INTRODUCTION — Behçet syndrome, also known as Behçet disease, is an inflammatory disease characterized by recurrent oral aphthous ulcers and numerous potential systemic manifestations. These include genital ulcers; skin lesions; and ocular, neurologic, vascular, articular, and gastrointestinal disease.
Many, but not all, clinical manifestations of Behçet syndrome are believed to be due to vasculitis. Among the systemic vasculitides, Behçet syndrome is remarkable for its ability to involve blood vessels of all sizes (small, medium, and large) on both the arterial and venous sides of the circulation.
The etiology and pathogenesis of Behçet syndrome are discussed in this review. The clinical manifestations, epidemiology, diagnosis, and treatment of this disorder are presented separately. (See "Clinical manifestations and diagnosis of Behçet syndrome" and "Treatment of Behçet syndrome".)
ETIOLOGY AND PATHOGENESIS — The underlying cause of Behçet syndrome is unknown. As with other autoimmune diseases, the disorder may represent aberrant immune activity triggered by exposure to an agent, perhaps infectious, in patients with a genetic predisposition to develop the disease. Both autoimmune and autoinflammatory features have been described. Major disease mechanisms in Behçet syndrome include the following [1]:
●Genetic influences, including association with certain human leukocyte antigens (HLA) as well as some non-HLA genes
●Altered host bacteria or bacteria response
●Altered innate immune function
●Altered populations of hematopoietic cells and associated cytokines
●Presence of immune complexes and autoantibodies
●Vascular endothelial activation and hypercoagulability
●Neutrophil activation
●Epigenetic alterations
Behçet syndrome is more common and often more severe along the ancient silk road, which extends from eastern Asia to the Mediterranean. Further discussion of Behçet syndrome epidemiology is presented separately. (See "Clinical manifestations and diagnosis of Behçet syndrome", section on 'Epidemiology'.)
Proposed triggering agents include viral and bacterial antigens or other environmental sources, such as chemicals or heavy metals. Direct infection of affected tissues has not been observed, although it is still a possible contributor. Unlike some other autoimmune diseases, cigarette smoking has not been shown to be a risk factor for the development of Behçet syndrome in most studies [2-4]. There have been case reports of Behçet-type disease manifestations in patients treated with interleukin (IL) 17 inhibitors including secukinumab [5-8].
Proteomics is the evaluation of the structure and function of proteins in an organism in order to better understand biologic systems. A proteomics study of 98 patients with Behçet syndrome and 31 healthy controls identified 220 differentially expressed proteins and in particular identified altered biologic processes involving complement activation, wound healing, angiogenesis, and leucocyte-mediated immunity, as well as identifying several potential biomarkers for vascular disease [9]. Another study identified 43 differentially expressed proteins, particularly involving toll-like receptor 9 and NF-kappaB signaling pathways, and also identified some potential biomarkers [10].
Genetic — Genetic predisposition to the disease is likely polygenic.
HLA genes — Increased risk of developing Behçet syndrome is associated with the presence of certain human leukocyte antigens, particularly HLA-B51 [11]. A meta-analysis of 4800 cases and 16,289 controls has shown a significant increase in the risk of HLA-B51/B5 carriers to develop Behçet syndrome compared with non-carriers (pooled odds ratio of 5.8) [12]. This relationship was consistent across multiple geographic locations, including Eastern Asia, Middle East/North Africa, Southern Europe, and Northern/Eastern Europe, but insufficient data were available for analysis of North American studies.
In individual studies, higher than baseline prevalences of HLA-B51 has been found in patients with Behçet syndrome in Italy (odds ratio of 5.9), in Germany, and in Middle Eastern and Far Eastern countries along the silk road (63 versus 9 percent in controls), of HLA-B52 (21 versus 9 percent) in Israel, and of HLA-B57 in the United Kingdom [13-19]. HLA-B5101 and, to a lesser extent, HLA-5108 alleles have been most closely linked in patients along the silk road [20]. Other HLA alleles may increase (HLA-B15, HLA-B27, HLA-B57, HLA-A26) or decrease (HLA-B49, HLA-A03) the risk for Behçet syndrome in various populations and in males and females [21-24]. However, the HLA contribution is estimated to be less than 20 percent [25].
There may also be a genetic contribution to disease severity. Presence of a HLA-B51 allele has been associated with worse disease in several studies [13,26-30].
Several possible mechanisms for the genetic linkage to HLA-B51 have been suggested:
●Alterations in the B pocket of the antigen-binding groove conformed by HLA-B51 may determine whether Behçet syndrome associated peptides bind and contribute to Behçet syndrome activity [31,32].
●Cross-reactivity between HLA-B51 and organ-specific antigens may exist [33].
●Linkage disequilibrium with other disease-associated genes has been reported on chromosome 6, including a tumor necrosis factor (TNF) promoter polymorphism in proximity to the HLA B gene locus, to the major histocompatibility complex class I chain-related gene A (MICA), a locus telomeric to the HLA-B site, and other nearby loci [17,19,34-39]. Several meta-analyses have demonstrated that the MICA A6 allele is associated with increased susceptibility to Behçet syndrome [40-42].
