The Epidemiology of Behçet’s Disease

Behçet’s disease (BD), a chronic vasculitis affecting any type of the blood vessels, was first described by a Turkish dermatologist Hulusi Behçet. Although it has a worldwide distribution, it is commonly seen in the Silk Road countries around the Mediterranean Sea. The country in which the disease is most commonly seen is Turkey with a prevalence of 20–602/100,000. The disease most appears between the second and fourth decades of the life. BD affects both genders equally. However, the gender distribution may differ among different regions.


Introduction
Behçet's disease (BD) is a chronic multisystem vasculitis, which affects any type and shape of blood vessels, particularly veins [1,2]. The disease was first described in 1937 by a Turkish dermatologist, Hulusi Behçet, as a triple symptom complex, aphthous stomatitis, genital ulcers and relapsing uveitis [3]. Most widely used classification criteria is suggested by The International Study Group (ISG) for BD in 1990 [4]. According to the ISG, the major criterion exactly required for the diagnosis is recurrent oral ulceration at least three times a year. Additionally, at least two of the minor criteria: genital ulceration, skin lesions (erythema nodosum, necrotic folliculitis, and papulopustular lesions), ocular lesions (posterior uveitis, total uveitis, and retinal vasculitis), and positive pathergy testing are required for the diagnosis [4].
Since 1982, the supported hypothesis about the etiopathogenesis of BD has been that the genetic material and the exogenous agents responsible for the disease were carried during the immigration of ancient nomadic tribes [15]. Many studies focus on immigrations so far have investigated how the genetic or environmental factors affect the development of BD. In 1997 in Germany, 218 patients with BD were investigated. Of these patients, 89 were German, 100 were Turkish, and 29 were from other nationalities. The prevalence of BD was found 0.16/100,000 in German population and 4.51/100,000 in Turkish population. The prevalence of BD in Turkish population was higher than German population. However, it was 5-18-fold lower than the prevalence found in Turkey. This study suggested that the genetic and environmental factors are both effective in the development of the disease [15]. Another similar study was performed in 2015 in the Rotterdam area of Netherland [5]. Eighty-four patients of Dutch, Turkish, or Moroccan origin with BD were identified. The prevalence of BD was found 1/100,000 in Dutch, 71/100,000 in Turkish and 39/100,000 in Moroccan population. The study mentioned that the prevalence of BD in different ethnic group was similar to that among the original countries of these patients. However, another study reported that no patient with BD was detected in Hawaii, where the Japan population is relatively high [11].
Regional and ethnic factors may affect the time of the diagnosis of the illness. The diagnosis of the disease is delayed in areas where the prevalence of the disease is lower [12]. In a study from Germany, it was reported that the time of diagnosis of BD in Turkish patients was earlier than in German patients. The diagnosis was later and more difficult in German patients than in Turkish patients, so that we should keep in mind that some German patients might be followed with wrong diagnosis for long times before the diagnosis of BD [15,35].
Patients with earlier onset have more severe disease [36]. In a study from Tunisia, BD patients with onset before age of 20 and after age of 40 were compared each other. Cutaneous involvement, pseudo folliculitis, and vena cava thrombosis were more frequent in patients with earlier onset. In contrast, joint involvement was more frequent in patients with later onset [28]. Mortality in the group with earlier onset was 2.46% but no patients had died due to BD in the group with later onset [28]. Some authors reported that BD patient with earlier onset had more ophthalmic manifestations and active course of the disease [37,38]. BD is uncommon in children. Patients with initial symptoms at age 16 years or lower are classified as juvenile-onset BD [39]. The prevalence of juvenile BD is unknown. However, in few series, it was reported that 3.3 and 26% of the patients with BD were juvenile-onset BD [2]. The clinical symptoms are not different from adults but the diagnosis may be delayed in pediatric patients because of mild symptoms [2]. Juvenile onset patients had more familial cases compared with adult-onset patients [39]. There are some different series presenting juvenile BD. In the study of Allali et al., one-third of the patient had family history [40]. In the series of Kone-Paut et al., family history was reported as 9 and 24.4%. But in adults, family history was found as 2.2% [41][42][43].
BD disease affects both the gender equally [12]. But the gender distribution may differ between different regions. A few studies showed that male predominance was seen in Middle Eastern countries, while female predominance was seen in Asian countries [1]. The male/female ratios from the studies are shown in Table 2.
Gender affects the clinical findings and the severity of the disease as well [12]. In a long-term study performed by Kural-Seyahi et al., it was implicated that the disease is more severe in male patients, and vascular disease might be the major risk factor of death in male patients [49]. Saadoun et al. supported that male sex, arterial involvement and a high number of BD flares were independently associated with the risk of mortality [50]. In 2015, Bonitsis et al. presented a meta-analysis of the gender-specific differences in BD. They investigated both the German registry of BD and systematic literature review meta-analysis (52 other publications from Turkey, Asia, Southern Europe, Northern Europe, South America, the USA, and North Africa/Middle East) [29]. They found that vascular disease (superficial and deep venous thrombosis and heart involvement), folliculitis, papulopustular skin lesions, positive pathergy test and ocular disease are more common in males, while erythema nodosum, genital ulcers and joint involvement are more common in females [29].

