Abstract
Behçet’s disease is a multisystem disorder with unknown etiology and a unique geographic distribution. The disease is characterized by recurrent skin–mucosa lesions and sight-threatening panuveitis. Vascular involvement, which is more common and more severe among males, has also equally characteristic features such as affecting mostly veins, having a significant tendency for thrombosis, and running a relapsing course. Lower extremity vein thrombosis (LEVT) is the most frequent manifestation, followed by vena cava inferior thrombosis. Pulmonary artery involvement (PAI), the most common form of arterial involvement, manifests as aneurysms and “in situ” thrombosis. PAI and Budd–Chiari syndrome are the leading causes of increased mortality. In vascular cluster, typically, several types of venous or arterial vascular involvement may accumulate in the same individual. LEVT or cerebral venous sinus thrombosis is often present in these subgroups as the first event. Immunosuppressive treatment is essential in preventing the attacks and increasing survival.
Introduction
Behçet’s disease (BD) is a multisystem disorder characterized by skin–mucosa lesions . It may also involve the eyes, blood vessels, joints, gastrointestinal system, and central nervous system. It is seen mainly in a distinct geography, extending from the Mediterranean basin and the Middle East to the Far East. Turkey has the highest prevalence rate (up to 42 per 10 4 ) . The etiopathogenesis is unknown. A complex genetic etiology could be responsible because of HLA–B51 (human leukocyte antigen) playing an important role in disease susceptibility, the high sibling recurrence rate, and relatively high monozygotic twin compatibility .
The mean age of onset is usually in the third decade. Both genders are affected equally; however, the disease runs a more severe course among men . The diagnosis is mainly clinical with no specific laboratory tests. The clinical course is characterized by frequent relapses and remissions . Disease burden tends to abate after 5–10 years . BD can cause substantial morbidity such as blindness, physical disability, cognitive impairment, and increased mortality .
Vascular involvement, although not included in the International Study Group (ISG) criteria , has good many characteristic features for BD. Here, these features are described and management options are reviewed.
Vascular involvement
General characteristics and differential diagnosis
BD is unique among other vasculitides as it has the propensity to affect the venous rather than the arterial side. It is also unique in that it has significant thrombotic tendency associated with vascular inflammation, which cannot be explained with thrombophilic factors . In fact, lower extremity vein thrombosis (LEVT) can be considered as its hallmark . Inferior or superior vena cava, hepatic veins, cerebral venous sinuses, and the right side of the heart are other common places of involvement on the venous side . Pulmonary arteries, which resemble venous structures because of thinner walls, less elasticity, and lower pressure, are often involved, while the aorta and peripheral arteries are less commonly diseased . Table 1 shows anatomic places of vascular involvement. Arterial disease is manifested mostly in the form of aneurysms and rarely in the form of thrombotic occlusions . This type of arterial involvement is quite distinct from the homogenous, concentric arterial wall thickness, which is commonly observed in Takayasu arteritis .
| 1. Lower extremity vein thrombosis (LEVT) |
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| 2. Inferior vena cava thrombosis (usually as an extension of LEVT) |
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| 3. Cerebral venous sinus thrombosis |
| 4. Pulmonary artery involvement (aneurysms/in situ thrombosis) |
| 5. Intracardiac thrombosis (mostly right side) |
| 6. Superior vena cava thrombosis |
| 7. Arterial involvement other than pulmonary arteries |
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| 8. Other rare venous or arterial involvement |
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Prevalence
As it is the case with every major organ involvement in BD, vascular involvement is seen mainly among men . The frequency shows a wide range (5–40%) in the published literature . This could be due to (a) the difference between the reference centers (dermatology/internal medicine), (b) inclusion of patients with different disease durations, and (c) ethnic variances (it is quite rare in the Far-East populations) . It is well known that the frequency of vascular involvement increases when an inception cohort is followed up prospectively (increasing from 20% to up to 40% in 20 years) .
