Giant Cell Arteritis

Pathophysiology

The cause of GCA remains unknown. Genetic and environmental factors are thought to be important in disease pathogenesis. The incidence of GCA is highest in northern European populations compared with Asians or African Americans, in whom the disease is rarely reported. Genetic polymorphisms, specifically in the HLA-DRB1 ^∗ 04 alleles, have been associated with genetic susceptibility. Although several bacterial and viral infectious agents have been implicated in disease pathogenesis, to date an inciting agent or event has not been identified.

GCA is a T-cell–dependent disease. The inflammatory process is thought to begin in the adventitial layer of the artery with activation of resident dendritic cells by way of Toll-like receptors. Activated dendritic cells in turn recruit and provide co-stimulatory signals to activate CD4 ⁺ T cells. Activated T cells produce proinflammatory cytokines, particularly interleukin-17 and interferon-gamma (INF-γ), which amplify the inflammatory response and stimulate macrophages. As a consequence of immunologic injury, the artery releases growth and angiogenic factors such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), which induce migration and proliferation of myofibroblasts, neoangiogenesis, and intimal proliferation. The histopathologic hallmark of GCA is transmural inflammation. The inflammatory infiltrate mainly consists of CD4 ⁺ T cells and macrophages. Macrophages tend to concentrate around the internal elastic lamina, and fragmentation of this elastic layer often occurs. Although most macrophages are singly distributed, they can coalesce to form multinucleated giant cells.

Clinical Features

About two thirds of patients with GCA present with new temporal or occipital headaches, often accompanied by scalp tenderness. Jaw claudication caused by ischemia of the muscles of mastication is present in one third of patients. However, presence of this symptom is associated with increased likelihood of GCA. Partial or complete vision loss can occur in 20% of patients and can progress to blindness. Other vision symptoms include amaurosis fugax and diplopia. Symptoms of polymyalgia rheumatica with prolonged morning stiffness of the shoulder and hip girdle are common and occur in 40% to 60% of patients. Additionally, systemic symptoms such as anorexia, weight loss, fatigue, and low-grade temperatures are also common clinical presentations. Less-common presenting symptoms include dry cough, sore throat, and hoarseness, which affect 10% of patients. Neurologic manifestations including stroke and transient ischemic attack are uncommon.

A subset of patients with GCA present with constitutional symptoms in the absence of cranial symptoms. GCA should be considered in the differential diagnosis for an elderly person who has a fever of unknown origin. Another subset of patients with GCA experience symptoms of vascular insufficiency affecting the extremities, particularly the upper extremities. Many of these patients do not have typical cranial manifestations, and up to 42% have a negative temporal artery biopsy. The diagnosis in these cases requires a high degree of clinical suspicion and appropriate imaging studies to evaluate for changes compatible with large vessel vasculitis.

Physical examination in GCA should focus on the cardiovascular system. Examination of the temporal arteries can reveal abnormalities such as nodularity, swelling, diminished pulse, or tenderness to palpation. Subclavian bruits, asymmetry in upper extremity blood pressures, or absent upper extremity pulses suggest extracranial involvement of the proximal upper extremity arteries. An aortic valve insufficiency murmur can indicate the presence of aortic root dilatation from involvement of the thoracic aorta.

Diagnosis

The American College of Rheumatology has established criteria for the classification of GCA ( Table 1 ). These criteria were developed to help distinguish GCA from other forms of vasculitis, and the presence of three or more of the criteria listed in Table 1 has a sensitivity of 94% and specificity of 91% for GCA.