**1. Introduction**

The first description of giant cell arteritis dates from 1890 by Hutchinson, who described an 80-year-old man with painful and inflamed temporal arteries which prevented him from wearing his hat [1]. Forty-seven years later Horton, Magath, and Brown described similar cases and called the syndrome temporal arteritis [2]. Originally thought to be a localized, self-limiting, and benign disorder, inflammation of the temporal arteries is now recognized as part of a widespread arteritis which untreated can lead to blindness and death.

Giant cell arteritis (GCA), previously called temporal arteritis and also known as Horton's disease, is defined by the 2012 Chapel Hill Consensus Conference as "arteritis, often granulomatous, usually affecting the aorta and/or its major branches, with a predilection for the branches of the carotid and vertebral arteries; often involves the temporal artery; onset usually in patients older than 50; often

associated with polymyalgia rheumatica" [3]. It is the most common primary systemic vasculitis in adults, mostly seen in North America and Western Europe, with the incidence increasing with the advancing age. Women are more affected than men in a 2.5:1 ratio. GCA classically targets large vessels with predominance for the aorta and its branches. Arterial inflammation may lead to vascular damage which can result in stenosis, occlusions, and even aneurysms. Therefore, this condition is related to serious loss of function including visual loss, upper limb ischemia, and stroke. Suspicion of giant cell arteritis is a medical emergency, and patients need to be quickly diagnosed and treated to prevent irreversible consequences of vessel inflammation.

## **2. Pathogenesis**

The immune and pathogenetic pathways responsible for the inflammation on the arterial walls in GCA are not fully understood yet. As in other autoimmune diseases, it is believed to be an environmental-triggered response occurring in genetic-predisposed individuals. The fact that it only affects older patients suggests that age-related damage on the vessel walls also plays a role in the development of the arteritis [4].

There is evidence of a cyclic pattern and yearly incidence of the onset of GCA, which led to the search for an environmental agent responsible for the initialization of the immune response. Many bacterial agents and viruses have been under research (*Chlamydia pneumonia*, *Burkholderia*, *cytomegalovirus*, *erythrovirus B19*, *herpes simplex*, and *parainfluenzae 1*, among others), but the studies failed in finding a causal correlation between infections and GCA so far [4].

GCA is associated with the major histocompatibility class II (MHC-II), particularly with HLA-DRB1\*04 alleles [5]. Outside the MHC region, variants on the PTPN22 locus and other genes related to vascular response to inflammation and vascular remodeling, such as plasminogen and prolyl 4-hydroxylase subunit alpha 2, also increased the risk of GCA.

Age-related damage on the arterial wall also has a role on the pathogenesis. There are biochemical and structural modifications in the vessel leading to loss of self-tolerance. Differences in the DNA methylation level of several genes have been reported in temporal arteries from GCA patients comparing with non-GCA controls.

There is evidence that the inflammation starts in the adventitia and progresses to the other layers of the arterial wall, culminating in transmural damage. Activated dendritic cells (DCs) have a central role in the immune response of GCA. These cells are present in the adventitia and express Toll-like receptors, which are activated via pathogen-associated molecular patterns (PAMPs) or microorganismassociated molecular patterns (MAMPs). The activation of DC breaks immune tolerance and renders the arteries, considered otherwise an immune privileged site, susceptible to inflammatory injury. DCs activate CD4+ T lymphocytes through costimulatory molecules (CD80 and CD86) and class II MHC. DC depletion in mice models with GCA strongly decreased vasculitis lesions, emphasizing its importance on the immune response.

Activated DCs produce cytokines such as IL-6, IL-18, IL-23, IL-32, and IL-33, which are chemotactic for T lymphocytes. T cells that infiltrate the temporal arteries from GCA patients are enriched Th1, Th17, and Th9 cells. Th1-response polarization via IL-12 synthesizes IFN-γ, and Th17 cells produce IL-17. While Th17 cells are inhibited by glucocorticoids, the Th1 response is not, being this last one implicated in sustaining chronic disease activity in GCA [6].

IFN-γ seems to be important for the development of vasculitis. The cytokine panel described above is found in both GCA patients and PMR patients without

**95**

of the cases.

*Giant Cell Arteritis: Current Advances in Pathogenesis and Treatment*

others), causing intimal hyperplasia and vascular occlusion.

immune checkpoint has been reported in GCA patients.

