Giant cell arteritis (GCA), also called Horton or granulomatous arteritis, is a large- and medium-sized blood vessel systemic vasculitis characterized by the granulomatous involvement of the aorta and its major branches (1, 2). Polymyalgia rheumatica (PMR) is a disease characterized by severe bilateral pain and aching involving the neck, shoulder, and pelvic girdles associated with morning stiffness (1). GCA and PMR mainly occur in white individuals age >50 years. Due to the progressive aging of the population in Western countries, both conditions have emerged as relatively common diseases in the elderly (1, 2).
We searched the Cochrane Library, Medline, and EMBase, mainly using the search terms “polymyalgia rheumatica [medical subject headings (MeSH)],” “giant cell arteritis,” and “temporal arteritis [MeSH].” We largely selected articles published in English over the past 10 years without excluding older studies that we considered to be highly relevant to the topics discussed in this review. Articles of exceptional relevance written in other languages were also assessed. We searched the reference lists of articles identified by this search strategy and selected those we considered relevant. We also included some review articles providing important overviews on the epidemiology of GCA and PMR.
Epidemiology of GCA and PMR
GCA shows a predisposition for the involvement of extracranial branches of the carotid artery (1). The vasculitic involvement of these arteries leads to the typical symptoms and classic clinical features of GCA such as bitemporal headache, jaw claudication, scalp tenderness, or abnormal temporal arteries (tender, nodular, swollen, and thickened arteries with decreased pulses) on physical examination (3). However, ocular ischemic complications, the most feared complications of this vasculitis, are generally early manifestations due to the vasculitic involvement of ocular vessels deriving from the internal carotid artery (4). In unselected patients with biopsy-proven GCA, visual ischemic complications occur in 25% and irreversible visual loss occurs in 10–15% of the patients (4). They are generally due to anterior ischemic optic neuropathy that is caused by interruption of blood flow in the posterior ciliary arteries to the optic nerve head. More rarely, visual loss is caused by central retinal artery occlusion, ischemic retrobulbar neuritis, or occipital infarction in the setting of a stroke involving the vertebrobasilar territory (4). Less common neurologic complications include transient ischemic attacks and cerebral infarctions, in particular in the vertebrobasilar territory (4), and audiovestibular dysfunction (5).
A temporal artery biopsy (TAB) is the gold standard test for the diagnosis of GCA (6). Because corticosteroid therapy is required in most cases for more than 1 year in GCA, the pathologic confirmation of this vasculitis is advisable.
Unlike GCA, there is no gold standard test for the diagnosis of PMR, and several conditions may mimic or present polymyalgic features (7). However, arthroscopic studies have confirmed the presence of synovitis in the proximal joints of PMR patients (8). Moreover, magnetic resonance imaging and ultrasonography have disclosed inflammation of subacromial and subdeltoid bursae in association with synovitis of the glenohumeral joints and tenosynovitis of the biceps, as well as the presence of trochanteric, iliopsoas, ischiogluteal, and low cervical interspace bursitis in patients with PMR (9–12).
PMR is more common than GCA (1), and it may present as an isolated entity (13) or may be the presenting feature in patients who later develop typical cranial manifestations of GCA. Population-based studies have shown the presence of “silent” biopsy-proven GCA in 9–21% of the patients presenting with PMR features (14). Also, PMR manifestations are observed in up to 40–50% of patients with biopsy-proven GCA (3).
