Giant-Cell Arteritis and Polymyalgia Rheumatica

Giant-cell arteritis, formerly called temporal arteritis or granulomatous arteritis, is an inflammatory vasculopathy that affects large and medium-size arteries. Arterial lesions are composed of T cells and macrophages, often arranged in granulomas. Vessel wall inflammation leads to luminal occlusion and tissue ischemia. The vascular bed of the cranial arteries is particularly susceptible, but the aorta and its primary and secondary branches can be affected as well. Tissue ischemia in the optic nerve, the masseter muscles, and the posterior circulation of the central nervous system is particularly important in causing the clinical manifestations of this vasculitis. Involvement of the subclavian and axillary arteries leads to upper-extremity ischemia, and giant-cell arteritis and aortitis cause aortic dilatation and aneurysm. Vessel wall inflammation almost always coexists with a syndrome of systemic inflammation. In polymyalgia rheumatica, a closely related entity, vessel wall inflammation is incomplete, and the systemic inflammation is combined with myalgias of the neck, shoulder, and pelvic girdle. Giant-cell arteritis and polymyalgia rheumatica frequently occur together in the same patient. Whereas the diagnosis of giant-cell arteritis can be proven by temporal artery biopsy, no pathognomonic test is currently available for polymyalgia rheumatica. Giant-cell arteritis is the most frequent primary vasculitis (1); the incidence is 15 to 25 per 100 000 in at-risk populations. The disease is most prevalent in white persons, particularly those of Scandinavian descent, and is rare in Hispanic persons (2). Women are more susceptible than men. The single most important risk factor is age. Susceptible persons are usually older than 50 years of age, and incidence rates increase with advancing age (3). Given that the population in developed countries is increasingly getting older, the number of people at risk can be expected to double in the next 25 years. Granulomatous arteritis can occur in individuals younger than 40 years of age; however, it then manifests as Takayasu arteritis. In contrast to giant-cell arteritis, Takayasu arteritis primarily targets the aorta and its proximal branches, compromising blood flow to major organs, such as the brain, the kidney, or entire extremities (4). Advances in the understanding of the immunologic events causing giant-cell arteritis have provided new opportunities for diagnostic testing and therapeutic interventions. Studies of the nature and diversity of the pathogenic immune response have established a conceptual framework within which different clinical phenotypes may be identified. The goal is to develop reliable diagnostic procedures that detect vasculitis in distinct vascular beds. Adaptation of therapeutic management to the specific needs of individual patients is on the horizon. Pathogenesis The molecular and cellular pathogenesis of medium- and large-vessel vasculitis has recently been reviewed (5). The clinical manifestations of giant-cell arteritis are a result of 2 different immunopathogenetic processes (Figures 1 and 2). Inflammatory cells infiltrate the arterial wall and cause structural damage that eventually leads to the vascular complications (Figure 1). In most patients, a syndrome of systemic inflammation is also present (Figure 2), but the systemic inflammatory response does not seem to be simply a spillover from the vascular lesions. The systemic and the vascular components of giant-cell arteritis seem to have different underlying pathomechanismsthe vascular inflammation results from abnormal adaptive immune responses, whereas the systemic inflammation bears the signature of an excessively activated innate immune system. Figure 1. Pathogenic mechanisms in the vascular lesions of giant-cell arteritis. IFN- Figure 2. The systemic inflammatory response in giant-cell arteritis and polymyalgia rheumatica. IL The Innate and Adaptive Immune Systems The immune system is composed of innate and adaptive branches, both involved in pathologic immune responses (6). Innate immunity is an ancient form of host defense. It relies on mechanisms that are not specific for a particular antigen or pathogen. Innate immune cells (neutrophils, monocytes or macrophages, and dendritic cells) rely on the principle of pattern recognition. Through a set of inherited receptors (such as Toll-like receptors), they sense infection and tissue invasion by recognizing molecular patterns that are shared by many microorganisms and dying cells (7). Upon stimulation, the innate immune system induces the production of cytokines and generates inflammation. By contrast, adaptive immunity is highly specific for an immunogen and has the remarkable property of memory. Adaptive immune responses are mediated by T cells and B cells that possess antigen-specific receptors. The enormous spectrum of the necessary antigen-specific receptors is generated by random recombination of gene