ABSTRACT
Behet’s disease (BD) is a multi-system inflammatory disorder dominated clinically by recurrent oral and genital ulceration, uveitis, and erythema nodosum. Behet’s disease runs a chronic course, with unpredictable exacerbations and remissions whose frequency and severity may diminish with time. Behet’s disease typically arises in young adults, although childhood-onset BD has also been reported. The disease can affect both genders and has a worldwide distribution, although it is more prevalent in countries of the ancient Silk Route. The cause of BD remains unknown, although an autoimmune reaction triggered by an infectious agent in a genetically predisposed individual has been suggested. The treatment of BD is symptomatic and empirical, but generally specific to the clinical features of each patient. The majority of affected individuals do not have life-threatening disease, although mortality can be associated with vascular-thrombotic and neurological disease.
KEY WORDS: Behet’s, disease, genital, ocular, oral.
(I) INTRODUCTION
Behet’s disease (BD) is a multi-system inflammatory disorder dominated clinically by recurrent oral and genital ulceration, uveitis, and erythema nodosum. The disease tends to wax and wane, the frequency and duration of exacerbations being unpredictable. Behet’s disease is a vasculitis, affecting vessels of different types, sizes, and localizations. Since the etiology of Behet’s disease is unknown, treatment tends to be empirical and is usually comprised of systemic corticosteroids and immunosuppressants.
The present review details current knowledge of Behet’s disease- a disorder of relevance to both the mouth and many other organ systems. A MEDLINE review up to July, 2004, was conducted. The computer search was complemented by a hand search of all bibliographic references from the reference lists of included literature.
(II) DIAGNOSTIC CRITERIA
Prior to 1990, five different criteria for the diagnosis of Behet’s disease had been suggested (Mason and Barnes, 1969; Behet’s Disease Research Committee of Japan, 1974; O’Duffy, 1974; Dilsen et al., 1986). Such a diversity in diagnostic criteria limited comparisons between relevant studies and hampered collaborative research. There are now internationally agreed diagnostic criteria for Behet’s disease, derived from a collaborative study of 914 patients in 12 centers from seven countries (International Study Group for Behet’s Disease, 1990). The agreed diagnostic criteria require the presence of recurrent oral ulceration (three times in one year) plus two of the following in the absence of other systemic disease: recurrent genital ulceration, eye lesions (uveitis or retinal vasculitis), skin lesions (erythema nodosum, pseudofolliculitis, papulo-pustular lesions, or acneiform nodules), or a positive pathergy test. This group of diagnostic criteria is simpler to use and has an improved discriminatory performance than its predecessors (Table 1).
(III) EPIDEMIOLOGY
The mean age at onset of BD is most commonly in the third decade, although the age at time of final diagnosis usually is in the fourth decade (Bang et al., 1997a). Both genders can be affected, although both male and female predominance has been described in studies of affected patients from different geographic regions of the world. A higher prevalence of BD has been observed in adult females in Korea (Bang et al., 1997a, 2001), Israeli Jews (Krause et al., 1999, 2001), Singapore (Tan et al., 1999), and Camas village of Turkey (Tuzun et al., 1996), while a higher prevalence of BD in males has been found in the West Indies (Lannuzel et al., 2002), Spain (Gonzalez-Gay et al., 2000; Baixauli et al., 2001), Israeli Arabs (Krause et al., 2001), London (Muhaya et al., 2000), Japan (Muhaya et al., 2000), Jordan (al Aboosi et al., 1996), Iran and Turkey (Gurler et al., 1997; Kaya et al., 2002), India (Pande et al., 1995), Lebanon (Ghayad and Tohme, 1995), Saudi Arabia (al Dalaan et al., 1994), and Kuwait (Mousa et al., 1986).
Table 1. International Study Group Criteria for Behet’s Disease (1990)a
Behet’s disease has a worldwide distribution (Table 2), although it has a higher prevalence in countries of the ancient Silk Route (from the Mediterranean basin to Japan), suggesting perhaps that an as-yet-unknown genetically determined factor was spread via the migration of old nomadic tribes.
Table 2. Demographics of Behet’s Disease in Various Countries
BD is most common in Turkey, where the reported prevalence ranges from 80/100,000 in nine villages near Istanbul to 370/100,000 in Camas village (Tuzun et al., 1996), and may be least common in the USA, where the incidence is about 1/300,000/year (O’Duffy, 1978).
BD has also been reported in many countries such as Israel (prevalence, 120/100,000) (Jaber et al., 2002), Japan (prevalence, 15/100,000) (Mizuki et al., 2000), Germany (prevalence, 2.26/ 100,000) (Zouboulis et al., 1997), Iran (prevalence, 16.7/100,000) (Davatchi et al., 1992), Iraq (prevalence, 17/100,000) (Al Rawi and Neda, 2003), and Spain (prevalence, 0.66/100,000) (Gonzalez-Gay et al., 2000). Of interest, it was recently found that the frequency of BD in the Afro-Caribbean population of Guadeloupe (French West Indies) was at least 3/100,000 (Lannuzel et al., 2002)-a rate higher than those reported in some Caucasian populations (and in a population unrelated to the aforementioned Silk Route).
