Pathogenesis of giant-cell arteritis: how targeted therapies are influencing our understanding of the mechanisms involved

Pathogenesis of giant-cell arteritis: how targeted therapies are influencing our understanding of... Abstract GCA is a chronic granulomatous vasculitis that affects large- and medium-sized vessels. Both the innate and the adaptive immune system are thought to play an important role in the initial events of the pathogenesis of GCA. Amplification cascades are involved in the subsequent development and progression of the disease, resulting in vascular inflammation, remodelling and occlusion. The development of large-vessel vasculitis in genetically modified mice has provided some evidence regarding potential mechanisms that lead to vascular inflammation. However, the participation of specific mechanistic pathways in GCA has not been fully established because of the paucity and limitations of functional models. Treatment of GCA is evolving, and novel therapies are being incorporated into the GCA treatment landscape. In addition, to improve the management of GCA, targeted therapies are providing functional proof of concept of the relevance of particular pathogenic mechanisms in the development of GCA and in sustaining vascular inflammation. targeted therapy, biologic therapy, giant cell arteritis, pathogenesis, treatment, inflammation, angiogenesis, vascular remodelling Rheumatology key messages Understanding of GCA pathogenesis stems mainly from histopathological/immunopathological/molecular features of temporal artery biopsies. Several animal models can develop large-vessel inflammation, but additional studies are needed to elucidate whether mechanistic pathways involved actually participate in GCA. Effects of targeted therapies in GCA offer insight into pathways involved in disease pathogenesis. Introduction GCA is a chronic granulomatous vasculitis with a tropism for large- and medium-sized vessels, particularly the carotid and vertebral arteries [1, 2]. Epidemiological studies report an estimated annual GCA incidence ranging from 1.1 to 32.8 cases per 100 000 individuals aged ⩾50 years; incidence varies according to geographic location [3, 4]. However, GCA patients with disease restricted to the large vessels may not have been identified in these studies because of the absence of systematic, cross-sectional imaging modalities. As a result, these epidemiological figures are likely to underestimate the true incidence of GCA. Histological examination of temporal artery biopsy (TAB) can often be used to identify GCA [5] (Figs 1 and 2), given the common involvement of the superficial temporal artery and its ease of access [6, 7]. Although imaging methods are important tools and are widely used for the diagnosis of GCA, abnormal TAB findings provide the best diagnostic specificity [8], and TAB samples may also provide a valuable source of tissue for investigating the pathogenesis of GCA. To date, our understanding of GCA pathogenesis is largely based on immunopathological and molecular studies performed with TAB samples. However, the majority of these studies are observational in nature, and conclusions are based mainly on the previously known functions of the molecules identified and their correlation with clinical or histological abnormalities. Functional studies evaluating mechanistic pathways in GCA are scarce. Fig. 1 View largeDownload slide Histopathological changes induced by GCA in temporal arteries (A) Normal temporal artery biopsy with clearly defined layers (I: intima; M: media; Ad: adventitia) and a preserved internal elastic lamina (arrowheads). (B) Temporal artery biopsy from a patient with giant cell arteritis highlighting the presence of typical transmural mononuclear infiltration (arrows) with disappearance of the organized medial layer and internal elastic lamina, along with prominent intimal hyperplasia (IH). Arrowheads point to some of the numerous giant-cells. Fig. 1 View largeDownload slide Histopathological changes induced by GCA in temporal arteries (A) Normal temporal artery biopsy with clearly defined layers (I: intima; M: media; Ad: adventitia) and a preserved internal elastic lamina (arrowheads). (B) Temporal artery biopsy from a patient with giant cell arteritis highlighting the presence of typical transmural mononuclear infiltration (arrows) with disappearance of the organized medial layer and internal elastic lamina, along with prominent intimal hyperplasia (IH). Arrowheads point to some of the numerous giant-cells. Fig. 2 View largeDownload slide Neovessel formation in giant-cell arteritis lesions Immunofluorescence staining of endothelial cells using an Alexa Fluor 488-conjugated mouse anti-human CD31 mAb (ImmunoTools) (yellow). Nuclei are stained with 4′,6-diamidino-2-phenylindole (blue). A: adventitia; I: intima; L: lumen; M: media. Fig. 2 View largeDownload slide Neovessel formation in giant-cell arteritis lesions Immunofluorescence staining of endothelial cells using an Alexa Fluor 488-conjugated mouse anti-human CD31 mAb (ImmunoTools) (yellow). Nuclei are stained with 4′,6-diamidino-2-phenylindole (blue). A: adventitia; I: intima; L: lumen; M: media. Advances in the treatment of GCA include testing of new targeted therapies. In addition to broadening the therapeutic armamentarium for this disease, the efficacy or inefficacy of novel therapies provides important functional proof of concept for the specific pathways involved in sustaining vascular inflammation in GCA. Current understanding of GCA pathogenesis Predisposing factors Epidemiological studies report differences in the incidence of GCA among ethnic groups, a higher risk in the ageing population (⩾50 years of age) and a female predominance; this suggests that GCA pathogenesis is driven by multiple factors, including genetic substrate, sex and alterations of the immune and arterial systems related to ageing [4, 9]. However, the role of age and sex in the development of GCA remains elusive. A genetic component in the pathogenesis of GCA is supported by observations of sporadic family clustering of affected members, along with the predominance of the disease in whites, particularly those from northern Europe or of northern European descent [10, 11]. Indeed, an increased risk of GCA is associated with polymorphisms in a variety of genes that mediate immune, inflammatory and vascular responses [11, 12]. Candidate gene studies have shown an association between GCA and genetic variants in the MHC region, particularly with class II HLA-DRB1*04 alleles (usually DRB1*0401, but also DRB1*0404) [11, 13]. Recently, large-scale fine mapping of genes related to immune responses confirmed a strong association between variants in the class II MHC region and GCA susceptibility [14]. The amino acids resulting from these risk variants are located in the antigen-binding cavity of HLA molecules. This finding suggests that GCA may be an antigen-driven disease, supporting the role of the adaptive immune system in development of the disease. A recent genome-wide association study has also revealed that, outside the MHC region, variants in genes related to vascular response to inflammation and remodelling, such as plasminogen and prolyl 4-hydroxylase subunit alpha 2, are also associated with GCA risk [15]. Initial events of GCA The initial triggering agent(s) in GCA has not been consistently identified. Several pathogens have been proposed as aetiological agents in GCA, but no definitive causal relationship with a particular microorganism or viral agent has been demonstrated [16, 17], and none of the pathogenic sequences detected in temporal arteries have been unequivocally associated with GCA [18]. However, these pathogenic sequences may play a role in the activation of pathogen sensing receptors given that innate immune mechanisms may also contribute to GCA [19]. Role of the innate immune system Cells of the innate immune system appear to play a role in the pathogenesis of GCA (Fig. 3A). Dendritic cells have been detected in normal or early inflamed large and medium-sized arteries [20–23] and may play an important role in the pathogenesis of GCA. The maturation of dendritic cells from a non-stimulatory to a T cell activating state in the arterial adventitia is thought to be a critical event in the initiation of GCA [22]. Dendritic cells can be activated via toll-like receptors, resulting in the production of chemokines (e.g. CCL19 and CCL21) that attract and retain additional dendritic cells [22, 23]. In addition, dendritic cells express activation (CD83) and co-stimulatory (CD86) molecules that are responsible for the activation of T cells [21, 22], which in turn are modulated by immune checkpoints. In GCA, inefficiency of the programmed death 1 (PD-1) receptor/programmed death ligand 1 (PD-L1) immune checkpoint has been observed in GCA-affected temporal arteries; this is thought to contribute to the excessive infiltration of activated T cells into affected medium- and large-sized blood vessels [24]. Fig. 3 View largeDownload slide Pathogenic mechanisms involved in vascular inflammation and remodelling in GCA Schematic representation of immunopathogenic mechanisms involved in inflammation and vascular remodelling in GCA. (A) Activation of dendritic cells and recruitment, activation and differentiation of CD4+ T cells and CD8+ T cells. (B) Recruitment and activation of monocytes and differentiation into macrophages. (C) Amplification of the inflammatory response. (D) Vascular remodelling and vascular occlusion. CXCL: chemokine (C-X-C motif) ligand; ICAM-1: intercellular adhesion molecule 1; VCAM-1: vascular cell adhesion molecule 1. Fig. 3 View largeDownload slide Pathogenic mechanisms involved in vascular inflammation and remodelling in GCA Schematic representation of immunopathogenic mechanisms involved in inflammation and vascular remodelling in GCA. (A) Activation of dendritic cells and recruitment, activation and differentiation of CD4+ T cells and CD8+ T cells. (B) Recruitment and activation of monocytes and differentiation into macrophages. (C) Amplification of the inflammatory response. (D) Vascular remodelling and vascular occlusion. CXCL: chemokine (C-X-C motif) ligand; ICAM-1: intercellular adhesion molecule 1; VCAM-1: vascular cell adhesion molecule 1. Role of the adaptive immune system Involvement of the adaptive immune system appears to be critical to the initial development of vascular inflammation in GCA-involved vessels (Fig. 3A). Observed oligoclonal T cell expansion in GCA lesions supports the participation of antigen-specific adaptive immune responses in GCA [25]. Pathogenic pathways mediated by both IFN-γ-producing Th1 and IL-17-producing Th17 cells are thought to play a role in the pathogenesis of GCA, contributing to systemic and vascular manifestations of the disease (Fig. 3A and B) [26]. Consistent with the relevant role of T cells in GCA, DNA methylation analysis of the temporal artery microenvironment in GCA has revealed that genes related to T cell activation and Th1/Th17 differentiation were hypomethylated in GCA lesions [27]. Increased production of the pro-inflammatory cytokine IFN-γ has been shown in GCA-involved arteries [28, 29], resulting in the expression of IFN-γ-induced products in lesions, including class II MHC antigens [30], endothelial adhesion molecules [31], inducible nitric oxide synthase [32] and chemokines [29, 33, 34]. IFN-γ is a potent activator of macrophages, the predominant cell population in GCA lesions, and is thought to drive the granulomatous reaction and transformation of macrophages to giant cells in these lesions [30]. More recent studies also suggest the involvement of Th17-mediated mechanisms in the development of GCA [35, 36]. Th17 cells produce the pro-inflammatory cytokine IL-17A, which has pleiotropic effects on a variety of cells, including macrophages, neutrophils, endothelial cells and fibroblasts, and actively contributes to inflammatory cascades [37]. Th1 and Th17 precursor cells (CD161+ CD4+ T lymphocytes) have been identified in the inflammatory infiltrates of TAB specimens from patients with GCA [38], and pro-inflammatory cytokines that promote Th17 differentiation have been observed in patients with GCA, including IL-1β, IL-21, TGF-β and IL-6 (Fig. 3C) [25, 32, 39, 40]. IL-12/23p40 and IL-23p19 subunits are expressed in GCA lesions [35], and the resulting cytokine, IL-23, is pivotal in maintaining Th17 differentiation. As a result, IL-17A expression is increased in GCA lesions [36]. These elevated levels of IL-17A are rapidly reduced in biopsies obtained from patients with GCA following treatment with glucocorticoids [36], suggesting that IL-17A suppression may contribute to the dramatic symptomatic improvement in patients with GCA who receive high-dose glucocorticoid therapy. Interestingly, strong expression of IL-17A in the involved arteries of patients with GCA was associated with a better response to glucocorticoid therapy with few relapses [36]. Regulatory T cells, which limit activation of the immune system and the accompanying inflammatory response, are also present in vascular lesions and are decreased in peripheral blood of patients with GCA [36, 38]. Given the well-recognized plasticity of T cell subsets, regulatory T cells may transiently lose their suppressive state and may themselves produce IL-17A in a strongly inflammatory microenvironment with abundant production of cytokines (e.g. GCA lesions) [36]. These abnormalities are reversed in peripheral blood regulatory T cells in patients with GCA treated with the anti-IL-6 receptor mAb, tocilizumab, highlighting the role of IL-6 in promoting a pro-inflammatory phenotype in regulatory T cells [41]. Although B cells are not abundant, their presence in GCA lesions has been observed [20, 42, 43], sometimes forming tertiary lymphoid structures [44]. While GCA has been primarily considered a T cell-mediated disease, it is important to note that B lymphocytes play a crucial role in T cell activation. In patients with active GCA, circulating levels of B cells are decreased, but recover following glucocorticoid treatment and are thought to be recruited into inflamed vessels [42]. In addition, IL-6 production by B cells is enhanced and B cell-activating factor is associated with disease activity in GCA [42, 45]. Additional evidence supporting the involvement of B cells in GCA includes scattered reports of therapeutic benefit following B cell depletion therapy with rituximab in relapsing patients [46, 47]. However, further clinical research to confirm the benefit of B cell-targeted therapy in GCA is currently lacking. Amplification cascades Following the initiating