Clinical and Experimental Medicine

, Volume 16, Issue 1, pp 1–12 | Cite as

Behçet syndrome: from pathogenesis to novel therapies

Review Article

Abstract

Behçet syndrome is a chronic disease hallmarked by inflammation of the blood vessels that is related to an autoimmune reaction caused by inherited susceptibility due to specific genes and environmental factors, probably components of infectious microorganisms, which turn on or get going the disease in genetically susceptible subjects. The more common clinical expression of the disease is represented by a triple-symptom complex of recurrent oral aphthous ulcers, genital ulcers, and uveitis, sometimes associated with inflammatory arthritis, phlebitis, iritis, as well as inflammation of the digestive tract, brain, and spinal cord. The treatment strategies used to manage the manifestations of Behçet syndrome have gradually progressed, and a number of new therapeutic resources have been implemented in recent years, allowing better control of pathogenic mechanisms, reducing symptoms and suffering, and ameliorating patient’s outcome.

Keywords

Behçet Vasculitis Arthritis Aphthae Uveitis Immunosuppression 

Introduction

Behçet’s disease (BD) is a vasculitis that affects the arteries and veins of all sizes, resulting in an alteration of the endothelial function [1, 2, 3, 4, 5], which comes out from the clinical point of view in the appearance of organic lesions at various levels [6]. There are no real diagnostic criteria for BD; nevertheless, the International Team for the Revision of the International Criteria for Behçet’s Disease (ITR-ICBD) established purely classifying criteria, frequently used as clinical guidance from doctors who suspect the pathology (Table 1) [7, 8]. BD has a higher incidence in the countries located along the ancient Silk Road, stretching from Asia to the Mediterranean countries. It is therefore very common in Turkey (80–370 cases per 100,000 inhabitants), but also in Japan, Korea, and China [9]. The prevalence in the USA and in Europe ranges from 0.12 to 7.5 patients per 100,000 inhabitants [10]. BD affects young patients aged between 20 and 40 years, generally of female gender in countries of northern Europe, and of male gender in the eastern Mediterranean region [9].
Table 1

