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Rheumatology 2001; 40: 652-655
© 2001 British Society for Rheumatology

Original Papers

Thrombosis in Behçet's disease: a retrospective survey from a single UK centre

P. R. J. Ames, A. Steuer, A. Pap1 and A. M. Denman

Department of Rheumatology, Northwick Park Hospital, London and
1 Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London, UK


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objective. To contribute to knowledge of vascular occlusion in Behçet's disease (BD), prevalence and relative risk for thrombosis were ascertained retrospectively in a cohort of Caucasian patients with the disease.

Patients. The study included 73 BD patients (36 males, 37 females, mean age 45±11 yr) attending the Immunology/Rheumatology Department of Northwick Park Hospital. A group of 146 patients without BD, attending the same department, served as a control group.

Results. Thrombosis was more frequent in BD patients than in controls (23/73, 32% vs 7/146, 5%, P<0.001). This was accounted for by a higher prevalence of venous thrombosis in BD patients (18/73, 25% vs 4/146, 3%, P<0.001). Gender-adjusted data revealed an 11-fold risk of developing any thrombosis and a 14-fold risk of developing venous thrombosis in BD. After adjusting for differences in age at first symptoms, male BD patients showed a 6-fold higher risk of vein thrombosis. Males reported more often thrombophlebitis (13/36, 36% vs 0/0, P<0.001), folliculitis (8/36, 22% vs 1/37, 3%, P<0.01) and retinal vasculitis (13/36, 36%, vs 4/37, 11%, P=0.01) than females, in whom arthralgia prevailed (23/37, 62%, vs 12/36, 33%, P=0.01).

Conclusion. In our population, BD confers a 14-fold risk of developing venous thrombosis. The risk is sixfold higher in male BD patients, who fare worse than females with regard to thrombophlebitis, folliculitis and retinal vasculitis.

KEY WORDS: Behçet's disease, Thrombosis, Arthritis, Vasculitis, Sex differences.


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Behçet's disease (BD) is a systemic vasculitis whose minimum diagnostic criteria (oral and genital ulcers) are often followed by a wide spectrum of clinical manifestations, including uveitis, thrombophlebitis, erythema nodosum, arthritis, gastrointestinal disease, and lung and neurological involvement [1]. Vascular involvement is also common in BD, presenting as venous and arterial thrombosis and as aneurysms, particularly of the pulmonary arteries [2]. Vascular disease seems to follow different geographical patterns in BD: a large survey from Turkey showed that vein thrombosis occurred more often than arterial thrombosis [3], whilst the reverse pattern has been described in BD patients from North America and Europe [4]. To contribute to these issues, we assessed retrospectively the occurrence of vascular occlusions in BD patients attending our clinics.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
The files of 120 BD patients who attended the rheumatology and immunology clinics of Northwick Park Hospital were reviewed. Of these patients, 73 (36 males, 37 females, mean age 45±11 yr) had been followed up regularly until January 1997 and were the subject of the present study. BD was defined according to established criteria [1]. To determine the relative risk of thrombosis in BD with regard to a normal population, we also assessed the occurrence of vascular occlusions in 146 consecutive non-BD patients (60 males, 86 females, mean age 53±17 yr) attending our general rheumatology and immunology out-patient clinics. They fell into one of the following seven disease categories: (i) rheumatoid arthritis, n=66 (disease duration 14±11 yr, median 11 yr, range 2–50 yr); (ii) osteoarthritis, n=20 (disease duration 8±3 yr, median 7 yr, range 3–19 yr); (iii) psoriatic arthritis, n=19 (disease duration 11±11 yr, median 7 yr, range 2–47 yr); (iv) ankylosing spondylitis, n=7 (disease duration 14±6 yr, median 17 yr, range 3–23 yr); (v) reactive arthritis, n=4 (disease duration 2.5±1 yr, median 2.5 yr, range 1–4 yr); (iv) non-inflammatory rheumatic conditions (scoliosis, soft tissue rheumatism, neck pain, low back pain), n=14 (disease duration 5±5 yr, median 4 yr, range 3–2 yr); (vii) immunological diseases, n=16 (disease duration 9±6 yr, median 6 yr, range 3–21 yr). The dates of birth, first symptoms of disease, diagnosis of disease, and thrombosis (year) were recorded for BD patients and controls. All participants were interviewed with specific regard to clinical features not formally documented in the case notes. At the time of their first thrombotic event, 17 BD patients were receiving some form of medication. This included prednisolone as a single agent in five patients and various combinations with azathioprine, thalidomide, chloroquine, cyclosporin and antilymphocyte globulin. Details of treatment are presented in Table 1Go, which also shows the number of patients who were smoking or were hypertensive at the time of thrombosis. Of the seven control patients who experienced thrombosis, three (all females) had rheumatoid arthritis [all were on non-steroidal anti-inflammatory drugs (NSAIDs), one was on methotrexate], two (one male, one female) had psoriatic arthritis (on NSAIDs, one smoker), one (female) had reactive arthritis (on NSAIDs) and one male had a frozen shoulder (smoker). None of these control thrombotics was hypertensive. None of the thrombotic females in either group was taking a contraceptive pill at the time of their thrombotic event. Vascular involvement had been assessed by Doppler ultrasound, venogram, computed tomography scanning and angio-magnetic resonance imaging. None of the patients had deficiency of the natural anticoagulants protein C, protein S or antithrombin.