segments. To avoid self-reactivity and autoimmunity, self-reactive T cells and B cells must be eliminated or suppressed. The value of highly diverse and specific receptors is obvious; however, adaptive immune responses are delayed because rare lymphocytes expressing the fitting receptor are infrequent and must be expanded to eliminate offending antigens (8, 9). Innate and acquired immunity are highly interconnected. Whereas the adaptive arm is superior in selectively identifying and memorizing antigen, it depends on the innate arm to find antigens in the tissue (to transport them to lymphoid organs) and to prime T cells. Primed T cells leave the secondary lymphoid organs, travel to peripheral tissue, re-identify the antigen, and initiate effector functions that eventually destroy the antigen and repair tissue damage. These effector functions are often delegated to cells of the innate immune system, such as monocytes or macrophages, and resident cells at the tissue site (10). Surveillance of tissues for pathogens, emerging tumors, and cellular breakdown products relies mostly on dendritic cells (11-13). Dendritic cells are placed in strategic positions in the tissue and are phagocytic. Upon activation, they become migratory and ferry antigens to the central lymphoid organs where T cells have an opportunity to test their antigen receptors for an exact fit. Recent data suggest that dendritic cell activation and differentiation hold seminal positions in the pathogenesis of giant-cell arteritis. Indeed, dendritic cells positioned in the wall of medium-size arteries emerge as the cellular link between a highly activated innate immune system, which causes the exuberant systemic inflammatory disease of giant-cell arteritis, and the formation of granulomas in the vessel wall (14). This novel disease model of granulomatous vasculitis proposes a stepwise process, beginning with the activation of innate immunity and progressing to the loss of self-tolerance in the artery. Persistent innate immune activation emerges as the major cause of the systemic inflammatory syndrome, whereas misguided adaptive responses mediate arteritis. The Vascular Lesion Vascular lesions of giant-cell arteritis are a consequence of inappropriate activation of the adaptive immune system, particularly T cells (15-17). As for many autoimmune diseases, infectious microorganisms have been suspected as possible instigators. The spectrum ranges from viral agents to bacterial organisms (for example, human parainfluenza type I virus, parvovirus B19, herpesvirus, chlamydia, and mycoplasma) (18-25). However, episodic reports of microbial antigens in affected temporal arteries have not been corroborated (26-28), and direct evidence for an immune response directed against pathogens in the vessel wall is lacking. It seems that the recruitment of macrophages carrying antigens from former infections is a regular event in inflammatory lesions, but this may have no role in initiating the disease process. CD4+ T cells and activated macrophages are the major components of vessel wall infiltrates. Lymphocytes and macrophages penetrate through all layers of the arterial wall, but the primary immunologic injury occurs in the adventitia (29). T cells seem to enter the artery through the vasa vasorum and not from the main lumen. In the adventitial layer, T cells encounter stimulatory signals, expand clonally (30, 31), and release cytokines, particularly interferon- (29). The major target cells for interferon- are macrophages, which are recruited into the vessel wall to form the prominent granulomatous reaction. Stimulated macrophages use a spectrum of effector pathways to mediate structural damage in the artery (16, 17). Two factors determine the course of the intra-wall inflammation: the type of T-cell differentiation (32) and the cellular and matrix composition of the affected blood vessel (16, 33). Intense stimulation of T cells with the production of high concentrations of interferon- in the tissue correlates with marked intimal hyperplasia and tissue ischemia (32). If T-cell differentiation in the vascular lesions is biased toward production of high levels of interleukin-2 and low levels of IFN-, the vasculitis evolves without luminal occlusion. At the end of this spectrum of vascular inflammation are patients with isolated polymyalgia rheumatica who lack vasculitis by histomorphologic criteria but have sufficient arterial infiltration of T cells and macrophages to allow for the in situ detection of interleukin-2, interleukin-1, and interleukin-6 transcripts (34). Macrophages residing in different regions of the arterial wall are committed to distinct effector mechanisms (Figure 2) (35). In the adventitia, they specialize in the production of proinflammatory cytokines that optimize T-cell stimulation. Macrophages in the smooth-muscle cell layer of the tunica media focus on oxidative stress and the production of matrix metalloproteinases (which are probably instrumental in the fragmenta