**1. Introduction**

Vasculitis is a heterogenous group of conditions characterized by inflammation of the vessel wall resulting in narrowing or occlusion of the vessel lumen, aneurysm formation and impairment of downstream organ functions [1–3]. Vasculitis is classified according to the predominant size of the vessels involved into large, medium or small vessel vasculopathy [1–3].

Giant cell arteritis (GCA) is an autoimmune disease of the blood vessels, a disease where the immune system not only fails to protect but actively damages the blood vessels [4]. It is the most frequent primary vasculitis in adults. It manifests in patients mid age and older (odds 1:500 in this age group) [1]. The estimated annual incidence worldwide is 2.4 to 32.8 cases per 104 [3, 5]. GCA is a large-vessel vasculitis which has tropism for thoracic aorta and its extracranial branches [3, 6]. It affects mostly ethnic groups of northern European descent [7], especially female gender (3:1 ratio) [7, 8], and immune response polymorphisms associated with HLA-DRB1\*04 alleles [9]. In a genome-wide association study collected from over 2000 GCA patients of European ancestry [9], two independent signals in the human leukocyte antigen MHC HLA II class region were reported recently to be strongly correlated with GCA [9]. Plasminogen and prolyl 4-hydroxylase subunit alpha 2 (an enzyme involved in collagen synthesis) have important roles in vascular damage and neoangiogenesis [9] and gene variants of both proteins are related to high GCA risk, suggesting a role of these factors in the underlying pathologic mechanisms of GCA [9]. The nongenetic etiopathogenesis of GCA is also not completely understood [1]. The role of environmental factors (the incidence of the disease increases seasonally) [7], viral (herpes-infected mice develop large vessel arteritis [10]) and bacterial infectious agents was reported [1, 7, 10].

The arterial adventitia (the external arterial layer where the GCA inflammation starts before it spreads inward) is rich in dendritic cells (DCs) [4]. These cells get activated by the interaction of their own toll-like receptors (TLRs) with pathogen-associated molecular patterns (PAMPs) [11]. Dendritic cells are immunosurveillance cells which belong to the vessel wall, and, when activated, synthesize proinflammatory cytokines leading to activation of GCA pathogenic cascade [12–14]. To date and to our knowledge, no unique triggering pathogen has yet been singled out in GCA [1, 4].

GCA has a large spectrum of clinical manifestations [1], and many times it goes undiagnosed until a considerable amount of damage is done and complications occur [1]. People with GCA often are referred to several specialists: ophthalmologist (for partial/total visual loss), neurologist or ORL (for severe headaches and jaw pain), rheumatologist (polymyalgia reaction); when in fact GCA is a problem caused by inflammation in arteries of large and medium size [1, 6]. Ischemic complications of GCA and other systemic complications might be resulting in significant comorbidities and death [8]. If treated promptly and properly, the life expectancy does not change [15].

Temporal artery biopsy (TAB) is a gold standard for diagnosis of GCA [1]. TAB reliability might be reduced by the segmented pattern in which the lesions occur in the blood vessel [16, 17] and by longer time treatment (over 2 weeks) [1, 18].

Due to the fact that imaging testing might not be readily available, the use of biomarkers in laboratory testing for GCA is highly valuable but there are no specific diagnostic or prognostic blood biomarkers yet found for GCA [1]. The main criteria used to diagnose GCA are the elevated inflammatory markers [1] usually associated with for ischemic events. Acute phase reactants frequently have high blood levels: erythrocyte sedimentation rate (ESR) and more sensitive C-reactive protein (CRP), elevated platelets and white blood cell numbers, elevated blood von Willebrand factor (VWF) [1, 19, 20]; and in addition, GCA is associated with normocytic normochromic anemia [1]. Elevated serum level of the proinflammatory cytokine interleukin 6 (IL6) is critical in GCA pathogenesis and perhaps the most sensitive marker in GCA [21].

GCA is usually evaluated together with another related condition, polymyalgia rheumatica (PMR) [22]. PMR is not a vasculitis, but its relationship to GCA requires discussion because in some patients PMR evolves into GCA and 40–50% of GCA patients have polymyalgic symptoms [23]. In 20% of PMR patients with subacute presentation (proximal stiffness located in the shoulder area), abnormal blood work and high ESR and CRP, the disease will progress to GCA [22]. Imaging and pathology studies have shown subclinical arteritis may be much more common with PMR patients [18]. It is possible these two conditions represent two distinct phenotypes of the same pathological entity [23].

#### *Cellular and Molecular Characteristics of Vascular Damage in Giant Cell Arteritis, the 'Unmet… DOI: http://dx.doi.org/10.5772/intechopen.97933*

The standard therapy for GCA patients is glucocorticosteroid treatment [18] because it makes GCA symptoms better immediately, especially in ischemic complications when it is lifesaving or avoids a permanent invalidity (partial/total visual loss) [21]. For instance, heightened vascular inflammation progressively affects more vessels, compromising carotid vessels and other branches from aorta, that supply blood to vital organs (GCA-related cerebrovascular events [24, 25] and GCArelated myocardial infarction [26]) [8]. GCA affects the eye as well, and patients can have sudden and painless visual loss [27]. Because of the risk of progressive visual loss, GCA is an ophthalmology emergency for which the treatment is highdose methylprednisolone pulse therapy (1000 mg i.v. for 3 days) within 24 h of the onset of GCA symptoms, which works as an effective 'emergency' treatment option to prevent evolving optic (and progressively central nervous system) [28] involvement [18]. If treatment is delayed more than 24 h, the blood supply to the eye can be cut off for enough time that restoration of vision might not occur. IV pulse therapy is followed with oral GS therapy [18].

In all, chronic administration of GS insures 90% of GCA patients will have GS-related side effects [29]. Therefore, a lot of research nowadays is focused on what treatment we can give instead of or in combination with GS to minimize side effects of GS in GCA, and in all the other types of vasculitis where we depend on GS for the immediate beneficial effects as well [30]. Ongoing clinical trial investigations are showing promising preliminary results. Most of the newer targets are not yet used in clinical practice because of toxicity, poor efficiency or because are under development, but nevertheless these biologics are key in deciphering the pathogenic mechanisms of GCA.

In this study we aim to (1) describe the characteristic aspects of vascular damage; (2) discuss several known mechanisms that cause vascular disfunction in GCA; (3) overview new therapeutic GS-sparing agents which might be a more productive way of avoiding the invalidating or life-threatening cardiovascular complications of GCA. We focus on the current knowledge updates about the GCA pathogenic mechanisms subsidiary to ischemic complications of the disease and their targeted treatment.
