Takayasu Arteritis and Giant Cell Arteritis: A Spectrum Within the Same Disease? : Medicine

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Takayasu Arteritis and Giant Cell Arteritis

A Spectrum Within the Same Disease?

Maksimowicz-McKinnon, Kathleen DO; Clark, Tiffany M. CNP; Hoffman, Gary S. MD, MS

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doi: 10.1097/MD.0b013e3181af70c1
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Abstract

INTRODUCTION

Although Takayasu arteritis (TAK) and giant cell arteritis (GCA) have been viewed as distinct disorders based on their "classic" ethnic and age predilections, consideration has been given to the possibility that these disorders exist as part of a spectrum of a single disease. To our knowledge this perspective was first proposed by Hall,14 who suggested that GCA, TAK, and polymyalgia rheumatica (PMR) comprised an "unholy trinity of a single disease. However, comparative cohort studies since that time have concluded that these disorders, based on differences in ethnicity, age, symptoms, and vascular manifestations, should be classified separately.1,17,26

The perception of clinicians that the widely recognized classic manifestations are distinct for each of these disorders may have led to bias in history taking, physical examination, and selection of diagnostic studies. This bias might have impaired our recognition of similarities between GCA and TAK. This notion is in part supported by recently published observations that have challenged the stereotypes surrounding TAK. For example, TAK in American15,20,24 and Italian patients42 is a disease of primarily young white, not Asian, women. Similarly, as imaging techniques have become less invasive and more widely used, it has become evident that large vessel involvement similar to that seen in TAK is more prevalent in GCA than previously recognized. Prospective vascular imaging studies using fluorodeoxyglucose-positron emission tomography have demonstrated large vessel uptake in 31% of PMR patients and in 85% of GCA patients.4,5

We undertook the current study to compare and contrast the clinical, laboratory, and imaging data in GCA and TAK so that we might explore the hypothesis that these disorders exist as parts of a spectrum of a single disease.

PATIENTS AND METHODS

Patients were identified from a registry maintained by 1 of the authors and checked for completeness by a chart survey that identified prior evaluation within the Center for Vasculitis Care and Research, ICD code for TAK or GCA, or imaging studies that included the entire aorta and its primary branches. The same history and physical examination forms were used for all patients with large vessel vasculitis. A single physician evaluated all patients. The study protocol was approved by the institutional review board of the Cleveland Clinic.

Participants

Seventy-five patients with TAK and 69 patients with GCA were evaluated at the Cleveland Clinic during 1992-2004. Only patients meeting American College of Rheumatology (ACR) criteria for TAK or GCA were included. Patients between the ages of 40 and 50 years at the time of disease onset were classified as having TAK unless 3 or more ACR criteria for GCA were present. Patients in that age range meeting 3 or more ACR criteria for GCA were classified as having GCA. ACR criteria do not classify patients in that age range (>40 and <50 years old) as having either TAK or GCA.1,17 In our cohort, 9 patients in this age range were identified, of which 2 met at least 3 criteria for GCA and were classified as such. Disease onset was defined as the initial time when signs or symptoms were identified that were compatible with TAK or GCA and not readily attributable to comorbid conditions.

Exclusions

Electronic medical records and paper chart reviews were performed to exclude confounding conditions associated with secondary large vessel vasculitis that could mimic TAK or GCA (for example, Cogan syndrome, sarcoidosis, Kawasaki disease, Behçet disease, syphilis, tuberculosis, Ehlers-Danlos syndrome, Marfan syndrome, and neurofibromatosis).

Statistical Analysis

Statistical analyses were performed using STATA software, version 9.0 (StataCorp, College Station, TX). Categorical data and proportions were compared using the chi-square or Fisher exact test, as indicated. P values less than 0.05 were considered significant.

Role of the Funding Source

Support for this study was provided by the Center for Vasculitis Care and Research, Cleveland Clinic. The funding source was not involved in study design, conduct, data analysis or data reporting.

RESULTS

Patient Demographics

Because age was part of the diagnostic criteria, the groups were significantly dissimilar in this respect. The mean age of TAK patients was 26 years (range, 8-46 yr), and of GCA patients was 67 years (range, 49-93 yr). Both groups were predominantly female (TAK 91%, GCA 82%) and white (TAK 88%, GCA 95%).