International criteria for Behçet’s disease diagnosis

Signs/symptoms

Score

Ocular lesions

2

Oral aphthae

2

Genital aphthae

2

Cutaneous lesions

1

Neurological manifestations

1

Vascular events

1

Positive pathergy test

1

Pathogenesis

The pathogenesis of BD is still not well known, and there are many possible mechanisms implicated. Among the more important are the association with HLA genotype of the patients, bacterial cross-reactivity with human peptides, cellular secretion of some clusters of cytokines, presence of autoantibodies and circulating immune complexes, hypercoagulability, and activation of the vascular endothelium [11]. Although some studies seem to show an influence equal to only 20 % on the pathogenesis of the disease [12], the increased risk of developing BD is associated with the presence of a particular HLA antigen pattern. In this regard, a recent meta-analysis showed that subjects with HLA-B51/B5 have an increased risk of developing BD compared to non-carriers of HLA-B51/B5 [13]. Other studies also show the prevalence of HLA-B51 in Italy, Germany, and Asia, HLA-B52 in Israel and HLA-B57 in England, HLA-B5101 and HLA-B5108 in the countries along the ancient Silk Road [14, 15, 16, 17, 18, 19]. Other evidences also seem to show the existence of a correlation between the presence of HLA-B51 and the severity of BD [20, 21, 22]. Although most of the cases of BD are sporadic, examples of increased incidence of BD have been reported within some families, in which the presence of the disease in a first-degree relative increased the risk of developing the disease. This figure also would agree with the increased presence of HLA-B51 in patients with familial forms compared to patients with sporadic forms [23, 24]. In addition to HLA genotype, according to some studies, in the pathogenesis of BD, the cross-reactivity between bacterial antigens and self-antigens of the host could have an important role, by virtue of their structural homology. Among the antigens in question, for example, have been implicated the so-called heat shock proteins (HSPs), proteins produced by many organisms in response to stress. T cells and/or B cells would recognize exposed bacterial and human epitopes, determining the start or perpetuation of the disease. In confirmation, in patients with BD were isolated high levels of IgG and IgA antibodies directed against HSPs of mycobacteria, which showed significant sequence homology with human mitochondrial HSPs [25], while another study also mentions the involvement of T cells in response to exposure to HSPs of mycobacteria [26]. The increase in circulating levels of autoantibodies could then match the exacerbation of the uveitis manifestations typical of BD [27]. Mycobacteria, however, were not the only bacteria implicated in the pathogenesis of BD. Several evidences would show a possible pathogenic role of Streptococci: increased salivary bacterial colonization by the Streptococcus mutans in patients with BD compared with healthy controls [28], a higher antibody titer directed toward the Streptococcus sanguinis in patients with BD compared with healthy controls [29, 30], and the prevalence of antibodies against streptococcal HSPs in patients with mucocutaneous manifestations [31]. Streptococcal antigens in the infected organism seem to increase the production by T lymphocytes of IL-6 and INFγ, as well as the concentrations of IL-8 and TNFα [32, 33, 34]. These findings are confirmed by another study, in which the improvement in mucocutaneous lesions was analyzed in two groups of patients, one of which consisted of 94 patients with BD treated with colchicine and benzathine penicillin, the other group composed of 60 patients with BD who underwent only colchicine therapy. This study showed a significantly higher improvement in the mucocutaneous lesions in the first group when compared to that obtained in the group of patients treated only with colchicine [35]. Another study instead calls into question antibodies directed against a cytotoxin of Helicobacter pylori, responsible for the vascular damage typical of BD through a mechanism of cross-reaction on endothelins. Such evidence seems demonstrated by the decrease in disease activity upon eradication of the bacterium [36]. Lastly, some studies suggest a virus-related etiopathogenesis of BD. The trigger role of the herpes simplex type 1 virus, found in the nuclei of the cells of some patients with BD, but according to other studies, not present in the saliva of patients with BD tested with polymerase chain reaction (PCR) method, remains controversial. Besides, the effectiveness of the therapy with acyclovir in a randomized trial conducted in patients with BD was not evidenced [37]. A different role would play the parvovirus B19, found in patients with BD but without ulcerative lesions of the skin in greater amounts than in healthy controls or patients with BD and with ulcerative cutaneous lesions [38]. In the pathogenesis of BD, a reduced function of innate immunity has been called into question, since in patients with BD have been found low levels of mannose binding lectin (MBL), a protein capable of activating the complement cascade upon binding to the mannose of the bacterial surface. Such low concentrations not only would correlate with the appearance of BD after infections and with the severity of disease, but would also be present in other autoimmune diseases, such as rheumatoid arthritis and lupus erythematosus systemicus [39, 40]. As part of innate immunity, an alteration in the expression of Toll-like receptors on lymphocytes of patients suffering from BD was recently evidenced [41, 42, 43], as well as an increased expression