BRIEF PAPER Clinical and Experimental Rheumatology 2001; 19 (Suppl. 24): S48-S50. Deep ABSTRACT stitute the most frequent vascular mani- Objective festation seen in 6.2 to 33 % cases of in Behcet’s disease We aimed to describe the epidemiologi - BD (1, 2). We carried out this study to cal and clinical aspects of d e t e rmine the fre q u e n cy, the cl i n i c a l M.H. Houman1 thrombosis (DVT) in Behçet’s disease characteristics and course of deep vein 1 (BD) and to determine the patients at thrombosis (DVT) in BD patients and I. Ben Ghorbel high risk for this . to define a subgroup of patients at high I. Khiari Ben Salah1 Methods risk for this complication. M. Lamloum1 Among 113 patients with BD according 2 to the international criteria for classifi - Patients and methods M. Ben Ahmed cation of BD, those with DVT were ret - The medical records of one hundred M. Miled1 rospectively studied.The diagnosis of and thirteen patients with BD were re- DVT was made in all cases using con - viewed in order to investigate the pa- 1Department of . La ventional venous angiography, venous tient’s , the clinical ma- Rabta Hospital, 2Department of Immuno- ultrasonography and/or thoracic or ab - nifestations and outcome of the disease logy, Institute Pasteur. Tunis, Tunisia. dominal computed tomograp hy. Pa - as well as the treatment prescribed.The Houman M Habib, MD; Ben Ghorbel tients were divided in two subgroups diagnosis of BD was made based on the Imed, MD; Khiari Ben Salah Imen; a c c o rding to the occurrence of DV T criteria established by the international Lamloum Mounir, MD; Ben Ahmed other than cereb ral thromboses. Th e study group for BD (3). Patients were Malika, MD; Miled Mohamed, MD. medical records of these patients were divided in two subgroups according to Please address correspondence to: reviewed in order to investigate their the occurrence of DVT other than cere- Pr. M. Habib Houman, Department of Internal Medicine, Hospital La Rabta past medical history and evaluate their bral thrombosis. The diagnosis of DVT 1007 Tunis, Tunisia. response to the treatment prescribed. was made using venous ultrasonogra- E-mail: [email protected] Clinical and genetic factors (HLA B51 phy in all cases, with abdominal com- Received on November 30, 2000; and MICA 6) that might contribute to puted tomography in 8 cases for inferi- accepted in revised form on April 6, 2001. DVT were analysed by comparing pa - or vena cava thrombosis (IVCT) and © Copyright CLINICAL AND tients with and without DVT. Results of t h o racic computed tomograp hy in 4 EXPERIMENTAL RHEUMATOLOGY 2001. our series were compared to those of cases for superior vena cava thrombo- other series in the literature. Statistical sis (SVCT); conventional venous an- Key words: Behçet’s disease, deep analysis was by Chi square with neces - giography was performed in one case. vein thrombosis, HLA linkage, MIC sary correction and Fischer tests. , and anti-thrombin genes. Results III levels were determined in all pa- Forty-four patients (38.9%) had deep tients. The anticardiolipin (aCL) and vein thrombosis of various systems with anti§2 Gly c o p rotein1 antibodies 81 localisations. Th e re we re 40 men (§2GP1) were measured in 24 patients and four women (mean age 28.1 years; by ELISA using IgG isotype. HLA- range 17-60). DVT appeared after the B51 allele was determined in 38 pa- onset of disease with a mean delay of tients using a complement-dep e n d e n t 3.8 ye a rs. In 6 cases, DVT reve a l e d m i c ro ly m p h o cyte toxicity assay; fi f- BD.When we evaluated the risk of DVT teen of these patients had DVT. Triplet coexistence with other clinical findings rep e at poly m o rphism of MICA wa s and genetic fa c t o rs (HLA B51 and analysed on a denaturating polyacryna- MICA 6), we found a significant posi - mide gel and alleles were visualised by tive correlation with sex, and positive autoradiograghy in 34 patients, 11 of pathergy test. whom had DVT. Results in both sub- Conclusion groups were compared by Chi-square In our series, occurrence of DVT was with necessary correction and Fischer significantly associated with male gen - tests. der and positive pathergy test. Results Introduction Of 113 patients with BD, 49 (43.3%) Behçet’s disease (BD) is a multisystem had vascular invo l vement. A m o n g disorder characterised mainly by recur- them 44 (38.9%) patients had DVT, 7 rent oral and genital ulcers and ocular arterial and 6 arterial throm- involvement. Neurologic and vascular boses. Seven patients presented both involvement are not rare and may be venous and arterial involvements. The life-threatening.Vein thromboses con- group of patients with DVT consisted

