Review Article | Published:

Behçet syndrome: a contemporary view

Nature Reviews Rheumatology volume 14, pages 107119 (2018) | Download Citation

  • A Corrigendum to this article was published on 24 January 2018

This article has been updated

Abstract

The presence of symptom clusters, regional differences in disease expression and similarities with, for example, Crohn's disease suggest multiple pathological pathways are involved in Behçet syndrome. These features also make formulating disease criteria difficult. Genetic studies have identified HLA-B*51 to be the important genetic risk factor. However, the low prevalence of HLA-B*51 in many patients with bone fide disease, especially in non-endemic regions, suggests other factors must also be operative in Behçet syndrome. This consideration is also true for the newly proposed 'MHC-I-opathy' concept. Despite lacking a clear aetiological mechanism and definition, management of manifestations that include major vascular disease (such as Budd–Chiari syndrome and pulmonary artery involvement), eye disease and central nervous system involvement has improved with the help of new technology. Furthermore, even with our incomplete understanding of disease mechanisms, the prognoses of patients with Behçet syndrome, including those with eye disease, continue to improve.

Key points

  • Both the disease presentation and evidence from basic studies suggest more than one pathogenetic mechanism is involved in Behçet syndrome. Recognized vascular manifestations in Behçet syndrome include venous claudication, bronchial arterial collaterals (causing haemoptysis) and 'silent' Budd–Chiari syndrome

  • The diagnostic specificity of certain manifestations, such as eye disease or vascular involvement, might be more pathognomonic than other manifestations, such as gastrointestinal ulcerations

  • In considering the clinical and the basic science findings in Behçet syndrome, the weight of evidence suggests Behçet syndrome should not to be grouped with other, seemingly related, conditions

Main

Although Behçet syndrome is increasingly being recognized, investigated and effectively managed, its aetiology remains unclear. Indeed, the difficulty in developing universal classification criteria stems from the geographical variation in prevalence and disease expression in addition to the accumulating evidence that Behçet syndrome has several clinical subsets. Paradoxically, the more we learn, the more difficult our task of understanding Behçet syndrome becomes. Perhaps for this very reason, we prefer, contrary to the prevailing view, to refer to Behçet's as a syndrome rather than a disease. Here, we discuss the emerging, most-recent evidence on the aetiology, manifestations and epidemiology of this syndrome. We also include updated information on prognosis and management for practicing rheumatologists.

Disease definition and differential diagnosis

As virtually no unique histological or laboratory features have been identified to help in diagnosis, clinical features are instead used to define and diagnose Behçet syndrome (Table 1). Although the International Study Group Criteria for Behçet Disease (ISBD) criteria1 are the most widely used criteria, two important limitations should be noted. Firstly, of the patients with Behçet syndrome who were used to formulate the criteria, close to 80% of patients were from the Middle East (where associated gastrointestinal involvement is infrequent2). Furthermore, the control group mainly comprised patients with various connective tissue diseases and not with Crohn's disease or ulcerative colitis; this might have occurred owing to simple oversight or because distinguishing Behçet syndrome from Crohn's disease is difficult. Secondly, the ISBD criteria did not consider symptom prevalence or syndrome prevalence, which is important given the settings in which these criteria were going to be used. To address these issues, a new set of criteria for classification and/or diagnosis of Behçet syndrome has been developed3, but, like the ISBD criteria, does not take into consideration the baseline probability of any one person having Behçet syndrome in the geographical region where these criteria will be used. This fact is important because Behçet syndrome shows marked geographical differences in prevalence (see below, Epidemiology). Importantly, referring to disease criteria as classification criteria rather than diagnostic criteria does not solve the issue of pre-test probabilities. We argue that separate classification and diagnostic criteria are unrealistic because a diagnosis is nothing more than the application of classification criteria in an individual patient4.

Table 1: Features helpful in the differential diagnosis of Behçet syndrome

Behçet syndrome, like all other syndromes, is a construct and we propose this construct has both strong and weak elements (Table 2). We define a strong element as a feature that attempts to define Behçet syndrome as a distinct nosological entity — that is, a pathological condition with a unique pathogenesis and more or less unique features that distinguish it from other pathological conditions. By contrast, the weak elements are those features that point to more than one common pathogenetic mechanism5. In addition, contrary to the strong elements, the value of weak elements in differential diagnosis might differ. Although the presence of subgroups are among the weak elements we list in Table 2, they can be useful in diagnosis. For example, the sudden onset of severe headache in a patient with inferior vena caval thrombosis in Behçet syndrome should immediately alert us to the possibility of the presence of a dural sinus thrombosis6.

Table 2: Strong and weak elements* to discriminate Behçet syndrome

Strong elements

Behçet syndrome is rarely present in the absence of a history of recurrent oral ulceration1. As such, it is an essential element of the construct because its absence strongly suggests another diagnosis. Three other strong elements have become apparent during the formal data analyses for the ISBD criteria1 in which the presence of genital ulcers, pathergy (whereby a skin prick a develops into a papule or a pustule) and eye involvement have shown highest numerical discriminatory value to be included in the criteria set. Furthermore, a subsequent factor analysis7 revealed that eye disease by itself without other variables was disease-defining for Behçet syndrome among 13 other variables examined. Indeed, eye disease as a strong element was also recently supported by a study from Tugal-Tutkun et al.8 in which ophthalmologists examining retinal photographs from patients and suitable diseased controls could identify ocular signs of Behçet syndrome that could be considered diagnostic even in the absence of other clinical information. Recurrent genital ulcerations had the highest discriminatory value in the ISBD criteria. Morphologically, they are similar to oral ulcers, but are deeper, larger and can take longer to heal. Genital scarring is usually strong evidence of the presence of Behçet syndrome. Interestingly, these lesions specifically locate on the scrotum in men and in the labia in women9, but are more-severe in men10. Finally, recent evidence suggests that testosterone increases neutrophil activity in Behçet syndrome11.

We also consider major vascular disease12,13,14 and parenchymal neurological involvement as strong elements. These manifestations are relatively rare compared with skin and mucosal lesions and eye disease, but owing to their unique features have substantial value in differential diagnosis. For example, pulmonary or peripheral arterial aneurysms in a young man (<45 years of age) in an endemic area is very suggestive of Behçet syndrome15. In addition, extensive lesions involving the brainstem, basal ganglia or isolated brainstem atrophy are quite unique to and diagnostic of Behçet syndrome16,17,18.

Weak elements

Gastrointestinal involvement in Behçet syndrome is one of the four weak elements of the construct (Table 2). Distinguishing Behçet syndrome from other inflammatory bowel diseases can be extremely difficult19 unless other pathologies are present. For example, a study of pathergy in our centre revealed 10% of patients with inflammatory bowel disease who also had features of Behçet syndrome tested positive to the pathergy skin test, showing how difficult it can be to differentiate Behçet syndrome from inflammatory bowel diseases in general20. Additionally, an Immunochip gene-association study among Turkish, Japanese and Iranian patients with Behçet syndrome identified significant risk loci in common with Crohn's disease21, supporting a common disease mechanism. Accordingly we propose gastrointestinal manifestations are weak elements in the diagnosis.

Another weak element of the construct of Behçet syndrome is the marked geographic variation in its prevalence and severity. Usually, less-severe disease expression is observed in non-endemic areas (see below, Epidemiology section). Although this variation could be the result of differing environmental and/or genetic factors affecting disease expression, the possibility of different disease mechanisms causing similar phenotypes cannot be ruled out given what we understand about Behçet syndrome.

We had previously divided Behçet syndrome into disease clusters or subtypes5 based on the tendency of certain features to cluster together. Two such clusters are acne–arthritis–enthesitis and vascular disease subsets. The acne–arthritis–enthesitis subset22 could have been the main reason for the initial inclusion of Behçet syndrome among the seronegative spondyloarthritides23 by the virtue of some shared clinical features. More recently, interest in this subset has reemerged24 (see below, MHC-I-opathy section). The vascular disease subset has received increased attention perhaps owing to a wider use of imaging to assess patients. Although vascular manifestations tend to cluster together during the disease course13, which suggests more than one common pathogenetic mechanism, these can be helpful in diagnosing Behçet syndrome. For example, the onset of haemoptysis in a patient with suspected Behçet syndrome alerts to the presence of a pulmonary artery aneurysm rather than pulmonary emboli, which are not common in Behçet syndrome probably owing to the adherent nature of the venous thrombi seen in this condition12.

