Extended venous thrombosis in Adamantiades‐Behçet’s disease

ARTICLE

Auteur(s) : Christos C. ZOUBOULIS

Department of Dermatology Charité University Medicine Berlin Campus Benjamin Franklin Fabeckstrasse 60-62 14195 Berlin, Germany

Article accepted on 16/02/2004

A 27-year-old Moroccan male patient was admitted to our Medical Center with increasing lumbar pain during movement, thigh muscle weakness and swelling of the knee and the ankle joints. He reported two episodes of orchitis 14 and 2 months previously, recurrent oral aphthous ulcers and mild arthritis of both knee and ankle joints, the lumbar spine and the right sternoclavicular joint since 13 months, recurrent iridocyclitis since 10 months and occasionally skin pustules. He received antibiotics during the orchitis episodes. Until 3 months ago he had been under oral prednisolone over 8 months (0.15 mg/kg/d, body weight 75 kg) which improved the ocular and articular symptoms.
The general clinical examination revealed aphthous lesions of the oral mucosa, swelling of the legs, indurations of the thighs and pain at pressure at the inguinal and plantar areas and the sural muscles. The ocular examination detected avascular peripheral areas at the left eye fundus and glass body opacities.
The laboratory examinations revealed pathologic values for c-reactive protein (CRP) 61.4 mg/l (normal value < 6; 15 days previously the value had been normal), blood sedimentation rate (BSG) 82 mmHg 1^st h/90 mmHg 2^nd h (3 months previously 20/40), leucocytes 14/nl (4-10), while antinuclear antibodies and rheumatic factor were not detected. The HLA phenotype was A23(9), A11, B51(5), B45(12), Bw4, Bw6, Cw2, Cw6. Ultrasound examination and CT scan of the abdomen and the legs revealed new thrombotic areas combined with a partially old thrombosis of both vena femoralaes, vena iliaca externa, vena iliaca communis and the vena cava inferior up to the level of the kidney veins (Fig. 1). The diameter of the thrombotic vessel lumen was partially doubled. X-Ray examinations of the thorax and the lumbar spine and bone scintigraphy were normal. In spite of high-dose anticoagulation therapy (heparin 1500 IU/h i.v.) the patient developed two lung arterial embolism episodes in the next 3 days..

Diagnosis: Adamantiades-Behçet’s disease of systemic type

Recurrent occurrence of aphthous ulcers, iridocyclitis and skin pustules fulfil the criteria required for diagnosis of Adamantiades-Behçet’s disease [1]. The diagnosis was corroborated by the detection of a positive pathergy test. Although not contributing to the diagnosis, recurrent arthritis, orchitis and thrombosis are common signs of the disease. Male gender, Arabic origin and presence of HLA-B51 [5] were prognostic factors for systemic involvement with potentially severe prognosis [2, 3].

Treatment and course

Prednisolone 2 mg/kg body weight and chlorambucil 0.1 mg/kg body weight p.o. were introduced. Surgical measurements were avoided because of the positive pathergy reaction and lysis was not indicated because of the partially old thrombosis. A subsequently developed pneumonia was treated with i.v. antibiotics. Oral anticoagulation with phenprocoumon and bone mineralization prophylaxis with calcium were subsequently administered.

Due to the clinical stability and the continuous CRP and BSG reduction to normal levels one month later (< 6 mg/l and 21/34, respectively), treatment was tapered to chlorambucil 0.05 mg/kg body weight, prednisolone 0.4 mg/kg body weight p.o., further to 0.15 mg/kg body weight at 2 months and to 0.1 mg/kg body weight at 8 months (CRP < 6, BSG 18/30). Recanalization of the vessels was observed at the latter time point. At 15 months treatment was switched to interferon α-2a (9 × 10⁶ IU s.c. 3 × /week) monotherapy, tapered to 6 × 10⁶ IU s.c. 3 × /week at 30 months and switched further to pegylated interferon α-2b (50 µg s.c. 1 × /week) at 36 months (CRP < 6, BSG 5/12).

