Intern Emerg Med DOI 10.1007/s11739-013-1036-5
IM - REVIEW
Behc¸et’s syndrome pathophysiology and potential therapeutic targets Giacomo Emmi • Elena Silvestri • Danilo Squatrito Mario Milco D’Elios • Lucia Ciucciarelli • Domenico Prisco • Lorenzo Emmi
•
Received: 15 September 2013 / Accepted: 13 December 2013 Ó SIMI 2014
Abstract Behc¸et syndrome is a systemic inflammatory disorder characterized by multiorgan involvement such as oral and genital ulcers, uveitis, skin lesions as well as by less frequent, but often more severe, central nervous system and vascular manifestations. The pathogenetic mechanisms are still incompletely known; however the interaction between a specific genetic background and environmental or infectious factors certainly contributes to the immune dysregulation that characterizes this disease. The discovery of new immunological pathways in Behc¸et syndrome pathogenesis may help us to set up new treatments. In this review, we will focus our attention on the possible mechanisms underlying Behc¸et syndrome pathogenesis and their potential role as novel therapeutic targets. Keywords Behc¸et syndrome pathophysiology Behc¸et treatment Biologic therapy Anti-TNF-a IL-1 blocking agents
Introduction
and retinal vasculitis, recurrent thrombophlebitis or deep vein thrombosis and central nervous system involvement. Local or systemic corticosteroids associated with traditional immunosuppressive drugs have been the main therapeutic choice for years. More recently, the use of biologic therapy seems to be more effective for refractory cases, especially in those with ocular and neurological manifestations. However, the pathogenesis of BS appears to be very complex and currently not fully understood; the main actors are represented by the genetic background (HLAB*51 and non-HLA genes) and the activation of both innate and adaptive immunity by several pathogens with consequent interaction between T lymphocytes (with a Th1 and Th17 phenotype) and activated neutrophils. All these players are involved in different pathogenetic pathways eventually leading to tissue damage in BS. The discovery of new immunological mechanisms underlying BS pathogenesis may help us to better understand the action of the new biological agents, in particular anti-TNF-a, anti-IL-1 and anti-IL6R. In this review we will focus our attention on the possible pathogenetic mechanisms underlying BS and the potential role of new biological drugs.
Behc¸et syndrome (BS) is a systemic vasculitis characterized by mucocutaneous and joint manifestations, panuveitis Pathophysiology G. Emmi (&) E. Silvestri M. M. D’Elios L. Ciucciarelli D. Prisco Department of Experimental and Clinical Medicine, University of Florence, L.go G. Brambilla 3, 50134 Florence, Italy e-mail: [email protected]; [email protected] E. Silvestri D. Squatrito M. M. D’Elios D. Prisco L. Emmi SOD Patologia Medica, Center for Autoimmune Systemic Diseases, Behc¸et Center and Lupus Clinic, AOU Careggi, Florence, Italy
Genetic background The human leukocyte antigen (HLA) class I allele, HLAB*51, represents the major susceptibility genetic factor underlying BS in many populations, especially along the ancient Silk Route which ranged from East Asia to the Middle East and the Mediterranean area [1, 2]. The frequency of the HLA-B*51 allele, as well as BS prevalence, is lower in the US and European populations than in Silk
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Route area populations, suggesting that the geographical difference of HLA-B*51 frequency affects the prevalence of the disease. On the other hand, the frequency of HLAB*51 in some ethnic groups (e.g., Italian and Portuguese) is similar to the frequency in the Silk Route areas, despite a much lower prevalence of BS [3] suggesting that unknown environmental factors, particularly distributed on the Silk Route, may interact with HLA-B*51 alleles and are probably necessary for the development of BS. Moreover, despite our knowledge about this allele, the genetic background of BS is mostly unknown, but the existence of HLA-B*51-negative BS patients suggests that other genetic factors contribute to the development of the disease. Novel candidate genes for BS have been recently identified through a genome-wide association study (GWAS). In particular, the HLA-A*26 allele is significantly associated with BS independently of HLA-B*51, suggesting that HLA-A*26 is the second major susceptibility allele for BS, especially in the Japanese population [4]. Recently, polymorphisms in the loci of the genes encoding for IL-10 (IL10), IL-23 receptor (IL23R), IL-12 receptorb (IL12B2) [5] and STAT4 [6] are reported to be associated with an increased risk of developing BS in Turkish, Japanese and Korean populations. Since these genes encode for pivotal proteins particularly involved in Th1 and Th17 regulation, it is highly probable that an immune response involving IL-10, IL-23 receptor, IL-12 receptor b and STAT4 contributes to BS development; in particular, the variant rs897200 in STAT4 is able to upregulate interleukin-17 production suggesting a probable role in BS pathogenesis [6]. Other BS susceptibility genes recently identified by GWAS are ERAP1 (encoding for the endoplasmic reticulum aminopeptidase 1, particularly involved in antigen presentation) and CCR1–CCR3, which encode for the b chemokine receptor family, playing an important role in the recruitment and activation of inflammatory cells [7]. In a recent study, rare and lowfrequency nonsynonymous variants (NSVs) in one gene involved in innate immune response (TLR4) is associated with BS; moreover, the Familial Mediterranean Fever gene (MEFV) mutation Met694Val seems to confer a BS risk on the Turkish population. Thus the disease-associated NSVs in MEFV and TLR4 support the hypothesis of the correlation between innate immune response and bacterial sensing mechanisms in BS pathogenesis [8]. Interestingly, recent genetic data suggest the existence of common inflammatory mechanisms between BS and spondyloarthritis; indeed, BS shares three risk loci with ankylosing spondylitis and psoriasis (MHC class I region and its ERAP1 interaction, ERAP1 and IL23R) and two loci with inflammatory bowel disease (IL10 and IL23R). The specific features of these entities may be related to