Clinical Manifestations of Disease

Signs and symptoms associated with disease onset are described in Figure 1. There were no statistically significant differences between groups in the prevalence of fever (p = 0.12) or arthralgia (defined as the new onset of pain localized to joints without evidence of synovitis) (p = 0.16), but myalgia (defined as the new onset of pain localized predominantly in muscles) occurred more often in patients with GCA than in those with TAK (p < 0.0001). Proximal arthralgia and myalgia consistent with PMR occurred in 13% of TAK and 30% of GCA patients. New headache, or the onset of headache dissimilar to prior episodes of cephalgia, was a presenting symptom in 52% of TAK patients, but was more common (70%) in GCA patients (p = 0.04). GCA patients had a 6-fold increase in jaw claudication (33% vs. 5 %; p < 0.0001) and a 3-fold increase in visual blurring (29% vs. 8%; p = 0.001) compared to patients with TAK, respectively. Diplopia (GCA 9%, TAK 0%; p = 0.01), amaurosis (GCA 11%, TAK 4%; p = 0.08), and scotoma (GCA 7%, TAK 4%; p = 0.48) were infrequent in both groups.

F1-5
FIGURE 1:
Signs and symptoms at presentation in patients with TAK and GCA. *Statistically significant difference between groups (p < 0.05).

Vascular Findings at Disease Onset

Signs and symptoms of large vessel disease at presentation were remarkably similar in GCA and TAK (Figure 2). Upper extremity claudication (32% vs. 19%) and pulselessness (41% vs. 17%) were reported more frequently in TAK than in GCA, respectively, with left upper extremity pulselessness being significantly more prevalent in TAK (p = 0.007). Blood pressure inequality between limbs (>15 mm Hg) was more common in TAK at presentation (p = 0.001). The prevalence of vascular bruits was comparable, with the exception of left carotid bruit, which was more frequent in TAK than in GCA (p = 0.01). The prevalence of transient ischemic attacks and stroke was comparable between the groups. Blindness (complete visual loss in at least 1 eye) occurred in 14% of GCA patients, while no TAK patients became blind. Hypertension occurred more often at disease onset in TAK, but this difference was not statistically significant (p = 0.18). Fifty-two percent of TAK patients who presented with new-onset hypertension had coexistent renal artery stenosis, while this occurred in 38% of patients with GCA. In both TAK and GCA, new-onset hypertension was positively associated with the presence of renal artery stenosis (p = 0.0001).

F2-5
FIGURE 2:
Vascular manifestations at presentation in patients with TAK and GCA. *Statistically significant difference between groups (p < 0.05). BP = blood pressure, CVA = cerebrovascular accident, HTN = hypertension, LE = lower extremity, TIA = transient ischemic attack, UE = upper extremity.

Vascular Involvement at Disease Onset

All arterial studies in TAK and GCA evaluated the entire aorta and the primary branch vessels. Large artery involvement defines TAK and was demonstrated in all cases at disease presentation. However, only 62% (43/69) of the GCA cohort had symptoms or signs that led to large vessel imaging (magnetic resonance imaging, computed tomography, or catheter-directed angiography). It cannot be inferred from these data whether those patients with GCA who were not studied by vascular imaging had asymptomatic, undetectable, or no arterial lesions. The prevalence of aortic, vertebral, and renal artery disease was similar between groups. Patients with TAK more often had carotid, subclavian, and iliac artery disease, while GCA patients had similar lesions, but had a greater frequency of axillary artery involvement (Figure 3).

F3-5
FIGURE 3:
Arterial involvement by imaging in patients with TAK and GCA.* In patients with TAK, 97% of lesions were stenotic and 3% were aneurysmal; 8% of patients had both stenoses and aneurysms. In patients with GCA, 75% of arterial lesions were stenotic, 62% of patients had aneurysmal involvement of the aorta, and 41% had both stenoses and aneurysms. *Underwent vascular imaging of the aorta and primary branches (62% of GCA, 100% of TAK). **Statistically significant difference between groups (p < 0.05).

Laboratory Findings

At presentation, elevation of acute phase reactants was common. Mean erythrocyte sedimentation rates were 68 versus 83 mm/h in TAK and GCA, respectively; and C-reactive protein levels were 7 versus 10 mg/dL in TAK and GCA, respectively. Mean hemoglobin and hematocrit levels were not significantly different between groups.

