2021 Large-Vessel Vasculitis Nature

PRIMER
Large-vessel vasculitis
Dan Pugh1, Maira Karabayas 2, Neil Basu3, Maria C. Cid4, Ruchika Goel5,
Carl S. Goodyear 3, Peter C. Grayson6, Stephen P. McAdoo 7, Justin C. Mason 8,
Catherine Owen9, Cornelia M. Weyand 10, Taryn Youngstein8 and Neeraj Dhaun 1 ✉
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.
Inflammation of large blood vessels, such as the aorta and TAK was first described in 1908 as a series of reti-
its main branches, most commonly presents as one of the nal vascular abnormalities by Japanese ophthalmologist
two primary large-vessel vasculitides — giant cell arteritis Mikito Takayasu and colleagues9. Its association with
(GCA) or Takayasu arteritis (TAK)1. Together, these two absent or diminished peripheral pulses led to the term
conditions are defined as large-vessel vasculitis (LVV). ‘pulseless disease’, and autopsy studies demonstrated a
GCA is an idiopathic inflammatory condition char- pan-arteritis involving the aorta and major branches10.
acterized by granulomatous arteritis in temporal artery Although early descriptions of the disease involved indi-
biopsy (TAB) specimens that was commonly referred viduals of Japanese origin, TAK is now recognized to
to as temporal arteritis when first described almost occur worldwide.
100 years ago2. Later, it was observed that patients with In general, both GCA and TAK are defined by gran-
this condition often develop constitutional symptoms ulomatous inflammation of the blood vessel wall and a
and features of extravascular inflammation attributed to maladaptive immune response to injury that promotes
an overlap with the more common inflammatory disor- intimal hyperplasia, adventitial thickening and intra-
der polymyalgia rheumatica (PMR)3. Several subsequent mural vascularization, which ultimately threaten vessel
autopsy studies showed arteritis within the aorta and integrity and tissue perfusion. Advances in the cellular
other great vessels4,5, and rapid improvements in vascular and molecular analysis of inflammatory lesions in LVV
imaging starting at the beginning of the twenty-first cen- have translated into an improved understanding of its
tury have enabled an even better understanding of the pathogenesis and mechanism-based diagnostic and
extent of large-vessel involvement6,7. It is now recognized therapeutic approaches that can be tailored to the needs
that GCA encompasses a broad phenotypic spectrum of of the individual patient. These treatments are being
medium and large artery inflammation. Nomenclature evaluated in increasingly complex and sophisticated
✉e-mail: has evolved to reflect this, with the terms large-vessel clinical trials, and the need for guidance on their use
bean.dhaun@ed.ac.uk GCA (LV-GCA), cranial GCA (C-GCA) and LV-GCA has driven exciting advances in vascular imaging.
https://doi.org/10.1038/ with cranial involvement now suggested depending on Disease outcomes in LVV are generally better than
s41572-021-00327-5 the site of inflammation8 (Fig. 1). in most systemic inflammatory conditions, including

NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2021) 7:93 1
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Author addresses approaches and therapeutic options is essential to

providing good care to patients with LVV.
1
British Hearth Foundation/University Centre for Cardiovascular Science, University This Primer provides an in-depth, global review
of Edinburgh, Edinburgh, UK. of the epidemiology, pathophysiology, diagnosis and
2
Centre for Arthritis & Musculoskeletal Health, University of Aberdeen, Aberdeen, UK. management of LVV, and highlights areas where ongo-
3
Institute of Infection, Immunity & Inflammation, University of Glasgow, Glasgow, UK.
ing and future research may be most impactful. Of note,
4
Department of Autoimmune Diseases, Institut d’Investigacions Biomèdiques August Pi I
Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain. inflammation of large vessels can also occur in a range
5
Department of Clinical Immunology & Rheumatology, Christian Medical College, of infectious, inflammatory and immune diseases; these
Vellore, India. conditions are detailed in Box 1 and are outside the scope
6
National Institute of Arthritis & Musculoskeletal & Skin Diseases, National Institutes of this Primer.
of Health, Bethesda, MA, USA.
7
Department of Immunology & Inflammation, Imperial College London, London, UK. Epidemiology
8
National Heart & Lung Institute, Imperial College London, London, UK. Incidence
9
Patient representative, Edinburgh, UK. GCA is the most common primary vasculitis world-
10
Centre for Translational Medicine, Stanford University, Stanford, California, USA. wide, although precise estimates of incidence vary with
the criteria used for case definition, which are based on
in small-vessel vasculitis. However, LVV is not benign either histological definition by TAB, diagnostic coding
and constitutional symptoms, such as fatigue, fever and or classification criteria. GCA occurs almost exclusively
weight loss, are common and disabling. Clinical mani- in those aged >50 years and the incidence increases
festations of arterial narrowing include vision loss and with age to peak in the eighth decade of life, where there
stroke in the short term and limb ischaemia and heart is a 40-fold increase in disease risk over those aged
failure in the long term. Patients with LVV also carry 50–59 years11–13. Women are more commonly affected
an increased risk of aortic aneurysm formation and than men, at a ratio of around 3:1 (refs12–15). Patients
rupture. Additionally, current therapeutic strategies with LV-GCA are younger at presentation, are more
involving prolonged immunosuppression are associated commonly female and more often present with bilateral
with consequences, including an increased risk of cardio arterial involvement than those with C-GCA16,17.
vascular disease and infection. Although treatment There is considerable global variation in GCA inci-
strategies now enable many patients to achieve disease dence, with estimates as high as 44 cases per 100,000 per-
remission, relapse is common. Further, individuals with sons over the age of 50 years in Northern Europe and as
LVV present to a range of medical or surgical specialties low as ~0.3 per 100,000 persons over the age of 50 years
and require inter-disciplinary management. As such, a in Southern Asia14,18–21 (Fig. 2). Similarly, the incidence
working knowledge of current nomenclature, diagnostic within Europe shows a marked north–south gradient
and is reported to be <10 cases per 100,000 persons over
the age of 50 years in Mediterranean populations11,19.
C-GCA LV-GCA TAK There is a particularly high prevalence amongst those
of Scandinavian ancestry, both within Northern Europe
and in Americans of Scandinavian descent, suggesting a
0% shared genetic risk across these populations. Conversely,
a lower reported incidence in Finland may reflect the
distinct genetic ancestry in this population22. GCA is
50% thought to be even less common in African, Asian and
Arab countries; however, formal epidemiological data
in these populations are limited, potentially owing to
100% a combination of lower disease burden, differences in
access to health care (and thus diagnosis) or lack of study
in low-income regions.
In Japan, where it was first described, TAK has an
estimated annual incidence of 1–2 cases per million
people23. In Europe, the annual incidence ranges from
0.4 to 3.4 per million24–27. Age of onset is usually between
Fig. 1 | Disease classification and arterial involvement in LVV. Although variation 10 and 40 years and is the major epidemiological feature
exists across the phenotypic spectrum of large-vessel vasculitis (LVV), patterns of arterial that distinguishes TAK from GCA, although late-onset
involvement may help to distinguish giant cell arteritis (GCA) and Takayasu arteritis (TAK). TAK is increasingly recognized28. TAK is also more
Here, the colour scale represents the typical frequency of arterial segment involvement common in women, who account for 80–90% of cases
across the LVV spectrum. Large-vessel GCA (LV-GCA) more commonly affects the in Europeans29. The sex ratio, however, is less skewed
axillary arteries, whereas TAK is more likely to affect the renal and mesenteric vessels262. towards women in China, India and Thailand, where
Symmetrical involvement of arterial territories is typical, with the possible exception of
it ranges between 3:1 and 4:1, implicating a potential
subclavian involvement in TAK in which the left subclavian is more commonly implicated
than the right263. In addition to the vessels depicted, the vertebral arteries may be role for regional environmental and genetic factors in
affected in both GCA and TAK. TAK may also involve the pulmonary arteries. Evidence pathogenesis30–32. A study in Japanese patients also sug-
from imaging studies and autopsy series suggests substantial overlap between cranial gests a recent shift in sex ratio towards men33. Notably,
GCA (C-GCA) and LV-GCA, such that many patients presenting with typical temporal the pattern of disease may differ between young-onset
symptoms will have evidence of large-vessel involvement if this is investigated262. and late-onset disease and between men and women.
2 | Article citation ID: (2021) 7:93 www.nature.com/nrdp
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Box 1 | Mimics of large-vessel vasculitis is consistently associated with inheritance of the

HLA-B allele HLA-B*52:01 in populations of multi-
Infectious disease • Rheumatoid arthritis ple ethnicities45. Of note, the inflammatory lesions in
• Bacterial infection • Sarcoidosis TAK include a large number of CD8+ T cells, which are
• Fungal infection • Systemic lupus erythematosus restricted by HLA class I polymorphisms46,47. Several
• HIV infection Connective tissue disease
large-scale genetic studies in the past decade have iden-
• Q fever tified additional HLA and non-HLA susceptibility loci
• Ehlers–Danlos syndromes
• Syphilis in ancestrally diverse populations46,48–51, which impli-
• Fibromuscular dysplasia
cate a variety of pro-inflammatory, regulatory immune
• Tuberculosis • Loeys–Dietz syndrome response and humoral pathways in disease pathogenesis.
Inflammatory disease • Marfan syndrome Susceptibility factors common to both GCA and TAK
• Ankylosing spondylitis • Neurofibromatosis have also been suggested, primarily within the IL12B
• Atherosclerosis • Pseudoxanthoma elasticum locus. IL12B encodes the IL-12 subunit p40, which
• Behçet syndrome Congenital vascular disease is shared between IL-12 and IL-23, both of which are
known to function as lineage-inducing cytokines for
• Clinically isolated aortitis • Aortic coarctation
T helper 1 (TH1) and TH17 cells52.
• Cogan syndrome • Mid-aortic syndrome
Reports of seasonal variation in GCA onset suggest
• Cryoglobulinaemic vasculitis Neoplastic disease that environmental factors may trigger disease in geneti-
• Granulomatosis with polyangiitis • Erdheim–Chester disease cally susceptible individuals53. Efforts so far have focused
• IgG4-related disease • Adverse effects from radiotherapy on identifying possible infectious triggers. Small epide-
• Polyarteritis nodosa • Adverse effects from immune-checkpoint miological, clinical and molecular studies have described
• Relapsing polychondritis inhibitor therapy potential links between GCA incidence and various
organisms, including varicella-zoster virus, Chlamydia
pneumoniae, Mycoplasma spp. and parvovirus B19
Renal artery involvement, active disease with constitu- (ref.54). However, as it is common for an elderly host to
tional symptoms and major ischaemic events, such as have encountered several infections and for there to be
myocardial infarction, renovascular hypertension and deposition of microbial products in tissue, these find-
stroke, are more common in younger patients31,34,35. ings do not prove causality for large-vessel inflamma-
Involvement of the thoracic aorta and its branch vessels tion and there is no consistent evidence of any particular
leading to upper limb claudication and pulse loss seems microorganism acting as a trigger for GCA55.
to be more common in women, whereas the renal and A higher incidence of M. tuberculosis infection has
iliac arteries are more commonly affected in men32,36. been reported in patients with TAK than in unaffected
individuals, with molecular mimicry between the micro-
Disease determinants and risk factors bial and human 65 kDa heat shock proteins proposed as
The geographical and ethnic variations in GCA inci- a triggering immunological event56. However, these data
dence suggest a considerable genetic contribution to dis- suffer from epidemiological confounding and further
ease aetiology. An association between the HLA class II studies are needed to support this hypothesis57. Of note,
region — in particular with HLA-DRB1*04 alleles — a study from India found the frequency of tuberculosis
and GCA has been recognized for some time37. Other to be 5.6% in patients with TAK, which is similar to the
studies have described links between GCA and genes general population30.
encoding cytokines such as tumour necrosis factor
(TNF)38 and their receptors; molecules associated with Mortality
endothelial function such as intercellular adhesion Data on mortality in GCA are conflicting (Box 2). In
molecule 1 (ICAM1)39 and vascular endothelial growth general, death in GCA is more likely due to accelerated
factor (VEGF)40; regulators of innate immunity such as atherosclerosis than from direct complications of the
Toll-like receptor 4 (TLR4)41; and regulators of adap- disease. Indeed, a 2017 meta-analysis demonstrated that
tive immunity such as the protein tyrosine phosphatase the leading causes of death in patients with GCA were
non-receptor type 22 (PTPN22)42. However, it was only cardiovascular disease (39%, excluding deaths related to
in 2017 that the first large genome-wide association aortic aneurysm rupture), cerebrovascular disease (14%),
study (GWAS) in GCA, which included >2,000 indi- infection (13%) and malignancy (12%), with the remain-
viduals of European ancestry, confirmed a strong HLA ing 22% accounted for by gastrointestinal, pulmonary
class II association43. This association is in keeping with and renal deaths, aortic aneurysm-related deaths, and
an underlying antigen-driven immune response in dis- deaths not specified58. These figures are less likely to hold
ease pathogenesis and the predominance of CD4+ T cells true in those with large-vessel complications. Indeed, the
within inflammatory lesions44. The GWAS also identi- mortality in patients with ruptured aortic aneurysms as
fied risk polymorphisms in genes encoding plasmino- a consequence of GCA (80%) is higher than in patients
gen (PLG) and an isoform of the α-subunit of collagen without GCA (65–75%)59. A 2021 meta-analysis observed
prolyl 4-hydoxylase essential for collagen biosynthesis decreasing mortality rates in patients with GCA over the
(P4HA2), which is consistent with alterations in vascular 50-year study period at a rate of 0.14 per 1,000 people per
remodelling in disease susceptibility. year60. It may be that regular monitoring and screening for
In contrast to the HLA class II association observed co-morbidities in patients with GCA has led to comparable
in GCA, disease susceptibility and severity in TAK mortality rates with that of the general population61.