Table 3. Demographics of Childhood-onset Behet’s Disease in Various Countries
About 2-3% of all affected individuals have childhood-onset BD (generally defined as definitive BD before the age of 16 years) (Saylan et al., 1999). Children of both genders can be affected, but there are few comparative studies of children and adults with BD. Onset of BD in children as young as 2 years of age has been reported (Kari et al., 2001), but most children develop clinical features between 7 and 13 years of age (Kone-Paut et al., 1998, 2002; Gul et al., 2000) (Table 3).
Childhood BD may be more likely to have a vague familial pattern than adulthood disease (Treudler et al., 1999).
(IV) CLINICAL FEATURES
Behet’s disease gives rise to a wide spectrum of clinical features characterized by unpredictable exacerbations and remissions (Table 4).
The clinical manifestations of BD may show geographic variation. For example, the pathergy reaction occurs in 57-65% of patients from the Middle East and Turkey (Ourler et al., 1997; Al Fahad and Al Araji, 1999; Krause et al., 1999), but has lower frequency in Western European countries (Davies et al., 1984; O’Duffy, 1994). Likewise, gastrointestinal disease, which occurs in about one-third of patients from Taiwan and a quarter of patients from Spain, rarely occurs in those from Jordan, Saudi Arabia, and Turkey (al Dalaan et al., 1994; al Aboosi et al., 1996; Gurler et al., 1997; Baixauli et al., 2001; Chen and Chang, 2001). In childhood BD, neurological and gastrointestinal disease may be more common in patients from France and Saudi Arabia, whereas cutaneous disease occurs more frequently in Turkey (Kone-Paut et al., 1998).
In addition to the site of residency, the ethnicity of a patient may influence the clinical features of BD. Ocular lesions may be more common in Turkish than German patients living in Germany (Zouboulis et al., 1997), and Israeli Arab patients may have more severe ocular disease (e.g., posterior uveitis) than Israeli Jewish patients from the same geographic region. Also, the disease severity of Jewish patients of North African origin may be higher than that of Jewish patients originating from Turkey, Iran, or Iraq (Krause et al., 2001). This may suggest that genetic factors play a stronger influencing role than any acquired factor upon the etiology and clinical presentation of BD.
Reports from different countries indicate a variable effect of pregnancy on the course of BD between patients, and even during different pregnancies in the same patient (Bang et al., 1997b; Marsal et al., 1997; Uzun et al., 2003), the increase in frequency and intensity of oral ulcer outbreaks being the main feature in most patients who showed exacerbation during their pregnancy (Uzun et al., 2003).
(a) Recurrent Oral (Aphthous-like) Ulcerations
Ulceration akin to recurrent aphthous stomatitis (RAS) occurs in all patients diagnosed with Behct’s disease. The oral ulceration is the initial clinical feature of up to 86.5% of adults and children with BD. In Turkey, 3.8% of patients followed up because of recurrent aphthous stomatitis develop BD (Ekmekci et al., 2003).
All three types of RAS-like ulcers (Porter et al., 1998) can arise in BD, although minor ulcers seem to be the most common presentation in BD (Whallett et al., 1999). One study suggested that major RAS-like ulcers may be more common in BD patients than in those with RAS (Krause et al., 1999). The oral ulcers of BD have the same periodicity as those of RAS and can affect any oral mucosal surface, although they may be more common on the soft palate and pharynx than in RAS (Main and Chamberlain, 1992). Some patients have almost continuous episodes of oral ulceration. Recurrent oral ulceration is often reported in other family members of patients with BD (Krause et al., 1999). As in RAS, tobacco smoking may reduce the severity of ulceration of BD (Silveira and McGrath, 1992; Ayata et al., 20\02; Kaklamani et al., 2003).
Table 4. Principal Clinical Features of Behet’s Disease
(b) Genital Ulcers
The genital ulcers of BD initially manifest as papules or pustules that later ulcerate. The ulcers are usually painful, superficial, and well-demarcated and have an edematous border and a yellow fibrin-covered base. The ulcers may be indurated and can become secondarily infected. In males, the ulcers are usually localized on the scrotum, penis, inguinal area, pubis, and perineum. In females, the vulvae, major and minor labia, cervix, and vagina are the most frequently affected sites. The ulcers usually heal in a few weeks, with scarring (Nazzaro, 1966); vaginal ulcers can give rise to bladder or urethral fistulae (Dunlop, 1979). The vaginal and vulval ulceration of BD can cause difficulty with micturation, dyspareunia, and may hinder walking (Kontogiannis and Powell, 2000).
Genital ulcers are rarely the initial manifestation of BD, are less common than oral ulcers, and, although arising in both children and adults, are more common in the latter (Krause et al., 1999). Peri-anal ulceration may occasionally arise in adults or children with BD (Kari et al., 2001).
(c) Ocular Disease
Ocular manifestations in adult BD patients include panuveitis, anterior uveitis, posterior uveitis, bilateral swelling of the optic nerve head, retinal vasculitis, and bilateral lamellar macular hole. Ocular involvement is usually bilateral, although severity of disease may differ between eyes. Ocular symptoms vary from a gritty sensation and blurring of vision to severe pain and blindness (al Aboosi et al., 1996). Ocular disease is the most common cause of significant morbidity in BD, since it may lead to visual loss in about five years if not treated (Shimizu et al., 1979). Blindness is possible.
