New insights into the pathogenesis of giant cell arteritis and hopes for the clinic

Abstract

Giant cell arteritis is a complex immune-mediated disease that involves large blood vessels in individuals older than 50 years. Recent studies have confirmed a strong association of this form of vasculitis with the HLA region, particularly with HLA class II genes. However, other non-HLA loci, such as protein tyrosine phosphatase non-receptor type 22, may also account for the susceptibility to giant cell arteritis. In addition, genetic variants located in genes encoding proinflammatory cytokines seem to influence the phenotypic expression of the disease, including the risk of severe ischemic complications, the presence of polymyalgia rheumatica and the higher incidence of relapses observed in some patients. The identification of putative genetic markers of disease severity could have clear therapeutic implications, as it may allow us to identify patients who are potentially responders to specific treatments.

Keywords:

• giant cell arteritis
• human leukocyte antigen
• IFN-γ
• IL-6
• polymyalgia rheumatica
• protein tyrosine phosphatase non-receptor type 22
• relapses
• temporal artery biopsy
• vascular endothelial growth factor
• visual ischemic complications

Financial & competing interests disclosure

The authors were supported by Instituto de Salud Carlos III (ISCIII), Spain, through the RETICS Programs RD12/0009/0004 and RD12/0009/0013 (RIER). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Giant cell arteritis (GCA) represents the most common form of vasculitis affecting people over 50 years old in Western countries.

• Different severe ischemic complications characterize GCA, including permanent visual loss.

• High-dose corticosteroids are prescribed as soon as the GCA diagnosis is suspected to avoid the risk of blindness, with no specific treatments developed for this disease.

• Although most cases are effectively managed with glucocorticoid monotherapy, relapses are commonly observed upon steroid tapering.

• We are still far from a complete understanding of the molecular mechanisms underlying GCA.

• T cells (specifically Th1, Th17, Th9 and Treg) seem to be pivotal players in GCA development, supporting the hypothesis of GCA as an antigen-driven disease.

• Current knowledge suggests that different T-cell populations may characterize distinct immunological signatures in GCA patients.

• Large-scale genetic studies clearly support the role of T cells in GCA, as the most associated loci correspond to the HLA region, protein tyrosine phosphatase non-receptor type 22 (involved in the T-cell receptor pathway) and leucine-rich repeat containing 32 (a Treg marker).

• Genes encoding proinflammatory cytokines, such as IL-6 and IFN-γ, and molecules with endothelial functions, like VEGF, have been associated with severity of the disease through candidate gene studies, and could represent good prognosis markers.

• The upcoming genome-wide association studies on large GCA sample sets may definitively shed light into the pathophysiology of GCA, helping us to establish novel and more effective therapeutic strategies.

Notes