Introduction

Behçet’s syndrome (BS) is a complex and intriguing vasculitis, with a peculiar vascular involvement. Indeed, BS is the model of inflammation-induced thrombosis, and new pathogenetic concepts have been raised regarding vascular involvement in patients affected by BS [1].

To date Behçet is considered a syndrome, since it includes a spectrum of different clinical phenotypes, instead of a single entity. Among many different phenotypes, the “vascular cluster” or “angio-Behçet” identifies a specific group of patients who suffer from recurrent inflammatory thrombosis involving the venous and, more rarely, the arterial vascular tree [2].

Different epidemiological studies confirmed that the most frequent type of vascular involvement in BS is superficial thrombosis, followed by deep vein occlusions, and more rarely, by aneurysm formation on the arterial side [2].

In this review, we will briefly describe the main histological, pathogenetic and clinical features of the vascular involvement in BS. Whereupon, we will focus on the clinical studies describing the different therapeutic approaches (mainly with immunosuppressants) of the more important kind of vascular manifestations.

Classification and histological features

The clinical importance of vascular thrombosis in BS is underlined by the more recent classification criteria, including for the first time in the scoring system a specific item for the vascular involvement. These new classification criteria allowed the clinicians to easily classify patients as having BS with predominant “vascular” clinical events, even in the absence of oral aphthosis [3].

Moreover, BS is classified, together with Cogan’s syndrome, as a “variable vessels” vasculitis, a term that underlies its atypical histological and clinical features [4]. Indeed, several important clinical and histological differences exist between BS and other systemic vasculitides: (a) contemporary involvement of both arteries and veins of all sizes in BS (venous in general more frequently affected than arteries); (b) no clearly reported increased risk of atherosclerosis compared to other vascular inflammatory diseases; (c) unique tendency for aneurysm formation in particular in the pulmonary arterial circulation; (d) usual absence of granulomatous inflammatory lesions in vessel wall, with elastic fibres usually spared.

The infiltrates in BS are predominantly constituted of neutrophils and lymphocytes. Unlike the histology of other systemic vasculitides, in BS, these cells are localised more around the vessels than inside the wall. This histologic “perivascular” pattern of BS, probably more similar to neutrophilic dermatosis than to classical systemic vasculitides, has been demonstrated in several districts, and in particular, in mucosal and ocular inflammatory lesions, as well as even in pulmonary aneurysms [5,6,7]. Similarly, the histopathology of a skin pathergy test at different time points reveals perivascular infiltrates of neutrophils and lymphocytes, however, without the typical features of a “true” vasculitis [8].

Pathophysiology of vascular inflammation in Behçet’s syndrome

BS is considered a very complex disease in which environmental, geographical, genetic, and immunological factors together with microbiome alterations, contribute to disease onset and persistence or recurrence of symptoms over time [9,10,11,12,13].

Regarding the subset of BS patients with vascular manifestations, during the past few years, new light has been shed on the correlation between inflammation and thrombosis. Cytokines such as IL1, IL6, IL17, TNF-α and CXCL8 (previously known as IL8) are now considered major players for BS pathogenesis. Moreover, it is now recognised that inflammation, as for many chronic inflammatory conditions, promotes thrombotic events through endothelial dysfunction, platelets hyperactivation and increased tissue factor (TF) expression. On the other hand, coagulative components such as fibrinogen, thrombin, factor Xa and factor VIIa are potentially able to interact with specific receptors (integrins, PARs 1-3-4 and PARs 2, respectively) on the immune system cells, and to amplify the inflammatory cascade [14, 15].

Neutrophil hyperfunction in BS was originally proposed in 1975, when increased chemotaxis was demonstrated, and more recently, new data have linked neutrophils to BS inflammatory organ damage [16]. Serum levels of CXCL8 and G-CSF, chemokines typically involved with neutrophils recruitment and activations, are indeed usually high in the active phase of BS [17]. Moreover, intense neutrophils perivascular infiltrates have also been described in pulmonary arteries complicated with rupture and haemoptysis [18].

The link between neutrophil-mediated inflammation and organ damage in Behçet’s syndrome is described in Fig. 1.