of Toll-like receptors 2 and 4 on monocytes of patients with the active form of BD [44, 45]. In BD, there is an alteration in the number and activation of T cells [46], as demonstrated for example by the aforementioned HSPs [26] or by activation of adenosine deaminase, an enzyme involved in the proliferation and differentiation of T cells [47, 48, 49]. In BD, there seems to be an involvement of both T-helper 1 (Th1) and Th2 cells [50, 51, 52]. In many studies of patients with BD, in fact there were high levels of Th1 lymphocytes [53, 54, 55, 56, 57, 58, 59], normally responsible for the secretion of cytokines such as IL2, IL6, IL8, IL12, IL18, TNFα, and IFNγ. Other studies seem to show a correlation between high levels of IL8, IL12, and TNFα and disease activity [60, 61, 62, 63, 64], for example in terms of exacerbation of ocular involvement [65] or new onset of posterior uveitis [66], as well as the presence of high levels of IL6 in patients with neurological involvement in the course of active disease [67]. In BD, however, have been demonstrated not only changes in the Th1 subpopulation, but also of Th2 lymphocytes, as demonstrated by the increase in the soluble portion of CD30, released by Th2 cells as effect of their activation and activity of BD itself. An important role is also played by the Th17 subpopulation, normally secreting IL-17, which seems to be increased and activated in active BD [68, 69, 70, 71, 72, 73]. Also the soluble fraction of CD28, an important regulator of the activation of T lymphocytes, seems to be increased in patients with active BD, correlating also with the activity of disease [74, 75, 76]. Elevated levels of IL2, IL6, and TNFα were found in patients with active uveitis in the course of BD subsequently treated with benefit with infliximab [77] and, although at lower concentrations than in patients with rheumatoid arthritis, even in the synovial fluid of patients with BD have been reported increased concentrations of IL2 and IL8, but lower concentrations of TNFα [78]. B lymphocytes also appear to play a prominent role in the pathogenesis of BD, considering that an increased level of antigen-driven circulating B lymphocytes have been demonstrated in patients with BD [79, 80]. Autoantibodies to numerous self-antigens were in fact described [81, 82], such as mucosal proteins, endothelial cells, and oxidized LDL, and as regards uveitis, autoantibodies directed against the α-tropomyosin antigen [83, 84], localized in the endoplasmic reticulum, which, after immunization induced in the laboratory, induced the appearance of cutaneous and uveitic lesions in rats very similar to those of patients suffering from BD, were also described. A number of factors play a role in the pathogenesis of vascular damage in patients with BD. The thrombotic risk is certainly increased for the vascular damage induced by vascular inflammation [85]; nevertheless, the presence of endothelial dysfunction has been demonstrated in these patients, in terms of endothelial activation with increased levels of nitric oxide (NO) and its metabolites in the plasma, synovial fluid and humor aqueous [86, 87, 88, 89, 90]. Some studies also show an increase in plasma concentrations of vascular endothelial growth factor (VEGF) in patients with elevated activity of BD [91] and in the cerebrospinal fluid of patients with neuro-Behçet [92]. A generalized state of hypercoagulability is also demonstrated by the finding in patients with BD of high levels of thrombin with reduction in physiological fibrinolysis, low concentrations of activated protein C [93, 94], increase in platelet activation [95], and lower plasma levels of tissue plasminogen activator tPA [96]. In BD patients, activation of polymorphonuclear (PMN) leukocytes, or neutrophil granulocytes also seems to be present, as a result of increased plasma concentrations of cytokines, such as IL8 and TNFα [97, 98]. Such PMN cells present increased motility and adhesion to endothelial cells in vitro, also in virtue of the increased expression of cell surface receptors, including CD11, CD18, ICAM1, and E-selectin [99]. This fact favors the migration and adhesion of neutrophils to inflamed vessel walls [100], as well as an increase in granulocyte colony stimulating factor (G-CSF), leukocyte growth factor, and increased apoptosis of neutrophil granulocytes [101]. In patients with neurological involvement, a pathogenic role of matrix metalloproteinase (MMP)-9 was also demonstrated in leukocyte invasion of the central nervous system (CNS) and cerebro-spinal fluid (CSF) of patients with BD compared to healthy controls [102]. In summary, therefore, the pathogenesis of BD could roughly be traced back to the intervention of an infectious antigen (viral or bacterial?), able to determine the activation and exposure of HLA class II antigens on antigen-presenting cells (APC), such as Langerhans cells, dendritic cells, B lymphocytes, and macrophages. Such cells, assisted by the presence of numerous circulating cytokines, such as IL6 and IL1, would present antigen to CD4+ T lymphocytes (Th1), determining proliferation and activation, with consequent release into the circulation of IFNγ, IL-2, and TNFβ, cytokines that are able to determine in turn the activation of B lymphocytes, which, by secreting antibodies, determine the formation of circulating immune complexes and subsequent activation of complement and neutrophil granulocytes [103]. Among other cytokines, IFNγ also impinges on macrophages, stimulating the production of IL1, TNF, IL8, and IL12 [104]. IL8 instead leads to the expression of adhesion molecules on endothelial cells and the subsequent chemotaxis and hyperactivation of neutrophils [105].

