Dec 15, 2007 - 1482. Gonzalez-Juanatey et al ... 5500; Hewlett-Packard, Palo Alto, CA) with a 10-MHz linear transducer. ..... Gonzalez-Gay MA, Garcia-Porrua C, Amor-Dorado JC, Llorca ... 30 year period in Olmsted County, Minnesota, USA.
Arthritis & Rheumatism (Arthritis Care & Research) Vol. 57, No. 8, December 15, 2007, pp 1481–1486 DOI 10.1002/art.23114 © 2007, American College of Rheumatology
ORIGINAL ARTICLE
Atherosclerosis in Patients With Biopsy-Proven Giant Cell Arteritis CARLOS GONZALEZ-JUANATEY,1 MARIA J. LOPEZ-DIAZ,1 JAVIER MARTIN,2 JAVIER LLORCA,3 MIGUEL A. GONZALEZ-GAY1
AND
Objective. To examine the presence of atherosclerosis in a series of giant cell arteritis (GCA) patients attended to in a community hospital and to determine whether clinical features or steroid therapy might be associated with the development of atherosclerotic disease. Methods. Forty consecutive patients diagnosed with biopsy-proven GCA, periodically followed at the rheumatology outpatient clinic of Hospital Xeral-Calde, Lugo (Spain), who had ended steroid therapy and had at least 3 years of followup were assessed for the presence of atherosclerosis by determination of the carotid intima-media thickness (IMT) and carotid plaques using high-resolution B-mode ultrasound. Forty matched controls were also studied. Results. GCA patients exhibited less carotid artery IMT than did matched controls (mean ⴞ SD 1.01 ⴞ 0.16 mm versus 1.13 ⴞ 0.20 mm; P ⴝ 0.005; difference in means 0.12, 95% confidence interval 0.04 – 0.20). Patients who required steroid therapy for >2 years had greater mean ⴞ SD carotid IMT (1.04 ⴞ 0.17 mm versus 0.95 ⴞ 0.15 mm) but the difference was not statistically significant (P ⴝ 0.10). A positive correlation between age at the time of the study and the carotid artery IMT in GCA patients was observed (r ⴝ 0.673, P < 0.001). However, adjusting for age, sex, and classic atherosclerosis risk factors, no significant correlation between carotid IMT and the routine laboratory markers of inflammation assessed at the time of disease diagnosis, disease duration, or cumulative prednisone dose was found. Conclusion. The present study demonstrates that atherosclerotic macrovascular disease is not increased in patients with GCA. KEY WORDS. Giant cell arteritis; Cardiovascular disease; Atherosclerosis; Carotid intima-media thickness; Corticosteroids.
INTRODUCTION Giant cell (temporal) arteritis (GCA) is the most common vasculitis in white individuals over the age of 50 in Western countries (1,2). It is characterized by the granulomatous involvement of large and medium-sized blood vessels of the aorta with predilection for the extracranial branches
Supported in part by the Galician Society for Rheumatology. 1 Carlos Gonzalez-Juanatey, MD, PhD, Maria J. LopezDiaz, MD, Miguel A. Gonzalez-Gay, MD, PhD: Hospital Xeral-Calde, Lugo, Spain; 2Javier Martin, MD, PhD: Consejo Superior de Investigaciones Cientificas, Granada, Spain; 3 Javier Llorca, MD, PhD: School of Medicine, University of Cantabria, Santander, Spain. Drs. Gonzalez-Gay and Gonzalez-Juanatey contributed equally to this work. Address correspondence to Miguel A. Gonzalez-Gay, MD, PhD, Rheumatology Division, Hospital Xeral-Calde, c) Dr. Ochoa s/n, 27004 Lugo, Spain. E-mail: miguelaggay@ hotmail.com. Submitted for publication March 7, 2007; accepted in revised form June 4, 2007.