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  		TABLE 1. Medication, smoker and blood pressure status of BD patients at the time of their thrombotic event

 
Statistical methods
Fisher's exact test was used for comparison of proportions of occlusion in 2x2 tables, and the Mantel–Haenszel test was used to test for heterogeneity between odds ratios for males and females. The t-test was used to compare normally distributed continuous variables and the Wilcoxon rank sum test to compare non-normally distributed variables. Multiple Cox regression was used to assess the differences in total and venous occlusions between BD patients and controls and between male and female patients with BD after controlling for covariates. In the comparison of BD patients with controls, the birth date was considered the entry time. When comparing males and females with BD, the date of first symptoms was considered the entry time. The assumption of proportional hazard was checked graphically between patients and controls, and between males and females. Logistic regression was used as confirmatory analysis for Cox models. The Stata 5.0 program (Stata Corporation, College Station, TX, USA) was used for calculations.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Comparison between BD patients and controls
BD patients were younger than control participants (P<0.001), and there were fewer males in the BD group than in the control group (41 vs 49%) (Table 2Go). BD patients suffered more venous and therefore total occlusions than control participants (Table 1Go). All venous occlusions in BD affected the lower limbs (one bilateral) but for one upper limb occlusion. Venous events recurred in the lower limbs of one female and one male BD patient and in the left renal vein of one male BD patient. Seven male BD patients were brought to medical attention because of venous thrombosis, and on that occasion they were found to meet criteria for BD. Similarly, three females suffered thrombosis (two venous, one arterial) shortly before or at diagnosis of BD. All control participants suffered venous occlusions in the lower limbs and none had recurrent events. The hazard rates (from birth date to the event or censoring) of developing venous and arterial thrombosis in BD are shown in Table 3Go.


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  		TABLE 2. Demographic data and thrombosis prevalence of BD patients and controls

 

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  		TABLE 3. Hazard rates of thrombosis in BD patients

 

Comparison between male and female BD patients
Male and female BD patients had similar age at first symptoms, age at diagnosis and duration of disease (Table 4Go). Males suffered a larger number of total occlusions than females (42 vs 22%, P=0.08). This was accounted for by a much higher prevalence of venous thrombosis in male than female patients (42 vs 8%, P=0.001). In contrast, arterial occlusions were more common in female than male patients (14 vs 0%, P=0.05) and were all represented by cerebrovascular accidents. The hazard rate of developing any thrombosis in male BD patients, after adjusting for age at first symptoms, was not significant [1.9, 95% confidence interval (CI) 0.8–4.6, P=0.15). However, the hazard rate of developing venous thrombosis in male BD patients after adjusting for differences in age at first symptoms was significant (6.0, 95% CI 1.7–21.0, P=0.005). Thrombophlebitis, folliculitis and retinal vasculitis were significantly more common in male BD patients than in females, who were affected significantly more often than males by arthralgia (Table 5Go). The prevalence of eye involvement was not different between thrombotic and non-thrombotic patients, whether male (73 vs 80%) or female (50 vs 51%). BD was familial in four patients (two males, two females). Amongst associated diseases, gout was diagnosed in one male patient and Crohn's disease in two female patients.