GCA is an antigen-driven disease with local T cell and macrophage activation in the vessel wall, and with an important role of proinflammatory cytokines (15, 16). Inflammation of the arterial wall and vessel occlusion through fast and concentric intimal hyperplasia leads to the severe ischemic complications observed in patients with GCA (17). Dendritic cells localized at the adventitia–media border of normal medium-sized arteries produce chemokines and recruit and locally activate T cells (18). Moreover, dendritic cells express a singular surface receptor profile, including a series of Toll-like receptors (TLRs). Ligands of TLR-4 promote activation and differentiation of adventitial dendritic cells into chemokine-producing effector cells with high-level expression of both CD83 and CD86, and mediate T cell recruitment through the release of interleukin-18 (IL-18) (18–20). Activated T cells experience clonal expansion and are stimulated to produce interferon-γ (IFN-γ). This leads to the differentiation and migration of macrophages and the formation of giant cells. In the adventitia, macrophages produce proinflammatory cytokines such as IL-1 and IL-6, whereas in the media and intima they contribute to arterial injury by producing metalloproteinases and nitric oxide. This destructive mechanism of the arterial wall is associated with a repair mechanism that includes the secretion of growth and angiogenic factors (platelet-derived growth factor and vascular endothelial growth factor) through the infiltration of mononuclear cells and multinucleated giant cells. These changes ultimately lead to the degradation of the internal elastic lamina and to occlusive luminal hyperplasia. In addition to IL-1 and IL-6, IFN-γ specifically seems to play a pivotal role in the pathogenesis (15) and in the clinical expression of GCA (21). In this regard, although IFN-γ is expressed in nearly 70% of the TAB samples from patients with GCA, it was not detected in TAB samples from patients with isolated PMR (15). High transcription of IFN-γ messenger RNA (mRNA) was associated with the formation of giant cells and with the evidence of cranial ischemic symptoms in GCA patients (21). The absence of IFN-γ expression in TAB samples from patients with isolated PMR suggests that its production may be crucial to the development of GCA (15). TAB specimens from GCA patients with ocular ischemia expressed high amounts of IFN-γ mRNA, whereas those from GCA patients with fever had less IFN-γ mRNA (16). Therefore, clinical correlates suggest a role of IFN-γ in the process of lumenal obstruction. By regulating giant cell formation, IFN-γ could indirectly control intimal hyperplasia. IFN-γ may dictate the functional properties of other cell populations in the vascular infiltrates and, by means of this mechanism, guide the response-to-injury reaction of the artery (21, 22). Interestingly, a CA repeat functional polymorphism in the first intron of the IFN-γ gene was associated with some clinical differences between biopsy-proven GCA and isolated PMR (23). This was also the case for specific clinical manifestations of GCA such as visual ischemic complications. With respect to this, an association between a 126-bp allele (high IFN-γ producer) with GCA patients with visual ischemic manifestations and the inverse correlation with the 128-bp allele (low IFN-γ producer) was found (23).
Incidence of GCA and PMR.
Over the last 25–30 years, GCA has been found to be the most common type of vasculitis in Europe and North America, especially in people age >70 years (1, 24, 25). GCA mainly affects white individuals (2, 25, 26), and it almost exclusively occurs in subjects age >50 years (25, 27–36). The incidence increases with age (32–36) and peaks in the 70–79 years age group (28, 32). In this regard, in Northwestern Spain, the incidence of GCA increased dramatically up to age 80 years and then decreased slowly (32, 37). GCA is also more common in women than in men (1). In Northern European countries, a 3:1 ratio of women to men was observed (33–35). A lower ratio of women to men was observed in Israel and Southern Europe (36, 37).
Most epidemiologic studies on GCA reported over the last 20 years support the evidence of an increase in the incidence of GCA with latitude in the Northern hemisphere (2). The highest incidence rates are reported in Scandinavian countries and North American populations of the same descent (29, 31, 33–35, 38–41). In these regions, the annual incidence rates are generally higher than 17/100,000 people per population age ≥50 years. The incidence of GCA is lower than 12/100,000 people per population age ≥50 years in Southern European and Mediterranean countries (24, 27, 28, 30, 32, 36, 37). A lower incidence of GCA was reported in black individuals from Tennessee (42) (Table 1). Also, GCA was found to be very uncommon in Asian populations (43). In this regard, a nationwide survey for GCA disclosed that the prevalence of this vasculitis in Japan was extremely low compared with other countries (44). With respect to this, the prevalence of GCA in patients age ≥50 years in 1997 was only 1.47/100,000 population in Japan (44). Moreover, permanent visual loss, jaw claudication, and PMR were infrequent among Japanese individuals with GCA (44).
Table 1. Incidence of giant cell arteritis in different regions of the world
Higher physician awareness was proposed as being responsible for the progressive increase of GCA reported in different parts of the world (2, 32). Several epidemiologic studies by our group supported a progressive increase in the incidence of this vasculitis in the Lugo region of Northwestern Spain until 2000 (32, 37, 45). However, we observed that the increased trend in the annual incidence rate of biopsy-proven GCA was no longer apparent in the 2001–2005 time period (32). In keeping with these observations, although a progressive increase in the incidence of GCA was initially reported in Jerusalem in the period 1980–1991 (30), a more recent report from the same group of investigators did not confirm a progressive increase in the incidence of GCA over the entire period 1980–2004 in that part of the world (36). Likewise, in a 50-year observation period in the population of Olmsted County, Minnesota, Salvarani et al found an increase in the rate of GCA between 1950 and 1979. However, GCA incidence in Olmsted County has been stable since then (41).