Medical Therapy and Disease Activity

Although the majority (>95%) of both TAK and GCA patients were able to attain disease remission with glucocorticosteroid therapy, disease relapse in both groups occurred frequently. The ability to sustain remission after tapering and discontinuing glucocorticosteroids was uncommon; this result was achieved in only 24% of GCA and 8% of TAK patients, even when using other immunosuppressive agents.

DISCUSSION

To our knowledge the current study is unique, in that we used a common evaluative tool for both forms of large vessel vasculitis and the same physician cared for the cohorts being compared. We found many similarities and differences in the clinical manifestations of TAK and GCA. We hoped to minimize bias in data collection by using the same data collection tool for both groups. Bias was nonetheless present in the GCA cohort in that only those patients (62%) with ischemic symptoms or findings (for example, pulse absence, or pulse or blood pressure asymmetry, or bruits) of large vessel disease had vascular imaging studies. This is a weakness in our comparison of these groups, and could contribute to either over- or underestimating the frequency of large vessel abnormalities in GCA.

The reliance on age to distinguish GCA and TAK is time honored but arbitrary, not based on knowledge of differences in etiology or pathogenesis. In fact, age is not used in certain parts of the world, such as Asia or India, to distinguish the 2 diseases. The emergence of large series of patients with TAK in the United States, Italy, Mexico, and the Middle East has raised questions about the notion that TAK is predominantly a disease of Asian women. In the United States and Italy, white women are the most frequently affected.

We have reviewed our experience with GCA and TAK to raise yet another question: are these diseases more alike than dissimilar? Our data can be used to support either of 2 arguments: 1) these diseases are separate and distinct, or 2) they might be the same disease, in which age-related factors may influence disease expression. We favor the latter interpretation, and find support for that interpretation in analyses of other autoimmune diseases that appear to have variable phenotypes in patients at different ages, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis, and dermatomyositis (Table 1). The concept of large vessel vasculitis as a spectrum of disease is not new, and was postulated even before the advent of noninvasive imaging techniques. Although one might argue that this distinction is merely a matter of nomenclature, we believe that changing our perspective in this regard could significantly alter current practices regarding disease surveillance and therapy.

T1-5
TABLE 1:
Rheumatic Disease Manifestations Based on Age at Disease Onset

There are numerous examples of skewing of disease phenotype based on hormonal influences, which may change with age. Hormonal changes at menarche and menopause and hormonal manipulations in animal models also support the hypothesis that estrogens and androgens play important roles in immune modulation and disease expression and severity. In murine models of SLE, female mice have earlier appearance of autoantibodies, onset and severity of nephritis, and decreased survival, compared to males.37 Furthermore, castration of male mice or estrogen administration results in earlier antibody production, more rapid progression of nephritis, and decreased survival, which can be aborted by the administration of androgen therapy. Additionally, androgen administration in castrated female mice leads to decreased autoantibody production and decreased mortality. Human studies also support the effects of sex hormones in the pathogenesis of SLE, where a 2005 study examining hormone replacement therapy in postmenopausal SLE patients demonstrated a significantly increased risk of disease flare associated with hormone replacement therapy.8 Additionally, 1 study comparing outcomes in SLE patients treated with cyclophosphamide found that women with premature ovarian failure following treatment had both fewer and less severe disease flares than those who continued menstruating.28 Several studies of lupus and pregnancy suggest a greater risk of disease flare during pregnancy.8,33 There is also evidence to support that RA is a hormonally influenced disease. Women with RA have a more severe disease course, with greater decreases in functional capacity and increased joint destruction, and are less likely to achieve disease remission, than men.13,19,22,38 Additionally, about 75% of women with RA note decreased disease activity with pregnancy.18

Immunosenescence, as a single factor or linked to concurrent hormonal or tissue substrate alterations, may account for some of the differences in rheumatic disease manifestations between young and aged populations. Advanced age is associated with alterations in both the immune and vascular systems (Table 2). A logical extension from these observations is that disease vulnerability and manifestations may be influenced by altered production and target tissue responsiveness to immunoregulatory mediators that change during the aging process.

