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Rheumatology Advance Access originally published online on February 12, 2008
Rheumatology 2008 47(4):472-475; doi:10.1093/rheumatology/kem385
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Prevalence of angina, myocardial infarction and intermittent claudication assessed by Rose Questionnaire among patients with Behcet's syndrome

S. Ugurlu1, E. Seyahi2 and H. Yazici2

1Department of Internal Medicine, Medical Faculty of Cumhuriyet University, Sivas and 2Division of Rheumatology, Department of Medicine, Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey.

Correspondence to: E. Seyahi, Halaskargazi Cad. No: 209-211, Huzur ap. D: 2, Sisli, Istanbul, 34360 Turkey. E-mail: eseyahi{at}yahoo.com


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To determine the risk of clinical cardiovascular disease in middle-aged patients with Behcet's syndrome (BS) compared with gender-matched non-BS subjects.

Methods. The prevalence of angina, myocardial infarction (MI), doctor diagnosed ischaemic heart disease (IHD) and intermittent claudication were sought by the Rose Angina Questionnaire in 225 (141 M/84 F) BS patients (mean age: 52 ± 8) with BS and 117 (74 M/43 F) controls (mean age: 50 ± 5). Information on atherosclerotic risk factors was also collected.

Results. The prevalence of angina, MI and doctor-diagnosed IHD were not different between BS patients and non-BS controls in the whole study population and when males and females were separately analysed. Angina tended to be more common among females compared with males among both patients and controls. Intermittent claudication was found to be significantly more common among BS patients, especially in males with venous disease.

Conclusions. The findings in this cross-sectional clinical study are in line with previous observations not indicating accelerated atherosclerosis in BS. Intermittent claudication might not be a suitable tool for the detection of peripheral atherosclerotic disease especially among BS patients having venous disease.

KEY WORDS: Behcet's syndrome, Atherosclerosis, Cardiovascular disease, Angina, Myocardial infarction, Peripheral arterial disease, Claudication


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
It is known that cardiovascular disease occurs at a significantly higher rate in patients with chronic inflammatory diseases, such as, SLE or RA, compared with controls [1–3]. Behcet's syndrome (BS) is a systemic disorder causing extensive vascular inflammation in both sides of the circulatory system with a predilection for the venous side [4].

There is no evidence that clinical cardiovascular disease with its associated mortality is increased in BS [4–9]. This, however, has not, up to now, been formally surveyed.

The World Health Organization angina pectoris questionnaire [the Rose Angina Questionnaire (RQ)] is a validated instrument to assess symptoms of typical angina pectoris in the general population [10]. It is highly specific when compared with physician diagnosed angina and is associated with coronary artery calcification and risk of coronary events [11–16]. We used the RQ to evaluate the prevalence of angina, myocardial infarction (MI) and claudication among patients with BS and controls.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
We studied consecutive patients with BS aged 40 and older who fulfilled International Study Group (ISG) criteria [17] for at least 10 yrs. Patients were registered in the multidisciplinary Behcet's syndrome research centre at the Cerrahpasa Medical Faculty in Istanbul. Apparently healthy volunteers, chosen among the hospital staff, participated in the study as non-diseased controls. A convenience sample with a male/female ratio of 3/2 and an age range of ±5 yrs of BS patients was studied. Oral informed consent was taken from each participant before study entry.

A standardized questionnaire was administered by a physician to all study participants. It included RQ for angina, possible MI and claudication; questions on past medical history of ischaemic heart disease (IHD) and atherosclerotic risk factors. Definite angina was defined as having pain or discomfort in the chest when walking uphill or hurrying and fulfilling all of the following criteria: (i) situated in the sternum or the left anterior chest with or without left arm, (ii) caused the subject to stop or slow down, (iii) went away when the subject stopped or slowed down and (iv) was relieved within 10 min. Possible MI with or without clinical history was defined as having experienced a severe pain across the front of the chest, lasting for a half an hour or more. Additionally, patients were asked whether they had any definite IHD recognized by a doctor such as hospitalization due to MI, coronary artery disease found in angiography or having had coronary artery bypass grafting or intracoronary stent implantation. Intermittent claudication was defined as pain that appeared in either leg in the calf, when the patient walked uphill or hurried, or when walking at an ordinary pace on the level ground and meeting all the following criteria: (i) never beginning when standing still or sitting, (ii) did not disappear while walking and (iii) forced the participant to stop or slow down. Six patients (5 M/1 F) with peripheral arterial aneurysms or occlusions due to BS were excluded from the analyses of claudication.