S-48 Deep vein thrombosis in Behçet’s disease / M.H. Houman et al. BRIEF PAPER of 40 men and four women whereas the Table I. Clinical and genetic features of BD patients with and without DVT. group of the remaining 64 pat i e n t s without DVT was composed of 37 men Behçet’s disease Behçet’s disease with DVT without DVT P and 27 women. Male pre d o m i n a n c e n = 44 n = 64 was significantly higher in the DVT pa- tient group (p = 0.0004). Mean age of Male 40 (90.9%) 37 (57.8%) 0.0004 patients at the moment of diagnosis of Age (years) 28.4 32 0.562 BD was ro u g h ly similar for pat i e n t s Buccal aphtosis 43 (97.7%) 64 (100%) 0.407 with (28.1 years) and without DVT (32 Genital aphtosis 33 (75%) 48 (75%) 0.821 years). The average delay to diagnosis Pseudofolliculitis 25 (56.8%) 30 (46%) 0.412 of DVT from the date of BD diagnosis Pathergy Test 34 (77.2%) 37 (57%) 0.036 was 3.1 years (range 0-18 years). DVT Erythema nodosum 20 (45.4%) 34 (53%) 0.556 revealed BD in 6 cases. Eighty-one lo- Ocular involvement 14 (31.8%) 30 (46%) 0.112 cations of DVT were detected. Forty- Articular involvement 26 (59%) 44 (68%) 0.407 three patients showed more than one Neurological 8 (18.1%) 6 (9%) 0.231 location. Twelve patients had a vena HLA B51 11 (25%) 13 (20%) 0.480 c ava thrombosis (VCT) among them MICA 6 8 (18%) 20 (31%) 0.287 only one had both superior and inferior V C T. Hep at i c ve n o u s t h ro m b o s i s Budd-Chiari syndrome. Of 20 patients (62% of cases) and this result is also in (Budd-Chiari syndrome) was seen in 5 with DVT treated with corticosteroids, agreement with those rep o rted by p atients. Clinical fe at u res of BD in 5 showed re c u rrence of thro m b o s i s , Wechsler (8). The second most com- p atients with and without DVT are while 4 of the remaining 24 patients mon localization of DVT was the vena summarised and compared in Table I. had this complication (p = 0.72). cava, observed in 10 patients. VCT was Pat h e rgy test was signifi c a n t ly more reported in 0.2 to 10%, more frequently f re q u e n t ly positive in patients with Discussion in West Mediterranean and European DVT (p = 0.030). Protein C, protein S Although vascular lesions are not in- patients (9). In our study, 6 patients had and anti-thrombin III levels were nor- cluded in the major diagnostic criteria hepatic which is a mal in all patients. Seven of 24 patients of BD, our results and other reported very rare complication of BD reported were positive for IgG aCL with no dif- investigations indicate that 1/4 to 1/2 of in 0.3 to 2.8 % of cases (7). fe rence between patients with and patients are likely to develop this com- In this study, pathergy positivity was without DVT, and no patient was posi- plication (2, 4). Venous thrombosis ap- the only statistically significant clinical tive for a§2GP1. Eleven patients with p e a red to be the major vascular in- feature which is more frequently ob- DVT and thirteen patients without vo l vement rep o rted in 7 to 33% of served in BD patients with DVT com- DVT were HLA B51 positive, the dif- cases with BD, and representing 85 to pared with those without DVT. A high- ference was not statistically significant 93% of vasculo-Behçet. It is signifi- er prevalence of positive pathergy test (p = 0.480). Eight patients with DVT c a n t ly more fre q u e n t ly observed in and erythema nodosum in vasculopathy and twenty patients without DVT were A rab and European populations (19- BD had also been previously reported MICA 6 positive, the difference was 34%) (5) than in Asian non-Arab popu- by Koç (4) and Muftüoglu (2) fro m not statistically significant either (p = lations (7-12.5%) (6). Turkey. 0.287). Our study confirms the male predomi- It is well known that HLA B51 is the All patients were treated with anticoag- nance reported by all previous studies most important genetic factor associat- ulant agents and colchicine (1mg/day). and which varied from 2.6% to 4.4% ed with BD in many ethnic groups (10). The consisted of a stan- (7). The mean age of patients with vas- But studies of the association of HLA d a rd intravenous hep a rin during ten cular involvement varied from 25 (7) to B51 with specific manifestations of BD days followed by acenocoumarol. Cor- 30 years (4) with no significant differ- s h owed controve rsial results (10-12). ticosteroids were prescribed to 20 pa- ence between the sexes as found in our In this study, the association of HLA tients and monthly intravenous pulses study. The reported most critical period B51 with DVT was not found. MICA 6 of cyclophosphamide were indicated in for developing DVT was 2 to 3.2 years allele has recently been shown to be si- 5 cases (two with IVCT and 3 with after the diagnosis of BD (4,7) and that gnificantly associated with BD in Japan SVCT). Complete clinical re c ove ry is in agreement with our results (3.1 (13). But studies of the association of f rom DVT was noticed in 24 cases