**3. Clinical features**

*Vascular Biology - Selection of Mechanisms and Clinical Applications*

a causal correlation between infections and GCA so far [4].

alpha 2, also increased the risk of GCA.

on the immune response.

in sustaining chronic disease activity in GCA [6].

inflammation.

**2. Pathogenesis**

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

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

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

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

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

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

**94**

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 with temporal artery biopsy positivity.

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 of the cases.

Systemic manifestations, such as fever, weight loss, and fatigue, are frequent (42, 50, and 40%, respectively). Some patients present only with constitutional symptoms, without headache or visual changes, and in those cases, the diagnosis can be challenging. GCA can be the cause of an obscure-origin fever in older patients.

Polymyalgia rheumatica (PMR) is the most common extracranial manifestation of GCA, and it may also be the first clinical sign of a vasculitis relapse. It is defined by pain/tenderness in proximal arms and legs, with morning stiffness and fast improvement with low-dose glucocorticoid treatment. PMR is seen in 50% of the patients with GCA, while only 20% of the patients with PMR have clinical signs of GCA. However, in patients with PMR with persistently high inflammatory markers and insufficient response to glucocorticoids, a careful investigation may reveal an oligo-symptomatic GCA requiring more aggressive treatment. GCA and PMR are different conditions that share many common features: they occur almost exclusively in patients aged 50 years or older, have similar gender ratios, are associated with the HLA-DRB1\*04 alleles and increased levels of serum acute-phase reactants, and respond to glucocorticoid therapy.

GCA is a systemic vasculitis with predominance for the aorta and its branches. Therefore, the patients may also present with chest pain and limb claudication. Large-vessel disease may complicate with aneurysms or stenosis development, resulting in increased mortality due to cardiovascular disease. Many patients with GCA develop clinical manifestations of large-vessel involvement, such as arm claudication (4%) and arterial bruits (21%).

Cerebrovascular events are less common ischemic complications, seen in 15% of the patients. They are mostly due to occlusive vasculitis of the carotid or vertebrobasilar arteries. Transitory or persistent ischemic attacks are the most common neurologic manifestations, but cognitive impairment and neuropathy are other possible complications. Neuropsychiatric symptoms (dementia, mood disorders, and psychosis) affect 3% of the patients. Audio vestibular dysfunction leading to sensorineural hearing loss has also been described in GCA.

Infrequent clinical manifestations include tongue, scalp or lip necrosis, and facial/submandibular swelling. Unlike visual loss, ischemic necrosis tends to improve after the glucocorticoid treatment is started. Peripheral synovitis is found in 15% of the patients.

Physical examination is frequently normal, but it may also reveal temporal artery abnormalities such as thickness, tenderness, and hyperemia, with normal, decreased, or absent pulse. Even though temporal artery abnormality is one of the five ACR classification criteria for GCA, it is seen in less than 30% of the patients. Peripheral pulses in arms and legs may be decreased or absent as well in large-vessel disease, and arterial bruits can be heard in such patients.

### **4. Diagnosis**

The American College of Rheumatology classification criteria for GCA, published in 1990, requires three or more of the following five criteria [1]: age 50 years and older [2], new onset of localized headache [3], temporal artery tenderness on palpation or decreased pulsation [4], an abnormal temporal artery biopsy, and [5] an erythrocyte sedimentation rate (ESR) of 50 mm/h or more (**Table 1**) [7]. These criteria are designed to be classificatory and not diagnostic, with sensitivity and specificity of 81.1% and 64.2%, respectively [8]. In the last years, new imaging techniques have emerged and can be helpful tools on diagnosis and disease activity assessment.

**97**

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

1. Age ≥ 50 years 1 2. New-onset headache 1 3. Temporal artery tenderness/decreased pulsation 1 4. Abnormal temporal artery biopsy 1 5. ESR ≥ 50 mm/1st hour 1

ESR higher than 50 mm/h is one of the five criteria for GCA classification according to the ACR. However, in recent years alternative acute-phase reactants have been proposed as more sensitive markers. Recently one study analyzed 26 markers in GCA and PMR comparing with healthy controls and found that three serum markers (B cell-activating factor [BAFF], CXCL9, and IL-6) were increased in both newly diagnosed GCA and newly diagnosed PMR patients. Serum BAFF and IL-6, but not CXCL9, were attenuated upon glucocorticoid-induced remission and showed the strongest association with disease activity in both GCA and PMR patients [9]. BAFF is an important regulator of B cell responses and has been linked to the development of many autoimmune diseases. Even though these markers are not used routinely in clinical practice yet, they are promising new tools in the

Platelets are also considered a serum marker for inflammation in GCA. The postulated mechanism of thrombocytosis in promoting inflammation stems from their early interaction with the endothelium in inflammatory states during which they provide adhesion molecules and chemotactic stimulation to aid in the recruitment of leukocytes and enhance the release of different inflammatory mediators [10]. The most used tests for measuring inflammation in clinical practice are ESR and CRP. One study showed that the optimal cutoff value for CRP in GCA was 26.9 mg/L (sensitivity 75% and specificity 51%) and for ESR was 53 mm/h (sensitiv-

Even though temporal artery biopsy is not essential for the diagnosis, one study found that sensitivity and specificity of ACR criteria for diagnosis of GCA before performing TAB were 68.5 and 58%, respectively, while sensitivity and specificity of ACR criteria after performing TAB biopsy were 89.8 and 64.5%, respectively [12]. The sensitivity rates are lower in the large-vessel phenotype of GCA, and even in patients with the temporal artery affected, skip lesions may contribute to a negative TAB.