events of GCA, amplification cascades play an important role in the development and progression of inflammatory infiltrates, the development of full-blown transmural inflammation, vascular wall injury and remodelling, the pathological substrate of clinical symptoms and complications of GCA [5, 19, 20, 29, 30, 32]. Macrophages play an important role in this process. Both pro-inflammatory (M1-like) and reparative (M2-like) macrophages are abundant in GCA vascular lesions, and appear to promote neovascularization and several mechanisms of arterial wall damage (e.g. reactive oxygen species, matrix metalloproteinase (MMP)-2 production; Fig. 3D) [32, 39, 48–50]. The production of cytokines by pro-inflammatory macrophages has prominent local and systemic effects, with a potential impact on disease manifestations and outcome in GCA. The intensity of the systemic inflammatory response in GCA correlates with expression of TNF-α, IL-1β, IL-6 and IL-33 (Fig. 3C) [39, 48]. Moreover, circulating TNF-α and IL-6, along with tissue expression of TNF-α, have been shown to correlate with relapses and disease persistence [39]. Inflammatory loops associated with GCA may be further reinforced by the upregulation of chemokines, endothelial adhesion molecules and colony-stimulating factors in lesions, resulting in the continuous recruitment and expansion of additional inflammatory cells [28, 29, 31, 33]. The formation of new vessels in vascular lesions of GCA (Fig. 2) may be promoted by macrophage production of angiogenic factors, such as VEGF, fibroblast growth factor-2 and PDGFs (Fig. 3D) [30, 49, 51]. Acute phase proteins, typically increased in patients with GCA, may also be angiogenic [52, 53]. The expression of endothelial adhesion molecules by neovessels facilitates the recruitment of additional leucocytes [30, 31, 54]. While angiogenesis is an important process in the progression and maintenance of chronic inflammatory diseases, such as GCA, inflammation-induced angiogenic activity may also play a compensatory role for ischaemia at distal sites in patients with GCA, thus protecting against ischaemic complications [55, 56]. The role of inflammation in arterial damage Damage of GCA-involved arteries may in part be related to the presence of cytotoxic lymphocytes in advanced lesions, which might contribute to the depletion of vascular smooth muscle cells (VSMCs) [57]. Oxidative damage and vessel wall injury may also arise as a result of reactive oxygen species produced by activated macrophages [32]. The destructive role of proteases in inflamed arteries is evidenced by upregulation of MMPs, MMP-9 and MMP-2, which have elastinolytic activity and are up-regulated in GCA lesions, whereas their natural inhibitors, tissue inhibitor of metalloproteinases (TIMP)-1 and -2, are down-regulated, yielding an increase in proteolytic balance [32, 50]. Indeed, increased MMP-9/MMP-2 proteolytic activity has been observed in GCA lesions and may contribute to the disruption of elastic fibres and abnormal vascular remodelling [50, 58] (Fig. 3D). Furthermore, the disruption of elastic fibres may favour aortic dilatation, which is an increasingly recognized and delayed complication of GCA [58–61]. Vascular remodelling and occlusion Patients with GCA may experience symptoms of vascular insufficiency and ischaemic complications due to vascular remodelling through intimal hyperplasia and vessel occlusion (Fig. 1B). Activated macrophages or injured VSMCs produce growth factors that trigger a vascular remodelling process leading to myofibroblast differentiation of VSMCs, migration towards the intimal layer and deposition of extracellular matrix proteins. Several of these factors are expressed in GCA lesions, including PDGFs, TGF-β and ET-1 (Fig. 3D); these factors may contribute to vascular remodelling by inducing myofibroblast activation and the production of matrix proteins [25, 62–64]. Indeed, blockade of the PDGF receptor by imatinib mesylate or blocking ET-1 receptors results in reduced myointimal cell outgrowth from cultured temporal arteries of patients with GCA [49, 51, 64]. Circulating concentrations of ET-1 are elevated in patients with GCA who have neuro-ophthalmic ischaemic complications, highlighting their potential role in vasospasm or vascular occlusion [63]. The participation of neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor, in the generation of intimal hyperplasia has been proposed given that they are expressed in GCA lesions and promote the proliferation and migration of VSMCs [65]. A number of microRNAs that regulate the functions of VSMCs are up-regulated in GCA lesions, further supporting their involvement in the generation of intimal hyperplasia [66]. Unfortunately, these vascular remodelling factors do not appear to be substantially down-regulated in GCA lesions following glucocorticoid therapy, suggesting that modulation of their potential impact in vessel stenosis and occlusion may require specific therapeutic approaches in large-vessel vasculitis [29, 35]. Functional models Several animal models of large-vessel inflammation have been generated and provide important clues about triggers and mechanisms potentially involved in vascular inflammation. IFN-γ-deficient mice infected with murine herpesvirus HV68 develop necrotizing large-vessel vasculitis [67, 68], suggesting that herpesvirus members can induce vascular inflammation. On the other hand, this evidence underlines the protective role of IFN-γ in maintaining virus latency and possibly in avoiding excessive vascular destruction [67, 68]. A mouse model of large-vessel arteritis demonstrated that mice deficient in the gene encoding the anti-inflammatory cytokine IL-1 receptor antagonist developed lethal arterial inflammation, thus suggesting a role of the IL-1 receptor antagonist in protecting the vessel wall from inflammatory stimuli [69]. Mice deficient in interferon regulatory factor 4 binding protein have increased expression of IL-21 and IL-17A, along with subsequent development of large-vessel vasculitis, which supports the hypothesis that IL-17 is involved in vascular inflammation [70]. Taken together, these models demonstrate that these molecules and their downstream pathways are relevant to vascular inflammation, but do not completely recapitulate the clinical, anatomical and histopathological features of GCA. Subcutaneous engraftment of GCA-involved temporal artery fragments into mice with severe combined immunodeficiency has been used for functional studies. In this model, T cell depletion with T cell-specific antibodies reduced T cell-dependent cytokines [71], dendritic cell depletion reduced inflammation in the explant [22] and depletion of tissue-infiltrating macrophages resulted in the production of reactive oxygen species [72]. Blockade of PD-1 has also been shown to exacerbate adoptively transferred vascular inflammation in engrafted normal arteries. Infiltrates are enriched in PD-1+ T cells, with enhanced production of multiple cytokines, including IFN-γ, IL-17 and IL-2, in vascular tissue [24]. Temporal artery culture in 3D matrix has been recently introduced to investigate pathogenic pathways. In this model, it has been shown that glucocorticoids decrease production of inflammatory cytokines but do not influence factors involved in vascular remodelling [29]. The induction of a pro-inflammatory phenotype in VSMCs by IFN-γ and their active role in recruiting monocytes has been demonstrated in this model [34]. Blocking PDGF receptor signalling with imatinib or endothelin-1 signalling with receptor antagonists has been shown to reduce myointimal cell outgrowth [51, 64]. These models have provided interesting insight into some relevant mechanisms of vascular inflammation and remodelling. However, they only examine target tissue isolated from a functional immune system to investigate the pathogenesis of vascular inflammation. Moreover, these models only allow assessment of changes in biomarkers given that clinically relevant disease outcomes such as pain, systemic symptoms, ischaemic complications and aortic dilatation cannot be investigated. Targeted therapies shed light on the pathogenic mechanisms of GCA Even if unsuccessful, research and development of novel targeted therapies provide unique information regarding the participation or irrelevance of specific pathways in disease pathogenesis. For example, investigation of immune checkpoints for cancer immunotherapy has provided interesting lessons. GCA has developed in some patients with malignant melanoma after blocking cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) with ipilimumab [73, 74], underlining the relevance of T cells and the immunological synapsis in triggering immune activation leading to GCA. Accordingly, abatacept, a recombinant Ig-CTLA-4 molecule, has demonstrated efficacy in maintaining remission in a recent randomized controlled trial [75]. Therapeutic interventions according to pathogenic mechanisms are summarized in Table 1. Table 1 Potential points of intervention according to pathogenic pathways in GCA Pathway  Potential pathological effect  Potential intervention  Potential drugs  Investigation status  Results  Dendritic cell activation  Attracts and retains additional dendritic cells and activates T cells  Blocking TLR receptors  NC  NP  Unknown  T cell activation (Th1 and Th17 cells)  Highly activated T cells, modulated by immune checkpoints, promote excessive infiltration of activated T cells into affected medium- and large-sized blood vessels [21–24]  Interfering with CD28-mediated activation  CTLA-4-Ig (Abatacept)  Phase 2 RCT (NCT00556439)  Positive [75]  B cell differentiation, B cell co-stimulatory signals or other B cell functions  Forms tertiary lymphoid structures [42, 44] and activates T cells  B cell depletion  Rituximab and others  Few case reports  Very low evidence [46, 87, 88]  Blocking BAFF/BLyS  NC  NP  Unknown  Blocking IL-6 receptor  Tocilizumab  Phase 2 (NCT01450137) and 3 (NCT01791153) RCT  Positive [85, 86]  Ongoing, open-label phase 4 (NCT03244709)  Not yet available  Blocking IL-6  Sirukumab  Ongoing phase 3 RCT (NCT02531633)  Not yet available  Th1 differentiation/effector pathways  Production of IFN-γ and IL-17 promoting systemic and vascular inflammation [26] Drives granulomatous reaction and transformation of macrophages to giant cells [30] Contributes to systemic and vascular manifestations of GCA [26]  Blocking IL-12  NC  NP  Unknown  Blocking IFN-γ  NC  NP  Unknown  Blocking TNF  Infliximab  Phase 2 RCT (NCT00076726)  Negative [77]  Etanercept  Phase 2 RCT  Inconclusive [78]  Adalimumab  Phase 2 RCT (NCT00305539)  Negative [79]  Th17 differentiation/effector pathways  Induces chronic inflammation and activates dendritic cells, endothelial cells and smooth muscle cells involved in arterial tissue damage [37, 38]  Blocking IL-6 receptor  Tocilizumab  Phase 2 (NCT01450137) and 3 (NCT01791153) RCT  Positive [85, 86]  Ongoing phase 4 (NCT03244709)  Not yet available  Open-label phase 2  Positive [87]  Blocking IL-6  Sirukumab  Ongoing phase 3 RCT (NCT02531633)  Not yet available  Blocking IL-23  NC  NP  Unknown  Blocking IL-1β  IL-1RA (anakinra)  Ongoing phase 3 RCT (NCT02902731)  Not yet available  Blocking IL-17  Secukinumab  RCT considered  Unknown  Both Th1 and Th17 differentiation pathways  Interaction between Th1 and Th17 pathways involved in promoting systemic and vascular inflammation [26]  Blocking IL-12/23p40  Ustekinumab  Open-label observational  Positive [89] (low evidence)  Ongoing phase 1/2 (NCT02955147)  Not yet available  Blocking IL-21  NC  NP  Unknown  Blocking JAK1 and JAK2  Baricitinib  Ongoing phase 2 RCT (NCT03026504)  Not yet available  Treg function  Usually Tregs have suppressive functions but, under the effects of IL-6, they become pro-inflammatory and contribute to systemic and vascular manifestations of GCA [36]  Blocking IL-6 receptor  Tocilizumab  Phase 2 (NCT01450137) and 3 (NCT01791153) RCT  Positive [85, 86]  Ongoing phase 4 (NCT03244709)  Not yet available  Open-label phase 2  Positive [87]  Blocking IL-6  Sirukumab  Ongoing phase 3 RCT (NCT02531633)  Not yet available  Macrophage survival/activation  Oxidative damage and vessel wall injury [30, 32] Contributes to systemic and vascular manifestations of GCA [26] Angiogenesis [49] May contribute to the disruption of elastic fibres and abnormal vascular remodelling [50] Progression and maintenance of inflammation [26, 30]  Blocking IFN-γ  NC  NP  Unknown  Blocking TNF  Infliximab  Phase 2 RCT (NCT00076726)  Negative [77]  Etanercept  Phase 2 RCT  Inconclusive [78]  Adalimumab  Phase 2 RCT (NCT00305539)  Negative [79]  Blocking CSF-1/CSF-1R  Unknown  RCT considered  Unknown  Blocking IL-6 receptor  Tocilizumab  Phase 2 (NCT01450137) and 3 (NCT01791153) RCT  Positive [85, 86]  Ongoing phase 4 (NCT03244709)  Not yet available  Open-label phase 2  Positive [87]  Blocking IL-6  Sirukumab  Ongoing phase 3 RCT (NCT02531633)  Not yet available  Tissue disruption  Production of matrix proteins [62]  Matrix metalloproteinase inhibitors  NC  NP  Unknown  ROS scavengers  NC  NP  Unknown  Abnormal vascular remodelling  Promotion of myo-intima proliferation and migration and ECM production leading to hyperplasia and vessel occlusion [30, 51, 62–64]  Endothelin receptor antagonists  NC  NP  Unknown  PDGF receptor blockade  NC  NP  Unknown  Anti-fibrotic agents  NC  NP  Unknown  Pathway  Potential pathological effect  Potential intervention  Potential drugs  Investigation status  Results  Dendritic cell activation  Attracts and retains additional dendritic cells and activates T cells  Blocking TLR receptors  NC  NP  Unknown  T cell activation (Th1 and Th17 cells)  Highly activated T cells, modulated by immune checkpoints, promote excessive infiltration of activated T cells into affected medium- and large-sized blood vessels [21–24]  Interfering with CD28-mediated activation  CTLA-4-Ig (Abatacept)  Phase 2 RCT (NCT00556439)  Positive [75]  B cell differentiation, B cell co-stimulatory signals or other B cell functions  Forms tertiary lymphoid structures [42, 44] and activates T cells  B cell depletion  Rituximab and others  Few case reports  Very low evidence [46, 87, 88]  Blocking BAFF/BLyS  NC  NP  Unknown  Blocking IL-6 receptor  Tocilizumab  Phase 2 (NCT01450137) and 3 (NCT01791153) RCT  Positive [85, 86]  Ongoing, open-label phase 4 (NCT03244709)  Not yet available  Blocking IL-6  Sirukumab  Ongoing phase 3 RCT (NCT02531633)  Not yet available  Th1 differentiation/effector pathways  Production of IFN-γ and IL-17 promoting systemic and vascular inflammation [26] Drives granulomatous reaction and transformation of macrophages to