Fig. 1
figure 1

Schematic representation of the main pathogenetic mechanisms in Behçet’s syndrome pathogenesis, with particular regard on to neutrophils

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A specific mechanism of programmed cell death (NETosis) has been recently described for neutrophils. This mechanism indicates the external release of structures containing adenylsated chromatin and known as Neutrophils Extracellular Traps (NETs). NETs together with neutrophils granules, contribute to the entrapment and killing of extracellular microorganisms. This physiological mechanism can be potentially altered and hyperactivated in some autoimmune diseases, and in particular, in small vessels vasculitides, maintaining inflammation and determining vascular damage [19].

Our group recently demonstrated for the first time in BS patients a crucial role of neutrophils in the pathogenesis of thrombotic events. In particular, our study shows in Behçet’s patients, fibrinogen post-translational modifications (carbonylation) and reduced fibrin susceptibility to plasmin lysis, due to increased leukocyte oxidative stress and ROS generation, mainly derived by neutrophils. These findings support a strong rational basis to understand why the thrombus of BS is less responsive to anticoagulation therapy and often more to immunosuppressive drugs or to biological agents [20].

Main clinical features of vascular manifestations in Behçet’s syndrome

Superficial venous thrombosis (SVT) and deep vein thrombosis (DVT) are the most frequent types of vascular involvement, affecting altogether up to 15–40% of patients with BS. Thrombophlebitis is usually diagnosed by direct physical examination; however, Doppler ultrasound can be a useful tool to confirm the diagnosis in doubtful or uncertain cases [21].

DVT in BS may involve both the superior and inferior limbs, with post thrombotic syndrome being a later complication for the most severe cases. Moreover, thrombosis of atypical sites is also an important clinical feature of BS. In particular, the following vascular districts have been described to be potentially involved: inferior and superior vena cava, suprahepatic veins with Budd–Chiari syndrome, portal vein, cerebral sinuses and right ventricle [22].

On the other hand, arterial involvement, although far less common and affecting only a minority of the patients, is considered a unique vascular feature of BS. Indeed, this condition is perhaps the only chronic inflammatory disease causing aneurysms potentially affecting both peripheral, visceral and pulmonary arteries. The true prevalence of aneurysms in BS is probably underestimated, since autopsy studies showed significantly more lesions than usually clinically detected [23].

Another peculiar BS feature is the co-occurrence of venous and arterial manifestations, starting in the latter usually before the venous ones. Venous thrombosis is often detected together with aneurysms and pseudo-aneurysms. In rare cases, pulsatile masses from peripheral arteries are also recognised as a complication of bigger aneurysms. Hence, BS should always be included and kept in mind in the differential diagnosis of diffuse or localised aneurysms, in particular, when these finding are not explained by more common causes (Table 1).

Table 1 Differential diagnosis of aneurysms/pseudoaneurysms
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Haemoptysis and cough are the main symptoms when haemorrhage complicates rupture of aneurysmatic pulmonary arteries. However, clinically silent aneurysms are often accidentally detected on lung X-ray or CT scan as vascular masses. Screening for such silent aneurysms is mandatory whenever anticoagulation is considered in Behçet patients, since such therapy significantly increases the risk of rupture and mortal haemorrhage [24].

The presence of arterial involvement in BS is a very important risk factor affecting both morbidity and on the long-term mortality, in particular when pulmonary aneurysms occur [25]. Moreover, about 80% of the patients with pulmonary arterial involvement were found to have concomitant venous thrombosis which consists mostly of lower-extremity DVT (66%), underlining the fact that probably the same inflammatory process is responsible for events both on the venous and the arterial side of the vascular tree. The contemporary occurrence of arterial pulmonary aneurysms and peripheral venous thrombosis is the hallmark of the so called Hughes–Stovin syndrome, nowadays considered by some authors as a clinical variant of vascular Behçet [26, 27].

Treatment of vascular involvement

Most appropriate management of vascular involvement in BS should be tailored on specific vessel disease [28].