TAB showing transmural inflammation is still considered the gold standard for the diagnosis of GCA and remains the most specific diagnostic test. It is a minimally invasive and well-tolerated surgical procedure that is generally performed in an outpatient surgery setting and carries a low risk of complications in experienced hands. The length of the artery needed for optimal histopathological analysis is 2 cm. For all these reasons, TAB is still recommended in all patients with a clinical suspicion of GCA. In addition to their diagnostic role, histological findings of positive TAB may have clinical and prognostic significance and thus implications for the patients' management.

diagnostic approach and disease activity assessment in GCA.

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

**4.1 Acute-phase reactants**

*ACR classification criteria for GCA (1990).*

Total

**Table 1.**

*GCA defined if score* ≥ *3.*

ity 66% and specificity 55%) [11].

**4.2 Temporal artery biopsy (TAB)**

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


#### **Table 1.**

*Vascular Biology - Selection of Mechanisms and Clinical Applications*

claudication (4%) and arterial bruits (21%).

sensorineural hearing loss has also been described in GCA.

disease, and arterial bruits can be heard in such patients.

patients.

therapy.

in 15% of the patients.

**4. Diagnosis**

and disease activity assessment.

Systemic manifestations, such as fever, weight loss, and fatigue, are frequent (42, 50, and 40%, respectively). Some patients present only with constitutional symptoms, without headache or visual changes, and in those cases, the diagnosis can be challenging. GCA can be the cause of an obscure-origin fever in older

Polymyalgia rheumatica (PMR) is the most common extracranial manifestation of GCA, and it may also be the first clinical sign of a vasculitis relapse. It is defined by pain/tenderness in proximal arms and legs, with morning stiffness and fast improvement with low-dose glucocorticoid treatment. PMR is seen in 50% of the patients with GCA, while only 20% of the patients with PMR have clinical signs of GCA. However, in patients with PMR with persistently high inflammatory markers and insufficient response to glucocorticoids, a careful investigation may reveal an oligo-symptomatic GCA requiring more aggressive treatment. GCA and PMR are different conditions that share many common features: they occur almost exclusively in patients aged 50 years or older, have similar gender ratios, are associated with the HLA-DRB1\*04 alleles and increased levels of serum acute-phase reactants, and respond to glucocorticoid

GCA is a systemic vasculitis with predominance for the aorta and its branches. Therefore, the patients may also present with chest pain and limb claudication. Large-vessel disease may complicate with aneurysms or stenosis development, resulting in increased mortality due to cardiovascular disease. Many patients with GCA develop clinical manifestations of large-vessel involvement, such as arm

Cerebrovascular events are less common ischemic complications, seen in 15% of the patients. They are mostly due to occlusive vasculitis of the carotid or vertebrobasilar arteries. Transitory or persistent ischemic attacks are the most common neurologic manifestations, but cognitive impairment and neuropathy are other possible complications. Neuropsychiatric symptoms (dementia, mood disorders, and psychosis) affect 3% of the patients. Audio vestibular dysfunction leading to

Infrequent clinical manifestations include tongue, scalp or lip necrosis, and facial/submandibular swelling. Unlike visual loss, ischemic necrosis tends to improve after the glucocorticoid treatment is started. Peripheral synovitis is found

Physical examination is frequently normal, but it may also reveal temporal artery abnormalities such as thickness, tenderness, and hyperemia, with normal, decreased, or absent pulse. Even though temporal artery abnormality is one of the five ACR classification criteria for GCA, it is seen in less than 30% of the patients. Peripheral pulses in arms and legs may be decreased or absent as well in large-vessel

The American College of Rheumatology classification criteria for GCA, published in 1990, requires three or more of the following five criteria [1]: age 50 years and older [2], new onset of localized headache [3], temporal artery tenderness on palpation or decreased pulsation [4], an abnormal temporal artery biopsy, and [5] an erythrocyte sedimentation rate (ESR) of 50 mm/h or more (**Table 1**) [7]. These criteria are designed to be classificatory and not diagnostic, with sensitivity and specificity of 81.1% and 64.2%, respectively [8]. In the last years, new imaging techniques have emerged and can be helpful tools on diagnosis

**96**

*ACR classification criteria for GCA (1990).*

#### **4.1 Acute-phase reactants**

ESR higher than 50 mm/h is one of the five criteria for GCA classification according to the ACR. However, in recent years alternative acute-phase reactants have been proposed as more sensitive markers. Recently one study analyzed 26 markers in GCA and PMR comparing with healthy controls and found that three serum markers (B cell-activating factor [BAFF], CXCL9, and IL-6) were increased in both newly diagnosed GCA and newly diagnosed PMR patients. Serum BAFF and IL-6, but not CXCL9, were attenuated upon glucocorticoid-induced remission and showed the strongest association with disease activity in both GCA and PMR patients [9]. BAFF is an important regulator of B cell responses and has been linked to the development of many autoimmune diseases. Even though these markers are not used routinely in clinical practice yet, they are promising new tools in the diagnostic approach and disease activity assessment in GCA.

