Pathogenesis of giant cell arteritis

INTRODUCTION — Giant cell arteritis (GCA) is a chronic inflammatory disease involving large- and medium-sized arteries and affecting individuals older than 50 years [1]. Involvement of the cranial branches of the carotid arteries is very common and, due to its easy access, biopsy of the superficial temporal artery is frequently performed to obtain histopathologic confirmation of GCA.

Histopathology and immunopathology studies reveal inflammation of the artery wall with predominance of CD4+ T lymphocytes and macrophages, which frequently undergo granulomatous organization with formation of giant cells [2]. There is a remarkable loss of vascular smooth muscle cells (VSMC) and elastic fibers that may eventually facilitate aneurysm formation. Inflammation-induced vascular remodeling leads to intimal hyperplasia and lumen occlusion, the source of the ischemic complications of the disease [1,2].

The pathogenesis of GCA is incompletely understood. The current pathogenic model has been largely built on immunopathology and molecular studies performed with temporal artery biopsies. Functional models where the participation of specific pathways can be mechanistically investigated are limited. The role of particular cells, molecules, or pathways has been investigated in temporal artery biopsy xenografts into severe combined immunodeficiency (SCID) mice or in ex vivo cultured arteries [3,4]. Clinical trials with targeted therapies are providing proof of concept about the relevance of specific pathways in the pathogenesis of vascular inflammation [5].

This topic will review the pathogenesis of GCA. The clinical manifestations, diagnosis, and treatment of this disorder are discussed separately. (See "Clinical manifestations of giant cell arteritis" and "Diagnosis of giant cell arteritis" and "Treatment of giant cell arteritis".)

PREDISPOSING FACTORS — Epidemiologic studies demonstrate predominance in older adults, females, and individuals of Northern European ancestry. Occasional family clustering has been reported. These data strongly suggest that senescence, sex, and genetic background all contribute to the pathogenesis of giant cell arteritis (GCA) [1]. The role of aging and sex remains elusive.

Along with candidate gene studies performed over the years, an international large-scale genotyping effort has confirmed a strong association between GCA and genetic variants in the major histocompatability complex (MHC) region, particularly human leukocyte antigen (HLA)-DRB1*04:04, HLA-DQA1*03:01, and HLA-DQB1*03:02. The derived risk amino acids are located in the antigen-binding pocket of the HLA molecule. These findings support the role of adaptive immunity and the concept that GCA may be an antigen-driven disease [6-8].

A genome-wide association study indicates that, in addition to MHC polymorphisms, variants in genes related to angiogenesis and vascular biology also predispose to GCA [7]. Additional variants in genes involved in T helper (Th) 1, Th17, and regulatory T-cell function associated with increased GCA risk have also been identified at a subgenome-wide significance level [6].

INITIAL EVENTS — The nature of the triggering agent(s) has not been identified with certainty (figure 1). Periodic increases in incidence observed in some epidemiologic studies suggest a role for environmental factors [9]. Various microbe and viral sequences have been detected in temporal artery lesions, but no convincing causal relationship has been demonstrated [10-14].

Dendritic cell and T lymphocyte activation — Dendritic cells, present in the adventitia of normal arteries, can be activated in giant cell arteritis (GCA) through pathogen- or damage-sensing receptors, such as toll-like receptors, and produce chemokines able to attract and retain dendritic cells as well as lymphocytes and macrophages. These data underline the participation of innate immunity in initial pathogenic events [15]. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is emerging as a relevant cytokine in dendritic cell and macrophage activation in GCA, influencing several steps in pathogenesis [16].

Once activated, dendritic cells are enabled to process and present antigens and strongly express activation markers (ie, CD83), major histocompatibility complex (MHC) class II, and costimulatory molecules (ie, CD86) required for antigen presentation and T-cell activation [15]. The involvement of antigen-specific adaptive immune responses is supported by the detection of oligoclonal expansion of T cells in GCA lesions [17]. Genes related to T-cell activation (ie, transcription factor nuclear factor of activated T cells [NFAT] and NFAT-regulated genes) are hypomethylated in GCA-involved arteries, supporting a central role for T lymphocytes in disease pathogenesis [18]. Immune checkpoints avoiding excessive T-cell activation may be deficient in GCA [19]. Their functional relevance is supported by the development of GCA in cancer patients treated with immune checkpoint inhibitors [20,21] and by the efficacy of abatacept (a soluble fusion protein comprising cytotoxic T-lymphocyte-associated protein 4 [CTLA-4] and the Fc portion of immunoglobulin [Ig] G1 [CTLA-Ig]) in GCA, reported in a phase II trial [22]. (See "Treatment of giant cell arteritis", section on 'Unproven or ineffective agents'.)

