1. Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2017.142
Figure 1 Pathogenetic pathways and treatment targets in giant cell arteritis
Figure 1 | Pathogenetic pathways and treatment targets in giant cell arteritis. a | During the initiation phase of giant cell arteritis (GCA), in which dendritic cells (DCs) within the adventitia are activated via pathogen-associated molecular patterns (PAMPs), microorganism-associated molecular patterns (MAMPs) and damage-associated molecular patterns (DAMPs), pro-inflammatory cytokines such as IL‑6, IL‑12 and IL‑23 are produced. In addition, naive T cells are activated via MHC class II molecules and the co‑stimulatory molecules CD80/86 on the DCs that interact with the T cell receptor complex and CD28 present on T cells. b | Upon maturation of DCs and resident macrophages, naive CD4+ T cells are stimulated to polarize into T helper 1 (TH1) cells and TH17 cells. Production of IFNγ and TNF by TH1 cells and IL‑17 and IL‑21 by TH17 cells enables these cells to recruit macrophages, which produce IL‑1, IL‑6, IL‑12, IL‑23, TNF and vascular endothelial growth factor (VEGF). Chemokines, which are produced by activated DCs and T cells, guide T cells, macrophages and B cells into the vessel wall. c | In the chronic phase of GCA, local hypoxia, together with the presence of macrophages and giant cells, amplifies the migration of both inflammatory cells and resident cells. In addition to cytokines (IL‑6 and TNF) and chemokines, factors important in the chronic phase of GCA include VEGF, platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) produced by macrophages and endothelin‑1 produced by endothelial cells and vascular smooth muscle cells (VSMCs), which activate inflammatory cells, VSMCs, stromal cells, pericytes and endothelial cells to induce the formation of new vessels and promote VSMC migration, fragmentation of the external and internal elastic lamina by metalloproteinases and endothelial cell proliferation. Ectopic lymphoid structures are formed within the adventitia in this phase of chronic inflammation and remodelling. Possible treatment approaches include prevention of DC activation in the initiation phase of GCA by use of antimicrobials, blockade of cytokines, chemokines, co‑stimulatory pathways, Notch and signalling pathways by use of biologic and/or synthetic drugs in both the initiation and amplification phases of GCA, and blocking growth factors (including VEGF, PDGF and FGF), neurotrophins and cytokines in the chronic phase of GCA. Green boxes show treatments for GCA proven effective in RCTs; grey boxes show other potential treatment options for GCA; the red box shows a treatment that failed to show efficacy in clinical trials.
Dejaco, C. et al. (2017) Giant cell arteritis and polymyalgia rheumatica: current challenges and opportunities
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