T2-5
TABLE 2:
Potential Influence of Age-Associated Changes in the Immune and Vascular System on Disease Expression in Large Vessel Vasculitis

The aging process influences arterial physical-chemical properties and vulnerability and responsiveness to injury or stimuli. For example, arterial smooth muscle cell content and proliferative capacity diminishes with age, which may play a role in aneurysm formation.23,29,34 Aging is associated with increased expression of matrix metalloproteinase-9 (MMP-9), a protease that plays a role in elastin degradation. Levels of MMP-9 are associated with vascular remodeling in GCA.36 It is possible that the presence of increasing degrees of arteriosclerosis and atherosclerotic disease might also alter both immunologic and intrinsic vascular responses to any injurious event.

Age and ethnicity-associated differences in the manifestations of large vessel vasculitis may arise from heterogeneity of arterial aging. For instance, in white patients, atherosclerosis occurs later and less extensively in intracranial compared to extracranial arteries. One study that examined intracranial and extracranial arteries across a spectrum of ages demonstrated that intracranial arteries have markedly higher levels of antioxidant enzyme activity in infancy compared to later in life.11 The decrease in enzyme levels with advanced age is paralleled by increased intracranial atherosclerosis. Of note is the finding that cranial atherosclerosis predominantly affects intracranial arteries in Japanese and African-American populations, groups that have a low prevalence of GCA.16,21,27,40 It is possible that the presence of arterial atherosclerotic disease alters vulnerability or is a surrogate of other factors that influence the expression of arteritis.

A logical question that arises when considering further study of the large vessel vasculitides to explore the possibility of a disease spectrum is the following: would changing our perspective of these disorders lead to any meaningful change in our approach to the care of patients with GCA and TAK? When considering the current approach to surveillance and therapy in these disorders, it is reasonable to posit that if, like TAK, GCA frequently involves large vessels and remains or becomes active in patients without clinical or serologic indicators of active disease, and this leads to potentially preventable morbidity and mortality, then the approach to GCA might be similar to that of TAK, with sequential imaging included as part of the standard of care.

It has become clear that patients with GCA, like those with TAK, frequently suffer relapsing disease. The pathologic data, although limited in numbers of patients studied by autopsy, support widespread large vessel involvement in GCA, even in patients with clinically quiescent disease.32 However, it is unclear how this affects outcomes in patients with GCA. Nuenninghoff et al,31 in a population-based study of patients with GCA, reported that although patients with thoracic aortic dissection in GCA have markedly increased mortality, patients with known large artery involvement did not have increased mortality when compared to those without large vessel disease. The authors did note that the study was underpowered to detect a difference in mortality less than 2.5-fold between groups, but perhaps the most important limitation was the lack of uniformly used vascular imaging, which may have allowed patients with asymptomatic large vessel involvement to be misclassified.

When considering the most likely consequences of ongoing large vessel vasculitis (arterial stenosis and/or aneurysm), it is possible, given the frequency of atherosclerotic vascular disease in patients in the affected age-group, that signs and symptoms of arterial disease, such as claudication, could easily be attributed to the latter. Data examining cardiovascular outcomes in GCA are conflicting. Prospective longitudinal studies that include periodic vascular imaging are needed to determine the actual prevalence of large vessel involvement, and what impact this has on morbidity and mortality, in order to determine whether sequential vascular imaging studies should be used in routine monitoring of patients with GCA. Furthermore, given our findings, practitioners caring for patients with GCA need to be mindful of the possibility of large vessel involvement, especially in the setting of aortic aneurysm or signs and symptoms of arterial insufficiency, and incorporate appropriate investigations (for example, vascular imaging) into their evaluation of these manifestations.

By using a common data-gathering tool for both GCA and TAK, we have attempted to minimize bias in data gathering. We have demonstrated a significant overlap in features of GCA and TAK. However, we have not proven that these conditions are the same disease, nor have we studied specific differences in tissue substrate or immunologic responsiveness in TAK and GCA. Nonetheless, our observations, and those from other young and elderly subsets with other autoimmune diseases, provide a framework to support the notion that immunosenescence and alterations in vessel substrate with aging could account for differences in disease vulnerability, response to arterial injury, and variation in the phenotype of a single disease entity.

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