Cardiovascular Manifestations in Behçet’s Disease

Abstract

Cardiovascular involvement in Behçet’s disease (BD) is considerably related to morbidity and mortality. However, the cardiovascular manifestation is sometimes difficult to distinguish from those of other causes. The suspicion of BD and proper treatment is pivotal in the management of BD. Histology demonstrates perivasculitis. Neutrophil seems to play an important role in the inflammation of BD. It is thought that inflammation causes venous thrombosis and arterial aneurysm. Characteristically, BD involves both arteries and veins of variable size in any region. Venous thrombosis needs immunosuppression, and inferior vena cava thrombosis and Budd-Chiari syndrome require intensive immunosuppressive therapy. Arterial involvement causes aneurysm which usually is treated by surgical or endovascular intervention with immunosuppression. Pulmonary artery aneurysm and cardiac involvement require multimodal managements.

Graphical Abstract

INTRODUCTION

Behçet’s disease (BD) is a chronic inflammatory disease classified as a variable vasculitis characterized oral ulcers, genital ulcers, and uveitis. Moreover, it can involve any organ systems including musculoskeletal, gastrointestinal, cardiovascular, and neurologic involvement.¹ The prevalence is high along the ancient Silk Road from Mediterranean countries to East Asia. The diagnosis is made on clinical manifestations as there is no specific laboratory tests or biomarkers. The International Study Group (ISG)’s diagnostic criteria² was published in 1990 and revised in 2014 as the International Criteria for BD³ to increase sensitivity by inclusion of neurologic and cardiovascular involvement, as shown in Table 1.

Table 1. Comparison of 1990 Criteria of ISG and 2014 ICBD.

Manifestation	ISG criteria (1990)	ICBD criteria (2014)
Oral lesion	○	○ (2 points)
Genital lesion	○	○ (2 points)
Skin lesions	○	○ (1 point)
Ocular lesions	○	○ (2 points)
Positive pathergy test	○	○ (1 point, optional)
Joint involvement	-	-
Intestinal involvement	-	-
Neurological involvement	-	○ (1 point)
Vascular involvement	-	○ (1 point)

ISG, International Study Group; ICBD, International Criteria for Behçet’s Disease.

Vascular involvement has been observed in approximately 5%–40% of BD patients.⁴,⁵ This wide range of vascular involvement could be due to the differences in ethnicity and disease duration. Moreover, it is well known that the frequency of vascular involvement is increased in a prospective study design (increased from 20% to 40% in 20 years).⁶ Vascular involvement in BD is manifested by an arterial aneurysm and venous thrombotic occlusion.⁷,⁸,⁹ Cardiac involvement is rare in BD, and it can be divided as endomyocardial involvement, valvular involvement, and coronary involvement. Endomyocardial involvement presents as intracardiac thrombosis or endomyocardial fibrosis. Valvulitis results in valvular insufficiency, frequently in association with aoritis.¹⁰,¹¹,¹² A significant portion of the population with cardiovascular manifestations had their first vascular event within 5 years of disease onset. Venous thrombosis in lower extremities occurs early in the disease course. Pulmonary artery involvement, vena caval thrombosis, and Budd-Chiari syndrome also occur within a few years of disease onset. However, non-pulmonary arterial involvement occurs at a later age. Moreover, in approximately 20% of the patients, vascular manifestation presents at disease onset, and in another 10% of the patients, vascular involvement occurs even before satisfying the ISG criteria.¹³

According to a recent study, cardiovascular involvement in BD patients was associated with male sex, smoking status, papulopustular lesions, and higher activated partial thromboplastin time.¹⁴

Although cardiovascular involvement is rare, it is related to morbidity and mortality in patients with BD.¹⁵ Early detection and appropriate management of cardiovascular involvement can improve the patient prognosis. Therefore, it is crucial to identify cardiovascular involvement in BD as early as possible.