●HLA-B51 positivity is associated in patients with Behçet syndrome with HAP10, a low activity variant of endoplasmic reticulum aminopeptidase 1 (ERAP1). Endoplasmic reticulum aminopeptidases trim peptides in the endoplasmic reticulum to facilitate loading of these peptides onto the class I major histocompatibility complex. Cellular studies with HAP10 have demonstrated the production of longer peptides, with resultant changes to the peptidome, which may act to stimulate immune activity [43-45]. A study of ERAP1 and ERAP2 knockout transfectant HLAB51:01 cells demonstrated alterations in the HLA-B51 peptidome [46]. Other polymorphisms of the ERAP1 gene have also been described in association with Behçet syndrome [47-49].
Though most cases of Behçet syndrome are sporadic, families with multiple affected members, known as familial clustering, have been reported, and having a first-degree relative with Behçet syndrome does increase risk for the disease [50-52]. HLA-B51 rates are higher in familial than in sporadic cases. Affected children of patients with Behçet syndrome may have an earlier age of onset, a property termed genetic anticipation [53]; this characteristic has been linked, in many genetic disorders, to an increased number of nucleotide repeats within each successive generation. In Behçet syndrome, for example, a triplet repeat microsatellite polymorphism of (GCT)n found within a major histocompatibility complex (MHC) Class I related gene was found to be associated with the disorder in one study of 77 affected patients in Japan [54].
Non-HLA genes — Non-HLA genes also play a role in determining susceptibility to disease. Genome-wide screening of affected families with more than one affected member has identified additional, non-HLA regions of potential interest [55]. Examples include associations between Behçet syndrome and:
●Polymorphisms of the intercellular adhesion molecule (ICAM) 1 gene, the endothelial nitric oxide synthase gene, TNF genes, the vascular endothelial growth factor (VEGF) gene, manganese superoxide dismutase gene, cytochrome P450 gene, the interleukin (IL) 10 gene, the IL-23 receptor gene, and many other genes [17,26,56-83]
●Missense mutations of the familial Mediterranean fever (MEFV) gene, encoding the protein pyrin that is expressed of the surface of neutrophils [84-87]
Altered bacteria and bacteria response — Altered host bacteria or response to bacteria may play a role in the pathogenesis of Behçet syndrome.
Molecular mimicry may play a role, and studies suggest a possible pathogenic role of certain bacterial antigens that have cross-reactivity with human peptides. The cross-reactive self-antigens may include the heat shock proteins, a family of 60 to 90 kDa proteins produced by many cells in response to stress. These proteins have significant sequence homology between humans and bacteria. T cells and/or antibodies may recognize epitopes shared by both host and infectious organism heat shock proteins, thereby initiating and/or perpetuating Behçet syndrome.
Elevated levels of antibodies against epitopes of mycobacterial heat shock protein, some of which have significant homology to human heat shock proteins, have been observed among patients with Behçet syndrome. One study evaluated the antigenicity of 47 synthetic peptides (each 15 amino acids in length) derived from the sequence of the mycobacterial 65 kD heat shock protein [88]. Increased levels of IgG and IgA antibodies against three of these synthetic peptides was observed, two of which had significant homology to two areas of a human mitochondrial 60 kD heat shock protein. Exacerbations of ocular disease coincided with enhanced levels of these autoimmune antibodies [89]. Furthermore, these peptides can induce uveitis when injected into Lewis rats.
A response to mycobacterial heat shock proteins by gamma-delta T cells may play a role in the pathogenesis of Behçet syndrome. One study found that 25 of 33 patients with Behçet syndrome showed significant increases in gamma-delta T cells in response to exposure to mycobacterial heat shock proteins; by comparison, only 2 of 55 control individuals exhibited such an increase [90].
Specific bacteria, particularly streptococci, may also be important contributors to the immune response among patients with Behçet syndrome:
●Skin testing to streptococcal antigens often induces hypersensitivity reactions and sometimes results in systemic exacerbations of Behçet syndrome [91].
●A study of 106 patients with Behçet syndrome from Turkey showed a higher rate of Streptococcal mutans salivary colonization compared with controls, and colonization was associated with low levels of serum mannose-binding lectin compared with controls [92]. Another study of 54 patients with Behçet syndrome compared with 25 healthy controls and 8 patients with recurrent aphthous stomatitis found variations in oral mucosal and salivary microbial communities between the groups [93].
●Indirect evidence for cross-reactivity is suggested by the finding that patients with Behçet syndrome are more likely than normals to have significant antibody titers to Streptococcus sanguis [94,95]; this organism, particularly some with uncommon serotypes, is found at increased levels in the oral cavities of patients with the disorder. Circulating antibodies have been detected to streptococcal heat shock proteins [96]. Patients with Behçet syndrome demonstrate increased reactivity to lipoteichoic acid, a streptococcal antigen.