giant cells [30] Contributes to systemic and vascular manifestations of GCA [26]  Blocking IL-12  NC  NP  Unknown  Blocking IFN-γ  NC  NP  Unknown  Blocking TNF  Infliximab  Phase 2 RCT (NCT00076726)  Negative [77]  Etanercept  Phase 2 RCT  Inconclusive [78]  Adalimumab  Phase 2 RCT (NCT00305539)  Negative [79]  Th17 differentiation/effector pathways  Induces chronic inflammation and activates dendritic cells, endothelial cells and smooth muscle cells involved in arterial tissue damage [37, 38]  Blocking IL-6 receptor  Tocilizumab  Phase 2 (NCT01450137) and 3 (NCT01791153) RCT  Positive [85, 86]  Ongoing phase 4 (NCT03244709)  Not yet available  Open-label phase 2  Positive [87]  Blocking IL-6  Sirukumab  Ongoing phase 3 RCT (NCT02531633)  Not yet available  Blocking IL-23  NC  NP  Unknown  Blocking IL-1β  IL-1RA (anakinra)  Ongoing phase 3 RCT (NCT02902731)  Not yet available  Blocking IL-17  Secukinumab  RCT considered  Unknown  Both Th1 and Th17 differentiation pathways  Interaction between Th1 and Th17 pathways involved in promoting systemic and vascular inflammation [26]  Blocking IL-12/23p40  Ustekinumab  Open-label observational  Positive [89] (low evidence)  Ongoing phase 1/2 (NCT02955147)  Not yet available  Blocking IL-21  NC  NP  Unknown  Blocking JAK1 and JAK2  Baricitinib  Ongoing phase 2 RCT (NCT03026504)  Not yet available  Treg function  Usually Tregs have suppressive functions but, under the effects of IL-6, they become pro-inflammatory and contribute to systemic and vascular manifestations of GCA [36]  Blocking IL-6 receptor  Tocilizumab  Phase 2 (NCT01450137) and 3 (NCT01791153) RCT  Positive [85, 86]  Ongoing phase 4 (NCT03244709)  Not yet available  Open-label phase 2  Positive [87]  Blocking IL-6  Sirukumab  Ongoing phase 3 RCT (NCT02531633)  Not yet available  Macrophage survival/activation  Oxidative damage and vessel wall injury [30, 32] Contributes to systemic and vascular manifestations of GCA [26] Angiogenesis [49] May contribute to the disruption of elastic fibres and abnormal vascular remodelling [50] Progression and maintenance of inflammation [26, 30]  Blocking IFN-γ  NC  NP  Unknown  Blocking TNF  Infliximab  Phase 2 RCT (NCT00076726)  Negative [77]  Etanercept  Phase 2 RCT  Inconclusive [78]  Adalimumab  Phase 2 RCT (NCT00305539)  Negative [79]  Blocking CSF-1/CSF-1R  Unknown  RCT considered  Unknown  Blocking IL-6 receptor  Tocilizumab  Phase 2 (NCT01450137) and 3 (NCT01791153) RCT  Positive [85, 86]  Ongoing phase 4 (NCT03244709)  Not yet available  Open-label phase 2  Positive [87]  Blocking IL-6  Sirukumab  Ongoing phase 3 RCT (NCT02531633)  Not yet available  Tissue disruption  Production of matrix proteins [62]  Matrix metalloproteinase inhibitors  NC  NP  Unknown  ROS scavengers  NC  NP  Unknown  Abnormal vascular remodelling  Promotion of myo-intima proliferation and migration and ECM production leading to hyperplasia and vessel occlusion [30, 51, 62–64]  Endothelin receptor antagonists  NC  NP  Unknown  PDGF receptor blockade  NC  NP  Unknown  Anti-fibrotic agents  NC  NP  Unknown  BAFF/BLyS: B cell activating factor/B lymphocyte stimulator; CD28: cluster of differentiation 28; CSF-1: colony-stimulating factor 1; CTLA-4: cytotoxic T-lymphocyte-associated antigen 4; ECM: extracellular matrix; IL-1RA: IL-1 receptor antagonist; JAK: janus kinase; NC: not currently under consideration; NP: not performed; PDGFs: platelet-derived growth factors; RCT: randomized controlled trial; ROS: reactive oxygen species; TLR: toll-like receptor. TNF-α is a potent, multifunctional, pro-inflammatory cytokine that promotes infiltration of leucocytes via the production of chemokines, the induction of adhesion molecule expression (E-selectin, intercellular adhesion molecule 1 and vascular adhesion molecule 1), and the production of MMPs [76]. The gene encoding TNF-α is hypomethylated in GCA lesions where it is highly expressed, and the association between increased expression of TNF-α and persistent disease activity has been observed in various studies [39], along with the benefit obtained with TNF blockade in other chronic inflammatory or granulomatous diseases. This evidence provided the rationale for conducting clinical trials to investigate TNF inhibition with infliximab, etanercept or adalimumab in GCA. Unfortunately, TNF-α blockade did not provide an advantage over placebo in maintaining remission in newly diagnosed patients [76–79]. The disappointing experience with TNF-α blockade underlines the fact that a biomarker of inflammation is not necessarily a therapeutic target and suggests that TNF-α functions may not be essential for the maintenance of vascular inflammation, or can be supplied by redundant pathways. IL-6 is a multifunctional cytokine secreted by numerous immune cells (e.g. macrophages, neutrophils, dendritic cells) and exerts pleiotropic effects on a variety of cell types [80]. The effects of IL-6 on the immune system include the activation of macrophages and neutrophils, differentiation of Th17 cells, inhibition of the suppressive activity of regulatory T cells, promotion and differentiation of B cells and stimulation of endothelial cells [80]. Furthermore, IL-6 is thought to play an important role in the switch from acute to chronic inflammation [80]. IL-6 transcripts are abundant in GCA lesions but are also present in normal temporal arteries, indicating a potential role in vascular homeostasis [29, 39]. IL-6 expression in lesions is also significantly higher in patients with GCA with a strong systemic inflammatory reaction [39]. Serum IL-6 is elevated in patients with GCA and correlates with disease activity [45, 81–83]. Moreover, persistently increased serum IL-6 is found in patients with relapsing disease [84]. Recently, IL-6 receptor blockade with tocilizumab was shown to be superior to placebo in maintaining remission and sparing glucocorticoids in phases 2 and 3 clinical trials, both in newly diagnosed and relapsing patients [85, 86]. These trials indicate that IL-6-dependent inflammatory pathways are highly relevant in maintaining inflammatory activity in GCA. Short-term clinical outcomes seem to be clearly improved by tocilizumab. Tocilizumab strongly inhibits the systemic inflammatory response, which is an important burden in patients with GCA, as well as cranial and polymyalgic clinical symptoms. However, the impact of tocilizumab on vascular inflammation and vascular remodelling, along with their associated vascular complications, needs to be evaluated; this will provide unique insights into pathogenic mechanisms of vascular inflammation and repair. Conclusions To date, our understanding of GCA pathogenesis is largely based on evidence from histopathological characteristics, the identification of cell populations and subpopulations in affected vessels or peripheral blood, the expression of activation and differentiation markers by these cells and the production of certain inflammatory molecules in GCA lesions. The role that infiltrating cells and their products play in the development of GCA is primarily based on the assumption of their known biologic functions and correlation with relevant histopathological features (e.g. neovascularization, intimal hyperplasia, giant-cell formation), clinical phenotypes or disease outcomes [19, 30]. Several animal models of large-vessel inflammation have provided evidence regarding potential mechanisms involved in vascular inflammation. However, the pathogenesis of GCA remains incompletely understood because of the scarcity of functional studies demonstrating the involvement of specific pathways. The recent introduction of targeted therapies into the treatment landscape for GCA may shed light on the participation of specific pathways in pathogenesis of the disease. In particular, research surrounding immune checkpoint inhibition and cytokine blockade (TNF-α and IL-6) has provided important insights into the roles that the immune system and vascular inflammation play in the development of GCA. Future research into current and novel targeted agents is needed to expand our knowledge regarding specific disease pathways involved in GCA-associated vascular inflammation and repair. Acknowledgements The authors thank Ester Planas-Rigol, PhD, Marc Corbera-Bellalta, PhD, Georgina Espígol Frigolé, MD, Sergio Prieto-González, MD, and José Hernández-Rodríguez, MD, of the Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), and Maxime Samson, MD, PhD, of University of Barcelona, Dijon University Hospital and University of Bourgogne Franche-Comté for their contributions to this manuscript. Editorial assistance in the preparation of this manuscript was provided by Maxwell Chang, of ApotheCom Associates (Yardley, PA). Support for this assistance was funded by F Hoffmann-La Roche Ltd, Basel, Switzerland. N.T.-G. and M.C.C. were funded by Ministerio de Economía, Industria y Competitividad (SAF 2014-57708-R and SAF 2017-88275-R). Supplement: This supplement was funded by F. Hoffmann-La Roche Ltd. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: M.C.C. has received consultation fees from Hoffman-La Roche and GlaxoSmithKline. The other author has declared no conflicts of interest. References 1 Salvarani C, Pipitone N, Versari A, Hunder GG. Clinical features of polymyalgia rheumatica and giant cell arteritis. Nat Rev Rheumatol  2012; 8: 509– 21. Google Scholar CrossRef Search ADS PubMed  2 Jennette JC, Falk RJ, Bacon PA et al.   2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum  2013; 65: 1– 11. Google Scholar CrossRef Search ADS PubMed  3 Lee JL, Naguwa SM, Cheema GS, Gershwin ME. The geo-epidemiology of temporal (giant cell) arteritis. Clin Rev Allergy Immunol  2008; 35: 88– 95. Google Scholar CrossRef Search ADS PubMed  4 Gonzalez-Gay MA, Martinez-Dubois C, Agudo M et al.   Giant cell arteritis: epidemiology, diagnosis, and management. Curr Respir Med Rev  2010; 12: 436– 42. 5 Hernandez-Rodriguez J, Murgia G, Villar I et al.   Description and validation of histological patterns and proposal of a dynamic model of inflammatory infiltration in giant-cell arteritis. Medicine  2016; 95: e2368. Google Scholar CrossRef Search ADS PubMed  6 Hall S, Persellin S, Lie JT et al.   The therapeutic impact of temporal artery biopsy. Lancet  1983; 2: 1217– 20. Google Scholar CrossRef Search ADS PubMed  7 Gonzalez-Gay MA. The diagnosis and management of patients with giant cell arteritis. J Rheumatol  2005; 32: 1186– 8. Google Scholar PubMed  8 Luqmani R, Lee E, Singh S et al.   The Role of Ultrasound Compared to Biopsy of Temporal Arteries in the Diagnosis and Treatment of Giant Cell Arteritis (TABUL): a diagnostic accuracy and cost-effectiveness study. Health Technol Assess  2016; 20: 1– 238. Google Scholar CrossRef Search ADS PubMed  9 Nordborg E, Nordborg C. Giant cell arteritis: epidemiological clues to its pathogenesis and an update on its treatment. Rheumatology  2003; 42: 413– 21. Google Scholar CrossRef Search ADS PubMed  10 Liozon E, Ouattara B, Rhaiem K et al.   Familial aggregation in giant cell arteritis and polymyalgia rheumatica: a comprehensive literature review including 4 new families. Clin Exp Rheumatol  2009; 27(1 Suppl 52): S89– 94. 11 Carmona FD, Gonzalez-Gay MA, Martin J. Genetic component of giant cell arteritis. Rheumatology  2014; 53: 6– 18. Google Scholar CrossRef Search ADS PubMed  12 Enjuanes A, Benavente Y, Hernandez-Rodriguez J et al.   Association of NOS2 and potential effect of VEGF, IL6, CCL2 and IL1RN polymorphisms and haplotypes on susceptibility to GCA—a simultaneous study of 130 potentially functional SNPs in 14 candidate genes. Rheumatology  2012; 51: 841– 51. Google Scholar CrossRef Search ADS PubMed  13 Cid MC, Ercilla G, Vilaseca J et al.   Polymyalgia rheumatica: a syndrome associated with HLA-DR4 antigen. Arthritis Rheum  1988; 31: 678– 82. Google Scholar CrossRef Search ADS PubMed  14 Carmona FD, Mackie SL, Martin JE et al.   A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility. Am J Hum Genet  2015; 96: 565– 80. Google Scholar CrossRef Search ADS PubMed  15 Carmona FD, Vaglio A, Mackie SL et al.   A genome-wide association study identifies risk alleles in plasminogen and P4HA2 associated with giant cell arteritis. Am J Hum Genet  2017; 100: 64– 74. Google Scholar CrossRef Search ADS PubMed  16 van Timmeren MM, Heeringa P, Kallenberg CG. Infectious triggers for vasculitis. Curr Opin Rheumatol  2014; 26: 416– 23. Google Scholar CrossRef Search ADS PubMed  17 Nagel MA, White T, Khmeleva N et al.   Analysis of varicella-zoster virus in temporal arteries biopsy positive and negative for giant cell arteritis. JAMA Neurol  2015; 72: 1281– 7. Google Scholar CrossRef Search ADS PubMed  18 Bhatt AS, Manzo VE, Pedamallu CS et al.   In search of a candidate pathogen for giant cell arteritis: sequencing-based characterization of the giant cell arteritis microbiome. Arthritis Rheumatol  2014; 66: 1939– 44. Google Scholar CrossRef Search ADS PubMed  19 Weyand CM, Goronzy JJ. Immune mechanisms in medium and large-vessel vasculitis. Nat Rev Rheumatol  2013; 9: 731– 40. Google Scholar CrossRef Search ADS PubMed  20 Cid MC, Campo E, Ercilla G et al.   Immunohistochemical analysis of lymphoid and macrophage cell subsets and their immunologic activation markers in temporal arteritis. Influence of corticosteroid treatment. Arthritis Rheum  1989; 32: 884– 93. Google Scholar PubMed  21 Krupa WM, Dewan M, Jeon MS et al.   Trapping of misdirected dendritic cells in the granulomatous lesions of giant cell arteritis. Am J Pathol  2002; 161: 1815– 23. Google Scholar CrossRef Search ADS PubMed  22 Ma-Krupa W, Jeon MS, Spoerl S et al.   Activation of arterial wall dendritic cells and breakdown of self-tolerance in giant cell arteritis. J Exp Med  2004; 199: 173– 83. Google Scholar CrossRef Search ADS PubMed  23 Cid MC, Grau JM, Casademont J et al.   Immunohistochemical characterization of inflammatory cells and immunologic activation markers in muscle and nerve biopsy specimens from patients with systemic polyarteritis nodosa. Arthritis Rheum  1994; 37: 1055– 61. Google Scholar CrossRef Search ADS PubMed  24 Zhang H, Watanabe R, Berry GJ et al.   Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis. Proc Natl Acad Sci U S A  2017; 114: E970– 9. Google Scholar CrossRef Search ADS PubMed  25 Weyand CM, Schonberger J, Oppitz U et al.   