Vascular Behçet's disease: new insights in the management of thrombosis

Keywords::

• adalimumab
• anti-TNF agents
• Behçet's disease
• biologic agents
• cardiovascular manifestations
• endothelial cell dysfunction
• recurrent thrombosis
• thrombosis
• vasculitis
• immunosuppressive therapy

Behçet's disease (BD) is considered a multisystemic vasculitis characterized, according to its first description in 1937 by Hulusi Behçet, by typical oral and genital ulcerations and uveitis, but also by skin, vascular, articular, neurological and gastrointestinal involvement [1]. BD has particular clinical features which usually allow to easily distinguish this condition from other systemic vasculitis; only in a few cases the detection of antineutrophil cytoplasmic antibodies (ANCA) and the use of PET might be useful to distinguish BD from small and large vessel vasculitis, respectively. Also the pathergy test and the research of HLA-B51 may be helpful to diagnose BD, especially in some ethnic groups [2].

Vascular involvement varies according to different studies, but generally it is more frequent in males and does not seem to be correlated with the HLA-B51; it has been recently demonstrated that factor V Leiden is significantly associated with BD and the presence of thrombosis, even only in Turkish population [2]. Vascular lesions have a high frequency (cardiovascular involvement occurs in 10–45% of BD patients) and serious prognosis (fatal outcome in about 20% of severe cases) [2]. Even if both arteries and veins may be involved, venous district is the most commonly affected site, and the terms vasculo-Behçet or angio-Behçet are used by some authors to define patients in whom large vessel lesions are the main feature [3].

While aneurysms and arterial occlusions are relatively uncommon, venous thrombosis is the most frequent vascular manifestation in BD patients, representing more than 75% of all vascular complications [3]. Thrombosis may occur anywhere in the venous system even if deep vein thrombosis (DVT) and superficial vein thrombophlebitis (SVT) of lower extremities are the typical manifestations, with a tendency to recur especially in males with active disease [3]. Venous thromboses in atypical sites (such as hepatic veins, vena cava and cerebral venous sinuses) have also been reported and BD should be always considered in the diagnostic work-up of patients with thrombosis in unusual sites, in particular in young males [3]. Among venous thromboses, SVT of the lower limbs, both spontaneous and induced, are the most frequent, possibly reflecting a pathergy-like effect in the venous wall. Of note, SVT should be differentiated from erythema nodosum [4], a typical manifestation of BD, which is usually very painful.

The coexistence of venous thrombosis and arterial aneurysms is a peculiar feature of BD: for instance, venous thrombosis of the lower limbs associated with pulmonary artery aneurysms (PAAs) is considered by some authors an incomplete form of BD [5]. Finally, the incidence of cardiac manifestations is between 1 and 6% of BD patients and the main characteristic lesions are pericarditis, intracardiac thrombosis, myocardial complication, endomyocardial fibrosis, endocarditis and coronary artery disease [6].

The pathophysiology of thrombosis in BD is not well known, but systemic inflammation seems to be the most important risk factor for thrombosis whereas thrombophilic factors are less relevant. Thus, BD may represent an example of inflammation-related thrombosis [7].

BD is a necrotizing, neutrophilic, obliterative perivasculitis, with infiltrates mainly constituted by neutrophils and mononuclear cells, with a predominance of CD3⁺CD4⁺ T lymphocytes and NK cells [2]. Moreover, growing data on the relevant role of Th17 cells in the inflammatory process of BD are reported in some studies. High levels of proinflammatory cytokines related to Th1 cells, such as IFN-γ, TNF-α, IL-1, IL-6, CXCL8 and IL-17A cytokines expressed by Th17 cells have been observed in BD patients [2]. These proinflammatory mediators are able to promote a prothrombotic state by different mechanisms, including endothelial cell dysfunction (ECD), enhanced platelet function, impaired fibrinolysis and clotting activation. ECD is emerging as a crucial feature in the pathogenesis of thrombosis in BD. A reduced bioavailability of nitric oxide (NO) has been observed in some patients with active BD [8,9] and polymorphisms of endothelial nitric oxide synthase (eNOS) could at least in part explain the different susceptibility to thrombosis of BD patients in different populations. High levels of markers of endothelial damage such as circulating von Willebrand factor (vWF) and thrombomodulin were reported in patients with active BD. VEGF, a marker of angiogenesis, and some adhesion molecules such as intracellular adhesion molecule 1 (ICAM1), E-selectin, produced by activated endothelial cells and P-selectin, mainly synthesized during platelet activation, have been also found in serum of BD patients [7,10]. A high plasma homocysteine concentration, frequently reported in BD patients with history of thrombosis, especially in active disease [11], could also impair endothelial function. Interestingly, flow-mediated dilatation of brachial artery (FMD), a marker of endothelial dysfunction, was reported to be significantly impaired in BD patients [12]. Controversial data were reported about the role of hemostatic factors in BD, especially prothrombin G20210A polymorphisms and coagulation factor V G1691A (factor V Leiden) [2,7]; instead deficiencies of natural anticoagulant proteins such as antithrombin (AT) and protein C (PC), protein S (PS) seem not to have a prominent role in thrombosis of BD patients [7]. Lipoprotein (a) was found increased in BD patients and might be involved in the pathogenesis of thrombosis by impairing fibrinolysis [7].