●Streptococcal antigens have been shown to increase IL-6 and interferon gamma secretion from the T lymphocytes of patients with Behçet syndrome and to upregulate their gamma delta T cells, which secrete IL-6, IL-8, and TNF-alpha [97-99].
●The importance of streptococcal infection was indirectly assessed by a prospective study which compared the efficacy of benzathine G penicillin plus colchicine in 94 patients with Behçet syndrome with that of colchicine alone in 60 patients [100]. Compared with colchicine alone, penicillin plus colchicine resulted in a significantly greater degree of improvement in mucocutaneous lesions.
●Studies have reported alterations in the microbiome in patients with Behçet syndrome [101-105]. An evaluation of the fecal microbiota of 22 patients with Behçet syndrome compared with 16 healthy cohabitating controls found significant differences in the microbiome signature of the patients with Behçet syndrome [101]. A study of 32 patients with active Behçet syndrome compared with 74 healthy controls found significant gut microbiome changes [102].
●Host response to Helicobacter pylori infection may play a role. This was illustrated in a study that found similar rates of serum H. pylori IgG levels between patients and controls but found a higher rate of H. pylori cytotoxin-associated gene-A antibodies in Behçet patients [106]. These antibodies have been postulated to be mediators of vascular damage in other conditions via cross-reaction with endothelin antigens. Helicobacter eradication in these patients decreased Behçet syndrome activity. A meta-analysis of six studies found a 1.39 times greater rate of H. pylori in patients with Behçet syndrome and improved mucocutaneous symptoms in treated patients [107].
Herpes simplex virus (HSV) has been investigated as a possible infectious trigger in Behçet syndrome. HSV type-1 genome has been isolated from the nuclei of lymphocytes in patients with Behçet syndrome, and immune complexes containing HSV-1 antigen have been reported. Other studies have not shown an association between HSV and Behçet syndrome, including polymerase chain reaction (PCR) testing of saliva and a randomized trial of acyclovir treatment that was not effective [20].
Parvovirus B19 was the subject of an investigation that used a semiquantitative technique to assess the amount of parvovirus B19 deoxyribonucleic acid (DNA) present in 40 patients and controls [18]. There was more B19 DNA present in the nonulcerative skin lesions of patients with Behçet syndrome than in the ulcerative skin lesions or in control patients [18].
Altered innate immune function — Mannose-binding lectin (MBL) is part of the innate immune system and activates the complement cascade after binding to carbohydrate structures on microorganisms. Low serum levels of MBL and MBL gene mutations have been observed in Behçet syndrome as well as in other autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Very low levels of MBL correlated with increased disease severity. Since MBL deficiencies are associated with increased risk of some infections, and since infectious disease has been associated with Behçet syndrome, MBL deficiencies may lead to impaired immune response against microorganisms and subsequent immune activation in Behçet syndrome [92,108].
Toll-like receptors are receptors on lymphocytes and some solid tissue cells which are directed against pathogenic microbes and which are a part of the innate immune system. Altered patterns of toll-like receptors have been described in Behçet syndrome [109-111]. Monocytes of patients with Behçet syndrome with active disease demonstrate increased activity of toll-like receptors 2 and 4, and, in one study, this was inversely correlated with 25-OH vitamin D levels [112,113]. Intestinal lesions in patients with Behçet syndrome expressed increased toll-like receptor 2 and 4 messenger ribonucleic acid (RNA) compared with healthy controls [114]. Messenger RNA of toll-like receptor 4 but not toll-like receptor 2 in peripheral blood mononuclear cells was elevated in a study of 47 active patients with active Behçet syndrome compared with controls, and methylation rate of toll-like receptor 4 but not toll-like receptor 2 was lower [115].
Cellular immunity and cytokines — In Behçet syndrome, there are alterations in the numbers of T cell subpopulations and evidence of cellular activation [1]. Autoreactive T cells appear to play a critical role in the pathogenesis of Behçet syndrome, and a trial of lymphocyte depletion with an anti-CD52 monoclonal antibody CAMPATH-1H appeared to reduce disease activity in 18 patients with Behçet syndrome [116]. As noted above, heat shock proteins or streptococcal antigens may play a role in stimulating oligoclonal T cell expansion [90]. Adenosine deaminase, an enzyme involved in lymphocyte proliferation, maturation, and differentiation, is activated in Behçet syndrome, particularly during disease exacerbations [117-119].
A T helper (Th) 1 predominant response has been observed in many studies of Behçet syndrome, but some studies have shown evidence for a Th2 response. In reality there may be a mix of Th1 and Th2 activity in Behçet syndrome [20,120-122]. Others have suggested that Th1 and Th17 may be involved in the disease's active phases, while Th2 may have an impact on disease course and severity [123].