Distinct vascular lesions in giant cell arteritis share identical T cell clonotypes. J Exp Med  1994; 179: 951– 60. Google Scholar CrossRef Search ADS PubMed  26 Deng J, Younge BR, Olshen RA, Goronzy JJ, Weyand CM. Th17 and Th1 T-cell responses in giant cell arteritis. Circulation  2010; 121: 906– 15. Google Scholar CrossRef Search ADS PubMed  27 Coit P, De Lott LB, Nan B, Elner VM, Sawalha AH. DNA methylation analysis of the temporal artery microenvironment in giant cell arteritis. Ann Rheum Dis  2016; 75: 1196– 202. Google Scholar CrossRef Search ADS PubMed  28 Weyand CM, Hicok KC, Hunder GG, Goronzy JJ. Tissue cytokine patterns in patients with polymyalgia rheumatica and giant cell arteritis. Ann Intern Med  1994; 121: 484– 91. Google Scholar CrossRef Search ADS PubMed  29 Corbera-Bellalta M, Garcia-Martinez A, Lozano E et al.   Changes in biomarkers after therapeutic intervention in temporal arteries cultured in Matrigel: a new model for preclinical studies in giant-cell arteritis. Ann Rheum Dis  2014; 73: 616– 23. Google Scholar CrossRef Search ADS PubMed  30 Cid MC, Font C, Coll-Vinent B, Grau JM. Large vessel vasculitides. Curr Opin Rheumatol  1998; 10: 18– 28. Google Scholar CrossRef Search ADS PubMed  31 Cid MC, Cebrian M, Font C et al.   Cell adhesion molecules in the development of inflammatory infiltrates in giant cell arteritis: inflammation-induced angiogenesis as the preferential site of leukocyte-endothelial cell interactions. Arthritis Rheum  2000; 43: 184– 94. Google Scholar CrossRef Search ADS PubMed  32 Rittner HL, Kaiser M, Brack A et al.   Tissue-destructive macrophages in giant cell arteritis. Circ Res  1999; 84: 1050– 8. Google Scholar CrossRef Search ADS PubMed  33 Cid MC, Hoffman MP, Hernandez RJ et al.   Association between increased CCL2 (MCP-1) expression in lesions and persistence of disease activity in giant-cell arteritis. Rheumatology  2006; 45: 1356– 63. Google Scholar CrossRef Search ADS PubMed  34 Corbera-Bellalta M, Planas-Rigol E, Lozano E et al.   Blocking interferon gamma reduces expression of chemokines CXCL9, CXCL10 and CXCL11 and decreases macrophage infiltration in ex vivo cultured arteries from patients with giant cell arteritis. Ann Rheum Dis  2016; 75: 1177– 86. Google Scholar CrossRef Search ADS PubMed  35 Visvanathan S, Rahman MU, Hoffman GS et al.   Tissue and serum markers of inflammation during the follow-up of patients with giant-cell arteritis—a prospective longitudinal study. Rheumatology  2011; 50: 2061– 70. Google Scholar CrossRef Search ADS PubMed  36 Espigol-Frigole G, Corbera-Bellalta M, Planas-Rigol E et al.   Increased IL-17A expression in temporal artery lesions is a predictor of sustained response to glucocorticoid treatment in patients with giant-cell arteritis. Ann Rheum Dis  2013; 72: 1481– 7. Google Scholar CrossRef Search ADS PubMed  37 Miossec P, Kolls JK. Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov  2012; 11: 763– 76. Google Scholar CrossRef Search ADS PubMed  38 Samson M, Audia S, Fraszczak J et al.   Th1 and Th17 lymphocytes expressing CD161 are implicated in giant cell arteritis and polymyalgia rheumatica pathogenesis. Arthritis Rheum  2012; 64: 3788– 98. Google Scholar CrossRef Search ADS PubMed  39 Hernandez-Rodriguez J, Segarra M, Vilardell C et al.   Tissue production of pro-inflammatory cytokines (IL-1beta, TNFalpha and IL-6) correlates with the intensity of the systemic inflammatory response and with corticosteroid requirements in giant-cell arteritis. Rheumatology  2004; 43: 294– 301. Google Scholar CrossRef Search ADS PubMed  40 Terrier B, Geri G, Chaara W et al.   Interleukin-21 modulates Th1 and Th17 responses in giant cell arteritis. Arthritis Rheum  2012; 64: 2001– 11. Google Scholar CrossRef Search ADS PubMed  41 Miyabe C, Miyabe Y, Strle K et al.   An expanded population of pathogenic regulatory T cells in giant cell arteritis is abrogated by IL-6 blockade therapy. Ann Rheum Dis  2017; 76: 898– 905. Google Scholar CrossRef Search ADS PubMed  42 van der Geest KS, Abdulahad WH, Chalan P et al.   Disturbed B cell homeostasis in newly diagnosed giant cell arteritis and polymyalgia rheumatica. Arthritis Rheumatol  2014; 66: 1927– 38. Google Scholar CrossRef Search ADS PubMed  43 Alba MA, Prieto-Gonzalez S, Hernandez-Rodriguez J, Cid MC. B lymphocytes may play a significant role in large-vessel vasculitis. Future Med  2012; 7: 475– 7. 44 Ciccia F, Rizzo A, Maugeri R et al.   Ectopic expression of CXCL13, BAFF, APRIL and LT-beta is associated with artery tertiary lymphoid organs in giant cell arteritis. Ann Rheum Dis  2017; 76: 235– 43. Google Scholar CrossRef Search ADS PubMed  45 van der Geest KS, Abdulahad WH, Rutgers A et al.   Serum markers associated with disease activity in giant cell arteritis and polymyalgia rheumatica. Rheumatology  2015; 54: 1397– 402. Google Scholar CrossRef Search ADS PubMed  46 Bhatia A, Ell PJ, Edwards JC. Anti-CD20 monoclonal antibody (rituximab) as an adjunct in the treatment of giant cell arteritis. Ann Rheum Dis  2005; 64: 1099– 100. Google Scholar CrossRef Search ADS PubMed  47 Alba MA, Espigol-Frigole G, Butjosa M et al.   Treatment of large cell vacsulitis. Curr Immunol Rev  2011; 7: 435– 42. Google Scholar CrossRef Search ADS   48 Ciccia F, Alessandro R, Rizzo A et al.   IL-33 is overexpressed in the inflamed arteries of patients with giant cell arteritis. Ann Rheum Dis  2013; 72: 258– 64. Google Scholar CrossRef Search ADS PubMed  49 Kaiser M, Younge B, Bjornsson J, Goronzy JJ, Weyand CM. Formation of new vasa vasorum in vasculitis. Production of angiogenic cytokines by multinucleated giant cells. Am J Pathol  1999; 155: 765– 74. Google Scholar CrossRef Search ADS PubMed  50 Segarra M, Garcia-Martinez A, Sanchez M et al.   Gelatinase expression and proteolytic activity in giant-cell arteritis. Ann Rheum Dis  2007; 66: 1429– 35. Google Scholar CrossRef Search ADS PubMed  51 Lozano E, Segarra M, Garcia-Martinez A, Hernandez-Rodriguez J, Cid MC. Imatinib mesylate inhibits in vitro and ex vivo biological responses related to vascular occlusion in giant cell arteritis. Ann Rheum Dis  2008; 67: 1581– 8. Google Scholar CrossRef Search ADS PubMed  52 Cid MC, Grant DS, Hoffman GS et al.   Identification of haptoglobin as an angiogenic factor in sera from patients with systemic vasculitis. J Clin Invest  1993; 91: 977– 85. Google Scholar CrossRef Search ADS PubMed  53 O'Neill L, Rooney P, Molloy D et al.   Regulation of inflammation and angiogenesis in giant cell arteritis by acute-phase serum amyloid A. Arthritis Rheumatol  2015; 67: 2447– 56. Google Scholar CrossRef Search ADS PubMed  54 Foell D, Hernandez-Rodriguez J, Sanchez M et al.   Early recruitment of phagocytes contributes to the vascular inflammation of giant cell arteritis. J Pathol  2004; 204: 311– 6. Google Scholar CrossRef Search ADS PubMed  55 Cid MC, Hernandez-Rodriguez J, Esteban MJ et al.   Tissue and serum angiogenic activity is associated with low prevalence of ischemic complications in patients with giant-cell arteritis. Circulation  2002; 106: 1664– 71. Google Scholar CrossRef Search ADS PubMed  56 Hernandez-Rodriguez J, Segarra M, Vilardell C et al.   Elevated production of interleukin-6 is associated with a lower incidence of disease-related ischemic events in patients with giant-cell arteritis: angiogenic activity of interleukin-6 as a potential protective mechanism. Circulation  2003; 107: 2428– 34. Google Scholar CrossRef Search ADS PubMed  57 Samson M, Ly KH, Tournier B et al.   Involvement and prognosis value of CD8+ T cells in giant cell arteritis. J Autoimmun  2016; 72: 73– 83. Google Scholar CrossRef Search ADS PubMed  58 Garcia-Martinez A, Hernandez-Rodriguez J, Arguis P et al.   Development of aortic aneurysm/dilatation during the followup of patients with giant cell arteritis: a cross-sectional screening of fifty-four prospectively followed patients. Arthritis Rheum  2008; 59: 422– 30. Google Scholar CrossRef Search ADS PubMed  59 Kermani TA, Warrington KJ, Crowson CS et al.   Large-vessel involvement in giant cell arteritis: a population-based cohort study of the incidence-trends and prognosis. Ann Rheum Dis  2013; 72: 1989– 94. Google Scholar CrossRef Search ADS PubMed  60 Garcia-Martinez A, Arguis P, Prieto-Gonzalez S et al.   Prospective long term follow-up of a cohort of patients with giant cell arteritis screened for aortic structural damage (aneurysm or dilatation). Ann Rheum Dis  2014; 73: 1826– 32. Google Scholar CrossRef Search ADS PubMed  61 Robson JC, Kiran A, Maskell J et al.   The relative risk of aortic aneurysm in patients with giant cell arteritis compared with the general population of the UK. Ann Rheum Dis  2015; 74: 129– 35. Google Scholar CrossRef Search ADS PubMed  62 Kaiser M, Weyand CM, Bjornsson J, Goronzy JJ. Platelet-derived growth factor, intimal hyperplasia, and ischemic complications in giant cell arteritis. Arthritis Rheum  1998; 41: 623– 33. Google Scholar CrossRef Search ADS PubMed  63 Lozano E, Segarra M, Corbera-Bellalta M et al.   Increased expression of the endothelin system in arterial lesions from patients with giant-cell arteritis: association between elevated plasma endothelin levels and the development of ischaemic events. Ann Rheum Dis  2010; 69: 434– 42. Google Scholar CrossRef Search ADS PubMed  64 Planas-Rigol E, Terrades-Garcia N, Corbera-Bellalta M et al.   Endothelin-1 promotes vascular smooth muscle cell migration across the artery wall: a mechanism contributing to vascular remodelling and intimal hyperplasia in giant-cell arteritis. Ann Rheum Dis  2017; 76: 1624– 34. Google Scholar CrossRef Search ADS PubMed  65 Ly KH, Regent A, Molina E et al.   Neurotrophins are expressed in giant cell arteritis lesions and may contribute to vascular remodeling. Arthritis Res Ther  2014; 16: 487. Google Scholar CrossRef Search ADS PubMed  66 Croci S, Zerbini A, Boiardi L et al.   MicroRNA markers of inflammation and remodelling in temporal arteries from patients with giant cell arteritis. Ann Rheum Dis  2016; 75: 1527– 33. Google Scholar CrossRef Search ADS PubMed  67 Dal Canto AJ, Virgin HW, Speck SH. Ongoing viral replication is required for gammaherpesvirus 68-induced vascular damage. J Virol  2000; 74: 11304– 10. Google Scholar CrossRef Search ADS PubMed  68 Dal Canto AJ, Swanson PE, O'Guin AK, Speck SH, Virgin HW. IFN-gamma action in the media of the great elastic arteries, a novel immunoprivileged site. J Clin Invest  2001; 107: R15– 22. Google Scholar CrossRef Search ADS PubMed  69 Nicklin MJ, Hughes DE, Barton JL, Ure JM, Duff GW. Arterial inflammation in mice lacking the interleukin 1 receptor antagonist gene. J Exp Med  2000; 191: 303– 12. Google Scholar CrossRef Search ADS PubMed  70 Chen Q, Yang W, Gupta S et al.   IRF-4-binding protein inhibits interleukin-17 and interleukin-21 production by controlling the activity of IRF-4 transcription factor. Immunity  2008; 29: 899– 911. Google Scholar CrossRef Search ADS PubMed  71 Brack A, Geisler A, Martinez-Taboada VM et al.   Giant cell vasculitis is a T cell-dependent disease. Mol Med  1997; 3: 530– 43. Google Scholar PubMed  72 Borkowski A, Younge BR, Szweda L et al.   Reactive nitrogen intermediates in giant cell arteritis: selective nitration of neocapillaries. Am J Pathol  2002; 161: 115– 23. Google Scholar CrossRef Search ADS PubMed  73 Goldstein BL, Gedmintas L, Todd DJ. Drug-associated polymyalgia rheumatica/giant cell arteritis occurring in two patients after treatment with ipilimumab, an antagonist of CTLA-4. Arthritis Rheumatol  2014; 66: 768– 9. Google Scholar CrossRef Search ADS PubMed  74 Hodi FS, Lawrence D, Lezcano C et al.   Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res  2014; 2: 632– 42. Google Scholar CrossRef Search ADS PubMed  75 Langford CA, Cuthbertson D, Ytterberg SR et al.   A randomized, double-blind trial of abatacept (CTLA-4Ig) for the treatment of giant cell arteritis. Arthritis Rheumatol  2017; 69: 846– 53. Google Scholar CrossRef Search ADS PubMed  76 Jarrot PA, Kaplanski G. Anti-TNF-alpha therapy and systemic vasculitis. Mediators Inflamm  2014; 2014: 493593. Google Scholar CrossRef Search ADS PubMed  77 Hoffman GS, Cid MC, Rendt-Zagar KE et al.   Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis: a randomized trial. Ann Intern Med  2007; 146: 621– 30. Google Scholar CrossRef Search ADS PubMed  78 Martinez-Taboada VM, Rodriguez-Valverde V, Carreno L et al.   A double-blind placebo controlled trial of etanercept in patients with giant cell arteritis and corticosteroid side effects. Ann Rheum Dis  2008; 67: 625– 30. Google Scholar CrossRef Search ADS PubMed  79 Seror R, Baron G, Hachulla E et al.   Adalimumab for steroid sparing in patients with giant-cell arteritis: results of a multicentre randomised controlled trial. Ann Rheum Dis  2014; 73: 2074– 81. Google Scholar CrossRef Search ADS PubMed  80 Roberts J, Clifford A. Update on the management of giant cell arteritis. Ther Adv Chronic Dis  2017; 8: 69– 79. Google Scholar CrossRef Search ADS PubMed  81 Roche NE, Fulbright JW, Wagner AD et al.   Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis. Arthritis Rheum  1993; 36: 1286– 94. Google Scholar CrossRef Search ADS PubMed  82 Dasgupta B, Panayi GS. Interleukin-6 in serum of patients with polymyalgia rheumatica and giant cell arteritis. Br J Rheumatol  1990; 29: 456– 8. Google Scholar CrossRef Search ADS PubMed  83 Weyand CM, Fulbright JW, Hunder GG, Evans JM, Goronzy JJ. Treatment of giant cell arteritis: interleukin-6 as a biologic marker of disease activity. Arthritis Rheum  2000; 43: 1041– 8. Google Scholar CrossRef Search ADS PubMed  84 Garcia-Martinez A, Hernandez-Rodriguez J, Espigol-Frigole G et al.   Clinical relevance of persistently elevated circulating cytokines (tumor necrosis factor alpha and interleukin-6) in the long-term followup of patients with giant cell arteritis. Arthritis Care Res  2010; 62: 835– 41. Google Scholar CrossRef Search ADS   85 Villiger PM, Adler S, Kuchen S et al.   Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet  2016; 387: 1921– 7. Google Scholar CrossRef Search ADS PubMed  86 Stone JH, Tuckwell K, Dimonaco S et al.   Trial of tocilizumab in giant-cell arteritis. N Engl J Med  2017; 377: 317– 28. Google Scholar CrossRef Search ADS PubMed  87 Samson M, Devilliers H, Heang K et al.   Tocilizumab as an add-on therapy to glucocorticoids during the first 3 months of treatment of giant cell arteritis: results of a French multicenter prospective open-label study [abstract]. Arthritis Rheumatol  2016; 68(Suppl 10): 977. 88 Mayrbaeurl B, Hinterreiter M, Burgstaller S, Windpessl M, Thaler J. The first case of a patient with neutropenia and giant-cell arteritis treated with rituximab. Clin Rheumatol  2007; 26: 1597– 8. Google Scholar CrossRef Search ADS PubMed  89 Conway R, O'Neill L, O'Flynn E et al.   Ustekinumab for the treatment of refractory giant cell arteritis. Ann Rheum Dis  2016; 75: 1578– 9. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. 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Pathogenesis of giant-cell arteritis: how targeted therapies are influencing our understanding of the mechanisms involved

