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Vascular manifestations of Behçet’s disease
Joint Bone Spine 70 (2003) 384–389 www.elsevier.com/locate/bonsoi
Case report
Vascular manifestations of Behçet’s disease Eighteen cases among 140 patients Aline Tohmé a,*, Noël Aoun b, Bassam El-Rassi a, Elie Ghayad a a
Department of Internal Medicine, Hôtel-Dieu de France Hospital of Beirut, School of Medicine, Saint Joseph University of Beirut, rue Adib Ishaac, Beirut, Lebanon b Department of Radiology, Hôtel-Dieu de France Hospital of Beirut, School of Medicine, Saint Joseph University of Beirut, rue Adib Ishaac, Beirut, Lebanon Received 26 February 2002; accepted 6 June 2002
Abstract Objectives. – To describe the features, prognosis, and treatment of vascular involvement in Behçet’s disease (BD). Patients. – Among 140 patients with BD seen at the Hôtel-Dieu Hospital in Beirut between 1980 and 2000, 18 (13%) had vascular involvement and were included in this retrospective study. All these patients fulfilled International Study Group criteria for BD. Results. – Men with BD were more likely to have vascular involvement (13/77, 17%) than women (5/63, 8%) (P = 0.12) and were younger at diagnosis of vascular disease (32 ± 7 vs. 36 ± 7.5 years; P < 0.01). Many patients had vascular disease at more than one site: 17 had thrombophlebitis, 10 had arterial thromboses, and one had an aneurysm. Thrombophlebitis was more common in men (82% vs. 18%; P < 0.03) and arterial occlusion in women (70% vs. 30%; P > 0.05). Caval thrombosis and arterial occlusions were the most serious complications. Combined treatment with glucocorticoids, anticoagulants, and immunosuppressants was effective in superior vena cava syndrome and extracranial arterial occlusion. Conclusion. – Vascular manifestations of BD are common in Lebanon, particularly venous lesions. Aneurysms are seen less often than arterial occlusions. Medical treatment may be sufficient in superior vena cava syndrome and arterial occlusion. © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. Keywords: Behçet’s disease; Vena cava; Budd-Chiari; Arteritis; Corticosteroids
1. Introduction
2. Patients and methods
Behçet’s disease (BD) is a systemic vasculitis of obscure origin, frequently encountered in Japan and in Mediterranean countries. Since no specific biological test is available, the diagnosis is based on several criteria, the most widely used being those of the International Group Study on BD [1]. Although vascular lesions constitute the pathological basis of the disease, their presence is not required for the diagnosis. Their frequency varies between 2% and 46% [2–5], with a predominance of venous lesions [3,4]. We will discuss the features, prognosis, and treatment of vascular involvement with BD in 18 patients.
Among outpatients and inpatients managed at the HôtelDieu de France Hospital in Beirut between 1980 and 2000, 140 had BD. Vascular involvement was present in 18 of these patients and forms the basis for this retrospective chart review study. All 18 patients met International Study Group on BD criteria [1] and underwent an immunological work-up (anti-nuclear antibodies, anti-ADN, C3 and C4 levels, and VDRL). Thrombophlebitis of the extremities was confirmed by echodoppler, vena cava and Budd–Chiari syndrome by cavography or magnetic resonance (MR) angiography, extracranial arterial lesions by angiography, and cerebral thrombosis by computed tomography (CT) or MR imaging (MRI). Glucocorticoids were administered in a dose of 1–2 mg/kg/d of prednisone or equivalent for 1 month, followed by slow tapering over 1 year (13 patients). Patients with vena cava syndrome (n = 5) or extracranial arterial
* Corresponding author. E-mail address: [email protected] (A. Tohmé). © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. doi:10.1016/S1297-319X(03)00076-9
A. Tohmé et al. / Joint Bone Spine 70 (2003) 384–389
385
Table 1 Clinical manifestations of BD in males and females Oral aphthae Genital aphthae Uveitis Erythema nodosa Pseudofolliculitis Articular manifestations Neurological manifestations Vascular manifestations Gastrointestinal manifestations
Males (n = 77) 77 (100%) 64 (83%) 49 (64%) 13 (17%) 29 (38%) 43 (56%) 15 (19%) 13 (17%) 7 (9%)
occlusion also received immunosuppressant therapy (cyclophosphamide, 1–2 mg/kg/d for 12–18 months; or chlorambucil, 0.1 mg/kg/d for 2 months followed by 2–4 mg/d for 12–18 months). For the statistical analysis, we used the t-test and the v2 of Yates for small samples. P values smaller than 0.05 were considered statistically significant.