Time to occur
The majority of the patients (75%) experience their first vascular event within 5 years of the disease onset. In particular, LEVT and cerebral venous sinus thrombosis (CVST) occur early during the disease course and can be considered as a predictive factor for future vascular involvement at other sites. Similarly, pulmonary artery involvement (PAI), vena cava thrombosis, and Budd–Chiari syndrome develop within a few years of the disease onset. However, non-pulmonary arterial disease occurs at a significantly later age .
It should be noted that in about 20% of the patients, vascular involvement occurs simultaneously with disease onset, and in another 10%, before fulfilling the ISG criteria . In this setting, Hughes–Stovin syndrome, which is known as the presence of pulmonary arterial involvement without the expected classical signs of BD, should be evaluated as BD, as well .
Vascular cluster and correlation of vascular events
BD should be considered a large family comprising different clinical subsets . Skin–mucosa lesions are found in almost all patients. These subsets can be described as (a) solo skin–mucosa involvement with no major organ involvement, (b) eye disease, (c) vascular disease, (d) seronegative spondyloarthropathy-like disease (enthesopathy and folliculitis), and (e) parenchymal neurological disease . The demographic characteristics, clinical outcome, and medical treatment may be different in these subsets. This leads us to think that different pathological pathways play a role in the pathogenesis of BD.
In the vascular disease subset, several types of vascular involvement may accumulate in the same individual . Significant correlations exist between CVST and PAI , intracardiac thrombosis and PAI , BCS, and inferior vena cava syndrome . It should be recalled that LEVT is often present in these associations and even precede them. Fig. 1 shows these associations in a theoretical scheme.
Etiopathogenesis
Fibrous thickening in all layers of the vessel wall and focal aneurysmal dilatation can be found often in the pathologic specimens of arterial disease . There is a thick thrombus formation that overlays aneurysms. Medial elastic fibers are interrupted and there is lymphocytic infiltration around the vaso vasorum. The pathology of venous disease consists of inflammatory thrombi formation that is typically adherent to the inflamed vessel wall. The vessel wall is thickened by the inflammation and frequently totally or partially occluded by the organized and “tissue”-like thrombus. This is not complicated by thromboembolism. Typical elements of vasculitis are scarce or absent. There is significant thrombotic tendency that could be triggered even by intravenous needle or cannula insertion . The pathogenesis of thrombosis in BD is unknown, and the underlying mechanisms are unclear; however, it is thought that it is largely due to endothelial damage and dysfunction rather than due to hypercoagulability . Prothrombotic factors, along with common prothrombotic polymorphisms, have been studied . The list includes factor V Leiden, factor VIIa, factor VIII, factor XII, anti-cardiolipins, homocysteine, tissue plasminogen activator, thrombomodulin, plasminogen activator inhibitor-1, von Willebrand factor, thrombin–antithrombin complex, prothrombin fragments, and lipoprotein (a). However, the data collected thus far have been conflicting.
Disease course and outcome
Vascular involvement is frequently associated with fever, high acute phase response, and constitutional symptoms ; usually, these could be accompanied by organ specific symptoms. As a rule, it has a relapsing course . In a prospective study, the cumulative relapse rate of LEVT was found to be about 20% in the first year and about 40% at 2 years . Relapses may occur everywhere; however, they occur more often on the same segment or on the continuous segment . Furthermore, vascular involvement causes severe morbidity and increased mortality . Additionally, even among patients with solo LEVT due to venous stasis, ulcers on the legs and claudication, important socioeconomical problems associated with unemployment may occur . Cost of illness also increases .
Types of involvement and associated clinical manifestations
LEVT
It is the most common type of vascular involvement in BD, forming 70% of all vascular events . The affected veins in the descending order of frequency are femoral (superficial, deep, and common), popliteal, saphenous (magna and parva), and crural veins .