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Abstract

Abstract GCA is a chronic granulomatous vasculitis that affects large- and medium-sized vessels. Both the innate and the adaptive immune system are thought to play an important role in the initial events of the pathogenesis of GCA. Amplification cascades are involved in the subsequent development and progression of the disease, resulting in vascular inflammation, remodelling and occlusion. The development of large-vessel vasculitis in genetically modified mice has provided some evidence regarding potential mechanisms that lead to vascular inflammation. However, the participation of specific mechanistic pathways in GCA has not been fully established because of the paucity and limitations of functional models. Treatment of GCA is evolving, and novel therapies are being incorporated into the GCA treatment landscape. In addition, to improve the management of GCA, targeted therapies are providing functional proof of concept of the relevance of particular pathogenic mechanisms in the development of GCA and in sustaining vascular inflammation. targeted therapy, biologic therapy, giant cell arteritis, pathogenesis, treatment, inflammation, angiogenesis, vascular remodelling Rheumatology key messages Understanding of GCA pathogenesis stems mainly from histopathological/immunopathological/molecular features of temporal artery biopsies. Several animal models can develop large-vessel inflammation, but additional studies are needed to elucidate whether mechanistic pathways involved actually participate in GCA. Effects of targeted therapies in GCA offer insight into pathways involved in disease pathogenesis. Introduction GCA is a chronic granulomatous vasculitis with a tropism for large- and medium-sized vessels, particularly the carotid and vertebral arteries [1, 2]. Epidemiological studies report an estimated annual GCA incidence ranging from 1.1 to 32.8 cases per 100 000 individuals aged ⩾50 years; incidence varies according to geographic location [3, 4]. However, GCA patients with disease restricted to the large vessels may not have been identified in these studies because of the absence of systematic, cross-sectional imaging modalities. As a result, these epidemiological figures are likely to underestimate the true incidence of GCA. Histological examination of temporal artery biopsy (TAB) can often be used to identify GCA [5] (Figs 1 and 2), given the common involvement of the superficial temporal artery and its ease of access [6, 7]. Although imaging methods are important tools and are widely used for the diagnosis of GCA, abnormal TAB findings provide the best diagnostic specificity [8], and TAB samples may also provide a valuable source of tissue for investigating the pathogenesis of GCA. To date, our understanding of GCA pathogenesis is largely based on immunopathological and molecular studies performed with TAB samples. However, the majority of these studies are observational in nature, and conclusions are based mainly on the previously known functions of the molecules identified and their correlation with clinical or histological abnormalities. Functional studies evaluating mechanistic pathways in GCA are scarce. Fig. 1 View largeDownload slide Histopathological changes induced by GCA in temporal arteries (A) Normal temporal artery biopsy with clearly defined layers (I: intima; M: media; Ad: adventitia) and a preserved internal elastic lamina (arrowheads). (B) Temporal artery biopsy from a patient with giant cell arteritis highlighting the presence of typical transmural mononuclear infiltration (arrows) with disappearance of the organized medial layer and internal elastic lamina, along with prominent intimal hyperplasia (IH). Arrowheads point to some of the numerous giant-cells. Fig. 1 View largeDownload slide Histopathological changes induced by GCA in temporal arteries (A) Normal temporal artery biopsy with clearly defined layers (I: intima; M: media; Ad: adventitia) and a preserved internal elastic lamina (arrowheads). (B) Temporal artery biopsy from a patient with giant cell arteritis highlighting the presence of typical transmural mononuclear infiltration (arrows) with disappearance of the organized medial layer and internal elastic lamina, along with prominent intimal hyperplasia (IH). Arrowheads point to some of the numerous giant-cells. Fig. 2 View largeDownload slide Neovessel formation in giant-cell arteritis lesions Immunofluorescence staining of endothelial cells using an Alexa Fluor 488-conjugated mouse anti-human CD31 mAb (ImmunoTools) (yellow). Nuclei are stained with 4′,6-diamidino-2-phenylindole (blue). A: adventitia; I: intima; L: lumen; M: media. Fig. 2 View largeDownload slide Neovessel formation in giant-cell arteritis lesions Immunofluorescence staining of endothelial cells using an Alexa Fluor 488-conjugated mouse anti-human CD31 mAb (ImmunoTools) (yellow). Nuclei are stained with 4′,6-diamidino-2-phenylindole (blue). A: adventitia; I: intima; L: lumen; M: media. Advances in the treatment of GCA include testing of new targeted therapies. In addition to broadening the therapeutic armamentarium for this disease, the efficacy or inefficacy of novel therapies provides important functional proof of concept for the specific pathways involved in sustaining vascular inflammation in GCA. Current understanding of GCA pathogenesis Predisposing factors Epidemiological studies report differences in the incidence of GCA among ethnic groups, a higher risk in the ageing population (⩾50 years of age) and a female predominance; this suggests that GCA pathogenesis is driven by multiple factors, including genetic substrate, sex and alterations of the immune and arterial systems related to ageing [4, 9]. However, the role of age and sex in the development of GCA remains elusive. A genetic component in the pathogenesis of GCA is supported by observations of sporadic family clustering of affected members, along with the predominance of the disease in whites, particularly those from northern Europe or of northern European descent [10, 11]. Indeed, an increased risk of GCA is associated with polymorphisms in a variety of genes that mediate immune, inflammatory and vascular responses [11, 12]. Candidate gene studies have shown an association between GCA and genetic variants in the MHC region, particularly with class II HLA-DRB1*04 alleles (usually DRB1*0401, but also DRB1*0404) [11, 13]. Recently, large-scale fine mapping of genes related to immune responses confirmed a strong association between variants in the class II MHC region and GCA susceptibility [14]. The amino acids resulting from these risk variants are located in the antigen-binding cavity of HLA molecules. This finding suggests that GCA may be an antigen-driven disease, supporting the role of the adaptive immune system in development of the disease. A recent genome-wide association study has also revealed that, outside the MHC region, variants in genes related to vascular response to inflammation and remodelling, such as plasminogen and prolyl 4-hydroxylase subunit alpha 2, are also associated with GCA risk [15]. Initial events of GCA The initial triggering agent(s) in GCA has not been consistently identified. Several pathogens have been proposed as aetiological agents in GCA, but no definitive causal relationship with a particular microorganism or viral agent has been demonstrated [16, 17], and none of the pathogenic sequences detected in temporal arteries have been unequivocally associated with GCA [18]. However, these pathogenic sequences may play a role in the activation of pathogen sensing receptors given that innate immune mechanisms may also contribute to GCA [19]. Role of the innate immune system Cells of the innate immune system appear to play a role in the pathogenesis of GCA (Fig. 3A). Dendritic cells have been detected in normal or early inflamed large and medium-sized arteries [20–23] and may play an important role in the pathogenesis of GCA. The maturation of dendritic cells from a non-stimulatory to a T cell activating state in the arterial adventitia is thought to be a critical event in the initiation of GCA [22]. Dendritic cells can be activated via toll-like receptors, resulting in the production of chemokines (e.g. CCL19 and CCL21) that attract and retain additional dendritic cells [22, 23]. In addition, dendritic cells express activation (CD83) and co-stimulatory (CD86) molecules that are responsible for the activation of T cells [21, 22], which in turn are modulated by immune checkpoints. In GCA, inefficiency of the programmed death 1 (PD-1) receptor/programmed death ligand 1 (PD-L1) immune checkpoint has been observed in GCA-affected temporal arteries; this is thought to contribute to the excessive infiltration of activated T cells into affected medium- and large-sized blood vessels [24]. Fig. 3 View largeDownload slide Pathogenic mechanisms involved in vascular inflammation and remodelling in GCA Schematic representation of immunopathogenic mechanisms involved in inflammation and vascular remodelling in GCA. (A) Activation of dendritic cells and recruitment, activation and differentiation of CD4+ T cells and CD8+ T cells. (B) Recruitment and activation of monocytes and differentiation into macrophages. (C) Amplification of the inflammatory response. (D) Vascular remodelling and vascular occlusion. CXCL: chemokine (C-X-C motif) ligand; ICAM-1: intercellular adhesion molecule 1; VCAM-1: vascular cell adhesion molecule 1. Fig. 3 View largeDownload slide Pathogenic mechanisms involved in vascular inflammation and remodelling in GCA Schematic representation of immunopathogenic mechanisms involved in inflammation and vascular remodelling in GCA. (A) Activation of dendritic cells and recruitment, activation and differentiation of CD4+ T cells and CD8+ T cells. (B) Recruitment and activation of monocytes and differentiation into macrophages. (C) Amplification of the inflammatory response. (D) Vascular remodelling and vascular occlusion. CXCL: chemokine (C-X-C motif) ligand; ICAM-1: intercellular adhesion molecule 1; VCAM-1: vascular cell adhesion molecule 1. Role of the adaptive immune system Involvement of the adaptive immune system appears to be critical to the initial development of vascular inflammation in GCA-involved vessels (Fig. 3A). Observed oligoclonal T cell expansion in GCA lesions supports the participation of antigen-specific adaptive immune responses in GCA [25]. Pathogenic pathways mediated by both IFN-γ-producing Th1 and IL-17-producing Th17 cells are thought to play a role in the pathogenesis of GCA, contributing to systemic and vascular manifestations of the disease (Fig. 3A and B) [26]. Consistent with the relevant role of T cells in GCA, DNA methylation analysis of the temporal artery microenvironment in GCA has revealed that genes related to T cell activation and Th1/Th17 differentiation were hypomethylated in GCA lesions [27]. Increased production of the pro-inflammatory cytokine IFN-γ has been shown in GCA-involved arteries [28, 29], resulting in the expression of IFN-γ-induced products in lesions, including class II MHC antigens [30], endothelial adhesion molecules [31], inducible nitric oxide synthase [32] and chemokines [29, 33, 34]. IFN-γ is a potent activator of macrophages, the predominant cell population in GCA lesions, and is thought to drive the granulomatous reaction and transformation of macrophages to giant cells in these lesions [30]. More recent studies also suggest the involvement of Th17-mediated mechanisms in the development of GCA [35, 36]. Th17 cells produce the pro-inflammatory cytokine IL-17A, which has pleiotropic effects on a variety of cells, including macrophages, neutrophils, endothelial cells and fibroblasts, and actively contributes to inflammatory cascades [37]. Th1 and Th17 precursor cells (CD161+ CD4+ T lymphocytes) have been identified in the inflammatory infiltrates of TAB specimens from patients with GCA [38], and pro-inflammatory cytokines that promote Th17 differentiation have been observed in patients with GCA, including IL-1β, IL-21, TGF-β and IL-6 (Fig. 3C) [25, 32, 39, 40]. IL-12/23p40 and IL-23p19 subunits are expressed in GCA lesions [35], and the resulting cytokine, IL-23, is pivotal in maintaining Th17 differentiation. As a result, IL-17A expression is increased in GCA lesions [36]. These elevated levels of IL-17A are rapidly reduced in biopsies obtained from patients with GCA following treatment with glucocorticoids [36], suggesting that IL-17A suppression may contribute to the dramatic symptomatic improvement in patients with GCA who receive high-dose glucocorticoid therapy. Interestingly, strong expression of IL-17A in the involved arteries of patients with GCA was associated with a better response to glucocorticoid therapy with few relapses [36]. Regulatory T cells, which limit activation of the immune system and the accompanying inflammatory response, are also present in vascular lesions and are decreased in peripheral blood of patients with GCA [36, 38]. Given the well-recognized plasticity of T cell subsets, regulatory T cells may transiently lose their suppressive state and may themselves produce IL-17A in a strongly inflammatory microenvironment with abundant production of cytokines (e.g. GCA lesions) [36]. These abnormalities are reversed in peripheral blood regulatory T cells in patients with GCA treated with the anti-IL-6 receptor mAb, tocilizumab, highlighting the role of IL-6 in promoting a pro-inflammatory phenotype in regulatory T cells [41]. Although B cells are not abundant, their presence in GCA lesions has been observed [20, 42, 43], sometimes forming tertiary lymphoid structures [44]. While GCA has been primarily considered a T cell-mediated disease, it is important to note that B lymphocytes play a crucial role in T cell activation. In patients with active GCA, circulating levels of B cells are decreased, but recover following glucocorticoid treatment and are thought to be recruited into inflamed vessels [42]. In addition, IL-6 production by B cells is enhanced and B cell-activating factor is associated with disease activity in GCA [42, 45]. Additional evidence supporting the involvement of B cells in GCA includes scattered reports of therapeutic benefit following B cell depletion therapy with rituximab in relapsing patients [46, 47]. However, further clinical research to confirm the benefit of B cell-targeted therapy in GCA is currently lacking. Amplification cascades Following the initiating events of GCA, amplification cascades play an important