Epidemiology of clinical findings
Regional and environmental factors may affect clinical findings of BD. Prevalence of different clinical findings may differ among the patients from different regions [12]. Frequency of presence of oral aphthosis is almost same in patients from all regions with the rate of 96-100% [1,12]. In Japan, 4.6-15% of endogen causes of uveitis are BD [13,51]. In a study from Japan, 69% of the patients had ocular findings [52]. But uveitis is quite rare in Australia [1]. Neurological features are more common in Caucasians (23%) than Middle Eastern series (3-10%) and frequency of seizures was found to be higher than Turkish series (27 and 5%, respectively) [53]. Another study detected that Sub-Saharan African BD patients had a higher frequency of CNS involvement compared to North African and European BD patients [54]. Intestinal BD is rare in Mediterranean countries but it is more common in Japanese BD patients [12]. Clinical findings of patients from different regions are shown in Table 4 [13,23,24,[28][29][30]55].

Pathergy reaction
Pathergy reaction is a nonspecific skin hyper reactivity to minor trauma. Positivity is defined as occurring of a papule or pustule, 24-48 h after intradermal injection of skin with 20 gauge needle [1]. Positive pathergy test is one of the diagnosis criteria of BD [4]. The pathergy reaction is highly sensitive and specific for BD in patients from Silk Road countries like Turkey, from some Mediterranean, the Middle Eastern countries and Japan. However, it is rarely observed in patients from Northern Europe, USA and Australia [1,56]. Although the pathergy test lost its sensitivity during the past 35 years, it is still a valuable diagnostic test [57]. Some studies from Japan and Turkey have reported a decrease in the positive pathergy reaction in BD [56]. In 1979, the skin pathergy positivity rate was found 84% in patients with BD in a study from Turkey [58]. In another study from Turkey in 1991, the rate was found 65% [59]. In a more recent study from Turkey, the rate of pathergy test positivity was  Table 4. Clinical findings of BD among some countries. detected as 39% [23]. The decrease of pathergy test positivity rate can be also seen in some Japanese studies. In a study from Japan in 1972 the rate of positive pathergy test was found 75%, while in an other study performed in 2011 this rate was found %50 [56]. These differences may be occurred due to different applying techniques. One of the important methods is using non-disposable/blunt needles. In 2000, it was reported that clinical evaluation of the pathergy test conducted intradermally with non-disposable/blunt needles is sufficient for both the diagnosis and determination of the activation of Behçet's disease [60]. Also it is shown that surgical cleaning of the test area before needle prick reduced the prevalence of pathergy test positivity rate [61]. This information suggests that the positive reaction might be a cutaneous response to some bacteria living on the surface of the skin. In a recent study, performed by Togashi et al. suggested that a new diagnostic pathergy test may solve the methodological problems [62]. They performed a skin prick test with filter-sterilized saliva on forearm skin. Of the patients with BD, 90% showed indurative erythema at the skin site pricked with self-saliva, and 60% of recurrent aphthous stomatitis patients showed weak reaction. They suggested that skin prick test using self-saliva can be a diagnostic test for differentiating BD from other mucocutaneous diseases [62].

Genetic factors and epidemiology
Although familial cases were reported, a Mendelian inheritance model specific to BD is not present [12]. In the western series, familial case rates were as follows: 0.7-2.7% in Italy, 3.6% in England and 4.5% in Portugal. The familial case rates were 11.9-13.4% in the studies from Tunisia, Israel, and Korea studies [12,15,64]. In a study from Turkey, family history was reported as 31.2% [65]. Multiple studies have demonstrated that BD is strongly associated with the presence of HLA-B5 and its split antigen HLA-B51 [12,66]. The association with HLA-B5 was first described by Ohno et al. in 1973 [56]. The genetic material of the BD might be carried in parallel with population movement between the Mediterranean and Asia. Supporting this content is that the distribution areas of this antigen among healthy control populations are the ancient trade route and the region in which BD is commonly seen [67]. HLA-B51 frequency is high in the Mediterranean countries but it is low in western countries like USA and England [12]. In recent studies, many new genes other than HLA-B51 (IL-10 signaling pathways, IL6-174 G/C, MMP-9, CLEC16A, NKFB1, IL-23 receptor gene, IL-18, IL-6, IL10, Vitamin D receptor, etc.) associated with BD were also identified [36]. Shigemura et al. studied on six patients over four generations with BD in 2016, and they found a common heterozygous missense mutation in A20/TNFAIP3; a gene known to regulate NF-κB signaling. Mutation in A20/TNFAIP3 was likely responsible for increased production of human inflammatory cytokines by reduced suppression of NF-κB activation. They suggested that this mutation may lead to the autosomal-dominant Mendelian mode of BD transmission in this family [68].