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Northern Europe Southern Europe

16.7–43.6 5.8–10.1
0.4–1.5 1.1–3.4
North America Southern Asia

1–19.8 0.3
2.6 1–2.4
South America Oceania

8.6 3.2–12.7
No data 0.4
GCA incidence Africa Middle East

(per 100,000 aged >50 years)
No data 4.9–11.3
TAK incidence
(per million) No data 2.1–2.2
Fig. 2 | Global incidence of large-vessel vasculitis. North America includes data from Alaska, USA264, Tennessee, USA265,
Minnesota, USA12,266, and Ontario, Canada267. South America includes data from Argentina268. Northern Europe includes
data from Norway14,27,269, the UK24,53, Iceland270, Denmark18,271 and Sweden26. Southern Europe includes data from Italy272,
Slovenia273 and Spain11,274. Middle East includes data from Turkey275, Israel276–278 and Kuwait279. Oceania includes data from
Australia280,281 and New Zealand282. Southern Asia includes data from Hong Kong21, Japan20,23 and South Korea65. GCA, giant
cell arteritis; TAK, Takayasu arteritis.
Mortality data for TAK are even less well defined a specialized CD8+ Treg cell population is mechanisti-
than those of GCA, owing to its low incidence. Overall, cally linked to mis-trafficking of intracellular vesicles.
10-year survival is reported to be ~90%62–66, although Additionally, studies have demonstrated that CD4+
this may not be that favourable given the young age at Treg cell number and function in peripheral blood are
which patients are diagnosed. Several studies suggest reduced in active GCA and can be improved with IL-6
that the standardized mortality of patients with TAK is blockade69,70. Deficiencies in the PD1/PDL1 inhibitory
twofold to threefold higher than of age-matched healthy pathway also contribute. These deficiencies remove a nat-
controls64,66,67. Systemic hypertension, major vascular ural brake of the adaptive immune system and render
complications and a progressive disease course were the artery vulnerable to autoimmune-driven inflamma-
associated with increased mortality risk in these studies. tion. Both endothelial cells and vascular dendritic cells
(DC) are naturally rich in PDL1 and function as protec-
Mechanisms/pathophysiology tive shields against activated, injurious PD1-expressing
Loss of arterial wall immune tolerance precedes a broad T cells by binding PD1 and downregulating T cell activity.
range of interlinked aberrant immunological responses In GCA, circulating and vascular DCs lack PDL1 expres-
involving both the innate and adaptive immune systems, sion and, therefore, activated pro-inflammatory T cells
which contribute to the development and progression of are left unopposed71,72. Blocking the PD1/PDL1 pathway
disease in LVV. Much of our understanding in this area results in enhanced vascular inflammation, increased
comes from tissue from individuals with GCA; therefore, production of the T cell cytokines IFNγ, IL-17 and IL-21,
although mechanistic differences exist between GCA excessive macrophage activation, and accelerated intimal
and TAK, the two conditions will be largely considered hyperplasia71,72. Reports of large-vessel inflammation
together here. developing in patients with cancer following treatment
with immune-checkpoint inhibitors further support
Loss of tolerance the immunoinhibitory PD1/PDL1 pathway as a critical
Under physiological conditions, the walls of medium element of the artery’s immune tolerance73. The third
and large arteries are shielded from inflammation and mechanism is leakiness of the endothelial barrier, which
autoimmunity by immune tolerance. Over the past normally prevents migration of circulating cells into
two decades, studies in GCA have implicated several the vessel wall. In LVV, inflammatory cells gain access
mechanisms that contribute to a loss of immune toler- to the tunica adventitia through the adventitial vasa
ance and subsequent disease induction and progression vasorum. In GCA, circulating monocytes produce excess
(Fig. 3). First, loss of anti-inflammatory regulatory T (Treg) matrix metalloproteases (MMPs), digest the subendo
cells leads to failed suppression of pro-inflammatory thelial basal lamina layer and enable T cells, which are also
T cells in lymph nodes68. The age-associated decline of independently capable of MMP2 and MMP9 production,
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to infiltrate74–77. Adventitial endothelial cells aberrantly GCA lesions, T cells have a functional bias towards TH1
express Jagged 1, a ligand for the receptor NOTCH1, and TH17 cells87,88. TH1 cells are important sites of IFNγ
and interact with circulating CD4+NOTCH1+ T cells74,78, production, which drives a low-grade inflammatory pro-
promoting their differentiation into tissue-invasive cess involving macrophage activation and recruitment.
effector cells that produce IL-17 and IFNγ. Finally, Stimulated macrophages amplify inflammation and
immature neutrophils enriched in the blood of patients injury by releasing an array of effector molecules, includ-
with GCA are potent producers of reactive oxygen spe- ing cytokines such as IL-6, IL-12, IL-23 and IL-1, growth
cies, enabling them to breach the endothelial barrier79. factors such as VEGF and platelet-derived growth factor
Inflammation-dependent neovascularization permits (PDGF), and MMPs such as MMP9, MMP7 and
further leukocyte–endothelial cell interaction and MMP2. Notably, VEGF plays a role in priming endo
inflammation propagation80. Loss of large-vessel immune thelial cells, which promotes further T cell influx
tolerance is also likely to be important in TAK but the and drives vascular remodelling, intimal thickening and
precise mechanisms remain elusive81. neovascularization74,89.
Granulocyte–macrophage colony-stimulating fac-
The ageing immune system tor (GM-CSF) is an upstream mediator of TH1 and
In contrast to TAK, the incidence of GCA increases TH17 cells and is largely expressed by macrophages
with age, suggesting that the ageing process may and endothelial cells. Inhibition of the GM-CSF receptor
influence disease development. Indeed, the accrual pathway in mouse models and explanted human tissue
of environmental insults over time results in epi results in suppression of vessel wall T cell infiltration and
genetic changes, with a bias towards inflammation and reductions in both intimal thickness and neovasculari-
autoimmunity82. Two likely synergistic mechanisms zation, suggesting a potent interplay between GM-CSF
may have a role in increasing GCA risk with age. The and the TH1 axis90–92. One of the important differences
first is immunosenescence, which is characterized by a between GCA and TAK is the glucocorticoid respon-
reduction in naive T cell and Treg cell numbers, produc- siveness of T cell-mediated inflammation; in GCA, TH17
tion of pro-inflammatory cytokines (TNF, IL-6, IL-1β), cells are more sensitive to glucocorticoid treatment than
and reduced cellular responsiveness to inflammatory TH1-dependent responses93,94; conversely, in TAK, TH1
signals83. The second is age-related vascular wall remod- cells seem more glucocorticoid-responsive than TH17
elling, defined by a reduction in number and function cells93,95.
of vascular smooth muscle cells (VSMCs), degenera- A consistent finding in LVV vasculitic infiltrates is a
tion of the media, calcium deposition, thickening of the broad spectrum of T cell effector cytokines beyond IFNγ
intima and biochemical modification of matrix proteins, and IL-17, including IL-9, IL-21 and IL-22 (refs90,96,97).
collectively leading to loss of elasticity and pliability83. It remains unclear whether a cytokine hierarchy
Unopposed, these processes create the ideal environ- exists, what the mechanisms for the induction of these
ment for chronic inflammation to dominate. Although cytokines are, whether they derive from a common cel-
no single infective trigger has been demonstrated in lular source or from functionally distinct T cell subsets,
GCA, persistent or cumulative infection with pathogens and whether they have distinguishing pathological roles.
and chronic antigenic stimulation could lead to loss of Mechanistic studies have implicated the NOTCH,
antigen-independent control by T cells and activation Janus kinase–signal transducer and activator of transcrip-
of vascular DCs83,84. tion (JAK–STAT), and mammalian target of rapamycin
Vascular inflammation Box 2 | Mortality in GCA

Once immune tolerance is lost in LVV, a cascade of
A review of 17 studies that together included 4,733
pro-inflammatory mediators leads to progressive tis- patients with a matched, general population control
sue damage. Vascular DCs are recognized as instigators group found an overall increase in mortality in giant
of pathogenesis given their position at the adventitia– cell arteritis (GCA) of ~20%58. Importantly, subgroup
media interface and their sensitivity to TLR activation analysis demonstrated that this increase was confined
and reduced PDL1 expression in patients with GCA85. to hospitalized patients and no increase was observed
Once vascular DCs are stimulated, they migrate and in the community setting. In line with these results, a
occupy the vessel wall44, recruiting and retaining further UK-based community study of nearly 10,000 patients
innate and adaptive immune cells; in parallel, infiltrating with GCA demonstrated increased mortality in the first
monocytes differentiate into macrophages and multi year following diagnosis, which was not sustained at
5 years283. A population-based study of >7,000 patients
nucleate giant cells. This inflammatory process can per-
in Israel similarly observed increased rates of mortality
sist for years even when disease is perceived as clinically within the first 2 years of diagnosis that was not
quiescent86. This concept of persistent vasculitis that is maintained at 10 years follow-up and was more
difficult to detect and quantify is supported by the clin- pronounced in those presenting at <70 years of age284.
ical evolution of disease, with aneurysm formation and An Italian population-based study involving 281 patients
progressive arterial occlusion occurring decades after with biopsy-proven GCA found reduced survival in
the initial diagnosis of GCA or TAK. those with large-vessel involvement at diagnosis149.
T cells recruited to and settling in the vessel wall pro- Similar results were observed in a US study of
duce a broad spectrum of effector cytokines, which coor- 204 patients with GCA, although in this study survival
dinate immune and vascular cells in tissue destruction was only reduced in those with aortic manifestations as
opposed to only involvement of other large vessels285.
and wall remodelling (Fig. 4). In granulomatous TAK and

