Large-vessel vasculitis

Abstract

Large-vessel vasculitis (LVV) manifests as inflammation of the aorta and its major branches and is the most common primary vasculitis in adults. LVV comprises two distinct conditions, giant cell arteritis and Takayasu arteritis, although the phenotypic spectrum of primary LVV is complex. Non-specific symptoms often predominate and so patients with LVV present to a range of health-care providers and settings. Rapid diagnosis, specialist referral and early treatment are key to good patient outcomes. Unfortunately, disease relapse remains common and chronic vascular complications are a source of considerable morbidity. Although accurate monitoring of disease activity is challenging, progress in vascular imaging techniques and the measurement of laboratory biomarkers may facilitate better matching of treatment intensity with disease activity. Further, advances in our understanding of disease pathophysiology have paved the way for novel biologic treatments that target important mediators of disease in both giant cell arteritis and Takayasu arteritis. This work has highlighted the substantial heterogeneity present within LVV and the importance of an individualized therapeutic approach. Future work will focus on understanding the mechanisms of persisting vascular inflammation, which will inform the development of increasingly sophisticated imaging technologies. Together, these will enable better disease prognostication, limit treatment-associated adverse effects, and facilitate targeted development and use of novel therapies.

Figure 1.. Disease classification and arterial involvement in large vessel vasculitis.

Although variation exists across the phenotypic spectrum of LVV, patterns of arterial involvement may help to distinguish GCA and TAK. Here, the scale represents typical frequency of arterial segment involvement across the LVV spectrum. LV-GCA more commonly affects the axillary arteries, whereas TAK is more likely to affect the renal and mesenteric vessels. Symmetrical involvement of arterial territories is typical, with the possible exception of subclavian involvement in TAK in which the left subclavian is more commonly implicated than the right. In addition to the vessels depicted, the vertebral arteries may be affected in both GCA and TAK. TAK may also involve the pulmonary arteries. Evidence from imaging studies and autopsy series suggests substantial overlap between cranial giant cell arteritis (C-GCA) and large-vessel giant cell arteritis (LV-GCA) such that many patients presenting with typical temporal symptoms will have evidence of large vessel involvement if this is investigated.

Figure 2.. Global incidence of large vessel vasculitis.

North America includes data from Alaska, USA, Tennessee, USA, Minnesota, USA^, and Ontario, Canada. South America includes data from Argentina. Northern Europe includes data from Norway^{, ,} , the UK^, , Iceland, Denmark^, and Sweden. Southern Europe includes data from Italy, Slovenia and Spain^, . Middle East includes data from Turkey, Israel^– and Kuwait. Oceania includes data from Australia^, and New Zealand. Southern Asia includes data from Hong Kong, Japan^, and South Korea. GCA, giant cell arteritis; TAK, Takayasu arteritis.

Figure 3.. Proposed factors contributing to a loss of immune tolerance of large arteries and initiation of inflammation in large vessel vasculitis.

Several mechanisms contribute to loss of immune tolerance in the arterial wall, ultimately leading to the initiation of inflammation in LVV. The age-associated decline in number and function of both CD4+ and CD8+ T_reg cells attenuates suppression of pro-inflammatory T cell populations. Decreased expression of PD-L1 by both dendritic cells and endothelial cells, as has been documented in GCA, removes a further check on T cell activation and pro-inflammatory cytokine release. Aberrant NOTCH pathway signalling leads to pro-inflammatory T cell differentiation. Production of several matrix metalloproteases (MMPs) is upregulated in GCA, allowing enhanced entry of inflammatory cells into the vessel wall. Reactive oxygen species produced by immature neutrophils in GCA also contribute to increased vessel wall permeability. Multiple genetic and environmental factors have been proposed which might trigger these mechanisms. In GCA, ageing is likely to play a role. Age-related reconfiguration of both the innate and adaptive immune systems — immunosenescence — and vessel wall remodelling create an environment which is susceptible to inflammation. Collaborative GWAS studies have identified both HLA and non-HLA genetic risk factors in both GCA and TAK. Links between infectious agents and LVV have been described, though no single micro-organism has been consistently implicated. DC, dendritic cell; EC, endothelial cell; GCA, giant cell arteritis; LVV, large vessel vasculitis; MMP, matrix metalloproteinase; NOX2, NADPH oxidase 2; PD-1, programmed death-1; PD-L1, programmed death ligand-1; ROS, reactive oxygen species; TAK, Takayasu arteritis; T_reg, T regulatory cell.