role in the development and progression of inflammatory infiltrates, the development of full-blown transmural inflammation, vascular wall injury and remodelling, the pathological substrate of clinical symptoms and complications of GCA [5, 19, 20, 29, 30, 32]. Macrophages play an important role in this process. Both pro-inflammatory (M1-like) and reparative (M2-like) macrophages are abundant in GCA vascular lesions, and appear to promote neovascularization and several mechanisms of arterial wall damage (e.g. reactive oxygen species, matrix metalloproteinase (MMP)-2 production; Fig. 3D) [32, 39, 48–50]. The production of cytokines by pro-inflammatory macrophages has prominent local and systemic effects, with a potential impact on disease manifestations and outcome in GCA. The intensity of the systemic inflammatory response in GCA correlates with expression of TNF-α, IL-1β, IL-6 and IL-33 (Fig. 3C) [39, 48]. Moreover, circulating TNF-α and IL-6, along with tissue expression of TNF-α, have been shown to correlate with relapses and disease persistence [39]. Inflammatory loops associated with GCA may be further reinforced by the upregulation of chemokines, endothelial adhesion molecules and colony-stimulating factors in lesions, resulting in the continuous recruitment and expansion of additional inflammatory cells [28, 29, 31, 33]. The formation of new vessels in vascular lesions of GCA (Fig. 2) may be promoted by macrophage production of angiogenic factors, such as VEGF, fibroblast growth factor-2 and PDGFs (Fig. 3D) [30, 49, 51]. Acute phase proteins, typically increased in patients with GCA, may also be angiogenic [52, 53]. The expression of endothelial adhesion molecules by neovessels facilitates the recruitment of additional leucocytes [30, 31, 54]. While angiogenesis is an important process in the progression and maintenance of chronic inflammatory diseases, such as GCA, inflammation-induced angiogenic activity may also play a compensatory role for ischaemia at distal sites in patients with GCA, thus protecting against ischaemic complications [55, 56]. The role of inflammation in arterial damage Damage of GCA-involved arteries may in part be related to the presence of cytotoxic lymphocytes in advanced lesions, which might contribute to the depletion of vascular smooth muscle cells (VSMCs) [57]. Oxidative damage and vessel wall injury may also arise as a result of reactive oxygen species produced by activated macrophages [32]. The destructive role of proteases in inflamed arteries is evidenced by upregulation of MMPs, MMP-9 and MMP-2, which have elastinolytic activity and are up-regulated in GCA lesions, whereas their natural inhibitors, tissue inhibitor of metalloproteinases (TIMP)-1 and -2, are down-regulated, yielding an increase in proteolytic balance [32, 50]. Indeed, increased MMP-9/MMP-2 proteolytic activity has been observed in GCA lesions and may contribute to the disruption of elastic fibres and abnormal vascular remodelling [50, 58] (Fig. 3D). Furthermore, the disruption of elastic fibres may favour aortic dilatation, which is an increasingly recognized and delayed complication of GCA [58–61]. Vascular remodelling and occlusion Patients with GCA may experience symptoms of vascular insufficiency and ischaemic complications due to vascular remodelling through intimal hyperplasia and vessel occlusion (Fig. 1B). Activated macrophages or injured VSMCs produce growth factors that trigger a vascular remodelling process leading to myofibroblast differentiation of VSMCs, migration towards the intimal layer and deposition of extracellular matrix proteins. Several of these factors are expressed in GCA lesions, including PDGFs, TGF-β and ET-1 (Fig. 3D); these factors may contribute to vascular remodelling by inducing myofibroblast activation and the production of matrix proteins [25, 62–64]. Indeed, blockade of the PDGF receptor by imatinib mesylate or blocking ET-1 receptors results in reduced myointimal cell outgrowth from cultured temporal arteries of patients with GCA [49, 51, 64]. Circulating concentrations of ET-1 are elevated in patients with GCA who have neuro-ophthalmic ischaemic complications, highlighting their potential role in vasospasm or vascular occlusion [63]. The participation of neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor, in the generation of intimal hyperplasia has been proposed given that they are expressed in GCA lesions and promote the proliferation and migration of VSMCs [65]. A number of microRNAs that regulate the functions of VSMCs are up-regulated in GCA lesions, further supporting their involvement in the generation of intimal hyperplasia [66]. Unfortunately, these vascular remodelling factors do not appear to be substantially down-regulated in GCA lesions following glucocorticoid therapy, suggesting that modulation of their potential impact in vessel stenosis and occlusion may require specific therapeutic approaches in large-vessel vasculitis [29, 35]. Functional models Several animal models of large-vessel inflammation have been generated and provide important clues about triggers and mechanisms potentially involved in vascular inflammation. IFN-γ-deficient mice infected with murine herpesvirus HV68 develop necrotizing large-vessel vasculitis [67, 68], suggesting that herpesvirus members can induce vascular inflammation. On the other hand, this evidence underlines the protective role of IFN-γ in maintaining virus latency and possibly in avoiding excessive vascular destruction [67, 68]. A mouse model of large-vessel arteritis demonstrated that mice deficient in the gene encoding the anti-inflammatory cytokine IL-1 receptor antagonist developed lethal arterial inflammation, thus suggesting a role of the IL-1 receptor antagonist in protecting the vessel wall from inflammatory stimuli [69]. Mice deficient in interferon regulatory factor 4 binding protein have increased expression of IL-21 and IL-17A, along with subsequent development of large-vessel vasculitis, which supports the hypothesis that IL-17 is involved in vascular inflammation [70]. Taken together, these models demonstrate that these molecules and their downstream pathways are relevant to vascular inflammation, but do not completely recapitulate the clinical, anatomical and histopathological features of GCA. Subcutaneous engraftment of GCA-involved temporal artery fragments into mice with severe combined immunodeficiency has been used for functional studies. In this model, T cell depletion with T cell-specific antibodies reduced T cell-dependent cytokines [71], dendritic cell depletion reduced inflammation in the explant [22] and depletion of tissue-infiltrating macrophages resulted in the production of reactive oxygen species [72]. Blockade of PD-1 has also been shown to exacerbate adoptively transferred vascular inflammation in engrafted normal arteries. Infiltrates are enriched in PD-1+ T cells, with enhanced production of multiple cytokines, including IFN-γ, IL-17 and IL-2, in vascular tissue [24]. Temporal artery culture in 3D matrix has been recently introduced to investigate pathogenic pathways. In this model, it has been shown that glucocorticoids decrease production of inflammatory cytokines but do not influence factors involved in vascular remodelling [29]. The induction of a pro-inflammatory phenotype in VSMCs by IFN-γ and their active role in recruiting monocytes has been demonstrated in this model [34]. Blocking PDGF receptor signalling with imatinib or endothelin-1 signalling with receptor antagonists has been shown to reduce myointimal cell outgrowth [51, 64]. These models have provided interesting insight into some relevant mechanisms of vascular inflammation and remodelling. However, they only examine target tissue isolated from a functional immune system to investigate the pathogenesis of vascular inflammation. Moreover, these models only allow assessment of changes in biomarkers given that clinically relevant disease outcomes such as pain, systemic symptoms, ischaemic complications and aortic dilatation cannot be investigated. Targeted therapies shed light on the pathogenic mechanisms of GCA Even if unsuccessful, research and development of novel targeted therapies provide unique information regarding the participation or irrelevance of specific pathways in disease pathogenesis. For example, investigation of immune checkpoints for cancer immunotherapy has provided interesting lessons. GCA has developed in some patients with malignant melanoma after blocking cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) with ipilimumab [73, 74], underlining the relevance of T cells and the immunological synapsis in triggering immune activation leading to GCA. Accordingly, abatacept, a recombinant Ig-CTLA-4 molecule, has demonstrated efficacy in maintaining remission in a recent randomized controlled trial [75]. Therapeutic interventions according to pathogenic mechanisms are summarized in Table 1. Table 1 Potential points of intervention according to pathogenic pathways in GCA Pathway  Potential pathological effect  Potential intervention  Potential drugs  Investigation status  Results  Dendritic cell activation  Attracts and retains additional dendritic cells and activates T cells  Blocking TLR receptors  NC  NP  Unknown  T cell activation (Th1 and Th17 cells)  Highly activated T cells, modulated by immune checkpoints, promote excessive infiltration of activated T cells into affected medium- and large-sized blood vessels [21–24]  Interfering with CD28-mediated activation  CTLA-4-Ig (Abatacept)  Phase 2 RCT (NCT00556439)  Positive [75]  B cell differentiation, B cell co-stimulatory signals or other B cell functions  Forms tertiary lymphoid structures [42, 44] and activates T cells  B cell depletion  Rituximab and others  Few case reports  Very low evidence [46, 87, 88]  Blocking BAFF/BLyS  NC  NP  Unknown  Blocking IL-6 receptor  Tocilizumab  Phase 2 (NCT01450137) and 3 (NCT01791153) RCT  Positive [85, 86]  Ongoing, open-label phase 4 (NCT03244709)  Not yet available  Blocking IL-6  Sirukumab  Ongoing phase 3 RCT (NCT02531633)  Not yet available  Th1 differentiation/effector pathways  Production of IFN-γ and IL-17 promoting systemic and vascular inflammation [26] Drives granulomatous reaction and transformation of macrophages to giant cells [30] Contributes to systemic and vascular manifestations of GCA [26]  Blocking IL-12  NC  NP  Unknown  Blocking IFN-γ  NC  NP  Unknown  Blocking TNF  Infliximab  Phase 2 RCT (NCT00076726)  Negative [77]  Etanercept  Phase 2 RCT  Inconclusive [78]  Adalimumab  Phase 2 RCT (NCT00305539)  Negative [79]  Th17 differentiation/effector pathways  Induces chronic inflammation and activates dendritic cells, endothelial cells and smooth muscle cells involved in arterial tissue damage [37, 38]  Blocking IL-6 receptor  Tocilizumab  Phase 2 (NCT01450137) and 3 (NCT01791153) RCT  Positive [85, 86]  Ongoing phase 4 (NCT03244709)  Not yet available  Open-label phase 2  Positive [87]  Blocking IL-6  Sirukumab  Ongoing phase 3 RCT (NCT02531633)  Not yet available  Blocking IL-23  NC  NP  Unknown  Blocking IL-1β  IL-1RA (anakinra)  Ongoing phase 3 RCT (NCT02902731)  Not yet available  Blocking IL-17  Secukinumab  RCT considered  Unknown  Both Th1 and Th17 differentiation pathways  Interaction between Th1 and Th17 pathways involved in promoting systemic and vascular inflammation [26]  Blocking IL-12/23p40  Ustekinumab  Open-label observational  Positive [89] (low evidence)  Ongoing phase 1/2 (NCT02955147)  Not yet available  Blocking IL-21  NC  NP  Unknown  Blocking JAK1 and JAK2  Baricitinib  Ongoing phase 2 RCT (NCT03026504)  Not yet available  Treg function  Usually Tregs have suppressive functions but, under the effects of IL-6, they become pro-inflammatory and contribute to systemic and vascular manifestations of GCA [36]  Blocking IL-6 receptor  Tocilizumab  Phase 2 (NCT01450137) and 3 (NCT01791153) RCT  Positive [85, 86]  Ongoing phase 4 (NCT03244709)  Not yet available  Open-label phase 2  Positive [87]  Blocking IL-6  Sirukumab  Ongoing phase 3 RCT (NCT02531633)  Not yet available  Macrophage survival/activation  Oxidative damage and vessel wall injury [30, 32] Contributes to systemic and vascular manifestations of GCA [26] Angiogenesis [49] May contribute to the disruption of elastic fibres and abnormal vascular remodelling [50] Progression and maintenance of inflammation [26, 30]  Blocking IFN-γ  NC  NP  Unknown  Blocking TNF  Infliximab  Phase 2 RCT (NCT00076726)  Negative [77]  Etanercept  Phase 2 RCT  Inconclusive [78]  Adalimumab  Phase 2 RCT (NCT00305539)  Negative [79]  Blocking CSF-1/CSF-1R  Unknown  RCT considered  Unknown  Blocking IL-6 receptor  Tocilizumab  Phase 2 (NCT01450137) and 3 (NCT01791153) RCT  Positive [85, 86]  Ongoing phase 4 (NCT03244709)  Not yet available  Open-label phase 2  Positive [87]  Blocking IL-6  Sirukumab  Ongoing phase 3 RCT (NCT02531633)  Not yet available  Tissue disruption  Production of matrix proteins [62]  Matrix metalloproteinase inhibitors  NC  NP  Unknown  ROS scavengers  NC  NP  Unknown  Abnormal vascular remodelling  Promotion of myo-intima proliferation and migration and ECM production leading to hyperplasia and vessel occlusion [30, 51, 62–64]  Endothelin receptor antagonists  NC  NP  Unknown  PDGF receptor blockade  NC  NP  Unknown  Anti-fibrotic agents  NC  NP  Unknown  Pathway  Potential pathological effect  Potential intervention  Potential drugs  Investigation status  Results  Dendritic cell activation  Attracts and retains additional dendritic cells and activates T cells  Blocking TLR receptors  NC  NP  Unknown  T cell activation (Th1 and Th17 cells)  Highly activated T cells, modulated by immune checkpoints, promote excessive infiltration of activated T cells into affected medium- and large-sized blood vessels [21–24]  Interfering with CD28-mediated activation  CTLA-4-Ig (Abatacept)  Phase 2 RCT (NCT00556439)  Positive [75]  B cell differentiation, B cell co-stimulatory signals or other B cell functions  Forms tertiary lymphoid structures [42, 44] and activates T cells  B cell depletion  Rituximab and others  Few case reports  Very low evidence [46, 87, 88]  Blocking BAFF/BLyS  NC  NP  Unknown  Blocking IL-6 receptor  Tocilizumab  Phase 2 (NCT01450137) and 3 (NCT01791153) RCT  Positive [85, 86]  Ongoing, open-label phase 4 (NCT03244709)  Not yet available  Blocking IL-6  Sirukumab  Ongoing phase 3 RCT (NCT02531633)  Not yet available  Th1 differentiation/effector pathways  Production of IFN-γ and IL-17 promoting systemic and vascular inflammation [26] Drives granulomatous reaction and transformation of macrophages to giant cells [30] Contributes to systemic and vascular