T lymphocyte functional differentiation — After activation, T lymphocytes differentiate into T helper (Th) 1 and Th17 functional subsets as supported by the expression of the key effector cytokines interferon (IFN) gamma and interleukin (IL) 17, respectively, in GCA lesions [23-27]. Cytokines produced by dendritic cells drive this process. On the one hand, IL-12 and IL-18 produced by dendritic cells stimulate Th1 differentiation [15,25]. On the other hand, IL-1-beta, IL-6, and IL-21, profusely expressed in GCA [23,24,27,28], promote Th17 differentiation, which is maintained by IL-23. IL-12 and IL-23 share a common subunit IL-12/23p40 expressed in GCA at low levels [29,30]. By contrast, the IL-23p19 subunit is strongly expressed and may have an independent proinflammatory function in GCA [30,31]. Additional cytokines suggesting wider diversity of T-cell subsets (ie, IL-9, IL-22) can be detected in GCA lesions, but their role has not been characterized [32,33].

Regulatory T cells limiting immune activation are also present in vascular inflammatory lesions from patients with GCA [25]. However, in a strongly inflammatory microenvironment and, particularly, under the influence of IL-6, regulatory T cells may not be suppressive and may produce IL-17A [25]. Restoring the suppressive function of regulatory T cells may partially underlie the therapeutic effect of blocking IL-6 receptor with tocilizumab in GCA [34,35]. (See "Treatment of giant cell arteritis", section on 'Tocilizumab'.)

Potential role of B lymphocytes — B lymphocytes cooperate in T-cell activation. While B cells are reduced in peripheral blood during active disease, they are present in GCA lesions, where they occasionally form tertiary lymphoid organs [2,36,37], particularly in aortic tissue [38]. However, the functional significance of this finding is not fully understood.

SUBSEQUENT EVENTS

Amplification cascades — Following T-cell activation and differentiation, amplification cascades are crucial to the development of transmural inflammation, and macrophages are major players in this process. Interferon (IFN) gamma and granulocyte-macrophage colony-stimulating factor (GM-CSF) are markedly expressed in giant cell arteritis (GCA)-involved arteries and have a crucial role in macrophage activation and granuloma formation [24,39]. Interleukin (IL) 17A, expressed in GCA [25], is also a potent proinflammatory cytokine with pleiotropic effects on a variety of cells including macrophages, endothelial cells, vascular smooth muscle cells (VSMC), and fibroblasts. The majority of infiltrating macrophages are nonclassical (CD16+), with strong proinflammatory functions [40]. Proinflammatory macrophages produce a variety of cytokines with potent systemic and/or local effects that probably have important effects on disease manifestations and outcome. Expression of IL-1-beta, tumor necrosis factor (TNF)-alpha, IL-33, and IL-6 correlates with the intensity of the acute phase response typical of GCA [24,28,41]. These and other cytokines induce production of chemokines and expression of endothelial adhesion molecules, which are seminal in recruiting additional lymphocytes and monocytes, thus promoting vascular inflammation [39,42]. Under the influx of cytokines, VSMC also acquire a proinflammatory phenotype and actively facilitate progression of inflammatory infiltrates through the muscular layer [39].

Some of these cytokines have been considered as therapeutic targets, based on their known biologic functions and their association with disease activity. While blockade of TNF-alpha with infliximab or adalimumab was not clinically beneficial [43,44], blocking the IL-6 receptor with tocilizumab has been demonstrated to reduce relapses and reduce the dose of glucocorticoids required for disease control [45]. A phase II trial has demonstrated that blocking GM-CSF receptor-alpha with mavrilimumab prolongs glucocorticoid-induced remission and reduces relapse rate [46]. These results support an important role for IL-6 and for GM-CSF receptor signaling in sustaining inflammatory activity. Since a complex network of additional cytokines may be involved, blocking converging downstream signaling molecules, such as Janus kinases (JAK) may be an effective treatment approach, as suggested by an experimental model and small trial [47,48]. (See "Treatment of giant cell arteritis", section on 'Tocilizumab' and "Treatment of giant cell arteritis", section on 'Unproven or ineffective agents'.)