Acute superficial LEVT is manifested as red nodular lesions that may mimic erythema nodosum, which is in fact a septal panniculitis found mostly in females and less commonly associated with large vessel involvement . At close inspection, superficial LEVT lesions are seen as string-like lesions following vein tracts. Acute deep LEVT, on the other hand, manifests with swelling, pain, and claudication. Chronic LEVT symptoms and signs include pain, edema, itching, leg hair fall, varicose vein formation, hyperpigmentation, induration, and ulceration . Fig. 2 shows a BD patient with chronic LEVT.
As shown in Table 2 , clinical and radiological characteristics of LEVT are different in BD than those observed in LEVT due to other causes. BD patients are more likely to be young males . Additionally, the most discriminative feature is that in BD, there are significantly more relapses that result in less complete recanalization, more collaterals, and more bilateral involvement . Consequently, this leads to a more severe disease course: severe post-thrombotic syndrome (PTS) is observed in about half and venous claudication is observed in one-third of patients . A recent study among patients with LEVT revealed that about 20% suffer from leg pain while walking on the treadmill set at a slow pace after a median of 190-m distance and 10% have to stop the test after a median of 263 m due to claudication .
| Patients with BD are more likely to be male and more likely to be younger. |
| There are significantly more relapses, less complete recanalization, more collateral formation, and more bilateral involvement. |
| Both superficial and deep veins are involved. |
| Post-thrombotic syndrome and venous claudication are considerably more frequent. |
Vascular inflammation is diffuse, involving continuous segments of the vessel wall. It is almost complicated by superimposed thrombus . Doppler ultrasonography can be helpful in differentiating acute from chronic LEVT . MRI (Magnetic resonance imaging) could be promising in evaluating vein wall thickness in the future; however, currently the method needs to be improved . We used positron emission tomography (PET)/computed tomography (CT) to detect acute and chronic forms of LEVT; however, it was observed that this technique is not an effective tool for venous involvement .
Vena cava inferior (VCI) thrombosis
VCI is divided into three anatomical parts: infrahepatic, hepatic, and suprahepatic. While all the three parts can be involved, the infrahepatic part is the most commonly involved, because of the extension of the LEVT. In BD, bilateral common femoral vein thrombosis carries 50% risk for iliac vein thrombosis and about 20% risk for VCI thrombosis . Hepatic and suprahepatic VCI thrombosis cause Budd–Chiari syndrome (BCS) , which will be discussed later.
Patients may suffer from lower back or abdominal pain during the acute presentation. Appearance of abdominal collateral veins is the hallmark. Additionally, swelling of lower extremities and rarely swelling of scrotum can be seen. Unless Budd–Chiari syndrome is present in a patient with previous history of relapsing LEVT, VCI thrombosis often develops insidiously.
Budd–Chiari syndrome
Although BD accounts for the single most frequent cause of Budd–Chiari syndrome in an endemic country such as Turkey , Budd–Chiari syndrome is a rare complication in BD with a frequency of <5% among patients with vascular involvement. The syndrome is generally defined as hepatic venous outflow obstruction at any level from the small hepatic veins to the atrio-caval junction. In BD, VCI (hepatic and or suprahepatic parts) involvement is essential; this can be isolated or accompanied by one or more hepatic veins . LEVT, iliac vein thrombosis, and infrahepatic VCI thrombosis are often concomitantly present. Certain demographic and clinical characteristics are useful to differentiate BCS due to BS (Behçet’s syndrome) from BCS associated with other causes ( Table 3 ). These include younger age, male predominance, and occlusion of the IVC rather than the hepatic veins.
| Patients with BD are more likely to be male and more likely to be younger. |
| Occlusion of the inferior vena cava is seen more frequently rather than the isolated occlusion of the hepatic veins. |
| There are silent patients in whom Budd–Chiari syndrome develops insidiously. |
| Portal vein thrombosis is rare. |
| There is a better response to immunosuppressives with or without anticoagulation compared with anticoagulation alone. |
| Vascular interventions are unsuccessful. |
In a recent survey, we observed that the patients had two different clinical presentations .