3. Results Vascular lesions were found in 18 of the 140 BD patients (13%) seen during the study period and were more common among males (13/77, 17%) than among females (5/63, 8%) (P = 0.12). The sex distribution of clinical manifestations in our patients is summarized in Table 1. Erythema nodosum and joint disease were more common in females (36% vs. 17% for erythema nodosum, P = 0.01; and 71% vs. 56% for joint disease, P = 0.05). Mean age was 28 ± 6 years at diagnosis of BD and 33 ± 7 years at diagnosis of vascular manifestations (32 ± 7 in males, and 36 ± 7.5 in females; P < 0.01); the mean interval between the two was 9 years. Clinical manifestations of BD in patients with (n = 18) and without (n = 122) vascular lesions are summarized in Table 2. Erythema nodosum and gastrointestinal manifestations were more common in patients with vascular lesions (44% vs. 23% for erythema nodosum, P < 0.05; and 28% vs. 6% for gastrointestinal manifestations, P < 0.001). The vascular manifestations are listed in Table 3. They occurred as the presenting symptoms in seven patients and started 3–15 years after the diagnosis of BD in the 11 remaining patients. Only two patients (cases 3 and 13) were taking glucocorti-
Females (n = 63) 63 (100%) 51 (81%) 38 (60%) 23 (36%) 20 (32%) 45 (71%) 8 (13%) 5 (8%) 5 (8%)
Total (n = 140) 140 (100%) 115 (82%) 87 (62%) 36 (26%) 49 (35%) 88 (63%) 23 (16%) 18 (13%) 12 (8.5%)
P NS NS NS <0.01 NS 0.05 NS 0.12: NS NS
coids for other manifestations of the disease at the diagnosis of vascular involvement, and one (case 2) was taking colchicine. Four patients had a family history of BD. Many patients had vascular involvement at multiple sites. In all, in the 18 patients, 28 vessels were involved: there were 17 venous thromboses, 10 arterial thromboses, and one arterial aneurysm (Table 3). The total number of thromboses was greater in males (17/22, 63%) than in females (10/27, 37%), although the difference was not statistically significant (P > 0.5). Venous thrombosis was significantly more common in males (14/17, 82%; 3/17, 18%; P < 0.03) and arterial thrombosis in women (7/10, 70%; 3/10, 30%; P > 0.05). Venous thrombosis occurred mainly in the lower limbs (9/17; popliteal vein, five cases; femoral vein, two cases; and greater saphenous vein, two cases). One patient had pulmonary embolism. Other sites of venous thrombosis were the superior vena cava (n = 2), the innominate and left subclavian veins (n = 1), and the hepatic veins (n = 2); one of the patients with hepatic vein thrombosis also had thrombosis of the inferior vena cava and popliteal veins. Endoscopy and upper gastrointestinal series performed in the two patients with thrombosis of the superior vena cava showed upper esophageal varices, which extended up to the cardia in one patient. The clinical picture in our two patients with hepatic vein thrombosis (Budd–Chiari syndrome) was massive ascites with abdominal collaterals and edema of the lower extremities, evolving over several months. Liver biopsy was done in one of these patients and showed sinusoidal dilatation and centrilobular congestion. Hepatic venography established the diagnosis in one patient (in 1988) by showing thrombosis of the hepatic veins and of the inferior vena cava at the level
Table 2 Clinical manifestations of BD in 18 patients with and 122 without vascular lesions
Oral aphthae Genital aphthae Uveitis Erythema nodosum Pseudofolliculitis Articular manifestations Neurological manifestations Gastrointestinal manifestations
With vascular lesions (n = 18) 18 (100%) 17 (94%) 10 (55%) 8 (44%) 4 (22%) 13 (72%) 5 (28%) 5 (28%)
Without vascular lesions (n = 122) 122 (100%) 98 (80%) 77 (63%) 28 (23%) 45 (37%) 75 (61%) 18 (15%) 7 (6%)
Total (n = 140)
P
140 (100%) 115 (82%) 87 (62%) 36 (26%) 49 (35%) 88 (63%) 23 (16%) 12 (8.5%)
NS NS NS <0.05 NS NS NS <0.001
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A. Tohmé et al. / Joint Bone Spine 70 (2003) 384–389
Table 3 Clinical features, treatment, and outcomes of vascular involvement with BD in 18 patients Patient (sex, Ageb agea) 1 (M, 25) 30 2 (M, 19) 22
Aphthae Uveitis Skin lesions Thrombophlebitis Arterial lesions O G + + + Pseudofolliculitis Right saphenous vein – + + – Hyperirritability Recurrent left saphenous – vein
Other manifestations Articular, GI Articular
3 (F, 25)
35
+
+
+
4 (M, 29) 5 (M, 26)
33 29
+ +
+ –
+ +
6 (M, 30) 7 (M.37) 8 (M, 28)
30 37 28
+ + +
+ + +
– – –
9 (M, 22)
30
+
+
+
10 (F, 20)
30
+
+
–
11 (M, 30)
30
+
+
–
12 (M, 23)
23
+
+
–
13 (F, 31)
44
+
+
+
14 (M, 25)
39
+
+
+
Left popliteal vein Right popliteal vein Right brachiocephalic trunk and left subclavian veins Erythema Left popliteal vein and nodosum superior vena cava Hyperirritability, Superior vena cava erythema nodosum Erythema Median and right nodosum hepatic veins Erythema Right popliteal vein, nodosum hepatic and inferior vena cava Hyperirritability, Cerebral vein erythema nodosum Pseudofolliculitis –
15 (F, 33)
43
+
+
–
Hyperirritability –
16 (F, 27)
27
+
+
+
Erythema nodosum
17 (M, 43)
43
+
+
+
–
18 (M, 33)
48
+
+
+
–
Erythema nodosum Pseudofolliculitis Erythema nodosum Pseudofolliculitis Hyperirritability Hyperirritability
Treatment Course
Right femoral vein
–
Epididymitis
C-AC Asymptomatic CC-AC Relapse puis CCCh-AC CC-AC Asymptomatic
Right femoral vein Right popliteal vein
– –
Articular Articular
C-AC C-AC
Asymptomatic Asymptomatic
– – –
Articular Articular, GI Articular
C-AC C-AC CCC-AC
Asymptomatic Asymptomatic Lost to follow-up
–
Articular
CCC-AC
Asymptomatic
–
Articular, GI CCC-AC (ascite, pleuropericarditis) – CCC-AC
Asymptomatic
–
– Left radial aneurysm
Articular, GI
–
Articular, GI
Left subclavian artery occlusion Coronary occlusion (anterior descending), renal arteries stenosis, left femoral, tibial and peroneal arteries stenosis Cerebral artery thrombosis Cerebral artery thrombosis Cerebral artery thrombosis
Articular Neurological, cardiac
Asymptomatic
CCCh-AC Asymptomatic et chirurgie CC Asymptomatic
CCCh-AC Intermittent claudication CCCh-AC Hypertension
Articular
CC-AC
Asymptomatic
–
CC-AC
Hemiparesis
–
CC-AC
Hemiparesis
a
Age at diagnosis of BD (years). Age at the onset of vascular lesion (years). O, oral; G, genital; GI, gastrointestinal; C, colchicine; AC, anticoagulants; CC, colchicine + corticosteroids; CCC, colchicine + corticosteroids + cyclophosphamide; CCCh: colchicine + corticoïdes + chlorambucil. b
of the second lumbar vertebra, with massive perivertebral venous circulation. The diagnosis in the second patient (1998) was confirmed by abdominal MR angiography, which showed absence of blood flow in the right and middle hepatic veins. The patient who had cerebral venous thrombosis presented with chronic headache without signs of intracranial hypertension. MRI showed thrombosis of the left lateral sinus [6]. Arterial thrombosis mainly involved the lower limbs and cerebral arteries. One patient had six occlusive arterial lesions, with involvement of the anterior descending coronary artery and both renal arteries (Figs. 1 and 2). Blood levels of
antithrombin III, protein C, and protein S, performed in seven patients, were normal, as were anticardiolipin antibody titers obtained in five patients. The Class I and II HLA type was determined in eight patients but did not show any relation with known antigens. Colchicine and anticoagulants were effective in five patients with venous thrombosis of the lower limbs. However, for symptom relief, glucocorticoid therapy was given in one patient (case 3) and glucocorticoid plus chlorambucil therapy in another (case 2). Patients with caval thrombosis and/or extracranial arterial lesions were given first-line treatment with a combination of glucocorticoids, immunosuppressants,
A. Tohmé et al. / Joint Bone Spine 70 (2003) 384–389
Fig. 1. A 43-year-old woman with BD. Lower limb angiography showing stenosis of the left superficial femoral artery.