While the role of immunosuppressive therapy is well acknowledged, a controversy exists regarding the value of anticoagulant treatment, and the usefulness of anticoagulation in different vascular manifestations related to BS is still unclear. Furthermore, the availably of an increasing number of immunomodulating drugs targeting different inflammatory mediators poses a concern on the choice of the most appropriate immunosuppressant agent [29].

In the following paragraphs, we summarise current literature evidence on the pharmacological management of the most frequent venous and arterial involvements (Fig. 2, Supplementary Table 1 and 2).

Fig. 2
figure 2

Schematic representation of the main studies assessing the efficacy of immunosuppressive and anticoagulant treatment in different Behçet’s vascular manifestations

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Venous involvement

Deep and superficial venous thrombosis in typical sites

In DVT, use of immunosuppressants is pivotal for the control of recurrences, whereas concomitant use of anticoagulation therapy is not associated with additional positive effects in reducing the risk of DVT relapse [30, 31]. In fact, occurrence of venous thrombotic events in BS is thought to be related to a sustained systemic inflammation rather than to a specific thrombophilic state [28]. Benefits of steroid or immunosuppressant therapy also override those of anticoagulants also in superficial venous thrombosis (SVT) [32, 33].

According to the 2018 EULAR recommendations, there are no definite data for preferring one immunosuppressant drug over another. However, evidence suggests the choice of azathioprine, cyclophosphamide (CYC) or cyclosporine-A [28].

Recently, the anti-TNF-α adalimumab (ADA), alone or in combination with other immunosuppressants, proved proves to be more effective than DMARDs alone in inducing clinical and ultrasound resolution of venous thrombosis. Moreover, ADA allows a more pronounced steroid tapering, while no additional benefits from anticoagulation were shown [33]. According to the 2018 EULAR recommendations, use of anti-TNF-α should be considered in patients with refractory thrombosis, while the addition of anticoagulants should be weighted on the risk of bleeding as well as of potentially coexistent pulmonary artery aneurysms [28].

Deep vein thrombosis in atypical sites

Vena cava thrombosis

An exception to the use of anticoagulants is perhaps represented by vena cava thrombosis (VCT). In a retrospective chart review of 29 patients by Hamzaoui et al. [34], treatment of VCT was based on anticoagulants, and concomitant treatment with corticosteroids and immunosuppressants (mainly CYC) was prescribed in 22 subjects. Good outcome was reported in 12 patients, whereas in four cases, extension of VCT occurred.

The use of CYC as a preference treatment in vena cava thrombosis is supported also by the last EULAR recommendations, that suggest CYC for patients with extensive thrombosis of large vessels such as vena cava, in view of its potential adverse events [28].

Budd–Chiari syndrome

In atypical thrombosis such as in the Budd–Chiari syndrome (BCS) in BS subjects, lack of use of immunosuppressant treatment in the first 6 months following the onset of symptomatic liver disease has been associated with poor prognosis, whereas anticoagulant or thrombolytic therapy does not seem to reduce mortality [35]. As for the specific contribution of anti-TNF biologics such as infliximab in BS-related BCS, evidence from the literature is still unclear [36].

Intracardiac thrombosis

In a series of eight cases reported by Ben Ghorbel et al. [37], treatment of intracardiac thrombosis (ICT) was mainly based on anticoagulants, colchicine, and prednisone, and concomitant immunosuppressive therapy with azathioprine (AZA) and/or CYC was used in five cases. ICT resolution was obtained in five cases and clinical remission in four. The effectiveness of the triple association of anticoagulants, immunosuppressants and corticosteroids in ICT is also confirmed in a retrospective study by Wang et al. [38]. Based on this study, use of this combination either as first line treatment or following surgery accounts for no ICT reoccurrence. When administered as first-line, these therapies accounted for complete resolution of ICT in 78% of cases.