Figure 4.. Mediators of inflammation in large vessel vasculitis.

Once immune tolerance has been overcome, a cascade of pro-inflammatory mediators leads to progressive tissue damage. Stimulated dendritic cells act as instigators by recruiting and retaining pro-inflammatory cells including monocytes and T cells. Monocytes differentiate into macrophages which amplify inflammation through release of an assortment of effector molecules. Recruited T cells differentiate into Th1 cells and Th17 cells, further driving the inflammatory cascade through release of cytokines including IFN-γ (Th1) and IL-17/IL-21 (Th17). Vascular inflammation is propagated by neo-vascularisation within the vessel wall which sustains the inflammatory milieu and allows further influx of inflammatory cells. Ultimately, persistent inflammation and attempted remodelling lead to vessel wall damage including intimal hyperplasia and fibrosis, with clinical manifestations including arterial stenosis, occlusion and aneurysm formation. DC, dendritic cell; EC, endothelial cell; ET-1, endothelin-1; GM-CSF, granulocyte macrophage colony stimulating factor; ICAM-1, intercellular adhesion molecule 1; 1IFN-γ, interferon-gamma; IL-, interleukin; JAK, Janus kinase; MMP, matrix metalloproteinase; PDGF, platelet derived growth factor; PD-1, programmed death-1; PD-L1, programmed death ligand-1; ROS, reactive oxygen species; TLR, toll-like receptor; TNF-α, tumour necrosis factor alpha; VCAM-1, vascular cell adhesion molecule 1; VSMC, vascular smooth muscle cell.

Figure 5.. Investigation and diagnosis of large vessel vasculitis.

Schematic outlining a simplified approach to the investigation and diagnosis of different large vessel vasculitis (LVV) clinical syndromes. Typical features of cranial giant cell arteritis (C-GCA) (case examples 1 and 2) include headache and jaw and scalp pain, together with constitutional symptoms. Visual disturbance (case example 2) should prompt rapid ophthalmological review. The diagnostic approach to a patient with a primarily cranial presentation of LVV should consider the pre-test probability of C-GCA, which will inform whether ultrasonography or temporal arterial biopsy (TAB) is the most appropriate initial investigation. Co-existing involvement of the aorta and associated great vessels should be considered in all patients with C-GCA. Case examples 3 and 4 depict more non-specific disease presentations typical of large vessel giant cell arteritis (LV-GCA) (case examples 3) and TAK (case examples 4). In these cases, imaging with either MRA, CTA and/or PET is required. BP, blood pressure; CTA, computed tomography angiogram; MRA, magnetic resonance angiogram; PET, positron emission tomography; TAK, Takayasu arteritis.

Figure 6.. Positron emission tomography/magnetic resonance (PET/MR) imaging in large vessel vasculitis.

(A) Whole body magnetic resonance angiography (MRA) showing luminal subclavian abnormalities (arrows) in a patient with Takayasu arteritis (TAK). (B) Fused coronal PET–MR showing ¹⁸F-fluorodeoxyglucose (FDG) uptake involving subclavian arteries (arrows), aortic arch, and distal aorta (arrowheads) in a patient with large vessel giant cell arteritis (LV-GCA). (C) Axial T1-VIBE MRI, which provides rapid, high-definition imaging, with and without fused PET, showing mural thickening (arrow) and FDG uptake (arrowhead) within the thoracic aorta of a patient with LV-GCA.

Figure 7.. Longitudinal follow-up imaging using ¹⁸F-fluorodeoxyglucose (FDG) PET.

Images show a 68-year-old female patient with large vessel giant cell arteritis (LV-GCA) at time of diagnosis (A) and at 6 (B) and 12 months (C) follow-up points during treatment with tapered glucocorticoids and tocilizumab. FDG uptake is seen throughout the aorta and subclavian arteries bilaterally at diagnosis and is attenuated at each time-point thereafter.

Figure 8.. Management of large vessel vasculitis.

Schematic outlining a simplified approach to the management of large vessel vasculitis (LVV). Despite the associated adverse effects, glucocorticoids remain the mainstay of treatment for both giant cell arteritis (GCA) and Takayasu arteritis (TAK). Addition of a glucocorticoid-sparing agent is recommended from the outset in TAK, and may be considered in some with GCA based on clinical features. Choice of glucocorticoid-sparing agent is largely dictated by physician preference. *Several novel therapeutic agents are currently under investigation in GCA and TAK and are outlined in box 5.