of the carotid artery (1,2). GCA incidence increases with age and peaks in groups of patients older than 70 years (3). GCA is associated with high inflammatory response, typically manifested by high levels of erythrocyte sedimentation rate (ESR), and involves elderly individuals who generally require steroid therapy for more than 1 year. However, although deaths due to infections or vascular complications are observed within the first year after the onset of disease (4) and aortic aneurysmal disease may be observed over the extended followup of these patients (5,6), epidemiologic reports encompassing unselected series of patients from different countries suggest that the long-term mortality in GCA is not increased compared with the general population of the same age (4,7,8). Several noninvasive imaging techniques offer a unique opportunity to study the relationship of surrogate markers to the development of atherosclerosis. One of these surrogate markers is the presence of endothelial dysfunction, considered as the earliest stage of atherosclerosis (9,10). An assessment of endothelial function by postocclusion flow-mediated vasodilatation of the brachial artery using high-sensitivity brachial ultrasonography disclosed the 1481
1482 presence of significantly impaired endothelial function in patients with GCA at the time of disease diagnosis (11). However, significant improvement in endothelial function following steroid therapy was observed (11). Such endothelial function improvement was still present when steroid treatment was ended, 2 years after disease diagnosis (11). Carotid intima-media thickness (IMT) of the common carotid artery, determined by high-resolution B-mode ultrasound of the common carotid artery, is another useful noninvasive surrogate marker of macrovascular atherosclerosis disease. Case-control studies have demonstrated that increased common carotid artery IMT determined by high-resolution B-mode ultrasound is a good indicator of generalized atherosclerosis and coronary artery disease (12–14), providing early information of atherosclerosis in subclinical stages of the disease in individuals at risk (15,16). The IMT corresponds to the width of the vessel intima and media, which consists of endothelium, connective tissue, and smooth muscle (16). This is also the site of lipid deposition and plaque formation (17). High-resolution B-mode ultrasound studies of the common carotid artery have disclosed the presence of subclinical atherosclerosis in chronic inflammatory diseases such as rheumatoid arthritis (18,19) or psoriatic arthritis (20). However, to our knowledge no information about ultrasound studies of the common carotid artery in patients with biopsy-proven GCA has been reported. In the present study, we assessed whether carotid IMT values in a cohort of unselected patients with GCA attended to in a community hospital were different from those observed in a matched population.
PATIENTS AND METHODS Patients. A series of patients with biopsy-proven GCA and the same number of matched controls were assessed in the present study. Forty consecutive patients diagnosed with biopsy-proven GCA with at least 3 years of followup who periodically attended a rheumatology outpatient clinic, were seen over a 7-month period (March to September 2006), and had ended steroid therapy were assessed for the presence of atherosclerosis by determination of the carotid IMT and carotid plaques using echo Doppler ultrasonography. Ultrasonography studies were performed between October and December 2006. All patients met the 1990 American College of Rheumatology criteria for the classification of GCA (21). Moreover, patients were diagnosed as having biopsy-proven GCA, provided that the temporal artery biopsy showed a compatible pathology report describing the characteristic mononuclear cell infiltration of the arterial wall with or without the presence of granulomas and/or multinucleated giant cells (22). Patients were treated by the same group of rheumatologists and were recruited from the Hospital Xeral-Calde. This hospital is the single referral center for rheumatic diseases for a well-defined, stable and ethnically homogenous, mixed rural and urban white population living in the region of Lugo in central Galicia (north-
Gonzalez-Juanatey et al western Spain) (23,24). The main characteristics of the Lugo population have previously been reported (25–27). GCA patients were initially treated with a prednisone dosage ranging between 40 and 60 mg/day for 3– 4 weeks. Methylprednisolone boluses (1 gm intravenously for 3 consecutive days) were also administered to patients presenting with visual ischemic complications. Then, prednisone dose was tapered to discontinuation as previously reported (4,26). At the time of the study 10 patients were receiving antiplatelet therapy (aspirin 100 –150 mg) and another 2 patients were taking anticoagulant therapy (acenocoumarin). Controls. Forty controls from the Lugo region frequency matched by age, body mass index, sex, cardiovascular risk factors, and ethnicity without family history of GCA, polymyalgia rheumatica (PMR), rheumatoid arthritis, psoriatic arthritis, or any connective tissue disease were studied. Controls