and anticoagulants. The clinical manifestations improved markedly over the first 18 months after treatment initiation in two of the three patients with superior vena cava syndrome (the remaining patient was lost to follow-up), in the patients with arterial occlusions, and in one of the two patients with Budd–Chiari syndrome. The other patient with Budd–Chiari syndrome also had thrombosis of the inferior vena cava that extended into the right atrium, requiring thrombectomy before the initiation of drug therapy. His condition remained stable for the next 10 years, when he required surgical excision of a radial artery aneurysm that was about to rupture.
4. Discussion The rate of occurrence of vascular manifestations in BD has ranged from 2% to 46% [2–5]. It was 13% in our series, with a marked male predominance (sex-ratio, 2.6/1). In a 1997 study in 2400 Turkish patients with BD, the prevalence
Fig. 2. A 39-year-old male with BD. Upper limb angiography disclosing complete occlusion of the left subclavian artery distal to the origin of the vertebral artery.
387
of vascular lesions was 17% and the risk of developing vascular lesions was five times greater in males [3]. The onset of vascular manifestations usually occurs within 10 years after the initial diagnosis of BD, the critical period being the first 2 years. They can constitute the presenting symptoms, as was the case in seven of our 18 patients. Many studies have underlined the importance of venous lesions in BD [3,4,7]. A study performed in the early 1990s in 137 Turkish patients showed venous lesions in 24% and arterial lesions in 3% of patients [8]. In a study from Saudi Arabia, 24% and 18% of patients had venous and arterial lesions, respectively [9]. A study of patients with angio-BD, conducted by Kabbaj et al. [4], found that venous lesions were by far the most common type, with 85% of cases; 10% of patients had arterial lesions and 5% had both. Conversely, in Japanese [10], North American, and European series [11], arterial lesions were more common than venous lesions. Ko et al. [12] found that arterial and venous lesions were equally common: 36% of their patients had venous lesions, 33% had arterial lesions, and 30% had both. In our series, 67% of patients had venous lesions, 28% had arterial lesions, and 5% had both. Venous thrombosis is frequently accompanied with skin lesions such as erythema nodosum and necrotic pseudofolliculitis [13]. We found erythema nodosum in 44% of our patients and pseudofolliculitis in 22%. A strong association with uveitis has been reported by some authors [8], who suggested that thrombosis in BD may predict ocular involvement [14]. This association was found in 55% of our patients. Venous thrombosis mainly involves the lower limbs. Distant venous emboli are uncommon: thus, in our series, pulmonary embolism occurred in a single patient, who had thrombosis of the femoral vein. Superior vena cava thrombosis manifested in our patients as edema of the head and neck with collateral circulation in the upper trunk. Upper esophageal varices developed in one patient. This type of varices has been described in mediastinal tumors such as intrathoracic goiter and thymoma, in mediastinal fibrosis, and in supraclavicular venous thrombosis but, to our knowledge, has never been reported in superior vena cava thrombosis due to BD. Inferior vena cava thrombosis should be suspected in patients with alternating venous thrombosis of the lower limbs or recurrent venous thrombosis in one limb. It has been suggested that inferior vena cava thrombosis may occur as an extension of thrombosis from the deep venous system of the lower limbs [13]. Budd–Chiari syndrome due to thrombosis of the hepatic veins can occur in BD, usually in the setting of inferior vena cava thrombosis. However, one of our patients with Budd–Chiari syndrome did not have thrombosis of the inferior vena cava [15]. Thrombosis in both the superior and the inferior vena cava has been also observed [13]. Arterial involvement has been reported in 0–3.6% of patients with BD [5,16]. This is probably an underestimation, however, since Lakhanpal et al. [10] found arterial lesions in 57 of 170 autopsied patients with BD. Arterial thromboses, usually believed to be less common than aneurysms [13],
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were more common in our patients and in the series studied by Le Thi Huong et al. [5] and Ko et al. [12]. The time from the diagnosis of BD to the diagnosis of arterial involvement has ranged from 3 to 25 years [8,17]. Multiple arterial thromboses can occur in a given patient. One of our patients had six concomitant arterial stenoses or occlusions, with involvement of the anterior descending coronary artery and both renal arteries. Takayasu-like syndrome with of upper limb claudication due to subclavian artery stenosis was seen in one of our patients. Myocardial infarcts caused by coronary artery aneurysm or thrombosis have been reported [18,19]. Rupture, which has been estimated to complicate 60% of aneurysms, is a major cause of death in BD [5,20]. Aneurysms can develop at sites of arterial puncture for angiography [5,12]. This led Ko et al. [12] to suggest CT or MR angiography rather than