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their different MHC class I associations (HLA-B*51 for BS, HLA-B*27 for ankylosing spondylitis and HLA-C*06 for psoriasis) [7]. Infectious factors A role of infectious agents as a possible trigger in BS pathogenesis has been hypothesized, and the most investigated microorganism is Streptococcus sanguinis; in particular, a role of oral flora has been considered, given the high frequency of oral ulcers, especially after dental work [9]. Indeed S. sanguinis has been detected more frequently in the oral flora of BS patients compared to healthy controls [10, 11], in particular uncommon S. sanguinis serotypes, such as KTH-1 [12]. Moreover, BS patients show skin test hypersensitivity with different streptococcal antigens [13], and recently a positive pathergy test has been found to be more sensitive with bacteria rich in self-saliva as compared to sterile saliva, probably due to the presence of oral Streptococcus [14]. It has been hypothesized that immunopathological responses can also be evoked in BS indirectly by different microbial products, such as heat shock proteins (Hsp), and these molecules may induce damage via several mechanisms. Hsp-specific T cells are well known for their ability to mediate tissue damage by both production of Th1 cytokines, such as IFN-c and TNF-a, and activation of cellmediated cytotoxicity [15]. Given the high homology between bacterial 65 kDa Hsp and human 65 kDa HSP [16], recurrent infections by Hsp-containing bacteria can determine, via molecular mimicry, the activation of immune response through pathogenic Hsp-specific T cells in genetically predisposed subjects. Actually, antibodies directed to several Hsp-65 epitopes have been demonstrated in BS patients, and, in particular, IgA antibodies specific to mycobacterial Hsp 65 are markedly increased [17]. It is noteworthy that antibodies specific to 65 kDa Hsp of both S. sanguinis and S. pyogenes, an antigen similar to mycobacterial Hsp-65, have been detected in BS. Some of the human and mycobacterial HSP/Hsp peptides have been shown to induce T-cell activation in patients with BS, as well as in an experimental mice model. When administered, both mycobacterial and human homologous peptides are able to induce uveitis, developing specific antibody response against HSP/Hsp peptides [18]. Streptococcus related BES-1 gene-derived peptides, homologous to Hsp-60 and retinal proteins, have been found to be able to stimulate peripheral blood mononuclear cells (PBMC) of BS patients [19]. Hsp-60 may act, directly or indirectly, via T cells, by stimulating the expression of VEGF and by inducing both vasculitis and thrombosis, via damaging endothelial cells [20]. Other cells of the immune system and cytokine networks leading to the production of
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IL-1 and IL-6 have been shown to be involved in the course of BS. cd T cells, which have a central role in the mucosal oral defense of the host, have been shown to be increased in the peripheral blood of patients with BS, especially during the active phase [21, 22] and following the stimulation with Hsp and other microbial antigens [21, 23]. These cells produce large amounts of inflammatory cytokines such as TNF-a and IFN-c [22].
IL-12 IL-6 CXCL10
IFN-γ IL-17
CXCL8
IL-18 BLys/APRIL
central nervous system involvement
eye involvement
vascular and muco-cutaneous involvement
Immune response BS is a systemic condition with a broad organ involvement, and therefore the therapeutic choice can vary on the basis of the specific organ area attacked by the disease. The immunopathological pathways underlying BS can partially explain the efficacy of the new therapeutic strategies used during recent years for this particular inflammatory condition. Several pathogens can activate innate immunity, especially neutrophils and cdT cells, and acquired immunity following antigen processing and presentation to naı¨ve T lymphocytes by antigen presenting cells (APCs). As mentioned above, the first response begins in the mucosa of patients with BS due to the recognition by cdT cells of bacterial Hsp largely homologous to human HSP, with non-MHC restricted mechanisms, and such homology maintains the immune response with a mechanism of molecular mimicry. cdT cells produce large amounts of TNF-a and IFN-c, with subsequent activation of macrophages and secretion of CXCL8, IL-1 and TNF-a [1]. A second way of activation of the immune response is also possible: antigen presentation by APC to naı¨ve CD4? T cells (in the context of MHC class II) leads to the production of IL-12 inducing a Th1 response. Recently, some data also demonstrate a possible role of Th17 cells and their cytokines in BS pathogenesis. Also, it is known that a milieu consisting of IL-6 or IL-1 with IL-23 is crucial for the differentiation of naı¨ve T lymphocytes into Th17 cells, and increased levels of IL-6 and IL-1 are documented in BS [24–26]. Furthermore, CD4 ? T cells producing IL-21 (crucial for the maintenance of differentiation of Th17) are significantly increased in the peripheral blood of patients with BS [27]. Neutrophils (together with lymphocytes) are the main responsible agents for tissue damage and have an intrinsic hyperactivation in BS patients, probably HLAB*51-related, since they are prone to be activated by IL-1, TNF-a and CXCL8 (mainly produced by macrophages) and by TNF-a, GM-CSF and CXCL8 produced by Th17 cells. CXCL8 acts on the recruitment and activation of neutrophils, which in turn are able to produce CXCL8, thus inducing an autocrine loop [1, 28]. The trans-endothelial crossing of neutrophils, induced by IL-1 and TNF-a overproduction, is made easier by the overexpression of
CCL3 CCL5 CXL8
Disease activity Fig. 1 Cytokine milieu, tissue damage and disease activity in Behc¸et syndrome patients
b-integrins on neutrophil surface and of ICAM 1 on previously activated endothelium [29]. Finally, an increased production of reactive oxygen species (ROS) by neutrophils, responsible for tissue damage, has been demonstrated in patients with BS; CXCL10 is also able to recall neutrophils into inflammatory sites [30] and this may explain the role of these cells upon the principal and most typical disease manifestations, such as pathergy lesions, hypopyon, pseudofolliculitis and vascular thrombosis (for cytokine milieu, tissue damage and disease activity, see Fig. 1). The pathogenesis of BS appears very complex; however, the main actors are represented by a genetic background (HLA-B*51 and non-HLA), the activation of both innate and adaptive immunity by several pathogens and the consequent interaction of T lymphocytes (with a Th1 and Th17 phenotype) with activated neutrophils, all of which are together responsible for tissue damage in BS. The discovery of new immunological pathways in BS pathogenesis may help us in understanding the mechanisms of action of the new biological agents, in particular anti-TNF-a, antiIL1 and anti-IL6R (for a schematic representation of BS pathogenesis, see also Fig. 2).