GCA, but INF-γ is only present in individuals with GCA. IFN-γ expression, in fact, is associated with increased risk of ischemic complications. Vascular smooth muscle cells, induced by IFN-γ, produce chemokines (CCL2, CXCL9, CXCL10, and CXCL11), leading to the recruitment of monocytes that merge to form multinucleated giant cells, the hallmark of GCA. The chemokines recruit more immune cells, amplifying the inflammatory response. Monocytes differentiate into macrophages in the arterial wall and produce IL-6, IL-1β, and TNF-α, responsible for the systemic inflammatory response which is characteristic of GCA. Toxic substances for the arteries are also produced by macrophages, such as reactive oxygen species, matrix metalloproteinase-2 (MMP-2), and MMP-9, which destroy cellular matrix proteins and cause destruction of the media and digestion of the internal elastic lamina. Th17 cells appear to be important in the initial stages of the disease, producing IL-17, IL-21, IL-22, and CCL20. IL-17 leads to the recruitment of macrophages, while IL-21 enhances the differentiation of cytotoxic cells, and IL-22 mediates hepatocyte stimulation and acute-phase amplification. CCL20 facilitates the

The vascular smooth muscle cells in inflamed arteries are believed to acquire pro-inflammatory properties and produce several growth factors (vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), among

B cells are not present in the arterial wall of all the patients with GCA, suggesting that its effect is not crucial in the pathogenesis. However, when present, they are activated and contribute for the amplification of the immune response and inflammation. Finally, defects in immune checkpoints have also been studied and appear to play a role in the immune activation observed in GCA. T cells express programmed death-1 (PD-1), which binds to its receptor in antigen-presenting cells, inducing T cell anergy and apoptosis, and the production of IL-10 by T cells or their polarization into T-reg lymphocytes. A defect in the immunoprotective PD-1/PD-L1

Headache is the most common symptom of GCA, and a new-onset headache (or worsening of a preexisting headache) in older adults should always raise the suspicion of this condition. The installation of the pain is usually acute/subacute. The typical pattern is a temporal headache, continuous throughout the day and resistant to standard analgesia, but it can also be felt over other cranial areas or be diffuse. Patients may also present with scalp tenderness or tongue/jaw pain. Jaw claudication, seen in 45% of the patients, is a relatively specific sign and correlates

Total or partial visual loss affects 15–20% of patients, mostly at disease onset. The main cause is anterior ischemic optic neuropathy due to vasculitis of the posterior ciliary arteries, which are branches of the ophthalmic artery and responsible for the blood supply of the optic nerve and the choroid. The optic neuropathy leads to visual loss, which is usually painless and with rapid onset. Occasionally, posterior ischemic optic neuropathy, occlusive vasculopathy of the central artery of the retina, or cortical ischemia can cause visual loss too. Blindness is irreversible in most cases, and when one eye is affected, the other one will likely (in half of the cases) be diseased too in a few days if the treatment is not promptly started. About 10% of patients develop amaurosis fugax, visual hallucinations, or diplopia, which are considered premonitory signs and can progress to blindness in half

*DOI: http://dx.doi.org/10.5772/intechopen.91018*

recruitment of more DCs and T cells.

**3. Clinical features**

with temporal artery biopsy positivity.

#### *Giant Cell Arteritis: Current Advances in Pathogenesis and Treatment DOI: http://dx.doi.org/10.5772/intechopen.91018*

GCA, but INF-γ is only present in individuals with GCA. IFN-γ expression, in fact, is associated with increased risk of ischemic complications. Vascular smooth muscle cells, induced by IFN-γ, produce chemokines (CCL2, CXCL9, CXCL10, and CXCL11), leading to the recruitment of monocytes that merge to form multinucleated giant cells, the hallmark of GCA. The chemokines recruit more immune cells, amplifying the inflammatory response. Monocytes differentiate into macrophages in the arterial wall and produce IL-6, IL-1β, and TNF-α, responsible for the systemic inflammatory response which is characteristic of GCA. Toxic substances for the arteries are also produced by macrophages, such as reactive oxygen species, matrix metalloproteinase-2 (MMP-2), and MMP-9, which destroy cellular matrix proteins and cause destruction of the media and digestion of the internal elastic lamina.

Th17 cells appear to be important in the initial stages of the disease, producing IL-17, IL-21, IL-22, and CCL20. IL-17 leads to the recruitment of macrophages, while IL-21 enhances the differentiation of cytotoxic cells, and IL-22 mediates hepatocyte stimulation and acute-phase amplification. CCL20 facilitates the recruitment of more DCs and T cells.

The vascular smooth muscle cells in inflamed arteries are believed to acquire pro-inflammatory properties and produce several growth factors (vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), among others), causing intimal hyperplasia and vascular occlusion.

B cells are not present in the arterial wall of all the patients with GCA, suggesting that its effect is not crucial in the pathogenesis. However, when present, they are activated and contribute for the amplification of the immune response and inflammation.

Finally, defects in immune checkpoints have also been studied and appear to play a role in the immune activation observed in GCA. T cells express programmed death-1 (PD-1), which binds to its receptor in antigen-presenting cells, inducing T cell anergy and apoptosis, and the production of IL-10 by T cells or their polarization into T-reg lymphocytes. A defect in the immunoprotective PD-1/PD-L1 immune checkpoint has been reported in GCA patients.