Clinical manifestations

The most common and frequent clinical feature of BD is certainly the presence of unsightly and painful oral aphthae and mucocutaneous ulcers, usually of magnitude more severe in male patients. More than two-thirds of the patients also present ocular involvement, more than a third vascular pathologies and finally roughly 10–20 % of patients present with involvement of the central nervous system. Less common instead is the involvement of joints, kidney, and peripheral nervous system [106]. The majority of BD patients at onset of disease present recurrent oral aphthae, histologically similar to the aphthae present in recurrent oral stomatitis, but more extensive, multiple, painful, round-bottomed, yellowish-white, with well-recognized border and surrounded by an erythematous halo. These ulcers are often the first clinical manifestations to appear and the last to disappear during the course of the disease. They are defined minor ulcers when the size is less than 1 cm, and major when the size is more than 1 cm. The latter can sometimes cause residual scars. The ulcers are usually recurrent and typically heal spontaneously in a period ranging from 7 to 20 days, becoming less common after 20 years or so of disease [107]. Genital ulcers affect approximately three-quarters of patients with BD. They are usually localized to the scrotum in males and the vulva in women. They are painful, sometimes evolving in scars and are less recurrent than oral ulcers, of which, however, retain the same morphological characteristics. Epididymitis and salpingitis, although rare, can occur in patients with BD [108, 109]. Also skin lesions are often present and recurrent in patients with BD. They consist of acneiform lesions, erythema nodosum, papulopustular lesions, nodules, pseudofolliculitis, and pyoderma gangrenosum-like lesions. They are present in more than 75 % of patients. Acneiform lesions are similar to the lesions of acne vulgaris, are often associated with articular involvement of arthritic type [110, 111], and are not sterile, since they are often colonized by Staphylococcus aureus and Prevotella [112]. Typical of BD is also the erythematous-papular or pustular reaction approximately 2 mm in diameter at pathergy test, i.e., 24–48 h after inoculation intradermally for at least 5 mm deep with a 20-gauge needle [113]. The ocular involvement in BD affects from 25 to 75 % of patients and, if not adequately treated, can lead to blindness. A typical expression of the disease is uveitis. It is characteristically episodic and bilateral and may affect the entire uvea (panuveitis). The hypopyon is instead a purulent anterior uveitis of severe entity that affects approximately 20 % of patients. Other ocular manifestations in patients with BD include posterior uveitis, retinal vasculitis, retinal vein thrombosis, and optic neuritis. These diseases are to be treated with immunosuppressive therapy quickly to avoid an irreversible reduction in visual acuity up to blindness. It can also cause the appearance of secondary cataract, glaucoma, conjunctival ulcers [114, 115], episcleritis, and sicca syndrome, which fortunately seem to be less common manifestations. Many clinical manifestations of BD are the obvious consequence of the involvement of the vessels (arterial and venous) of all calibers and are more common in male patients. The involvement of the arteries is more common at the level of small vessels; nevertheless, the involvement of medium and large caliber vessels is not uncommon. In fact, in one-third of patients, there is involvement of the carotid artery, pulmonary artery, iliac arteries, aorta, and femoral and popliteal arteries [116], while less frequent is the involvement of the cerebral and renal arteries [117, 118]. The histological feature is the presence of a peri- and intra-vascular inflammatory infiltrate provoking stenosis, bleeding, blood clots, and aneurysms. From a clinical point of view, these histological changes translate into increased risk of acute myocardial infarction due to the involvement of the coronary arteries (however, a rare event) and carotid atherosclerosis [111]. The involvement of the pulmonary artery clinically leads to the onset of hemoptysis, accompanied by fever, cough, pleuritic chest pain, and dyspnea [119, 120]. There may be the onset of pulmonary artery aneurysms, usually involving the larger branches of the artery, and pulmonary embolism with possible fatal outcome if treated only with anticoagulants, not recognizing and quickly addressing the underlying inflammatory vascular etiology [121]. Pulmonary infarction seems to be less common. In contrast, the involvement of the venous vessels is more frequent, resulting clinically in the presence of occlusion of the superior and inferior vena cava, Budd–Chiari syndrome, thrombosis of the dural venous sinuses, superficial and deep venous thrombosis of the legs, often early in the course of disease [122]. In a study conducted on 493 patients with BD, about fifty-three patients had venous thrombosis, fourteen of which thrombosis of the portal vein, eight patients thrombosis of the inferior vena cava, and two patients thrombosis of the portal vein, and the inferior vena cava concomitantly [123]. BD can also show joint involvement, histologically apparent for inflammation evidenced by synovial biopsies [124], and clinically characterized by asymmetric arthritis, non-deforming and non-erosive, which particularly affects the medium and large joints (knees, elbows, and hips) of variable duration from 7 to 20 days, but causing aches and functional limitation similar to those that affect patients suffering from rheumatoid arthritis, as demonstrated by a study that evaluated by means of the Multidimensional Health Assessment Questionnaire (MHAQ) the functional limitation of patients with BD and arthritic involvement [125]. Renal involvement in BD is less common and severe than in other types of vasculitis and may present with proteinuria, hematuria and renal failure usually mild. In a study conducted on 159 BD patients with renal involvement, 51 of them had glomerulonephritis, 4 interstitial nephritis, 35 renal artery aneurysm, and 69 patients secondary amyloidosis [126]. Also the cardiac involvement is uncommon in BD patients and is characterized by the appearance of pericarditis, endocarditis, myocarditis, coronary arteritis, and aneurysms, with or without acute myocardial infarction, mitral valve prolapse, valvular insufficiency [127, 128, 129, 130]. Regarding the involvement of the gastrointestinal tract, BD patients may have anorexia, nausea, vomiting, diarrhea, abdominal pain, and oral and bowel ulcerations, particularly at the level of the terminal ileum and the ascending colon. These ulcers are often indistinguishable from those that affect patients with Crohn’s disease, which therefore should be considered in the differential diagnosis of BD.

