Unraveling giant cell arteritis: From immunopathology to emerging targeted therapies (2026 update).

Giant cell arteritis (GCA) is the most common systemic vasculitis in the elderly mainly because of cellular senescence and "inflammaging" It results from granulomatous inflammation primarily affecting the aorta and its major branches. Recent advances highlight vascular dendritic cell (DC) activation via TLRs as the initiating event, leading to chemokine-mediated recruitment and polarization of CD4+ T cells mainly into Th1/Th17 subsets. These effector T cells drive monocyte differentiation into pro-inflammatory macrophages and giant cell formation, with subsequent matrix metalloproteinase production causing elastic lamina destruction and vascular remodeling. This vascular remodeling involves activation of endothelial cells, fibroblasts and smooth muscle cells followed by a differentiation in myofibroblast in the intima. Neutrophils may play an underestimated role. Current treatments remain limited to glucocorticoids, methotrexate and tocilizumab though relapse rates remain high. This narrative review synthesizes the DC-T-macrophage-fibroblast cascade and evaluates emerging biologics: abatacept showed phase 2 efficacy but real-world inferiority to tocilizumab; ustekinumab yielded conflicting results across small series; secukinumab failed phase 3 despite promising phase 2 data; anakinra lacked benefit in a truncated trial. In contrast, Mavrilimumab, an anti-GM-CSF-R, is showing promising results. JAK inhibitors such as upadacitinib (a JAK1 inhibitor; SELECT-GCA phase 3) are also promising, having demonstrated superior sustained remission compared with placebo, leading to regulatory approvals in 2025. These findings underscore opportunities to target upstream DC activation, macrophage polarization, and vascular remodeling pathways, potentially transforming GCA management beyond IL-6 inhibition.