Finally, we consider the different response to various drugs as weak element in our construct. The effectiveness or ineffectiveness of a certain agent to control various manifestations of a disease can give us clues about the underlying disease mechanisms25. For example, colchicine is useful for arthritis and erythema nodosum but not particularly effective for skin-mucosa ulcers26 whereas thalidomide is good for oral ulcers but can exacerbate the erythema nodosum27. In addition, etanercept is excellent for treating oral ulcers but has no effect on the pathergy reaction28. We consider these varying responses as another indicator of our proposal that more than one disease mechanism is operative in Behçet syndrome.

As is perhaps true in any other disease of unknown aetiology, more information is needed before we are able to develop precise classification or diagnostic criteria. In the meantime, we propose that the weak elements of the construct of Behçet syndrome tell us we should continue to evaluate emerging aetiological clues carefully.

Aetiology and pathogenesis

As for many other inflammatory rheumatological diseases of unknown aetiology, Behçet syndrome had been considered an autoimmune disease for many years. Supportive of this notion were data showing T cell responses to heat shock proteins of Streptoccus spp. and Mycobacterium tuberculosis as well as autoantibodies against endothelial cells, enolase and retinal S-antigen. However, these events were generally considered to only be related to tissue injury and not directly to the disease pathogenesis29. Some clinically important differences between Behçet syndrome and other autoimmune diseases have also been noted, including sex differences in disease expression and a lack of comorbidities with other autoimmune diseases30. Interestingly, antibodies to human and mouse neurofibrils that crossreact with Streptococcus spp. and M. tuberculosis heat shock proteins have recently been shown in Behçet syndrome31, bringing revived consideration of an adaptive immune response in the pathogenesis — as one would expect in an autoimmune disease.

Behçet syndrome has also been considered an autoinflammatory disease32. It is reasonable to consider Behçet syndrome as a polygenic autoinflammatory disease when Crohn's disease is considered as such. For example, pro-inflammatory IL-1β is increased in active Behçet syndrome, including in the aqueous humour33. Additionally, variants of MEFV (encoding pyrin, mutations in which play a central part in inflammation in familial Mediterranean fever) as well as mutations in genes encoding the Toll-like receptors, which are important in innate immunity34, are also present in a minority of patients with Behçet syndrome. However, the proposed clinical similarities between Behçet syndrome and monogenic autoinflammatory diseases such as familial Mediterranean fever are not quite convincing35. Indeed, two paramount differences are that almost all autoinflammatory diseases begin in childhood whereas Behçet syndrome frequently begins after puberty and that prominent vasculitis is not a common feature of autoinflammatory conditions whereas at least in a major subset of those with Behçet syndrome patients display vascular involvement. Furthermore, IL-1β blockade, which has been quite successful in treating autoinflammatory diseases, has not been convincingly successful in Behçet syndrome36.

Here, we propose that because a common and dominant pathological factor for Behçet syndrome has not been identified, and that it is possible that there is no single common denominator, referring to Behçet's as a syndrome rather than a disease is preferable. That is, the current evidence for disease definition and disease mechanisms in Behçet's suggests 'splitting', in which searching for what is unique about Behçet's, will be more fruitful than 'lumping' in which likeness with other conditions is sought. We will briefly elaborate on 'lumping' in discussing attempts to consider Behçet syndrome as a MHC-I-opathy.

MHC-I-opathy?

The concept of seronegative spondyloarthritides (SpA) was introduced in 1974 to describe rheumatoid factor negative inflammatory arthritis, which predominantly involves the axial skeleton and sacroiliac disease. Patients with this group of diseases are also frequent carriers of HLA-B*27. Initially, Behçet syndrome had been included in this group23; however, it was soon realized that patients with Behçet syndrome were carriers of HLA-B*51 rather than HLA-B*27 and that axial skeletal arthritis was not prominent in these patients, leading to the removal of Behçet's from the SpA concept37. Recently, the debate on whether this classification was correct has been rekindled, owing to two observations24. Firstly, important data have emerged that some of the inflammatory pathways considered operative in the seronegative SpA ankylosing spondylitis (AS) and psoriatic arthritis (PsA), such as the IL-10 and IL-23–IL-17 pathways, have also been observed in Behçet syndrome24,38. Secondly, as mentioned, acne and arthritis commonly occur in patients with Behçet syndrome and these patients also commonly have enthesitis22, which is a phenotypic feature related to the SpA.

Evidence in support of Behçet syndrome being related to AS and PsA also stems from the most important genetic risk factor for Behçet syndrome, HLA-B*51 (Ref. 24), which is an MHC class I allele. The gene was found to be epistatic with ERAP1, which encodes endoplasmic reticulum aminopeptidase 1 — a molecule in the endoplasmic reticulum that prepares (trims) peptides for presentation to effector cells by MHC class I molecules38,39,40. Importantly, polymorphisms in ERAP1 have also been reported as important as susceptibility loci for PsA and AS41,42. Mechanistically, altered trimming of either exogenous (such as microbial) or endogenous peptides by the ERAP1 variants might render them disease-promoting or disease-preventing.

Given that Behçet syndrome, AS and PsA are associated with variants in HLA genes encoding MHC class I, it is interesting to note that variants in these genes are also either disease-promoting (in AS) or disease-preventing (in Behçet syndrome24). This observation has led to the concept of 'MHC-I-opathy' (Ref. 24), and is supported by the following observations. Firstly, the different HLA allele associations determine disease tissue-localized manifestations; for example, HLA-B*51 is associated with eye or skin disease in Behçet syndrome, HLA-C*0602 is associated with skin lesions and increased disease severity in PsA and HLA-B*27 is associated with enthesitis and eye involvement in AS. Secondly, localized areas of stress, such as the entheses in AS and Behçet syndrome, or the skin, such as in the pathergy phenomenon in Behçet syndrome and the Koebner phenomenon in psoriasis are important in triggering innate immunity. Thirdly, the immune and inflammatory responses in these diseases all share elements of both innate and adaptive pathways.

In the MHC-I-opathy concept, more weight is given to the innate immune response than to the adaptive immune response, suggesting that the adaptive response facilitates the induction of inflammation rather the inflammation driving the disease24. This emphasis is similar to that which has been placed on the innate immune response as central in the pathogenesis of AS and PsA43. The adaptive immune response aspect of the MHC-I-opathy concept is mediated by cytotoxic T cells, in which putative antigens presented by the MHC class I molecules activate T helper 1 (TH1) and TH17 cell pro-inflammatory activity24. However, other cell interactions might be culpable in the pathogenesis of Behçet syndrome. For example, although altered antigen presentation by the MHC encoded by HLA-B*51 in patients not carrying protective ERAP1 polymorphisms is indeed important in causing tissue injury, the mechanism might not rely on cytotoxic T cells44. Instead, antigen presentation might occur mainly to natural killer cells44. Additionally, the presence of HLA-B*51 does not readily explain the cytokine polarization profile observed in the condition44.

Not restricted to a discussion of the MHC-I-opathy concept, which does not seemingly assign a specific role to HLA-B*51 in cytokine polarization44, a consideration of the mechanisms of cytokine control is also needed. In Behçet syndrome, the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway is important45; Tulunay and colleagues investigated this canonical pathway in peripheral blood mononuclear cells from those with Behçet syndrome using whole-genome microarray profiling46. They observed increased JAK–STAT signalling in both CD 4+ T cells and CD4+ monocytes compared with the healthy controls. The authors speculated this signalling stems from activity of TH1 and TH17-type cytokines, such as IL-2, IFNγ, IL-6, IL-17 and IL-23, and not through TH2 cell activation as one would expect in an MHC class II-associated autoimmune disease.