Symptomatic presentation
Patients present with abdominal pain, ascites, collaterals on the abdominal wall, edema on the scrotum, and diffuse swelling in the lower extremities. If there is a diffuse thrombosis causing complete occlusion, signs of hepatic failure such as jaundice, encephalopathy, splenomegaly, hypersplenism, and bleeding from esophageal varices can be observed. In those patients who present with ascites, the clinical outcome is severe . The mortality rate is expected to be 60% within a median of 10 months after the diagnosis . Hepatic failure leading to encephalopathy or coma is the major cause of death. In our recent survey, we found that after a median of 8 years of follow-up, those who survived had prominent veno-venous collaterals, caudate lobe hypertrophy, and splenomegaly .
Silent presentation
Moreover, there are patients with BD in whom Budd–Chiari syndrome may develop insidiously, without ascites or any other symptoms associated with liver failure. These “silent” cases are usually found during the chronic phase with efficient collateral formation. Although we do not know the true prevalence rate of these cases, a recent survey revealed that they constitute one-fourth of the cohort eventually followed for Budd–Chiari syndrome . These patients are diagnosed while screening for the presence of vascular involvement elsewhere in the body. The fact that the majority is diagnosed after 2000 suggests that this subgroup was recognized after the recent availability of the more advanced imaging techniques. Patients with silent presentation have significantly more favorable outcome with less than 10% expected mortality.
Vena cava superior (VCS) thrombosis
VCS thrombosis is considerably less seen than VCI thrombosis. Patients present with dyspnea and swelling on the face, neck, and/or upper extremities, along with prominent jugular veins. During the chronic phase, once the edema has decreased, dyspnea on exertion may still persist and head and neck fullness may be exacerbated by bending forward or lying down. VCS thrombosis is less commonly associated with LEVT and usually has a benign course, and we think that the relapsing course is rare . It might rarely be complicated with recurrent hemoptysis, pleural effusion, chylothorax, and sleep apnea disorder . Fig. 3 shows neck, thoracic, and abdominal collaterals in a patient with long-standing VCS thrombosis.
Cerebral venous sinus thrombosis (CVST)
CVST occurs relatively at a younger age, usually very shortly after the onset of the disease, in contrast to parenchymal neurological involvement that occurs in a late stage . It is common among children . In some cases, CVST may even develop before the onset of ISG fulfillment. It is strongly associated with vascular involvement elsewhere in the body and most of the time precedes its development. Therefore, similar to LEVT, it can be considered as a predictor for further vascular involvement. On the other hand, it rarely coexists with parenchymal CNS disease. Similarly, venous infarction occurs infrequently. Nevertheless, pyramidal signs, hemiparesis, behavioral changes, and seizures are reported.
In the light of these findings (early onset, strong vascular association, and less frequent association with parenchymal CNS disease), CVST may be considered as a typical vascular involvement rather than a neurological involvement.
CVST presents usually with symptoms of increased intracranial pressure such as severe and persistent headache, nausea, vomiting, diplopia, and fever . Ophthalmic examination shows papilloedema. Apart from the rare presence of third or sixth nerve palsy, neurological examination is normal. Neurosensorial hearing deficit may occur in some patients. Cerebrospinal fluid examination reveals no specific findings; however, high pressure may be found. Relapsing course is quite rare; however, visual acuity or field may be impaired and optic atrophy may develop . Caution is required when following up patients in whom cerebrospinal fluid pressure is persistently elevated.
Superior sagittal and transverse sinuses are affected most of the time. When compared to CVST due to other causes, CVST due to BD occurs mostly among young males, presents often with a subacute clinical onset, and manifests less often with focal deficits and seizures ( Table 4 ). Additionally, venous infarcts are rarely observed.
| Patients are mostly young males. |
| There is often a subacute clinical onset. |
| Manifests less often with focal deficits and seizures. |
| Venous infarcts are rarely observed. |
Pulmonary artery Involvement (PAI)
PAI is uncommon with a prevalence rate of less than 5%; however, it is the most common form of arterial involvement. Pulmonary artery aneurysms (PAA), with its quite characteristic massive hemoptysis, bilateral hilar opacities on imaging, and significant mortality are rather well known ( Fig. 4 ). We have obtained more information about PAI in recent years . These are listed below:
- a)
Although the disease still has male predominance, the number of women with PAI has increased .