Therapy

The autoimmune pathogenesis of BD advocates the consequent use of immunosuppressive drugs. The glucocorticoids are used for BD of medium–high severity and in particular are used at initial high dosage in the acute forms and subsequently reduced to maintenance dose or discontinuation of the administration, in relation to the clinical needs of the patient [131, 132]. Generally, the intravenous bolus of methylprednisolone (1 g) administered for 3 days is reserved for patients with severe and progressive organ disease. Although trials that have studied colchicine use have shown contradictory results [133, 134, 135, 136, 137], this drug is widely used in the treatment of BD, in particular in the treatment of the signs and symptoms of skin and mucosa, such as genital ulcers and erythema nodosum, but also in the reduction in arthritic symptoms sometimes associated with BD [134]. Also azathioprine is among the immunosuppressive drugs mainly evaluated over time in several studies of patients with BD. Among them, a randomized, double-blind, placebo-controlled study compared in the two arms BD patients treated with glucocorticoids and azathioprine versus patients treated with placebo and glucocorticoids [138]. This study showed that patients without initial ocular involvement in therapy with azathioprine showed a low incidence of new onset of ocular pathology, as well as patients with initial ocular involvement treated with azathioprine showed lower incidence of occurrence of hypopyon compared to patients in therapy with glucocorticoid and placebo. Patients treated with azathioprine also had a lower incidence of occurrence of oral and genital ulcers and arthritic manifestations [138]. Azathioprine has been shown to be effective even in 157 patients with posterior uveitis, and panuveitis associated with BD. After azathioprine treatment, 52 % of them showed complete remission of ocular disease and 41 % of them responded partially [139]. Cyclophosphamide, on the contrary, has shown in the few studies carried out a good control of neurological and vascular involvement, but not of the ocular pathology [140]. In the only trial comparing cyclophosphamide and cyclosporine in 23 patients with uveitis, the latter improved visual acuity in contrast to what happened in patients treated with cyclophosphamide [141]. The effectiveness of cyclosporine has been demonstrated instead in many trials, in particular in the therapeutic management of patients with BD and ocular mucocutaneous and articular involvement [141, 142, 143]. It is usually used in combination with glucocorticoids [144] and, in more severe cases, in combination with other immunosuppressants, such as azathioprine [135]. The effectiveness of the drug is confirmed by reports of reactivation of the disease after the temporary suspension of the administration of cyclosporine [144]. Although it is very effective in the treatment of ocular involvement of BD, even compared to chlorambucil in a randomized trial of 40 patients [145], cyclosporine should be used with caution in the treatment of neuro-Behçet, as also highlighted in a retrospective study of 117 patients in which cyclosporine showed a lower efficacy compared with other immunosuppressive drugs [146], in spite of an increased risk of occurrence of side effects, such as hypertension, increased serum creatinine [147], and neurotoxicity, sometimes indistinguishable from the one linked to the primary disease [148]. Also anti-TNFα biological drugs have shown to be effective in the treatment of patients with BD, in particular infliximab and etanercept [149, 150]. As for infliximab, in a prospective study the drug was administered at a dose of 5 mg/kg i.v., in addition to the usual therapy, in BD patients with relapses of ocular pathology. The majority of patients improved rapidly, and all of them improved anyway within 28 days of the administration. In particular, 100 % of patients attained resolution of reduced visual acuity, as well as vitritis and retinitis, and 94 % of patients attained resolution of retinal vasculitis [151]. In a retrospective study of 28 patients, infliximab has been shown to be effective even in BD patients with intestinal involvement, maintaining the efficiency even during a median patients’ follow-up of 30 months [152]. Among the anti-TNFα agents, also etanercept has been studied in a randomized trial conducted for 4 weeks in 40 BD patients with mucocutaneous lesions and/or arthritis. In this study, etanercept has been shown to be more effective than placebo in maintaining the patient free from skin lesions and oral ulcers, but not from genital ulcers [153]. Similarly, in a trial study, also adalimumab was effective in improving the ocular involvement of patients suffering from BD [154]. Interferon (IFN)-α2a and IFN-α2b showed also in several trials [155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165] a good therapeutic efficacy in the control of neurological, mucocutaneous, and arthritic and ocular manifestations of BD. IFN was effective in the treatment of uveitis and mucocutaneous manifestations unresponsive to other immunosuppressive drugs, with the appearance of reactivation of disease after discontinuation of the therapy [166]. Mycophenolate, despite some case reports of effectiveness [167], has not been shown to be beneficial in BD patients with mucocutaneous involvement [168]. Thalidomide monotherapy instead showed, in a randomized placebo-controlled trial, discreet effectiveness after 4 weeks of treatment of oral ulcers and after 8 weeks of therapy of genital ulcers and cutaneous lesions [169]. Besides, in a randomized trial in which patients treated with rituximab in combination with methotrexate and prednisolone were compared to patients treated with cyclophosphamide in combination with azathioprine and prednisolone, the first group showed greater efficacy in the treatment of retinal vasculitis [170]. There are instead limited studies regarding the use of tocilizumab, pentoxifylline, plasmapheresis, and intravenous immunoglobulin in the treatment of BD [171, 172].