conventional angiography when endovascular treatment is not being considered. Venous thrombosis may involve two mechanisms, vasculitis of the large veins and hypercoagulability. Panvasculitis, which is characteristic of BD, manifests as lymphocytic inflammatory infiltrates mainly involving the media and the adventitia at the acute phase and as a marked fibrotic reaction later on [12,13]. Thrombogenesis in BD is due to inhibition of the fibrinolytic action of plasma and to enhanced platelet aggregation related to elevation in the von Willebrand factor level and to depression of prostacyclin production [PGI2] due to endothelial cell dysfunction [13,21]. High endothelin 1 levels have been reported in patients with angio-BD [22]. Recently, low levels of free protein S with a decrease in the activity of this compound were found in BD patients, mainly those with venous thrombosis. Acquired protein S deficiency related to autoimmunity has been suggested as a factor in the pathogenesis of venous thrombosis in BD [23]. Antithrombin III and protein C levels were normal in BD patients, and no circulating lupus anticoagulant was found [24]. Anticardiolipin antibodies have been detected, but their relation with thrombosis in BD is unclear [25]. Antineutrophil cytoplasmic antibodies [26] and anti-endothelial cell antibodies were absent in patients with angio-BD [27]. Anticoagulants are used in combination with antiinflammatory drugs for the treatment of venous thrombosis. Glucocorticoids can be given during flares of venous disease. First-line treatment with a combination of immunosuppressants, glucocorticoids, and anticoagulants seems superior over glucocorticoids plus anticoagulants in the treatment of superior vena cava syndrome, multiple extracranial arterial occlusions, and occlusions of the large arteries [5,28]. Occlusion of a single artery does not require aggressive treatment, since collateral circulation is usually present [13]. Caution is in order when using anticoagulants in patients with pulmonary artery aneurysms, given the risk of fatal hemoptysis. Chronic Budd–Chiari syndrome can be treated medically. Thus, both our patients with this condition and five of the seven medically treated patients studied by Orloff and Orloff survived with follow-ups of 4 months to 7 years. Acute Budd–Chiari syndrome, in contrast, does not respond to
medical treatment and causes death by acute liver failure. Early surgical decompression of the portal system can ensure survival [15]. Surgery is also indicated in refractory arterial thrombosis and in aneurysms given the risk of rupture [5]. Percutaneous endovascular procedures have been successfully performed for occlusions and aneurysms in patients with BD [19,20,29].
5. Conclusion In our series, venous thromboses were more common in males and arterial occlusions in females. In contrast to most series, arterial occlusions were more common than aneurysms. Pulmonary embolism was exceedingly rare. Arterial occlusions and superior vena cava syndrome can be treated medically by a combination of immunosuppressants, glucocorticoids, and anticoagulants. However, further studies are needed to develop standardized treatments for each type of lesion.
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International Study Group for Behçet’s Disease. Criteria for diagnosis of Behçet’s disease. Lancet 1990;335:1078–80. Kuzu MA, Ozaslan C, Koksoy C, Gutler A, Tuzuner A. Vascular involvement in Behçet’s disease: 8-year audit. World J Surg 1994;18: 948–53. Gurler A, Boyvat A, Tursen U. Clinical manifestations of Behçet’s disease: an analysis of 2147 patients. Yonsei Med J 1997;38:423–7. Kabbaj N, Benjelloun G, Gueddari FZ, Dafiri R, Imani F. Vascular involvement in Behçet’s disease. Based on 40 patient records. J Radiol 1993;74:649–56. Le Thi Huong D, Wechsler B, Papo T, Piette JC, Blétry O, Vitoux JM, et al. Arterial lesions in Behçet’s disease. A study in 25 patients. J Rheumatol 1995;22:2103–13. Tohmé A, Haddad F, Ghayad E. Manifestations neurologiques de la maladie de Behçet. Ann Med Interne 1997;148:118–24. Ames PRJ, Steuer A, Pap A, Denman AM. Thrombosis in Behçet’s disease: a retrospective survey from a single UK centre. Rheumatology 2001;40:652–5. Koc Y, Gullu I, Akpek G, Akpolat T, Kansu E, Kiraz S, et al. Vascular involvement in Behçet’s disease. J Rheumatol 1992;19:402–10. Al-Dalaan AN, al Balaa SR, el Ramahi K, al-Kawi Z, Bohlega S, Bahabri S, et al. Behçet’s disease in Saudi Arabia. J Rheumatol 1994;21:658–61. Lakhanpal S, Tani K, Lie JT, Katoh K, Ishigatsubo Y, Ohokubo T. Pathologic features of Behçet’s syndrome: a review of Japanese autopsy registry data. Hum Pathol 1985;16:790–5. James DG, Thomson A. Recognition of the diverse cardiovascular manifestations in Behçet’s disease. Am Heart J 1982;103:457–8. Ko G-Y, Byun JY, Choi BG, Cho SH. The vascular manifestations of Behçet’s disease: angiographic and CT findings. Br J Radiol 2000;73: 1270–4. Hamza M. Maladie de Behçet. 4th ed. In: Kahn MF, editor. Maladies et syndromes systémiques. Paris: Flammarion Médecine-Sciences; 2000. p. 883–924. Demiroglu H, Barista I, Dundar S. Risk factor assessment and prognosis of eye involvement in Behçet’s disease in Turkey. Ophthalmology 1997;104:701–5.