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NOX2
CD4+
CD8+/ T cell
↓ Treg cell CD4+ Treg cell
function ↓ Suppression
Ageing of CD4+ T cells
GCA > TAK ↓ Function
Genetic factors EC
• HLA class II (GCA)
- HLA-DRB1 PD1/PDL1 Unopposed
↓ PDL1 T cell
- HLA-DQA1 pathway
expression activation
• HLA class I (TAK) dysfunction
- HLA-B
- MICA DC Initiation and
Digestion of propagation of
MMP9 basal lamina
Infections inflammation
↑ MMP ↑ MMP9 and T cell in LVV
• Varicella zoster production
production infiltration
• Chlamydia Monocyte
pneumoniae
• Mycoplasma sp. NOTCH1+
• Parvovirus B19 T cell
• Mycobacterium NOTCH Aberrant Differentiated
tuberculosis pathway Jagged 1 T cells
activation expression
Iatrogenic factors EC
Immune-checkpoint
inhibitor therapy
ROS ↑ ROS
↑ Endothelial ↑ Endothelial
permeability ROS production permeability
Immature ROS
neutrophil
Fig. 3 | Proposed factors contributing to a loss of immune tolerance of large arteries and initiation of inflammation
in LVV. Several mechanisms contribute to the loss of immune tolerance in the arterial wall, ultimately leading to the initiation
of inflammation in large-vessel vasculitis (LVV). The age-associated decline in number and function of both CD4+ and
CD8+ regulatory T (Treg) cells attenuates suppression of pro-inflammatory T cell populations. Decreased expression of PDL1
by both dendritic cells (DCs) and endothelial cells (ECs), as has been documented in giant cell arteritis (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. The production of several matrix metalloproteases (MMPs) is upregulated in GCA,
enabling enhanced entry of inflammatory cells into the vessel wall. Reactive oxygen species (ROS) produced by immature
neutrophils in GCA also contribute to increased vessel wall permeability. Multiple genetic and environmental factors have
been proposed that might trigger these mechanisms. In GCA, ageing likely has a role. Age-related reconfiguration of both
the innate and adaptive immune systems — immunosenescence — and vessel wall remodelling create an environment
that is susceptible to inflammation. Collaborative genome-wide association studies have identified both HLA and non-
HLA genetic risk factors in both GCA and Takayasu arteritis (TAK). Links between infectious agents and LVV have been
described but no single microorganism has been consistently implicated.
(mTOR) signalling pathways as being important in both pathological feature between GCA and TAK is the
GCA and TAK pathogenesis98,99. In humanized mouse composition of vessel wall infiltrates. Both share an
models of LVV, blocking NOTCH signalling reduced abundance of highly activated T cells and macrophages
T cell activity, downregulating both TH1 and TH17 cell organized into granulomata44,89; however, in TAK, aor-
pathways78. Transcriptomic analysis of arterial tissue has tic wall infiltrates contain a relatively large population
indicated a critical, pro-inflammatory role for JAK–STAT of cytotoxic CD8+ T cells (reflecting the association of
signalling in GCA, and treatment of immunodeficient TAK with HLA class I polymorphisms) and natural
mice carrying engrafted, inflamed human arteries with killer (NK) cells. CD8+ T cells account for ~15% of
small-molecule JAK–STAT inhibitors is highly effective infiltrating cells in aortic TAK lesions and are also seen
in suppressing vasculitis and the production of associ- in greater numbers in the circulation of patients with
ated cytokines100. mTOR complex 1 (mTORC1) activa- TAK compared with healthy controls47,103. However,
tion plays a crucial role in polarizing T cells towards a studies have also demonstrated elevated circulating
pro-inflammatory, effector cell status and has been demon- CD8+ T cells in patients with GCA and CD8+ T cells
strated within the endothelium of the aortic wall and in have also been noted within diseased temporal artery
TH1 and TH17 cells derived from inflammatory lesions tissue — a finding that is associated with a more aggres-
in both GCA and TAK101,102, implicating mTOR signalling sive disease phenotype104. In contrast to GCA, CD16+
as a universal pathogenic pathway in LVV. Further, NK cells may represent up to 20% of all immune cells
immunophenotyping using DNA methylation profiling in TAK lesions47, suggesting a pathogenic role for cyto-
has identified a pathogenic role for the calcineurin/nuclear toxicity in mediating vessel wall injury; however, his-
factor of activated T cells (NFAT) pathway, another tological examination in TAK most often occurs years
potential target for future therapeutics82. after disease onset as opposed to early examination of
In addition to differences in glucocorticoid respon- TAB in GCA, which may account for some of the above
siveness within the TH17 axis, another distinguishing differences.
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Vascular injury and remodelling series of in vitro and in vivo experiments using serum
Persistent intramural inflammation leads to struc- and aortic tissue from both healthy controls and patients
tural changes within the diseased vessel wall, includ- with TAK, mast cells were responsible for increased ves-
ing neovascularization, which sustains resident sel wall permeability, neovascularization and fibrosis;
vascular inflammation and enables further recruitment these cells represent a potential therapeutic target108.
of pro-inflammatory leukocytes80. Ultimately, a mal-
adaptive vascular repair process is initiated whereby Extravascular systemic inflammation
stromal cell populations — primarily endothelial cells, Emerging data suggest that vascular inflammation in
VSMCs and fibroblasts — expand and differentiate LVV is often combined with an extravascular systemic
to drive laminar necrosis, intimal hyperplasia and inflammatory component and that these may operate
fibrosis105. VSMCs are thought to be key players in this independently with regard to disease mechanisms, clin-
process, undergoing phenotypic modulation by resident ical phenotypes and therapeutic responses. This sys-
macrophages and TH1 cells through PDGF and endothe- temic inflammatory response in LVV is characterized
lin 1 signalling106,107. Activated VSMCs proliferate and by a florid acute phase reaction manifesting as anaemia
invade the intima where they deposit extracellular and thrombocytosis, liver function abnormalities, and
matrix proteins. The resultant intimal expansion leads to marked elevations in the erythrocyte sedimentation
eventual luminal stenosis and ischaemic complications. rate (ESR) and levels of C-reactive protein (CRP) in
In the past few years, studies have highlighted the role the blood, with a clinical phenotype of fever, malaise
of mast cells in the pathogenesis of TAK lesions. In a and myalgia. Acute-phase proteins are produced by
Adventitia ↓ PDL1
expression IL-6 IL-23
Vasa vasorum TLR IL-1β IL-12 IL-18
Granuloma
T cell
Immature DC Mature DC activation Immunoglobulin
Media
VSMC
MMP Multinucleated VEGF
giant cell
IL-1 Plasma cell
Monocyte Macrophage GM-CSF
PDGF
IL-21
MMP TNF B cell
ROS IL-6 IL-17
IL-12 Phagocytosis
IL-23 TH17 cell
Immature Mature
CD4+ T cell Neovascularization
fibroblast fibroblast
IFNγ
PD1 TLR
Naive ET1 TH1 cell
T cell Notch JAK
Intima
Endothelial cell
VSMC migration
Intimal
Vasa hyperplasia
vasorum ↓ PDL1 IL-23p19
expression T cell influx
Endothelial cell priming

↑ ICAM1 ↑ VCAM1 and proliferation
Aberrant Jagged 1 expression expression
expression
Fig. 4 | Mediators of inflammation in large-vessel vasculitis. Once vessel wall, which sustains the inflammatory milieu and enables further
immune tolerance has been overcome, a cascade of pro-inflammatory influx of inflammatory cells. Ultimately, persistent inflammation and
mediators leads to progressive tissue damage. Stimulated dendritic cells attempted remodelling lead to vessel wall damage, including intimal
(DCs) act as instigators by recruiting and retaining pro-inflammatory cells, hyperplasia and fibrosis, with clinical manifestations, including arterial
including monocytes and T cells. Monocytes differentiate into stenosis, occlusion and aneurysm formation. ET1, endothelin 1; GM-CSF,
macrophages, which amplify inflammation through the release of an granulocyte–macrophage colony-stimulating factor; ICAM1, intercellular
assortment of effector molecules. Recruited T cells differentiate into adhesion molecule 1; JAK, Janus kinase; MMP, matrix metalloproteinase;
T helper 1 (TH1) cells and TH17 cells, further driving the inflammatory cascade PDGF, platelet-derived growth factor; ROS, reactive oxygen species; TLR,
through the release of cytokines, including IFNγ (TH1) and IL-17/IL-21 (TH17). toll-like receptor; TNF, tumour necrosis factor; VCAM1, vascular cell
Vascular inflammation is propagated by neovascularization within the adhesion molecule 1; VSMC, vascular smooth muscle cell.