Th1 lymphocytes, which produce cytokines IL-2, IL-6, IL-8, IL-12, IL-18, TNF-alpha, and interferon gamma, are increased in many studies in patients with Behçet syndrome [20,120,124-130]. Some studies have shown that serum levels of IL-12, soluble TNF-alpha receptors, and IL-8 may correlate with disease activity [131-135], while others have noted increased production of such cytokines from peripheral blood mononuclear cells of patients with Behçet syndrome regardless of disease activity [136]. Twenty-four patients with active ocular Behçet syndrome demonstrated elevated levels of IgA, C3, C4, IL-6, IL-8, and TNF-alpha compared with controls; a study of 43 patients with active versus inactive Behçet posterior uveitis showed activity correlated with increased serum levels of IL-6, IL-8, TNF-alpha, VEGF, and malondialdehyde (MDA) [128,137]. Elevated cerebrospinal fluid IL-6 levels have been observed in patients with Behçet syndrome with active neurologic disease and may be a marker of disease activity and persistence [138]. Increased IL-8, monocyte chemoattractant protein 1, interferon-gamma, and IL-12 messenger RNA were observed in biopsy specimens from 20 patients with active Behçet syndrome compared with healthy controls; no increase in IL-4 and IL-13 was observed in this study [127]. Increased expression of IL-23 messenger RNA has been described in Behçet erythema nodosum-like lesions [139]. It has been suggested that plasmacytoid dendritic cells and type I interferons play a role in polarizing the immune activity toward Th1 activity [140].
Th2 phenotype associated changes have also been observed. Studies have shown peripheral blood mononuclear cells from patients with Behçet syndrome produce increased amounts of IL-4, IL-10, and IL-13 [50,121,141]. Analysis of T cell subpopulations in patients with Behçet syndrome has shown relative increases in the CD8:CD4 ratio, with relative reductions in percentages of suppressor T cells, particularly in patients with active disease. Levels of serum soluble CD30, which is released from CD4+ Th2 cells and which is a marker of TH2 activity, is elevated in patients with Behçet syndrome with active disease.
T helper 17 (Th17) cells, which produce IL-17 and which are distinct from Th1 and Th2 lymphocytes, have been found to be increased and activated in patients with Behçet syndrome and may explain some of the apparently conflicting findings regarding Th1 and Th2 activity in this disorder [142-150]. A study of serum, bronchoalveolar lavage, and cerebrospinal fluid in 95 patients with active Behçet manifestations compared with 55 controls found elevated IL-26 levels, which have been found to promote the generation of TH17 cytokines [150].
Changes in T cell subsets have been identified in a number of studies, including increased numbers of T cells carrying the activation markers CD29 and CD69 [20,151-154]. Patients with Behçet syndrome have relatively high levels of gamma-delta T cells in the circulation and at inflammatory sites [88,90,151,155,156]; such cells are also present in peripheral blood in higher numbers during active versus quiescent Behçet syndrome (9 versus 2 percent, respectively) [155]. Gamma-delta T cell activation may be polyclonal; the response may be to a variety of antigenic stimuli [157]. Soluble CD28, which may play a role in T cell regulation, is elevated in the serum of patients with active Behçet syndrome, levels may correlate with disease activity, and polymorphisms of CD28 and CTLA-4 (which binds CD28) have been associated with Behçet syndrome [57,74,158]. HLA-B51 restricted CD8+ cytotoxic T lymphocytes autoreactive to MHC class I chain related gene A (MICA), a protein preferentially expressed on epithelial and endothelial cells in a stress-dependent manner, have been described in patients with Behçet syndrome [159].
Flow cytometric analysis of immune cells from the aqueous humor of patients with active Behçet uveitis showed elevated levels of CD8+ T cells and CD3+CD56+ NK T cells [160]. Other studies have also shown T lymphocyte infiltration into the eye in Behçet syndrome by CD4+ Th1 cells [161-163]. Th1 cytokines are elevated in the aqueous humor and serum of patients with Behçet uveitis [164,165]. Ocular fluid from patients with Behçet syndrome with active uveitis demonstrated inflammatory cytokines, including interferon, IL-2, TNF, IL-6, and IL-17, and activated ocular CD4+ T cells produced large amounts of TNF and IL-17, which were blocked in the presence of the TNF inhibitor infliximab [142].
Synovial fluid in Behçet syndrome demonstrates lower levels of inflammatory cytokines than that in patients with rheumatoid arthritis, a more erosive disease. One study showed elevated levels of IL-8 and soluble IL-2 receptor but relatively lower levels of TNF-alpha, IL-1 beta, IL-1 receptor antagonist, and transforming growth factor (TGF) beta than the synovial fluid from patients with rheumatoid arthritis. Another study showed elevated levels of IL-1 beta but lower levels of IL-18, TNF-alpha, and matrix metalloproteinase (MMP)-3 compared with rheumatoid arthritis [166]. Bronchoalveolar lavage from patients with Behçet pulmonary disease shows higher levels of IL-18 and interferon-gamma before and after LPS stimulation than in controls.