A. Tohmé et al. / Joint Bone Spine 70 (2003) 384–389 [15] Orloff LA, Orloff MJ. Budd–Chiari syndrome caused by Behçet’s disease: treatment by side-to-side portacaval shunt. J Am Coll Surg 1999;188:396–407. [16] Chajek T, Fainaru M. Behçet’s disease. Medicine 1975;54:179–96 Report of 41 cases and a review of the literature. [17] Hamza M. Large artery involvement in Behçet’s disease. J Rheumatol 1987;14:554–9. [18] Drobinski G, Wechsler B, Pavie A, Artigon JY, Marek P, Godeau P, et al. Emergency percutaneous coronary dilatation for acute myocardial infarction in Behçet’s disease. Eur Heart J 1987;8:1133–6. [19] Ipek G, Omeroglu SN, Mansuroglu D, Kirali K, Uzun K, Sismanoglu M. Coronary artery bypass grafting in a 26-year-old man with total occlusion of the left main coronary artery related to Behçet’s disease. J Thorac Cardiovasc Surg 2001;122:1247–9. [20] Park JH, Chung JW, Joh JH, Song SY, Shin SJ, Chung KS, et al. Aortic and arterial aneurysms in Behçet’s disease: management with stentgrafts-initial experience. Radiology 2001;220:745–50. [21] Özoran K, Düzgün N, Gürler A, Yutkak H, Tokgöz G. Plasma von Willebrand factor, tissue plasminogen activator, plasminogen activator inhibitor, and antithrombin III levels in Behçet’s disease. Scand J Rheumatol 1995;24:376–82.
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[22] Ural AU. Increased plasma endothelin-1 levels in active Behçet’s disease. Clin Rheumatol 1997;16:59–61. [23] Guermazi S, Hamza M, Dellagi K. Protein S deficiency and antibodies to protein S in patients with Behçet’s disease. Thromb Res 1997;26: 197–204. [24] Mader R, Ziv M, Adawi M, Mader R, Lavi I. Thrombophilic factors and their relation to thromboembolic and other clinical manifestations in Behçet’s disease. J Rheumatol 1999;26:2404–8. [25] Tokay S, Direskeneli H, Yurdakul S, Akoglu T. Anticardiolipin antibodies in Behçet’s disease: a reassessment. Rheumatology 2001;40: 192–5. [26] Hamza M, Meyer. Negative antineutrophil cytoplasmic antibodies in Behçet’s disease. Ann Rheum Dis 1990;49:817. [27] Lee KH, Bang D, Choi ES, Chin WH, Lee ES, Lee S. Presence of circulating antibodies to a disease-specific antigen on cultured human dermal microvascular endothelial cells in patients with Behçet’s disease. Arch Dermatol Res 1999;291:374–81. [28] Ehrlich GE. Vasculitis in Behçet’s disease. Int Rev Immunol 1997;14: 81–8. [29] Kasirajan K, Marek JM, Langsfeld M. Behçet’s disease: endovascular management of a ruptured peripheral arterial aneurysm. J Vasc Surg 2001;34:1127–9.
Case report
Vascular manifestations of Behçet’s disease Eighteen cases among 140 patients Aline Tohmé a,*, Noël Aoun b, Bassam El-Rassi a, Elie Ghayad a a
Department of Internal Medicine, Hôtel-Dieu de France Hospital of Beirut, School of Medicine, Saint Joseph University of Beirut, rue Adib Ishaac, Beirut, Lebanon b Department of Radiology, Hôtel-Dieu de France Hospital of Beirut, School of Medicine, Saint Joseph University of Beirut, rue Adib Ishaac, Beirut, Lebanon Received 26 February 2002; accepted 6 June 2002
Abstract Objectives. – To describe the features, prognosis, and treatment of vascular involvement in Behçet’s disease (BD). Patients. – Among 140 patients with BD seen at the Hôtel-Dieu Hospital in Beirut between 1980 and 2000, 18 (13%) had vascular involvement and were included in this retrospective study. All these patients fulfilled International Study Group criteria for BD. Results. – Men with BD were more likely to have vascular involvement (13/77, 17%) than women (5/63, 8%) (P = 0.12) and were younger at diagnosis of vascular disease (32 ± 7 vs. 36 ± 7.5 years; P < 0.01). Many patients had vascular disease at more than one site: 17 had thrombophlebitis, 10 had arterial thromboses, and one had an aneurysm. Thrombophlebitis was more common in men (82% vs. 18%; P < 0.03) and arterial occlusion in women (70% vs. 30%; P > 0.05). Caval thrombosis and arterial occlusions were the most serious complications. Combined treatment with glucocorticoids, anticoagulants, and immunosuppressants was effective in superior vena cava syndrome and extracranial arterial occlusion. Conclusion. – Vascular manifestations of BD are common in Lebanon, particularly venous lesions. Aneurysms are seen less often than arterial occlusions. Medical treatment may be sufficient in superior vena cava syndrome and arterial occlusion. © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. Keywords: Behçet’s disease; Vena cava; Budd-Chiari; Arteritis; Corticosteroids
1. Introduction
2. Patients and methods
Behçet’s disease (BD) is a systemic vasculitis of obscure origin, frequently encountered in Japan and in Mediterranean countries. Since no specific biological test is available, the diagnosis is based on several criteria, the most widely used being those of the International Group Study on BD [1]. Although vascular lesions constitute the pathological basis of the disease, their presence is not required for the diagnosis. Their frequency varies between 2% and 46% [2–5], with a predominance of venous lesions [3,4]. We will discuss the features, prognosis, and treatment of vascular involvement with BD in 18 patients.