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hepatocytes in response to stimulation by cytokines, mandatory to diagnose LV-GCA and TAK. In 2018, the
including IL-6 and others, although the triggers for European Alliance of Associations for Rheumatology
unleashing this cytokine cluster remain unknown. The (EULAR, previously the European League Against
ease of measuring ESR and CRP enables swift assess- Rheumatism) proposed management recommendations
ment of this extravascular component; however, these for LVV that advocated for multidisciplinary diagnostic
metrics cannot measure the burden of inflammation evaluation by specialists8. Given the potential for irre-
within the vessel wall. versible vision loss associated with diagnostic delay,
fast-track referral pathways have been developed for
B cells in LVV patients with GCA and demonstrate improved clinical
Chronic tissue inflammation is associated with the for- outcomes and reduced health-care costs115.
mation of tertiary lymphoid organs and, in LVV, these
are exemplified by the accumulation of lymphoid aggre- Presentation and initial investigation
gates in the perivascular tissue of atherosclerotic arteries Clinical features of LVV can occur owing to vascu-
and the aneurysmal aortic wall109,110. B cell clusters have lar inflammation, ischaemia or both (Box 3). In some
been reported in the adventitial layer of TAK-affected cases, a diagnosis of LVV is suspected in an asympto-
aorta, whereas organized B cell infiltrates have also been matic patient based on findings from vascular exami-
confirmed within the aneurysmal aortic wall of patients nation or imaging studies35. Vision disturbance requires
with LV-GCA110,111. Varying in complexity, these struc- urgent ophthalmological assessment to reduce rates of
tures are rich in both T cells and B cells and may have permanent vision loss116, and treatment initiation at
both pro-inflammatory and anti-inflammatory func- the time of referral is recommended if the diagnosis
tions. Systemic inflammation in GCA is associated with of LVV is strongly suspected and always when sight is
changes in circulating B cell numbers and their ability threatened115.
to produce IL-6 (ref.112). A potential pathogenic role of Initial investigations (Table 1) are influenced by pre-
autoantibodies has been suggested in TAK following the senting features, physician preference and availability
identification of endothelial cell autoantigens in these of imaging modalities (Fig. 5). As the presenting fea-
patients113. A role for B cells in TAK pathogenesis is also tures of LVV may be non-specific, these should aim to
supported by the findings of a large GWAS study pub- exclude mimics such as infection or malignancy (Box 1).
lished in 2021 (ref.51). Additionally, work in TAK has Elevated levels of inflammatory markers such as ESR or
highlighted a novel follicular helper T cell signature that CRP can be observed in most patients with active dis-
may promote B cell activation and function114. ease, although it may be more modestly elevated in TAK
compared with GCA35,117,118.
Diagnosis, screening and prevention
No validated diagnostic criteria exist for GCA or TAK. Imaging versus histological diagnosis
Historically, diagnosis of GCA was based on a constel- TAB is a useful investigation for suspected C-GCA or
lation of symptoms, ideally with histological confirma- LV-GCA with cranial involvement. Previously consid-
tion of vasculitis. Incorporation of vascular imaging into ered the gold standard for diagnosis, advances in the
diagnostic assessment may complement or even replace reliability of vascular imaging techniques have meant
tissue diagnosis in C-GCA and is generally considered that reliance on TAB in some centres has declined115.
Indeed, several high-quality studies have demonstrated
Box 3 | Clinical features of giant cell arteritis and Takayasu arteritis equivalent diagnostic accuracy between imaging and
TAB115. Additionally, at least in the case of ultrasonog-
Systemic symptoms • Neck painb raphy, imaging is more cost-effective and less invasive119.
• Anorexia • Neurological deficit The clinical pre-test probability of GCA should be taken
• Arthralgia • Scalp tendernessb into account when considering which investigation
• Fatigue • Tongue claudicationb might best suit the individual115,120. Ultrasonography
• Lethargy • Vision disturbanceb alone may be sufficient to both exclude GCA in cases
• Low-grade fever of low pre-test probability and confirm GCA in cases of
Examination findings
• Myalgia high pre-test probability. TAB is recommended in those
• Aortic regurgitationa cases with an uncertain pre-test probability or in which
• Sweats • Carotidyniaa ultrasonography has failed to confirm the diagnosis.
• Weight loss • Discrepancy between right and left arm The slight shift in focus towards imaging for diagno-
Symptoms of tissue/organ blood pressure sis has been accelerated by the increased recognition of
ischaemia • Hypertensiona large-vessel involvement in GCA — something that TAB
• Abdominal paina • Ophthalmic abnormalitiesb fails to identify6. Despite this, TAB is still an important
• Chest paina • Reduced or absent pulsesa consideration in the diagnostic pathway of C-GCA and,
• Coughb • Scalp tendernessb in many parts of the world, particularly North America,
• Dyspnoeaa • Tender and/or thickened temporal remains the recommended first-line investigation in sus-
• Headacheb arteriesb pected C-GCA121,122. TAB has no role in the diagnosis of
• Jaw claudicationb • Vascular bruits TAK, in which temporal artery involvement is unusual.
• Lightheadednessa
Histological diagnosis of TAK is only possible in excep-
a
More prevalent in Takayasu arteritis. tional circumstances or in the postoperative setting, such
• Limb claudicationa b
More prevalent in giant cell arteritis286.
as following aortic valve replacement.
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Table 1 | Laboratory investigations for large-vessel vasculitis (compression sign) provides a diagnostic sensitivity of
77% and specificity of 96%123. Although ultrasonography
Investigation Rationale is useful for assessing the temporal and axillary arter-
Recommended for all ies — two common sites of inflammation in GCA — its
Full blood count A ‘reactive’ full blood count (for example, thrombocytosis, use to detect pathology in the aorta is limited. However,
normochromic normocytic anaemia or leukocytosis) may assessment of the carotid and subclavian vessels by
reflect systemic inflammatory processes ultrasonography may have utility in TAK124.
Urea and electrolytes Although large-vessel vasculitis rarely affects kidney Ultrasonography is safe, inexpensive and widely
test function directly, baseline results may help inform available, although differences in performance and data
treatment interpretation can lead to reduced inter-reporter relia-
Liver function test Non-specific abnormalities, such as transaminitis or bility. The Role of Ultrasound Compared with Biopsy
isolated raised alkaline phosphatase, may be observed of Temporal Arteries in the Diagnosis and Treatment of
Serum albumin test May be reduced owing to a systemic inflammatory process GCA (TABUL) study, the largest study of its kind,
and can track recovery recruited 381 patients with a suspected new diagnosis
C-reactive protein test Non-specific marker of inflammation of GCA to undergo both ultrasonography (axillary and
temporal) and TAB within 10 days of starting treatment.
Erythrocyte Non-specific marker of inflammation
sedimentation rate Ultrasonography had superior sensitivity over TAB (54%
versus 39%) but inferior specificity compared with clin-
Additional tests not recommended for all
ical diagnosis of GCA as the reference standard (81%
Anti-neutrophil Useful to exclude small-vessel vasculitis if part of differential versus 100%)119. The lower-than-expected diagnostic
cytoplasm antibody test diagnosis
accuracy of ultrasonography in this study may relate
Anti-nuclear antibody Non-specific but useful to exclude alternate systemic to the inexperience of some operators. Indeed, sensi-
test inflammatory conditions if part of differential diagnosis tivity improved by 17% once operators had completed
Rheumatoid factor/ Useful to exclude rheumatoid arthritis if part of differential at least 10 scans. However, the diagnostic sensitivity
anti-cyclic citrullinated diagnosis; may detect cryoglobulinaemia of TAB is also operator dependent, influenced both by
peptides test
specimen adequacy and the expertise of the reporting
Complement test May be elevated as part of the inflammatory response; low pathologist119. Where diagnostic uncertainty exists, there
complement C3 and/or C4 suggest alternative diagnoses may be a role for both ultrasonography and TAB115,119.
such as systemic lupus erythematosus, cryoglobulinaemia
and bacterial endocarditis
MRI. Although prone to less inter-operator variability
Cryoglobulin test Useful to exclude cryoglobulinaemia, which may present
with systemic features and mimic large-vessel inflammation than ultrasonography, MRI is more expensive and less
widely available. MRI provides a thorough assessment
Quantitative serum Useful to exclude monoclonal gammopathy and of the vessel wall and can accurately identify luminal
immunoglobulin tests IgG4-related disease, which may present with systemic
symptoms and large-vessel inflammation abnormalities when combined with MR angiography
(MRA). MRI–MRA is generally considered first-line
Protein electrophoresis Useful to exclude monoclonal gammopathy
imaging for suspected TAK as it requires no radiation
Microbial investigations Used if infection is suspected clinically; hepatitis serology is exposure and these patients are generally younger and
useful if polyarteritis nodosa is part of differential diagnosis
may require interval scans, although few data support
its accuracy120,125. MRI–MRA may be appropriate first-
Choice of initial imaging modality line imaging for suspected LV-GCA; however, there is
Multiple imaging modalities are available to assess the little to support its superiority over CT or PET. When
extent and severity of LVV, including ultrasonography, ultrasonography is unavailable in suspected C-GCA,
MRI, CT and 18F-fluorodeoxyglucose (FDG)-PET. Each high-resolution MRI of the cranial arteries provides
modality has advantages and disadvantages and use comparable diagnostic accuracy123.
is typically guided by the clinical scenario and local
expertise. It is recommended that imaging of the aorta CT angiography. CT angiography (CTA) is quicker and
and major branches is considered in all patients, even more widely available than MRI, with a sensitivity of
in those with a primarily cranial presentation, as the 73% and specificity of 78% for diagnosing LV-GCA126.
presence of great vessel involvement may influence EULAR does not recommend its use for cranial disease
treatment strategy and prognosis (Fig. 5). Of note, the and, although it is an option for suspected large-vessel
diagnostic accuracy of the imaging modalities described disease, the ability of CTA to identify vessel wall oedema
declines quickly following treatment with glucocorti- and inflammation is probably inferior to MRI120. Further,
coids and imaging is best performed within 1 week of obligatory radiation exposure makes CTA less favourable
starting therapy119,120,122. Accordingly, the use of imaging for younger patients with TAK. CT may be a useful initial
for disease monitoring presents many challenges and is investigation in situations where LVV is one of several
considered separately (Box 4). possible diagnoses. In such cases (for example, pyrexia
of unknown origin), CT may be the preferred imaging
Ultrasonography. In suspected C-GCA, ultrasonogra- modality either alone or in combination with PET.
phy is considered by many to be the initial investiga-
tion of choice120. Demonstration of features including a PET. FDG-PET imaging provides a functional map of
thickened temporal artery wall (halo sign) and a vessel large-vessel inflammation. Contiguous, high-grade vas-
that remains visible following compression of the lumen cular FDG uptake affecting multiple arterial territories

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Primarily cranial presentation Primarily systemic/large-vessel presentation
Case example 1 Case example 2 Case example 3 Case example 4

• 75-year-old man • 72-year-old woman • 60-year-old man • 30-year-old woman
• Unilateral headache, • Unilateral headache, • Weight loss, fatigue, • Lethargy, anorexia
jaw claudication scalp tenderness night sweats, myalgia • Right arm claudication
• Lethargy, myalgia, • Myalgia, fatigue • Initial investigations • Uneven upper limb BP,
weight loss • Right eye reduced normal absent right arm
• Right temporal artery visual acuity • Concern of LVV radial pulse
firm, tender
Same day ophthalmology
review
‘Fast-track’ specialist review Urgent specialist review Urgent specialist review
Targeted laboratory investigations Targeted laboratory Targeted laboratory