were community based. They were recruited from family physician health centers of the Lugo region. Twelve of these controls were receiving platelet antiaggregation agents or anticoagulation therapy at the time of the study. Informed consent was obtained from all cases and controls. The local institutional committee approved the study. Definitions. Classic atherosclerosis risk factors. Information about cholesterol, triglycerides and glucose levels, blood pressure, height, weight, and smoking history was available for all cases at the time of study. The same information was also available for the controls. Hypertension was defined as a systolic blood pressure ⱖ140 mm Hg or as a diastolic blood pressure ⱖ90 mm Hg, or the need for antihypertensive treatment. Dyslipidemia was defined as total cholesterol and/or triglyceride levels in fasting plasma ⱖ240 mg/dl and ⱖ160 mg/dl, respectively, or the need for cholesterol- or triglyceride-lowering medication. Diabetes was defined by the 1979 National Institutes of Health National Diabetes Data Group criteria (28) as fasting overnight venous plasma glucose concentration ⱖ7.8 mmoles/liter (140 mg/dl) on 2 separate occasions, a glucose level ⱖ11.1 mmoles/liter (200 mg/dl) 2 hours after taking 75 gm of oral glucose on 2 separate occasions, or need for antidiabetic therapy. Obesity was defined as a body mass index (calculated as weight in kg divided by height in m2) ⬎30 kg/m2 at enrollment. As previously reported (6,29), smoking history was treated as a dichotomous variable in this analysis. Current smokers comprised patients or controls who smoked at the time of the study or who had smoked within 10 years before the time of the ultrasonography study, and the remaining patients (former or never smokers) were those who had never smoked or had stopped smoking at least 10 years before the study. Clinical definitions. Clinical definitions of GCA manifestations in patients from the Lugo population have been reported elsewhere (30 –32). Patients with biopsy-proven GCA were considered to have severe ischemic manifestations if they experienced visual manifestations (transient visual loss including amaurosis fugax, permanent visual loss, or diplopia), cerebrovascular accidents (stroke and/or transient ischemic attacks), jaw claudication, or large-
Atherosclerosis in GCA artery stenosis of the extremities that caused signs of occlusive manifestations (limb claudication) of recent onset (30,33,34). A relapse was considered to have occurred if after a definite objective improvement with steroid treatment there was a flare of clinical features of the disease associated with an increase in ESR, which was again suppressed by resumption of or increase in steroid dose. Ultrasonographic study. Carotid IMT was measured in the right common carotid artery as previously reported (19,20,35). Atherosclerotic plaque in the common carotid artery was defined as a distinct protrusion (⬎1.5 mm) into the vessel lumen. The study was performed using highresolution B-mode ultrasound (Hewlett-Packard SONOS 5500; Hewlett-Packard, Palo Alto, CA) with a 10-MHz linear transducer. In all cases a single cardiologist (CG-J) who was blinded to clinical information performed all the studies. Intraobserver reliability of the IMT measurements was tested in 15 patients and 15 controls within 1 week of the first ultrasonographic examination (intraclass correlation coefficient 0.86, linear correlation coefficient 0.97). Statistical analysis. Continuous data were expressed as the mean ⫾ SD, median, and interquartile range and categorical variables as percentages. Because controls were frequency-matched, continuous variables were compared using Student’s t-test or Mann-Whitney U test. Proportions were compared by chi-square test or Fisher’s exact test. Correlation between carotid IMT and continuous variables was tested via estimation of Pearson’s partial correlation coefficient (r) adjusting for age at the time of the study, sex, and classic atherosclerosis risk factors. Twosided P values less than 0.05 were considered to indicate statistical significance. Analyses were performed using Stata 8/SE (StataCorp, College Station, TX).
RESULTS Clinical characteristics of patients at the time of GCA diagnosis. The mean age at the time of GCA diagnosis in this series of biopsy-proven GCA patients was 72.8 years (median 75 years). The mean ⫾ SD time since the end of steroid treatment was 32.5 ⫾ 27.9 months. Women (62.5%) outnumbered men. Thirty patients (75%) presented with headache, 16 (40%) presented with PMR, 16 (40%) had severe ischemic manifestation, and 7 (17.5%) had visual ischemic complications at the time of disease diagnosis. Other clinical features or laboratory data observed at the time of disease diagnosis are shown in Table 1. Differences between GCA patients and controls. When the ultrasonographic study was performed, the mean age of GCA patients was 78.6 years. Thirteen (32.5%) had experienced relapses, none of them associated with visual ischemic manifestations or stroke. However, at the time of the ultrasonographic study all patients had ended steroid therapy (mean duration of treatment 32.1 months, mean cumulative prednisone dosage 8,775 mg).