During the first 52-month follow-up period single oral aphthous ulcers were only occasionally observed. Eye lesions were absent and the vascular changes were continuously improved. At that point, treatment was discontinued by a general practitioner, who attributed the development of eczematous lesions on the lower extremities to interferon-α (Fig. 2). Two weeks later, recurrent erythema nodosum-like lesions and skin pustules occurred on the lower extremities. Four months after discontinuation of treatment the patient presented to our Department with disseminated, painful, partially ulcerated lesions of nodular vasculitis and swelling of the legs. After excluding a new thrombosis, prednisolone 1 mg/kg body weight was administered with marked improvement in 48 hours. Subsequently, treatment with interferon α-2a (3 × 10⁶ IU s.c. 3 × /week) was re-initiated..

Venous thrombosis in Adamantiades-Behçet’s disease

Adamantiades-Behçet’s disease is a multisystemic, inflammatory disorder with a chronic recurrent course, characterised by the classical clinical triad of recurrent oral aphthous ulcers, genital ulcers and iritis/uveitis [1, 4]. The disease occurs worldwide with endemic prevalence in the Eastern Mediterranean area and in Central and East Asia [3]. The aetiopathogenesis of the disease remains unknown; whereas genetic factors, infectious agents, environmental pollution, immunological mechanisms, endothelial and clothing factors have been implicated and studied intensively [5]. The major involvement of certain ethnic groups and the wide variation of the prevalence of the disease in the same ethnic group in association to the geographic area of residence indicate environmental triggering of a genetically determined disorder. Several sets of clinical diagnostic criteria have been presented, whereas the criteria of the International Study Group for Behçet’s disease are mostly used [1].
The disease may affect small and large vessels in almost all organs [6, 7]. Several authors pointed out a vascular reaction or vasculitis in the framework of the illness [8, 9]. Systemic involvement can be severe and can lead to a lethal outcome [10]. Vein thrombosis is a key feature and represents the most frequent vascular manifestation of the disease (up to 35% of systemic vascular lesions) [11-13]. Arterial involvement is rare and usually appears in the form of aneurysms (65%) and thromboses (35%) as a consequence of multicentric arteriitis [7, 14]. Already in the year 1946, Benediktos Adamantiades accorded the so-called “thrombophlebitis” a special contribution [15] and later, in 1953, he included it in his diagnostic criteria as the fourth cardinal sign of the disease [16]. Lately, the inclusion of vessel manifestation to the diagnostic criteria of Adamantiades-Behçet’s disease has again been matter of discussion [17]. Superficial or deep veins of any size can be involved in a recurrent migratory manner. Spontaneous manifestation and occurrence after vein puncture or intravenous injections have been observed. While occlusion of the veins of the extremities is relatively frequent, brain, lung and kidney vessels can also be involved [18-20]. Obstruction of the vena cava superior and/or the vena cava inferior is not rare [21]. After occlusion of the hepatic veins, a Budd-Chiari syndrome can develop [22]. Benign intracranial hypertonus (pseudotumor cerebri) occurs after obstruction of the cerebral sinus and manifests clinically with headach, sickness and oedema of the ocular papillae [18]. Development of varicose veins at the thorax and/or the abdominal area as well as in the oesophagus is dependent on the localisation of the occluded veins.
Coagulation disorders have been reported but they cannot explain the different thrombotic manifestations which are probably the consequence of an abnormal response of the vascular endothelial cells [7, 23]. Vasculitic endothelial injury may trigger or enhance the pathological hemostatic process [5, 24]. Increased anticardiolipin antibodies in serum and plasma granulocyte elastase-α 1-proteinase inhibitor complex levels have been shown to be associated with a risk of systemic thrombosis in Adamantiades-Behçet’s disease [2, 25, 26], while data on the significance of homocysteine serum levels are contradictory [27-29].
Conservative treatment is required at the acute phase of thrombosis, since surgical intervention is often associated with re-occlusion or lethal course of the disease [30] (Table I). Anticoagulation as monotherapy is not sufficient, since thrombosis can occur despite anticoagulant treatment [31]. Heparin infusion or fibrinolytics (streptokinase) have to be administered for treatment of acute thrombosis of the large veins. Long-term treatment drugs are coumarin or warfarin. High dose corticosteroids (prednisolone 100-250 mg/d) as intervention therapy in the acute phase combined with immunosuppressive drugs (azathiorine, chlorambucil, cyclophosphamide or cyclosporine A) are additionally required, like in other vasculitides [1]. Interferon-α has been shown to be efficient as long-term treatment [32]. n

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