- b)
PAA are not the only form of PAI. Solo “in situ” pulmonary artery thrombosis (PAT) is another form that is observed in about one-third of the patients ( Fig. 5 ) . Indeed, with the advancing imaging techniques, the frequency of PAT seems to increase more.
Fig. 5
MRI scan shows pulmonary artery thrombosis on the descending branch of the right pulmonary artery in a patient with BD (arrow).
- c)
A wide range of pulmonary parenchymal lesions such as nodules, consolidations, and cavities are shown to be part of this involvement as well .
- d)
Arterial lesions could disappear successfully with only immunosuppressives in up to 70% patients; nevertheless, the mortality rate is still 25% .
- e)
Mild pulmonary artery hypertension can be seen among patients with PAI .
- f)
Bronchial arterial collaterals emerge as another cause of hemoptysis in patients with remission .
PAI occurs early during the disease course and develops in about 80% of the cases at the same time or a mean 2–3 years after LEVT. Apart from LEVT, it is also strongly associated with CVST and intracardiac thrombosis. With these features, PAI differs from extra-pulmonary artery disease that has a later age of onset and a less strong association with venous disease . Anatomically, the right side of the heart and pulmonary arteries seem to be continuum of the vena cava. Moreover, the characteristic patho-physiology of pulmonary arteries (thin walls, less elasticity, and lower pressure) places these vascular structures somewhere between veins and peripheral arteries. All these justify why pulmonary arteries are the favorite arterial sites of involvement in BD.
In recent surveys, we and other researchers have observed that about one-third of the patients with PAI present with isolated PAT , while the remaining patients present with PAA with or without PAT. “In situ” PAT has a clinical and prognostic picture similar to that of PAA . Hemoptysis is less likely to be abundant in PAT; additionally, other non-specific chest symptoms along with fever and high acute phase response are similar in both conditions. Moreover, anatomic features of PAA and PAT do also resemble: both are bilateral and affect mostly branches of the lower lobes.
Aneurysms or thrombosis are not the sole lesions found in the imaging studies. Ground glass lesions, nodulary infiltrations, consolidations, cavities, mediastinal LAP, pleural and pericardial effusions, and intracardiac filling defects are often observed as well ( Figs. 6–8 ). It might be argued whether they are due to infection; however, certain evidences contradict this argument: (a) Subpleural nodules and consolidations are more commonly found during the flares or at the onset of the disease; they disappear or decrease in number once the inflammation is controlled. (b) They are located mostly on the inferior lobes, similar to arterial lesions. Cavities develop during the follow-up, supposedly from necrosis or infarction areas. A recent study showed that these lesions are rarely observed in BD patients with no PAI, suggesting that they are quite specific for PAI. Histopathological examinations of the nodular infiltrations disclose bronchiolitis obliterans organizing pneumonia, granuloma, or infarction .
Imaging of patients with PAI should be performed with CT or MRI. Chest radiographies alone miss many lesions. PET/CT seems to be not useful in detecting vascular disease .
Aneurysms or thrombosis may disappear or regress in about 70% of the cases with only immunosuppressives . Relapse rate was found to be around 20% . Mortality rate is about 25% at 7 years, despite tight controls, frequent visits, and aggressive medical management. Increased diameter of the aneurysms and high pulmonary artery pressures at presentation are bad prognostic factors for the survival. Some suggest that patients with in situ PAT have a favorable outcome . In our recent survey, we found no difference in the mortality rates between the two forms of PAI . It is also interesting that about half of the patients who survive remain symptom free, while the remaining patients complain of infrequent small bouts of hemoptysis with or without dyspnea on mild exertion. A very recent study revealed that hemoptysis, observed during the follow-up after the remission of arterial disease, is due to bronchial arterial collaterals . Arterial embolization of these collaterals could be attempted albeit with some complications .
