statistical Analysis

Demographic and clinical characteristics of patients with LVV associated to GCA were presented as mean (standard deviation) or percentages for categorical variables. For continuous variables that did not follow a normal distribution, data were reported as median and interquartile range (IQR). Univariable differences between groups were assessed through Student’s t-test, the Mann–Whitney U-test, Chi squared test or Fisher’s exact test according to the normal distribution or the number of subjects. All analyses were conducted using Stata software, version 17/SE (StataCorp, College Station, TX, USA), with a two-sided significance level set at 5%. A p-value less than 0.05 was considered statistically significant.

3. Results

3.1. Spectrum of patients with LVV

During the period of study 80 patients were diagnosed with LVV by PET-CT.
Most were due to systemic vasculitis (n=64; 80%), especially GCA (n=54; 67.5%). In this regard, besides 5 patients diagnosed with Takayasu arteritis, another 5 patients who showed increased FDG uptake in large vessels were diagnosed with classic Polyarteritis or ANCA-associated vasculitis. Other conditions included the presence of rheumatic diseases (n=4; 3.2%), tumors (n=9; 7.2%), and infections (n=3; 2.4%) (Table 1).

3.2. Clinical differences between GCA patients according to the predominant phenotype

Fifty-four of the 80 patients with LVV were diagnosed with GCA. Since FDG-PET was generally not performed in patients presenting with the classic cranial GCA pattern of the disease, the majority of them, 41 (75.9%) of 54 patients, met the definition of GCA with predominant extracranial phenotype.
The differences between patients with a predominantly cranial or extracranial pattern of the disease are shown in Table 2.
In this sense, patients with predominantly cranial characteristics were older at the time of diagnosis of the disease (mean ± SD: 75.5 ± 7 .6 years versus 68.1 ± 9.9 years, p=0.017). In contrast, patients with extracranial LVV-GCA had a longer delay in diagnosis from symptom onset compared to those with the classic cranial GCA phenotype (median [IQR]: 12 [4-18] versus 4 [3-8]; p=0.006). All patients with the predominant cranial phenotype had a diagnosis confirmed by a positive biopsy and/or ultrasound of the temporal artery, while none of the 22 with extracranial LVV-GCA in whom one of these tests was performed had positive results. Despite differences in the presence of cranial ischemic manifestations, as only 1 of 41 patients with predominantly extracranial LVV-GCA complained of headache at diagnosis, patients with extracranial LVV-GCA more commonly had PMR than those with predominant cranial ischemic manifestations (46.3% versus 15.4%; p=0.057). Similarly, patients with extracranial LVV-GCA more frequently had fever >38°C at diagnosis, but the difference was not statistically significant. No differences in the presence of constitutional syndrome were observed between patients with predominant cranial or extracranial features. In this regard, it is possible that the high frequency of constitutional characteristics in patients with cranial GCA may have been one of the reasons for requesting PET-CT in these patients. Finally, patients with a predominantly extracranial LVV-GCA pattern had a milder inflammatory response manifested by lower ESR, CRP, and platelet levels and higher hemoglobin values.

3.3. FDG-PET-CT differences between patients with the classic cranial LVV-GCA phenotype and dose with extracranial LVV-GCA phenotype.

Since patients with predominantly cranial and extracranial patterns of the disease showed clinical differences, we aimed to address whether differences in FDG uptake might exist. However, as shown in Table 3, no significant differences were observed. In this sense, subclavian and brachiocephalic involvement was slightly more common in patients with predominant cranial features. In contrast, a non-significant increase in lower extremity artery involvement was found in those with predominant extracranial LVV-GCA.