Among outpatients and inpatients managed at the HôtelDieu de France Hospital in Beirut between 1980 and 2000, 140 had BD. Vascular involvement was present in 18 of these patients and forms the basis for this retrospective chart review study. All 18 patients met International Study Group on BD criteria [1] and underwent an immunological work-up (anti-nuclear antibodies, anti-ADN, C3 and C4 levels, and VDRL). Thrombophlebitis of the extremities was confirmed by echodoppler, vena cava and Budd–Chiari syndrome by cavography or magnetic resonance (MR) angiography, extracranial arterial lesions by angiography, and cerebral thrombosis by computed tomography (CT) or MR imaging (MRI). Glucocorticoids were administered in a dose of 1–2 mg/kg/d of prednisone or equivalent for 1 month, followed by slow tapering over 1 year (13 patients). Patients with vena cava syndrome (n = 5) or extracranial arterial
* Corresponding author. E-mail address: [email protected] (A. Tohmé). © 2003 Éditions scientifiques et médicales Elsevier SAS. All rights reserved. doi:10.1016/S1297-319X(03)00076-9
A. Tohmé et al. / Joint Bone Spine 70 (2003) 384–389
385
Table 1 Clinical manifestations of BD in males and females Oral aphthae Genital aphthae Uveitis Erythema nodosa Pseudofolliculitis Articular manifestations Neurological manifestations Vascular manifestations Gastrointestinal manifestations
Males (n = 77) 77 (100%) 64 (83%) 49 (64%) 13 (17%) 29 (38%) 43 (56%) 15 (19%) 13 (17%) 7 (9%)
occlusion also received immunosuppressant therapy (cyclophosphamide, 1–2 mg/kg/d for 12–18 months; or chlorambucil, 0.1 mg/kg/d for 2 months followed by 2–4 mg/d for 12–18 months). For the statistical analysis, we used the t-test and the v2 of Yates for small samples. P values smaller than 0.05 were considered statistically significant.
3. Results Vascular lesions were found in 18 of the 140 BD patients (13%) seen during the study period and were more common among males (13/77, 17%) than among females (5/63, 8%) (P = 0.12). The sex distribution of clinical manifestations in our patients is summarized in Table 1. Erythema nodosum and joint disease were more common in females (36% vs. 17% for erythema nodosum, P = 0.01; and 71% vs. 56% for joint disease, P = 0.05). Mean age was 28 ± 6 years at diagnosis of BD and 33 ± 7 years at diagnosis of vascular manifestations (32 ± 7 in males, and 36 ± 7.5 in females; P < 0.01); the mean interval between the two was 9 years. Clinical manifestations of BD in patients with (n = 18) and without (n = 122) vascular lesions are summarized in Table 2. Erythema nodosum and gastrointestinal manifestations were more common in patients with vascular lesions (44% vs. 23% for erythema nodosum, P < 0.05; and 28% vs. 6% for gastrointestinal manifestations, P < 0.001). The vascular manifestations are listed in Table 3. They occurred as the presenting symptoms in seven patients and started 3–15 years after the diagnosis of BD in the 11 remaining patients. Only two patients (cases 3 and 13) were taking glucocorti-
Females (n = 63) 63 (100%) 51 (81%) 38 (60%) 23 (36%) 20 (32%) 45 (71%) 8 (13%) 5 (8%) 5 (8%)
Total (n = 140) 140 (100%) 115 (82%) 87 (62%) 36 (26%) 49 (35%) 88 (63%) 23 (16%) 18 (13%) 12 (8.5%)
P NS NS NS <0.01 NS 0.05 NS 0.12: NS NS
coids for other manifestations of the disease at the diagnosis of vascular involvement, and one (case 2) was taking colchicine. Four patients had a family history of BD. Many patients had vascular involvement at multiple sites. In all, in the 18 patients, 28 vessels were involved: there were 17 venous thromboses, 10 arterial thromboses, and one arterial aneurysm (Table 3). The total number of thromboses was greater in males (17/22, 63%) than in females (10/27, 37%), although the difference was not statistically significant (P > 0.5). Venous thrombosis was significantly more common in males (14/17, 82%; 3/17, 18%; P < 0.03) and arterial thrombosis in women (7/10, 70%; 3/10, 30%; P > 0.05). Venous thrombosis occurred mainly in the lower limbs (9/17; popliteal vein, five cases; femoral vein, two cases; and greater saphenous vein, two cases). One patient had pulmonary embolism. Other sites of venous thrombosis were the superior vena cava (n = 2), the innominate and left subclavian veins (n = 1), and the hepatic veins (n = 2); one of the patients with hepatic vein thrombosis also had thrombosis of the inferior vena cava and popliteal veins. Endoscopy and upper gastrointestinal series performed in the two patients with thrombosis of the superior vena cava showed upper esophageal varices, which extended up to the cardia in one patient. The clinical picture in our two patients with hepatic vein thrombosis (Budd–Chiari syndrome) was massive ascites with abdominal collaterals and edema of the lower extremities, evolving over several months. Liver biopsy was done in one of these patients and showed sinusoidal dilatation and centrilobular congestion. Hepatic venography established the diagnosis in one patient (in 1988) by showing thrombosis of the hepatic veins and of the inferior vena cava at the level
Table 2 Clinical manifestations of BD in 18 patients with and 122 without vascular lesions
Oral aphthae Genital aphthae Uveitis Erythema nodosum Pseudofolliculitis Articular manifestations Neurological manifestations Gastrointestinal manifestations