Platelets are also considered a serum marker for inflammation in GCA. The postulated mechanism of thrombocytosis in promoting inflammation stems from their early interaction with the endothelium in inflammatory states during which they provide adhesion molecules and chemotactic stimulation to aid in the recruitment of leukocytes and enhance the release of different inflammatory mediators [10].

The most used tests for measuring inflammation in clinical practice are ESR and CRP. One study showed that the optimal cutoff value for CRP in GCA was 26.9 mg/L (sensitivity 75% and specificity 51%) and for ESR was 53 mm/h (sensitivity 66% and specificity 55%) [11].

#### **4.2 Temporal artery biopsy (TAB)**

Even though temporal artery biopsy is not essential for the diagnosis, one study found that sensitivity and specificity of ACR criteria for diagnosis of GCA before performing TAB were 68.5 and 58%, respectively, while sensitivity and specificity of ACR criteria after performing TAB biopsy were 89.8 and 64.5%, respectively [12]. The sensitivity rates are lower in the large-vessel phenotype of GCA, and even in patients with the temporal artery affected, skip lesions may contribute to a negative TAB.

TAB showing transmural inflammation is still considered the gold standard for the diagnosis of GCA and remains the most specific diagnostic test. It is a minimally invasive and well-tolerated surgical procedure that is generally performed in an outpatient surgery setting and carries a low risk of complications in experienced hands. The length of the artery needed for optimal histopathological analysis is 2 cm. For all these reasons, TAB is still recommended in all patients with a clinical suspicion of GCA. In addition to their diagnostic role, histological findings of positive TAB may have clinical and prognostic significance and thus implications for the patients' management.

GCA is characterized histopathologically by mononuclear infiltrates in all layers of the arterial wall. Macrophages and T cells are present in granuloma formation, and multinucleated giant cells are localized close to the fragmented internal elastic lamina. Neutrophils, eosinophils, and plasma cells are rare. Proliferation of the intima results in occlusive vasculopathy. Neoangiogenesis is frequent and at times prominent, and fibrinoid necrosis is typically absent (**Figures 1** and **2**) [13].

The positivity of TAB declines after glucocorticoid treatment is started, and the biopsy should ideally be performed within 2 weeks from the onset of the therapy.

#### **Figure 1.**

*Histopathological analysis of a patient from the Rheumatology Division of the University of Sao Paulo showing a transmural lymphomonocytary infiltrate and important narrowing of the vessel lumen. HE 100×. Image gently provided by the Pathological Anatomy Division of the University of Sao Paulo, School of Medicine.*

#### **Figure 2.**

*Histopathological analysis of a patient from the Rheumatology Division of the University of Sao Paulo showing a transmural lymphomonocytary infiltrate and the presence of a granuloma. HE 100×. Image gently provided by the Pathological Anatomy Division of the University of Sao Paulo, School of Medicine.*

**99**

**Figure 3.**

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

with glucocorticoids rapidly reduces the sensitivity of imaging [15].

*Temporal artery duplex scan of a patient from the Rheumatology Division of the University of Sao Paulo, School of Medicine with GCA showing thickness in the vascular wall and the noncompressible "halo" sign.*

Importantly, the therapy should never be delayed for the performance of a biopsy,

For patients with a negative temporal artery biopsy, clinical assessment remains

In 2018, the European League Against Rheumatism (EULAR) published recommendations about the use of imaging techniques in large-vessel vasculitis (LVV), which included GCA and Takayasu's arteritis. According to these recommendations, in patients with suspected GCA, an early imaging test is recommended to complement the clinical criteria for diagnosing GCA, assuming high expertise and prompt availability of the imaging technique [15]. However, imaging should not delay initiation of treatment. The choice of the individual imaging method depends on the predominant clinical symptoms and local settings. In settings where imaging modalities are not readily available or expertise with imaging in GCA is questionable, a biopsy should still be favored in first place. Besides, if positive histology is already available, additional imaging may not be needed for the diagnosis. In centers, however, where imaging (and TAB) is readily available and performed with high quality, the task force recommends that imaging should be preferred as the first test because of low invasiveness, ready availability of imaging results, and assessment of a larger extent of potentially inflamed arteries at the same examination, therefore contributing to a lower number of false-negative results. Imaging should be performed before or as early as possible after initiation of therapy, best within 1 week, because treatment

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

a mainstay of diagnosis.

**4.3 Imaging techniques**

especially when visual symptoms are present [14].

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

Importantly, the therapy should never be delayed for the performance of a biopsy, especially when visual symptoms are present [14].

For patients with a negative temporal artery biopsy, clinical assessment remains a mainstay of diagnosis.