A microbial trigger?

As in other inflammatory conditions of unknown aetiology, interest in finding a microbial cause for Behçet syndrome has been pursued47. However, thus far no single pathogen has emerged as a likely candidate. Oral infections, which had originally been proposed by Behçet himself to be a trigger48, have continued to be proposed as disease-inciting49. A collaborative study, the first formal microbiome study in Behçet syndrome50, proposed a distinct salivary signature. This study revealed less bacterial diversity in individuals with Behçet syndrome than among healthy controls; in a subset of patients, periodontal treatment corrected the oral health issues but not the bacterial distribution. Whether these findings in the oral flora are causative of Behçet syndrome or a consequence of the condition is unclear51.

The intestinal microbiota are also beginning to be studied in Behçet syndrome and a proposal for a specific microbiome signature — namely, a paucity of genera Roseburia and Subdoligranulum along with a decrease in butyrate production — has been made and, more recently, an abundance of bifidobacteria has been described52,53. In line with these findings, mutations in FUT2, which encodes the fucosyltransferase 2 present in intestinal and oral epithelial cells, has been reported in Behçet syndrome54 — similar to what has been reported in patients with Crohn's disease55. Epithelial α1,2-fucose molecules formed by the enzymatic action of fucosyltransferase 2 are important to bacterial symbiosis in the gut and also form a barrier against pathogenic bacteria56; mutations in FUT2 impair this barrier.

Epigenetics

Epigenetic information is becoming increasingly available in Behçet syndrome. For example, differential methylation of genes associated with cytoskeletal remodelling and cell adhesion in circulating CD4+ T cells and monocytes have been identified in patients with Behçet syndrome57. Importantly, these changes revert to normal after treatment, particularly for genes involved in microtubule structure (KIFA2 and TPPP)58, suggesting that, with further validation, methylation patterns might be useful as biomarkers or theurapeutic targets.

Micro RNAs, another main form of epigenetic influence have also been studied. TH17 cell effects have attracted particular attention in the light of miR-155 expression; however, the work is still in its nascent state and the results are somewhat conflicting58. In brief, epigenetic influences are particularly important and deserve more attention in Behçet syndrome in that they might be instrumental in explaining the geographical and envorinmental differences that are prominent in this condition59.

Summary

As we try to outline above, there is more to know about the disease mechanisms in Behçet syndrome. Importantly, we currently have much better insight about how HLA-B*51, the most established risk factor for Behçet syndrome, might be operative in pathogenesis. On the other hand, the frequency of HLA-B*51 is 60% even in areas where Behçet syndrome is endemic60 and is much lower in other regions. This frequency certainly implies the HLA B*51 association cannot wholly explain what we call Behçet's today. Furthermore, none of the data discussed adequately address important manifestations of Behçet syndrome, such as thrombosis (with its resistant thrombi61) or the unique parenchymal brain disease. Taken together, we consider the current evidence supporting the notion that Behçet's is a syndrome rather than a disease.

Epidemiology

Further underlying the complexity of classification and definition of Behçet syndrome are regional differences in disease expression. Behçet syndrome is sometimes referred to as the Silk Route disease because of its frequency in the Middle East and far-east Asia (Fig. 1); these regions have traditionally been considered the endemic areas for the condition62. However, increasing awareness of the condition along with the recent increases in human migration is changing this view. For example, Behçet syndrome was traditionally viewed as very rare among black individuals, but a study from Dakar, Senegal, reported a case series of 50 patients with Behçet syndrome with a proposed yearly incidence of 3.84 per 100,000 population63. Another study showed that 70% of patients in southern Sweden were of non-Swedish ancestry64; studying immigrant populations in traditionally non-endemic areas can provide useful insights into gene–environment interactions and enable us to identify environmental and perhaps modifiable risk factors.

Figure 1: The prevalence of Behçet syndrome.
Figure 1

Prevalence (shown as people per 100,000 population) of Behçet syndrome is higher along the ancient Silk Route (for example, Turkey, Iran, Japan and Korea) than in other parts of the world123. Prevalence also increases from north to south, with much lower figures in the United Kingdom than in Italy and Spain. Immigration patterns also seem to have an increasing influence on Behçet syndrome prevalence in Europe and have provided interesting insights. For example, studies from Germany and the Netherlands have shown that although prevalence is higher in immigrant populations than the general German or Dutch populations, this prevalence is somewhat lower than that in the countries of origin65,66.

For example, both Germany and the Netherlands have sizeable Middle-Eastern immigrant populations65,66. In both countries, the prevalence of Behçet syndrome among immigrants is lower than that reported in their countries of origin, but higher than that among native Germans and Dutch65,66. The Dutch study from Rotterdam reported that a minority of patients from immigrant backgrounds (14 out of 72 patients, 19%) were indeed born in the Netherlands66. Accordingly, it would be of interest to know the prevalence among those who had recently migrated to the Netherlands compared with second-generation or third-generation immigrants to better understand the role of environment factors in pathogenesis.

In contrast with the German and Dutch studies, data from immigrants living in Paris, France, have indicated that the frequency of Behçet syndrome is not different than that in the countries of origin67, which would provide another avenue for understanding the influence of environmental factors on prevalence. However, the study was a survey-based report in socially under-privileged areas of Paris, which raises the possibility of socioeconomic factors influencing the results.

In the United States, an estimated prevalence of 5.2 per 100,000 population was reported between 1996 and 2005 (Ref. 68). Contemporary US data has been collected in New York, New York, since 2005 (Ref. 69). Among 313 consecutive patients, those with a northern European background had more gastrointestinal disease (81 out of 172 patients, 47%) compared with the group of patients who were ethnically from endemic areas (40 out of 141 patients, 28%); this difference was statistically significant (P = 0.001)69. For the whole New York cohort, less eye disease and vascular involvement than other centres from Turkey and Japan was reported69. Approximately one-third of patients had eye disease in each group; interestingly with only one blind eye in total. Similarly, milder disease has also been reported among patients from other non-endemic areas70.

Clearly, more comparative epidemiology work is needed in Behçet syndrome to guide us in diagnosis, for fair allocation of resources and perhaps decipher the disease mechanisms in this very complex condition. Perhaps in comparative formal hospital-based surveys, which use the frequencies of other diseases, such as rheumatoid arthritis, that do not have apparent differences in frequency across different geographies, Behçet's can be of help71.

Clinical manifestations

Clinical manifestations in Behçet syndrome are variable and characterized by unpredictable periods of recurrences and remissions, although the frequency and severity tend to abate with time. Skin-mucosa lesions are the most common manifestation and are usually the presenting symptoms, whereas ocular, vascular and neurological involvement are less common but more serious10,12,14,17,18. The overall mortality rate of patients with Behçet syndrome is significantly increased among younger men (<25 years of age) and early in the disease course among those with major organ involvement. In a 20 year follow-up study of a large inception cohort in our dedicated clinic (n = 428, of which 286 were male and 142 were female), a total of 42 (39 male, 3 female) patients had died at the end of the survey10. Age-matched standardized mortality ratios were specifically increased among young males (that is, the 14–24 years of age and 25–34 years of age groups) whereas older males (35–50 years of age) and females had a normal lifespan. Furthermore, the mortality rate was highest early after disease onset (the first 7 years) and had a tendency to decrease with time. Major causes of mortality were large vessel disease and parenchymal central nervous system (CNS) disease. Later, a French group showed a mortality rate of 5% during a median follow-up of 8 years in a cohort of 817 patients72. Factors associated with mortality in this study were similar to what we observed10.

Quality of life is impaired in Behçet syndrome, with fatigue being an important problem that is correlated with quality of life, disease activity, depression, anxiety and physical functioning73,74,75,76. Suicidal ideation is more frequent among patients with major organ involvement; pain, impaired quality of life, depression, CNS involvement and past prednisolone use have been shown to be independent predictors of suicidal ideation77.