investigations investigations
Ultrasonography, TAB or both
considering pre-test probability of GCA
Consider MRA/CTA/PET for investigation of LV involvement MRA/CTA/PET MRA/PET/CTA
C-GCA ± LV involvement LV-GCA TAK
Fig. 5 | Investigation and diagnosis of LVV. Schematic outlining a simplified approach to the investigation and diagnosis
of different large-vessel (LV) 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 which of ultrasonography
or temporal arterial biopsy (TAB) is the most appropriate initial investigation115. 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 LV-GCA (case example 3) and Takayasu arteritis (TAK) (case example 4). In these cases, imaging
with either MR angiography (MRA), computed tomography angiography (CTA) and/or PET is required. BP, blood pressure.
is typical of active LVV127 (Fig. 6). Alternative causes of imaging data to be collected simultaneously with the
vascular FDG uptake, primarily atherosclerosis, can functional data, albeit with considerable radiation
introduce diagnostic uncertainty, and several quanti- exposure. More recently, hybrid scanners combining
fication methods have been proposed to distinguish PET with MRI have demonstrated promising results
LVV from atheroma and other mimics127. Areas of produced with a fraction of the radiation exposure of
maximal FDG uptake are typically referenced against CT134,135 (Fig. 7). Further studies will determine whether
background uptake values such as those from the liver hybrid PET–MRI is a useful diagnostic tool in LVV.
or venous blood pool, with cumulative arterial terri- Additionally, advances in PET radiotracers may enable
tory scores, such as the PET Vasculitis Activity Score active vascular inflammation to be distinguished from
(PETVAS), used to reflect disease burden128. A 2015 other pathologies such as atherosclerosis136. Radioligands
meta-analysis of the diagnostic efficacy of PET across with specific affinity for activated macrophages, such as
11 studies — 4 in GCA (57 patients) and 7 in TAK 11
C-(R)-PK11195, have shown promise in small studies
(191 patients) — demonstrated pooled sensitivities and demonstrating the ability to track inflammation and dif-
specificities of 90% and 98% for GCA and 87% and 73% ferentiate active LVV from inactive disease137. PET may
for TAK, respectively129. Evidence suggests that PET may be of particular value in cases of diagnostic uncertainty,
also be useful to detect vascular pathology in the cranial for example, to exclude occult malignancy, whether
arteries130,131 and that baseline PET metrics may have a combined with CT or MRI.
role in predicting disease course132.
The drawbacks of PET include limited access, high Disease relapse
cost and long procedure times. Further, vascular FDG Risk of relapse is high and remains elevated for years
uptake is attenuated rapidly following treatment ini- after diagnosis of LVV. EULAR guidelines define major
tiation. A study examining the diagnostic accuracy of relapse as the recurrence of clinically active disease
PET following the introduction of high-dose predni- alongside features of ischaemia or radiologically con-
solone in 24 patients with active LVV showed that the firmed aortic inflammation, and minor relapse as the
FDG signal was reduced after 3 days of treatment; recurrence of disease not fulfilling these criteria8.
although the signal at this time point was still diagno Relapse risk in GCA has been reported as ~30–75%
stic in 100% of patients, by 10 days, this figure had fallen over the disease course and is particularly high within
to 36%133. the first 2 years following diagnosis138,139. A retrospec-
PET also requires a second imaging modality to tive US cohort study of 286 patients with biopsy-proven
map the low-definition functional image. Traditionally, GCA reported a relapse rate of 74% over a median
this has been CT, which enables impressive structural period of 5.1 years, with female patients and those with
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pre-existing hypertension and diabetes at greatest risk140. of established vascular disease, treatment, anxiety or an
Involvement of the aorta and major branches seems to entirely separate disease process. Similarly, arm clau-
confer an increased relapse risk in GCA16. For patients dication — a symptom of LVV — may be modifiable
with TAK, disease relapse rates are ~20% at 1 year with treatment if owing to active vessel inflammation
and ~50% at 10 years141 and male sex, elevated CRP and or may be chronic and treatment refractory if related to
carotidynia at presentation are associated with higher vascular damage. Rigorous assessment at presentation
relapse risk141. Accurate disease monitoring is key to the and care continuity within the same clinical team are
early recognition and treatment of relapse; such tools important to expeditiously recognize subsequent disease
are important for tracking persisting, low-grade inflam- progression.
mation that has been demonstrated in preclinical and
clinical studies but does not meet the criteria for relapse Laboratory markers. CRP and ESR are often used for
and may be clinically silent44,86. disease monitoring but may not correlate with clinical
or vascular disease activity once treatment has started.
Disease monitoring In a study of biopsy-proven GCA, 24 of 25 patients had
Disease monitoring is crucial to accurately match treat- a normal ESR by day 28 of glucocorticoid treatment142;
ment intensity with disease activity. Although several 15 patients relapsed with a total of 31 relapses. Of these
disease activity assessment tools have been proposed, patients, 42% had a normal ESR at time of relapse. In this
none has been widely accepted for use either clinically study, IL-6 was a more sensitive marker of active disease
or for research purposes. Consequently, escalation and than ESR and IL-6 remained high in 67% of patients
de-escalation of treatment are based on a combination achieving complete clinical remission, whereas ESR
of clinical assessment, laboratory investigations and was high in only 12.5%, supporting low-grade inflam-
imaging. mation. In a study of 112 patients with LVV — 56 with
GCA, 56 with TAK — the researchers found no corre-
Clinical assessment. Accurate monitoring of disease lation with ESR and only a modest correlation between
activity by clinical assessment alone can be challenging CRP and outcome measures, including physician and
in the later phases of LVV. Symptoms such as fatigue and patient-reported outcomes and PET imaging143.
pain may reflect active inflammation or be consequences New biomarkers of LVV disease activity with better
performance characteristics compared with clinical and
imaging-based reference standards are urgently needed.
Box 4 | Advantages and disadvantages of different imaging modalities for Advances in our understanding of disease pathogene-
LVV monitoring sis have identified potential candidates; for example, in
2003, one study demonstrated a correlation between
Assessing the response to treatment and monitoring vascular complications are impor-
tant aspects of long-term disease management in large-vessel vasculitis (LVV) and can
TAK disease activity and MMP3 and MMP9 (ref.144).
be achieved with various non-invasive imaging techniques287. Interval ultrasonography Another study found that circulating PTX3 was higher
is rarely used for disease monitoring owing to operator dependence and reliance on the in patients with clinically active TAK than in those with
involvement of accessible vessels. MRI has the potential to be a useful tool, particularly inactive disease, healthy controls and acute infection,
as lack of radiation exposure enables interval scanning. Vessel-wall-based metrics, and elevated levels of circulating PTX3 distinguished
including mural thickness, increased mural signal and mural enhancement following active disease from inactive disease better than CRP or
administration of contrast agents, may inform ongoing disease activity, although further ESR145. Elevated PTX3 levels also correlated with active
study is required288. In a prospective study in 84 patients, correlation with clinical GCA, particularly in those with recent optic nerve
assessment of disease activity was less reliable with MR angiography than with PET; ischaemia146. Several other candidate biomarkers remain
however, these modalities offered complementary information289. Vascular damage,
under investigation, including serum amyloid A, osteo-
including areas of previously identified stenosis or dilation, may be best monitored with
MR angiography, with scoring systems now capable of quantifying vascular damage
pontin, amino-terminal pro-B-type natriuretic peptide
longitudinally252,253. CT angiography (CTA) may also be used to monitor vascular dam- (NT-pro-BNP) and calprotectin; however, none has
age, although it is less able to detect active disease once treatment has started290. CTA been incorporated into widespread clinical use. Potential
may be more useful when combined with PET and, although hybrid PET–CT is associ- novel biomarkers may have a role beyond diagnosis
ated with more radiation exposure than CTA alone, its use may be justified by the addi- and disease monitoring, including prognostication and
tional functional information gained. One study investigated PET–CT as a disease assessment of vascular and end-organ damage, although
monitoring tool in 56 patients with LVV and a control group consisting of 59 individuals, further work is required147.
including healthy volunteers, disease mimics and patients with hyperlipidaemia. They
found a sensitivity of 85% and specificity of 83% for distinguishing active vasculitis from Imaging. The ideal imaging modality for disease mon-
comparators128. However, PET–CT did detect active inflammation in 58% of patients
itoring in LVV should be safe, widely available, cost-
who were in clinically determined remission, suggesting either an inability to distin-
guish active disease from vascular remodelling and atherosclerosis or the presence of
effective and able to distinguish persisting vascular
low-grade disease. This phenomenon has also been noted with other imaging modali- inflammation from vascular remodelling and alternative
ties and remains a source of intense investigation. Such drawbacks mean that the role conditions — most notably atherosclerosis. There is no
of PET–CT in disease monitoring remains far less established than its role in diagnosis. current consensus on how frequently imaging should be
Hybrid PET–MRI overcomes many of the problems associated with PET–CT and may performed in this setting and decisions should be made
provide a more detailed assessment of disease activity with reduced radiation exposure on an individual basis. The advantages and disadvan-
(~20% of PET–CT)134,135. PET–MRI use is increasing in other cardiovascular disorders, tages of different imaging modalities for LVV disease
including coronary artery disease, cardiac sarcoidosis and cardiomyopathy291,292. Data to monitoring are highlighted in Box 4. This is an area of
support longitudinal PET–MRI scanning over other imaging modalities are limited, but unmet need as highlighted by the 2018 EULAR LVV
early results suggest feasibility and further research is ongoing134,293.
research agenda120.

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a b c
Fig. 6 | Longitudinal follow-up imaging using FDG-PET. Images show a 68-year-old woman with large-vessel giant cell
arteritis (LV-GCA) at time of diagnosis (part a) and at the 6-month (part b) and 12-month (part c) follow-up points during
treatment with tapered glucocorticoids and tocilizumab. 18F-fluorodeoxyglucose (FDG) uptake is seen throughout the
aorta and subclavian arteries bilaterally at diagnosis and is attenuated at each time point thereafter.
Disease activity assessment tools. A robust disease TAK is more commonly associated with large-vessel
severity scoring system for LVV is needed. Although complications than GCA153. Complications, in order of
several assessment tools exist, these are mostly used as frequency, include new arterial occlusion (42%), stroke
end points in clinical trials rather than for clinical pur- or transient ischaemic attack (20%), new or worsening
poses (Table 2). Unfortunately, there is no well-defined aneurysm (11%), end-stage kidney disease (10%), myo-
reference standard of disease activity against which new cardial infarction (6%), heart failure (6%), and aortic
tools may be compared, presenting a major challenge regurgitation (5%)141. These are more likely in those
for clinical trials. with progressive disease, in those with thoracic aorta
involvement and in those with retinopathy141.
Disease complications
Unchecked vascular inflammation may lead to a range Management
of disease complications in LVV. Vision loss is the most There are two stages in the pharmacological treatment
feared complication of GCA in the short term and occurs of LVV. Induction of disease remission, which aims to
in ~15–20% of patients148. Anterior ischaemic optic neuro suppress initial vascular inflammation and typically
pathy is the most common pathology contributing to requires high doses of glucocorticoids, and remission
vision loss and may be halted by prompt initiation of maintenance (Fig. 8). The evidence base for treatment is
glucocorticoids. Symptoms such as diplopia and blurred more robust for GCA, whereas the treatment of TAK
vision may improve with treatment; however, complete is largely based on expert opinion.
monocular vision loss is unlikely to recover and the goal
of therapy, in this case, is to prevent bilateral vision loss. Remission induction
Encouragingly, vision loss is far less common during Although never subjected to evaluation in randomized
disease relapse compared with initial presentation — an controlled trials, glucocorticoids are the mainstay of treat-
important consideration during treatment reduction or ment for remission induction in LVV. Glucocorticoids
withdrawal138. induce rapid symptom relief and reduce the risk of vision
Large-vessel involvement in GCA is associated with loss in GCA. The optimal initial dose of glucocorticoids
higher mortality, a potentially greater risk of relapse and and their route of administration has not been thoroughly
higher cumulative glucocorticoid exposure16,149. A 2019 investigated but is usually 40–60 mg of oral prednisolone
retrospective analysis comparing 183 patients with LVV or equivalent per day, as recommended by EULAR and
aged 50–60 years with 183 patients aged >60 years found ACR guidelines for both GCA and TAK8,122. For a more
that patients in the younger group had a higher inci- rapid and intensive effect, patients with GCA-related
dence of aortic and peripheral vascular involvement and sight-threatening symptoms may be given pulsed intra-
required more treatment than older patients150. Similarly, venous methylprednisolone; however, there is little evi-
in a cohort of 332 patients with GCA, 14% of those with dence to support this approach and it may increase the
large-vessel involvement at diagnosis had developed risk of glucocorticoid-related complications as seen with
aortic aneurysms within ~4 years, compared with 5% its use in other vasculitides154. Low initial oral predniso-
of those with C-GCA at outset16. In a large UK study, lone doses may be considered (25–30 mg/day) in select
the risk of aortic aneurysm formation in GCA was two- patients with TAK with a lower risk of complications;
fold higher than in matched controls151. Further, owing for example, those without lesions that threaten arte-
in large part to a continued reliance on glucocorticoids, rial flow. TAK may present without clinical, serological
complications of treatment remain a considerable cause or imaging-based evidence of disease activity; in such
of morbidity in GCA with adverse effects occurring in patients, the benefit of treatment with glucocorticoids
>80% of treated patients152. or other disease-modifying therapies is unknown.
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An open-label study of 18 patients with GCA tested for TAK due to the greater propensity for relapse, and a
the ability of the IL-6 receptor antagonist tocilizumab target dose of ≤10 mg/day should be achieved at 1 year157.
to induce disease remission following three intravenous Although tapering is needed to reduce glucocorticoid-
pulses of methylprednisolone155; 78% of patients achieved related adverse effects, LVV relapses in 34–75% of
remission within 24 weeks and 72% were relapse free at patients when glucocorticoids are reduced158, most
week 52. Out of 18 patients, 5 (28%) stopped treatment commonly at doses of prednisolone <20 mg/day139.
owing to non-response or tocilizumab-related adverse In general, glucocorticoid minimization results in
events. Although tocilizumab monotherapy may induce higher relapse rates159 and clinical trials have shown
disease remission following brief glucocorticoid expo- that only ~20% of patients with GCA in placebo arms
sure, remission induction is slow and persisting disease maintain sustained remission at 1 year after an aggres-
activity may lead to ongoing symptoms or irreversible sive glucocorticoid taper and early discontinuation at
complications such as anterior ischaemic optic neu- 22–26 weeks160,161. Most patients require longer treat-
ropathy, as developed by one patient during the study. ment periods. In a randomized controlled trial (RCT)
Thus, tocilizumab monotherapy cannot currently be published in 2017, two different tapering regimens were
recommended for remission induction. compared, with discontinuation of glucocorticoids at
26 or 52 weeks. At 1 year, relapses had occurred in 68%
Remission maintenance and 49% of patients, respectively161. With respect to
Disease remission in LVV is defined as the absence of TAK, a rapid glucocorticoid taper resulted in relapses
any clinical features attributable to active disease, nor- in ~60–80% of patients at the end of follow-up162,163.
malization of laboratory parameters and a halt in the Glucocorticoid monotherapy may be considered as
progression of vascular imaging abnormalities8. an option for maintaining disease remission in GCA as
~40% of patients can reach the target of ≤5 mg/day at
Glucocorticoids. Once initial disease control is achieved, 1 year, a dose considered safe164. When used in this way,
glucocorticoids are tapered to reduce adverse effects, glucocorticoid treatment should be continued for a min-
usually after 2–4 weeks. The optimal pace of tapering imum of 2 years8. Conversely, glucocorticoid monother-
has not been established and probably varies between apy is less effective in TAK141,162,163. As TAK evolves as a
patients. In general, to achieve a compromise between more chronic and relapsing disease than GCA, the early
relapse risk and glucocorticoid-related adverse effects, addition of disease-modifying therapy is recommended8.
which are common 156 and particularly common in
elderly patients152, it is recommended that tapering Disease-modifying or glucocorticoid-sparing treat-
should aim to achieve 15–20 mg of prednisolone (or ments. Most published guidelines recommend the use
equivalent) per day after 2–3 months and ≤5 mg/day of a disease-modifying agent in patients with GCA who
after 1 year. Glucocorticoid tapering is usually slower have relapsing or refractory disease, or in those with an
a b c
Fig. 7 | PET–MRI in large-vessel vasculitis. a | Whole-body MR angiography showing luminal subclavian abnormalities
(arrows) in a patient with Takayasu arteritis (TAK). b | Fused coronal PET–MRI showing 18F-fluorodeoxyglucose (FDG) uptake
involving subclavian arteries (arrows), aortic arch and distal aorta (arrowheads) in a patient with large-vessel giant cell
arteritis. 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 large-vessel giant cell arteritis.