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Table 1. Main clinical features at the time of disease diagnosis in a series of 40 biopsy-proven giant cell arteritis patients from the Lugo region (northwest Spain)* Variable
Value
Age at the time of diagnosis, years Mean ⫾ SD 72.8 ⫾ 6.7 Median (IQR) 75 (70–78) Women:men 25:15 Delay to diagnosis, mean ⫾ SD weeks 10.4 ⫾ 13.1 Constitutional syndrome† 16 (40.0) Fever (temperature ⱖ38°C) 2 (5.0) Headache 30 (75.0) Abnormal temporal artery on physical 28 (70.0) examination Polymyalgia rheumatica 16 (40.0) Jaw claudication 11 (27.5) Visual ischemic manifestations‡ 7 (17.5) Permanent visual loss 2 (5.0) Stroke 0 (0.0) Severe ischemic manifestations§ 16 (40.0) ESR, mean ⫾ SD mm/hour 91.1 ⫾ 22.6 Hemoglobin, mean ⫾ SD gm/dl 12.1 ⫾ 1.8 Platelet count, mean ⫾ SD mm3 387,550 ⫾ 124,409 * Values are the number (percentage) unless otherwise indicated. IQR ⫽ interquartile range; ESR ⫽ erythrocyte sedimentation rate. † Asthenia, anorexia, and weight loss of at least 4 kg. ‡ Transient visual loss including amaurosis fugax, permanent visual loss, or diplopia. § At least 1 of the following features: visual manifestations, cerebrovascular accidents (stroke and/or transient ischemic attacks), jaw claudication, or limb claudication of recent onset.
A cross-sectional study was performed to establish clinical and ultrasonographic differences between patients and controls (Table 2). GCA patients exhibited less carotid IMT than did matched controls (mean ⫾ SD 1.01 ⫾ 0.16 mm versus 1.13 ⫾ 0.20 mm; P ⫽ 0.005; difference in means 0.12, 95% confidence interval 0.04 – 0.20) (Figure 1). However, as expected in unselected elderly individuals, carotid plaques were commonly observed in both GCA patients (n ⫽ 33 [82.5%]) and controls (n ⫽ 35 [87.5%]; P ⫽ 0.53) (Table 2). However, given the advanced age of the study groups, a very high prevalence of atherosclerosis was expected and found in both patients and controls. To further investigate whether the absence of an increase in subclinical measures of atherosclerosis in GCA patients compared with controls might result from just such a high background prevalence of atherosclerosis in this age group, we assessed whether subclinical measures of atherosclerosis might be different in younger patients and controls. GCA patients and controls younger than 75 years of age at the time of the study were compared. At that time 9 patients and 9 controls were younger than 75 years of age. However, the carotid artery IMT in patients and controls was similar (0.90 ⫾ 0.17 mm versus 0.88 ⫾ 0.18 mm; P ⫽ 0.72). This was also the case for carotid plaques (5 of 9 in patients and controls; P ⫽ 1.00). Differences in the carotid IMT according to clinical features of the disease. No significant differences in the carotid IMT according to specific clinical features (consti-
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Table 2. Differences observed at the time of the study between 40 biopsy-proven giant cell arteritis patients and 40 controls* Variable Age, mean ⫾ SD years Men/women Classic atherosclerosis risk factors Hypertension Hypercholesterolemia Diabetes mellitus Obesity Current smokers Individuals who experienced relapses Duration of therapy, months Mean ⫾ SD IQR Cumulative prednisone dose, mg Mean ⫾ SD IQR Duration of followup from disease diagnosis Mean ⫾ SD IQR Carotid IMT, mean ⫾ SD mm Carotid plaques
Patients (n ⴝ 40)
Controls (n ⴝ 40)
P
78.6 ⫾ 6.5 15/25 21 (52.5) 18 (45.0) 6 (15.0) 1 (2.5) 2 (5.0) 3 (7.5) 13 (32.5)
78.8 ⫾ 7.2 15/25 22 (55.0) 19 (47.5) 8 (20.0) 3 (7.5) 2 (5.0) 4 (10.0)
0.90 1.00 0.82 0.82 0.49 0.62 1.00 0.69
1.13 ⫾ 0.20 35 (87.5)
0.005 0.53
32.1 ⫾ 15.7 20–40 8,775 ⫾ 3,391 5,832–11,951 64.5 ⫾ 22.0 50–76 1.01 ⫾ 0.16 33 (82.5)
* Values are the number (percentage) unless otherwise indicated. IQR ⫽ interquartile range; IMT ⫽ intima-media thickness.