Information on potential risk factors for cardiovascular diseases was also obtained and arterial blood pressure along with height and weight were measured. Previous or current cigarette use was considered a positive smoking history. Having a first-degree relative with MI, stroke or any other type of cardiovascular disease was considered as positive family history of cardiovascular disease. Diabetes mellitus was defined as being a current user of oral hypoglycaemic agents or insulin. Hypertension was defined as having a systolic blood pressure of >140 mmHg or a diastolic blood pressure of >90 mmHg or using anti-hypertensive drugs. Clinical characteristics and information on disease duration and corticosteroid use were obtained from the charts. Previous or current use was considered as positive corticosteroid history. Disease duration was calculated from the time the patient fulfilled the ISG criteria. No blood studies were done.

Statistics
Continuous variables with a normal distribution were expressed as means ± S.D.s and the comparisons of such data were made by using Student's t-tests. Categorical variables were compared using the chi-square test or Fisher's exact tests, where appropriate. Binary logistic regression models with adjustments for age and for the presence or absence of hypertension and smoking were made for the presence of angina, MI, doctor-diagnosed IHD and claudication. Also, the association between angina, MI, claudication and doctor-diagnosed IHD and study variables such as age, gender, disease duration, the use of corticosteroids or azathioprine, disease subtypes (vascular or ophthalmological) and all atherosclerotic risk factors assessed in this study were evaluated with univariate analyses. Significant results were re-analysed by multiple logistic regression tests.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
We studied 225 (141 M/84 F) patients with BS and 117 (74 M/43 F) controls. Table 1 shows clinical characteristics and mean disease duration of BS patients. Female patients had significantly less vascular and eye disease, compared with males (P < 0.001 for each) (Table 1).


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  		TABLE 1. Age, disease duration and clinical characteristics of patients with Behcet's syndrome

 
A total of 91 (63 M/28 F) (40%) patients had a prior history of corticosteroid use. However, at the time of the study, 12 (9 M/3 F) (5%) were using corticosteroids. Also at the time of the study, 40 (22 M/18 F) (18%) patients were taking colchicine and only 15 (10 M/5 F) (7%) were taking azathioprine. The use of aspirin was somewhat more common among BS patients (n = 46; 38 M/8 F) (20%) than among controls (n = 10; 7 M/3 F) (9%); (P = 0.07). Statin use was present in a few patients (n = 3) and controls (n = 5).

Patients with BS were more likely to be older and hypertensive and less likely to smoke compared with controls (Table 2). The prevalence of angina, MI and doctor-diagnosed IHD was not different between patients and controls; however, claudication was significantly more common among BS patients (Table 2). These were also true, when we made adjusted analyses for age and for the presence or absence of hypertension and smoking (data not shown).


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  		TABLE 2. Demographic characteristics, cardiovascular risk factors and prevalence of ischaemic heart disease predictors assessed by Rose Questionnaire among patients and controls

 
When males and females were analysed separately, again, the prevalence of angina, MI and doctor-diagnosed IHD did not differ between patients and controls (Table 2). On the other hand, the prevalence of claudication was significantly more frequent only among the male patients (19/136 vs 2/74, P = 0.008). When subgroup analyses were done, this significant difference remained robust only among those with vascular disease; male patients with vascular involvement had more claudication (15/67) than those without (4/69) (P < 0.006). All 15 male patients with vascular disease, who reported to have claudication, had lower extremity deep vein thrombosis.

Angina was more common among female patients with BS (17/84; 20%), compared with male patients (15/141; 11%) (P = 0.046). A similar trend was also observed among controls in which more females (9/43; 21%) than males (10/74; 14%) had angina (P = 0.294). No such gender predilection was observed in the evaluation of MI and doctor-diagnosed IHD among both patients and controls. Claudication was more common among male patients (23/141), compared with female patients (2/84) (P = 0.001). The frequency of those who had claudication did not differ between males and females among the controls (males: 2/74 vs females: 1/43, P = 1.0).