Potential therapeutic targets TNF-a Tumor necrosis factor a (TNF-a) is a major cytokine mainly produced by macrophages involved in many systemic inflammatory conditions, such as rheumatoid arthritis (RA), Crohn disease (CD) and psoriasis [31].
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Intern Emerg Med Fig. 2 Schematic representation of Behc¸et syndrome pathogenesis
genetic background
pathogens
innate immune response/γδT cells T cells activation Th1/Th17 cells CXCL8 neutrophils
tissue damage
PATHERGY
VASCULAR INVOLVEMENT
Pathophysiological basis Conflicting results have been reported on TNF-a concentration in sera of BS patients, but spontaneous and LPSstimulated production of TNF-a is markedly increased in BS patients, despite the absence of any correlation with disease activity [32]. More recently, a remarkable up-regulation of both TNFR II and IL-12Rb1 was observed in vitro, particularly in the presence of TNF-a [33]. cdT cells produce a greater amount of IFN-c and TNF-a in active BS patients compared to inactive ones [22, 34], while Vc9/Vd2 T cells activated in patients with active BS express increased levels of TNF-a receptors and IL-12 receptors [35]. In mice models, TNF-a plays a key role in the pathogenesis of ocular inflammation [36], and serum and intraocular TNF-a have been detected, especially in patients with active BS [32]. Therapeutic implications Over the last few years, three anti-TNF-a agents have been successfully used in patients with BS: infliximab—IFX (chimeric anti-TNF-a monoclonal antibody), adalimumab—ADA (fully human anti-TNF-a monoclonal antibody) and etanercept—ETN (fusion protein human p75 TNF-a receptor IgG1) [37]. Due to preliminary evidence, some BS patients with refractory posterior uveitis were treated with at least four infusions of IFX, usually at the
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HYPOPYON
PSEUDOFOLLICULITIS
dose of 5 mg/kg. All patients experienced a rapid remission of ocular inflammation over a few days. The efficacy of IFX in ocular manifestations of BS patients has been confirmed over the following years by additional studies [38]. IFX is also effective in different manifestations of BS, and recently its efficacy has been reported in patients with severe entero-Behc¸et, as well as neuro-Behc¸et [39, 40]. Following previous case reports, ADA, 40 mg/every 2 weeks, was also reported to be effective in treating all clinical features of 19 BS patients [41]. ETN was effective in the treatment of mucocutaneous manifestations of BS in a double-blind placebo-controlled study of 40 male patients [42]. Increasing evidence confirms the safety and efficacy of anti-TNF-a agents in the treatment of all resistant manifestations of BS. Moreover, IFX has been granted, by the Japanese Health Authorities, approval for BS with ocular and neurological involvement. To the best of our knowledge, only one case report about the successful use of golimumab exists [43]. In our experience, anti-TNF-a agents are very useful in every BS involvement. In particular, we used anti-TNF-a agents in 47 patients with resistant BS (nine of them used more than one anti-TNF-a): ADA is presently used in 29 of 32 treated patients (three discontinuations) with mucocutaneous, gastrointestinal, ocular and vascular involvement, with beneficial clinical effect. In severe neurological and ocular involvement and also in mucocutaneous resistant cases, IFX yields, in our experience (18 treated patients), more rapid
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and effective responses, while ETN has been used preferably for mucocutaneous involvement (personal unpublished data). IL-1 Interleukin 1 (IL-1), a highly active pro-inflammatory cytokine, is a master regulator in inflammation, together with TNF-a and IL-6; nowadays, blocking IL-1 has been proved to be useful in RA and autoinflammatory diseases (AID) [44]. Pathophysiological basis IL-1 has been found to be increased in sera [45] and synovial fluid [46] of BS patients. More recently, the time of onset of the disease has been correlated with single nucleotide polymorphisms (SNP) of IL-1 [47, 48]. The central role of innate immunity in BS pathogenesis is suggested not only by the increased levels of IL-1 in this condition, but also by the good therapeutic response to IL-1 blocking agents in AID. These disorders are genetically inherited entities that cause uncontrolled and spontaneous inflammatory events, in the absence of antigen-specific T-cell response or circulating autoantibodies. Since BS shares some common features with them, some suggest that it may be classified among these disorders [49, 50].