As observed in populations of Scandinavian background (34, 40), we found that the increase in the incidence of GCA observed between 1981 and 2000 in Northwestern Spain was also associated with a constant relationship between the rate of positive and negative TAB samples (32, 37, 45). We believe that higher physician awareness may be responsible for the diagnosis of GCA in individuals with less typical manifestations of this vasculitis. This fact might also explain the negative trend manifested by a progressive and significant decline in the number of biopsy-proven GCA patients who had visual ischemic manifestations or irreversible visual loss over the entire period 1981–2005 in Northwestern Spain (32). As shown in Figure 1, a new reappraisal of the incidence of biopsy-proven GCA in the Lugo region of Northwestern Spain over the period 1982–2006, specifically performed for this review article, confirmed that the previously described increase in the number of patients diagnosed with biopsy-proven GCA in Northwestern Spain was not associated with an increase in the number of patients who experienced visual ischemic events or permanent visual loss.
As reported for GCA, the incidence of PMR has been found to be higher in individuals of Scandinavian background (33, 46–48). In this regard, the annual incidence rate of PMR in Ribe County, Denmark, over the period 1982–1985 was 68.3/100,000 for the population age ≥50 years (33). Likewise, the incidence of PMR in Göteborg, Sweden, between 1985 and 1987 for the population age ≥50 years was 50/100,000 (47). In the North American region of Olmsted County, Minnesota, where the population has strong Scandinavian background, the annual incidence rate of PMR for individuals age ≥50 years between 1970 and 1991 was 52.5/100,000 population (48). In contrast, as described for GCA, the annual incidence of PMR is lower in Southern European countries. In this regard, the annual incidence rate of PMR in Reggio Emilia, Italy, over the period 1980–1988 for the population age ≥50 years was 12.7/100,000 (28). Likewise, the annual incidence rate in Lugo, Spain, for the population age ≥50 years over the period 1987–1996 was 18.7/1000,000 for overall PMR (associated or not with GCA) and 13.5/100,000 for subjects with isolated pure PMR (49) (Table 2).
Table 2. Incidence of polymyalgia rheumatica in different parts of the world
Influence of environmental factors and infectious agents.
It has been proposed that environmental factors and infectious agents are a possible influence in the pathogenesis of GCA and PMR (2). Several infectious agents have been investigated as possible triggers in a susceptible host, with inconclusive results. Simultaneous fluctuations of the incidence of GCA and PMR in different regions of Denmark, supporting an association with Mycoplasma pneumoniae, parvovirus B19, and Chlamydia pneumoniae epidemics, were found (46). An association of parvovirus B19 with GCA was also suggested by Gabriel et al (50). French investigators found an association of GCA with human parainfluenza virus type 1 (51). According to these investigators, the reinfection with human parainfluenza virus type 1 was associated with the onset of GCA, particularly in biopsy-proven patients (51). Salvarani et al reported a regular epidemic-like cyclic pattern in incidence rates of GCA over a 42-year period in Olmsted County, Minnesota (29). These authors observed peaks in the incidence every ∼7 years (29).
Cyclic fluctuations of age-adjusted GCA incidence with 3 distinctive peaks 8–10 years apart were found by Bas-Lando et al in Jerusalem over the period 1980–2004 (36). However, no cyclic pattern in the incidence of GCA was observed in very distant regions of Europe such as Göteborg, Sweden (34), and Lugo, Northwestern Spain (32).
Some investigators have also reported a seasonal distribution of GCA. Peaks of incidence of biopsy-proven GCA were found in late winter and autumn in Sweden (34). Based on the onset of symptoms, peaks of incidence were observed during the summer months in the UK (52). Peaks in January and May were reported in Scotland (53), and an increased incidence of GCA in late spring and early summer was observed in Israel (36). However, in an epidemiologic study that encompassed all biopsy-proven GCA patients diagnosed in the Lugo region of Northwestern Spain over the period 1981–2005, we only observed a slight decline in the onset of the disease between June and September, and we did not confirm a seasonal pattern for GCA distribution in Northwestern Spain (32). Also, we did not find an association between GCA incidence and altitude in Lugo (54). In keeping with our results, 4 different recent studies did not confirm any association between the presence of parvovirus B19, C pneumoniae, or human herpesvirus DNA in TAB specimens and the histologic evidence of biopsy-proven GCA (55–58).