4. Discussion

This retrospective study that included 80 patients highlights the value of PET-CT in the diagnosis of LVV. This is especially true in patients with GCA without cranial ischemic manifestations who present with nonspecific features or with PMR. Furthermore, the presence of LVV in conditions other than GCA or Takayasu supports the claim that LVV can occur in other systemic vasculitides, rheumatic autoimmune rheumatic diseases, and other unrelated conditions such as tumors or infections.
PET scanning has high sensitivity and specificity for the diagnosis of GCA, and at the same time, the negative predictive value of a PET scan for GCA is also very high [10]. Increased vascular FDG uptake has been reported in more than two-thirds of GCA patients. As observed in our series, more than 50% of patients with GCA have vasculitis involvement in the thoracic and abdominal aorta and the subclavian arteries [11]. In keeping with our results, vasculitis affecting the femoral arteries has also been reported [11]. PET-CT has also been found to be very useful in making the diagnosis of GCA in patients presenting with atypical manifestations of GCA [12].
PMR may be the initial manifestation of GCA and imaging techniques, particularly PET-CT, can reveal LVV in at least one third of patients presenting with isolated PMR [13]. Therefore, a question that needs further investigation is whether PET-CT should be routinely performed in patients with PMR. In this sense, we are in favor of performing a PET-CT in patients with PMR refractory to doses of prednisone of 20-25 mg/day or in patients who present PMR with atypical manifestations such as a predominance of the pelvic girdle manifestations, in patients with PMR who have severe inflammatory low back pain or in those with limb claudication, although arterial pulse asymmetry may not be clinically evident [4,6].
Although PET-CT is not generally used in patients with suspected GCA in whom cranial manifestations are clinically evident, recent studies indicate that PET-CT may also be useful in making the diagnosis of GCA in patients who present with predominant cranial manifestations [14,15]. In this regard, in a prospective study that included 64 patients with newly suspected GCA who underwent PET-CT and temporal artery biopsy within the first 72 hours of starting glucocorticoid treatment, the sensitivity of PET-CT was 92% and specificity was 85% using the temporal artery biopsy as a reference. Compared with clinical diagnosis, PET-CT had a sensitivity of 71% and a specificity of 91% [15].
Another question we wanted to address in this study was whether the clinical spectrum of LVV-GCA in our series differed from that in other southern European populations. To do so, we used data published in Reggio-Emilia, Italy, since twenty years ago we reported that the clinical spectrum of biopsy-proven GCA in this Italian region did not differ from that found in a population in Spain [16]. With respect to this, Boiardi et al evaluated vascular involvement in a series of 127 patients with LVV-GCA diagnosed between 1996 and 2016, who in most cases were followed up at the tertiary center of Reggio Emilia Hospital (Italy) [17]. The differences in terms of LVV involvement between this Italian series and our series are shown in Table 4. The extent of the disease in this series was not established exclusively by PET-CT since the diagnosis of LVV was made by color Doppler ultrasound, CT angiography, magnetic resonance angiography, and/or PET-CT scan [17].
In the Italian series, involvement of the carotid, axillary, and brachial arteries was significantly more frequent than in our series. In contrast, brachiocephalic involvement was reported less frequently. However, LVV involvement of the thoracic and abdominal aorta and the iliac and femoral arteries was similar (Table 4).
A possible explanation for the differences between these series may be due to the use of different imaging techniques to make the diagnosis of LVV in Reggio Emilia. Furthermore, an analysis of the clinical manifestations showed that in our series the indication for performing PET-CT in search of GCA was more focused on patients without typical cranial manifestations of GCA. In this sense, we had a longer delay in the diagnosis of GCA than in Reggio-Emilia (10.1 vs. 5.3 weeks). In addition, classic cranial ischemic manifestations of GCA, such as headache (36.2% vs. 24.1%), scalp tenderness (15.7% vs. 3.7%), abnormal temporal artery on physical examination (34.4% versus 3.7%) or jaw claudication (17.3% versus 3.7%) was more frequently reported in patients from the Reggio-Emilia series of LVV-GCA.
Consistent with our findings, in a series of 60 GCA patients who underwent PET-CT at the onset of GCA, Malich et al demonstrated that the most commonly involved arteries were the ascending aorta (72%), followed by the brachiocephalic trunk (62%), aortic arch (60%) and descending aorta (60%) [18].
Although patients with GCA often present with cranial manifestations and extracranial involvement of the large vessels, in some cases GCA presents with only extracranial involvement of the disease without any classic cranial features of this vasculitis. At this point we are tempted to establish two well-differentiated phenotypes of the disease. However, we are aware that we must be very cautious in saying that there are two disease phenotypes as experts may be reluctant to accept this point. However, it has been established that patients with predominantly extracranial GCA, manifested by large vessel involvement of arteries other than the cranial ones, have clinical differences compared to those found in patients with GCA who present the classic cranial manifestations of the disease [3,19]. In this sense, patients with the predominant extracranial LVV-GCA phenotype are generally younger, have a longer duration of symptoms before GCA diagnosis, have more disease relapses, show less commonly a positive temporal artery biopsy, and generally require longer duration of treatment. Furthermore, these patients have features of PMR more frequently than those with the predominantly cranial GCA pattern [19,20,21]. Therefore, the presence of PMR may constitute a warning sign for the possible presence of an underlying LVV [22,23]. Regrettably, genetic studies so far have not shed light to discriminate between patients with a predominant cranial or extracranial pattern of the disease. In this regard, both biopsy-proven GCA patients with the classic cranial pattern of the disease and those with a with LVV-GCA without any cranial ischemic manifestations share a strong association with the HLA region, in particular with HLA-DRB1*04:01 [21,24]. Moreover, the genetic predisposition to develop severe ischemic complications mediated by polymorphisms of the vascular endothelium growth factor observed in biopsy-proven GCA patients with the classic cranial features of the disease was also observed in patients with extracranial LVV-GCA who had ischemic manifestations [25,26].
In conclusion, regardless of the clinical expression of the disease, PET-CT is an excellent tool to identify the presence of LVV. This technique is especially useful in individuals in whom the classic cranial ischemic manifestations of the disease are not clinically apparent.