Pathophysiological basis IL-6 levels were demonstrated to be related to disease activity in BS [54, 55] and, in particular, this cytokine seems to play a pivotal role in central nervous system (CNS) involvement, as demonstrated by the high levels detected in the CSF [56]. Therapeutic implications Tocilizumab (TCZ) is a humanized anti-IL-6 receptor antibody, capable of binding both soluble and membranebound IL-6 receptor [57]. To date, TCZ has been successfully used for the treatment of three patients with refractory BS, two of whom had neuro-Behc¸et [58–60]. At the moment we do not have any personal experience with TCZ in neuro-BS patients. IFN-a Interferons (IFNs) are proteins released by host cells in response to pathogens or tumor cells; about ten distinct IFNs have been identified, and seven of these have been described for humans. IFN are typically divided among three classes: type I, type II and type III IFN. IFN-a is a pleiotropic cytokine belonging to type I IFN [61]. Pathophysiological basis
Therapeutic implications Three IL-1-blocking agents have been approved: the IL-1 receptor antagonist anakinra, the neutralizing monoclonal anti-IL-1b antibody canakinumab and the soluble decoy receptor rilonacept. Recently, IL-1b inhibition was proved successful in treating the ocular involvement of BS (two patients with canakinumab) [38], while anakinra was successfully used in a patient with a prevalent mucocutaneous involvement [51]. Moreover, in a phase II study, all seven patients with BS and refractory ocular involvement receiving gevokizumab, a monoclonal antibody targeted at IL-1b, achieved a rapid complete remission [52]. In our experience both anakinra [53] and canakinumab exert a beneficial effect on BS patients with refractory eye involvement resistant to other therapy (personal unpublished data).
Notably IFN-a, mainly produced by pDCs, is increased in patients with BS, particularly when the disease is active [24]. It has been shown to up-regulate IL-10, and thus to inhibit IL-17 production in PBMC of BS patients [62]. Therapeutic implications Over the years, a consistent body of evidence of efficacy of IFN-a in the treatment of BS has been provided by several trials, demonstrating its efficacy especially in mucocutaneous manifestations, but also with some positive benefits on arthritis frequency and thrombophlebitis [63]. Promising results have also been obtained by IFN-a use in BS ocular involvement for sight-threatening refractory uveitis [64, 65] with long-term efficacy and safety data [66]. Limiting factors for its use are the frequent side effects including flu-like symptoms.
IL-6 IL-6 is one of the most important mediators of fever and of the acute phase response; it is mainly produced by macrophages and, together with IL-1 with IL-23, is also crucial for the differentiation of naı¨ve T lymphocytes into Th17 cells, which are considered to play an important role in BS pathogenesis [25].
Anti-B cells therapy Pathophysiological basis Even though B lymphocytes do not seem to play a central role in the pathogenesis of BS, the B-cell activating factor
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Intern Emerg Med Fig. 3 Pathogenesis of Behc¸et syndrome and potential therapeutic targets
V A S C U L I T I S
PMN PMN
TNF-α
IL-17F/A
CXCL8/GM-CSF
TNF-α
IL-17F/A
PMN
IL-21
IFN-γ
Th1/Th17
PMN
Th17
CXCL8
IL-1
CXCL8 TNF-α
IL-10
IL-6
IL-1
IL-12Rβ2
Th1
M IFN-γ
IFN-γ
M
IL-23 IL-1
TNF-α
IL-6
IL-12R
IL-1
naïve Th
IL-23
γδ T IL-12
IL-12
IFN- α
mDC pDC
APC
BAFF/BLys
microorganisms APRIL
B CD20
genetic susceptibility
(BAFF) is overexpressed in the CNS of patients with neuro-BS [67] as well as in patients with cutaneous and pulmonary manifestations [68, 69]. BAFF is mainly produced by macrophages and neutrophils and is crucial for the survival of mature B cells [70].
membrane-bound BAFF or APRIL [73, 74], so that not all signaling through BAFF receptors is blocked (see Fig. 1). No data are at present available on the potential effectiveness of Belimumab in BS, especially in central nervous system involvement (for the potential therapeutic target based on BS pathogenesis, see Fig. 3).
Therapeutic implications Rituximab
Conclusions
Rituximab (RTX), an anti-CD20 ? monoclonal antibody, is mainly used for RA, but growing evidence and case reports suggest its off-label use in several conditions, such as vasculitis and lupus nephritis [71]. Its administration at a dose of 1,000 mg/intravenously repeated after 2 weeks every 6 months has been successful in 20 BS patients with severe ocular involvement [72].
Behc¸et syndrome is a systemic inflammatory condition characterized by several localizations, such as mucocutaneous and articular manifestations, panuveitis and retinal vasculitis, recurrent thrombophlebitis/thrombosis and central nervous system involvement. Its pathogenesis appears very complex; however, the main actors are represented by a genetic predisposition (mainly HLA dependent), the activation of both innate and adaptive immunity by several pathogens, with consequent interaction of both T lymphocytes (mainly Th1 and Th17 phenotype) and activated neutrophils: all together these different players are responsible for tissue damage in BS. The discovery of new immunological pathways in BS pathogenesis may help us to better understand the mechanisms of action of the new biological agents, in particular anti-TNF-a, anti-IL-1 and anti-IL6R. Indeed, local or systemic corticosteroids associated with traditional immunosuppressive drugs have been the main therapeutic choice for years. More recently, the use
Belimumab Belimumab is a monoclonal antibody against the B-lymphocyte stimulator BAFF/BlyS, recently approved as additional therapy for adult patients with systemic lupus erythematosus (SLE) [73]. BAFF is able to bind to three different receptors: transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), B-cell maturation antigen (BCMA) and BAFF receptor (BAFF-R) [73]. Belimumab is able to bind to soluble, but not
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of biologic therapy seems to be more effective for refractory cases, especially in those with ocular and neurological manifestations. Anti-TNF-a agents seem to be more effective in the control of all the protean manifestations of BS, in particular mucocutaneous, ocular, neurological and vascular. Accumulating reports suggest that also IL-1 blocking agents may be useful for refractory BS patients, especially for those with uveitis, while anti-IL6R agents seem to be a promising therapeutic choice for CNS manifestations. Acknowledgments The authors wish to thank the Associazione Italiana Sindrome e Malattia di Behc¸et (SIMBA) for its support to their studies. Conflict of interest
None.
