New biomarker ratios show promise in early giant cell arteritis detection in patients with polymyalgia rheumatica

A recent study published in the Rheumatic and Musculoskeletal Diseases Open has highlighted the potential role of specific serum biomarker ratios in enhancing diagnostic accuracy of giant cell arteritis (GCA) in patients with polymyalgia rheumatica (PMR). Given the frequent overlap in clinical presentations of PMR and GCA, identifying biomarkers that reflect vascular inflammation could aid in distinguishing cases of GCA among patients presenting with isolated PMR. 

The study analyzed serum biomarkers in 45 patients with isolated PMR and 29 with overlapping PMR and GCA, measuring markers associated with systemic inflammation (such as interleukin-6 (IL-6) and CXCL9), vascular remodeling (MMP-2, MMP-3, MMP-9), and endothelial function (sCD141, sCD146, ICAM-1, VCAM-1, and vWFA2).  

The findings revealed that GCA patients had elevated serum levels of sCD141 and CXCL9, while patients with isolated PMR showed higher levels of MMP-3 and IL-6. The combinations of CXCL9/IL-6 and MMP-3/sCD141 ratios showed promise as diagnostic markers, with AUCs of 0.76 and 0.79, respectively. Notably, patients with subclinical GCA showed high diagnostic accuracy with sCD141 and the MMP-3/sCD141 ratios achieved AUCs of 0.81 and 0.77, respectively, suggesting their utility in detecting cases where symptoms are subtle or absent but vascular inflammation persists. Identifying subclinical GCA is critical, as these cases might otherwise go unrecognized, potentially delaying appropriate treatment. 

In GCA, inflammation occurs within the walls of large arteries, resulting in vascular remodeling and ischemic symptoms. The in situ production of interferon-gamma (IFN-γ) by Th1 cells initiates vascular smooth muscle cell (VSMC) activation, leading to the release of chemokines like CCL2, CXCL9, CXCL10, and CXCL11. This cascade recruits further Th1 cells, CD8+ T cells, and CCR2+ monocytes, which differentiate into macrophages producing high levels of interleukin-6 (IL-6) and matrix metalloproteinases (MMPs). IL-6 is a major contributor to systemic inflammation, while MMPs, particularly MMP-2 and MMP-9 produced by both macrophages and VSMCs, drive vascular remodeling by degrading extracellular matrix proteins, causing media destruction and fragmentation of the internal elastic lamina, a hallmark of GCA versus PMR. 

Endothelial cells also play a key role in GCA pathogenesis, with T cells thought to be recruited via the adventitial vasa vasorum where endothelial cells express adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Prior studies have shown elevated soluble thrombomodulin (sCD141) levels in GCA and Takayasu arteritis. Thrombomodulin, a transmembrane protein on endothelial cells, is crucial in limiting inflammatory infiltration of the endothelium. Additionally, recent research has identified serum angiopoietin-2 and MMP-3 as potential biomarkers distinguishing GCA from PMR in affected populations. 

 These biomarker ratios could complement routine inflammatory markers, such as C-reactive protein and erythrocyte sedimentation rate, which have shown limited sensitivity in distinguishing GCA within PMR populations. The findings indicate that a CXCL9/IL-6 or MMP-3/sCD141 ratio may be particularly beneficial in identifying high-risk PMR patients who may require further examination for GCA. Further prospective studies with larger sample sizes are necessary to confirm these findings and validate these biomarker ratios within an independent cohort. If confirmed, these ratios could offer rheumatologists a valuable tool for early identification of GCA among PMR patients, particularly those with a subclinical presentation. 

Reference 

Ramon A, Greigert H, Goueslard K, Cladière C, Ciudad M, Ornetti P, Audia S, Maillefert JF, Bonnotte B, Samson M. Diagnostic accuracy of serum biomarkers to identify giant cell arteritis in patients with polymyalgia rheumatica. RMD Open. 2024 Aug 8;10(3):e004488.