Major Vessel Involvement in Behçet's Disease: An Update
Pulmonary artery aneurysms (PAA) are the most common pulmonary lesion in Behçet's disease and are the most lethal complication of the disease. The most common presenting symptom is hemoptysis. PAA almost exclusively affects men and has a strong association with the vasculo-Behcet phenotype. Patients usually have deep venous thrombosis and may have caval or intracardiac thrombus formation and systemic arterial aneurysms.
The inflammatory process in PAA appears to be located primarily in the vasa vasorum. In vessels dependent on this diseased vascular supply, ischemia of the vessel wall occurs with weakening and the formation of true aneurysms, or disruption and hemorrhagic dissection of the layers resulting in the formation of false aneurysms. Thus, it is not uncommon to see true and pseudoaneurysms side by side in Behçet's disease. These lesions erode into bronchi leading to hemoptysis which may be massive and lethal. The development of adventitial fibrosis and thrombus formation may lower the risk of aneurysm rupture. The histopathology of the vessel wall in PAA reveals thrombosis and recanalization with proliferation of small vessels in the vascular wall. Perivascular CD45RO T cells and CD68 monocytes are found and CD20 B cells are seen surrounding the proliferative changes. It is postulated that the formation of an inflammatory thrombus is the primary event in aneurysm formation with weakening of the vascular wall from neovascularization associated inflammatory cells. The strong association of PAA with venous thrombosis at other sites would support this hypothesis.
The co-occurrence of PAA and deep venous thrombosis in isolation is referred to as the Hughes–Stovin syndrome which may be a forme fruste of Behçet's disease. Because PAA is associated with thrombophlebitis and if pulmonary emboli are suspected, anticoagulants may be initiated in these patients resulting in more bleeding and death. Considering the rarity of pulmonary emboli in Behçet's disease, hemoptysis should be viewed with a very high index of suspicion for PAA.
PAA are typically confined to the main pulmonary arteries and their lobar branches. Perihilar or parenchymal nodular opacities occur, are frequently multiple and bilateral and can usually be seen on chest radiograph, but their appearance can be entirely nonspecific. CT scanning has largely replaced angiography as the diagnostic procedure of choice. A retrospective survey of CT scans showed that PAA are frequently accompanied with peripheral parenchymal nodules or consolidations, predominantly subpleural, some of them were evolving into cavitary lesions. Parenchymal infiltrates appeared with flare-ups of fever, chest pain, cough, and dyspnea in some patients and subsided with increasing dose of corticosteroids and other immunosuppressives. Figure 3 is an example of pulmonary artery aneurysms on CT scanning.
(Enlarge Image)
Figure 3.
Pulmonary artery aneurysms on computed tomography scan in a patient with Behçets disease
The 1-year mortality associated with PAA has been reported to be 50% in a cohort of patients from Istanbul diagnosed before 1992. PAA were found to be the major contributing factor to the overall mortality of Behçet's disease. In the most recent report from Istanbul on 26 cases with PAA diagnosed after 1992, a much more favorable survival rate of 80% at 5 years was found, mainly due to earlier recognition and rapid, aggressive and prolonged treatment.
Pulmonary vasculitis in Behçet's disease may also result in thrombosis, stenosis or occlusion of lung vessels, but clots found in the lungs result from in-situ thrombosis rather than emboli. Other pulmonary problems seen in Behçet's disease patients, including pleural effusion and chylous pleural effusions, are the result of vascular complications. In a recently presented study mild elevations in pulmonary arterial pressure were found in Behçet's disease patients with PAA. This was associated with an impaired exercise tolerance, decreased diffusing capacity and high pro-BNP levels, suggesting that small vessels of the lung might also be diseased in these patients.
Emergency surgery for ruptured pulmonary aneurysms has a very high mortality rate and should be avoided unless hemorrhage is life threatening. Endovascular embolization techniques have been used successfully to thrombose bleeding PAA, but aneurysm size or vena cava thrombosis may limit the use of this technique in some patients. The Amplatzer duct occluder device has been used successfully to treat large aneurysms.
All attempts should be made to treat PAA with aggressive medical therapy. The current protocol used by an Istanbul (Cerrahpaşa) group includes three 1 g pulses of methylprednisolone followed by prednisolone 1 mg/kg/day, tapered over 2–5 months and discontinued thereafter if possible. Intravenous cyclophosphamide, 1 g, is given monthly for the first year and then every other month for the second year. Following this maintenance treatment with azathioprine, 2.5 mg/kg/day may be employed. Recurrent hemoptysis is treated according to the initial protocol. Not all patients respond to cyclophosphamide and some patients have developed PAA while taking cyclophosphamide for other indications. Two cases of successful treatment of PAA, failing treatment with immunosuppressive agents, with anti-TNF agents have been published. A single patient with resistant PAA treated with hematopoietic stem cell transplantation was reported to be a complete responder.