Oral ulceration

Oral ulcerations are usually the first as well as the most frequent symptoms. Minor aphthous ulcers (<10 mm in diameter) are the most common type. Although quite similar to recurrent aphthous stomatitis, oral ulcers in Behçet syndrome could be multiple, more painful and more frequent. Local trauma, certain types of food, menstruation and cessation of smoking are described as triggering factors78. The frequent occurrence of attacks of oral ulceration during early Behçet's was found to predict the development of major organ involvement among male patients79. Oral ulcers continue to develop for many years after disease onset80, but all other manifestations usually resolve10.

Eye involvement

Lesions — such as a smooth-layered hypopyon (a leukocytic exudate in the anterior chamber of the eye), superficial retinal infiltrates with retinal haemorrhages and branch retinal vein occlusion with vitreous haze — were identified as pathognomonic for Behçet syndrome uveitis as indicated above8. Specialized imaging techniques such as optical coherence tomography (OCT) and fluorescein angiography are becoming useful tools in the diagnosis and assessment of disease activity81,82,83. Additionally, central foveal thickness has been suggested as a non-invasive measure to assess inflammatory activity in early uveitis82 and localized non-glaucomatous retinal nerve fibre layer defects, as an indicator of posterior pole involvement83.

The prognosis of eye disease has improved in recent years. For example, Chung et al.84 reported that mean visual acuity was better among patients whose first visit to a dedicated Behçet syndrome clinic in Korea was between 2004 and 2010, than those who registered between 1994 and 2000. Similarly, Cingu et al.85 reported that the risk of losing useful vision was lower in patients in Turkey who presented between 2000 and 2004 than in patients who presented between 1990 and 1994. They observed that the risk of having loss of useful vision at 3 years of follow-up decreased from 27.6% (43 out of 156 eyes) in the 1990s to 12.9% (26 out of 201 eyes) in the 2000s. In line with this finding, risk of having loss of useful vision was 13% at 10 years of follow-up in a study by Taylor et al.86 in the United States and 14.4% at 1-year of follow-up in a study by Accorinti et al.87 in Italy.

Vascular involvement

Except for non-pulmonary arterial disease, which occurs at a later age (≥40 years of age), 75% of patients with Behçet syndrome experience their first vascular event within 5 years of disease onset13. Additionally, the cumulative relapse rate of vascular events was found to be 23% at 2 years and 38% at 5 years13. In the vascular subset (see above and Table 2), several types of vascular manifestation tend to occur in the same individual, creating statistically significant associations across all patients; for example, cerebral venous sinus thrombosis and pulmonary artery involvement (PAI) tend to co-occur, as do intracardiac thrombosis and PAI, and Budd–Chiari syndrome and inferior vena cava syndrome12,13,14.

Lower extremity vein thrombosis (superficial and deep) is the most common form of vascular involvement and leads to severe post-thrombotic syndrome and venous claudication88 (Fig. 2a). PAI can manifest as pulmonary arterial aneurysms and single in situ pulmonary arterial thromboses12 (Fig. 2b). A wide range of pulmonary parenchymal lesions such as nodules, consolidations and cavities are also part of the vascular manifestations12. Mild elevation of pulmonary arterial pressure can be associated with PAI89 and bronchial arterial collaterals emerge as another cause of haemoptysis in patients with Behçet syndrome who are in remission90. Aneurysms or thromboses can regress in 70% of patients with immunosuppressive treatment12. The relapse rate is 20% and mortality rate is 25% at 7 years, despite tight control of disease activity, frequent medical visits and aggressive management12. Increased diameter of the aneurysms and high pulmonary arterial pressures at presentation are poor prognostic factors for survival12.

Figure 2: Vascular involvement in Behçet syndrome.
Figure 2

Vascular involvement is an early and relapsing event in Behçet syndrome and occurs in up to 40% of patients. a | Ulceration on the distal tibia in a 34-year-old male patient. Superficial and deep femoral vein thromboses were the initial symptoms, which recurred despite immunosuppressive treatment. Eventually, post-thrombotic syndrome with ulceration, oedema, induration, hyperpigmentation and superficial skin collaterals developed. b | Bilateral, multiple pulmonary arterial aneurysms (arrows) on a CT scan of a 28-year-old male with Behçet syndrome who presented with haemoptysis, chest pain, dyspnoea and fever. Additionally, mural thrombosis inside the aneurysms can be observed. c | Thorax of a 26-year-old male with juvenile-onset Behçet syndrome who presented with ascites, abdominal pain and fever. The hepatic segment of the inferior vena cava and all three hepatic veins were occluded with thrombi. Intensive immunosuppressive treatment resolved most of the symptoms, although he subsequently developed bilateral gynaecomastia and diffuse abdominal collaterals, which can be ascribed to residual mild liver insufficiency.

Budd–Chiari syndrome mostly involves the inferior vena cava (the suprahepatic and hepatic segments) and the hepatic veins. In patients who present with ascites (Fig. 2c), the mortality rate is 60% within a median of 10 months after diagnosis14. However, in some patients, Budd–Chiari syndrome develops gradually without ascites. Imaging studies using ultrasonography or CT show that these individuals have efficient collateral formations. These 'silent' patients have more favourable outcomes, with <10% expected mortality at 7 years14.

CNS involvement

CNS disease occurs in 5–10% of patients with Behçet syndrome, mostly in the form of parenchymal brain involvement. Brainstem involvement is the most characteristic type of involvement. Pyramidal signs, hemiparesis, behavioural–cognitive changes, sphincter disturbances and/or impotence are the main clinical manifestations of CNS involvement. Psychiatric problems might also develop in some patients91.

Sometimes, the clinical presentation of CNS disease in Behçet syndrome can be taken for multiple sclerosis, in which case MRI findings are helpful91. In contrast to the large extensive lesions of CNS involvement in Behçet syndrome, multiple sclerosis has more discrete and smaller brainstem lesions. Optic neuritis, sensory symptoms and spinal cord involvement, which are common in multiple sclerosis, are seldom observed in Behçet syndrome. White matter lesions are also different: in multiple sclerosis, lesions tend to be supratentorial and periventricular with corpus callosum involvement, whereas in Behçet syndrome, lesions are small, bihemispheric and subcortical. The cerebrospinal fluid patterns also differ: pleocytosis is more prominent in multiple sclerosis, whereas oligoclonal band positivity (that is, the gold-standard test for multiple sclerosis) is rarely observed in Behçet syndrome91.

Compared with patients with multiple sclerosis, patients with Behçet syndrome who have CNS involvement have poorer performance on several measures of cognitive status92. Moreover, a subgroup of patients with Behçet syndrome may present with multiple sclerosis-like features on MRI93. These patients were more likely to be female, to have increased number of neurological attacks, to have a higher rate of oligoclonal band and to have less pleocytosis. This implicates that disease mechanisms in multiple sclerosis and Behçet syndrome might be similar. Finally, quantitative analysis of the brainstem by MRI has been suggested as an effective diagnostic tool for, as well as in monitoring the evaluation of disease activity in, chronic progressive Behçet syndrome with CNS involvement94 (Fig. 3).

Figure 3: CNS involvement in Behçet syndrome.
Figure 3

Cranial MRI scans a 30-year-old male patient with Behçet syndrome of 12 years' duration. Central nervous system (CNS) involvement began 10 years after diagnosis with severe headache, speech difficulties, swallowing problems and cognitive disturbances. a | MRI T2-weighted axial sequence show pontine (arrow) and cerebellar (arrowhead) atrophy. b | Also evident are an ischaemic lesion on the pons (arrow) and fourth ventricle dilatation (arrowhead), which are other characteristic lesions of brainstem atrophy. c | Sagittal sequence similarly shows the same lesions (arrow).

Finally, Noel et al.95 investigated the outcomes of a large cohort of patients (n = 115) with CNS involvement, excluding dural sinus thrombosis. The authors found that after a median follow-up of 6 years, 30% of patients relapsed after immunosuppressive treatment, 25% of patients became dependent on care takers and 10% had died95.