Angiogenic factors, such as vascular endothelial growth factor (VEGF), fibroblast growth factors (FGFs), and platelet-derived growth factors (PDGFs), mainly produced by macrophages, induce neovascularization and amplify vascular inflammation by providing new entries through which additional leukocytes will invade the vessel wall and supply the metabolic demands of the inflammatory process [42,49]. VEGF induces jagged 1 expression by endothelial cells from vasa vasorum and may trigger notch-dependent T lymphocyte differentiation [50]. Interestingly, in the context of vascular inflammation, angiogenesis may have a compensatory role preventing ischemia, and a strong angiogenic response is associated with reduced neuro-ophthalmic ischemic complications [49,51].

Vascular injury — The medial layer of inflamed arteries is invaded by inflammatory cells, resulting in a substantial loss of VSMC. The mechanisms for VSMC damage have not been investigated in depth. Cytotoxic CD8+ lymphocytes are present in the infiltrates and may induce VSMC apoptosis [52]. Macrophages produce reactive oxygen species leading to oxidative damage and may also contribute to vessel wall injury [53].

Expression of matrix metalloproteases MMP9 and MMP2, which have elastinolytic activity, is increased in GCA lesions, whereas their natural inhibitors TIMP1 and TIMP2 are reduced. This imbalance results in increased proteolytic activity in GCA infiltrates, leading to the disruption of the internal elastic lamina, typically observed in affected arteries [54]. Extensive disruption of the elastic fibers, as observed in the aorta, may favor delayed complications, such as aortic aneurysm, which is an increasingly recognized complication of the disease [55].

Vascular remodeling and occlusion — Activated macrophages and injured VSMC produce growth factors and other products able to promote myofibroblast differentiation of VSMC. Myofibroblasts migrate towards the intimal layer and produce extracellular matrix proteins, resulting in intimal hyperplasia and arterial occlusion. Several growth factors are expressed in GCA lesions and may participate in vascular remodeling, including endothelin-1, PDGFs, transforming growth factor-beta 1 (TGF-beta 1), and neurotrophic factors [56-60]. Micro ribonucleic acids (RNAs) modulating myofibroblast differentiation, some of them regulated by PDGFs, have been recently identified in lesions [61,62]. Among growth factors expressed in lesions, endothelin-1 and PDGFs have been functionally explored [56-59]. PDGF receptor signaling blockade with imatinib mesylate results in reduced myointimal cell growth from cultured arteries [56]. A similar effect is observed with endothelin-1 receptor antagonists [58,60]. Increased circulating concentrations of endothelin-1 have been observed in patients with neuro-ophthalmic ischemic complications, suggesting a role in vascular occlusion [56]. Because expression of endothelin-1, PDGFs, and TGF-beta-1 is not substantially reduced by short-term exposure to glucocorticoids, specific targeting of vascular remodeling factors may be necessary to prevent or reduce vascular stenoses and occlusion [3,4,23,56].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vasculitis" and "Society guideline links: Giant cell arteritis and polymyalgia rheumatica".)

SUMMARY

●The pathogenesis of giant cell arteritis (GCA) is incompletely understood. GCA is an immune-mediated disease occurring in susceptible individuals, but the nature of the triggering agent(s) is unknown. (See 'Introduction' above and 'Predisposing factors' above.)

●After initial events involving both innate and adaptive immune responses, amplification cascades in multiple inflammatory pathways lead to the progression of inflammatory infiltrates through the artery wall. Vascular components actively participate in this process. (See 'Initial events' above and 'T lymphocyte functional differentiation' above and 'Amplification cascades' above.)

●Inflammation results in injury with vascular smooth muscle cell (VSMC) loss and elastic fiber breakdown, weakening the arterial muscular layer. (See 'Vascular injury' above.)

●Vascular response to inflammation leads to vascular remodeling, with resultant intimal hyperplasia and vessel occlusion. (See 'Vascular remodeling and occlusion' above.)

●The effects of targeted therapies provide proof of concept regarding the relative contribution of different pathways sustaining and promoting vascular inflammation and remodeling in GCA. (See 'Amplification cascades' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Gene G Hunder, MD, who contributed to an earlier version of this topic review.