PATHOGENESIS

Genetic and environmental factors contribute to the disease onset and flare over time.¹⁶ In a meta-analysis, HLA-B51, MHC class I allele, was consistently associated with BD.¹⁷ Genome-wide association studies have revealed interleukin (IL)-10, IL-23R-IL-12RB2, IL-1A-IL-1B, CCR1, and ERAP1 as additional susceptibility genes for BD.¹⁸,¹⁹,²⁰ Although microorganisms like Streptococcus sanguis and herpes simplex virus I had been implicated,²¹,²² no single pathogen has proved as a causative agent until now. Microbiome may contribute to the pathogenesis.²³

Immunological factors were also related to the pathogenesis, resulting in tissue injury. Neutrophil hyperactivation, NK cells, Th 1 cells, and Th 17 cells are frequently suggested as a prominent immunologic abnormality.²⁴,²⁵,²⁶ In studies of BD patients with vascular manifestations, inflammation has been linked to thrombosis. Although the pathogenesis of thrombosis is not known clearly, it is now recognized that inflammation promotes thrombosis through endothelial dysfunction, platelet hyperactivation, and increased tissue factor expression.⁹,²⁷,²⁸ On the other hand, coagulation components, including fibrinogen, thrombin, factor Xa, and factor VIIa, can potentially influence through specific receptors on the immune cells and amplify the inflammatory pathway.²⁹,³⁰ Cytokines, such as IL-1, IL-6, IL-17, tumor necrosis factor alpha (TNFα), and C-X-C Motif Chemokine Ligand 8 (CXCL8), are also considered to be critical players in the pathogenesis. Recent research results have linked neutrophil hyperfunction to BD-induced inflammatory organ damage.³¹ Serum levels of CXCL8 and granulocyte colony-stimulating factor, mediators typically involved in neutrophil recruitment and activation, are usually elevated in active BD.³² The external release of structures containing DNA by neutrophils, namely neutrophil extracellular traps, contributes to the killing of extracellular microorganisms. This physiological process can potentially be altered and activated in BD; thus, maintaining inflammation and causing vascular damage.³¹ The link between risk factors and vascular involvement in BD is described in Fig. 1.

Fig. 1. Schematic representation of the pathogenesis in Behçet’s disease in relation to vascular involvement.

In the histology of BD, inflammatory cells are localized more around the vessels than inside the wall, unlike the histology of other systemic vasculitides. The inflammatory lesions in BD predominantly comprise infiltrating neutrophils and lymphocytes.³³ This perivascular pattern of BD, similar to that of neutrophilic dermatosis, has been found in several organs, including mucosal ulcers, ocular lesions, and even in pulmonary aneurysms.³⁴,³⁵,³⁶ Fibrous thickening of the vessel wall and focal aneurysmal dilatation with an overlying thrombus can often be demonstrated in the specimens of arterial disease.³⁷ Medial elastic fibers are destructed and there is lymphocytic infiltration around the vasa vasorum. Inflammation of the vasa vasorum in the medial layer destroys results in elastic fibers and subsequent arterial dilatation.³⁸ The pathology of venous disease comprises formation of an inflammation-induced thrombus, which is typically adherent to the inflamed vessel wall. The vessel wall is thickened due to inflammation, and it is accompanied by an organized thrombus. This is usually not complicated by thromboembolism. The typical histology of vasculitis, vessel wall infiltration by inflammatory cells, is hardly seen.³⁷

CLINICAL MANIFESTATIONS

Vascular lesions in BD can involve both the arteries and veins, and venous involvement accounts for more than 80% of vascular BD.³⁹ Although BD is classified as a variable vessel vasculitis, it has atypical clinical and histological features compared with other vasculitis.⁴⁰ There is a unique tendency for aneurysm formation in arteries. In addition, there is no granulomatous inflammation in the vessel wall.⁴¹

The vascular involvement in BD is emphasized by the more recent classification criteria, which include, for the first time, a specific item for the vascular involvement in the scoring system. Thus, it is possible to classify the patients with predominant cardiovascular disease as BD, even without oral ulcer.³