5. Significance and Innovation

FDG-PET-CT may be an important diagnostic tool in patients with suspected LVV, in particular of GCA patients without cranial ischemic manifestations of the disease.
No significant differences in the PET-CT large vessel involvement were found between the patients with GCA who were considered to have a predominantly extracranial phenotype when compared with those who also had cranial ischemic manifestations of GCA.

Author Contributions

Conceptualization, E.H-R. and M.A. G-G.; Methodology, E.H-R., L.C..L-K, M.M.B-A., L.M-D. and M.A. G-G.; Software, I.F-A, J.A.M-L.; Validation, E.H-R., L.C..L-K, M.M.B-A., L.M-D. and M.A. G-G, Formal analysis, E.H-R., I.F-A. , S.C. R.L. and M.A. G-G.; Investigation, E.H-R., A.T-R.,T.B-S. and M.A. G-G.; Resources, M.A. G-G.; Writing–original draft, E.H-R. , S.C, R.L. and M.A. G-G; Supervision, M.A. G-G. All authors have read and agreed to the submitted version of the manuscript.

Funding

Funding for this study were provided by the Instituto de Salud Carlos III (Spain) through grant FIS PI22/01263 (PI: Dr. Miguel A. González-Gay) and the Spanish Red de Investigación RICORS RD21/0002/0025 (PI: Miguel A. González-Gay).

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethic Committee of IIS-Fundación Jiménez Díaz, Madrid, Spain.

Informed Consent Statement

Patient consent was waived due to the retrospective design of the study.

Data Availability Statement

The data presented in this study are available on request from the corresponding author.

Acknowledgments

We thank Antonio Herrero González, Head of the Big Data Department at the Jiménez Díaz Foundation Hospital, Madrid, Spain for his available help in this study.

Conflicts of Interest

The authors declare no conflict of interest.