Gastrointestinal involvement

Gastrointestinal involvement in Behçet syndrome resembles Crohn's disease in its presentation, with abdominal pain and diarrhoea that may be accompanied by bleeding, and is an uncommon manifestation in geographies other than in far-east Asia2. Behçet syndrome usually causes round or oval ulcers most commonly in the terminal ileum96. Ulcers are usually deep, large and single with a tendency to perforate or cause massive bleeding. Mucosal biopsies show chronic or active mucosal inflammation as well as vasculitic findings in a small proportion of patients96. Faecal calprotectin levels are associated with disease activity, similar to Crohn's disease97. Even with treatment, relapses may occur in 20% of patients96.

Management and outcome measures

The goals of management in Behçet syndrome are to rapidly suppress inflammatory exacerbations and to prevent relapses to maintain good quality of life and preserve organ function. A treat-to-target strategy has not been well established owing to a lack of standardized outcome measures that define remission, low disease activity or a target score (or level of change from baseline) that predict a better outcome. Although several outcomes and outcome measures have been used in clinical trials, many of these have not been validated or widely accepted98. The variability in outcomes and outcome measures has made it difficult to compare the efficacy of treatment modalities and help make treatment decisions99. Furthermore, the assessment of Behçet syndrome is complicated owing to the frequently relapsing but less-disabling skin, mucosal and joint involvement against a backdrop of the less-frequent but more-serious (and even life threatening) nature of major organ involvement. Efforts are ongoing to develop a core set of outcome measures for Behçet syndrome clinical trials100.

Despite these difficulties, management can still be individualized depending on what we know regarding the prognoses of patients with Behçet syndrome. This approach is also emphasized in the 2016 EULAR recommendations101. Younger patients and male patients who have higher risk of severe disease should be followed-up closely for the development of major organ involvement and treated aggressively when such involvement is noted.

Skin, mucosal and joint involvement

The management of patients with only skin, mucosal and joint involvement is determined by the frequency and severity of their lesions and the extent to which these lesions impair their quality of life. The patient's perception and preferences are important in making treatment decisions as these lesions do not cause damage and are neither organ-threatening nor life-threatening.

Topical treatments such as corticosteroids help to decrease the severity and duration of lesions and can be used without the need of continuous systemic treatment in patients whose recurrences are infrequent and do not cause much discomfort. Systemic treatment modalities are used when it is necessary to prevent recurrences. Colchicine is usually the initial choice of treatment owing to its safety profile and low cost (Fig. 4). However, it has limited efficacy, especially for oral ulcers. Lactobacilli lozenges might be used102. Apremilast (a phosphodiesterase 4 inhibitor) was shown to be relatively safe and effective for oral and genital ulcers103. Thalidomide, IFNα and etanercept are other alternatives for refractory skin, mucosal and joint lesions27,28,104.

Figure 4: Management of Behçet syndrome.
Figure 4

Treatment is individualized to each patient according to the type and severity of organ involvement, patient age, patient sex and disease duration. In our centre (Cerrahpaşa Medical Faculty, Turkey) patients with only skin-mucosa involvement and joint involvement can be managed with topical agents and colchicine. Those who continue to have bothersome lesions despite these measures can be prescribed immunosuppressive or immunomodulatory agents such as azathioprine, IFNα, thalidomide, apremilast or anti-TNF agents. In patients with eye, vascular, central nervous system (CNS) or gastrointestinal involvement immunosuppressive agents such as azathioprine are used as first-line treatments. Biological agents such as IFNα or anti-TNF antibodies are used in patients refractory to immunosuppression. Cyclophosphamide is usually the first choice for the initial treatment of arterial aneurysms that are life threatening. Pulmonary lobectomies in cases of giant pulmonary arterial aneurysms, or surgical resection of peripheral large aneurysms, can also be performed after immunosuppressive treatment. Glucocorticoids can be used for rapid suppression of inflammatory flares to prevent damage in all types of involvement. 5-ASA, 5-aminosalicylic acid. *Mild cases. Moderate and severe cases.

In terms of emerging treatments, a small open-label study of anakinra (an IL-1 receptor antagonist) for skin-mucosa involvement showed that only two out of six patients had no oral ulcers on two consecutive monthly visits105. The dose had to be increased (to 200 mg per day from 100 mg per day) in all but one patient after 1 month. Additionally, an open-label prospective study of ustekinumab (which inhibits IL-12 and IL-23) showed a decrease in the median number of oral ulcers from two ulcers to one ulcer after 12 weeks106.

Major organ involvement

Patients with major organ involvement should be treated effectively to prevent damage. Posterior uveitis is managed with immunosuppressive agents such as azathioprine, ciclosporin, IFNα and anti-TNF antibodies (such as infliximab) together with glucocorticoids. The decision to use IFNα or anti-TNF agents as first-line treatment or to save these for patients with uveitis who fail or relapse on azathioprine and/or ciclosporin depends on the severity of the eye involvement, experience of the physician and reimbursement policies. Furthermore, head-to-head controlled trials are needed to demonstrate the superiority of IFNα or anti-TNF agents in Behçet syndrome and to identify any patient characteristics that would mandate the use of one of these agents or the other.

Anti-IL-1, anti-IL-6 and anti-IL-17 agents have also been tried in patients with refractory eye disease. A pilot study and an uncontrolled phase II study, both with small numbers of patients, showed beneficial results with the IL-1 blocker gevokizumab107,108; the randomized controlled trial of this agent was terminated as it did not achieve its primary end point36. Secukinumab (which inhibits IL-17A) had also failed to meet its primary end point of reduction of uveitis recurrence in a randomized controlled trial109. A systematic review of case reports and a small case series with tocilizumab (an IL-6 receptor inhibitor) in patients refractory to IFNα and infliximab suggest that this agent may be effective in protecting visual acuity, reducing central macular thickness and improving fluorescein angiography findings110,111.

Arterial aneurysms are treated with high-dose glucocorticoids and monthly cyclophosphamide pulses followed by maintenance therapy with azathioprine112 (Fig. 4). Surgery might be required for peripheral artery aneurysms113. Anti-TNF agents can be used in patients who fail to respond to this regimen114. Consensus among experts is that immunosuppressive treatments such as azathioprine or ciclosporin should be used for deep vein thromboses as in Behçet syndrome these result from inflammation of the venous wall rather than a pro-coagulant state115. The use of anticoagulants is controversial because case–control studies have not shown a beneficial effect in preventing relapses of deep vein thromboses116, but controlled data are needed to verify this finding and to understand whether other benefits, such as preventing post-thrombotic syndrome, exist.

Parenchymal CNS involvement is treated with high-dose glucocorticoids together with immunosuppressive therapy such as azathioprine or anti-TNF agents; ciclosporin is avoided as it is neurotoxic117. The role of IL-6 blockers, which seem promising for CNS involvement based on a small case series110 (in which high IL-6 levels were observed in the cerebrospinal fluid of patients with CNS disease118,119) need to be further explored.

The initial management of gastrointestinal involvement is with 5-aminosalicylic acid derivatives in patients with mild disease. In those with moderate or severe gastrointestinal involvement, azathioprine is recommended96. Anti-TNF agents and thalidomide can be used in patients with refractory gastrointestinal involvement120 (Fig. 4).

Finally, a systematic review of patients with Behçet syndrome treated with haematopoietic stem cell transplantation for either refractory major organ involvement or a comorbid haematological condition showed that this approach was successful in inducing remission of Behçet syndrome lesions in 18 of 19 patients121. However graft-versus-host disease and infections occurred in some of the patients and one patient died owing to infection after 2 months.

Conclusions

The management of Behçet syndrome is increasingly successful, even if the precise definition of the condition is lacking. Indeed, Behçet syndrome is a complex construct with what we propose as strong and weak elements. The strong elements are those clinical findings the presence or absence of which differentiate Behçet's from other diseases or syndromes. The weak elements, on the other hand, are features that suggest more than one pathogenetic mechanism might be involved in Behçet's and might also be useful in differential diagnosis.