manifestations of GCA [26]  Blocking IL-12  NC  NP  Unknown  Blocking IFN-γ  NC  NP  Unknown  Blocking TNF  Infliximab  Phase 2 RCT (NCT00076726)  Negative [77]  Etanercept  Phase 2 RCT  Inconclusive [78]  Adalimumab  Phase 2 RCT (NCT00305539)  Negative [79]  Th17 differentiation/effector pathways  Induces chronic inflammation and activates dendritic cells, endothelial cells and smooth muscle cells involved in arterial tissue damage [37, 38]  Blocking IL-6 receptor  Tocilizumab  Phase 2 (NCT01450137) and 3 (NCT01791153) RCT  Positive [85, 86]  Ongoing phase 4 (NCT03244709)  Not yet available  Open-label phase 2  Positive [87]  Blocking IL-6  Sirukumab  Ongoing phase 3 RCT (NCT02531633)  Not yet available  Blocking IL-23  NC  NP  Unknown  Blocking IL-1β  IL-1RA (anakinra)  Ongoing phase 3 RCT (NCT02902731)  Not yet available  Blocking IL-17  Secukinumab  RCT considered  Unknown  Both Th1 and Th17 differentiation pathways  Interaction between Th1 and Th17 pathways involved in promoting systemic and vascular inflammation [26]  Blocking IL-12/23p40  Ustekinumab  Open-label observational  Positive [89] (low evidence)  Ongoing phase 1/2 (NCT02955147)  Not yet available  Blocking IL-21  NC  NP  Unknown  Blocking JAK1 and JAK2  Baricitinib  Ongoing phase 2 RCT (NCT03026504)  Not yet available  Treg function  Usually Tregs have suppressive functions but, under the effects of IL-6, they become pro-inflammatory and contribute to systemic and vascular manifestations of GCA [36]  Blocking IL-6 receptor  Tocilizumab  Phase 2 (NCT01450137) and 3 (NCT01791153) RCT  Positive [85, 86]  Ongoing phase 4 (NCT03244709)  Not yet available  Open-label phase 2  Positive [87]  Blocking IL-6  Sirukumab  Ongoing phase 3 RCT (NCT02531633)  Not yet available  Macrophage survival/activation  Oxidative damage and vessel wall injury [30, 32] Contributes to systemic and vascular manifestations of GCA [26] Angiogenesis [49] May contribute to the disruption of elastic fibres and abnormal vascular remodelling [50] Progression and maintenance of inflammation [26, 30]  Blocking IFN-γ  NC  NP  Unknown  Blocking TNF  Infliximab  Phase 2 RCT (NCT00076726)  Negative [77]  Etanercept  Phase 2 RCT  Inconclusive [78]  Adalimumab  Phase 2 RCT (NCT00305539)  Negative [79]  Blocking CSF-1/CSF-1R  Unknown  RCT considered  Unknown  Blocking IL-6 receptor  Tocilizumab  Phase 2 (NCT01450137) and 3 (NCT01791153) RCT  Positive [85, 86]  Ongoing phase 4 (NCT03244709)  Not yet available  Open-label phase 2  Positive [87]  Blocking IL-6  Sirukumab  Ongoing phase 3 RCT (NCT02531633)  Not yet available  Tissue disruption  Production of matrix proteins [62]  Matrix metalloproteinase inhibitors  NC  NP  Unknown  ROS scavengers  NC  NP  Unknown  Abnormal vascular remodelling  Promotion of myo-intima proliferation and migration and ECM production leading to hyperplasia and vessel occlusion [30, 51, 62–64]  Endothelin receptor antagonists  NC  NP  Unknown  PDGF receptor blockade  NC  NP  Unknown  Anti-fibrotic agents  NC  NP  Unknown  BAFF/BLyS: B cell activating factor/B lymphocyte stimulator; CD28: cluster of differentiation 28; CSF-1: colony-stimulating factor 1; CTLA-4: cytotoxic T-lymphocyte-associated antigen 4; ECM: extracellular matrix; IL-1RA: IL-1 receptor antagonist; JAK: janus kinase; NC: not currently under consideration; NP: not performed; PDGFs: platelet-derived growth factors; RCT: randomized controlled trial; ROS: reactive oxygen species; TLR: toll-like receptor. TNF-α is a potent, multifunctional, pro-inflammatory cytokine that promotes infiltration of leucocytes via the production of chemokines, the induction of adhesion molecule expression (E-selectin, intercellular adhesion molecule 1 and vascular adhesion molecule 1), and the production of MMPs [76]. The gene encoding TNF-α is hypomethylated in GCA lesions where it is highly expressed, and the association between increased expression of TNF-α and persistent disease activity has been observed in various studies [39], along with the benefit obtained with TNF blockade in other chronic inflammatory or granulomatous diseases. This evidence provided the rationale for conducting clinical trials to investigate TNF inhibition with infliximab, etanercept or adalimumab in GCA. Unfortunately, TNF-α blockade did not provide an advantage over placebo in maintaining remission in newly diagnosed patients [76–79]. The disappointing experience with TNF-α blockade underlines the fact that a biomarker of inflammation is not necessarily a therapeutic target and suggests that TNF-α functions may not be essential for the maintenance of vascular inflammation, or can be supplied by redundant pathways. IL-6 is a multifunctional cytokine secreted by numerous immune cells (e.g. macrophages, neutrophils, dendritic cells) and exerts pleiotropic effects on a variety of cell types [80]. The effects of IL-6 on the immune system include the activation of macrophages and neutrophils, differentiation of Th17 cells, inhibition of the suppressive activity of regulatory T cells, promotion and differentiation of B cells and stimulation of endothelial cells [80]. Furthermore, IL-6 is thought to play an important role in the switch from acute to chronic inflammation [80]. IL-6 transcripts are abundant in GCA lesions but are also present in normal temporal arteries, indicating a potential role in vascular homeostasis [29, 39]. IL-6 expression in lesions is also significantly higher in patients with GCA with a strong systemic inflammatory reaction [39]. Serum IL-6 is elevated in patients with GCA and correlates with disease activity [45, 81–83]. Moreover, persistently increased serum IL-6 is found in patients with relapsing disease [84]. Recently, IL-6 receptor blockade with tocilizumab was shown to be superior to placebo in maintaining remission and sparing glucocorticoids in phases 2 and 3 clinical trials, both in newly diagnosed and relapsing patients [85, 86]. These trials indicate that IL-6-dependent inflammatory pathways are highly relevant in maintaining inflammatory activity in GCA. Short-term clinical outcomes seem to be clearly improved by tocilizumab. Tocilizumab strongly inhibits the systemic inflammatory response, which is an important burden in patients with GCA, as well as cranial and polymyalgic clinical symptoms. However, the impact of tocilizumab on vascular inflammation and vascular remodelling, along with their associated vascular complications, needs to be evaluated; this will provide unique insights into pathogenic mechanisms of vascular inflammation and repair. Conclusions To date, our understanding of GCA pathogenesis is largely based on evidence from histopathological characteristics, the identification of cell populations and subpopulations in affected vessels or peripheral blood, the expression of activation and differentiation markers by these cells and the production of certain inflammatory molecules in GCA lesions. The role that infiltrating cells and their products play in the development of GCA is primarily based on the assumption of their known biologic functions and correlation with relevant histopathological features (e.g. neovascularization, intimal hyperplasia, giant-cell formation), clinical phenotypes or disease outcomes [19, 30]. Several animal models of large-vessel inflammation have provided evidence regarding potential mechanisms involved in vascular inflammation. However, the pathogenesis of GCA remains incompletely understood because of the scarcity of functional studies demonstrating the involvement of specific pathways. The recent introduction of targeted therapies into the treatment landscape for GCA may shed light on the participation of specific pathways in pathogenesis of the disease. In particular, research surrounding immune checkpoint inhibition and cytokine blockade (TNF-α and IL-6) has provided important insights into the roles that the immune system and vascular inflammation play in the development of GCA. Future research into current and novel targeted agents is needed to expand our knowledge regarding specific disease pathways involved in GCA-associated vascular inflammation and repair. Acknowledgements The authors thank Ester Planas-Rigol, PhD, Marc Corbera-Bellalta, PhD, Georgina Espígol Frigolé, MD, Sergio Prieto-González, MD, and José Hernández-Rodríguez, MD, of the Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), and Maxime Samson, MD, PhD, of University of Barcelona, Dijon University Hospital and University of Bourgogne Franche-Comté for their contributions to this manuscript. Editorial assistance in the preparation of this manuscript was provided by Maxwell Chang, of ApotheCom Associates (Yardley, PA). Support for this assistance was funded by F Hoffmann-La Roche Ltd, Basel, Switzerland. N.T.-G. and M.C.C. were funded by Ministerio de Economía, Industria y Competitividad (SAF 2014-57708-R and SAF 2017-88275-R). Supplement: This supplement was funded by F. Hoffmann-La Roche Ltd. Funding: No specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: M.C.C. has received consultation fees from Hoffman-La Roche and GlaxoSmithKline. The other author has declared no conflicts of interest. References 1 Salvarani C, Pipitone N, Versari A, Hunder GG. Clinical features of polymyalgia rheumatica and giant cell arteritis. Nat Rev Rheumatol  2012; 8: 509– 21. Google Scholar CrossRef Search ADS PubMed  2 Jennette JC, Falk RJ, Bacon PA et al.   2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum  2013; 65: 1– 11. Google Scholar CrossRef Search ADS PubMed  3 Lee JL, Naguwa SM, Cheema GS, Gershwin ME. The geo-epidemiology of temporal (giant cell) arteritis. Clin Rev Allergy Immunol  2008; 35: 88– 95. Google Scholar CrossRef Search ADS PubMed  4 Gonzalez-Gay MA, Martinez-Dubois C, Agudo M et al.   Giant cell arteritis: epidemiology, diagnosis, and management. Curr Respir Med Rev  2010; 12: 436– 42. 5 Hernandez-Rodriguez J, Murgia G, Villar I et al.   Description and validation of histological patterns and proposal of a dynamic model of inflammatory infiltration in giant-cell arteritis. Medicine  2016; 95: e2368. Google Scholar CrossRef Search ADS PubMed  6 Hall S, Persellin S, Lie JT et al.   The therapeutic impact of temporal artery biopsy. Lancet  1983; 2: 1217– 20. Google Scholar CrossRef Search ADS PubMed  7 Gonzalez-Gay MA. The diagnosis and management of patients with giant cell arteritis. J Rheumatol  2005; 32: 1186– 8. Google Scholar PubMed  8 Luqmani R, Lee E, Singh S et al.   The Role of Ultrasound Compared to Biopsy of Temporal Arteries in the Diagnosis and Treatment of Giant Cell Arteritis (TABUL): a diagnostic accuracy and cost-effectiveness study. Health Technol Assess  2016; 20: 1– 238. Google Scholar CrossRef Search ADS PubMed  9 Nordborg E, Nordborg C. Giant cell arteritis: epidemiological clues to its pathogenesis and an update on its treatment. Rheumatology  2003; 42: 413– 21. Google Scholar CrossRef Search ADS PubMed  10 Liozon E, Ouattara B, Rhaiem K et al.   Familial aggregation in giant cell arteritis and polymyalgia rheumatica: a comprehensive literature review including 4 new families. Clin Exp Rheumatol  2009; 27(1 Suppl 52): S89– 94. 11 Carmona FD, Gonzalez-Gay MA, Martin J. Genetic component of giant cell arteritis. Rheumatology  2014; 53: 6– 18. Google Scholar CrossRef Search ADS PubMed  12 Enjuanes A, Benavente Y, Hernandez-Rodriguez J et al.   Association of NOS2 and potential effect of VEGF, IL6, CCL2 and IL1RN polymorphisms and haplotypes on susceptibility to GCA—a simultaneous study of 130 potentially functional SNPs in 14 candidate genes. Rheumatology  2012; 51: 841– 51. Google Scholar CrossRef Search ADS PubMed  13 Cid MC, Ercilla G, Vilaseca J et al.   Polymyalgia rheumatica: a syndrome associated with HLA-DR4 antigen. Arthritis Rheum  1988; 31: 678– 82. Google Scholar CrossRef Search ADS PubMed  14 Carmona FD, Mackie SL, Martin JE et al.   A large-scale genetic analysis reveals a strong contribution of the HLA class II region to giant cell arteritis susceptibility. Am J Hum Genet  2015; 96: 565– 80. Google Scholar CrossRef Search ADS PubMed  15 Carmona FD, Vaglio A, Mackie SL et al.   A genome-wide association study identifies risk alleles in plasminogen and P4HA2 associated with giant cell arteritis. Am J Hum Genet  2017; 100: 64– 74. Google Scholar CrossRef Search ADS PubMed  16 van Timmeren MM, Heeringa P, Kallenberg CG. Infectious triggers for vasculitis. Curr Opin Rheumatol  2014; 26: 416– 23. Google Scholar CrossRef Search ADS PubMed  17 Nagel MA, White T, Khmeleva N et al.   Analysis of varicella-zoster virus in temporal arteries biopsy positive and negative for giant cell arteritis. JAMA Neurol  2015; 72: 1281– 7. Google Scholar CrossRef Search ADS PubMed  18 Bhatt AS, Manzo VE, Pedamallu CS et al.   In search of a candidate pathogen for giant cell arteritis: sequencing-based characterization of the giant cell arteritis microbiome. Arthritis Rheumatol  2014; 66: 1939– 44. Google Scholar CrossRef Search ADS PubMed  19 Weyand CM, Goronzy JJ. Immune mechanisms in medium and large-vessel vasculitis. Nat Rev Rheumatol  2013; 9: 731– 40. Google Scholar CrossRef Search ADS PubMed  20 Cid MC, Campo E, Ercilla G et al.   Immunohistochemical analysis of lymphoid and macrophage cell subsets and their immunologic activation markers in temporal arteritis. Influence of corticosteroid treatment. Arthritis Rheum  1989; 32: 884– 93. Google Scholar PubMed  21 Krupa WM, Dewan M, Jeon MS et al.   Trapping of misdirected dendritic cells in the granulomatous lesions of giant cell arteritis. Am J Pathol  2002; 161: 1815– 23. Google Scholar CrossRef Search ADS PubMed  22 Ma-Krupa W, Jeon MS, Spoerl S et al.   Activation of arterial wall dendritic cells and breakdown of self-tolerance in giant cell arteritis. J Exp Med  2004; 199: 173– 83. Google Scholar CrossRef Search ADS PubMed  23 Cid MC, Grau JM, Casademont J et al.   Immunohistochemical characterization of inflammatory cells and immunologic activation markers in muscle and nerve biopsy specimens from patients with systemic polyarteritis nodosa. Arthritis Rheum  1994; 37: 1055– 61. Google Scholar CrossRef Search ADS PubMed  24 Zhang H, Watanabe R, Berry GJ et al.   Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis. Proc Natl Acad Sci U S A  2017; 114: E970– 9. Google Scholar CrossRef Search ADS PubMed  25 Weyand CM, Schonberger J, Oppitz U et al.   