The VGR GCA Cohort: Ultrasound, Biopsy and Biomarkers - Novel Methods for Diagnosis, Monitoring and Prognosis in Giant Cell Arteritis.

Background Giant cell arteritis (GCA) is the most common form of vasculitis in older adults and is characterized by inflammation of medium- and large-sized arteries. The disease can cause serious complications such as vision loss, aortic aneurysm, and stroke. Treatment is mainly based on long-term glucocorticoid therapy. Despite this, 30-60% of patients experience disease relapse during treatment, and many develop steroid-related side effects. There are substantial knowledge gaps regarding optimal treatment stratification, reliable differentiation between active inflammation and chronic vascular remodeling, and the ideal extent of vascular ultrasound examination for diagnostic accuracy.

Overall Aim and Specific Objectives The overarching aim of this study is to determine which ultrasound parameters and novel blood biomarkers have prognostic, monitoring, and diagnostic value in GCA. The goal is to enable more individualized therapy and to reduce the risk of both over- and undertreatment.

Specific objectives are:

• To identify ultrasound parameters and biomarkers with prognostic value for long-term treatment response.
• To identify ultrasound parameters and biomarkers that distinguish active from inactive inflammation during treatment and at diagnosis.
• To evaluate whether an extended vascular ultrasound protocol improves diagnostic accuracy compared with the current European (EULAR) recommendations, and to assess whether ultrasound-detected neovascularization corresponds to histological neovascularization in temporal artery biopsy specimens.

Current Research Context Diagnostic advances in GCA have recently been driven by imaging techniques, particularly ultrasound. The European Alliance of Associations for Rheumatology (EULAR) currently recommends ultrasound assessment of the temporal and axillary arteries in suspected GCA. Quantitative parameters such as intima-media thickness (IMT) and scoring systems (e.g., Halo count and the OMERACT GCA Ultrasonography Score, OGUS) are used to assess vascular wall inflammation. However, these methods primarily evaluate cranial arteries and the axillary arteries. Studies using PET-CT have shown that extracranial vascular involvement is common and associated with a higher relapse risk and longer treatment duration. We have previously developed an extended ultrasound protocol that includes a broader set of extracranial arteries. In a retrospective study, we demonstrated that this extended protocol improves diagnostic accuracy compared to the EULAR-recommended approach.

Distinguishing active inflammation from chronic vascular alterations remains difficult. IMT may remain thickened even after resolution of inflammation. Neovascularization, detectable using modern low-flow ultrasound software, reflects microcirculation and angiogenesis in the vessel wall. Recent studies have demonstrated that neovascularization can be visualized in smaller temporal arteries in patients with active GCA, and that its presence correlates with more extensive disease. Neovascularization thus appears to represent a morphological marker of active inflammation. These previous data together with findings from Takayasu arteritis suggest that ultrasound-detected neovascularization could complement IMT as a sensitive indicator of disease activity. Based on these insights, we aim to integrate both IMT and neovascularization into a composite ultrasound score with potential prognostic and monitoring value.

Currently, disease activity in GCA is primarily assessed using CRP and ESR, which have limited sensitivity and specificity, especially in patients treated with IL-6 inhibitors. Novel biomarkers directly linked to vascular wall inflammation and destruction have been identified in experimental models. Interleukin-9 (IL-9) has been shown to promote inflammation and vascular injury in GCA models, while IL-9 blockade reduces disease severity. Angiopoietin-2 is involved in angiogenesis, and matrix metalloproteinase-3 (MMP-3) contributes to vascular wall degradation. These biomarkers are promising but have not yet been evaluated in clinical GCA cohorts.

A total of 100 individuals with GCA are required for the primary outcome, assuming an alpha level of 0.05, a power of 0.90, and an estimated dropout rate of 25%. Based on an estimated GCA prevalence of 30% among referred patients, approximately 340 ultrasound examinations will be needed to achieve the target sample size.

In summary, diagnostic imaging of GCA has advanced considerably through ultrasound, yet the prognostic and monitoring applications of this technique remain largely unexplored, particularly in combination with novel vascular biomarkers. This study will integrate advanced vascular ultrasound with biomarker analyses to improve diagnostic precision, disease monitoring, and individualized treatment strategies in GCA.