Background/Aims: Giant cell arteritis (GCA) is primarily managed with high-dose glucocorticoids despite significant toxicity.

Tocilizumab offers a glucocorticoid-sparing alternative, but access is limited, and high glucocorticoid dependence remains a major therapeutic challenge. Here, we delineate the molecular landscape of early glucocorticoid response in GCA tissue, revealing biological insights and candidate pathways for therapeutic intervention. Additionally, we identify molecular predictors of refractory/relapsing disease that may improve GCA management.

Methods: RNA-sequencing of baseline temporal artery biopsies from GCA (n=108; mean age=73.9 [59-91]; %female=58.8) and non-GCA individuals (n=16; mean age=65 [46-84]; %female=68.7) was performed. Differential expression (DE) analysis across stratified groups based on glucocorticoid exposure (median=5 days [0-23]) was conducted to reveal genes/pathways persistently dysregulated or suppressed during treatment. All findings were corrected for multiple testing.

Results: DE analysis revealed extensive transcriptional changes across steroid exposure groups (≤3, 4-6, ≥7days) with a predominance of upregulated genes (~75%) and the greatest number of DE genes (n=3,902) during early response (≤3days). After ≥7days, upregulated genes and pathways diverged from the core immune activation signature, showing more vascular and stromal profiles. The cytokine/cytokine receptor pathway was one of the most significantly dysregulated pathways across all timepoints (p=7.12x10-¹⁸). Upregulation of multiple CC and CXC subfamily chemokines was observed at ≤3days, with CCL4 and CXCL1/2/3/13 remaining persistently elevated after ≥7days of treatment. Dysregulated signalling cascades such as JAK-STAT pathway (p=5.1x10-²) were observed in patients who experienced refractory/relapsing disease.