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increased risk of glucocorticoid-related adverse effects8. TAK is often more difficult to control than GCA
Increasingly, physicians are opting for these treatments owing to more frequent relapses. No RCT of broad-
earlier in the GCA treatment pathway, with some adopt- spectrum immunosuppressive agents has been per-
ing initial combination therapy as standard practice in formed in TAK. MTX, azathioprine, mycophenolate
patients with large-vessel involvement122. Indeed, this and leflunomide have all been reported as potentially
approach has been incorporated within the latest ACR useful157,177. Unless other therapies fail, cyclophospha-
guidelines122. In TAK, the combination of glucocorti- mide is not generally recommended in TAK because of
coids and a glucocorticoid-sparing agent is considered its adverse effects on fertility. Physician expertise, patient
first-line owing to the potential for higher relapse rates preferences, comorbidity and adverse effects usually
and disease progression in those treated with glucocorti- dictate the choice of treatment.
coids alone8,30,165. Novel biologic agents are now available
for use in LVV in addition to traditional broad-spectrum Targeted biologic therapies for GCA. Improved under-
glucocorticoid-sparing agents. standing of specific disease pathways involved in the
Methotrexate (MTX) has been tested in three ran- pathogenesis of LVV has paved the way for targeted bio-
domized, double-blind, placebo-controlled trials in logic therapies (Fig. 4), some of which have demonstrated
patients with newly diagnosed GCA166–168. An indi- efficacy in phase II and phase III clinical trials and others
vidual patient-level meta-analysis of all three studies that are currently under investigation.
demonstrated a reduced risk of disease relapse and After a promising phase II trial178, the efficacy of the
reduced cumulative glucocorticoid exposure in those IL-6 receptor-blocking humanized monoclonal antibody
treated with MTX compared with glucocorticoids tocilizumab was demonstrated in the phase III Giant Cell
alone169; however, a second meta-analysis did not rep- Arteritis Actemra (GiACTA) trial, which included both
licate this finding170. MTX doses used in these trials newly diagnosed and relapsing patients with GCA161.
were generally low (7.5–15 mg/week) and higher doses, Treatment with tocilizumab resulted in a significantly
although not formally tested, have been used in clinical increased proportion of patients in sustained remission
practice. Observational, real-life data also support an at week 52, a longer time to disease flare, decreased
effect of MTX on reducing GCA disease relapses and cumulative glucocorticoid doses, and improvements in
glucocorticoid dose171. quality of life over placebo161,179. Weekly dosing achieved
The glucocorticoid-s paring activity of several better disease control than dosing every other week,
other immunosuppressive agents has been reported particularly in relapsing and refractory cases161.
in low-quality studies (mostly retrospective or case A number of observational clinical studies, includ-
series) including leflunomide 172, mycophenolate173, ing a higher proportion of relapsing patients with GCA
dapsone174 and cyclophosphamide175,176. In a small, than previous clinical trials, have used tocilizumab as an
randomized trial, cyclosporin did not show significant add-on therapy180. These patients had fewer disease flares
glucocorticoid-sparing activity and azathioprine showed than those in the GiACTA trial, possibly because low-dose
a glucocorticoid-sparing effect in a mixed population of glucocorticoid or concomitant immunosuppressive treat-
patients with GCA and PMR175. ments were not discontinued in a substantial proportion
of patients180,181. However, one study also showed more
infections in patients treated with tocilizumab182.
Table 2 | Disease activity assessment tools Tocilizumab has been a major therapeutic advance
Tool GCA Description Validated and is now licensed for the treatment of GCA in both
or TAK in LVV the USA and Europe. However, >40% of patients are
unable to maintain disease remission despite adherence
Birmingham Both Designed to quantify disease activity for any No
Vasculitis vasculitis syndrome but only successfully to recommended glucocorticoid tapering, and extended
Activity Score258 validated in small-vessel vasculitis and follow-up data show that only 40% of initial responders
remains less applicable to LVV maintain treatment-free disease remission after 3 years.
National TAK Combines clinical assessment, laboratory No This is supported by observational data181,183. Thus,
Institutes of investigations and imaging; 74% correlation tocilizumab may need to be continued for longer than
Health criteria259 with physician global assessment260 the 52 weeks initially assessed in the GiACTA trial and
DEI.Tak260 TAK Detailed in certain aspects such as Yes other options are needed184.
cardiovascular examination findings; Routinely measured acute phase reactants are abro-
does not consider imaging or laboratory gated by tocilizumab185. This could be disadvantageous
investigations and cannot easily distinguish
active disease from established vascular as there is the potential for undetected, low-g rade
complications large-vessel inflammation with tocilizumab use and
glucocorticoid minimization. Indeed, case reports have
ITAS and TAK Similar to DEI.Tak but with even greater Yes
ITAS-activity261 weighting applied to cardiovascular demonstrated histologically active vasculitis despite
involvement; ITAS-activity also considers clinically quiescent disease and suppressed acute-
C-reactive protein and erythrocyte phase reactants in those receiving tocilizumab186,187.
sedimentation rate; validation in 177 In these cases, imaging biomarkers may be useful188–190.
patients showed good inter-rater reliability
but correlation with physician global Until more long-term follow-up data are available, many
assessment was limited health-care providers reserve tocilizumab for patients
DEI.Tak, Disease Extent Index-Takayasu; GCA, giant cell arteritis; ITAS, Indian Takayasu Clinical with, or at risk of, glucocorticoid-related adverse effects
Activity Score; TAK, Takayasu arteritis; LVV, large-vessel vasculitis. or for patients with relapsing disease.
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Confirmed diagnosis of GCA Confirmed diagnosis of TAK
Start prednisolone at 40–60 mg/day Start prednisolone Start glucocorticoid-

+
at 40–60 mg/day sparing agent
Reduce prednisolone in stratified High risk of adverse events with Reduce prednisolone in stratified
way aiming for <5 mg/day by 1 year prednisolone or other concerning way aiming for <10 mg/day
or before features? by 1 year or before
Relapse or refractory disease? Relapse or refractory disease?
Escalate prednisolone Start glucocorticoid- Escalate prednisolone Consider alternative