Most studies report ocular disease in 43% to 65% of patients with BD. Inflammatory eye disease develops at least three years after the oral ulceration of BD (Imai, 1971). However, in a minority of patients (7.3%; range, 0.5-12.5%), ocular disease can be the initial clinical feature (Kim et al., 1994; Pande et al., 1995; Bang et al., 1997a; Gurler et al., 1997; Zouboulis et al., 1997; Krause et al., 2001). Behet’s disease accounts for up to 20% of Japanese patients with uveitis (Mishima et al., 1979).
Patients with predominantly anterior uveitis have a relatively good visual prognosis. The time between the onset of uveitis and the resulting complications is related to the severity, frequency, and number of inflammatory episodes. In general, male patients have a poorer prognosis than females (Yazici et al., 1984a).
The presence of HLA-B51 increases susceptibility to ocular disease (Nishiyama et al., 2001), and Factor V (FV Leiden) mutation may be an additional risk factor for the development of ocular disease, particularly retinal vaso-occlusion (Verity et al., 1999a).
(d) Cutaneous Lesions
The most frequent cutaneous features of BD are papulopustular lesions, erythema nodosum, and erythema nodosum-like disease. Papulo- pustular lesions are cutaneous sterile folliculitis or acne-like lesions on an erythematous base which initially manifest as papules and evolve into pustules within 24 to 48 hours. These lesions usually arise simultaneously, most frequently on the skin of the back, face, and chest. The papulo-pustular lesions are characterized histopathologically by a lymphocytic vasculitis (Lakhanpal et al., 1988).
Erythema nodosum-like lesions frequently occur in BD. These are most frequently observed on the lower extremities (although they can occur on the upper extremities) and are characterized by painful purplish nodules (Saylan et al., 1999). The nodules are surrounded by a peripheral halo, do not ulcerate, and resolve spontaneously, leaving behind areas of hyperpigmentation. Usually, there are only three or four lesions, although they can be more numerous. The histopathology of the erythema nodosum lesions shows a focal small- vessel vasculitis and perivascular lymphocytic infiltrate, particularly involving the venules, with panniculitis (Chun et al., 1989). Other cutaneous lesions, such as necrotic folliculitis and aphthosis, may also be seen in BD, but to a lesser extent.
Cutaneous involvement of BD shows some geographic differences and varies from 35% in Jordan and Turkey to 91% in Taiwan (al Aboosi et al., 1996; Eldem et al., 1998; Chen and Chang, 2001).
The frequency of cutaneous lesions in BD is similar in adults and children (Eldem et al., 1998; Kone-Paut et al., 1998). There is no correlation between the number of papulopustular lesions and patient age, gender, duration of disease, or age of onset of BD. However, papulo-pustular lesions may be significantly more likely in BD patients with a positive pathergy test (Alpsoy et al., 1998).
The non-specific hyperactivity reaction observed in response to minor cutaneous trauma in BD is known as the pathergy phenomenon. It was initially described by Blobner in 1937 and later was reviewed by Katzenellenbogen and Feuerman (1965). In a positive pathergy test, pricking the skin with a sterile needle, with or without the injection of a small amount of saline, gives rise to a 1- to 2-mm papule usually surrounded by an erythematous halo. The papule may remain unchanged or transform into a 1- to 5-mm pustule. The pustule becomes prominent 24 hours after needle insertion, becomes maximum in size after 48 hours, and disappears within 4-5 days.
Interaction of cellular adhesion molecules together with endothelial proliferation may play an important role in the formation of skin pathergy reaction lesions in patients with BD (Inaloz et al., 2004).
There is geographic variation in the frequency of occurrence of pathergy in Behet’s disease. It is highest in patients residing in regions of the ancient Silk Routes and decreases sharply outside these regions.
The pathergy phenomenon is usually positive during the active phases of BD and becomes negative or weakly positive when disease remits (Fresko et al., 1993). The frequency of positivity of the pathergy reaction in BD is higher in males than in females. The age of onset of BD does not affect the intensity of the reaction (Yazici et al., 1985). The pathergy test may not be specific to BD-indeed, it has been observed in healthy individuals (Aral et al., 1986).
The intensity of the pathergy reaction may vary within the same patient at different times, and there is usually intraobserver and inter-observer variation. Many factors influence the results of the pathergy test: needle gauge, sharpness of the tip, direction of needle penetration, in situ injection or just a skin puncture with no injection, the number of skin punctures, the delay in reading the result, the description of a positive reaction, and, finally, where to draw the line between a positive and a negative result. All these factors may influence the pathergy test result (Davatchi et al., 2003), and since the pathergy test is not standardized, it is perhaps unsurprising that a wide range of different results has been obtained by different groups.
The variable association of pathergy test positivity with BD and its occurrence among healthy subjects prevent it from being used as a screening test (Yurdakul et al., 1988). An alternative and more quantitative method of testing for abnormal inflammatory responsiveness is to examine erythema following the injection of monosodium urate crystals into the forearm skin. Normally, erythema is maximal 24 hours after injection and has resolved by 48 hours. In contrast, the response in BD tends to persist for 48 hours or longer. In Turkish patients, this test was 61% sensitive and 100% specific for BD when compared with other rheumatological diseases (Cakir et al., 1991).