Venous involvement

Superficial venous thrombosis (SVT) and deep vein thrombosis (DVT) are the most common presentations of vascular involvement. Superficial thrombophlebitis can be diagnosed by physical examination. For DVT, doppler ultrasound examination can also be useful to confirm the diagnosis.⁴²,⁴³ DVT may involve both the upper and lower limbs, sometimes resulting in post-thrombotic syndrome, venous stasis disorder presenting with edema, pain swelling, skin changes, and ulcer of the affected limb,⁴⁴ in the most severe cases. Moreover, thrombosis occurs at atypical sites in BD, such as the inferior and superior vena cava (SVC), suprahepatic veins, portal vein, and right ventricle.⁴⁵

SVC thrombosis is less frequently found than inferior vena cava (IVC) thrombosis. Patients complain of dyspnea and swelling on the face, neck, and arms/or upper extremities. While swelling has decreased, dyspnea on exertion may persist. In patients with long-standing SVC thrombosis, collaterals around the neck, chest, and abdomen may be observed. SVC thrombosis is less commonly associated with thrombosis of the lower extremity, and the clinical course is benign and the relapse is unusual. Rarely, it is complicated with hemoptysis, pleural effusion, chylothorax, and sleep apnea.⁹,¹³,⁴⁵

IVC is divided into infrahepatic, hepatic, and suprahepatic portions. Although all of the three parts can be involved, the infrahepatic IVC is the most frequently involved site, and it is associated with extension of the iliac vein and common femoral vein thrombosis.⁴⁶ Hepatic and suprahepatic IVC thrombosis cause Budd-Chiari syndrome.⁴⁷ Patients may complain of pain in the lower back or abdomen at acute stage. The formation of abdominal collateral veins is an important feature. In addition, lower extremities can be swollen. When Budd-Chiari syndrome develops in a patient with a previous venous thrombosis, IVC thrombosis should be suspected.

Although BD is the most frequent etiology of Budd-Chiari syndrome in an endemic area,⁴⁸ Budd-Chiari syndrome is found in less than 5% of patients with vascular involvement. The syndrome is caused by hepatic venous outflow obstruction at any level from the hepatic veins to the right atrium. In BD, hepatic and suprahepatic IVC are usually involved.⁴⁸,⁴⁹,⁵⁰ Venous thrombosis of the lower extremity, iliac vein thrombosis, and infrahepatic IVC thrombosis often occur simultaneously. Younger age, male sex, and IVC thrombosis rather than the hepatic vein thrombosis suggest Budd-Chiari syndrome due to BD rather than Budd-Chiari syndrome related to other causes. According to a recent survey, patients presented with two clinical presentations, symptomatic and silent presentations.⁴⁷ Patients sometimes presented with symptoms such as abdominal pain, ascites, abdominal collaterals, scrotal edema, and swelling of the lower extremities. In patients with these symptoms, the clinical course was severe and mortality was high due to hepatic failure.⁴⁷,⁴⁹ Otherwise, there were patients with BD who may develop Budd-Chiari syndrome silently. These patients had a more favorable prognosis with lower mortality compared to those with symptomatic presentation.⁴⁷

Arterial involvement

Arterial involvement, although affecting less than 5% of the patients, is considered a characteristic feature of BD. However, the proportion of arterial involvement in BD has probably been underestimated, since autopsy studies have shown more arterial involvement than those clinically detected.⁵¹ Perhaps BD is the only chronic inflammatory disease that causes aneurysms in the peripheral, visceral, and pulmonary arteries. Arterial involvement is a late event, developing after 5–10 years of disease onset.¹³ A large majority of patients present with aneurysms rather than thrombosis.⁵²,⁵³ The commonly affected sites are the infrarenal abdominal aorta and iliac, femoral, popliteal, and carotid arteries (Fig. 2).⁵⁴ The clinical signs depend on the affected arterial site. Patients may present with a pulsatile and/or painful mass. Lower extremity aneurysms may cause leg pain and claudication, and they may rarely present with digital ulcers. Computed tomography (CT) or magnetic resonance imaging is used to visualize anatomical detail. PET/CT can also be helpful. The differential diagnosis of aneurysms or pseudoaneyurysms includes traumatic or spontaneous dissection, iatrogenic causes (catheterization, biopsy, or surgery), fibromuscular dysplasia, mycotic aneurysm, other vasculitides (giant cell arteritis, Takayasu’s arteritis, polyarteritis nodosa), and atherosclerotic aneurysm.⁴¹ The most important feature of BD aneurysm compared to an atherosclerotic aneurysm is a dense fibrotic and lymphatic tissue surrounding the aneurysm. Usually, saccular pseudoaneurysms are observed. The relapse rate after intervention is approximately 20%. Immunosuppressive treatment before and after surgical intervention has reduced the relapse rate. The mortality rate in these patients has significantly decreased from 17% to 5% as of 1997.⁵²,⁵³