The inflammatory response in Behçet syndrome may be accentuated by refractoriness of activated T cells and neutrophils to apoptosis. T cells from patients with Behçet syndrome demonstrate resistance to spontaneous and CD95-induced apoptosis, and this may be mediated by NF-kappaB via regulation of apoptosis-related factors and death receptors [167]. Circulating neutrophils are resistant to apoptosis in the remission stage of Behçet uveitis [168].
Neopterin is secreted by monocytes and macrophages as a result of interferon-gamma secretion by activated T lymphocytes and may, therefore, be an indicator of cellular immune activation. Elevated serum and urine neopterin levels have been observed in patients with Behçet syndrome compared with controls [169,170].
Alterations in cellular signaling pathways in Behçet syndrome has been described. One study showed activation of the JAK1/STAT3 pathway in CD14(+) monocytes and CD4(+) T cells in nine patients with Behçet syndrome compared with nine healthy controls [171].
Autoantibody and immune complex formation — In addition to cellular immune activation, there is also evidence of humoral immune activation in Behçet syndrome. Increased numbers of circulating B lymphocytes have been observed; this appears to be antigen driven, not simply a polyclonal increase [20,172,173].
Autoantibodies appear to play a role in the pathogenesis of Behçet syndrome. Autoantibodies have been described against a number of targets including oral mucosal antigens, endothelial cells, T cell costimulatory molecule CTLA-4, killer immunoglobulin-like receptors, oxidized low-density lipoprotein, and kinectin [174-179]. Anti-Saccharomyces cerevisiae antibodies (ASCA) have been observed in patients with Behçet syndrome [180,181].
Autoimmune activity against retinal self-antigens appears to be important in the pathogenesis of Behçet uveitis [182]. Retinal-S antigen is localized to the photoreceptor of the retina, and has been shown to be a potent uveitic autoantigen [183]. Peripheral blood S-antigen responsive lymphocytes are elevated during exacerbations of ocular inflammation in patients with Behçet syndrome [184,185]. Other suspected Behçet syndrome retinal autoantigens are alpha tropomyosin, selenium binding protein, and interphotoreceptor retinoid binding protein [186-188]. Alpha-tropomyosin or kinectin is a membrane protein predominantly confined to the endoplasmic reticulum [186,189,190]. Immunization of rodents with alpha-tropomyosin can cause inflammation of the uveal tract and the skin, reminiscent of lesions seen in Behçet syndrome. Antikinectin antibodies are present at modestly higher rates and titers in patients with Behçet syndrome than in patients with other autoimmune connective tissue diseases [179].
Endothelial activation and altered coagulation — Endothelial dysfunction is a characteristic finding in Behçet syndrome [191]. Endothelium-dependent flow-mediated dilation is reduced [192,193]. Endothelial activation in affected blood vessels is a mediator of vascular inflammation as well as thrombosis in Behçet syndrome [174,175,194,195].
A number of molecules have been identified that interact to mediate endothelial dysfunction in Behçet syndrome. Nitric oxide (NO) is a highly reactive molecule associated with inflammatory activity and endothelial function. A number of lines of research have documented the role of NO in endothelial activation in Behçet syndrome, including increased serum, erythrocyte, synovial, and aqueous humor NO concentrations in Behçet syndrome, and elevated levels of NO metabolites compared with controls [175,196-200]. Polymorphisms of endothelial NO synthase genes and related genes have been associated with susceptibility to Behçet syndrome in some populations [56,58,60,64]. Elevated levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, have been observed in Behçet syndrome [201].
Increased oxidative stress has been observed in patients with Behçet syndrome. Findings have included increased plasma MDA, reduced glutathione:oxidized glutathione ratio, reduced superoxide dismutase, and elevated catalase [192,202].
Elevated mean plasma homocysteine levels have been observed in Behçet syndrome, and this has been found to be associated with NO concentrations and decreased flow-mediated vessel dilatation [203,204]. A number of studies have shown an association between Behçet syndrome and elevated homocysteine levels; hyperhomocysteinemia may be an acquired and potentially reversible risk factor for Behçet syndrome, may be a clinical marker of disease activity, and may be associated with thrombosis [20,169,205-207]. Increased rates of vitamin B12 and folate deficiency in patients with Behçet syndrome may contribute to hyperhomocysteinemia [208].
Vascular endothelial growth factor levels are higher in patients with Behçet syndrome and have been associated with increased disease activity and NO concentrations [73,209-211]. Cerebrospinal fluid VEGF levels were higher in a group of patients with Behçet syndrome with neurologic involvement compared with patients with noninflammatory neurologic diseases [212]. Polymorphisms of the VEGF gene are associated with Behçet syndrome, but not in all populations [56,58,59,213].
