This first-in-human study demonstrates that [68Ga]Ga-DOTA-Siglec-9 PET/CT detects vascular inflammation in GCA and shows attenuation with prednisolone exposure, positioning it as a promising potential molecular imaging biomarker in GCA.
Key Findings
Results
[68Ga]Ga-DOTA-Siglec-9 PET/CT successfully detected vascular inflammation in patients with newly diagnosed giant cell arteritis in a first-in-human application.
This was a proof-of-concept study exploring the diagnostic potential of VAP-1 targeting [68Ga]Ga-DOTA-Siglec-9 PET/CT as an inflammation-specific molecular imaging biomarker.
Eight patients with newly diagnosed GCA were compared with eight relapsing patients and eight controls.
Tracer uptake (SUVmean/SUVmax) was quantified in aortic, supra-aortic, and extravascular (shoulder/hip) regions.
The study represents the first-in-human use of this tracer in GCA.
Results
Vascular tracer uptake was positively associated with ultrasound-assessed subclavian artery intima-media thickness.
A positive association was found between ultrasound-assessed subclavian artery intima-media thickness and tracer uptake (r=0.67, p=0.035).
Patients underwent both [68Ga]Ga-DOTA-Siglec-9 PET/CT and vascular ultrasound.
This correlation supports the validity of the PET/CT signal as reflecting structural vascular inflammation.
Results
Prednisolone exposure was inversely associated with vascular tracer uptake across multiple vascular regions.
SUVmean showed a negative association with prednisolone exposure: r=-0.51, p=0.043.
SUVmax also showed a negative association with prednisolone exposure: r=-0.62, p=0.010.
SUVmean showed a stronger overall negative association than SUVmax.
This inverse relationship suggests the imaging signal is treatment-responsive.
Results
Soluble VAP-1 (sVAP-1) levels were reduced in newly diagnosed GCA compared with both relapsing patients and controls.
sVAP-1 levels were significantly lower in newly diagnosed GCA compared with relapsing patients (p=0.0145).
sVAP-1 levels were also significantly lower in newly diagnosed GCA compared with controls (p=0.0446).
sVAP-1 was inversely associated with MMP2 (r=-0.56, p=0.037) and MMP9 (r=-0.47, p=0.089).
These findings support a functional VAP-1/MMP axis underlying the imaging signal.
Results
MMP2 and MMP3 levels were negatively associated with vascular tracer uptake.
MMP2 and MMP3 were negatively associated with vascular uptake in multiple regions.
At the aortic arch specifically, the association was r=-0.59, p=0.027.
MMP2, MMP3, and MMP9 were measured in patients and controls as potential biomarkers related to vascular inflammation.
These inverse associations between MMPs and tracer uptake further support the proposed VAP-1/MMP axis.
Discussion
The study identified a functional VAP-1/MMP axis as a proposed mechanism underlying the [68Ga]Ga-DOTA-Siglec-9 PET/CT imaging signal in GCA.
Reduced sVAP-1 levels in newly diagnosed GCA and inverse associations between MMP2/MMP3 and tracer uptake support this mechanistic interpretation.
VAP-1 (vascular adhesion protein-1) is the molecular target of the [68Ga]Ga-DOTA-Siglec-9 tracer.
The authors concluded that these findings 'support a functional VAP-1/MMP axis underlying the imaging signal.'
This mechanistic finding provides a biological rationale for the observed imaging results.
What This Means
This research suggests that a new type of PET/CT scan using a radioactive tracer called [68Ga]Ga-DOTA-Siglec-9 can detect blood vessel inflammation in patients with giant cell arteritis (GCA), a disease that causes inflammation of large blood vessels and can lead to serious complications including vision loss. The tracer works by targeting a protein called VAP-1 that is present on inflamed blood vessel walls. In this small proof-of-concept study involving 8 newly diagnosed patients, 8 relapsing patients, and 8 healthy controls, the scan showed uptake in inflamed vessels that correlated with ultrasound measurements of vessel wall thickening, suggesting it accurately reflects the degree of inflammation.
Importantly, the imaging signal decreased in patients who had been exposed to prednisolone (a standard steroid treatment for GCA), suggesting the scan can track how well treatment is working. The study also found that blood levels of VAP-1 and certain enzymes called matrix metalloproteinases (MMPs) were altered in GCA and correlated with the imaging signal, pointing to a biological mechanism — a 'VAP-1/MMP axis' — that may explain why the tracer accumulates in inflamed vessels.
This research matters because assessing disease activity in GCA is currently difficult — existing blood tests and imaging tools lack specificity. This first-in-human study positions [68Ga]Ga-DOTA-Siglec-9 PET/CT as a potentially more precise, inflammation-specific tool for diagnosing GCA and monitoring treatment response, though larger studies are needed to confirm these findings.