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

Terrades-García, Nekane; Cid, María C.

doi:10.1093/rheumatology/kex423

Cited by 38 publications

(62 citation statements)

References 84 publications

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“…Large-scale screening is needed for their presence in the peripheral blood, coupled with IHC of the arterial vessel walls of patient biopsies. Furthermore, no appropriate animal models of GCA are currently available to mimic the clinical process of disease initiation and progression, though functional models have been developed to directly study arterial and large-vessel damage and inflammation ( 8 ). This has hindered our understanding of exact pathophysiological roles of immature neutrophil in GCA.…”

Section: Discussionmentioning

confidence: 99%

“…Progress has been slow in developing reliable techniques to monitor disease activity, progression, and treatment response ( 4 , 5 ). The GCA diagnosis is based on histological examination or imaging to demonstrate inflammation of the affected vessels ( 6 ), as well as the identification of macrophages and T cells and the production of inflammatory and growth signals in the lesions ( 7 , 8 ). Proinflammatory cytokines such as IL-6 and its soluble receptors, pattern recognition receptor pentraxin-3 and vascular endothelial growth factor (VEGF), have been suggested as biomarkers in GCA ( 9 , 10 ).…”

Section: Introductionmentioning

confidence: 99%

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ROS-producing immature neutrophils in giant cell arteritis are linked to vascular pathologies

Wang

Khoyratty

et al. 2020

JCI Insight

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Giant cell arteritis (GCA) is a common form of primary systemic vasculitis in adults, with no reliable indicators of prognosis or treatment responses. We used single cell technologies to comprehensively map immune cell populations in the blood of patients with GCA and identified the CD66b + CD15 + CD10 lo/– CD64 – band neutrophils and CD66b hi CD15 + CD10 lo/– CD64 +/bright myelocytes/metamyelocytes to be unequivocally associated with both the clinical phenotype and response to treatment. Immature neutrophils were resistant to apoptosis, remained in the vasculature for a prolonged period of time, interacted with platelets, and extravasated into the tissue surrounding the temporal arteries of patients with GCA. We discovered that immature neutrophils generated high levels of extracellular reactive oxygen species, leading to enhanced protein oxidation and permeability of endothelial barrier in an in vitro coculture system. The same populations were also detected in other systemic vasculitides. These findings link functions of immature neutrophils to disease pathogenesis, establishing a clinical cellular signature of GCA and suggesting different therapeutic approaches in systemic vascular inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ROS-producing immature neutrophils in giant cell arteritis are linked to vascular pathologies

Wang

Khoyratty

et al. 2020

JCI Insight

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“…38,70,71 IL-6 signaling might contribute to the formation of aortic aneurysms through mechanisms aside from atherosclerosis, thus explaining the large effect. For instance, IL-6 signaling is a key pathway in the pathogenesis of large vessel vasculitides, 72 which are strongly associated with the formation of aortic aneurysms. 16,73,74 Our analysis provides no evidence for an association of genetically downregulated IL-6 signaling with cardioembolic stroke.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 signaling effects on ischemic stroke and other cardiovascular outcomes: a Mendelian Randomization study

Georgakis¹,

Malik²,

Franceschini³

et al. 2019

Preprint

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Background: Studies in humans and experimental models highlight a role of interleukin-6 (IL-6) in cardiovascular disease. Indirect evidence suggests that inhibition of IL-6 signaling could lower risk of coronary artery disease. However, whether such an approach would be effective for ischemic stroke and other cardiovascular outcomes remains unknown. Methods: In a genome-wide association study (GWAS) of 204,402 European individuals, we identified genetic proxies for downregulated IL-6 signaling as genetic variants in the IL-6 receptor (IL6R) locus that were associated with lower C-reactive protein (CRP) levels, a downstream effector of IL-6 signaling. We then applied two-sample Mendelian randomization (MR) to explore associations with ischemic stroke and its major subtypes (large artery stroke, cardioembolic stroke, small vessel stroke) in the MEGASTROKE dataset (34,217 cases and 404,630 controls), with coronary artery disease in the CARDIoGRAMplusC4D dataset (60,801 cases and 123,504 control), and with other cardiovascular outcomes in the UK Biobank (up to 321,406 individuals) and in phenotype-specific GWAS datasets. All effect estimates were scaled to the CRP-decreasing effects of tocilizumab, a monoclonal antibody targeting IL-6R. Results: We identified 7 genetic variants as proxies for downregulated IL-6 signaling, which showed effects on upstream regulators (IL-6 and soluble IL-6R levels) and downstream effectors (CRP and fibrinogen levels) of the pathway that were consistent with pharmacological blockade of IL-6R. In MR, proxies for downregulated IL-6 signaling were associated with lower risk of ischemic stroke (Odds Ratio [OR]: 0.89, 95%CI: 0.82-0.97) and coronary artery disease (OR: 0.84, 95%CI: 0.77-0.90). Focusing on ischemic stroke subtypes, we found significant associations with risk of large artery (OR: 0.76, 95%CI: 0.62-0.93) and small vessel stroke (OR: 0.71, 95%CI: 0.59-0.86), but not cardioembolic stroke (OR: 0.95, 95%CI: 0.74-1.22). Proxies for IL-6 signaling inhibition were further associated with a lower risk of myocardial infarction, aortic aneurysm, atrial fibrillation and carotid plaque. Conclusions: We provide evidence for a causal effect of IL-6 signaling on ischemic stroke, particularly large artery and small vessel stroke, and a range of other cardiovascular outcomes. IL-6R blockade might represent a valid therapeutic target for lowering cardiovascular risk and should thus be investigated in clinical trials.

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“…The systemic inflammatory response is associated with the innate immune system. Innate immune systems cells (vascular dendritic cells and monocytes) draw proinflammatory cytokines like Interleukin (IL) 6 which are associated with the production of acute phase proteins in the liver (mainly C-reactive protein) (11, 12). The systemic inflammatory response is glucocorticoid and anti-IL-6 sensitive resulting in reduced clinical symptoms in GCA (11).…”

Section: The Pathophysiology Of Gcamentioning

confidence: 99%

The Treatment of Giant Cell Arteritis in Different Clinical Settings

Pfeil

Oelzner

Hellmann³

2019

Front. Immunol.

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This paper aims to raise awareness of the different disease courses, comorbidities, and therapy situations in patients with giant cell arteritis (GCA), which require a differentiated approach and often a deviation from current treatment guidelines. With the approval of tocilizumab (TOC), which specifically binds to both soluble and membrane-bound IL-6 receptor and inhibits IL-6 receptor-mediated signaling, the spectrum of available effective treatment options has been significantly broadened. TOC yields an extensive range of possible applications that go beyond a glucocorticoid-saving effect. In this context, the treatment of GCA is dependent on the disease course as well as the associated comorbidities. The different stages of GCA in association to co-morbidities require a detailed treatment strategy.

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

Cited by 38 publications

References 84 publications

ROS-producing immature neutrophils in giant cell arteritis are linked to vascular pathologies

ROS-producing immature neutrophils in giant cell arteritis are linked to vascular pathologies

Interleukin-6 signaling effects on ischemic stroke and other cardiovascular outcomes: a Mendelian Randomization study

The Treatment of Giant Cell Arteritis in Different Clinical Settings

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