With vascular lesions (n = 18) 18 (100%) 17 (94%) 10 (55%) 8 (44%) 4 (22%) 13 (72%) 5 (28%) 5 (28%)
Without vascular lesions (n = 122) 122 (100%) 98 (80%) 77 (63%) 28 (23%) 45 (37%) 75 (61%) 18 (15%) 7 (6%)
Total (n = 140)
P
140 (100%) 115 (82%) 87 (62%) 36 (26%) 49 (35%) 88 (63%) 23 (16%) 12 (8.5%)
NS NS NS <0.05 NS NS NS <0.001
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Table 3 Clinical features, treatment, and outcomes of vascular involvement with BD in 18 patients Patient (sex, Ageb agea) 1 (M, 25) 30 2 (M, 19) 22
Aphthae Uveitis Skin lesions Thrombophlebitis Arterial lesions O G + + + Pseudofolliculitis Right saphenous vein – + + – Hyperirritability Recurrent left saphenous – vein
Other manifestations Articular, GI Articular
3 (F, 25)
35
+
+
+
4 (M, 29) 5 (M, 26)
33 29
+ +
+ –
+ +
6 (M, 30) 7 (M.37) 8 (M, 28)
30 37 28
+ + +
+ + +
– – –
9 (M, 22)
30
+
+
+
10 (F, 20)
30
+
+
–
11 (M, 30)
30
+
+
–
12 (M, 23)
23
+
+
–
13 (F, 31)
44
+
+
+
14 (M, 25)
39
+
+
+
Left popliteal vein Right popliteal vein Right brachiocephalic trunk and left subclavian veins Erythema Left popliteal vein and nodosum superior vena cava Hyperirritability, Superior vena cava erythema nodosum Erythema Median and right nodosum hepatic veins Erythema Right popliteal vein, nodosum hepatic and inferior vena cava Hyperirritability, Cerebral vein erythema nodosum Pseudofolliculitis –
15 (F, 33)
43
+
+
–
Hyperirritability –
16 (F, 27)
27
+
+
+
Erythema nodosum
17 (M, 43)
43
+
+
+
–
18 (M, 33)
48
+
+
+
–
Erythema nodosum Pseudofolliculitis Erythema nodosum Pseudofolliculitis Hyperirritability Hyperirritability
Treatment Course
Right femoral vein
–
Epididymitis
C-AC Asymptomatic CC-AC Relapse puis CCCh-AC CC-AC Asymptomatic
Right femoral vein Right popliteal vein
– –
Articular Articular
C-AC C-AC
Asymptomatic Asymptomatic
– – –
Articular Articular, GI Articular
C-AC C-AC CCC-AC
Asymptomatic Asymptomatic Lost to follow-up
–
Articular
CCC-AC
Asymptomatic
–
Articular, GI CCC-AC (ascite, pleuropericarditis) – CCC-AC
Asymptomatic
–
– Left radial aneurysm
Articular, GI
–
Articular, GI
Left subclavian artery occlusion Coronary occlusion (anterior descending), renal arteries stenosis, left femoral, tibial and peroneal arteries stenosis Cerebral artery thrombosis Cerebral artery thrombosis Cerebral artery thrombosis
Articular Neurological, cardiac
Asymptomatic
CCCh-AC Asymptomatic et chirurgie CC Asymptomatic
CCCh-AC Intermittent claudication CCCh-AC Hypertension
Articular
CC-AC
Asymptomatic
–
CC-AC
Hemiparesis
–
CC-AC
Hemiparesis
a
Age at diagnosis of BD (years). Age at the onset of vascular lesion (years). O, oral; G, genital; GI, gastrointestinal; C, colchicine; AC, anticoagulants; CC, colchicine + corticosteroids; CCC, colchicine + corticosteroids + cyclophosphamide; CCCh: colchicine + corticoïdes + chlorambucil. b
of the second lumbar vertebra, with massive perivertebral venous circulation. The diagnosis in the second patient (1998) was confirmed by abdominal MR angiography, which showed absence of blood flow in the right and middle hepatic veins. The patient who had cerebral venous thrombosis presented with chronic headache without signs of intracranial hypertension. MRI showed thrombosis of the left lateral sinus [6]. Arterial thrombosis mainly involved the lower limbs and cerebral arteries. One patient had six occlusive arterial lesions, with involvement of the anterior descending coronary artery and both renal arteries (Figs. 1 and 2). Blood levels of
antithrombin III, protein C, and protein S, performed in seven patients, were normal, as were anticardiolipin antibody titers obtained in five patients. The Class I and II HLA type was determined in eight patients but did not show any relation with known antigens. Colchicine and anticoagulants were effective in five patients with venous thrombosis of the lower limbs. However, for symptom relief, glucocorticoid therapy was given in one patient (case 3) and glucocorticoid plus chlorambucil therapy in another (case 2). Patients with caval thrombosis and/or extracranial arterial lesions were given first-line treatment with a combination of glucocorticoids, immunosuppressants,
A. Tohmé et al. / Joint Bone Spine 70 (2003) 384–389
Fig. 1. A 43-year-old woman with BD. Lower limb angiography showing stenosis of the left superficial femoral artery.
and anticoagulants. The clinical manifestations improved markedly over the first 18 months after treatment initiation in two of the three patients with superior vena cava syndrome (the remaining patient was lost to follow-up), in the patients with arterial occlusions, and in one of the two patients with Budd–Chiari syndrome. The other patient with Budd–Chiari syndrome also had thrombosis of the inferior vena cava that extended into the right atrium, requiring thrombectomy before the initiation of drug therapy. His condition remained stable for the next 10 years, when he required surgical excision of a radial artery aneurysm that was about to rupture.
4. Discussion The rate of occurrence of vascular manifestations in BD has ranged from 2% to 46% [2–5]. It was 13% in our series, with a marked male predominance (sex-ratio, 2.6/1). In a 1997 study in 2400 Turkish patients with BD, the prevalence
Fig. 2. A 39-year-old male with BD. Upper limb angiography disclosing complete occlusion of the left subclavian artery distal to the origin of the vertebral artery.