The clinical picture of Behçet syndrome is further complicated by a lack of specific histopathology or laboratory components that can be used in diagnosis. As said, the precise disease mechanisms that underlie the symptoms are not fully deciphered and difficult to do so owing, in part, to regional differences in disease expression. Despite advances in molecular genetics and in understanding potentially implicated inflammatory pathways (for example, those related to HLA-B*51) the current construct of what comprises Behçet syndrome remains rather complex. More basic, translational and clinical work is needed, with emphasis placed on understanding phenotypic expression and geographic influence. Additionally, as evidence continues to emerge on Behçet syndrome, a clearer definition should emerge — we believe, encouraging a splitters approach and allowing Behçet syndrome not to be grouped with other, somewhat related, conditions122.

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Reviewer information

Nature Reviews Rheumatology thanks Ahmet Gul and Robert Moots for their contribution to the peer review of this work.

Change history

  • 24 January 2018

    In the original version of this article, the indicated dosage of colchicine, 1.5 mg per day, was incorrectly given as 1.5 mg/kg per day in figure 4. This error has now been corrected in the print, PDF and HTML versions of this article.

References

  1. 1.

    International Study Group for Behçet's Disease. Criteria for diagnosis of Behçet's disease. Lancet 335, 1078–1080 (1990).

  2. 2.

    Gastrointestinal Behçet's disease: a review. World J. Gastroenterol. 21, 3801 (2015).

  3. 3.

    et al. The International Criteria for Behçet's Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria. J. Eur. Acad. Dermatol. Venereol. 28, 338–347 (2013).

  4. 4.

    & Diagnosis and/or classification of vasculitis. Curr. Opin. Rheumatol. 28, 3–7 (2016).

  5. 5.

    , & Behçet syndrome: is it one condition? Clin. Rev. Allergy Immunol. 43, 275–280 (2012).

  6. 6.

    , , & Cerebral venous thrombosis is associated with major vessel disease in Behçet's syndrome. Ann. Rheum. Dis. 63, 1693–1694 (2004).

  7. 7.

    , , , & Target organ associations in Turkish patients with Behçet's disease: a cross sectional study by exploratory factor analysis. J. Rheumatol. 29, 2393–2396 (2002).

  8. 8.

    , , , & Validity and agreement of uveitis experts in interpretation of ocular photographs for diagnosis of Behçet uveitis. Ocul. Immunol. Inflamm. 22, 461–468 (2013).

  9. 9.

    , , , & The frequency of scarring after genital ulcers in Behçet's syndrome: a prospective study. Int. J. Dermatol. 45, 554–556 (2006).

  10. 10.

    et al. The long-term mortality and morbidity of Behçet syndrome. Medicine 82, 60–76 (2003).

  11. 11.

    et al. Activation of neutrophils by testosterone in Behçet's disease. Clin. Exp. Rheumatol. 25 (Suppl. 45), S46–S51 (2007).

  12. 12.

    et al. Pulmonary artery involvement and associated lung disease in Behçet disease. Medicine 91, 35–48 (2012).

  13. 13.

    et al. Vascular involvement in Behçet's syndrome: a retrospective analysis of associations and the time course. Rheumatology 53, 2018–2022 (2014).

  14. 14.

    et al. An outcome survey of 43 patients with Budd-Chiari syndrome due to Behçet's syndrome followed up at a single, dedicated center. Semin. Arthritis Rheum. 44, 602–609 (2015).

  15. 15.

    , , & The unique features of vasculitis in Behçet's syndrome. Clin. Rev. Allergy Immunol. 35, 40–46 (2008).

  16. 16.

    et al. Masked assessment of MRI findings: is it possible to differentiate neuro-Behçet's disease from other central nervous system. Neuroradiology 41, 255–260 (1999).

  17. 17.

    et al. Behçet's disease: diagnostic and prognostic aspects of neurological involvement. J. Neurol. 248, 95–103 (2001).

  18. 18.

    , , & The Neuro-Behçet Study Group. Clinical patterns of neurological involvement in Behçet's disease: evaluation of 200 patients. Brain 122, 2171–2182 (1999).

  19. 19.

    , , & Intestinal Behçet and Crohn's disease: two sides of the same coin. Pediatr. Rheumatol. 15, 33 (2017).

  20. 20.

    et al. Frequency of pathergy phenomenon and other features of Behçet's syndrome among patients with inflammatory bowel disease. Clin. Exp. Rheumatol. 26, S91–95.

  21. 21.

    et al. Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility. Nat. Genet. 49, 438–443 (2017).

  22. 22.

    , , & Increased enthesopathy among Behçet's syndrome patients with acne and arthritis: An ultrasonography study. Arthritis Rheum. 58, 1539–1545 (2008).

  23. 23.

    , , & Associations between ankylosing spondylitis, psoriatic arthritis, Reiter's disease, the intestinal arthropathies, and Behcet's syndrome. Medicine 53, 343–364 (1974).

  24. 24.

    , , , & 'MHC-I-opathy' — unified concept for spondyloarthritis and Behçet disease. Nat. Rev. Rheumatol. 11, 731–740 (2015).

  25. 25.

    et al. Enthesitis: from pathophysiology to treatment. Nat. Rev. Rheumatol. 13, 731–741 (2017).

  26. 26.

    et al. A double-blind trial of colchicine in Behçet's syndrome. Arthritis Rheum. 44, 2686–2692 (2001).

  27. 27.

    Thalidomide in the treatment of the mucocutaneous lesions of the Behcet syndrome. Ann. Intern. Med. 128, 443 (1998).

  28. 28.

    et al. Short-term trial of etanercept in Behçet's disease: a double blind, placebo controlled study. J. Rheumatol. 32, 98–105 (2005).

  29. 29.

    Autoimmunity versus autoinflammation in Behcet's disease: do we oversimplify a complex disorder? Rheumatology 45, 1461–1465 (2006).

  30. 30.

    The place of Behçet's syndrome among the autoimmune diseases. Int. Rev. Immunol. 14, 1–10 (1997).

  31. 31.

    et al. Behçet disease serum is immunoreactive to neurofilament medium which share common epitopes to bacterial HSP-65, a putative trigger. J. Autoimmun. 84, 87–96 (2017).

  32. 32.

    Behçets disease as an autoinflammatory disorder. Curr. Drug Targets Inflamm. Allergy 4, 81–83 (2005).

  33. 33.

    et al. Cytokines in human intraocular inflammation. Curr. Eye Res. 11, 187–191 (1992).

  34. 34.

    et al. Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet disease. Proc. Natl Acad. Sci. USA 110, 8134–8139 (2013).

  35. 35.

    & Behçet's disease and other autoinflammatory conditions: what's in a name? Clin. Exp. Rheumatol. 23 (Suppl. 38), S1–S2 (2005).

  36. 36.

    US National Library of Medicine. ClinicalTrials.gov (2017).

  37. 37.

    in Rheumatology 5th edn (eds Hochberg, M., Silman, A., Smolen, J., Weinblatt, M. & Weisman, M.) 1123–1127 (Mosby Elsevier, 2011).

  38. 38.

    et al. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet's disease. Nat. Genet. 42, 698–702 (2010).

  39. 39.

    et al. Behcet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity. Proc. Natl Acad. Sci. USA 111, 8867–8872 (2014).

  40. 40.

    et al. Genome-wide association analysis identifies new susceptibility loci for Behçet's disease and epistasis between HLA-B*51 and ERAP1. Nat. Genet. 45, 202–207 (2013).

  41. 41.

    et al. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat. Genet. 43, 761–767 (2011).

  42. 42.

    Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat. Genet. 42, 985–990 (2010).

  43. 43.

    , , & Pathogenesis of spondyloarthritis: autoimmune or autoinflammatory? Curr. Opin. Rheumatol. 24, 351–358 (2012).

  44. 44.