Pulmonary Arterial Vasculitis
Pulmonary artery aneurysms (PAA) are the most common pulmonary lesion in Behçet's disease and are the most lethal complication of the disease. The most common presenting symptom is hemoptysis. PAA almost exclusively affects men and has a strong association with the vasculo-Behcet phenotype. Patients usually have deep venous thrombosis and may have caval or intracardiac thrombus formation and systemic arterial aneurysms.
The inflammatory process in PAA appears to be located primarily in the vasa vasorum. In vessels dependent on this diseased vascular supply, ischemia of the vessel wall occurs with weakening and the formation of true aneurysms, or disruption and hemorrhagic dissection of the layers resulting in the formation of false aneurysms. Thus, it is not uncommon to see true and pseudoaneurysms side by side in Behçet's disease. These lesions erode into bronchi leading to hemoptysis which may be massive and lethal. The development of adventitial fibrosis and thrombus formation may lower the risk of aneurysm rupture. The histopathology of the vessel wall in PAA reveals thrombosis and recanalization with proliferation of small vessels in the vascular wall. Perivascular CD45RO T cells and CD68 monocytes are found and CD20 B cells are seen surrounding the proliferative changes. It is postulated that the formation of an inflammatory thrombus is the primary event in aneurysm formation with weakening of the vascular wall from neovascularization associated inflammatory cells. The strong association of PAA with venous thrombosis at other sites would support this hypothesis.
The co-occurrence of PAA and deep venous thrombosis in isolation is referred to as the Hughes–Stovin syndrome which may be a forme fruste of Behçet's disease. Because PAA is associated with thrombophlebitis and if pulmonary emboli are suspected, anticoagulants may be initiated in these patients resulting in more bleeding and death. Considering the rarity of pulmonary emboli in Behçet's disease, hemoptysis should be viewed with a very high index of suspicion for PAA.
PAA are typically confined to the main pulmonary arteries and their lobar branches. Perihilar or parenchymal nodular opacities occur, are frequently multiple and bilateral and can usually be seen on chest radiograph, but their appearance can be entirely nonspecific. CT scanning has largely replaced angiography as the diagnostic procedure of choice. A retrospective survey of CT scans showed that PAA are frequently accompanied with peripheral parenchymal nodules or consolidations, predominantly subpleural, some of them were evolving into cavitary lesions. Parenchymal infiltrates appeared with flare-ups of fever, chest pain, cough, and dyspnea in some patients and subsided with increasing dose of corticosteroids and other immunosuppressives. Figure 3 is an example of pulmonary artery aneurysms on CT scanning.
(Enlarge Image)
Figure 3.
Pulmonary artery aneurysms on computed tomography scan in a patient with Behçets disease
The 1-year mortality associated with PAA has been reported to be 50% in a cohort of patients from Istanbul diagnosed before 1992. PAA were found to be the major contributing factor to the overall mortality of Behçet's disease. In the most recent report from Istanbul on 26 cases with PAA diagnosed after 1992, a much more favorable survival rate of 80% at 5 years was found, mainly due to earlier recognition and rapid, aggressive and prolonged treatment.
Pulmonary vasculitis in Behçet's disease may also result in thrombosis, stenosis or occlusion of lung vessels, but clots found in the lungs result from in-situ thrombosis rather than emboli. Other pulmonary problems seen in Behçet's disease patients, including pleural effusion and chylous pleural effusions, are the result of vascular complications. In a recently presented study mild elevations in pulmonary arterial pressure were found in Behçet's disease patients with PAA. This was associated with an impaired exercise tolerance, decreased diffusing capacity and high pro-BNP levels, suggesting that small vessels of the lung might also be diseased in these patients.
Therapeutic Considerations
Emergency surgery for ruptured pulmonary aneurysms has a very high mortality rate and should be avoided unless hemorrhage is life threatening. Endovascular embolization techniques have been used successfully to thrombose bleeding PAA, but aneurysm size or vena cava thrombosis may limit the use of this technique in some patients. The Amplatzer duct occluder device has been used successfully to treat large aneurysms.
All attempts should be made to treat PAA with aggressive medical therapy. The current protocol used by an Istanbul (Cerrahpaşa) group includes three 1 g pulses of methylprednisolone followed by prednisolone 1 mg/kg/day, tapered over 2–5 months and discontinued thereafter if possible. Intravenous cyclophosphamide, 1 g, is given monthly for the first year and then every other month for the second year. Following this maintenance treatment with azathioprine, 2.5 mg/kg/day may be employed. Recurrent hemoptysis is treated according to the initial protocol. Not all patients respond to cyclophosphamide and some patients have developed PAA while taking cyclophosphamide for other indications. Two cases of successful treatment of PAA, failing treatment with immunosuppressive agents, with anti-TNF agents have been published. A single patient with resistant PAA treated with hematopoietic stem cell transplantation was reported to be a complete responder.