dose if possible sparing agent dose if possible glucocorticoid-sparing agent
Sustained remission Sustained remission
Continue prednisolone taper Continue prednisolone taper
Choice of glucocorticoid-sparing agent Other considerations Choice of glucocorticoid-sparing agent Other considerations
• Tocilizumab • MMF • Antiplatelet agents • Tocilizumab • MMF • Antiplatelet agents
• Methotrexate • Investigational • Surgical/endovascular • Methotrexate • Investigational • Surgical/endovascular
therapies* intervention • TNF inhibitors therapies* intervention
Fig. 8 | Management of LVV. 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). The addition of a glucocorticoid-sparing agent is recommended from the outset in
TAK and may be considered in some with GCA on the basis of clinical features. The choice of glucocorticoid-sparing agent
is largely dictated by physician preference. MMF, mycophenolate mofetil; TNF, tumour necrosis factor. *Several novel
therapeutic agents are currently under investigation in GCA and TAK and are outlined in Box 5.
Mavrilimumab is a fully humanized monoclonal response and remains elevated in relapsing patients194,195.
antibody targeting the GM-CSF receptor-α subunit. TNF inhibitors, including infliximab, etanercept and
Expression of GM-CSF and its receptor are increased adalimumab, have been subjected to RCT evalua-
in GCA tissue and preliminary results in functional tion in patients newly diagnosed with GCA and have
models suggest a role for GM-CSF in key pathogenic failed to demonstrate significant benefits160,196,197. These
aspects of GCA, including DC activation, T cell differ- data underline that a biomarker of disease activity
entiation, pro-inflammatory macrophage activation and may not necessarily be a viable therapeutic target and
angiogenesis92. A 2021 phase II study demonstrated that TNF inhibitors are not recommended for patients with
mavrilimumab alongside a 26-week prednisolone taper GCA8.
was superior to placebo plus a 26-week prednisolone
taper in increasing the time to disease flare. Sustained Ongoing phase II/III trials. Novel models using murine
disease remission at week 26 was achieved in 83% of engraftment of human arterial tissue followed by induc-
mavrilimumab recipients and in 50% of those receiv- tion of LVV-like inflammation now enable the assess-
ing placebo191. It is noteworthy that acute-phase reac- ment of therapeutic strategies specific to large vessels198.
tants retain their clinical value under mavrilimumab Work using such models has suggested a potential role
treatment and therefore mavrilimumab has promise for JAK inhibitors in GCA100. The JAK1 inhibitor upad-
as a novel therapeutic option for patients with GCA, acitinib is now being evaluated for the treatment of GCA
although efficacy and safety need to be confirmed in in a randomized multicentre, double-blinded, placebo-
larger trials. controlled trial199. Several other phase II and phase III
Abatacept is a fusion protein comprised of CTLA4 trials in patients with GCA are ongoing and results are
and the Fc region of IgG1 that inhibits CD28-mediated eagerly awaited (Box 5).
T cell activation. In a phase II RCT recruiting patients
with active disease, after an initial 3-month combination Targeted biologic therapies for TAK. As TAK is less
treatment with glucocorticoids and abatacept, patients common than GCA and assessment of disease activity
in remission were randomized to continue abatacept or may be more difficult, there are fewer clinical trials in
receive placebo in addition to standardized glucocorti- these patients. The efficacy of tocilizumab was tested
coid taper with discontinuation at 28 weeks. Relapse-free in an RCT including 36 patients with relapsing TAK162.
survival at 12 months was slightly higher in the abatacept Although the primary end point (time to relapse) did not
arm than in the placebo arm (48% versus 31%)192. The reach statistical significance between treatment arms,
efficacy of abatacept is currently being explored in an there were favourable trends and no safety concerns
investigator-sponsored phase III RCT193. were raised. Extended follow-up of this trial200, observa-
TNF is strongly expressed in GCA lesions, is ele- tional studies and case series support a sustained benefit
vated in serum from patients with a strong acute-phase of tocilizumab in TAK201–203. TNF inhibitors are used in

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Box 5 | Ongoing studies in GCA and TAK Revascularization and aneurysm repair
Revascularization procedures have an important role
GCA in the management of patients with TAK. They may be
• An investigator-sponsored phase III trial testing the efficacy of the CD28-mediated necessary when vascular lesions cause complications
T cell activation inhibitor abatacept in giant cell arteritis (GCA) following such as uncontrolled renovascular hypertension; are
demonstration of improved relapse-free survival in a phase II trial193. organ-threatening, for example, in the case of critical
• An investigator-sponsored phase III trial with the recombinant IL-1 receptor carotid or vertebral stenosis; or if they persist despite
antagonist anakinra294; IL-1 is strongly expressed in GCA194,295 and may have an optimal pharmacological treatment8,157. Percutaneous
important role at multiple steps in the pathogenesis cascade. angioplasty and open surgical approaches are both pos-
• A phase III randomized controlled trial (RCT) blocking IL-17 with secukinumab296; sible and outcomes are broadly similar210. Simple bal-
IL-17 expression is increased in GCA and rapidly decreases with glucocorticoid loon angioplasty may be preferable to stenting as in-stent
treatment, indicating that IL-17 suppression by high-dose glucocorticoids may
stenosis seems to be more frequent than in athero
underline their beneficial effects94.
sclerotic lesions in observational studies211,212. The use
• A phase II RCT evaluating guselkumab, a monoclonal antibody that neutralizes the
of paclitaxel-coated balloon renal artery angioplasty is
IL-23p19 subunit297; IL-23, a heterodimer composed of p40 and p19 subunits, is a
relevant cytokine in maintaining the T helper 17 (TH17) cell differentiation pathway in
being evaluated in an RCT213. Immunomodulatory ther-
GCA; the IL-23p19 subunit is expressed in excess over its partner IL-12/23p40 (ref.298) apy should be optimized before any attempted revascu-
and may have independent pro-inflammatory activities299. larization and procedures should ideally be performed
• A small, open-label, investigator-sponsored, phase II RCT of ustekinumab, a monoclonal in patients in established disease remission214. Reduced
antibody against the IL-12/23p40 subunit (ref.300); IL-12/23p40 is expressed at low patency, restenosis and complications are more frequent
levels in GCA lesions298 and blocking IL-12p40 may reduce the activity of molecules when manipulating arteries with active disease214.
related to TH1 and TH17 differentiation in GCA lesions298; non-controlled studies Revascularization is infrequently needed in GCA,
regarding the effect of ustekinumab have been inconclusive301,302. a disease with a lower incidence of stenosis than TAK.
• A phase III, multicentre trial of the efficacy of the JAK1 inhibitor upadacitinib199. Its use for limb-artery stenoses has been reported215,216.
• An open-label trial of the endothelin receptor antagonist bosentan in GCA has Percutaneous angioplasty should be considered in
been proposed but is not yet recruiting303; in vitro data suggest a potential role for patients with stroke or transient ischaemic attacks
endothelin receptor antagonism as a means of inhibiting vascular smooth muscle cell owing to proximal carotid or vertebral stenoses217,218.
proliferation in large-vessel vasculitis107. Aortic aneurysm repair may be needed in both TAK
• An investigator-sponsored phase III trial comparing tocilizumab, a monoclonal and GCA and requires joint long-term management
antibody against the IL-6 receptor, and methotrexate (MTX)304. with cardiothoracic surgeons8,157.
• Phase III clinical trials of sirukumab and sarilumab (both of which target IL-6 activity)
in patients with GCA were initiated but terminated early by the sponsor; preliminary Cardiovascular disease risk
data with sirukumab showed positive trends305. Chronic low-grade inflammation and prolonged gluco
TAK corticoid exposure contribute to an increased risk of
cardiovascular disease in LVV. This is due in part to
• An open-label, randomized study comparing MTX with the JAK1/3 inhibitor
tofacitinib in patients with mild-to-moderate Takayasu arteritis (TAK)306. the development of risk factors such as hypertension,
diabetes and hypercholesterolaemia, which should be
• A phase III, multicentre RCT of the efficacy of the JAK1 inhibitor upadacitinib307.
managed according to standard guidelines. Population
• A phase III RCT targeting the IL-12/23p40 subunit with ustekinumab; proposed
studies have demonstrated an increased risk of myo-
following promising case series results308.
cardial infarction, stroke and atherosclerotic periph-
• A multicentre phase II RCT comparing tocilizumab with infliximab in patients
eral vascular disease in GCA versus healthy controls219.
with refractory or relapsing TAK (not yet recruiting)309; this study will hopefully
provide clarification regarding the efficacy of different biologic therapies in this A Canadian retrospective cohort study comparing
patient group. 1,141 patients with GCA and 200,000 healthy controls
aged >65 years without pre-existing cardiovascular dis-
ease showed an adjusted hazard ratio (HR) of 2.1 for the
clinical practice for those with refractory disease, and composite end point of coronary artery disease, stroke,
increasingly in some centres as first-line glucocorticoid- peripheral vascular disease, aortic aneurysm or aortic
sparing therapy, although no RCT data support their dissection in GCA220. These findings were replicated in
efficacy157,204. Retrospective analyses suggest better out- a smaller and more carefully matched study, which sug-
comes in patients with TAK receiving biologic therapies gested a HR of 1.8 for myocardial infarction and 2.0 for
than broad-spectrum immunosuppressive agents202–205. stroke in GCA221. By contrast, a UK data linkage study
A multicentre study led by the French Takayasu Network examined cardiovascular outcomes in >10,000 patients
examining outcomes in 209 patients with TAK treated with either PMR, GCA or both as well as in >100,000
with either tocilizumab or TNF inhibitors found no matched controls and found no difference in cardiovas-
difference in rates of complete remission at 6 months cular disease incidence, although follow-up was limited
(~70%) and prevention of relapse205. Abatacept was to ~3 years222.
tested in a phase II RCT and, in contrast to GCA, failed Cardiovascular disease may be more readily observed
to demonstrate any benefit over placebo in patients in younger patients with TAK owing to their longer life
with TAK163. Case series and non-controlled small expectancy66,223, although supporting data are more
studies have reported satisfactory responses to different limited than in GCA. Arterial stiffness, an independent
agents including ustekinumab206,207, rituximab208 and predictor of all-cause and cardiovascular mortality, is
JAK inhibitors209. Several other agents remain under increased in patients with TAK compared with healthy
investigation (Box 5). controls224,225. Another study found an increased burden
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of carotid atherosclerotic plaque in 30 patients with TAK at diagnosis, >60% had difficulty with routine activi-
compared with 50 matched healthy controls226. Plaque ties of daily living and 23% were unable to work due to
burden was similar to a third group of patients with disability153.
systemic lupus erythematosus. Recognizing that standardized health question-
Although antiplatelet agents have been used in some naires may not accurately capture the complexities of
centres, current evidence does not support their rou- LVV disease effects, efforts are ongoing to construct
tine use in GCA227. Prophylactic aspirin prescription disease-specific, patient-reported outcome measures in
is more common in TAK and is supported by a small, both GCA and TAK. A Delphi exercise conducted by
retrospective study that reported a reduction in ischae- the Outcome Measures in Rheumatology (OMERACT)
mic events228. However, >90% of patients included had group evaluated which disease-related items were of
existing cardiovascular disease. Accordingly, antiplatelet most value to both clinicians and patients when deter-
agents should be considered on an individualized basis mining disease activity in LVV with the aim of creating
in both GCA and TAK, for example, in patients with a multi-dimensional tool for use in future studies234. The
coronary arteritis, a history of amaurosis or symptomatic outcomes identified as most important to patients were
supra-aortic disease. As novel treatments continue to fatigue, pain and the emotional impact of disease.
improve outcomes, cardiovascular risk reduction will Owing to the absence of any one single reliable
become increasingly important, particularly in young measure of disease activity in LVV, assessments of qual-
patients. ity of life and other patient-reported outcomes have
been evaluated as potential disease biomarkers for use
Quality of life both clinically and in trials. In a US-based prospective
Several studies have demonstrated impaired quality of cohort study of 112 participants — 56 with GCA, 56
life as a consequence of LVV229–231 comparable to that in with TAK — patient global assessment of disease activ-
rheumatoid arthritis230. This may be due to the effects ity scores were independently associated with clinically
of active disease, disease complications or the adverse active disease231. This study demonstrated a complex
effects of immunosuppressive therapies. Quality-of- relationship between other patient-reported outcomes
l ife effects are unique to each affected patient (Boxes 6,7). and clinical outcomes based on laboratory analysis,
For example, in many patients with C-G CA, con- imaging and physician assessment. Accordingly, com-
cerns about vision loss dominate232. In patients with posite measures of disease activity, combining clinical
large-vessel involvement, the adverse effects on quality and patient-reported outcomes, including quality-of-life
of life seem consistent between GCA and TAK despite assessment, may provide a more accurate reflection of
the age difference between cohorts231. disease activity.
Qualitative studies have attempted to determine Understanding that attainment of disease remission
the specific patient-reported outcomes that are most is only one aspect of a patient’s disease burden may be
influenced by LVV232,233. A study in patients with TAK an important step towards improving the patient jour-
in both the USA and Turkey suggested that almost all ney in the longer term. Interestingly, the GiACTA trial
areas of day-to-day life were affected, including employ- reported that attainment of remission by pharmaco-
ment, family life, finance and self-care233. During periods logical therapy only modestly affected quality-of-life
of active disease, fatigue and pain were the dominant indices161. Non-pharmacological interventions including
factors reducing quality of life, whereas, during remis- exercise and psychological therapy may improve qual-
sion, the emotional burden of disease was more sub- ity of life (as demonstrated in other rheumatological
stantial. Functional impairment in this young patient conditions235) as could supporting access to employment
group should not be underestimated; in a US cohort where possible236. Future work should continue to focus
of 30 patients with TAK with a median age of 27 years on what matters most to patients in order to provide
sustained improvements in quality of life.
Box 6 | Patient experience — before diagnosis
Outlook
On the evening of Christmas Eve 2018, I was very tired and felt as if I had a virus. The past decade has seen substantial advances in our
The next day, during a walk on the beach promenade, I had to rest at several benches. understanding and ability to manage LVV. However,
In retrospect, I had pain in exactly the place where everyone who knows about it would morbidity remains high; in GCA, vision loss is fre-
say: ‘that person has temporal arteritis’. quent and, in TAK, premature mortality is a continued
I was unwell at home for a long time, eventually seeing my family doctor in February concern237. Further, adverse effects from immunosup-
when the coughing showed no signs of abating and I still felt very unwell. The symptoms
pressive therapy, particularly glucocorticoids, are an
lessened with a course of antibiotics but a week later, they were worse. I had no energy
and no appetite. At night I woke up coughing and had nightly sweats. My head was
unresolved dilemma. Key aspirations for the next dec-
constantly ‘bunged up’. A nose spray with steroids made no difference. My hand was ade will include improved understanding of pathogen-
often in the temporal arteritis position and I developed a rash on my back and chest. esis, earlier diagnosis and more targeted therapeutic
I was referred to a bowel clinic on suspicion of cancer, and from there to a general approaches underpinned by clinical trial data.
medicine clinic. By this time, my family thought I was dying, and my family doctor was Molecular and cellular studies of the arterial wall
also very concerned. In March, I was diagnosed with anaemia and type 2 diabetes. I also in LVV are improving understanding of disease
had vision disturbances referred to as visual migraines. By the time of my appointment pathogenesis. Recognition of the differences between
at the general medicine clinic, I was aching all over with what the consultant said was GCA and TAK, with a clear definition of shared and
polymyalgia rheumatica. The consultant had to help me onto the couch and said that disease-specific pathogenic mechanisms, will be criti-
my spine revealed how much weight I had lost.
cal for targeted treatment strategies84. Access to tissue