(e) Neurological Involvement
The neurological complications of BD predominantly involve the central nervous system (CNS), although, rarely, there may be involvement of muscle and peripheral nerves. CNS disease is a potentially serious complication of BD and may manifest as pseudotumor cerebri, brain-stem involvement, neuropsychiatric symptoms, and meningo-encephalitis (Martini, 1995). CNS disease of BD can be divided into two categories, namely, parenchymal and vascular. Any area of the CNS may be affected, but the most frequent clinical presentations consist of bilateral pyramidal signs, headache, mental disorders (memory defects, disinhibition, and apathy), hemiparesis (usually unilateral), sphincter dysfunction, brain stem findings, and the pyramido-cerebellar syndrome (Akman- Demir et al., 1996).
There is considerable variation (from 2.2 to 44%) in the frequency of neurological disease in patients with BD (Main and Chamberlain, 1992; al Dalaan et al., 1994; Gurler et al., 1997; Krause et al., 1998; Gonzalez-Gay et al., 2000; Chen and Chang, 2001). Headache seems to be the most common clinical feature of neurological disease in BD, affecting up to 47% of examined groups (Krause et al., 1999).
Children with BD may have a greater tendency than adults to develop CNS disease (other than headaches) with significant cerebral involvement (Krause et al., 1999). Neurological complications may be more common in pediatric BD patients from France and Saudi Arabia than in those from Turkey and Iran. These complications include meningitis, benign intracranial hypertension, hemiparesis or paraparesis, seizures, and peripheral neuropathy (Kone-Paut et al., 1998). There is an increased frequency of seizures in adults with BD, and it is twice as prevalent as that seen in epilepsy (Aykutlu et al., 2002).
(f) Vascular Disease
Behet’s disease gives rise to a chronic relapsing systemic vasculitis involving arteries and veins of various sizes. The vascular involvement may consist of thrombophlebitis, deep vein thrombosis, and arterial obstruction. Aneurysms, particularly of the pulmonary arteries, may also develop (Yazici et al., 1998). Worldwide, vascular involve\ment in BD is common, although there is some geographic variation in frequency. Vascular complications are slightly less common in children (from 10.5 to 21%) (Kone-Paut et al., 1998, 2002; Krause et al., 1999) than in adults (from 8 to 26.5%) (al Dalaan et al., 1994; al Aboosi et al., 1996; Ourler et al., 1997; Kone-Paut et al., 1998; Krause et al., 1999, 2001; Baixauli et al., 2001), although the disease can be more severe in children than in adults (Kone-Paut et al., 1998).
Venous involvement usually arises within five years of the initial presentation of BD (Koc et al., 1992) and indeed can be the initial feature of the disease. Superficial and deep vein thrombosis are common features, although embolization is uncommon. Recurrent thrombophlebitis of the legs may lead to stasis dermatitis and crural ulcers (Koc et al., 1992). Thrombosis of the inferior vena cava and hepatic veins in patients with Budd-Chiari syndrome and BD carries a poor prognosis (Bayraktar et al., 1997).
Arterial disease is less common than the venous complications of BD but has greater morbidity. The most frequently affected vessels, in decreasing order, are the pulmonary, femoral, popliteal, subclavian, and carotid arteries. Arterial involvement predisposes to aneurysm formation or arterial occlusion.
(g) Renal Disease
Several renal disorders have been associated with BD and can be divided into five groups, namely, (1) glomerulonephritis (GN), (2) amyloidosis, (3) renal vascular involvement, (4) interstitial nephritis, and (5) other problems such as complications of drug therapy or genito-urinary system abnormalities (Akpolat et al., 2002).
The frequency of renal problems varies from 0% to 55%. This wide difference may reflect inadequate investigation of some reported patients and/or a lack of significant relevant systemic features suggestive of renal disease. Indeed, in a recent report, the most common renal problems of BD were asymptomatic hematuria and proteinuria (Akpolat et al., 2002).
(h) Gastrointestinal Disease
Gastrointestinal disease is most frequent in patients from Japan (from 50 to 60%) (Shimizu et al., 1979), followed by those from the UK (from 38 to 50%) (Whallett et al., 1999; Kari et al., 2001), and is least common in Turkish patients with BD (2.8%) (Ourler et al., 1997).
Mucosal ulcers are the most common gastrointestinal (GI) feature of BD (Krause et al., 1999). The ulceration predominantly occurs in the ileocecal region but can occur throughout the GI tract, including the esophagus (Jankowski et al., 1992). Depending upon the site of involvement, the ulceration can give rise to dysphagia, abdominal pain, diarrhea (occasionally bloody), intestinal perforation, and peri-anal fistula formation.
Children with BD have a tendency toward more non-specific GI symptoms than do adults, and this probably accounts for the higher incidence of abdominal pain and diarrhea in affected children (Krause et al., 1999; Kone-Paut et al., 2002).
(i) Cardiac Disease
Valvular disease (Chikamori et al., 1990), myocardial infarction and aneurysms (Ioakimidis et al., 1993; Siepmann and Kirch, 1997), intracardiac thrombus (Mogulkoc et al., 2000), and endomyocardial fibrosis (Huong et al., 1997) have been observed in patients with BD. Of significance, mitral valve prolapse and dilatation of the proximal aorta were observed in 50% and 30% of patients with BD, respectively (Morelli et al., 1997).
