Giant cell arteritis: pathogenic mechanisms and new potential therapeutic targets

Abstract

Giant cell arteritis (GCA) is the most common idiopathic systemic vasculitis in persons aged 50 years or greater. Treatment options for GCA, to-date, have been limited and have consisted primarily of glucocorticoids. Significant advances in the understanding of the genetic and cellular mechanisms in GCA are leading to identification of potential pathogenic targets. The recent success of interleukin-6 blockade in the treatment of GCA has opened the landscape to targeted biologic therapy. T cells, particularly T helper 1 and T helper 17 cell lineages have been identified as key inflammatory cells in both active and chronic vascular inflammatory lesions. Therapeutic agents, including abatacept and ustekinumab, which can impede both vasculitogenic cell lines are of particular interest. Inhibition of signalling pathways, including the janus kinase-signal tranducers and activation of transcription (JAK-STAT) and Notch pathways are evolving options. Tocilizumab has shown clear benefit in both newly diagnosed and relapsing patients with GCA and approval of this medication for treatment of GCA has led to rapid incorporation into treatment regimens. More information is required to understand the long-term outcomes of tocilizumab and other investigational targeted therapeutics in the treatment of GCA.

Keywords: Biologics; Giant cell arteritis; Pathogenesis; Therapeutics; Vasculitis.

Fig. 1

Vascular dendritic cells (vasDC) activate T helper 1 (Th1) and T helper 17 (Th17) cells by presenting antigen in the context of human leukocyte antigen (HLA) molecules. Abatacept can bind to CD80/86 and therefore block the required co-stimulatory signal required for T cell activation. Both B cells and vasDCs secrete interleukin (IL)-6 which stimulates Th17 cells via binding to its respective the T cell receptor (TCR). Sirukumab blocks soluble IL-6 whereas tocilizumab and sarilumab target the soluble and membrane-bound IL-6 receptor (IL-6R). IL-12 and IL-23 are secreted by vasDCs and antigen presenting cells and stimulate Th1 and Th17 cells, respectively. Ustekinumab binds the p40 subunits of both IL-12 and IL-23. Major effector cytokines produced by Th1 cells include IL-2 and interferon gamma (IFN-γ) and cytokines produced by Th17 cells include IL-17, IL-21 and IL-22

Fig. 2

Effector cytokines can stimulate transcription of proinflammatory signals through the Janus kinase–signal transducers and activators of transcription (JAK-STAT) signalling pathway. Intracellular JAK and tyrosine kinase (TYK) proteins are activated when a ligand binds to its receptor which induces phosphorylation and activation, which in turn activate STAT proteins. The STAT proteins dimerize and translocate to the nucleus where they bind STAT-specific response elements in target gene promotors and regulate gene transcription; including proinflammatory signals. JAK inhibitors (e.g. baricitinib and tofacitinib) are able to abrogate signalling cascades from more than one effector cytokine pathway