    , , & Is Behçet's disease a 'class 1-opathy'? The role of HLA-B*51 in the pathogenesis of Behçet's disease. Clin. Exp. Immunol. 191, 11–18 (2017).

  45. 45.

    , , & Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat. Rev. Rheumatol. 12, 25–36 (2015).

  46. 46.

    et al. Activation of the JAK/STAT pathway in Behcet's disease. Genes Immun. 16, 170–175 (2014).

  47. 47.

    & Behçet's syndrome and micro-organisms. Best Pract. Res. Clin. Rheumatol. 25, 389–406 (2011).

  48. 48.

    Über residivierende aphtose, durch ein virus verursachte geschwüre am mund, am auge und den genitalen [German]. Dermatol. Wochenschrift. 105, 1152–1158 (1937).

  49. 49.

    , , & The role of infectious agents in the pathogenesis, clinical manifestations and treatment strategies in Behçet's disease. Clin. Exp. Rheumatol. 25 (Suppl. 45), S27–S33 (2007).

  50. 50.

    et al. Sequencing of 16S rRNA reveals a distinct salivary microbiome signature in Behçet's disease. Clin. Immunol. 169, 28–35 (2016).

  51. 51.

    , , , & The oral mucosal and salivary microbial community of Behçet's syndrome and recurrent aphthous stomatitis. J. Oral Microbiol. 7, 27150 (2015).

  52. 52.

    et al. Bifidobacteria abundance-featured gut microbiota compositional change in patients with Behcet's disease. PLoS ONE 11, e0153746 (2016).

  53. 53.

    et al. Behçet's syndrome patients exhibit specific microbiome signature. Autoimmun. Rev. 14, 269–276 (2015).

  54. 54.

    et al. FUT2: filling the gap between genes and environment in Behçet's disease? Ann. Rheum. Dis. 74, 618–624 (2013).

  55. 55.

    , , , & Fucosyltransferase 2: a genetic risk factor for primary sclerosing cholangitis and Crohn's disease — a comprehensive review. Clin. Rev. Allergy Immunol. 48, 182–191 (2014).

  56. 56.

    , & Epithelial glycosylation in gut homeostasis and inflammation. Nat. Immunol. 17, 1244–1251 (2016).

  57. 57.

    et al. Epigenome-wide scan identifies a treatment-responsive pattern of altered DNA methylation among cytoskeletal remodeling genes in monocytes and CD4+ T cells from patients with Behçet's disease. Arthritis Rheumatol. 66, 1648–1658 (2014).

  58. 58.

    , & An update on the role of epigenetics in systemic vasculitis. Curr. Opin. Rheumatol. (2017).

  59. 59.

    , & Genetics of Behçet's disease. Curr. Opin. Rheumatol. 28, 39–44 (2016).

  60. 60.

    , , , & Relationships of HLA-B51 or B5 genotype with Behçet's disease clinical characteristics: systematic review and meta-analyses of observational studies. Rheumatology 51, 887–900 (2012).

  61. 61.

    et al. Neutrophil activation promotes fibrinogen oxidation and thrombus formation in Behçet's disease. Circulation 133, 302–311 (2015).

  62. 62.

    , , , & Behcet's disease, the Silk Road and HLA-B51: historical and geographical perspectives. Tissue Antigens 54, 213–220 (1999).

  63. 63.

    et al. Behçet's disease in black skin. A retrospective study of 50 cases in Dakar. J. Dermatol. Case Rep. 9, 98–102 (2015).

  64. 64.

    , , & Incidence, prevalence and clinical characteristics of Behcet's disease in southern Sweden. Rheumatology 52, 304–310 (2012).

  65. 65.

    et al. Prevalence of Adamantiades-Behçet's disease in Germany and the municipality of Berlin: results of a nationwide survey. Clin. Exp. Rheumatol. 24 (Suppl 42), S125 (2006).

  66. 66.

    et al. Behçet's disease, hospital-based prevalence and manifestations in the Rotterdam area. Neth. J. Med. 73, 471–477 (2015).

  67. 67.

    et al. Population-based prevalence study of Behçet's disease: differences by ethnic origin and low variation by age at immigration. Arthritis Rheum. 58, 3951–3959 (2008).

  68. 68.

    et al. Epidemiology and clinical characteristics of behçet's disease in the US: a population-based study. Arthritis Rheum. 61, 600–604 (2009).

  69. 69.

    , , , & Clinical characteristics, treatment and ethnic/racial differences in the manifestations of 518 Behcet's syndrome patients in the United States [abstract]. Arthritis. Rheum. 62 (Suppl.), 1284 (2010).

  70. 70.

    et al. Epidemiology and clinical course of Behçet's disease in the Reggio Emilia area of Northern Italy: a seventeen-year population-based study. Arthritis Rheum. 57, 171–178 (2007).

  71. 71.

    et al. The prevalence of Behçet disease in the north of Jordan: a hospital based epidemiological survey. Clin. Exp. Rheumatol 35 (Suppl.), S51–S54 (2017).

  72. 72.

    et al. Mortality in Behçet's disease. Arthritis Rheum. 62, 2806–2812 (2010).

  73. 73.

    , , , & Impact of Behcet's syndrome on health-related quality of life: influence of the type and number of symptoms. Rheumatology 49, 2165–2171 (2010).

  74. 74.

    et al. Fatigue is correlated with disease activity but not with the type of organ involvement in Behçet's syndrome: a comparative clinical survey. Clin. Exp. Rheumatol. 33, S107–112.

  75. 75.

    et al. Fatigue in patients with Behcet's syndrome: relationship with quality of life, depression, anxiety, disability and disease activity. Int. J. Rheum. Dis. (2016).

  76. 76.

    , & Behçet's syndrome patients have high levels of functional disability, fatigue and pain as measured by a Multi-dimensional Health Assessment Questionnaire (MDHAQ). Clin. Exp. Rheumatol. 26 (Suppl. 50), S110–S113 (2008).

  77. 77.

    , , & Suicidal ideation among patients with Behçet's syndrome. Clin. Exp. Rheumatol. 33 (Suppl. 94), S30–S35 (2015).

  78. 78.

    et al. Dietary and nondietary triggers of oral ulcer recurrences in Behçet's disease. Arthritis Care Res. 69, 1429–1436 (2017).

  79. 79.

    et al. Frequent oral ulceration during early disease may predict a severe disease course in males with Behçet's syndrome. Clin. Exp. Rheumatol. 30 (Suppl. 72), S32–S34 (2012).

  80. 80.

    et al. Unmet need in Behcet's disease: most patients in routine follow-up continue to have oral ulcers. Clin. Rheumatol. 33, 1773–1776 (2014).

  81. 81.

    , , & Review for diagnostics of the year: multimodal imaging in Behçet uveitis. Ocul. Immunol. Inflamm. 25, 7–19 (2016).

  82. 82.

    et al. Quantitative analysis of structural alterations in the choroid of patients with active Behçet uveitis. Retina (2017).

  83. 83.

    , , , & Nonglaucomatous localized retinal nerve fiber layer defects in Behçet uveitis. Am. J. Ophthalmol. 159, 475–481.e1 (2015).

  84. 84.

    , , , & Changes in ocular manifestations of Behçet disease in Korean patients over time: a single-center experience in the 1990s and 2000s. Ocul. Immunol. Inflamm. 23, 157–161 (2014).

  85. 85.

    , , & Comparison of presenting features and three-year disease course in Turkish patients with Behçet uveitis who presented in the early 1990s and the early 2000s. Ocul. Immunol. Inflamm. 20, 423–428 (2012).

  86. 86.

    et al. Behçet disease: visual prognosis and factors influencing the development of visual loss. Am. J. Ophthalmol. 152, 1059–1066 (2011).

  87. 87.

    , , , & Ocular Behçet's disease: changing patterns over time, complications and long-term visual prognosis. Ocul. Immunol. Inflamm. 25, 29–36 (2016).

  88. 88.

    et al. Clinical and ultrasonographic evaluation of lower-extremity vein thrombosis in Behcet syndrome. Medicine 94, e1899 (2015).