(j) Musculoskeletal Disease
There is considerable variation (e.g., from 15 to 88% of examined patient groups) in the incidence of musculoskeletal disease in BD (Pande et al., 1995; Zouboulis et al., 1997; Krause et al., 1999; Tan et al., 1999; Kaya et al., 2002). Arthralgia or arthritis can be the first manifestation of BD in 0.5% to 7% of patients (Gurler et al., 1997; Zouboulis et al., 1997). Mono-arthritis is the most frequent pattern of involvement, although asymmetrical polyarthritis can occur. The knee is the most frequently affected joint, although the ankle, hand, wrist, and elbow can also be affected. The arthritis of BD is usually transient, lasting two months or less. Long-term arthritic disease is rare (Yurdakul et al., 1983).
(k) Other Clinical Features of Behet’s Disease
Amyloidosis
Amyloidosis in BD is rare and has a 50% mortality rate after an average duration of 3.4 years (range 1 to 11). Amyloidosis in BD may be associated with nephrotic syndrome or significant proteinuria. Peripheral and pulmonary arterial involvement and arthritis are the strongest predictors of amyloidosis in BD (Melikoglu et al., 2001).
Periodontal disease
There may be increased deposits of plaque and higher periodontal index scores in patients with active BD compared with healthy control subjects, although there does not appear to be a notably increased susceptibility to early tooth loss. An elevation of circulating antibodies to Actinobacillus actinomycelemcomitans has been reported in patients with BD (Celenligil-Nazliel et al., 1999).
Recurrent epididymo-orchitis
Reports have described the prevalence of epididymitis in BD as 4% (al Dalaan et al., 1994), 4.6% (Cho et al., 2003), 5% (al Aboosi et al., 1996), 12.3% (Kaklamani et al., 2000), and 19.2% (Cetinel et al., 1998). Epididymitis is usually accompanied by multi-organ involvement and thus is a feature of severe BD (Cho et al., 2003).
Budd-Chiari syndrome
Budd-Chiari syndrome (sudden occlusion of the major hepatic veins) is a rare and serious complication of BD. Although the mortality rate of BD is less than 10% (Orloff and Orloff, 1999; Kural-Seyahi et al., 2003), the development of Budd-Chiari syndrome in patients with BD has been associated with a mortality rate of 61% (Orloff and Orloff, 1999).
(V) ETIOPATHOGENESIS
The cause of BD is not known, but an autoimmune reaction triggered by an infectious or environmental agent (possibly local to a geographic region) in a genetically predisposed individual seems most likely. However, if BD has an autoimmune basis, it is unusual, since there is no female preponderance, no association with other autoimmune diseases or HLA antigens typically associated (A1, B8, DR3, DR4) with such disease, and no associated specific autoantibodies. There are, however, scattered reports of neonatal BD in the children of mothers with BD (Fam et al., 1981; Eglin et al., 1982), possibly caused by transplacental transfer of an as-yet- unidentified antibody.
(a) Suggested Infectious Etiologies
Early studies isolated probable HSV-1 from oral ulcers (Kilbourne and Horsefall, 1951). HSV-1 DNA has been identified in peripheral blood lymphocytes and monocytes of patients with BD (Eglin et al., 1982; Bonass et al., 1986), and elevated circulating antibodies to HSV-1 have been reported in patients with BD. However, HSV-1 DNA was not detected in oral ulcers of BD (Studd et al., 1991).
Etiological links between hepatitis viruses and Behet’s disease seem unlikely, since a significantly elevated frequency of hepatitis A virus (HAV), Hepatitis B virus (HBV), or Hepatitis C virus (HCV) seropositivity has not been observed in patients with BD (Hamuryudan et al., 1995; Oguz et al., 1995; Aksu et al., 1999).
There is considerable evidence that Streptococcus sanguis may have some etiological role in BD. Individuals with BD may have higher numbers of S. sanguis in the mouth (Isogai et al., 1990b), higher serum antibody liters to this organism (Lehner et al., 1991; Yokota et al., 1992), or increased T-cell reactivity to S. sanguis antigens than appropriate control subjects (Hirohata et al., 1992). In addition, elevated serum antibody liters to uncommon serotypes of S. sanguis (strains 113-20, 114-23, and 118-1) have been detected in some patienls with BD (Yokota et al., 1992). Patients with BD may have hypersensitivity reactions to various strains of streptococci but not to other bacterial antigens (Kaneko S et al., 1997). Higher streptococcal antigen titer levels have been demonstrated in BD patients than in controls or in patients with uveitis not associated with BD (Namba et al., 1986).
It has been suggested that patients may have an infection focus, such as dental caries or tonsillitis, before clinical manifestation of BD (Tsuchida et al., 1997). Streptococci are often isolated from these infectious foci, and streptococcal antigens are mitogenic for lymphocytes from patients with BD (Kaneko et al., 1985). Denial treatment and streptococcal antigen skin-testing can induce clinical features in patients with previously stable BD (Mizushima et al., 1988), and the pathergy can be suppressed following surgical cleaning of the skin (Fresko et al., 1993).
In vitro production of inflammatory cytokines (interleukins [IL]- 1, IL-6, IL-8, interferon gamma, and tumor necrosis factor-alpha [TNF-α]) by peripheral blood mononuclear cells and T- lymphocytes of patients with BD is enhanced following stimulation wilh streptococcal-related antigens (Hirohala et al., 1992; Kaneko F et al., 1997). In addition, neutrophil activation in BD appears to be correlated wilh the proportion of 5. sanguis within the oral flora (Isogai et al., 1990a).