IgM-antiendothelial antibodies were found to be reactive with alpha enolase in some Korean patients with Behçet syndrome [214]. A follow-up study demonstrated IgM-antiendothelial antibodies in patients with Behçet syndrome (56 percent), systemic sclerosis (71.4 percent), rheumatoid arthritis (65 percent), Takayasu (50 percent), dermatomyositis (52.9 percent), and mixed connective tissue disease (45.5 percent); these antibodies were associated with the presence of vascular lesions in patients with Behçet syndrome [215]. Leptin is expressed by endothelial cells, and increased levels in Behçet syndrome may correlate with disease activity [216]. Endothelial cell activation and a generalized hypercoagulable state were observed in 24 patients with ocular Behçet syndrome characterized by increased mean levels of factor VIII, factor XI, von Willebrand factor antigen and ristocetin, antithrombin III, and fibrinogen [217].
A generalized hypercoagulable state appears to exist in many patients with Behçet syndrome. Thrombin formation is increased, and fibrinolysis is decreased [20,218,219]. Lower activated protein C (APC) and soluble thrombomodulin concentrations in the plasma of patients with Behçet syndrome have been observed. Thrombomodulin, present on the endothelial cell surface, binds thrombin, and the substrate specificity of thrombin thus bound is changed so that it preferentially activates protein C rather than cleaving fibrinogen. The APC generated at the endothelial surface is an important inhibitor of coagulation. (See "Overview of hemostasis".)
The findings of significantly decreased mean concentrations of plasma APC among 39 Spanish patients with Behçet syndrome versus healthy controls, and of lower levels of APC among patients with Behçet syndrome who had a prior thromboembolic episode versus those who had not, suggest that an acquired deficiency of APC in Behçet syndrome may contribute to the risk of thrombosis [220]. Platelet activity is increased in patients with Behçet syndrome [221]. Studies have shown decreased erythrocyte deformability in Behçet syndrome [222,223]. Tissue-type plasminogen activator levels are lower in patients with deep venous thrombosis who have Behçet syndrome than in those who do not have Behçet syndrome; this suggests a defect in fibrinolysis in Behçet syndrome [224].
A study of 98 patients with Behçet syndrome and 70 controls demonstrated in the patients with Behçet syndrome impaired thrombin-catalyzed fibrin formation and fibrin susceptibility to plasmin-induced lysis, associated with increased plasma oxidative stress markers, and increased neutrophil NADPH oxidase activity and reactive oxygen species production, which supports the role of neutrophil activation in thrombus formation in Behçet syndrome [225].
Thrombophilic factors such as factor V Leiden and prothrombin G20210A gene have not been linked to Behçet syndrome, although patients with Behçet syndrome with coexisting thrombophilic factors may be at higher risk for thrombosis [226,227]. Levels of the fibrinolytic inhibitors thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) were higher in patients with Behçet syndrome than in controls, particularly in those patients with thrombosis [228].
However, the majority of available evidence suggests that the pathogenesis of thrombosis in Behçet syndrome is not due to a hypercoagulable state as much as it is due to vascular damage induced by inflammation or intrinsic endothelial dysfunction that, by itself, serves as a source of thrombogenic stimuli [229-232].
Patients with Behçet syndrome have increased intima-media thickness and decreased arterial distensibility compared with controls [233].
Neutrophil activation — Polymorphonuclear leukocytes (PMNs) are activated in Behçet syndrome.
In Behçet syndrome, PMN motility is increased. Increased circulating levels of cytokines such as IL-8 and TNF-alpha lead to activation of PMNs and the endothelial surface [234,235]. Cell surface markers indicative of activation, such as CD64, are increased in patients with active disease to levels similar to those of patients with sepsis [236]. PMNs exhibit increased motility and enhanced adhesion to endothelial cells in vitro, a property due, in part, to increased expression of cell surface receptors including CD11a, CD18, and ICAM-1 [237]. Neutrophil binding to the endothelium is also facilitated by upregulated surface expression of adhesion molecules such as E-selectin. Increased E-selectin on the luminal surface favors neutrophil adhesion and facilitates neutrophil migration into the wall of the affected vessel and beyond [194].
Measurements of serum-soluble levels of this activity have been observed. Serum-soluble ICAM-1 is increased in patients with Behçet syndrome, and the concentration may correlate with disease activity [118,238]. The serum of patients with active Behçet syndrome may promote increased E-selectin presentation [121]. Some of this may be due to anti-endothelial antibodies [194]. Serum-soluble levels of selectin have been shown to be elevated in patients with active untreated disease but not if it is treated or inactive [239,240]. A study of patients with Behçet retinal vasculitis showed elevated levels of soluble E-selectin, s-ICAM-1, and Interferon-beta. In vitro studies showed that these were produced by activated retinal vascular endothelial cells and that this could be inhibited by pretreatment with anti-Toll-like receptor 3 [241].
The protein actin is required for PMN mobility. The presence of high levels of a truncated actin with an N-terminus of Met-44 has been observed in neutrophils from patients with Behçet syndrome; PMN-elastase responsible for this cleavage has been isolated. Resulting altered PMN activity has been described [242,243].