Fig. 2. Commonly involved arteries in Behçet’s disease.

Another peculiar feature of BD is the involvement of both veins and arteries together, starting in the latter usually before the venous manifestations. Venous thrombosis is often detected during the evaluation of arterial aneurysms and pseudoaneurysms. Thus, BD should always be included in the differential diagnosis of diffuse or localized aneurysms. The arterial involvement in BD is an important risk factor of both morbidity and mortality.⁵⁵

Pulmonary artery aneurysm

BD is the most common cause of pulmonary artery aneurysms (PAAs).⁵⁶ Moreover, PAA is one of the characteristic manifestations of BD and is commonly present in young men.³⁸,⁵⁷,⁵⁸ Although the prevalence of PAA in patients with BD is not well known, 1.1% of the patients had PAA in a large BD center.⁵⁸ Aneurysms are usually pseudoaneurysms with an overlying thrombus. Those lesions may cause ischemia and even infarction in the lung. PAA may be single or multiple, and it can cause bronchopulmonary artery fistulas. PAAs are commonly found in the right lower lobe, but they can also be found in the right and left main pulmonary arteries.⁵⁹ The majority of patients with PAAs also have extrapulmonary venous thrombi or thrombophlebitis. Hemoptysis and cough are the main symptoms when rupture of PAA complicates. Other symptoms include chest pain and cough.⁶⁰,⁶¹ However, clinically silent aneurysms are often accidentally detected as vascular masses on lung X-ray or CT scan. PAA is an important risk factor for high mortality. The occurrence of PAAs and DVT is referred to as Hughes–Stovin syndrome.⁶²

Cardiac involvement

Cardiac involvement is not common in BD. Several cases of endocarditis, myocarditis, pericarditis, coronary arteritis, aortic aneurysm, ventricular thrombosis, congestive cardiomyopathy, and valvular dysfunction have been reported.¹² Some cardiac complications may precede other manifestations of the disease.

Intracardiac thrombus

It is a serious complication of BD.⁶³,⁶⁴ It is predominantly found in younger male patients. More than half of the patients were found to have an intracardiac thrombus (ICT) when BD was first recognized. The thrombus usually involves the ventricles rather than the atria and the right heart more often than the left.⁶⁵ Occasionally, both ventricles are affected, and rarely only left ventricle is involved.⁶⁶ An ICT often coexists with pulmonary involvement.⁶⁷,⁶⁸ Pulmonary thromboembolism was reported in 67% of the patients with ICT.⁶⁹ The main clinical symptoms of ICT are fever, hemoptysis, cough, and dyspnea.

Valvular heart diseases

Patients suffered from non-specific symptoms, such as chest discomfort, dyspnea on exertion, palpitation, and heart failure.⁷⁰ Lack of specific symptoms and laboratory tests delayed the diagnosis of BD. Aortic valves were mostly involved, followed mitral and tricuspid valves.¹⁰,¹² Echocardiography showed aortic regurgitation with redundant prolapsing aortic cusp, sometimes with intracardiac mass lesions in the right ventricle.¹⁰ Sinus of Valsalva aneurysms and aortitis are the most common cardiac complications of BD. BD particularly involves the aortic root.⁷¹,⁷²,⁷³ A echocardiographic study reported that aortic aneurysm was detected in up to 48% of the cases of BD,⁷⁴ while another study reported a frequency varying between 5% and 30%.⁷⁵ Aortic root dilatation could be an early stage of the aneurysm. Sinus of Valsalva aneurysms can be accompanied by aneurysms in other arteries and/or coronary arteries.⁷² Patients may present with myocardial infarction, syncope, and fatigue. Aortic regurgitation can develop secondary to a chronic aneurysm of the aortic root.⁷⁶