Increased serum levels of IgA anlibodies to the mycobacterial 65- kDa heat-shock protein (HSP; which cross-reads with strains of S. sanguis) have been reported in patients wilh BD (Lehner et al., 1991). The expression of HSP60 in epidermal regions is up-regulated at lesional sites in BD, and antibodies to streptococcal HSP60 might cause tissue damage (Ergun et al., 2001).
There are thus increasing data supporting the notion that BD may have a bacterial trigger, but how this trigger induces disease is currently unknown.
(b) Immunopathogenic Aspects
The major immunological features of BD consist of increased T- and B-cell responses to heat-shock proteins (HSP), increased neutrophil activity, and alterations in cytokine levels, although the interrelationships between and among these features are not clear.
Heat-shock proteins are a group of intrace\llular proteins which scavenge for other intracellular proteins under denaturating stress conditions such as infection, hypoxia, trauma, and toxic drugs (Lamb and Young, 1990; Direskeneli and Saruhan-Direskeneli, 2003). Significant sequence homology exists between mammalian and microbial HSPs. For example, they may share antigenic epitopes with herpes simplex viruses and streptococci-micro-organisms that have been implicated in the pathogenesis of BD (Lehner, 1997; Direskeneli and Saruhan-Direskeneli, 2003).
In several recent studies of patients with BD, increased numbers of γδ T-cells have been found in peripheral blood and in affected tissues, a phenotypically distinct subset of these cells being observed at sites of inflammation (Mizuki et al., 2000). In addition, levels of circulating γδ T-cells may increase in active disease (Hasan et al., 1996). Such γδ T-cells are found in epithelial surfaces and are thought to regulate inflammatory and immune processes. They participate in early responses against micro-organisms by responding to non-peptide antigens in a non-MHC restricted fashion. In humans, the predominant circulating subset Vγ9 Vδ2 γδ T-cells recognize phosphoantigens and antigenic alkylamines-both of which are abundant among bacteria and mammalian metabolites. This subset of γδ T-cells can acquire a cytotoxic-effector function upon in vitro culture with both bacterial and viral antigens (Hasan et al., 1996).
Activated γδ T-cells, capable of producing IFN-γ and TNF-α, are present in the peripheral blood in significantly higher numbers in patients with BD than in those with RAS and in healthy controls (Freysdottir et al., 1999). Such γδ T- cells are expanded in the peripheral blood mononuclear cell population during active BD (Bank et al., 2003). One possible mechanism driving this expansion might be an inappropriate response to products of micro-organisms present in the mucosal ulcers (Bank et al., 2003). Since activation of peripheral blood mononuclear cells with peptides of the mycobacterial 65-kDa HSP and homologous human peptides from mitochondria specifically stimulates the γδ subset of T-cells from BD patients, and not from patients who have only recurrent oral ulcers (and not BD), this response might provide the basis for a diagnostic test for BD (Hasan et al., 1995, 1996). Similar to T-cell studies, cross-reactivity has also been demonstrated for anti-HSP60 antibodies. Both anti- streptococcal and anti-retinal HSP60 antibodies are elevated in the sera of BD patients with uveitis (Tanaka et al., 1999).
Several studies have suggested that neutrophil and monocytc activity may be increased in BD (Mizushima, 1986; Takeno et al., 1995). Superoxide production is increased in the neutrophils of BD patients compared with appropriate control subjects, and this increase seems to be related to the presence of the HLA-B51 (Takeno et al., 1995). In addition, the migration of neutrophils during attacks, but not during remission, increases in BD (Carletto et al., 1997). Production of TNF-α, IL-6, and the neutrophil chemoattractant IL-8 by monocytes has also been found to be elevated (Mege et al., 1993).
An elevation of IL-10 can occur in BD, and a correlation between IL-12 and the soluble tumor necrosis factor receptor 75 (TNFR-75) levels with disease activity has been observed, suggesting a Th1- type immune response in active disease (Turan et al., 1997). However, although noting enhanced IL-4, IL-10, and IL-13 production, some studies also noted lower IL-12 production in active BD patients when compared with inactive BD, recurrent aphthous stomatitis, and control patients, thus suggesting that the immune system in BD may be characterized by a divergent cytokine production profile of mixed Th1/Th2 (Th0) cell types (Raziuddin et al., 1998; Aridogan et al., 2003).
To date, neither in vitro nor in vivo models of the immunopathogenesis of BD remain. Disease might commence with exposure to some external factor, such as antigens of streptococci or herpes virus, which may induce γδ T-cell proliferation and activation. Subsequently, the inflammatory cytokines could stimulate neutrophils and monocytes. It is still not known whether any alteration in the local oral microbial environment truly triggers the immune response in BD, or whether another defect of mucosal immunity is involved.
(c) Genetic Aspects
A genetic basis to Behet’s disease is suggested by the geographic distribution of affected individuals, the observed association with certain HLA haplotypes, and familial aggregation of some affected individuals. However, the inheritance of Behet’s disease does not follow Mendelian patterns.
A relationship between HLA-B5 and BD has been confirmed in several studies of patients with BD from Middle Eastern and Mediterranean countries (al Dalaan et al., 1994; Ghayad and Tohme, 1995; Pande et al., 1995; Davatchi et al., 1997; Krause et al., 1998; Al Fahad and Al Araji, 1999), but the relationship between this HLA antigen and BD is not prominent in patients from either the US or the UK (Bird Stewart, 1986).