BD is probably the only disease in which both arterious and venous involvement respond to immunosoppressive rather than anticoagulant treatment: the European League Against Rheumatism (EULAR) suggests the use of corticosteroids (CS), azathioprine (AZA), cyclophosphamide (CYC) or cyclosporine A (CsA) [13] because these anti-inflammatory agents are able to promote a rapid and persistent suppression of the vascular lesions and to prevent the expansion of thrombosis and its recurrence. In particular, AZA and CsA associated with CS at low dose are considered the first-line therapy of DVT and SVT, while CYC is preferred in the treatment of arterial involvement [13].

Of note, except for cerebral venous sinus thrombosis, anticoagulant therapy is not recommended in BD patients [13]. Indeed, the pathophysiology of thrombosis in BD, where systemic inflammation promotes the prothrombotic state leading to a thrombus tightly adherent to the vessel wall with a low rate of embolism [4], the conflicting data on hemostatic alterations, the not unusual association between PAA and thrombosis and the inefficacy of anticoagulants reported in several studies support immunosuppressive therapy rather than anticoagulation in BD patients.

Sometimes thrombosis in BD is refractory to traditional immunosuppressive therapy and tends to recur, so that more therapeutic options are required. Thus, other approaches have been considered based on pathophysiological considerations. TNF-α is a major cytokine mainly produced by macrophages involved in many systemic inflammatory conditions [14] and spontaneous and LPS-stimulated production of TNF-α are increased in BD patients. Over the last years, three anti-TNF agents have been used in patients with BD: the chimeric monoclonal anti-TNF-α antibody infliximab (IFX), the fully human anti-TNF-α antibody adalimumab (ADA) and the fusion protein etanercept (ETN) [15]. IFX in particular resulted effective on different manifestations of BD [1], recently obtaining the approval in ocular and neurological involvements by the Japanese Health Authorities; ADA has also been reported to have beneficial effect in treating all clinical features of 19 BD patients [16].

In our experience, anti-TNF agents result very useful in every BD involvement: adalimumab is presently used in 29 patients with mucocutaneous, gastrointestinal and ocular involvement, with beneficial effect, while IFX result effective especially in more severe neurological and ocular disease (personal unpublished data). Despite the experience with anti-TNF-α agents for major vessels involvement is limited to case reports, cases of vasculo-Behçet patients resistant or intolerant to conventional immunosuppressive strategies who were successfully treated with anti-TNF-α agents have been increasingly described. In our Center among 28 patients with vasculo-Behçet, 10 (5 males and 5 females) refractory to traditional immunosuppression were successfully treated with adalimumab, 40 mg/every 2 weeks. Recurrent DVT and SVT of lower extremities were the most common lesions in five patients, while other atypical vein localizations were portal vein (two patients), pelvic, hepatic, splenic and superior mesenteric veins (one patient). An additional patient manifested thrombosis of pulmonary arteries associated with multiple aneurysms of peripheral arteries. Moreover, we treated with adalimumab a patient affected by multiple arterial and venous lesions (DVT and SVT of lower legs, inferior vena cava, intracardiac and cerebral venous thromboses associated with femoral artery aneurysm) with good clinical outcome.

Of note, in all these patients recurrent vascular events were observed during traditional immunosuppressive treatments or anticoagulation, thus requiring a new therapeutic strategy. In our experience, adalimumab induced a rapid response in these patients with improvement of clinical and imaging findings, with a good tolerability (no serious adverse reactions) and safety (no systemic complications as well as infections or malignancies), and with a low rate of recurrences (only one case with SVT recurred, successfully treated by increasing the dosage of CS).

Conclusions

Traditional immunosuppressive therapy represents at present the first treatment choice to thrombosis in BD patients. For patients with recurrent or refractory thrombosis or intolerant to AZA, CYC and CsA, anti-TNF-α agents, and in our experience particularly adalimumab, could represent an important new therapeutic option and in a near future might be used as first-line treatment for vasculo-BD. However, the best therapeutic choice for thrombosis in BD should be evaluated by randomized controlled clinical trials with a larger number of patients to confirm these preliminary data. Further challenges will be the identification of the optimal dosage, the duration of treatment and the related safety and cost issues.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.