387
of vascular lesions was 17% and the risk of developing vascular lesions was five times greater in males [3]. The onset of vascular manifestations usually occurs within 10 years after the initial diagnosis of BD, the critical period being the first 2 years. They can constitute the presenting symptoms, as was the case in seven of our 18 patients. Many studies have underlined the importance of venous lesions in BD [3,4,7]. A study performed in the early 1990s in 137 Turkish patients showed venous lesions in 24% and arterial lesions in 3% of patients [8]. In a study from Saudi Arabia, 24% and 18% of patients had venous and arterial lesions, respectively [9]. A study of patients with angio-BD, conducted by Kabbaj et al. [4], found that venous lesions were by far the most common type, with 85% of cases; 10% of patients had arterial lesions and 5% had both. Conversely, in Japanese [10], North American, and European series [11], arterial lesions were more common than venous lesions. Ko et al. [12] found that arterial and venous lesions were equally common: 36% of their patients had venous lesions, 33% had arterial lesions, and 30% had both. In our series, 67% of patients had venous lesions, 28% had arterial lesions, and 5% had both. Venous thrombosis is frequently accompanied with skin lesions such as erythema nodosum and necrotic pseudofolliculitis [13]. We found erythema nodosum in 44% of our patients and pseudofolliculitis in 22%. A strong association with uveitis has been reported by some authors [8], who suggested that thrombosis in BD may predict ocular involvement [14]. This association was found in 55% of our patients. Venous thrombosis mainly involves the lower limbs. Distant venous emboli are uncommon: thus, in our series, pulmonary embolism occurred in a single patient, who had thrombosis of the femoral vein. Superior vena cava thrombosis manifested in our patients as edema of the head and neck with collateral circulation in the upper trunk. Upper esophageal varices developed in one patient. This type of varices has been described in mediastinal tumors such as intrathoracic goiter and thymoma, in mediastinal fibrosis, and in supraclavicular venous thrombosis but, to our knowledge, has never been reported in superior vena cava thrombosis due to BD. Inferior vena cava thrombosis should be suspected in patients with alternating venous thrombosis of the lower limbs or recurrent venous thrombosis in one limb. It has been suggested that inferior vena cava thrombosis may occur as an extension of thrombosis from the deep venous system of the lower limbs [13]. Budd–Chiari syndrome due to thrombosis of the hepatic veins can occur in BD, usually in the setting of inferior vena cava thrombosis. However, one of our patients with Budd–Chiari syndrome did not have thrombosis of the inferior vena cava [15]. Thrombosis in both the superior and the inferior vena cava has been also observed [13]. Arterial involvement has been reported in 0–3.6% of patients with BD [5,16]. This is probably an underestimation, however, since Lakhanpal et al. [10] found arterial lesions in 57 of 170 autopsied patients with BD. Arterial thromboses, usually believed to be less common than aneurysms [13],
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were more common in our patients and in the series studied by Le Thi Huong et al. [5] and Ko et al. [12]. The time from the diagnosis of BD to the diagnosis of arterial involvement has ranged from 3 to 25 years [8,17]. Multiple arterial thromboses can occur in a given patient. One of our patients had six concomitant arterial stenoses or occlusions, with involvement of the anterior descending coronary artery and both renal arteries. Takayasu-like syndrome with of upper limb claudication due to subclavian artery stenosis was seen in one of our patients. Myocardial infarcts caused by coronary artery aneurysm or thrombosis have been reported [18,19]. Rupture, which has been estimated to complicate 60% of aneurysms, is a major cause of death in BD [5,20]. Aneurysms can develop at sites of arterial puncture for angiography [5,12]. This led Ko et al. [12] to suggest CT or MR angiography rather than conventional angiography when endovascular treatment is not being considered. Venous thrombosis may involve two mechanisms, vasculitis of the large veins and hypercoagulability. Panvasculitis, which is characteristic of BD, manifests as lymphocytic inflammatory infiltrates mainly involving the media and the adventitia at the acute phase and as a marked fibrotic reaction later on [12,13]. Thrombogenesis in BD is due to inhibition of the fibrinolytic action of plasma and to enhanced platelet aggregation related to elevation in the von Willebrand factor level and to depression of prostacyclin production [PGI2] due to endothelial cell dysfunction [13,21]. High endothelin 1 levels have been reported in patients with angio-BD [22]. Recently, low levels of free protein S with a decrease in the activity of this compound were found in BD patients, mainly those with venous thrombosis. Acquired protein S deficiency related to autoimmunity has been suggested as a factor in the pathogenesis of venous thrombosis in BD [23]. Antithrombin III and protein C levels were normal in BD patients, and no circulating lupus anticoagulant was found [24]. Anticardiolipin antibodies have been detected, but their relation with thrombosis in BD is unclear [25]. Antineutrophil cytoplasmic antibodies [26] and anti-endothelial cell antibodies were absent in patients with angio-BD [27]. Anticoagulants are used in combination with antiinflammatory drugs for the treatment of venous thrombosis. Glucocorticoids can be given during flares of venous disease. First-line treatment with a combination of immunosuppressants, glucocorticoids, and anticoagulants seems superior over glucocorticoids plus anticoagulants in the treatment of superior vena cava syndrome, multiple extracranial arterial occlusions, and occlusions of the large arteries [5,28]. Occlusion of a single artery does not require aggressive treatment, since collateral circulation is usually present [13]. Caution is in order when using anticoagulants in patients with pulmonary artery aneurysms, given the risk of fatal hemoptysis. Chronic Budd–Chiari syndrome can be treated medically. Thus, both our patients with this condition and five of the seven medically treated patients studied by Orloff and Orloff survived with follow-ups of 4 months to 7 years. Acute Budd–Chiari syndrome, in contrast, does not respond to
medical treatment and causes death by acute liver failure. Early surgical decompression of the portal system can ensure survival [15]. Surgery is also indicated in refractory arterial thrombosis and in aneurysms given the risk of rupture [5]. Percutaneous endovascular procedures have been successfully performed for occlusions and aneurysms in patients with BD [19,20,29].
5. Conclusion In our series, venous thromboses were more common in males and arterial occlusions in females. In contrast to most series, arterial occlusions were more common than aneurysms. Pulmonary embolism was exceedingly rare. Arterial occlusions and superior vena cava syndrome can be treated medically by a combination of immunosuppressants, glucocorticoids, and anticoagulants. However, further studies are needed to develop standardized treatments for each type of lesion.
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