HLA-B51, one of the split antigens of HLA-B5, has also been found to be increased in frequency in BD patients, and has been reported as 54.1% in Turkey (Kaya et al., 2002), 57% in Japan (Mizuki et al., 1997), 75.9% in Greece (Mizuki et al., 2002), 70.4% in Israeli Jews, and 76.2% in Israeli Arab patients (Krause et al., 2001). HLAB*5101 is the most frequently detected of the B51 alleles in the normal population and in patients with BD. It was observed in 98.1% in sampled Japanese families and at the same frequency in BD patients who are B51-positive (Mizuki and Ohno, 1996). In Israel, HLAB*5101 was the predominant allele in 62% of HLA-B51-positive Israeli BD patients and in 78% of Jewish BD patients (Paul et al., 2001). The HLAB*5108 allele may be increased in patients with BD from Italy and Saudi Arabia (Mizuki et al., 2001a). The predominant suballeles in both patient and control groups of Turkish and German patients was found to be HLA-B*5101 and B*5108, although with a slightly increased frequency of HLA-B*5108 in the diseased individuals (Kotter et al., 2001). These results might be brought about due to different HLA-B*51 allelic distributions among various ethnic groups, implying that BD spread in Asian and Eurasian populations, along with its association allele HLA-B*51, before it diverged into suballeles (Mizuki et al., 2001a).
It has been suggested that the association of HLA-B51 may be more relevant to affected male than female patients (Zouboulis et al., 1997; Choukri et al., 2001). It is still not known whether HLA-B51 participates directly in the pathogenesis of BD or is associated with it only because of linkage disequilibrium with a nearby gene (Mizuki et al., 1995)-a notion supported by the knowledge that BD still arises in the absence of HLA-B51 alleles (Mizuki and Ohno, 1996).
Strong associations between the major histocompatibility complex class I chain-related gene A (MICA) allele and TNF alleles (TNFFB*2 Nco RFLP) and BD have been reported (Mizuki et al., 1992; Verity et al., 1999b). Recently, a highly divergent MHC class I chain-related gene family, MIC, was identified within the class I MHC region. Among the five MIC genes identified so far, two genes, MICA and MICB, are functional genes located between the HLA-B and TNF genes (Bahrain and Spies, 1996; Groh et al., 1996). The major histocompatibility complex (MHC) class I chain-related gene A (MIC- A) has been proposed as a candidate gene for BD susceptibility. MIC- A is located 46 kb centromeric to the HLA-B gene on chromosome 6. This gene is mainly expressed in epithelial cells, fibroblasts, endothelial cells, and monocytes (Bahram et al., 1994; Zwirner et al., 1998). The function of the MICA gene product is still unknown, but its amino acid sequence suggests that it may bind peptides or other short ligands and participate in antigen presentation or T- cell recognition (Bahram et al., 1994; Zwirner et al., 1998). Of relevance to BD, strong associations between the MICA-A6 allele and BD in Israeli Arab, but not in Israeli non-Ashkenazi Jewish, patients have been described (Cohen et al., 2002).
More recent evidence suggests that MICA is not an independent susceptibility gene for BD. HLA-B51 was found to be the most strongly, and primarily, associated marker in Jordanian BD patients, and the significant increase in the allele frequencies of MICA-A6, C1-4-1-217, and C1-2-5-188 in the patient groups was explained by a linkage disequilibrium with HLA-B51 (Mizuki et al., 2001b). Similar findings in three different populations have also been described (Japanese, Greek, and Italian) (Mizuki et al., 2000), suggesting that the pathogenic gene of BD is HLA-B51 itself, but unlikely to be other genes located in the vicinity of HLA-B.
It remains theoretically possible that a particular isoform of MICA might act in combination with B51 to increase the risk or severity of the condition, since the MICA gene product may have immunomodulatory functions and is predicted to interact with the γδT-cell receptor (Russell et al., 2001).
A novel association between BD and the HLA-C locus has been reported. The HLA-Cw* 1602 allele was found in 12.5% of patients from Spain and not in any of the controls. Although HLA-Cw* 1602 is known to be in linkage disequilibrium with HLA-B51, the authors reasoned that this was unlikely to be the explanation for their finding, in that the frequency of other more commonly known Cw alleles was not found to be increased (Sanz et al., 1998).
The factor V Leiden mutation, a well-known cause of activated protein C resistance that results in a propensity for thrombosis, has attracted interest, particularly in view of a thrombotic tendency of some patients with BD. While Lesprit et \al. (1995) found no evidence for this propensity, Gul et al. (1996) showed it to be present among 38% of patients with BD and deep vein thrombosis, compared with 9% of patients without this complication. In addition, 60% and 38% of patients with thrombotic complications of BD, compared with 18% and 0% of patients without thrombosis, had this mutation, as reported from Turkey (Oner et al., 1998) and Saudi Arabia (Mammo et al., 1997), respectively. These studies also emphasize that other, as-yet-unidentified, factors are important for the observed increase in thrombotic complications.