Neuro-Behçet: anatomical pathology, neuroimmunology, and therapy

The neurological involvement, when present, usually appears after an average of about 5 years after diagnosis of the disease and affects 5 % of patients with BD [173, 174, 175], although prospective studies evaluating neuro-Behçet patients with follow-up of about 20 years reported a frequency of cerebral involvement of 13 % in male patients and 5.6 % in female patients [176]. A similar gender-related difference has also been reported in some vascular complications of BD [176]. The most common form of neurological involvement in BD affects the brain parenchyma, is due to vasculitis of small vessels (intra-axial form), or can be linked to the presence of venous sinus thrombosis and, therefore, defined by some authors as “vascular-Behçet”(extra-axial form) [177, 178]. In recent years, the number of clinical cases of patients suffering from silent neuro-Behçet, characterized by the presence of alterations in neuroimaging, which does not correspond to a clear clinical manifestation, is also increased. These cases are defined subclinical neurological involvement [179]. The parenchymal involvement of the intra-axial form is most frequently characterized by the presence of focal or multifocal abnormalities, accompanied or not by headache, and consisting in pyramidal, cerebellar and cognitive deficits, including memory deficit [180] and behavioral disorders [179]. Less common are seizures and signs of involvement of the spinal cord, as well as isolated optic neuritis, aseptic meningitis, and extrapyramidal syndrome [179, 181, 182]. Some patients may also experience a form of psycho-neuro-Behçet characterized by the presence of emotional lability, euphoria, disinhibition, agitation, and obsessive behavior, not attributable to treatment with glucocorticoids or other drugs [183]. Headache is one of the most common symptoms of BD, is typically migrant, and is not associated closely with brain intraparenchymal alteration [176, 184], but rather to the systemic inflammation that accompanies exacerbations of BD [184]. The neuromuscular involvement instead is considered rare and includes multiple mononeuritis, distal sensorimotor neuropathy, and myositis with focal or generalized involvement [175, 178, 181, 185, 186, 187, 188]. Neuromuscular involvement may be coincidental or secondary to certain drugs used in the treatment of BD [7], such as thalidomide and colchicine, and is sometimes diagnosed only by electroneuromyography in patients with silent clinical symptomatology [178, 188]. The clinical course of neuro-Behçet can be acute in many cases [173, 174, 175] or be characterized by periods of relapse or subtly progress toward a chronic phase, leading to progressive and untreatable changes in behavior and ataxia, in anticipation of a neurological deterioration resulting in a significant disability [173, 174, 175]. In some cases, it may appear as a quite progressive form from the beginning [189, 190, 191]. The extra-axial form affects approximately 10–20 % of patients with neuro-Behçet [173, 175, 181, 192, 193] and, often being secondary to venous sinus thrombosis, can determine intracranial hypertension with papilledema and paresis of the cranial nerves (especially trochlear nerve), although fortunately for the majority of patients the main symptom is constituted by a slight intensity headache [173, 175, 181, 192, 193]. The arterial involvement in neuro-Behçet is generally rather rare and can determine occlusion of the carotid arteries, vertebral artery dissection or