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  		TABLE 4. Demographic data of BD patients according to sex

 

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  		TABLE 5. Clinical manifestations of BD patients according to sex

 


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
BD is characterized by a prothrombotic state which contributes to the development of vascular occlusions affecting both the venous and the arterial system [2]. The prevalence of vascular involvement varies from 7.7 to 43% according to the ethnicity of the population under study [3, 5–11]. In addition, vascular disease and some other clinical manifestations of BD appear gender-related and tend to cluster together. A survey of 137 Turkish BD patients from the early 1990s revealed 3% arterial and 24% venous involvement, the latter being more common in males [3]. A later study of 2400 Turkish BD patients confirmed the previous data, in that the prevalence of vascular involvement (including aneurysms) was 17%, the risk of developing vascular complications being fivefold higher in male than female BD patients [10]. Similarly, deep vein thrombosis was diagnosed in 25% and arterial thrombosis in 18% of BD patients from Saudi Arabia, but with no gender relationship [9]. On the contrary, series published in the previous decade reported a lower frequency of venous lesions than arterial complications in Japanese [12], North American and European BD patients [4]. The 32% prevalence of any thrombosis from our all-British/Caucasian population is in overall agreement with the previous figures but challenges the latter issue, as our male patients presented a 48% involvement of the venous system compared with the 8% involvement in females. This equals a sixfold hazard rate of developing venous thrombosis, as in the Turkish study mentioned above [10]. On the other hand, the 7% arterial occlusions in the present study were all represented by cerebrovascular accidents in female BD patients. The reasons for this sex bias are unknown.

Thrombosis may also have a negative effect on other clinical manifestations. Besides the male sex, thrombosis was significantly associated with [3] and predictive of [13, 14] eye involvement in BD, whereas ocular involvement was reported almost twice as often in male than female BD patients [10]. The higher prevalence of retinal vasculitis in our male patients would be in keeping with the latter observation, but we did not find any association between vascular occlusion and eye involvement in either sex. With regard to other clinical manifestations of BD, arthritis has been described as a more common feature in the West than in the Middle East or the Mediterranean basin [15]. This appears the case in our series, in which females bore the brunt of joint involvement. However, clinical manifestations, including arthritis, were not sex-related in an Israelian cohort [16] whereas female prevalence of joint involvement has been reported from Korea [17].

Thrombosis-related symptoms led to the diagnosis of BD in 19% of our male patients and 8% of our female patients. This highlights the possibility that some BD features may be under-recognized by patients and physicians alike, until the occurrence of a major event leads to specialist attention being sought. In the series of Krause et al. [16], thrombosis was the presenting feature in 4% of male BD patients, who also showed an earlier age of onset of disease compared with female BD patients. A similar trend was noted in our patients, although it did not reach statistical significance.

A drawback of the present survey is the lack of investigation of the newer genetic risk factors for thrombosis. Factor V Leiden (FVL) was identified in 30–37.5% of BD patients from Turkey and Saudi Arabia, where it contributed significantly to the thrombotic tendency of BD [18–20], but from Israel data do not support a role for any inherited thrombophilia in the hypercoagulability of BD [21]. However, our figures are not seriously flawed because the prevalence of FVL varies according to geographical area and it does not show a sex association [22]. In addition, our control subjects, who were attending our rheumatology and immunology clinics, were, on average, 10 yr older than BD patients, balancing somewhat the higher thrombotic risk of our BD patients.

In conclusion, a British/Caucasian person developing BD will carry a 14-fold relative risk of undergoing a venous occlusion and a 5.4-fold relative risk of suffering an arterial event. Potential male patients face a higher probability of skin and eye involvement, whereas female patients will complain more of joint pain. In general, our findings are not dissimilar from those in other ethnic groups of BD patients around the world, they confirm the geographical variability of the clinical manifestations of BD, and they place Great Britain on the map of BD profiling of north-western Europe.


   Notes
 
Correspondence to: P. R. J. Ames, 75 Canterbury House, Royal Street, London SE17EH, UK. Back


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Submitted 3 November 2000; Accepted 11 December 2000


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