Central nervous system venous thrombosis

Anticoagulation is also required in the management of central nervous system venous thrombosis (CNSVT) [39]. In a recent study by Uluduz et al. [40], 108 subjects with central venous sinus thrombosis (CVST) were initially treated with pulsed steroid and low-molecular-weight heparin; after the first month of treatment, this therapy was replaced with warfarin. Warfarin alone was also used as an effective maintenance treatment. According to a retrospective observational study by Saadoun et al. [41], up to 90% of patients responded to anticoagulant treatment without severe haemorrhagic complications. Furthermore, concomitant use of immunosuppressants did not influence the risk of sequalae or relapses as compared to use of anticoagulants alone. In a recent study by Shi et al. [42], co-treatment with corticosteroids, immunosuppressants, anticoagulants and dehydration accounted for remission of CVST in more than 85% of subjects.

Arterial involvement

In arterial lesions, use of immunosuppressants should always be taken into account, since they have been positively associated with the achievement of complete remission, as well as with lower risk of post-operative complications. In these patients, benefit from the concomitant use of anticoagulants is mainly ascribable to the reduction in the risk of post-operative thrombosis.

Pulmonary artery involvement

Immunosuppressants are the mainstay of treatment in pulmonary artery involvement (PAI) [43, 44], whereas use of anticoagulants in this condition is negligible.

In subjects refractory to immunosuppressants, embolisation, lobectomy, cavitectomy, and decortication can be considered [43, 45, 46].

In addition, when therapy with conventional immunosuppressants is ineffective, anti-TNF-α agents (mainly infliximab) can represent a life-saving treatment [47]. Nevertheless, doubts related to the occurrence of PAI during anti-TNF-α treatment, as well as safety concerns, have been reported [47].

As for pulmonary artery aneurysm (PAA), pharmacological treatment is mainly based on immunosuppressants, namely CYC or AZA, alone or in combination with corticosteroids [24, 48]. Based on a retrospective study by Hamuryudan et al. [24] such a treatment accounts for a 5-year overall survival rate of 62% (even assuming that all subjects lost during follow-up had died). In an observational study by Uzun et al. [49], five PAA patients were treated with colchicine and corticosteroids, plus CYC and embolisation. Despite treatment, mortality rate was high, and four out of five patients died.

Use of CYC in association with high-dose corticosteroids in PAA is strongly suggested by the 2018 EULAR recommendations, while use of anti-TNF-α should be considered for refractory cases [28].

Pseudoaneurysm

In patients with pseudoaneurysm, corticosteroids and immunosuppressants, prednisone alone or in combination with AZA seems a pivotal pre-surgery therapy, before endovascular treatment [50, 51]. In the days after surgery, successful use of hydrocortisone plus CYC has been reported. The use of oral immunosuppressants therapy following surgical intervention has been associated with successful prevention of pseudoaneurysm recurrences [50].

Conclusions

BS can be considered a “neutrophilic perivasculitis”, characterised by peculiar vascular manifestations. Indeed, BS can involve both arterial and venous vessels, of any size and in any body district, often simultaneously [4]. Behçet is not a single unique entity, but rather a syndrome with different clinical phenotypes. In this context, patients with a predominant vascular involvement belong to the “vascular cluster.” [52]. The vascular involvement in BS is one of the most important in terms of morbidity and mortality, however, improvement in the treatment has occurred [28].

In general, control of vascular thrombosis is achieved with immunosuppressants drugs rather than anticoagulants. The latter indeed seems not effective in patients with BS in preventing recurrent thrombotic events, which are thought to be caused by an inflammatory process rather than a thrombophilic state. An exception to the use of anticoagulant in BS appears to be due to cerebral veins thrombosis, since some data seem to indicate a partial benefit of such therapy. However in selected BS patients for whom anticoagulation seems a useful treatment to add to immunosuppressants, it is strongly recommended to perform a CT lung scan before starting such therapy, in order to rule out the presence of occult pulmonary artery aneurysms, and to prevent the consequent risk of rupture and bleeding.

With regard to immunosuppressive therapy, the use of AZA and cyclosporine in association with low-dose corticosteroids should be considered in DVT and SVT cases, while treatment with CYC can be effectively prescribed for arterial involvement [28]. More recently, anti-TNF-α agents have been increasingly reported as an alternative treatment for acute and long-term management of vascular Behçet [28, 33], while proving effective also in the control of general BS manifestations [53,54,55,56,57,58].