thrombosis, aneurysm, and intracranial arteritis [182, 194, 195, 196, 197, 198, 199]. The evolution of the extra-axial form is generally slow, although there are cases reported in the scientific literature of acute onset epilepsy and focal neurological signs [177]. From a neuropathological point of view, the intra-axial form of neuro-Behçet in the acute phase is characterized by the presence of perivascular infiltration of T lymphocytes and monocytes, and few B cells, resulting in apoptosis of some neurons [200]. This figure would lead, according to some authors, to consider neuro-Behçet as a “perivasculitis” [200, 201, 202]. From the purely neuroimmunological point of view in the intra-axial form instead, analysis of cerebrospinal fluid, when performed, showed the presence of leukocytosis and proteinorrachia [173, 174, 175], as well as high concentrations of IL6, that many studies have shown to have a central role in determining the neuronal damage, up to apoptosis of the cell [203, 204, 205]. In neuro-Behçet patients with intra-axial pattern, brain magnetic resonance imaging (MRI) is usually diagnostic and shows lesions most often localized to diencephalon, basal ganglia, and, less frequently, at the level of the periventricular area and subcortical white matter [206]. As mentioned, much less common is the involvement of the spinal cord and, if this occurs, MRI shows a particular involvement in the cervical area [6]. Besides, in the extra-axial pattern, the more frequent involvement of the post-capillary venules makes arteriography a little useful imaging technique to finalize the diagnosis [6]. The neurological involvement in BD is considered a major cause of disability, since about 50 % of patients experience moderate-to-severe disability during the 10 years following the diagnosis [175]. The cerebellar involvement, the chronic rather than acute course and pleocytosis accompanied by proteinorrachia are considered unfavorable prognostic factors [173, 179], whereas patients with headache, acute onset, and extra-axial form are considered to be at lower risk [179]. The treatment of the intra-axial form is different depending on whether it is acute episodical or chronic progressive. In the first case, glucocorticoids are preferentially used, although their use does not prevent the possible progression of the pathology. Generally, oral prednisolone (1 mg/kg for at least 4 weeks or until clinical improvement) or high-dose intravenous methylprednisolone (1 g/day for at least 5 days) is used and then scaled appropriately and kept in the next 2–3 months in order to prevent early flares [207, 208]. For the chronic progressive form, several immunosuppressive agents (colchicine, azathioprine, cyclophosphamide, methotrexate, IFN) have been used, and although each of them has led patients to a clinical benefit, none of them have been part of a study design adequately powered [207, 208, 209, 210]. Typically, such patients are treated with the addition of an immunosuppressant (azathioprine or cyclophosphamide) to corticosteroids. We advise against the use of cyclosporine because of its possible neurotoxicity [211, 212, 213], while there are reports of clinical efficacy in patients treated with methotrexate (5–15 mg/week) [214] and, recently, also in patients treated with anti-TNFα biological drugs, such as infliximab [215, 216, 217, 218, 219, 220]. The pattern of extra-axial neuro-Behçet, as already mentioned, is treated with the use of anticoagulants and glucocorticoids [177, 192, 207], although some authors prefer to use only glucocorticoids [193].