Increased amount of reactive oxygen species suggest neutrophil mediated immunity [20,244,245]. Endogenous free radical scavenging enzymes appear to be reduced in Behçet syndrome, creating an imbalance in the oxidant antioxidant equilibrium [20,117].
Serum granulocyte colony-stimulating factor (G-CSF) levels and neutrophil apoptosis are increased in active patients with Behçet syndrome compared with controls [246].
Markers of neutrophil activity have been proposed as possible indicators of disease activity and severity. These include polymorphonuclear elastase, plasma myeloperoxidase, and advanced oxidation protein products [118,247,248].
Neutrophil extracellular traps (NETs) are networks of extracellular fibers generated by neutrophils and that bind pathogens. A series of studies has demonstrated that circulating neutrophils from patients with Behçet syndrome versus controls more readily release NETs, and this was inhibited by colchicine and dexamethasone. The study also showed that serum from patients with Behçet syndrome stimulated neutrophils from healthy volunteers to release more NETs, endothelial cells from healthy volunteers were inhibited when cultured with NETs from patients with Behçet syndrome, and NETs were identified around blood vessels in specimens from patients with Behçet syndrome and vasculitis [249]. Another study found that circulating NETs and neutrophil-derived NETs were higher in Behçet syndrome patients, and the NETs promoted macrophage activation and facilitated T cell differentiation [250].
Matrix metalloproteinases play a role in leucocyte invasion of the central nervous system. Elevated levels of matrix metalloprotein-9 have been described in patients with Behçet syndrome compared with controls, and levels correlated with CSF neutrophil and mononuclear cells in a study of patients with Behçet syndrome with neurologic disease [251].
Behçet arthritis is characterized by synovial inflammation with significant neutrophilic greater than lymphocytic inflammation [252].
Monocytes from patients with Behçet syndrome have enhanced activity, with increased differentiation and expression of adhesion molecules and cytokines, which, in turn, leads to neutrophil activation [20,253,254].
Epigenetic alterations — Epigenetic changes may contribute to the pathophysiology of Behçet syndrome [255]. Epigenetics is the study of phenotypic cellular changes that occur due to changes in how genes are read or utilized by the cell and not due to changes in the gene sequences themselves.
Alterations of DNA methylation of immune cells in Behçet syndrome has been described. DNA methylation, addition of a methyl group to a carbon in cytosine rings within CpG dinucleotides, results in gene transcription repression. Hypomethylation allows ongoing transcription activity, and alterations in DNA methylation have been described in a number of immune diseases. A study of DNA methylation of monocytes and CD4+ T cells from 16 patients with Behçet syndrome compared with 12 healthy controls showed altered methylation patterns in genes involved in cytoskeletal dynamics, and these alterations were changed by disease treatment [256]. Other studies have also described alterations in DNA methylation in patients with Behçet syndrome [257].
PATHOLOGY — Histologic examination of involved tissue in patients with Behçet syndrome frequently reveals a vasculitis, although this finding may not be demonstrated in all lesions [1,258]. The classic Behçet lesion is necrotizing leukocytoclastic obliterative perivasculitis and venous thrombosis with lymphocytic infiltration of capillaries, veins, and arteries of all sizes. Cellular infiltration is often in a perivascular distribution; neutrophils and CD4+ T lymphocytes are present around the vasa vasorum and perivascular area. When a frank leukocytoclastic vasculitis is present, there may be endothelial swelling, extravasation of erythrocytes, and fibrinoid necrosis of blood vessel walls. Thrombosis is often present [20].
Mucocutaneous lesions demonstrate lymphocytic infiltration, immunoglobulin and complement deposition, and liquefaction-degeneration at the dermal-epidermal junction in association with necrosis and ulcer formation [259,260].
Neutrophilic and mononuclear infiltrates are frequently observed in spontaneous acute lesions and following testing for pathergy [1,261]. Histopathologic evaluation of 23 positive pathergy responses revealed mixed type inflammatory cell infiltrate in 39.1 percent, lobular panniculitis without vasculitis in 8.7 percent, neutrophilic infiltrate in 8.7 percent, and lymphocytic infiltration in 21.7 percent, with endothelial swelling and thickening in 17.3 percent, erythrocyte extravasation in 26 percent, perivascular cell infiltrate in 13 percent, lymphocytic vascular reaction in 8.6 percent, lymphocytic vasculitis in 13 percent, and leukocytoclastic vasculitis in 21.7 percent [262].
Papulopustular lesions may show leukocytoclastic vasculitis with IgM, IgG, C3, and fibrin deposits, consistent with an immune complex vasculitis [263,264]. Pustular skin lesions are often not sterile and may contain Staphylococcus aureus and Prevotella species [265].
