Establishing C-X-C motif chemokine receptor 4 as a novel imaging target in giant cell arteritis

BACKGROUND: PET imaging in giant cell arteritis (GCA) is crucial for diagnosis. New tracers such as C-X-C motif chemokine receptor 4 (CXCR4) enable to directly visualize inflammatory cells as they are expressed on leukocytes. We aimed to test the value of CXCR4-targeted PET in GCA. METHODS: Ten treatment-naïve patients with confirmed large-vessel GCA underwent both [18F]FDG and [68Ga]PentixaFor PET/CT scans within a median of two days, without any therapy in between. Thirteen arterial segments per patient were analyzed. Visual interpretation and quantitative target-to-background ratios (TBR; arterial SUVmax divided by superior vena cava SUVmean) were calculated, including per-patient mean TBRs. Five patients without clinical or diagnostic evidence of vasculitis served as Non-GCA controls. Flow cytometry was used to quantify CXCR4 expression on leukocyte subsets, reported as normalized median fluorescence intensity (NMFI). RESULTS: All GCA patients showed positive scan findings on both [18F]FDG and [68Ga]PentixaFor PET/CT. Mean vascular TBRs were 2.43 ± 0.90 for FDG and 1.76 ± 0.76 for PentixaFor (P = 0.07), indicating similar large-vessel uptake. Segment-level analysis showed no significant differences in 10/13 vascular regions, although FDG uptake was higher in selected arteries. PentixaFor TBR was significantly lower in Non-GCA controls (1.15 ± 0.10 vs. 1.76 ± 0.76; P = 0.01), supporting its specificity for inflammation. Blood pool SUVmean did not differ, suggesting minimal signal spill-in. CXCR4 expression was highest on naïve T-helper cells and monocytes. CONCLUSIONS: CXCR4-targeted [68Ga]PentixaFor PET/CT provides an imaging pattern comparable to [18F]FDG PET/CT in untreated GCA and reliably differentiates between inflamed and non-inflamed vessels. These findings support CXCR4 PET as a promising, mechanistically grounded imaging approach that merits further evaluation in larger patient cohorts. CLINICAL TRIAL NUMBER: ClinicalTrials.gov NCT05604482. Registered 3 November 2022.