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Box 7 | Patient experience — following diagnosis

The specialist at the general medicine clinic referred me for a PET scan and I was diagnosed with large-vessel vasculitis
with thickening in the aorta, which I had never heard of before. Soon after my diagnosis, a colleague said to me:
‘My step-mother had that and almost lost her kidney and my friend was on chemo for another type of vasculitis.’ Suddenly,
I had a life-challenging disease. I read leaflets about vasculitis but there were none for large-vessel vasculitis because it is
so rare. I tried hard to get well, to be physically active and to eat well, but was exhausted most of the time and often fell
asleep. I had trouble walking up stairs and showering and dressing were sometimes so tiring that I went back to bed.
For the polymyalgia rheumatica symptoms, the steroids worked wonders. I was euphoric — out of pain within 2 hours
after the first dose — but soon after this, my lips and fingers tingled, my body was restless and my mind was racing and
out of focus. I could not concentrate, could not organize myself and spoke rapidly. I was hungry, then very tired. Then, the
dip: 4 h where I just did not care about anything. This happened every single day after taking the steroid medication. I also
had the round face, the round stomach, the fatty lump on my arm and pouches of fat in odd places.
Throughout the period of this illness, I saw a counsellor. I do not know how I would have managed without her.
She helped me face how hard it was to be ill, how much it changed me, how I struggled to work and how to keep going.
I was able to talk about how out of control I felt, as if I was going mad. My grown-up daughter was also amazing in her
support. She helped me to let go and accept that all I had to do was to focus on getting well, instead of thinking I was
useless, incompetent and without a role in life.
I now feel strongly reassured by my rheumatologist, who supports me to remain calm about the continuing effects of
taking steroids, which at this moment I feel I might probably be taking forever. Without this support, I would be very lost,
as I still struggle to associate my symptoms with my disease.
is a considerable challenge for these studies, although of sensitively and specifically identifying active disease,
the use of TAB has accelerated progress in GCA, includ- monitoring treatment response, and distinguishing
ing identification of the importance of NOTCH ligand vascular and extravascular components of disease147,241.
Jagged 1 (ref.78). The ageing immune system is pertinent Collaborative effort will facilitate the collection of sam-
to GCA, with defects in both the PD1/PDL1 immuno ples in sufficient numbers and diversity for application
inhibitory checkpoint72 and immunosuppressive func- in novel technologies able to identify biomarkers and
tion of CD8+ Treg cells reported238. Further definition of pathogenic pathways in complex autoimmune diseases.
the relative importance of lesion CD4+ and CD8+ T cells These include proteomic and metabolomic platforms,
in LVV103 and investigation of persistent tissue-resident alongside genomic approaches, such as single-cell and
T cells will help direct novel treatment approaches99,100. single-nucleus RNA sequencing. Although individual
The role of additional cell types in the various novel biomarkers may be useful, interest is focused on
stages of LVV, for example, NK cells46 and suppressor the use of clusters as biomarkers, for example, groups
neutrophils239, and their potential as therapeutic targets of metabolites242. Indeed, a logistic regression model
merit further study. Indeed, the role of both B cells and based on a group of eight cytokines has been reported
the vascular endothelium in the pathogenesis of GCA to accurately distinguish active and inactive TAK243.
and TAK has received renewed attention. Antibodies Further, microRNA (miRNA) screening has revealed
to endothelial protein C receptor and scavenger recep- overexpression of pro-synthetic miRNAs and under
tor class B member 1 may induce endothelial cell expression of contractile miRNAs in TAB samples from
activation113. However, the importance of the endothe- patients with GCA244.
lium in facilitating leukocyte trafficking into the arte- Advances in imaging technology, including the
rial wall and how this might be targeted therapeutically advent of total-body PET, novel PET tracers, hybrid
remain to be determined. PET–MR scanners and high-resolution MRI, offer
Collaborative GWAS studies have yielded path- important opportunities for cardiovascular imaging.
ogenic insights and revealed potential therapeutic PET–CT has proved a sensitive and specific method for
targets. Alongside identification of novel disease sus- LVV diagnosis, although its role in patient follow-up
ceptibility loci, prominent roles for NK cells, mono- is not well defined and recent studies have identified
cytes, macrophages, T cells and potentially B cells have important caveats that suggest additional PET tracers are
been reported43,46,51,52. A large multi-ancestral GWAS for required for this purpose8,120,245,246. Issues also surround
TAK identified candidate disease susceptibility loci and the interpretation of persistent, MRI-detected arterial
devised a new genetic risk score in addition to reinforc- wall enhancement in patients with LVV with apparent
ing and extending the identification of HLA risk factors treatment-induced clinical remission188. Various PET
and non-HLA susceptibility loci51. A TAK risk locus tracers are under investigation for their potential use in
identified in IL6 was shown to influence the monocyte vascular inflammation imaging247. Although much of this
anti-inflammatory gene GPNMB through chromatin work is centred around atherosclerosis, it may ultimately
looping and recruitment of an epigenetic repressive translate to vasculitis. PET tracers explored for use in
complex240 and further functional analyses of genetic LVV include ligands for translocator protein (TSPO)248,249
variants identified are now required. and, more recently, the somatostatin receptor type 2
Detection of low-grade arterial wall inflammation ligands 68Ga- D otatate and 18F- FET- β AG- TOCA as
in LVV remains sub-optimal, especially in the presence part of an ongoing PET–MRI clinical study250,251. The
of normalized acute-phase proteins. There is an urgent need to minimize radiation exposure, particularly in
need for novel plasma and imaging biomarkers capable young patients, remains paramount. New PET scanners
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limiting exposure times and increasing use of MRI are The paucity of randomized, placebo-controlled clin-
important steps in this direction. ical trials in LVV is well recognized256, but the landscape
One outstanding imaging challenge is the need is changing (Box 5). Novel trial designs, such as that
to develop standardized and validated quantification proposed for BIOVAS, may prove valuable. An impor-
techniques for non-invasive imaging120 such as those tant hurdle in LVV clinical trials is the lack of widely
reported for MRI252,253 and PET imaging245. Composite accepted methods for grading disease activity, remission
imaging scores suitable for use in patient monitoring and damage. The OMERACT group are currently devel-
and as defined end points in clinical trials are urgently oping a core set of domains and outcome measures to
needed. address this issue257.
Multi-n ational studies will accelerate progress Although considerable challenges remain, progress
and indeed pooling of multicentre imaging data has is good and prospects have never been better. Advances
led to improved understanding of LVV phenotypic will soon facilitate earlier diagnosis, better define disease
clusters254,255 that will likely lead to the recognition of remission, reduce morbidity and may enable the devel-
additional LVV subgroups150. Stratification followed by opment of glucocorticoid-free therapeutic protocols
prospective monitoring to investigate distinct patterns of with the aim of achieving reliable, relapse-free treatment
risk and complications will ultimately enable personal- withdrawal for patients with LVV.
ized treatment approaches. Determining homogeneous
disease subgroups is essential for future clinical trials. Published online xx xx xxxx
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Chapel Hill Consensus Conference Nomenclature of 1982–1985. Arthritis Rheum. 30, 294–299 (1987). in Takayasu’s arteritis. Semin. Arthritis Rheum. 50,
Vasculitides. Arthritis Rheum. 65, 1–11 (2013). 19. Salvarani, C. et al. Epidemiologic and immunogenetic 576–581 (2020).
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(2019). treatment on computed tomography angiography D.P. and M.K. are funded by Clinical Academic Fellowships
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based study of Takayasu´s arteritis in eastern arteritis. A prospective, longitudinal study. Medicine CAF/21/05, respectively). M.C.C. is funded by the Ministerio
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PRIMER

Author addresses approaches and therapeutic options is essential to

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Box 1 | Mimics of large-​vessel vasculitis is consistently associated with inheritance of the

Northern Europe Southern Europe

North America Southern Asia

South America Oceania

GCA incidence Africa Middle East

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Vascular inflammation Box 2 | Mortality in GCA

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Endothelial cell priming

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Primarily cranial presentation Primarily systemic/large-vessel presentation

Case example 1 Case example 2 Case example 3 Case example 4

‘Fast-track’ specialist review Urgent specialist review Urgent specialist review

Targeted laboratory investigations Targeted laboratory Targeted laboratory

Consider MRA/CTA/PET for investigation of LV involvement MRA/CTA/PET MRA/PET/CTA

C-GCA ± LV involvement LV-GCA TAK

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Conﬁrmed diagnosis of GCA Conﬁrmed diagnosis of TAK

Start prednisolone at 40–60 mg/day Start prednisolone Start glucocorticoid-

Relapse or refractory disease? Relapse or refractory disease?

Escalate prednisolone Start glucocorticoid- Escalate prednisolone Consider alternative

Sustained remission Sustained remission

Continue prednisolone taper Continue prednisolone taper

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Box 7 | Patient experience — following diagnosis

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Box 1 | Mimics of large-vessel vasculitis is consistently associated with inheritance of the