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IM - REVIEW
Behc¸et’s syndrome pathophysiology and potential therapeutic targets Giacomo Emmi • Elena Silvestri • Danilo Squatrito Mario Milco D’Elios • Lucia Ciucciarelli • Domenico Prisco • Lorenzo Emmi
•
Received: 15 September 2013 / Accepted: 13 December 2013 Ó SIMI 2014
Abstract Behc¸et syndrome is a systemic inflammatory disorder characterized by multiorgan involvement such as oral and genital ulcers, uveitis, skin lesions as well as by less frequent, but often more severe, central nervous system and vascular manifestations. The pathogenetic mechanisms are still incompletely known; however the interaction between a specific genetic background and environmental or infectious factors certainly contributes to the immune dysregulation that characterizes this disease. The discovery of new immunological pathways in Behc¸et syndrome pathogenesis may help us to set up new treatments. In this review, we will focus our attention on the possible mechanisms underlying Behc¸et syndrome pathogenesis and their potential role as novel therapeutic targets. Keywords Behc¸et syndrome pathophysiology Behc¸et treatment Biologic therapy Anti-TNF-a IL-1 blocking agents
Introduction
and retinal vasculitis, recurrent thrombophlebitis or deep vein thrombosis and central nervous system involvement. Local or systemic corticosteroids associated with traditional immunosuppressive drugs have been the main therapeutic choice for years. More recently, the use of biologic therapy seems to be more effective for refractory cases, especially in those with ocular and neurological manifestations. However, the pathogenesis of BS appears to be very complex and currently not fully understood; the main actors are represented by the genetic background (HLAB*51 and non-HLA genes) and the activation of both innate and adaptive immunity by several pathogens with consequent interaction between T lymphocytes (with a Th1 and Th17 phenotype) and activated neutrophils. All these players are involved in different pathogenetic pathways eventually leading to tissue damage in BS. The discovery of new immunological mechanisms underlying BS pathogenesis may help us to better understand the action of the new biological agents, in particular anti-TNF-a, anti-IL-1 and anti-IL6R. In this review we will focus our attention on the possible pathogenetic mechanisms underlying BS and the potential role of new biological drugs.
Behc¸et syndrome (BS) is a systemic vasculitis characterized by mucocutaneous and joint manifestations, panuveitis Pathophysiology G. Emmi (&) E. Silvestri M. M. D’Elios L. Ciucciarelli D. Prisco Department of Experimental and Clinical Medicine, University of Florence, L.go G. Brambilla 3, 50134 Florence, Italy e-mail: [email protected]; [email protected] E. Silvestri D. Squatrito M. M. D’Elios D. Prisco L. Emmi SOD Patologia Medica, Center for Autoimmune Systemic Diseases, Behc¸et Center and Lupus Clinic, AOU Careggi, Florence, Italy
Genetic background The human leukocyte antigen (HLA) class I allele, HLAB*51, represents the major susceptibility genetic factor underlying BS in many populations, especially along the ancient Silk Route which ranged from East Asia to the Middle East and the Mediterranean area [1, 2]. The frequency of the HLA-B*51 allele, as well as BS prevalence, is lower in the US and European populations than in Silk
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Route area populations, suggesting that the geographical difference of HLA-B*51 frequency affects the prevalence of the disease. On the other hand, the frequency of HLAB*51 in some ethnic groups (e.g., Italian and Portuguese) is similar to the frequency in the Silk Route areas, despite a much lower prevalence of BS [3] suggesting that unknown environmental factors, particularly distributed on the Silk Route, may interact with HLA-B*51 alleles and are probably necessary for the development of BS. Moreover, despite our knowledge about this allele, the genetic background of BS is mostly unknown, but the existence of HLA-B*51-negative BS patients suggests that other genetic factors contribute to the development of the disease. Novel candidate genes for BS have been recently identified through a genome-wide association study (GWAS). In particular, the HLA-A*26 allele is significantly associated with BS independently of HLA-B*51, suggesting that HLA-A*26 is the second major susceptibility allele for BS, especially in the Japanese population [4]. Recently, polymorphisms in the loci of the genes encoding for IL-10 (IL10), IL-23 receptor (IL23R), IL-12 receptorb (IL12B2) [5] and STAT4 [6] are reported to be associated with an increased risk of developing BS in Turkish, Japanese and Korean populations. Since these genes encode for pivotal proteins particularly involved in Th1 and Th17 regulation, it is highly probable that an immune response involving IL-10, IL-23 receptor, IL-12 receptor b and STAT4 contributes to BS development; in particular, the variant rs897200 in STAT4 is able to upregulate interleukin-17 production suggesting a probable role in BS pathogenesis [6]. Other BS susceptibility genes recently identified by GWAS are ERAP1 (encoding for the endoplasmic reticulum aminopeptidase 1, particularly involved in antigen presentation) and CCR1–CCR3, which encode for the b chemokine receptor family, playing an important role in the recruitment and activation of inflammatory cells [7]. In a recent study, rare and lowfrequency nonsynonymous variants (NSVs) in one gene involved in innate immune response (TLR4) is associated with BS; moreover, the Familial Mediterranean Fever gene (MEFV) mutation Met694Val seems to confer a BS risk on the Turkish population. Thus the disease-associated NSVs in MEFV and TLR4 support the hypothesis of the correlation between innate immune response and bacterial sensing mechanisms in BS pathogenesis [8]. Interestingly, recent genetic data suggest the existence of common inflammatory mechanisms between BS and spondyloarthritis; indeed, BS shares three risk loci with ankylosing spondylitis and psoriasis (MHC class I region and its ERAP1 interaction, ERAP1 and IL23R) and two loci with inflammatory bowel disease (IL10 and IL23R). The specific features of these entities may be related to