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Table 1. Spectrum of large vessel involvement in a tertiary hospital of Spain.
Table 1. Spectrum of large vessel involvement in a tertiary hospital of Spain.
Number of patients (%)
n=80
Systemic vasculitis 64 (80)
Primary Large Vessel Vasculitis 59 (73.8)
Giant cell arteritis 54 (67.5)
Cranial Phenotype 13 (16.3)
Extracranial Phenotype 41 (51.3)
Takayasu arteritis 5 (6.3)
Classic Polyarteritis 2 (2.5)
ANCA-associated vasculitis 3 (3.8)
Retroperitoneal fibrosis 1 (1.3)
Rheumatoid arthritis 1 (1.3)
Ankylosing Spondylitis 1 (1.3)
Systemic lupus erythematosus 1 (1.3)
Sarcoidosis 1 (1.3)
Infections 3 (3.8)
Tumors 9 (11.3)
Table 2. Main clinical features of patients with GCA in whom a PET-CT was performed according to the clinical phenotype: Classic cranial LVV-GCA or extracranial LVV-GCA.
Table 2. Main clinical features of patients with GCA in whom a PET-CT was performed according to the clinical phenotype: Classic cranial LVV-GCA or extracranial LVV-GCA.
Classic cranial LVV-GCA phenotype Extracranial LVV-GCA phenotype p
n=13 n=41
Age at diagnosis (mean ± SD) 75.5 ± 7.6 68.1 ± 9.9 0.017
Women, n (%) 12 (92.3) 31 (75.6) 0.26
Positive biopsy and/or US of TA, n (%) 13 (100) 0/22* (0) < 0.001
Delay to diagnosis weeks (median [IQ range]) 4 (3-8) 12 (4-18) 0.006
Headache, n (%) 12 (92.3) 1 (2.4) < 0.001
Scalp tenderness (%) 2 (15.4) 0 (0) 0.055
Abnormal temporal artery on physical examination, n (%) 2 (15.4) 0 (0) 0.055
Jaw claudication, n (%) 2 (15.4) 0 (0) 0.055
Polymyalgia rheumatica, n (%) 2 (15.4) 19 (46.3) 0.057
Visual manifestations, n (%) 4 (30.8) 0 (0) 0.002
Permanent visual loss, n (%) 2 (15.4) 0 (0) 0.055
Constitutional syndrome, n (%) 12 (92.3) 32 (78.0) 0.42
Fever> 38ºC 1 (7.7) 11 (26.8) 0.25
Arthralgia/Myalgia 6 (46.2) 21 (51.2) 0.75
ESR mm/1st hour (mean ± SD) 101 (71-120) 68 (39-119) 0.12
ESR > 40 mm/1st h. at diagnosis, n (%) 12 (90) 28 (68) 0.15
CRP mg/dl (mean ± SD) 3.8 (2.6-7.9) 3.0 (1.0-7.6) 0.43
Hemoglobin g/dl(mean ± SD) 11.6 ± 1.3 12.3 ± 1.6 0.072
Platelets x1000/mm3 (mean ± SD) 410 ± 134 370 ± 147 0.25
TA: Temporal artery. US: Ultrasonography. * Number of patients in whom a TA or US of the TA was performed.
Table 3. FDG-PET-CT differences between patients with the classic cranial LVV-GCA phenotype and dose with extracranial LVV-GCA phenotype.
Table 3. FDG-PET-CT differences between patients with the classic cranial LVV-GCA phenotype and dose with extracranial LVV-GCA phenotype.
Extracranial LVV-GCA
n= 41 (%)		 Cranial-LVV-GCA
n= 13 (%)		 p
Carotid 14 (34.1) 5 (38.5) 0.78
Subclavian 23 (56) 10 (76.9) 0.21
Brachiocephalic 22 (53.7) 9 (69.2) 0.36
Axillary 7 (17) 1 (7.6) 0.66
Humeral 2 (4.9) 0 (0) 0.99
Vertebral 3 (7.3) 2 (15.4) 0.58
Thoracic aorta 31 (75.6) 9 (69.2) 0.45
Ascending 28 (68.3) 9 (69.2) 0.99
Aortic arch 27 (65.9) 9 (69.2) 0.99
Descending 28 (68.3) 9 (69.2) 0.99
Abdominal 20 (48.8) 7 (53.8) 0.75
Iliac 15 (36.6) 3 (23.1) 0.50
Femoral 10 (24.4) 1 (7.6) 0.26
Table 4. Comparisons of involved vascular artery at diagnosis between 54 patients with LVV-GCA diagnosed in Madrid (Spain) and 127 patients with LVV-GCA diagnosed in Reggio Emilia (Italy).
Table 4. Comparisons of involved vascular artery at diagnosis between 54 patients with LVV-GCA diagnosed in Madrid (Spain) and 127 patients with LVV-GCA diagnosed in Reggio Emilia (Italy).
Madrid, Spain
n= 54 (%)		 Reggio Emilia, Italy
n= 127 (%)		 p
Carotid 19/54 (35.2) 79/126* (62.8) 0.001
Subclavian 33/54 (61.1) 86/126 (68.3) 0.35
Brachiocephalic 31/54 (57.4) 28/126 (22.2) <0.001
Axillary 8/54 (14.8) 46/126 (36.5) 0.004
Humeral 2/54 (3.7) 18/126 (14.3) 0.04
Vertebral 5/54 (9.3) 8/125 (6.4) 0.50
Thoracic aorta 40/54 (74.1) 81/106 (76.4) 0.74
Ascending 37/54 (68.5) 61/107 (57.0) 0.28
Aortic arch 36/54 (66.7) 72/118 (61.0) 0.48
Descending 37/54 (68.5) 73/106 (69.8) 0.96
Abdominal 27/54 (50.0) 68/116 (58.6) 0.29
Iliac 18/54 (33.3) 31/100 (31.0) 0.77
Femoral 11/54 (20.4) 26/100 (26.0) 0.44
Number of positive/Number tested*.
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