Implication of genetic factors.
A genetic component, in particular in patients with biopsy-proven GCA, has been reported (59). With respect to this, in addition to an association with HLA–DRB1*04 alleles (60) and tumor necrosis factor microsatellite polymorphisms (61), we have recently reported an independent association of MICA and HLA–B genes with the genetic susceptibility to GCA (62), suggesting that several genes within the major histocompatibility complex may have independent effects in the susceptibility to GCA. Moreover, many other studies have shown the implication of genetic variants in key components of immune and inflammatory pathways in GCA and PMR susceptibility (59, 63), because GCA and PMR are polygenic diseases. An increased risk of having visual ischemic complications in biopsy-proven GCA patients and an increased frequency of relapses in patients with PMR were found to be associated with the carriage of HLA–DRB1*04 alleles (4, 49). Moreover, a functional variant of the vascular endothelial growth factor gene was associated with severe ischemic complications in patients with GCA (64). The polymorphism of the intercellular adhesion molecule 1 was also associated with PMR and GCA susceptibility in Italians and conferred an increased risk of relapses in those with PMR (65). The association of both HLA–DRB1*0401 and the intercellular adhesion molecule 1 codon 241 G homozygosity was significantly associated with an increased risk of relapses in patients with isolated PMR from Northwestern Spain (66).
Influence of traditional cardiovascular risk factors.
Twenty years ago, a retrospective case–control study on 88 biopsy-proven GCA patients disclosed an association between smoking and disease development (67). More recently, Duhaut et al, in a prospective multicenter case–control study on 207 biopsy-proven GCA patients, described a strong association between smoking and previous atheromatous disease in women and GCA (68). Based on a series of 210 biopsy-proven GCA patients assessed for the risk of severe ischemic complications, we observed that the presence of traditional risk factors of atherosclerosis before the diagnosis of this vasculitis, in particular a history of hypertension, significantly increased the risk of developing severe ischemic complications of GCA (69). Also, patients with traditional atherosclerosis risk factors were found to have fever less commonly than those without classic atherosclerosis risk factors (69).
According to these data, the presence of atherosclerosis risk factors at the time of diagnosis of the disease may influence the development of severe ischemic complications in patients with this vasculitis. However, the reason why GCA patients with traditional atherosclerosis risk factors have a lower frequency of fever remains to be an intriguing question. It is possible that, due to a severe and maintained inflammatory response, fever might represent the clinical expression of an angiogenic activity, which might play a compensatory role for ischemia in patients with GCA. According to that, GCA patients with atherosclerosis would be unable to establish appropriate angiogenic compensatory mechanisms and, due to this, they might have more vascular ischemic complications (69).
The role of biopsy in the incidence of GCA.
As discussed before, a TAB is the gold standard test for the diagnosis of GCA (70). However, GCA affects vessels focally and segmentally, yielding areas of inflammatory vasculitic lesions juxtaposed with areas of normal artery (70, 71). Histologic signs of inflammation may be missed in TABs performed in arteritis-free segments.
In most series of GCA, 10–20% of biopsy samples are negative, although the rate may be as high as 40% (6, 71, 72). Interestingly, 2 population-based studies have shown that patients with negative biopsy samples have less frequency of severe ischemic complications than those with biopsy-proven GCA (6, 73).
Taylor-Gjevre and colleagues described that a threshold length of 1.0 cm of a post–formalin-fixed arterial segment was associated with an increased diagnostic yield of GCA (74). They recommended collecting a minimum TAB length of 1.5 cm to allow for tissue shrinkage during fixation that was estimated to be ∼10%. More recently, Mahr et al reported that a post–formalin-fixed TAB length of at least 0.5 cm could be sufficient to make a histologic diagnosis of GCA (75).
TAB is generally performed on the most symptomatic side (70, 76). However, due to the segmental inflammatory involvement of the temporal artery, a contralateral biopsy may be required in patients with high clinical suspicion of GCA (70). In a retrospective study from the Mayo Clinic in Rochester, Minnesota, 14% of 234 patients were diagnosed with biopsy-proven GCA because TAB was performed on the second side (76). In a prospective study, Ponge et al performed 200 bilateral TABs. They found 42 patients with a positive TAB sample in at least 1 side. Interestingly, 4 GCA patients (10%) would have been missed if only unilateral TAB had been performed (77). Also, a second contralateral biopsy was required to make a diagnosis of biopsy-proven GCA in 5 (9%) of 57 patients diagnosed with GCA in Northwestern Spain between 1981 and 1990 (78). These observations indicate that patients with high clinical suspicion of GCA and a negative TAB sample on the most symptomatic side should undergo contralateral biopsy.