Coronary arterial diseases

Coronary lesions manifest as angina pectoris, acute myocardial infarction, or arrhythmia.¹² However, in a case series, more than half patients were asymptomatic—coronary lesions were usually found during the evaluation of peripheral arterial disease.⁷⁷ Coronary angiography showed stenosis or total occlusion, aneurysm, or thrombus.⁷⁸ Coronary arterial disease was associated with high mortality of about 30% in acute period, despite surgery.⁷⁷

TREATMENT

Management of vascular involvement in BD should be adjusted according to the vessel involved.⁷⁹ The clinical significance of immunosuppressive therapy is well known, and a number of immunosuppressants targeting specific inflammatory mediators have become available.⁸⁰

Venous involvement

In acute DVT at typical sites, use of immunosuppressants is critical for the prevention of recurrences, whereas anticoagulation therapy is not associated with the reduction of DVT relapse.⁵,⁸¹ In fact, venous thrombosis in BD is thought to be caused by inflammation rather than by hypercoagulability.⁷⁹ Azathioprine may be the preferred first-line treatment. However, according to the 2018 European League Against Rheumatism (EULAR) recommendations, there are no definite data for preferring a specific immunosuppressive drug over another. However, evidence suggests the choice of azathioprine, cyclophosphamide, or cyclosporine.⁷⁹ In case of serious venous involvement, including SVC and IVC thrombosis, hepatic vein thrombosis, and intracardiac thrombosis, cyclophosphamide or anti-TNFα treatment are need as in arterial involvement. In view of its potential adverse events of cyclophosphamide, including hemorrhagic cystitis, infection, malignancy, and infertility,⁸² the use of cyclophosphamide is preferred for patients with extensive thrombosis of large vessels, such as vena cava thrombosis, by the latest EULAR recommendations.⁷⁹

For refractory venous thrombosis, adalimumab alone or in combination with other immunosuppressants has been proven to be more effective than conventional immunosuppressants in reducing venous thrombosis clinically and sonographically. In addition, anticoagulation may be used to decrease the risk of post-thrombotic syndrome.⁴⁶ Moreover, adalimumab allows more pronounced steroid dose tapering.⁸³ According to the 2018 EULAR recommendations, use of anti-TNFα should be considered in patients with refractory thrombosis.⁷⁹

In Budd–Chiari syndrome, the lack of immunosuppressive treatment in the first 6 months after symptomatic presentation has been associated with mortality, whereas anticoagulant or thrombolytic therapy was not related to the prognosis.⁴⁷ Evidence is still lacking regarding the specific contribution of anti-TNFα in Budd-Chiari syndrome in BD.⁸⁴

Arterial involvement

Immunosuppressive treatment for arterial lesions should always be considered since they have been associated with remission, as well as with a lower risk of post-operative complications. In these patients, use of anticoagulants is beneficial for reduction in the risk of post-operative thrombosis.

Arterial aneurysms, the most dreadful manifestation of BD, is treated with pulse corticosteroid therapy followed by high-dose steroid, together with cyclophosphamide or anti-TNFα. Surgical or endovascular interventions with effective immunosuppression may be required for peripheral arterial and aortic aneurysms.

With respect to surgical interventions, there is no consensus regarding the optimal intervention modality or optimal graft type. However, peri- and post-operative immunosuppressive treatments have been suggested to reduce surgical complications and relapses. If the diagnosis of BD is missed prior to intervention, there may be high frequency of surgical failure, recurrence, and postoperative mortality.⁸⁵ Before or immediately after endovascular treatment, corticosteroids and immunosuppressants also seem to be a crucial therapy for the prevention of recurrence of a pseudoaneurysm.⁸⁵,⁸⁶

