A case of Hughes–Stovin syndrome (incomplete Behçet’s disease) with extensive arterial involvement

Hughes–Stovin syndrome (HSS) was named after two British physicians, Drs. John Patterson Hughes and Peter George Ingle Stovin. They described the syndrome in two male patients with deep venous thrombosis and segmental pulmonary artery aneurysms in 1959 [1]. The current consensus is that HSS results from a vasculitis similar to that in Behçet’s disease (BD). Several investigators have suggested that HSS is actually a variant of BD rather than a discrete clinical entity [2‐4]. However, the link between HSS and BD remains speculative because the etiologies of both disorders are still uncertain. The association stems from the observation that HSS is occasionally seen as a feature in BD and may even be the presenting manifestation of the syndrome, but HSS lacks the classical triad of BD (oral ulceration, genital ulceration, and eye disease) [2]. In this report we describe a young man with the features of HSS presenting with extensive arterial involvement of the legs as well as extensive venous thrombophlebitis and pulmonary arterial aneurysms with in situ thrombosis.

A 35-year-old male patient presented in our emergency clinic with acute onset of bilateral lower limb pain and features of acute ischemia more evident on the left side with absent pulsations of the dorsalis pedis and popliteal arteries on the left side and absent dorsalis pedis artery pulsation on the right. The patient gave a past history highly suggestive of ischemic claudication of both lower limbs, especially on the left side, and low-grade fever. He also had a history of recurrent thrombophlebitis of the lower limb veins for 1 year. Urgent power Doppler study of both lower limb veins showed marked luminal attenuation of the great saphenous veins bilaterally, with thickened wall and areas of non/partial compressibility denoting underlying phlebitis without active thrombosis or venous occlusion. The patient was admitted to our facility for further assessment and investigations. Initial laboratory investigations showed; ESR first hour 44 mm/h, CRP 4.3 mg/dl, Hgb 11.7 gm/dL, WBC count (8.8), platelet count (197,000), normal values for the factor V Leiden mutation gene, factor II-prothrombin mutation, normal homocysteine level (12.36 mcmol/L; normal range 6.26–15.01 mcmol/L), normal protein C, and normal protein S values. Immunological profile showed negative ANA, no anti-DNA antibodies, negative anti-cardiolipin antibodies (IgG and IgM), negative P‑ANCA, and C‑ANCA. Normal D-dimer levels (1.01 mg/L) and normal procalcitonin levels (0.04 ng/ml) were found. Urgent computed tomography (CT) angiography for the aorta and arterial trees of the lower limbs demonstrated segmental occlusion of the superficial femoral artery with collateral refilling of the popliteal artery. In addition, acute diffuse thrombosis was seen affecting the distal 1/3 of the abdominal aorta and left common iliac artery with refilling of its distal 1/3 via collateral circulation (Fig. 1). Furthermore, the left anterior and posterior tibial arteries were markedly attenuated, denoting occlusive disease along their courses, apart from distal short segmental collateral refilling of the distal left posterior tibial arterial segment with poor distal runoff (Fig. 1). The patient was put on anti-coagulation therapy with sc heparin necessitated by the critical ischemia, and after 1 week developed a cough and mild respiratory distress without concomitant hemoptysis. Pulmonary CT angiography was ordered and revealed filling defects in the left pulmonary lower lobar segmental and sub-segmental arterial branches with associated left lung lower lobe consolidation (Fig. 2) and celiac trunk aneurysmal dilatation shortly after its origin (Fig. 2d). After rheumatological consultation and taking into account the critical ischemia of the left lower limb, the patient underwent urgent vascular intervention in the form of left lower limb angioplasty and aorto-iliac, popliteal, and tibio-peroneal thrombo-embolectomy, and received post-operative anti-coagulation with warfarin. The diagnosis of HSS was made with extensive venous and arterial affection as there were no findings indicating Behçet’s disease (BD). The arterial as well as venous affection and the pulmonary CT angiography showing filling defects represent in situ thrombosis, as there was no deep vein thrombosis (DVT) that might have caused pulmonary thromboembolism. Eye investigation by a specialist excluded uveitis and the patient gave no history of recurrent and/or mouth ulcers.