Erythema nodosum type lesions in Behçet syndrome demonstrate lobular or mixed lobular and septal panniculitis; demonstrate variable numbers of neutrophils, lymphocytes, and histiocytes; and often show leukocytoclastic vasculitis.
Ocular Behçet lesions may show leukocyte infiltration around blood vessels, occlusive retinal perivasculitis, and thrombosis. Nongranulomatous panuveitis is characteristic. During active disease, neutrophils may be present in the anterior chamber of the eye, as well as the corneal epithelium, iris, ciliary body, and choroids [20].
Central nervous system lesions in Behçet syndrome demonstrate perivascular cuffing of T lymphocytes and monocytes, as well as apoptosis of affected neurons [266]. Involved areas include the spinal cord, brainstem (including the pons, medulla oblongata, and midbrain), cerebellum, basal ganglia, thalamus, internal capsule, and periventricular white matter.
Although renal involvement is infrequent and usually mild, when present, renal histology may show mesangial proliferation, proliferative glomerulonephritis, crescent formation, and deposits of immunoglobulin, complement, and immune complex in the glomeruli [267].
Behçet arthritis is characterized by synovial inflammation with significant neutrophilic greater than lymphocytic inflammation [252].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Behçet syndrome" and "Society guideline links: Vasculitis".)
SUMMARY
●Pathogenesis – Many, but not all, clinical manifestations of Behçet syndrome are believed to be due to vasculitis. Among the systemic vasculitides, Behçet syndrome is remarkable for its ability to involve blood vessels of all sizes (small, medium, and large) on both the arterial and venous sides of the circulation. (See 'Etiology and pathogenesis' above.)
●Pathology – Histologic examination of involved tissue in patients with Behçet syndrome frequently reveals a vasculitis, although this finding may not be demonstrated in all lesions. The classic Behçet lesion is necrotizing leukocytoclastic obliterative perivasculitis and venous thrombosis with lymphocytic infiltration of capillaries, veins, and arteries of all sizes. Cellular infiltration is often in a perivascular distribution; neutrophils and CD4+ T lymphocytes are present around the vasa vasorum and perivascular area. Other histologic findings may include panniculitis in erythema nodosum-like lesions and neutrophilic and mononuclear infiltrates in spontaneous acute lesions and following testing for pathergy. (See 'Pathology' above.)
●Etiology – The underlying cause of Behçet syndrome is unknown. As with autoimmune diseases, the disorder may represent aberrant immune activity triggered by exposure to an agent, perhaps infectious, in patients with a genetic predisposition to develop the disease. (See 'Etiology and pathogenesis' above.)
●Genetics – Genetic predisposition to the disease is likely polygenic. Genetic influences include association with certain human leukocyte antigens (HLA), including HLA-B51, but both HLA and non-HLA genes may play a role. (See 'Genetic' above and 'HLA genes' above and 'Non-HLA genes' above.)
●Bacterial antigens – Studies suggest a possible pathogenic role of certain bacterial antigens that have cross-reactivity with human peptides. Different studies have implicated various antigens and organisms, including heat shock proteins, streptococcal antigens, Helicobacter pylori, Herpes simplex virus, and parvovirus B19. (See 'Altered bacteria and bacteria response' above.)
●Innate immunity – Altered innate immune function has been suggested by some studies. These include investigations suggesting deficiencies in mannose-binding lectin and alterations in the expression of toll-like receptors. (See 'Altered bacteria and bacteria response' above and 'Altered innate immune function' above.)
●T-cell autoreactivity – There are alterations in the numbers of T cell subpopulations and evidence of cellular activation. Autoreactive T cells appear to play a critical role in the pathogenesis of Behçet syndrome. A T helper (Th) 1 predominant response has been observed in many studies of Behçet syndrome, but some studies have shown evidence for a Th2 response. There may be a mix of Th1 and Th2 activity in Behçet syndrome and increased activity of Th17 cells. (See 'Cellular immunity and cytokines' above.)
●Humoral immunity – In addition to cellular immune activation, there is also evidence of humoral immune activation in Behçet syndrome, and autoantibodies have been described against a number of targets. Immune complexes may also play a role. (See 'Autoantibody and immune complex formation' above.)
●Endothelial dysfunction – Endothelial dysfunction is a characteristic finding in Behçet syndrome. Endothelium-dependent flow-mediated dilation is reduced, and endothelial activation in affected blood vessels is a mediator of vascular inflammation as well as thrombosis in Behçet syndrome. (See 'Endothelial activation and altered coagulation' above.)
●Polymorphonuclear leukocytes – Polymorphonuclear leukocytes (PMNs) are activated in Behçet syndrome; PMNs exhibit increased motility and enhanced adhesion to endothelial cells in vitro. (See 'Endothelial activation and altered coagulation' above and 'Neutrophil activation' above.)
●Epigenetics – Epigenetic changes may contribute to the pathophysiology of Behçet syndrome. Alterations of DNA methylation of immune cells in Behçet syndrome has been described. (See 'Epigenetic alterations' above.)
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