Towards Therapeutic Targeting of Fibroblasts in Giant Cell Arteritis

Giant cell arteritis (GCA) is characterized by chronic vascular inflammation and pathological remodeling. While current therapies primarily rely on broad immunosuppression by glucocorticoids, they fail to halt pathologic remodeling and heal the arteries. Fibroblasts are highly plastic cells that may present the link between chronic inflammation and pathological remodeling. This narrative review aims to give an overview of the possible therapeutic strategies targeting fibroblasts in GCA.

Recent studies have identified and mapped the distribution of various fibroblast subtypes in arteries affected by GCA, highlighting their potential role in both the chronicity of vascular inflammation and pathological remodeling. Advances in molecular tools such as (spatial) transcriptomics and proteomics, along with in vitro models enhance our understanding of the role of fibroblasts in the pathogenesis of GCA and help to identify new fibroblast-related pathways amenable for therapeutic intervention.

Evidence for an effect of pharmacological agents currently used to treat GCA, like glucocorticoids, methotrexate, leflunomide and the interleukin-6 receptor blocker tocilizumab on vascular fibroblasts is limited. New targeted therapies recently approved for GCA, such as the JAK-STAT inhibitor upadacitinib, or other drugs recently or currently being tested in clinical trials offer new opportunities for modulation of vascular fibroblasts in GCA. Depletion of specific pathological fibroblast subtypes or modulation of fibroblast differentiation towards reparative of homeostatic phenotypes, combined with targeted immunosuppression may contribute to vascular healing in GCA.