Shortly after, the patient started with pulse methylprednisolone therapy (1000 mg/day) iv bolus infusion for 3 consecutive days, followed by pulse cyclophosphamide 750 mg/iv bolus infusion over 30 min with ample hydration. Later, the patient was scheduled to receive pulse cyclophosphamide 750 mg on a monthly basis for at least 1 year. Oral prednisolone 40 mg/day was started after the pulse steroid therapy. The patient showed much improvement with no ischemic insults during the 6‑month period of follow-up without any reported new ischemic events and the oral prednisolone dosage could be tapered.

Although the exact etiology and pathogenesis of HSS is unknown, the current consensus is that vasculitis is the primary pathologic process underlying HSS [5]. The population-based incidence of HSS cannot be exactly determined. It usually affects young adults, especially males [6, 7]. Being an extremely rare disease, there are no formally described diagnostic criteria or pathognomonic laboratory investigations for this syndrome.

Generally, HSS is characterized by thrombophlebitis and multiple pulmonary aneurysms associated with in situ thrombosis, as in our case [5, 8]. Thus, if a patient presents with this set of findings and the clinician is able to exclude other causes, the patient has either HSS or BD. However, BD can be ruled out by its classic distinctive features (eye inflammation, recurrent mouth and genital ulceration) which are absent in HSS. This is how HSS was diagnosed in the majority of the case reports in the literature [4].

We performed a PubMed search of the available HSS case reports with typical and atypical vascular manifestations and also case reports where it is discussed whether HSS is an outcome of BD or a separate clinical entity; findings are summarized in Table 1.

Recurrent phlebitis in HSS frequently involves the large vessels, resulting in thromboembolism, with reports of thrombosis of the cardiac chambers, jugular vein, iliac vein, femoral vein, and dural sinuses as previously described in detail by Khalid and Saleem [4]. Various venous thrombotic events occurring during the course of BD have also been described in HSS, e. g., inferior sagittal sinus thrombosis [2], superior sagittal and transverse sinus thrombosis [9], inferior vena cava thrombosis [7], inferior vena cava (IVC) and intra-cardiac mural thrombosis [8], basilic vein thrombosis [5], and IVC and portal vein thrombosis [10].

No previous report described such extensive arterial involvement in HSS as observed in our case. This fits with the finding that pulmonary artery aneurysms in HSS proved to be vasculitis of the pulmonary arteries upon histopathological examination [11]. An important detail that merits consideration here is that the clot in the pulmonary arteries in HSS or BD is mostly due to arterial vasculitis rather than to venous thromboembolism, especially in patients without DVT. Also, the thrombi in the lower extremities are tightly adherent to the inflamed veins with no tendency for propagation in BD and HSS patients [5]. Likewise, in our case, no saphenous vein thrombosis was found, just luminal attenuation on both sides, denoting underlying phlebitis. At the same time, small pulmonary artery aneurysms were seen associated with in situ thrombosis which are not due to pulmonary embolism and/or thromboembolism from the peripheral deep venous system. BD, being a systemic vasculitis, may affect virtually all types and sizes of vessels involving pulmonary arteries, veins, and septal capillaries [12].

It is generally agreed that the treatment of pulmonary vasculitis in HSS and BD follows the same lines, because, at present, these are the only two conditions known to predispose to pulmonary artery aneurysms with underlying pulmonary arterial vasculitis [2, 6]. The new updated EULAR recommendations for the management of Behçet disease advise the use of high-dose glucocorticoids and cyclophosphamide for treatment of pulmonary artery aneurysms, while monoclonal anti-TNF antibodies should be considered in refractory cases. For patients who have or who are at a high risk of major bleeding, embolization should be preferred to open surgery. For the management of acute deep vein thrombosis in BD, glucocorticoids and immunosuppressives such as azathioprine, cyclophosphamide, or cyclosporine-A are recommended. For both aortic and peripheral artery aneurysms, medical treatment with cyclophosphamide and corticosteroids should be applied first, before considering intervention to repair. Surgery or stenting should not be delayed if the patient is symptomatic [13].

In BD patients, pulmonary hemorrhage is one of the main causes of death and prognosis is poor if pulmonary aneurysms are left untreated [2, 6]. But if the patient also has extensive acute arterial ischemia with thrombosis, starting anticoagulation may be necessary, as in our case; this has to be decided in every single case. The issue of anticoagulation in patients with HSS and BD is complex and further studies are needed before definite recommendations can be made, as stressed by the fact that the use of anticoagulants and antifibrinolytic agents in BD is not currently recommended by EULAR [13].