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their different MHC class I associations (HLA-B*51 for BS, HLA-B*27 for ankylosing spondylitis and HLA-C*06 for psoriasis) [7]. Infectious factors A role of infectious agents as a possible trigger in BS pathogenesis has been hypothesized, and the most investigated microorganism is Streptococcus sanguinis; in particular, a role of oral flora has been considered, given the high frequency of oral ulcers, especially after dental work [9]. Indeed S. sanguinis has been detected more frequently in the oral flora of BS patients compared to healthy controls [10, 11], in particular uncommon S. sanguinis serotypes, such as KTH-1 [12]. Moreover, BS patients show skin test hypersensitivity with different streptococcal antigens [13], and recently a positive pathergy test has been found to be more sensitive with bacteria rich in self-saliva as compared to sterile saliva, probably due to the presence of oral Streptococcus [14]. It has been hypothesized that immunopathological responses can also be evoked in BS indirectly by different microbial products, such as heat shock proteins (Hsp), and these molecules may induce damage via several mechanisms. Hsp-specific T cells are well known for their ability to mediate tissue damage by both production of Th1 cytokines, such as IFN-c and TNF-a, and activation of cellmediated cytotoxicity [15]. Given the high homology between bacterial 65 kDa Hsp and human 65 kDa HSP [16], recurrent infections by Hsp-containing bacteria can determine, via molecular mimicry, the activation of immune response through pathogenic Hsp-specific T cells in genetically predisposed subjects. Actually, antibodies directed to several Hsp-65 epitopes have been demonstrated in BS patients, and, in particular, IgA antibodies specific to mycobacterial Hsp 65 are markedly increased [17]. It is noteworthy that antibodies specific to 65 kDa Hsp of both S. sanguinis and S. pyogenes, an antigen similar to mycobacterial Hsp-65, have been detected in BS. Some of the human and mycobacterial HSP/Hsp peptides have been shown to induce T-cell activation in patients with BS, as well as in an experimental mice model. When administered, both mycobacterial and human homologous peptides are able to induce uveitis, developing specific antibody response against HSP/Hsp peptides [18]. Streptococcus related BES-1 gene-derived peptides, homologous to Hsp-60 and retinal proteins, have been found to be able to stimulate peripheral blood mononuclear cells (PBMC) of BS patients [19]. Hsp-60 may act, directly or indirectly, via T cells, by stimulating the expression of VEGF and by inducing both vasculitis and thrombosis, via damaging endothelial cells [20]. Other cells of the immune system and cytokine networks leading to the production of
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IL-1 and IL-6 have been shown to be involved in the course of BS. cd T cells, which have a central role in the mucosal oral defense of the host, have been shown to be increased in the peripheral blood of patients with BS, especially during the active phase [21, 22] and following the stimulation with Hsp and other microbial antigens [21, 23]. These cells produce large amounts of inflammatory cytokines such as TNF-a and IFN-c [22].
IL-12 IL-6 CXCL10
IFN-γ IL-17
CXCL8
IL-18 BLys/APRIL
central nervous system involvement
eye involvement
vascular and muco-cutaneous involvement
Immune response BS is a systemic condition with a broad organ involvement, and therefore the therapeutic choice can vary on the basis of the specific organ area attacked by the disease. The immunopathological pathways underlying BS can partially explain the efficacy of the new therapeutic strategies used during recent years for this particular inflammatory condition. Several pathogens can activate innate immunity, especially neutrophils and cdT cells, and acquired immunity following antigen processing and presentation to naı¨ve T lymphocytes by antigen presenting cells (APCs). As mentioned above, the first response begins in the mucosa of patients with BS due to the recognition by cdT cells of bacterial Hsp largely homologous to human HSP, with non-MHC restricted mechanisms, and such homology maintains the immune response with a mechanism of molecular mimicry. cdT cells produce large amounts of TNF-a and IFN-c, with subsequent activation of macrophages and secretion of CXCL8, IL-1 and TNF-a [1]. A second way of activation of the immune response is also possible: antigen presentation by APC to naı¨ve CD4? T cells (in the context of MHC class II) leads to the production of IL-12 inducing a Th1 response. Recently, some data also demonstrate a possible role of Th17 cells and their cytokines in BS pathogenesis. Also, it is known that a milieu consisting of IL-6 or IL-1 with IL-23 is crucial for the differentiation of naı¨ve T lymphocytes into Th17 cells, and increased levels of IL-6 and IL-1 are documented in BS [24–26]. Furthermore, CD4 ? T cells producing IL-21 (crucial for the maintenance of differentiation of Th17) are significantly increased in the peripheral blood of patients with BS [27]. Neutrophils (together with lymphocytes) are the main responsible agents for tissue damage and have an intrinsic hyperactivation in BS patients, probably HLAB*51-related, since they are prone to be activated by IL-1, TNF-a and CXCL8 (mainly produced by macrophages) and by TNF-a, GM-CSF and CXCL8 produced by Th17 cells. CXCL8 acts on the recruitment and activation of neutrophils, which in turn are able to produce CXCL8, thus inducing an autocrine loop [1, 28]. The trans-endothelial crossing of neutrophils, induced by IL-1 and TNF-a overproduction, is made easier by the overexpression of
CCL3 CCL5 CXL8
Disease activity Fig. 1 Cytokine milieu, tissue damage and disease activity in Behc¸et syndrome patients
b-integrins on neutrophil surface and of ICAM 1 on previously activated endothelium [29]. Finally, an increased production of reactive oxygen species (ROS) by neutrophils, responsible for tissue damage, has been demonstrated in patients with BS; CXCL10 is also able to recall neutrophils into inflammatory sites [30] and this may explain the role of these cells upon the principal and most typical disease manifestations, such as pathergy lesions, hypopyon, pseudofolliculitis and vascular thrombosis (for cytokine milieu, tissue damage and disease activity, see Fig. 1). The pathogenesis of BS appears very complex; however, the main actors are represented by a genetic background (HLA-B*51 and non-HLA), the activation of both innate and adaptive immunity by several pathogens and the consequent interaction of T lymphocytes (with a Th1 and Th17 phenotype) with activated neutrophils, all of which are together responsible for tissue damage in BS. The discovery of new immunological pathways in BS pathogenesis may help us in understanding the mechanisms of action of the new biological agents, in particular anti-TNF-a, antiIL1 and anti-IL6R (for a schematic representation of BS pathogenesis, see also Fig. 2).