Pulmonary artery hypertension
In a retrospective outcome survey, we showed that high systolic pulmonary artery pressure (sPAP) levels at initial presentation were associated with mortality among patients with PAI (20). Mildly elevated levels of sPAP were found in the remaining patients, which remained stable during the follow-up . Furthermore, in a cross-sectional study we measured sPAP levels by echocardiography and found that BD patients with PAI had normal or mildly elevated sPAP levels (ranging between 35 and 45 mmHg) when compared to patients with scleroderma . Additionally, they were found to have somewhat low DLco levels and mildly elevated prohormone of brain natriuretic peptide levels. We concluded that mild degrees of PAH, which was clinically less symptomatic compared to that in scleroderma patients, could develop in BD, especially when pulmonary arteries are involved.
Cardiac involvement
Cardiac involvement is rare in BD. It may manifest as intracardiac thrombosis, pericarditis, myocarditis, endocarditis with valvular regurgitation, endomyocardial fibrosis, coronary arteritis, and sinus of Valsalva aneurysms .
- i.
Intracardiac thrombosis is the most common form of cardiac involvement . It is strongly associated with PAI such that, when detected, it also becomes mandatory to evaluate pulmonary arteries with thorax CT. Because of this strong association, clinical presentation is quite similar to that observed in PAI. Fever, dyspnea, and chest pain are common. Usually, it does not cause pulmonary artery hypertension or heart failure. Organizing thrombus containing inflammatory cell infiltrates is mostly located on the right side of the heart, probably because of the vena cava extension. It is reported to be tightly adhered to the underlying endocardium or myocardium . The myocardium underlying the attachment of the intracardiac mass is also infiltrated by lymphocytes and other inflammatory cells. Its response to immunosuppressive agents is favorable. Relapses are infrequent. Its prognosis is quite similar to PAI as well. It may disappear or turn into a fibrotic band during the disease course with only medical treatment. It may sometimes leave a calcified scar on the endocardium. If there is no severe complication such as valve insufficiency or pulmonary hypertension, surgery is not advised.
- ii.
Coronary artery lesions manifest usually as aneurysms with or without cardiac ischemia . Typically, patients are young and lesions are proximal.
- iii.
Valvular insufficiency: In the majority of patients, the aortic valve is involved, followed by the mitral and tricuspid valve . Patients may present with heart failure then are diagnosed with BD. The aortic root is also involved with aortic valvulitis. Histopathological examination shows inflammation at various stages, with microabscess formation and fibrinous degeneration. Rarely, the valve could be thickened and replaced by fibrosis . Emboli from these lesions are uncommon because of their tight attachments to the endocardium or myocardium. Surgery along with immunosuppressives could be helpful in the management of this type of involvement. Postoperative complications include leakage and relapses, which in turn may require reoperations.
Peripheral arterial involvement
This is a late event, developing after a mean of 5–10 years of the disease onset . Its frequency is less than 5%. Male dominance is more pronounced when compared to PAI. A great majority presents with aneurysms rather than thrombotic occlusions . Commonly affected arterial sites are the infrarenal abdominal aorta and iliac, femoral, popliteal, and carotid arteries. Clinical signs depend on the affected arterial site. Pulsatile and/or painful mass are the clinical signs and symptoms. Lower extremity aneurysms may present with leg pain and claudication and rarely with digital ulcers. CT or MRI are used to visualize vascular lesions in detail. PET/CT could be also helpful.
