Assessment of Inflammation and Calcification in Pseudoxanthoma Elasticum Arteries and Skin with 18F-FluroDeoxyGlucose and 18F-Sodium Fluoride Positron Emission Tomography/Computed Tomography Imaging: The GOCAPXE Trial

Abstract

Background: Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease characterized by elastic fiber fragmentation and ectopic calcification. There is growing evidence that vascular calcification is associated with inflammatory status and is enhanced by inflammatory cytokines. Since PXE has never been considered as an inflammatory condition, no incidence of chronic inflammation leading to calcification in PXE has been reported and should be investigated. In atherosclerosis and aortic stenosis, positron emission tomography combined with computed tomographic (PET-CT) imaging has demonstrated a correlation between inflammation and calcification. The purpose of this study was to assess skin/artery inflammation and calcification in PXE patients. Methods: 18F-FluroDeoxyGlucose (18F-FDG) and 18F-Sodium Fluoride (18F-NaF) PET-CT, CT-imaging and Pulse wave velocity (PWV) were used to determine skin/vascular inflammation, tissue calcification, arterial calcium score (CS) and stiffness, respectively. In addition, inorganic pyrophosphate, high-sensitive C-reactive protein and cytokines plasma levels were monitored. Results: In 23 PXE patients, assessment of inflammation revealed significant 18F-FDG uptake in diseased skin areas contrary to normal regions, and exclusively in the proximal aorta contrary to the popliteal arteries. There was no correlation between 18F-FDG uptake and PWV in the aortic wall. Assessment of calcification demonstrated significant 18F-NaF uptake in diseased skin regions and in the proximal aorta and femoral arteries. 18F-NaF wall uptake correlated with CS in the femoral arteries, and aortic wall PWV. Multivariate analysis indicated that aortic wall 18F-NaF uptake is associated with diastolic blood pressure. There was no significant correlation between 18F-FDG and 18F-NaF uptake in any of the artery walls. Conclusion: In the present cross-sectional study, inflammation and calcification were not correlated. PXE would appear to more closely resemble a chronic disease model of ectopic calcification than an inflammatory condition. To assess early ectopic calcification in PXE patients, 18F-NaF-PET-CT may be more relevant than CT imaging. It potentially constitutes a biomarker for disease-modifying anti-calcifying drug assessment in PXE.

Cutaneous and Vascular Deposits of 18F-NaF by PET/CT in the Follow-Up of Patients with Pseudoxanthoma Elasticum

“…Our group has reported that in PXE patients this radiopharmaceutical is also deposited in the flexural areas of the skin (especially the neck and axillae), and that this deposit relates well to the severity of the lesions observed in physical examinations [8]. Identical data have been published more recently [9].…”

Therapy of Pseudoxanthoma Elasticum: Current Knowledge and Future Perspectives

“…In PXE, atherogenesis is not yet fully understood. Although positron-emission tomography scans did not assess vascular inflammation in PXE patients [ 100 ], the presence of capillary alterations may indicate a role for the hypoxia-induced formation of reactive oxygen species as a second messenger in the pathophysiology of PXE [ 13 ]. A dysregulation of blood lipids also is part of the PXE phenotype [ 12 , 101 , 102 ].…”

[18F]FDG and [18F]NaF as PET markers of systemic atherosclerosis progression: A longitudinal descriptive imaging study in patients with type 2 diabetes mellitus

“…7,8 Importantly, in a crosssectional study, focal arterial [ 18 F]FDG uptake did not correlate with [ 18 F]NaF uptake. 9 Furthermore, arterial [ 18 F]FDG PET uptake was not associated with calcification progression on computed tomography (CT) and specific sites of increased [ 18 F]FDG uptake and calcification rarely overlapped. 10 However, since inflammation is the precursor of calcification development and previous studies observed that both processes are not present simultaneously, 9,11 we hypothesize that [ 18 F]FDG-assessed arterial inflammation may be associated with [ 18 F]NaF-assessed arterial microcalcification over time.…”

“…9 Furthermore, arterial [ 18 F]FDG PET uptake was not associated with calcification progression on computed tomography (CT) and specific sites of increased [ 18 F]FDG uptake and calcification rarely overlapped. 10 However, since inflammation is the precursor of calcification development and previous studies observed that both processes are not present simultaneously, 9,11 we hypothesize that [ 18 F]FDG-assessed arterial inflammation may be associated with [ 18 F]NaF-assessed arterial microcalcification over time. The primary aim of this proofof-concept study is the assessment of the prospective association of baseline systemic arterial [ 18 F]FDG activity with systemic [ 18 F]NaF PET during five years of follow-up in asymptomatic patients with T2DM.…”