Conclusions

The chronic vasculitis underlying the clinical manifestations that characterize Behçet syndrome is provoked by environmental triggers, in all probability bacterial or viral, which set out or stimulate an autoimmune response in genetically susceptible subjects. Oral aphthous ulcers, genital ulcers, and uveitis typically wax and wane, occasionally occurring with inflammatory arthritis, phlebitis, iritis, as well as inflammation of the digestive tract, brain, and spinal cord. In recent times, innovative therapeutic strategies have advanced management of pathogenic mechanisms, enhanced control of clinical manifestations, and improved patient’s outcome and life expectancy.

Notes

Acknowledgments

The study was supported by the “5 × 1,000” voluntary contribution and by a Grant (GM) from the Italian Ministry of Health (RC1201ME04, RC1203ME46, RC1302ME31, and RC1403ME50) through Department of Medical Sciences, Division of Internal Medicine and Chronobiology Unit, IRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”, Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo (FG), Italy.

Conflict of interest

The authors declare that there are no conflicts of interest with respect to the authorship and/or publication of this article.

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© Springer-Verlag Italia 2014

Authors and Affiliations

  1. 1.Division of Internal Medicine and Chronobiology Unit, Department of Medical SciencesIRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”San Giovanni RotondoItaly
  2. 2.Division of Internal Medicine and Rheumatology Unit, Department of Medical SciencesIRCCS Scientific Institute and Regional General Hospital “Casa Sollievo della Sofferenza”San Giovanni RotondoItaly

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