TAB should be performed soon after the onset of treatment. However, failing to do so within several days after the initiation of corticosteroid therapy should not be a reason for not performing TAB in patients with suspected GCA (70). In this regard, Achkar and colleagues confirmed the presence of histopathologic findings of GCA in TAB samples of 9 patients who had received more than 15 mg/day of prednisone for more than 14 days before the biopsy (79).
In the presence of elevated acute-phase reactant levels, new features in elderly individuals such as headache or an unexplained pain located above the neck should prompt us to consider the possibility of GCA and the need for TAB (70). However, GCA may present without clinically evident vascular involvement (80). Some of these patients without overt vascular manifestations may present with fever of unknown origin (80).
In Northwestern Spain, TAB is usually considered in patients with isolated PMR if they have constitutional syndrome and/or an erythrocyte sedimentation rate greater than 80 mm/first hour. Following this protocol, we found 9% positive TAB samples from a series of 89 patients presenting with isolated PMR (37). However, a retrospective study aimed to establish the best set of predictors for a positive TAB sample in patients with PMR disclosed that in those patients age <70 years and without cranial features of GCA, the risk of GCA was so low that the biopsy could be initially avoided and the patient treated with low-dose corticosteroids (81).
Ocular ischemic complications are the major source of chronic disability among GCA patients (1, 4). In some cases, the development of blindness may be preceded by episodes of amaurosis fugax (4). Other severe vascular complications may be observed in patients with GCA (1, 4). The most common are strokes due to occlusions of large arteries mainly in the vertebrobasilar territory, which occur more commonly at the time of GCA diagnosis or within the first 4 weeks after the onset of corticosteroid therapy (1, 4), and aortic aneurysm rupture, generally several years after the diagnosis of this vasculitis, as a result of the arteritic involvement (82, 83). Relapses are also common in patients with PMR (49). Recurrences of PMR are not exceptional (49).
Interestingly, endothelial dysfunction, which is considered to be an early step in the atherogenesis process, was found in biopsy-proven GCA patients at the time of disease diagnosis (84). However, corticosteroid therapy yielded a rapid improvement of endothelial function in these patients (84). Ultrasonography studies disclosed that carotid intima-media thickness, another surrogate marker of atherosclerosis that predicts the risk of cardiovascular events in both the general population and in patients with rheumatoid arthritis (85), was not increased in biopsy-proven GCA patients who had ended corticosteroid therapy compared with matched controls (86). Likewise, in assessing a large and well-defined homogenous cohort of patients diagnosed with PMR, Maradit Kremers and colleagues found that long-term corticosteroid therapy required for the treatment of PMR was not associated with a higher risk of heart failure, myocardial infarction, or cerebrovascular disease (87). They disclosed a trend for a protective effect of long-term corticosteroid therapy used for the treatment of this chronic inflammatory disease (87). Taking all of these results together, it is possible that the strong antiinflammatory and immunomodulatory effects of corticosteroids might play a potential protective role in reducing the risk of accelerated atherogenesis in patients with these two conditions. Although some studies have described an increased mortality due to cardiovascular disease in both PMR and GCA (47, 88), most long-term survival studies have shown no excess mortality in these patients in different parts of the world (2, 49, 89–92).
GCA and PMR are common and often overlapping conditions in the elderly in Western countries. Higher physician awareness may have been responsible for the progressive increase in the incidence of these conditions observed in different parts of the world. However, the presence of peaks in the incidence and a cyclic pattern observed in some studies suggests that infectious agents may play a role in the pathogenesis of both diseases. They could be the triggers for the development of these conditions in genetically predisposed individuals. Although ischemic complications, in particular irreversible visual loss or aortic aneurysmal disease, may occur in patients with GCA and relapses are not uncommon in PMR, most population-based studies have shown no excess mortality in GCA and PMR.
All authors were involved in contributions to study conception and design, acquisition of data, or analysis and interpretation of data, and drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Gonzalez-Gay had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.