tutional syndrome, severe ischemic complications, or PMR; P ⱖ 0.14) or severe abnormality (ESR ⬎100 mm/ hour, platelet count ⬎450,000/mm3, hemoglobin ⬍10 gm/ dl) of laboratory data at the time of disease diagnosis (P ⱖ 0.30) were found. Patients who required steroid therapy for ⬎2 years had greater carotid IMT than those who were able to discontinue prednisone in ⬍2 years (mean ⫾ SD 1.04 ⫾ 0.17 mm versus 0.95 ⫾ 0.15 mm), but the difference was not statistically significant (P ⫽ 0.10). Likewise, no significant differences were observed between patients who experienced relapses of the disease (1.00 ⫾ 0.16 mm)
and those who did not (1.01 ⫾ 0.17; P ⫽ 0.83). This was also the case for patients who were receiving antiplatelet or antiaggregation therapy at the time of the study (1.04 ⫾ 0.14 mm) and those who were not (1.00 ⫾ 0.18 mm; P ⫽ 0.44). Correlation between carotid artery IMT and laboratory variables, treatment, and disease duration in GCA patients. As expected, a positive correlation between age at the time of the study and carotid artery IMT in GCA patients was observed (r ⫽ 0.673, P ⬍ 0.001). This was also the case for the control group (r ⫽ 0.731, P ⬍ 0.001). However, adjusting for age, sex, and classic atherosclerosis risk factors, no significant correlation between carotid IMT and routine laboratory markers of inflammation (ESR, hemoglobin, and platelet count) assessed at the time of disease diagnosis was found (P ⱖ 0.23). This was also the case when correlation between carotid IMT and duration of steroid therapy (P ⫽ 0.61) or cumulative prednisone dose (P ⫽ 0.65) was assessed.
DISCUSSION
Figure 1. Carotid ultrasonographic study in patients with biopsyproven giant cell arteritis (GCA) and controls. Individual and mean values (horizontal lines) expressed as carotid intima-media thickness (IMT) in mm are shown.
The present study demonstrates that unselected biopsyproven GCA patients do not have increased prevalence of macrovascular disease in the form of increased carotid artery IMT compared with ethnically matched controls. These observations are consistent with a previous report from our group that disclosed normalization of endothelial function following steroid therapy (11) and no increased mortality due to ischemic heart disease in biopsy-proven GCA patients from northwestern Spain (36). There are a number of potential limitations in this study.
Atherosclerosis in GCA First, GCA patients were required to have completed at least 3 years of followup, including some time being treated with steroids. This might result in a survivorship bias. However, in a previous study we observed that the overall mortality in GCA patients was not higher than that observed in the general population of the same age in Lugo (4). In this regard, mortality was low from disease diagnosis until the end of the first year of treatment, and continued being low with minimal increase during the following years (4). Second, the number of GCA patients assessed in the present study was relatively small. Third, in this series the number of patients receiving aspirin and anticoagulants was quite low. Finally, because patients were matched for different variables, we cannot exclude the possibility and consequences of overmatching. This fact might be a statistical limitation in the present study. Recent studies have challenged the classic assumption that steroids are responsible for a proatherogenic effect in patients with chronic rheumatic diseases (19,37,38). In line with these observations, a recent epidemiologic study from Mayo Clinic investigators disclosed that long-term steroid therapy was not associated with increased cardiovascular morbidity in individuals with PMR (39). Moreover, despite having a high cumulative prednisone dosage of almost 5 gm, a trend toward a steroid-protective effect was observed in that series (39). These results are in accordance with former population-based epidemiologic studies that excluded an increased cardiovascular mortality in patients with PMR from different parts of the world (8,32,40). Certainly, PMR and GCA are closely related and frequently overlapping diseases (41). However, both duration of therapy and cumulative steroid dose are much higher in patients with GCA (2). In this regard, in the present study the mean cumulative prednisone dosage was 8.77 gm and the mean duration of therapy was 32.1 months. However, no correlation between this high cumulative prednisone dose and carotid IMT was found. A potential role of antiaggregation and anticoagulation therapy in decreasing the frequency of ischemic complications associated with GCA has been postulated (42,43). However, although we cannot exclude a potential beneficial effect of these drugs in the outcome of patients with this inflammatory disease, our results did not show significant differences in the carotid IMT between GCA patients treated with aspirin or acenocoumarin and those not treated. In conclusion, our observations indicate that atherosclerotic macrovascular disease is not increased in patients with GCA.
AUTHOR CONTRIBUTIONS 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. Study design. Gonzalez-Juanatey, Llorca, Gonzalez-Gay. Acquisition of data. Gonzalez-Juanatey, Lopez-Diaz, GonzalezGay. Analysis and interpretation of data. Gonzalez-Juanatey, Martin, Llorca, Gonzalez-Gay. Manuscript preparation. Gonzalez-Juanatey, Llorca, GonzalezGay. Statistical analysis. Llorca, Gonzalez-Gay.
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