Giant cell arteritis (GCA) is a granulomatous vasculitis of the aorta and its medium-sized branch vessels. CD4 T cells, macrophages, and dendritic cells (DCs) build granulomatous infiltrates that injure the vessel wall and elicit a maladaptive response to injury. Pathological consequences include fragmentation of elastic membranes, destruction of the medial layer, microvascular neoangiogenesis, massive outgrowth of myofibroblasts, and lumen-occlusive intimal hyperplasia. Antigens have been suspected to drive the local activation of vasculitogenic CD4 T cells, but recent data have suggested a more generalized defect in the threshold setting of such T cells, rendering them hyperreactive. Under physiological conditions, immune checkpoints provide negative signals to curb T cell activation and prevent inflammation-associated tissue destruction. This protective mechanism is disrupted in GCA. Vessel wall DCs fail to express the immunoinhibitory ligand programmed cell death ligand-1, leaving lesional T cells unchecked. Consequently, programmed cell death protein-1-positive CD4 T cells can enter the immunoprivileged vessel wall, where they produce a broad spectrum of inflammatory cytokines (interferon-γ, IL-17, and IL-21) and have a direct role in driving intimal hyperplasia and intramural neoangiogenesis. The deficiency of the programmed cell death protein-1 immune checkpoint in GCA, promoting unopposed T cell immunity, contrasts with checkpoint hyperactivity in cancer patients in whom excessive programmed cell death ligand-1 expression paralyzes the function of antitumor T cells. Excessive checkpoint activity is the principle underlying cancer-immune evasion and is therapeutically targeted by immunotherapy with checkpoint inhibitors. Such checkpoint inhibitors, which unleash anticancer T cells and induce immune-related toxicity, may lead to drug-induced vasculitis.

Immune checkpoint dysfunction in large and medium vessel vasculitis

Giant cell arteritis (GCA) is the most common type of primary vasculitis in Western countries. Polymyalgia rheumatica (PMR) is the second most common inflammatory rheumatic disease of the elderly after rheumatoid arthritis. Glucocorticoids are the cornerstone of treatment for GCA and PMR, which are interrelated diseases. Glucocorticoids are effective, but adverse effects occur in a high proportion of patients. Careful use of glucocorticoids and the application of preventive strategies can minimize these adverse effects. Possible long-term complications of GCA include aneurysm and stenosis of vessels, even in patients with apparently clinically inactive disease; acute blindness is rare during glucocorticoid treatment. In PMR, whether subclinical chronic inflammation can lead to long-term damage is less clear. Management of both GCA and PMR is hampered by the lack of universally accepted definitions of remission and other disease states, such as low disease activity or vessel damage without active disease. In this Review, we outline current evidence on the monitoring and long-term management of patients with GCA and PMR, including the tapering of treatment.

Monitoring and long-term management of giant cell arteritis and polymyalgia rheumatica.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and giant cell arteritis (GCA) are the most common primary systemic vasculitides of the adult population, while polymyalgia rheumatica (PMR) is a clinical syndrome often associated with GCA. Incidence and prevalence rates of AAV have been increasing in the last decades, whereas those of GCA and PMR have remained stable. The mutual interplay between environmental and genetic risk factors leading to the development of these diseases has been further analyzed in the last years. The role of infectious agents has repeatedly been studied with regard to Staphylococcus aureus, associated with relapse in granulomatosis with polyangiitis, and Herpes zoster, potentially contributing to GCA development. Remission of disease and prevention of disease-related complications are the most important outcomes for all systemic vasculitides. Although these goals are achieved in the majority of patients receiving modern therapies, the prevention of treatment-related complications, especially glucocorticoid side effects, is still an unmet need that is common to AAV, GCA, and PMR.

Update on the epidemiology, risk factors, and outcomes of systemic vasculitides

Objectives Comprehensive analyses of cause-specific death patterns in GCA are sparse. We studied the patterns and time trends in GCA-related mortality using a large death certificate database. Methods We obtained multiple-cause-of-death data from the French national death certificate database for 1980-2011. GCA-associated deaths were defined as decedents ⩾55 years old with GCA listed as an underlying or non-underlying cause of death. Time trends of death rates were analysed and the mean age at death with GCA and in the general population ⩾55 years old were calculated. Standardized mortality odds ratios (SMORs) were calculated for 17 selected causes of death (based on 2000-11 data). Results The analyses pertained to approximately 15 000 death certificates listing GCA (including approximately 6300 for 2000-11). Annual standardized death rates for GCA increased to a peak in 1997 and then decreased (Spearman's correlation test, both P < 0.0001). Mean age at death was higher for GCA than for general population decedents (Student's t-test, P < 0.0001). GCA deaths were frequently or strongly associated with aortic aneurysm and dissection (1.85% of death certificates, SMOR: 3.09, 95% CI: 2.48, 3.82), hypertensive disease (20.78%, SMOR: 2.22, 95% CI: 1.97, 2.50), diabetes mellitus (11.27%, SMOR: 1.96, 95% CI: 1.72, 2.23), certain infectious and parasitic diseases (12.12%, SMOR: 1.76, 95% CI: 1.55, 2.00) and ischaemic heart disease (16.54%, SMOR: 1.45, 95% CI: 1.35, 1.64). Conclusion GCA is associated with increased risk of dying from large-vessel disease, other cardiovascular diseases and potentially treatment-related co-morbidities. These findings help provide better insights into the outcomes of GCA.

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Mortality causes and trends associated with giant cell arteritis: analysis of the French national death certificate database (1980-2011).

Cardiovascular events and the role of accelerated atherosclerosis in systemic vasculitis.

Objective. To evaluate the risk of cerebrovascular disease and cardiovascular disease (CVD) in patients with giant cell arteritis (GCA), and to identify predictors.

Methods. The UK Clinical Practice Research Datalink 1991–2010 was used for a parallel cohort study of 5827 patients with GCA and 37,090 age-, sex-, and location-matched controls. A multivariable competing risk model (non-cerebrovascular/CV-related death as the competing risk) determined the relative risk [subhazard ratio (SHR)] between patients with GCA compared with background controls for cerebrovascular disease, CVD, or either. Each cohort (GCA and controls) was then analyzed individually using the same multivariable model, with age and sex now present, to identify predictors of CVD or cerebrovascular disease.

Results. Patients with GCA, compared with controls, had an increased risk SHR (95% CI) of cerebrovascular disease (1.45, 1.31–1.60), CVD (1.49, 1.37–1.62), or either (1.47, 1.37–1.57). In the GCA cohort, predictors of “cerebrovascular disease or CVD” included increasing age, > 80 years versus < 65 years (1.98, 1.62–2.42), male sex (1.20, 1.05–1.38), and socioeconomic status, most deprived quintile versus least deprived (1.34, 1.01–1.78). These predictors were also present within the non-GCA cohort.

Conclusion. Patients with GCA are more likely to develop cerebrovascular disease or CVD than age-, sex-, and location-matched controls. In common with the non-GCA cohort, patients who are older, male, and from the most deprived compared with least deprived areas have a higher risk of cerebrovascular disease or CVD. Further work is needed to understand how this risk may be mediated by specific behavioral, social, and economic factors.

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Joe Maskell

Papers

Which Patients with Giant Cell Arteritis Will Develop Cardiovascular or Cerebrovascular Disease? A Clinical Practice Research Datalink Study.