There are certain characteristic differences when compared to atherosclerotic aneurysms. These are listed in Table 5 . The most important observation is that there is usually a dense fibrotic and lymphatic tissue surrounding the aneurysm. Saccular pseudoaneurysms are mainly seen. Histopathological examination shows infiltration of inflammatory cells, especially around the vasa vasorum, disruption of internal elastic membrane, and loss of elastic and muscle fibers in the media, in the active stages . Dense periadventitial fibrosis and intimal fibrosis along with organized thrombi are observed in the chronic stages . Typically, giant cells and granuloma formation are not seen; however, rarely atherosclerotic changes can be concomitantly present.
| Peripheral diameters of the abdominal aorta are within the normal range. |
| There are significant amount of inflammatory fibrotic tissue and enlarged lymph nodes surrounding the aneurysm. |
| Adjacent veins might be thrombosed. |
| Aneurysm formation is usually painful and therefore can be detected easily. |
| Some aneurysms that are totally thrombosed or calcified are followed up without surgical intervention. |
| Recurrences from the bypasses are frequent. |
| Occlusions of the grafts and ligations are well tolerated due to the rich collateral network. |
The mortality rate in these patients decreased significantly from 17% to 5% when compared to that observed before 1997 . The relapse rate from the anastomotic site or previously uninvolved sites is around 20%. Immunosuppressive treatment before and after surgical intervention has been shown to reduce the relapse rate. Graft occlusion rate despite immunosuppressive treatment however is around 40%. This complication is interestingly well tolerated presumably due to the rich collateral formation.
Management of vascular disease
Immunosuppressive treatment is essential . It has been shown to reduce the relapse rate and to prolong survival in several retrospective studies . The addition of anticoagulation has been shown to have no additional efficacy .
Medical treatment
Life-threatening conditions such as PAI, Budd–Chiari syndrome, and peripheral arterial aneurysms/occlusions are managed with aggressive medical treatment, including cyclophosphamide and glucocorticoid pulses. Other types of venous thrombosis are treated usually with azathioprine with or without short-term glucocorticoids or interferon alpha .
The current protocol of aggressive treatment used by our group includes three 1-g pulses of methylprednisolone followed by prednisolone 1 mg/kg/day, tapered and if possible stopped over 6 months. Intravenous cyclophosphamide, 1 g, is given monthly for 6 or 12 months; then if remission is maintained, it is switched to azathioprine, 2.5 mg/kg/day. In resistant cases, anti-TNF agents could be also used effectively.
Anticoagulation
The treatment of vascular disease in BD requires unquestionably immunosuppressive agents with or without glucocorticoids. Whether to add anticoagulants to prevent relapses has been an issue of debate for a long time . Several retrospective studies showed the inefficacy of the anticoagulation alone in preventing recurrences and no thrombophilia has been demonstrated . In addition, because of the sticky hard nature of thrombi, we believe that the risk for emboli is small and that true pulmonary thromboembolism is extremely rare in BS. Rather, pulmonary thromboemboli is formed “in situ” as a complication to the underlying extensive vasculitis. Nevertheless, therapeutic approach in thrombosis in BD differs significantly between rheumatologists . Our general approach is to not anticoagulate BD patients with venous thrombosis; instead, treating these patients with immunosuppressive agents alone. Furthermore, our experience with fibrinolytic therapy has also been unsuccessful . Surgery of venous thrombosis leads to many complications; therefore, it is not suggested.
Vascular interventions and surgeries
PAI
Endovascular embolization can be useful in medical treatment refractory cases. This method is unsuccessful in ruptured or giant aneurysms and may cause several complications . Surgical resection without immunosuppressive initiation is also not successful as often aneurysms are multiple and located at different parts of the lungs. Lobectomies, however, could be an alternative in the management of giant aneurysms in selective cases . Endarterectomy, on the other hand, does not seem to be a feasible choice, because of the vasculitis involving all three layers of the vessel wall.
Peripheral arterial involvement
Aneurysms of the peripheral arteries should be corrected surgically . Aorto-bi-iliac bypass is the preferred surgical intervention for the infrarenal aortic aneurysms. Synthetic graft insertion is used for the extremity aneurysms. In selected cases, ligation can give satisfactory results; nevertheless, postoperative claudication is frequent. Quite similar to pathergy phenomenon, recurrences from the anastomotic areas of the bypasses are frequent. Some patients with totally thrombosed or calcified aneurysms are followed up without surgical intervention.
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