Giant Cell Arteritis and Polymyalgia Rheumatica

Definition

Polymyalgia rheumatica and giant cell arteritis, also called temporal arteritis, are companion systemic inflammatory disorders of unknown etiology that is propagated by antigen-driven, cell-mediated immune mechanisms that may be associated with specific genetic markers. These disorders represent a spectrum from severe proximal aches and pains and constitutional symptoms to an occlusive granulomatous vasculitis of medium and large vessels that can lead to permanent blindness or other organ and tissue damage. These disorders occur primarily in patients older than age 50 years, are more common in women than in men, and are highly responsive to corticosteroids.

Epidemiology

In the United States, the average annual incidence of polymyalgia rheumatica is 52.5 per 100,000 patients ages 50 years and older and increases with age. The prevalence is about 0.5 to 0.7%. Internationally, the frequency varies, with the highest rates occurring in the Scandinavian countries. The incidence and prevalence of giant cell arteritis are approximately one third those of polymyalgia rheumatica.

Pathobiology

The etiology of polymyalgia rheumatica and giant cell arteritis are unknown, but both demonstrate familial aggregation and have a genetic association with human leukocyte antigen (HLA)-DR4 and a demonstrated sequence polymorphism encoded within the hypervariable region of the HLA-DRβ1∗ 04 gene. Infectious triggers of giant cell arteritis have been postulated. For example, some but not all studies have found varicella-zoster virus antigen in temporal artery biopsies of patients with giant cell arteritis. Bacterial and viral DNA also has been demonstrated in the arterial wall of patients with giant cell arteritis using advanced DNA imaging techniques. Disease in genetically predisposed patients also may be triggered by endogenous antigens such as elastin, and the inflammatory manifestations are directed by specific patterns of cell-mediated, type 1 helper T cell (T _H 1)-associated cytokines. The cytokine production by the mononuclear cells in the involved tissues appears to influence the clinical phenotype.

In the pathogenesis of giant cell arteritis, the adventitia is considered the immunologic center where toll-like receptors (TLRs) are highly expressed on dendritic cells and resident tissue macrophages. Macrophages and T lymphocytes enter the vessel wall through the vasa vasorum with the aid of adhesion molecules and come into contact with an inciting antigen. Activated CD4 cells produce interferon-γ that attracts macrophages to the arterial wall. Some of these macrophages fuse at the intima-media to form multinucleated giant cells. These cells produce vascular endothelial growth factor, which triggers neovascularization, both at the intima-media junction and at the level of the vasa vasorum. The subsequent immunologic events lead to a characteristic topography of mononuclear cells throughout the vessel wall. Products of the giant cells and macrophages at the intima-media junction include collagenase and nitric oxide, both of which probably contribute to tissue damage. The pathologic impact of cytokines leads not only to the characteristic medial damage but also to significant intimal hyperplasia that eventually, if it is not treated, may cause luminal narrowing and tissue ischemia.

In giant cell arteritis, a transmural (involving all layers of the vessel) inflammatory infiltrate, comprised of predominantly mononuclear cells and commonly with giant cells, is found in the superficial temporal arteries as well as in other large and medium-sized arteries. In elderly patients, fragmentation of the internal elastica is characteristic and helps differentiate this vascular lesion from that of atherosclerosis. Often, macrophages containing fragments of elastic tissue are found at the intima-media junction, which is the histologic center of the inflammatory process. Intimal proliferation may be prominent and lead to luminal narrowing. Damage to the elastica and loss of vascular smooth muscle cells likely contribute to the recognized increased risk of aneurysms later in the disease course.

In polymyalgia rheumatica, mononuclear cell inflammation can be found not only in the proximal joints, such as the shoulders, but also in the surrounding tendons, bursae, and soft tissues consistent with enthesitis. Although muscle pains may be present, no significant muscle inflammation is found.

Clinical Manifestations

Polymyalgia rheumatica and giant cell arteritis are systemic inflammatory disorders that occur primarily in patients older than age 50 years, in women more than in men (2:1), and more commonly in Whites. Shared characteristics of the two disorders include significant cytokine-driven constitutional symptoms, such as fever, fatigue, and weight loss, as well as a markedly elevated erythrocyte sedimentation rate (ESR), anemia, and thrombocytosis.