years). And, as noticed by Koç et al. (4) MICA poly m o rphism with specifi c (77%), signs of chronic venous insuffi- the frequency of vascular lesions ap- manifestations of BD were very rare c i e n cy (increased leg circ u m fe re n c e, pears to have a tendency to decrease and failed to show such an association dermatitis, hyperpigmentation and skin after 5 years from the time of BD diag- (11). In our study too, no association of ulceration) were seen in 6 patients. Re- nosis BD with MICA 6 was found. currence of thrombosis was observed in Our study indicates that DVT affects The mechanism of vein thrombosis in 9 cases and one patient died of severe most frequently the lower extremities BD remains unknown. Several studies

S-49 BRIEF PAPER Deep vein thrombosis in Behçet’s disease / M.H. Houman et al. failed to associate specific frequently in males patients with posi- M, CALGUNERI M: Budd-Chiari Syndrome: abnormalities with this disease (14). In t ive pat h e rgy test and erythema no- A common complication of Behçet’s disease. Am J Gastroenterol 1997; 92: 858-62. our study, neither deficiency in protein dosum. 8. WECHSLER B, HUONG LT, GODEAU P: Les C, protein S and anti-thrombin III nor manifestations vasculaires de la maladie de resistance to activated protein C, aCL References Behçet. Artères et veines 1994; 8: 157-64. and a§2GP1 levels seemed to be corre- 1. NADJI A, SHAHRAM F, DAVATCHI F, AKABI- 9. HOUMAN. MH,LAMLOUM M,BEN GHORBEL AN M,GHARIBOOST F,JAMSHIDI A: Vascular I,KHIARI BEN SALAH I,MILED M:Vena cava lated with vascular thrombosis in BD. i nvo l vement in Behcet’s disease, rep o rt of thrombosis in Behçet’s disease. Analysis of a Hence, thrombosis in BD seems to be 323 cases. In OLIVIERI I,SALVARANI C,CAN- series of 10 cases. Ann Med Interne 1999; related more to than to clot- TINI F (Eds.): 8th International Congress on 150: 587-90. ting disorders. The optimal treatment B e h ç e t ’s disease. Program and A b s t ra c t s . 10. AZIZLERI G, AKSUNGUR V L , SARICA R, Milano: Prex, 1998: 194. AKYOL E, OVUL C:The association of HLA- of vascular thrombosis in BD remains 2. MÜFTÜOGLU A,YURDAKUL S,YAZICI H , et B5 antigens with specific manifestations of controversial. antiplatelet agents such al.:Vascular involvement in Behçet’s disease. B e h ç e t ’s disease. D e rm at o l ogy 1994; 188: as low-dose and dipyridamole A rev i ew of 129 cases. I n: LEHNER T, 293-5. BARNES CG ( E d s . ) : Recent A dvances in 11. CHO CS,PARK KS,PARK SH, et al.: Associa- are recommended in cases of venous Behçet’s Disease. London: Royal Society of tion of MICA polymorphism with HLA-B51 involvement, but a controversy exists Medicine Services Intern ational Congre s s and disease severity in Korean patients with on this subject. Koç did not recommend and Symposium Series No. 103, 1986: 255- B e h ç e t ’s disease. Yonsei Med J 2000; 41 Aspirin to patients with BD in view of 60. (Suppl):13. 3. INTERNATIONAL STUDY GROUP FOR BEH- 12. GÜL, UYAR FA, INANC M, et al.: HLA-B51 their re s u l t s , wh i ch showed re d u c e d Ç E T’S DI S E A S E: C ri t e ria for diagnosis of heterozygosity has no prominent effect on the biosynthesis of prostacyclin in BD (4). Behçet’s Disease . Lancet 1990; 335: 1078- severity of Behçet’s disease. Yonsei Med J As we think that vascular changes lead- 80. 2000; 41 (Suppl.): 13. ing to vasculitis and thrombosis are im- 4. KOÇ Y, GÜLLÜ I, AKPEK G, et al.:Vascular 13. MIZUKI N, OTA M,KIMURA M, et al.: Triplet involvement in Behçet’s disease. J Rheumatol repeat polymorphism in the transmembrane p o rtant pat h o l ogical fe at u res of BD 1992; 19: 402-10. region of the MICA gene: A strong associa- ( 1 5 ) , we recommend and administer 5. MADANAT W, FAYYAD F, ZUREIKAT H:Juve- tion of six GCT repetitions with Behçet’s dis- corticosteroids in all cases of DVT, as- nile Behçet’s disease in Jordan. In OLIVIERI I, e a s e. P roc Natl Acad Sci USA 1997; 94: sociated with immunosuppressive ther- SALVARANI C,CANTINI F (Eds.). 8th Interna - 1298-303. tional Congress on Behçet’s disease. Program 14. MADER R, ZIV M, ADAWI M , et al.:Throm- apy in cases with vena cava or cerebral and Abstracts. Milano: Prex, 1998: 178. bophilic factors and their relation to thrombo- venous involvement. 6. BANG D,YOON KH, CHUNG HG, CHOI EH, embolic and other clinical manifestations in According to our results and to previ- LEE ES, LEE S: Epidemiological and clinical B e h ç e t ’s disease. J Rheumatol 1999; 26: o u s ly rep o rted inve s t i gations (2,4,7), features of Behçet’s disease in Korea. Yonsei 2404-8. Med J 1997; 38: 428-36. 15. LEHNER T: Immunopathogenesis of Behçet’s we can conclude that DVT occurs more 7. BAYR A K TA R Y, BALKANCI F, BAYR A K TA R disease. Ann Med Interne 1999; 150: 483-7.

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