Distinct vascular lesions in giant cell arteritis share identical T cell clonotypes. J Exp Med  1994; 179: 951– 60. Google Scholar CrossRef Search ADS PubMed  26 Deng J, Younge BR, Olshen RA, Goronzy JJ, Weyand CM. Th17 and Th1 T-cell responses in giant cell arteritis. Circulation  2010; 121: 906– 15. Google Scholar CrossRef Search ADS PubMed  27 Coit P, De Lott LB, Nan B, Elner VM, Sawalha AH. DNA methylation analysis of the temporal artery microenvironment in giant cell arteritis. Ann Rheum Dis  2016; 75: 1196– 202. Google Scholar CrossRef Search ADS PubMed  28 Weyand CM, Hicok KC, Hunder GG, Goronzy JJ. Tissue cytokine patterns in patients with polymyalgia rheumatica and giant cell arteritis. Ann Intern Med  1994; 121: 484– 91. Google Scholar CrossRef Search ADS PubMed  29 Corbera-Bellalta M, Garcia-Martinez A, Lozano E et al.   Changes in biomarkers after therapeutic intervention in temporal arteries cultured in Matrigel: a new model for preclinical studies in giant-cell arteritis. Ann Rheum Dis  2014; 73: 616– 23. Google Scholar CrossRef Search ADS PubMed  30 Cid MC, Font C, Coll-Vinent B, Grau JM. Large vessel vasculitides. Curr Opin Rheumatol  1998; 10: 18– 28. Google Scholar CrossRef Search ADS PubMed  31 Cid MC, Cebrian M, Font C et al.   Cell adhesion molecules in the development of inflammatory infiltrates in giant cell arteritis: inflammation-induced angiogenesis as the preferential site of leukocyte-endothelial cell interactions. Arthritis Rheum  2000; 43: 184– 94. Google Scholar CrossRef Search ADS PubMed  32 Rittner HL, Kaiser M, Brack A et al.   Tissue-destructive macrophages in giant cell arteritis. Circ Res  1999; 84: 1050– 8. Google Scholar CrossRef Search ADS PubMed  33 Cid MC, Hoffman MP, Hernandez RJ et al.   Association between increased CCL2 (MCP-1) expression in lesions and persistence of disease activity in giant-cell arteritis. Rheumatology  2006; 45: 1356– 63. Google Scholar CrossRef Search ADS PubMed  34 Corbera-Bellalta M, Planas-Rigol E, Lozano E et al.   Blocking interferon gamma reduces expression of chemokines CXCL9, CXCL10 and CXCL11 and decreases macrophage infiltration in ex vivo cultured arteries from patients with giant cell arteritis. Ann Rheum Dis  2016; 75: 1177– 86. Google Scholar CrossRef Search ADS PubMed  35 Visvanathan S, Rahman MU, Hoffman GS et al.   Tissue and serum markers of inflammation during the follow-up of patients with giant-cell arteritis—a prospective longitudinal study. Rheumatology  2011; 50: 2061– 70. Google Scholar CrossRef Search ADS PubMed  36 Espigol-Frigole G, Corbera-Bellalta M, Planas-Rigol E et al.   Increased IL-17A expression in temporal artery lesions is a predictor of sustained response to glucocorticoid treatment in patients with giant-cell arteritis. Ann Rheum Dis  2013; 72: 1481– 7. Google Scholar CrossRef Search ADS PubMed  37 Miossec P, Kolls JK. Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov  2012; 11: 763– 76. Google Scholar CrossRef Search ADS PubMed  38 Samson M, Audia S, Fraszczak J et al.   Th1 and Th17 lymphocytes expressing CD161 are implicated in giant cell arteritis and polymyalgia rheumatica pathogenesis. Arthritis Rheum  2012; 64: 3788– 98. Google Scholar CrossRef Search ADS PubMed  39 Hernandez-Rodriguez J, Segarra M, Vilardell C et al.   Tissue production of pro-inflammatory cytokines (IL-1beta, TNFalpha and IL-6) correlates with the intensity of the systemic inflammatory response and with corticosteroid requirements in giant-cell arteritis. Rheumatology  2004; 43: 294– 301. Google Scholar CrossRef Search ADS PubMed  40 Terrier B, Geri G, Chaara W et al.   Interleukin-21 modulates Th1 and Th17 responses in giant cell arteritis. Arthritis Rheum  2012; 64: 2001– 11. Google Scholar CrossRef Search ADS PubMed  41 Miyabe C, Miyabe Y, Strle K et al.   An expanded population of pathogenic regulatory T cells in giant cell arteritis is abrogated by IL-6 blockade therapy. Ann Rheum Dis  2017; 76: 898– 905. Google Scholar CrossRef Search ADS PubMed  42 van der Geest KS, Abdulahad WH, Chalan P et al.   Disturbed B cell homeostasis in newly diagnosed giant cell arteritis and polymyalgia rheumatica. Arthritis Rheumatol  2014; 66: 1927– 38. Google Scholar CrossRef Search ADS PubMed  43 Alba MA, Prieto-Gonzalez S, Hernandez-Rodriguez J, Cid MC. B lymphocytes may play a significant role in large-vessel vasculitis. Future Med  2012; 7: 475– 7. 44 Ciccia F, Rizzo A, Maugeri R et al.   Ectopic expression of CXCL13, BAFF, APRIL and LT-beta is associated with artery tertiary lymphoid organs in giant cell arteritis. Ann Rheum Dis  2017; 76: 235– 43. Google Scholar CrossRef Search ADS PubMed  45 van der Geest KS, Abdulahad WH, Rutgers A et al.   Serum markers associated with disease activity in giant cell arteritis and polymyalgia rheumatica. Rheumatology  2015; 54: 1397– 402. Google Scholar CrossRef Search ADS PubMed  46 Bhatia A, Ell PJ, Edwards JC. Anti-CD20 monoclonal antibody (rituximab) as an adjunct in the treatment of giant cell arteritis. Ann Rheum Dis  2005; 64: 1099– 100. Google Scholar CrossRef Search ADS PubMed  47 Alba MA, Espigol-Frigole G, Butjosa M et al.   Treatment of large cell vacsulitis. Curr Immunol Rev  2011; 7: 435– 42. Google Scholar CrossRef Search ADS   48 Ciccia F, Alessandro R, Rizzo A et al.   IL-33 is overexpressed in the inflamed arteries of patients with giant cell arteritis. Ann Rheum Dis  2013; 72: 258– 64. Google Scholar CrossRef Search ADS PubMed  49 Kaiser M, Younge B, Bjornsson J, Goronzy JJ, Weyand CM. Formation of new vasa vasorum in vasculitis. Production of angiogenic cytokines by multinucleated giant cells. Am J Pathol  1999; 155: 765– 74. Google Scholar CrossRef Search ADS PubMed  50 Segarra M, Garcia-Martinez A, Sanchez M et al.   Gelatinase expression and proteolytic activity in giant-cell arteritis. Ann Rheum Dis  2007; 66: 1429– 35. Google Scholar CrossRef Search ADS PubMed  51 Lozano E, Segarra M, Garcia-Martinez A, Hernandez-Rodriguez J, Cid MC. Imatinib mesylate inhibits in vitro and ex vivo biological responses related to vascular occlusion in giant cell arteritis. Ann Rheum Dis  2008; 67: 1581– 8. Google Scholar CrossRef Search ADS PubMed  52 Cid MC, Grant DS, Hoffman GS et al.   Identification of haptoglobin as an angiogenic factor in sera from patients with systemic vasculitis. J Clin Invest  1993; 91: 977– 85. Google Scholar CrossRef Search ADS PubMed  53 O'Neill L, Rooney P, Molloy D et al.   Regulation of inflammation and angiogenesis in giant cell arteritis by acute-phase serum amyloid A. Arthritis Rheumatol  2015; 67: 2447– 56. Google Scholar CrossRef Search ADS PubMed  54 Foell D, Hernandez-Rodriguez J, Sanchez M et al.   Early recruitment of phagocytes contributes to the vascular inflammation of giant cell arteritis. J Pathol  2004; 204: 311– 6. Google Scholar CrossRef Search ADS PubMed  55 Cid MC, Hernandez-Rodriguez J, Esteban MJ et al.   Tissue and serum angiogenic activity is associated with low prevalence of ischemic complications in patients with giant-cell arteritis. Circulation  2002; 106: 1664– 71. Google Scholar CrossRef Search ADS PubMed  56 Hernandez-Rodriguez J, Segarra M, Vilardell C et al.   Elevated production of interleukin-6 is associated with a lower incidence of disease-related ischemic events in patients with giant-cell arteritis: angiogenic activity of interleukin-6 as a potential protective mechanism. Circulation  2003; 107: 2428– 34. Google Scholar CrossRef Search ADS PubMed  57 Samson M, Ly KH, Tournier B et al.   Involvement and prognosis value of CD8+ T cells in giant cell arteritis. J Autoimmun  2016; 72: 73– 83. Google Scholar CrossRef Search ADS PubMed  58 Garcia-Martinez A, Hernandez-Rodriguez J, Arguis P et al.   Development of aortic aneurysm/dilatation during the followup of patients with giant cell arteritis: a cross-sectional screening of fifty-four prospectively followed patients. Arthritis Rheum  2008; 59: 422– 30. Google Scholar CrossRef Search ADS PubMed  59 Kermani TA, Warrington KJ, Crowson CS et al.   Large-vessel involvement in giant cell arteritis: a population-based cohort study of the incidence-trends and prognosis. Ann Rheum Dis  2013; 72: 1989– 94. Google Scholar CrossRef Search ADS PubMed  60 Garcia-Martinez A, Arguis P, Prieto-Gonzalez S et al.   Prospective long term follow-up of a cohort of patients with giant cell arteritis screened for aortic structural damage (aneurysm or dilatation). Ann Rheum Dis  2014; 73: 1826– 32. Google Scholar CrossRef Search ADS PubMed  61 Robson JC, Kiran A, Maskell J et al.   The relative risk of aortic aneurysm in patients with giant cell arteritis compared with the general population of the UK. Ann Rheum Dis  2015; 74: 129– 35. Google Scholar CrossRef Search ADS PubMed  62 Kaiser M, Weyand CM, Bjornsson J, Goronzy JJ. Platelet-derived growth factor, intimal hyperplasia, and ischemic complications in giant cell arteritis. Arthritis Rheum  1998; 41: 623– 33. Google Scholar CrossRef Search ADS PubMed  63 Lozano E, Segarra M, Corbera-Bellalta M et al.   Increased expression of the endothelin system in arterial lesions from patients with giant-cell arteritis: association between elevated plasma endothelin levels and the development of ischaemic events. Ann Rheum Dis  2010; 69: 434– 42. Google Scholar CrossRef Search ADS PubMed  64 Planas-Rigol E, Terrades-Garcia N, Corbera-Bellalta M et al.   Endothelin-1 promotes vascular smooth muscle cell migration across the artery wall: a mechanism contributing to vascular remodelling and intimal hyperplasia in giant-cell arteritis. Ann Rheum Dis  2017; 76: 1624– 34. Google Scholar CrossRef Search ADS PubMed  65 Ly KH, Regent A, Molina E et al.   Neurotrophins are expressed in giant cell arteritis lesions and may contribute to vascular remodeling. Arthritis Res Ther  2014; 16: 487. Google Scholar CrossRef Search ADS PubMed  66 Croci S, Zerbini A, Boiardi L et al.   MicroRNA markers of inflammation and remodelling in temporal arteries from patients with giant cell arteritis. Ann Rheum Dis  2016; 75: 1527– 33. Google Scholar CrossRef Search ADS PubMed  67 Dal Canto AJ, Virgin HW, Speck SH. Ongoing viral replication is required for gammaherpesvirus 68-induced vascular damage. J Virol  2000; 74: 11304– 10. Google Scholar CrossRef Search ADS PubMed  68 Dal Canto AJ, Swanson PE, O'Guin AK, Speck SH, Virgin HW. IFN-gamma action in the media of the great elastic arteries, a novel immunoprivileged site. J Clin Invest  2001; 107: R15– 22. Google Scholar CrossRef Search ADS PubMed  69 Nicklin MJ, Hughes DE, Barton JL, Ure JM, Duff GW. Arterial inflammation in mice lacking the interleukin 1 receptor antagonist gene. J Exp Med  2000; 191: 303– 12. Google Scholar CrossRef Search ADS PubMed  70 Chen Q, Yang W, Gupta S et al.   IRF-4-binding protein inhibits interleukin-17 and interleukin-21 production by controlling the activity of IRF-4 transcription factor. Immunity  2008; 29: 899– 911. Google Scholar CrossRef Search ADS PubMed  71 Brack A, Geisler A, Martinez-Taboada VM et al.   Giant cell vasculitis is a T cell-dependent disease. Mol Med  1997; 3: 530– 43. Google Scholar PubMed  72 Borkowski A, Younge BR, Szweda L et al.   Reactive nitrogen intermediates in giant cell arteritis: selective nitration of neocapillaries. Am J Pathol  2002; 161: 115– 23. Google Scholar CrossRef Search ADS PubMed  73 Goldstein BL, Gedmintas L, Todd DJ. Drug-associated polymyalgia rheumatica/giant cell arteritis occurring in two patients after treatment with ipilimumab, an antagonist of CTLA-4. Arthritis Rheumatol  2014; 66: 768– 9. Google Scholar CrossRef Search ADS PubMed  74 Hodi FS, Lawrence D, Lezcano C et al.   Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol Res  2014; 2: 632– 42. Google Scholar CrossRef Search ADS PubMed  75 Langford CA, Cuthbertson D, Ytterberg SR et al.   A randomized, double-blind trial of abatacept (CTLA-4Ig) for the treatment of giant cell arteritis. Arthritis Rheumatol  2017; 69: 846– 53. Google Scholar CrossRef Search ADS PubMed  76 Jarrot PA, Kaplanski G. Anti-TNF-alpha therapy and systemic vasculitis. Mediators Inflamm  2014; 2014: 493593. Google Scholar CrossRef Search ADS PubMed  77 Hoffman GS, Cid MC, Rendt-Zagar KE et al.   Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis: a randomized trial. Ann Intern Med  2007; 146: 621– 30. Google Scholar CrossRef Search ADS PubMed  78 Martinez-Taboada VM, Rodriguez-Valverde V, Carreno L et al.   A double-blind placebo controlled trial of etanercept in patients with giant cell arteritis and corticosteroid side effects. Ann Rheum Dis  2008; 67: 625– 30. Google Scholar CrossRef Search ADS PubMed  79 Seror R, Baron G, Hachulla E et al.   Adalimumab for steroid sparing in patients with giant-cell arteritis: results of a multicentre randomised controlled trial. Ann Rheum Dis  2014; 73: 2074– 81. Google Scholar CrossRef Search ADS PubMed  80 Roberts J, Clifford A. Update on the management of giant cell arteritis. Ther Adv Chronic Dis  2017; 8: 69– 79. Google Scholar CrossRef Search ADS PubMed  81 Roche NE, Fulbright JW, Wagner AD et al.   Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis. Arthritis Rheum  1993; 36: 1286– 94. Google Scholar CrossRef Search ADS PubMed  82 Dasgupta B, Panayi GS. Interleukin-6 in serum of patients with polymyalgia rheumatica and giant cell arteritis. Br J Rheumatol  1990; 29: 456– 8. Google Scholar CrossRef Search ADS PubMed  83 Weyand CM, Fulbright JW, Hunder GG, Evans JM, Goronzy JJ. Treatment of giant cell arteritis: interleukin-6 as a biologic marker of disease activity. Arthritis Rheum  2000; 43: 1041– 8. Google Scholar CrossRef Search ADS PubMed  84 Garcia-Martinez A, Hernandez-Rodriguez J, Espigol-Frigole G et al.   Clinical relevance of persistently elevated circulating cytokines (tumor necrosis factor alpha and interleukin-6) in the long-term followup of patients with giant cell arteritis. Arthritis Care Res  2010; 62: 835– 41. Google Scholar CrossRef Search ADS   85 Villiger PM, Adler S, Kuchen S et al.   Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet  2016; 387: 1921– 7. Google Scholar CrossRef Search ADS PubMed  86 Stone JH, Tuckwell K, Dimonaco S et al.   Trial of tocilizumab in giant-cell arteritis. N Engl J Med  2017; 377: 317– 28. Google Scholar CrossRef Search ADS PubMed  87 Samson M, Devilliers H, Heang K et al.   Tocilizumab as an add-on therapy to glucocorticoids during the first 3 months of treatment of giant cell arteritis: results of a French multicenter prospective open-label study [abstract]. Arthritis Rheumatol  2016; 68(Suppl 10): 977. 88 Mayrbaeurl B, Hinterreiter M, Burgstaller S, Windpessl M, Thaler J. The first case of a patient with neutropenia and giant-cell arteritis treated with rituximab. Clin Rheumatol  2007; 26: 1597– 8. Google Scholar CrossRef Search ADS PubMed  89 Conway R, O'Neill L, O'Flynn E et al.   Ustekinumab for the treatment of refractory giant cell arteritis. Ann Rheum Dis  2016; 75: 1578– 9. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. 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