Pulmonary artery involvement

Pulmonary artery involvement deserves special consideration in the management due to the complexity and difficulties of treatment. Immunosuppressants are the mainstay of treatment,⁶¹,⁸⁷ whereas the role of anticoagulants is negligible. In subjects who are refractory to immunosuppressants, embolization or surgical treatment can be considered.⁶¹,⁸⁸,⁸⁹

With respect to PAA, pharmacological treatment mainly consists of immunosuppressants, mainly cyclophosphamide or azathioprine, alone or in combination with corticosteroids.⁹⁰,⁹¹ Use of cyclophosphamide with high-dose corticosteroids in PAA is strongly suggested by the 2018 EULAR recommendations, while treatment with anti-TNFα should be considered for refractory cases.⁷⁹ In addition, when conventional immunosuppressants is ineffective, anti-TNFα therapy can be a life-saving measure.⁵⁸ Nevertheless, the occurrence of PAA during anti-TNFα treatment has been reported.⁵⁸ Despite treatment, the mortality rate of PAA was high.⁹²

If medical therapy fails or complications occur, arterial embolization or surgical treatment is considered. Localized aneurysms can be treated with surgical resection, such as cavitectomy or lobectomy. For multiple aneurysms, arterial embolization can be an appropriate option. Endovascular intervention may also be a reasonable alternative to surgery in severe hemoptysis.⁹³,⁹⁴ Embolization, with or without immunosuppression, has brought better outcomes than surgery without immunosuppression. Surgery is very difficult to perform due to arterial fragility and the subsequent increased risk of recurrence. Therefore, it should be considered only in refractory cases or cases with massive hemoptysis.⁹⁵

Cardiac involvement

Intracardiac thrombus

Treatment of ICT consisting of anticoagulants, colchicine, prednisone, and concomitant azathioprine and/or cyclophosphamide was used in five cases.⁹⁶ All five patients showed the ICT resolution and four patients among them achieved clinical remission. In another retrospective study, triple therapy of anticoagulants, immunosuppressants, and corticosteroids demonstrated effectiveness in ICT.⁹⁷ Based on the study, this therapy as either first-line treatment or following surgery can be used for ICT treatment. As first-line treatment, this triple combination obtained complete resolution of ICT in 78% of the cases. Complete resolution of the ICT with immunosuppressive therapy, including steroids, azathioprine, and cyclosporine, can also be achieved without the concomitant use of anticoagulants. Surgery may be considered in cases of unresponsiveness to medical therapy, ineffective thrombolysis, hemodynamics instability, or massive ICT. Surgery alone does not lead to complete resolution and ICT often recurs after surgery without immunosuppression.¹²

Valvular heart disease

Mild-to-moderate aortic regurgitation can be treated medically, while severe aortic regurgitation requires aortic valve replacement and aortic root replacement. Due to tissue frailty and frequent aortic root involvement, surgical treatment for aortic regurgitation in BD can be associated with postoperative valvular detachment and prosthetic dehiscence.⁹⁸ Thus, appropriate surgical technique includes aortic valve replacement with reinforcement of aortic root or with aortic root replacement.⁷⁰,⁷²,⁷⁶ Some studies have suggested the importance of considering BD in cases of valve dehiscence in early postoperative period.⁹⁹ Moreover, concomitant immunosuppressive therapy is the utmost important. The corticosteroid and immunosuppressant or even biologics should be started before surgery¹⁰⁰,¹⁰¹ or even in post-operative period.¹⁰²

CONCLUSION

BD can simultaneously involve both the arteries and veins in any region. Vascular involvement in BD is very important in terms of morbidity and mortality.

In general, vascular thrombosis is controlled with immunosuppressive drugs. In arterial lesions, surgical therapy is usually required, and concomitant immunosuppressive therapy should always be considered as it has been positively associated with complete remission as well as with a reduction of postoperative complications. For cardiac involvement, appropriate surgery with timely immunosuppression is mandatory.

With respect to immunosuppressive therapy, the use of azathioprine and cyclosporine in combination with corticosteroids should be considered in cases of DVT and SVT, while cyclophosphamide can be used for arterial involvement or venous thrombosis in special large veins. More recently, the use of anti-TNFα agents has been increased for acute and long-term management of vascular BD.