Among patients with BS, angina was found to be associated with age, being female and with the presence of hypertension. However only age remained significant in the multiple regression analyses [odds ratio (OR): 1.05; 95% CI: 1.00, 1.10, P = 0.05]. Furthermore, doctor-diagnosed IHD was associated again only with age. Claudication was associated with age, male gender and having venous thrombosis; whereas only venous thrombosis was found to be significant in the multiple logistic regression analyses (OR: 0.18; 95% CI: 0.06, 0.56; P = 0.003).


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
In this survey, the prevalence of IHD and its predictors were similar between BS patients and apparently healthy controls. These results are in conformity with our previous mortality survey that did not suggest an increased cardiovascular mortality in BS [4] and also with the relatively low frequency of coronary calcification even among patients with severe long-standing disease [9]. B-mode ultrasonography studies that did not find an accelerated subclinical atherosclerosis in the carotid and femoral arteries in patients with BS [18–21] are also in line with our current observations. There are, however, studies with relatively small sample sizes that had found increased prevalence of carotid artery plaques compared with controls in BS [22, 23]. Thus, we reasoned that it would be important to also formally survey for clinical symptoms of IHD among a sizeable group of BS patients. A study similar in methodology had shown that patients with RA were more likely to have a diagnosis of angina compared with controls [24] supporting a large number of studies that reported a high prevalence of both clinical and subclinical, increased atherosclerosis [2, 3].

In this survey, as in several others [25–27], angina tended to be more common among females. The reasons are unclear. A bias in patient reporting or a tendency to have exertional chest pain unrelated to coronary artery disease among women is speculated [25–27].

We found that claudication was more common among male BS patients with vascular disease and especially among those with lower extremity deep vein thrombosis (15/62; 24%). On the other hand, when those with vascular disease were excluded no difference was found between patients and controls in claudication. We believe that symptoms of claudication seem to be closely associated with venous insufficiency in BS, rather than true peripheral arterial disease. Perhaps, what is really described here is ‘venous claudication’, which is defined by several authors in the past as exercise related thigh or leg pain resulting from severe venous outflow impairment [28–30]. This, however, is reported to be rare and has not yet been investigated in depth [31, 32]. The presence of venous claudication in venous disease in BS had not been recognized before. Also, whether only venous impairment, or arterial impedance or both play a role in the pathogenesis is intriguing and should be further investigated.

There were some limitations of our study. The evaluation of peripheral arterial disease by using claudication questionnaires might be somewhat misleading. Intermittent claudication as assessed by RQ is reported to be specific for peripheral arterial disease [33]; however, its sensitivity is quite low (<5%) [34–36]. Moreover, it fails to distinguish between multiple causes of leg pain [28]. Unlike angina questionnaires that are validated for IHD, investigating claudication might not be a suitable tool for the detection of peripheral atherosclerotic disease.

Secondly, our cross-sectional study design may not represent the true cardiovascular burden in BS. BS patients who had severe disease and/or severe IHD or those who had died may not attend the outpatient clinic. This might also be true for those having mild disease.

We had selected our patients among those with a disease course longer than 10 yrs in order to increase our sensitivity of finding atherosclerosis. On the other hand, it might well be that among a group of patients with a shorter disease duration we might have picked up some increased atherosclerosis, similar to what has been observed in RA [37]. We, however, suggest that if this were the case, it would have some reflection (even if statistically not significant) on our patient population late in disease. The data at hand do not show such trend. Nevertheless, whether atherosclerosis is present or not in the early years of BS would be of interest to formally look at.

Since no electrocardiograms (EKGs) were taken, neither Minnesota criteria for IHD could be sought [38] nor silent myocardial ischaemia could be evaluated. Finally unavailability of lipid levels is yet another issue, in that lipid levels are found to be correlated with presence of angina [39].

Notwithstanding these issues, the findings in our controlled survey among a large well-defined group of patients with BS are certainly in conformity with our previous observations of not finding increased atherosclerosis in BS. This makes us more confident in our observations. Furthermore, our description of venous claudication in BS for the first time is interesting and certainly needs more scrutiny.

Formula

Disclosure statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 30 September 2007; revised version accepted 20 December 2007.
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