Potential therapeutic targets TNF-a Tumor necrosis factor a (TNF-a) is a major cytokine mainly produced by macrophages involved in many systemic inflammatory conditions, such as rheumatoid arthritis (RA), Crohn disease (CD) and psoriasis [31].
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Intern Emerg Med Fig. 2 Schematic representation of Behc¸et syndrome pathogenesis
genetic background
pathogens
innate immune response/γδT cells T cells activation Th1/Th17 cells CXCL8 neutrophils
tissue damage
PATHERGY
VASCULAR INVOLVEMENT
Pathophysiological basis Conflicting results have been reported on TNF-a concentration in sera of BS patients, but spontaneous and LPSstimulated production of TNF-a is markedly increased in BS patients, despite the absence of any correlation with disease activity [32]. More recently, a remarkable up-regulation of both TNFR II and IL-12Rb1 was observed in vitro, particularly in the presence of TNF-a [33]. cdT cells produce a greater amount of IFN-c and TNF-a in active BS patients compared to inactive ones [22, 34], while Vc9/Vd2 T cells activated in patients with active BS express increased levels of TNF-a receptors and IL-12 receptors [35]. In mice models, TNF-a plays a key role in the pathogenesis of ocular inflammation [36], and serum and intraocular TNF-a have been detected, especially in patients with active BS [32]. Therapeutic implications Over the last few years, three anti-TNF-a agents have been successfully used in patients with BS: infliximab—IFX (chimeric anti-TNF-a monoclonal antibody), adalimumab—ADA (fully human anti-TNF-a monoclonal antibody) and etanercept—ETN (fusion protein human p75 TNF-a receptor IgG1) [37]. Due to preliminary evidence, some BS patients with refractory posterior uveitis were treated with at least four infusions of IFX, usually at the
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HYPOPYON
PSEUDOFOLLICULITIS
dose of 5 mg/kg. All patients experienced a rapid remission of ocular inflammation over a few days. The efficacy of IFX in ocular manifestations of BS patients has been confirmed over the following years by additional studies [38]. IFX is also effective in different manifestations of BS, and recently its efficacy has been reported in patients with severe entero-Behc¸et, as well as neuro-Behc¸et [39, 40]. Following previous case reports, ADA, 40 mg/every 2 weeks, was also reported to be effective in treating all clinical features of 19 BS patients [41]. ETN was effective in the treatment of mucocutaneous manifestations of BS in a double-blind placebo-controlled study of 40 male patients [42]. Increasing evidence confirms the safety and efficacy of anti-TNF-a agents in the treatment of all resistant manifestations of BS. Moreover, IFX has been granted, by the Japanese Health Authorities, approval for BS with ocular and neurological involvement. To the best of our knowledge, only one case report about the successful use of golimumab exists [43]. In our experience, anti-TNF-a agents are very useful in every BS involvement. In particular, we used anti-TNF-a agents in 47 patients with resistant BS (nine of them used more than one anti-TNF-a): ADA is presently used in 29 of 32 treated patients (three discontinuations) with mucocutaneous, gastrointestinal, ocular and vascular involvement, with beneficial clinical effect. In severe neurological and ocular involvement and also in mucocutaneous resistant cases, IFX yields, in our experience (18 treated patients), more rapid
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and effective responses, while ETN has been used preferably for mucocutaneous involvement (personal unpublished data). IL-1 Interleukin 1 (IL-1), a highly active pro-inflammatory cytokine, is a master regulator in inflammation, together with TNF-a and IL-6; nowadays, blocking IL-1 has been proved to be useful in RA and autoinflammatory diseases (AID) [44]. Pathophysiological basis IL-1 has been found to be increased in sera [45] and synovial fluid [46] of BS patients. More recently, the time of onset of the disease has been correlated with single nucleotide polymorphisms (SNP) of IL-1 [47, 48]. The central role of innate immunity in BS pathogenesis is suggested not only by the increased levels of IL-1 in this condition, but also by the good therapeutic response to IL-1 blocking agents in AID. These disorders are genetically inherited entities that cause uncontrolled and spontaneous inflammatory events, in the absence of antigen-specific T-cell response or circulating autoantibodies. Since BS shares some common features with them, some suggest that it may be classified among these disorders [49, 50].