  89. 89.

    et al. The estimated pulmonary artery pressure can be elevated in Behçet's syndrome. Respir. Med. 105, 1739–1747 (2011).

  90. 90.

    et al. Bronchial artery enlargement may be the cause of recurrent haemoptysis in Behçet's syndrome patients with pulmonary artery involvement during follow-up. Clin. Exp. Rheumatol. 34 (Suppl. 102), 92–96 (2016).

  91. 91.

    & The spectrum of nervous system involvement in Behçet's syndrome and its differential diagnosis. J. Neurol. 256, 513–529 (2009).

  92. 92.

    et al. Cognitive impairment in neuro-Behcet's disease and multiple sclerosis: a comparative study. Int. J. Neurosci. 122, 650–656 (2012).

  93. 93.

    et al. Behçet's disease patients with multiple sclerosis-like features: discriminative value of Barkhof criteria. Clin. Exp. Rheumatol. 33 (Suppl. 94), S80–S84 (2015).

  94. 94.

    , & Quantitative analysis of brainstem atrophy on magnetic resonance imaging in chronic progressive neuro-Behçet's disease. J. Neurol. Sci. 337, 80–85 (2014).

  95. 95.

    et al. Long-term outcome of neuro-Behçet's disease. Arthritis Rheumatol. 66, 1306–1314 (2014).

  96. 96.

    et al. Characteristics, treatment, and long-term outcome of gastrointestinal involvement in Behcet's syndrome. Medicine 95, e3348 (2016).

  97. 97.

    et al. Fecal calprotectin level looks promising in identifying active disease in Behçet's syndrome patients with gastrointestinal involvement: a controlled and pilot study [abstract]. Ann. Rheum. Dis. 75, AB0574 (2016).

  98. 98.

    et al. Outcome measures used in clinical trials for Behcet syndrome: a systematic review. J. Rheumatol. 41, 599–612 (2014).

  99. 99.

    et al. Current status, goals, and research agenda for outcome measures development in Behcet syndrome: report from OMERACT 2014. J. Rheumatol. 42, 2436–2441 (2015).

  100. 100.

    et al. Developing a core set of outcome measures for Behçet disease: report from OMERACT 2016. J. Rheumatol. 44, 1750–1753 (2017).

  101. 101.

    New EULAR guidelines on Behçet's. RheumNow (2016).

  102. 102.

    , , & Lactobacilli lozenges in the management of oral ulcers of Behçet's syndrome. Clin. Exp. Rheumatol. 24 (Suppl. 42), S83–S86 (2006).

  103. 103.

    et al. Apremilast for Behçet's syndrome — a phase 2, placebo-controlled study. N. Engl. J. Med. 372, 1510–1518 (2015).

  104. 104.

    et al. Interferon alfa-2a in the treatment of Behçet disease: a randomized placebo-controlled and double-blind study. Arch. Dermatol. 138, 467–471 (2002).

  105. 105.

    et al. Treatment of mucocutaneous manifestations in Behçet's disease with anakinra: a pilot open-label study. Arthritis Res. Ther. 19, 69 (2017).

  106. 106.

    et al. Ustekinumab for Behçet's disease. J. Autoimmun. 82, 41–46 (2017).

  107. 107.

    et al. Interleukin-1β-regulating antibody XOMA 052 (gevokizumab) in the treatment of acute exacerbations of resistant uveitis of Behçet's disease: an open-label pilot study. Ann. Rheum. Dis. 71, 563–566 (2011).

  108. 108.

    et al. Safety and efficacy of gevokizumab in patients with behçet's disease uveitis: results of an exploratory phase 2 study. Ocul. Immunol. Inflamm. 25, 62–70 (2016).

  109. 109.

    et al. Secukinumab in the treatment of noninfectious uveitis: results of three randomized, controlled clinical trials. Ophthalmology 120, 777–787 (2013).

  110. 110.

    , & Tocilizumab in severe and refractory Behcet's disease: four cases and literature review. Semin. Arthritis Rheum. 45, 733–737 (2016).

  111. 111.

    , & Tocilizumab for the treatment of Behçet uveitis that failed interferon alpha and anti-tumor necrosis factor-alpha therapy. Ocul. Immunol. Inflamm. (2017).

  112. 112.

    et al. Pulmonary artery aneurysms in Behçet syndrome. Am. J. Med. 117, 867–870 (2004).

  113. 113.

    et al. Management and prognosis of nonpulmonary large arterial disease in patients with Behçet disease. J. Vasc. Surg. 55, 157–163 (2012).

  114. 114.

    et al. Pulmonary artery involvement in Behçet's syndrome: effects of anti-Tnf treatment. Semin. Arthritis Rheum. 45, 369–373 (2015).

  115. 115.

    & To anticoagulate or not to anticoagulate vascular thrombosis in Behçet's syndrome: an enduring question. Clin. Exp. Rheumatol. 34 (Suppl. 95), S3–S4 (2016).

  116. 116.

    et al. Behçet disease with vascular involvement. Medicine. 94, e494 (2015).

  117. 117.

    et al. Cyclosporine for Behçet's uveitis: is it associated with an increased risk of neurological involvement? Clin. Exp. Rheumatol. 26 (Suppl. 50), S84–S90 (2008).

  118. 118.

    et al. Cerebrospinal fluid interleukin-6 in progressive Neuro-Behçet's syndrome. Clin. Immunol. Immunopathol. 82, 12–17 (1997).

  119. 119.

    et al. Interleukin-6 in neuro-Behçet's disease: association with disease subsets and long-term outcome. Cytokine 44, 373–376 (2008).

  120. 120.

    , , , & TNF-alpha antagonists and thalidomide for the management of gastrointestinal Behçet's syndrome refractory to the conventional treatment modalities: a case series and review of the literature. Clin. Exp. Rheumatol. 33 (Suppl. 94), S129–S137 (2015).

  121. 121.

    et al. Bone marrow transplantation for Behcet's disease: a case report and systematic review of the literature. Rheumatology 53, 1136–1141 (2014).

  122. 122.

    Behçet's syndrome in the 2000s: “Where is the wisdom we have lost in knowledge?” Clin. Exp. Rheumatol. 34, (Suppl. 102) S23–S25 (2016).

  123. 123.

    & in Behçet's Syndrome 1st edn (eds Yazici, Y. & Yazici, H.) 35–52 (Springer, 2010).

Download references

Acknowledgements

The authors thank H. Direskeneli (Marmara University, Turkey) for his valuable comments during manuscript preparation.

Author information

Affiliations

  1. Academic Hospital, Internal Medicine (Rheumatology), Nuhkuyusu cad. Uskudar, Istanbul, 34668, Turkey.

    • Hasan Yazici
  2. University of Istanbul, Cerrahpaşa Medical Faculty, Department of Internal Medicine, Division of Rheumatology, 181 Kocamustafapaşa, Fatih, 34098 Istanbul, Turkey.

    • Emire Seyahi
    •  & Gulen Hatemi
  3. New York University School of Medicine, NYU Hospital for Joint Diseases, Department of Medicine (Rheumatology), 333 East 38th Street, New York, NY, 10016, USA.

    • Yusuf Yazici

Authors

  1. Search for Hasan Yazici in:

  2. Search for Emire Seyahi in:

  3. Search for Gulen Hatemi in:

  4. Search for Yusuf Yazici in:

Contributions

All authors researched the data for the article, contributed substantially to the discussions of its content, wrote the manuscript and reviewed the manuscript before submission.

Competing interests

E.S. has received honoraria or speaker's fees from Pfizer, MSD, Mustafa Nevzat and UCB Pharma. G.H. has received honoraria, speaker fees and/or research grants from Abbvie, BMS, Celgene, Mustafa Nevzat, MSD, Pfizer and UCB Pharma. Y.Y. has received research grants from BMS, Celgene and Genentech, and has received consulting fees from Celgene. H.Y. declares no competing interests.

Corresponding author

Correspondence to Hasan Yazici.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrrheum.2017.208

Further reading