Pathophysiological basis IL-6 levels were demonstrated to be related to disease activity in BS [54, 55] and, in particular, this cytokine seems to play a pivotal role in central nervous system (CNS) involvement, as demonstrated by the high levels detected in the CSF [56]. Therapeutic implications Tocilizumab (TCZ) is a humanized anti-IL-6 receptor antibody, capable of binding both soluble and membranebound IL-6 receptor [57]. To date, TCZ has been successfully used for the treatment of three patients with refractory BS, two of whom had neuro-Behc¸et [58–60]. At the moment we do not have any personal experience with TCZ in neuro-BS patients. IFN-a Interferons (IFNs) are proteins released by host cells in response to pathogens or tumor cells; about ten distinct IFNs have been identified, and seven of these have been described for humans. IFN are typically divided among three classes: type I, type II and type III IFN. IFN-a is a pleiotropic cytokine belonging to type I IFN [61]. Pathophysiological basis
Therapeutic implications Three IL-1-blocking agents have been approved: the IL-1 receptor antagonist anakinra, the neutralizing monoclonal anti-IL-1b antibody canakinumab and the soluble decoy receptor rilonacept. Recently, IL-1b inhibition was proved successful in treating the ocular involvement of BS (two patients with canakinumab) [38], while anakinra was successfully used in a patient with a prevalent mucocutaneous involvement [51]. Moreover, in a phase II study, all seven patients with BS and refractory ocular involvement receiving gevokizumab, a monoclonal antibody targeted at IL-1b, achieved a rapid complete remission [52]. In our experience both anakinra [53] and canakinumab exert a beneficial effect on BS patients with refractory eye involvement resistant to other therapy (personal unpublished data).
Notably IFN-a, mainly produced by pDCs, is increased in patients with BS, particularly when the disease is active [24]. It has been shown to up-regulate IL-10, and thus to inhibit IL-17 production in PBMC of BS patients [62]. Therapeutic implications Over the years, a consistent body of evidence of efficacy of IFN-a in the treatment of BS has been provided by several trials, demonstrating its efficacy especially in mucocutaneous manifestations, but also with some positive benefits on arthritis frequency and thrombophlebitis [63]. Promising results have also been obtained by IFN-a use in BS ocular involvement for sight-threatening refractory uveitis [64, 65] with long-term efficacy and safety data [66]. Limiting factors for its use are the frequent side effects including flu-like symptoms.
IL-6 IL-6 is one of the most important mediators of fever and of the acute phase response; it is mainly produced by macrophages and, together with IL-1 with IL-23, is also crucial for the differentiation of naı¨ve T lymphocytes into Th17 cells, which are considered to play an important role in BS pathogenesis [25].
Anti-B cells therapy Pathophysiological basis Even though B lymphocytes do not seem to play a central role in the pathogenesis of BS, the B-cell activating factor
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Intern Emerg Med Fig. 3 Pathogenesis of Behc¸et syndrome and potential therapeutic targets
V A S C U L I T I S
PMN PMN
TNF-α
IL-17F/A
CXCL8/GM-CSF
TNF-α
IL-17F/A
PMN
IL-21
IFN-γ
Th1/Th17
PMN
Th17
CXCL8
IL-1
CXCL8 TNF-α
IL-10
IL-6
IL-1
IL-12Rβ2
Th1
M IFN-γ
IFN-γ
M
IL-23 IL-1
TNF-α
IL-6
IL-12R
IL-1
naïve Th
IL-23
γδ T IL-12
IL-12
IFN- α
mDC pDC
APC
BAFF/BLys
microorganisms APRIL
B CD20
genetic susceptibility
(BAFF) is overexpressed in the CNS of patients with neuro-BS [67] as well as in patients with cutaneous and pulmonary manifestations [68, 69]. BAFF is mainly produced by macrophages and neutrophils and is crucial for the survival of mature B cells [70].
membrane-bound BAFF or APRIL [73, 74], so that not all signaling through BAFF receptors is blocked (see Fig. 1). No data are at present available on the potential effectiveness of Belimumab in BS, especially in central nervous system involvement (for the potential therapeutic target based on BS pathogenesis, see Fig. 3).
Therapeutic implications Rituximab
Conclusions
Rituximab (RTX), an anti-CD20 ? monoclonal antibody, is mainly used for RA, but growing evidence and case reports suggest its off-label use in several conditions, such as vasculitis and lupus nephritis [71]. Its administration at a dose of 1,000 mg/intravenously repeated after 2 weeks every 6 months has been successful in 20 BS patients with severe ocular involvement [72].
Behc¸et syndrome is a systemic inflammatory condition characterized by several localizations, such as mucocutaneous and articular manifestations, panuveitis and retinal vasculitis, recurrent thrombophlebitis/thrombosis and central nervous system involvement. Its pathogenesis appears very complex; however, the main actors are represented by a genetic predisposition (mainly HLA dependent), the activation of both innate and adaptive immunity by several pathogens, with consequent interaction of both T lymphocytes (mainly Th1 and Th17 phenotype) and activated neutrophils: all together these different players are responsible for tissue damage in BS. The discovery of new immunological pathways in BS pathogenesis may help us to better understand the mechanisms of action of the new biological agents, in particular anti-TNF-a, anti-IL-1 and anti-IL6R. Indeed, local or systemic corticosteroids associated with traditional immunosuppressive drugs have been the main therapeutic choice for years. More recently, the use
Belimumab Belimumab is a monoclonal antibody against the B-lymphocyte stimulator BAFF/BlyS, recently approved as additional therapy for adult patients with systemic lupus erythematosus (SLE) [73]. BAFF is able to bind to three different receptors: transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), B-cell maturation antigen (BCMA) and BAFF receptor (BAFF-R) [73]. Belimumab is able to bind to soluble, but not
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of biologic therapy seems to be more effective for refractory cases, especially in those with ocular and neurological manifestations. Anti-TNF-a agents seem to be more effective in the control of all the protean manifestations of BS, in particular mucocutaneous, ocular, neurological and vascular. Accumulating reports suggest that also IL-1 blocking agents may be useful for refractory BS patients, especially for those with uveitis, while anti-IL6R agents seem to be a promising therapeutic choice for CNS manifestations. Acknowledgments The authors wish to thank the Associazione Italiana Sindrome e Malattia di Behc¸et (SIMBA) for its support to their studies. Conflict of interest
None.
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