(VI) MANAGEMENT
The treatment of BD is symptomatic and empirical, but is generally specific to the clinical features of each patient. Treatment is usually multidisciplinary, requiring close collaboration among specialists in oral medicine, dermatology, ophthalmology, and others. Male patients and those with early-onset disease usually require more aggressive treatment than do other affected individuals (Imai et al., 1997; Yazici and Ozyazgan, 1999).
There are few controlled studies of the management of BD, and since BD has such a variable clinical presentation and course, it may be difficult to evaluate the efficacy of any one therapy (Yazici and Barnes, 1991). Most relevant studies have focused upon ocular inflammation, mucocutaneous manifestations, and arthritis as end- points, with vascular and neurological manifestations seldom being sufficiently frequent to be included in statistical analyses. There has been recent progress, however, in the development of clinical scoring systems to assess response to treatment (Bhakta et al., 1999). Table 5 summarizes the therapeutic approaches to the treatment of BD.
The treatment of BD remains unsatisfactory due to the rarity and heterogeneity of the condition, uncertainties about the relevant etiology and pathogenesis, and the lack of data from well- controlled clinical trials. In particular, the management of severe manifestations, such as vascular and neurological involvement, remains entirely empirical. There is now an urgent need to establish the exact beneficial effects of new therapies such as IFN-α, anti-TNFα agents, and newer immunosuppressive agents such as tacrolimus and mycophenolate mofetil in a methodological manner.
(VII) PROGNOSIS
Behet’s disease runs a chronic course with unpredictable exacerbations and remissions, the frequency and severity of which may diminish with time. The disease generally runs an improving or stable course after the first five years. After the fourth decade, the clinical severity reduces, with clinical complications generally recurring at longer intervals (Bardak, 1999). Hence, the prognosis of patients with BD is generally favorable, once the initial insult abates (Yazici, 2002).
However, central nervous system involvement and major vessel disease are exceptions, since their onset may occur 5-10 years into the course of the disease (Kural-Seyahi et al., 2003). Mortality as measured by the standardized mortality ratio (SMR) also tends to decrease significantly with the passage of time (Kural-Seyahi et al., 2003).
The age of onset does seem to be a prognostic factor, with patients with early onset, before 25 years of age, having a poorer prognosis than those with onset after 40 years of age (Yazici et al., 1984b). Recent studies focused upon demographic features and prognosis. Male gender and early age at onset were associated with the more severe presentations of the disease, which included vascular thrombotic, ocular, gastrointestinal, or central nervous system manifestations (Demiroglu and Dundar, 1997; Bang et al., 2003; Kural-Seyahi et al., 2003).
Table 5. Therapies for Behet’s Disease
Nevertheless, there is considerable variation between and among patients. While BD runs an indolent course in some patients, with mucocutaneous manifestations dominating the clinical picture, others have serious complications, such as uveitis and vascular occlusive disease, that can lead to significant morbidity (Koc et al., 1992). Morbidity is high; ocular and neurological involvement may result in significant disability and can greatly diminish quality of life. Perhaps optimistically, however, the numbers of those developing blindness due to BD may be falling (Yazici, 2002).
Mortality was found to occur in 9.8% of BD patients (Kural- Seyahi et al., 2003), mainly due to major vessel disease, neurological involvement, and perforated intestinal ulcers (Yazici et al., 1996; Kural-Seyahi et al., 2003). Vascular involvement may be the major cause of death in BD (Kural-Seyahi et al., 2003). Mortality in BD is specifically increased among young males (Yazici et al., 1996; Kural-Seyahi et al., 2003).
Data that treatment ultimately prolongs the lives of BD patients are lacking, and neoplastic disease, as well as treatment morbidities, has been reported to occur concurrent with BD. The neoplastic disease may include solid tumors and hematological or lymphoid malignancies. Treatment-related morbidities may include surgical morbidity and radiotherapy-related morbidity (Cengiz et al., 2001).
HLA-B51 positivity generally does not determine the prognosis and response to therapy. A comparative study from Turkey and the United Kingdom found no association between the presence of the HLA-B51 allele and clinical severity of the disease (Demiroglu and Dundar, 1997).
There has been considerable progress in the treatment of ophthalmic and mucocutaneous lesions of BD during the last two decades. Unfortunately, this is not true for the vascular- thrombotic and neurological lesions with which the mortality in BD is mainly associated (Yazici, 2002).
(VIII) CONCLUSION
Behet’s disease remains an elusive disorder, having variable clinical presentations and unknown etiology, and lacking any specific therapy. Behet’s disease thus remains a significant challenge to clinicians of many specialties. However, in view of the establishment of well-defined diagnostic clinical criteria, it should now be possible to investigate the cause and therapy of this potentially serious disorder with greater focus than was previously possible. In particular, there would seem to be a need to develop a clinical and DNA data bank using worldwide-recognized clinical criteria (and the pathergy test method) to review more clearly the microbial associations of BD and to undertake well-organized randomized controlled trials of both antimicrobials and immunologically active agents. Through such work, it should be possible to establish more clearly the etiology and hence more effective treatment and preventive strategies for BD.
ACKNOWLEDGMENTS
Special thanks to the Saudi Arabian Armed Forces Medical Services and Cultural Bureau Office in London for sponsoring Dr. Al Otaibi.
Received March 16, 2004; Accepted August 1, 2004
REFERENCES
Akman-Demir G, Baykan-Kurt B, Serdaroglu P, Gurvit H, Yurdakul S, Yazici H, et al. (1996). Seven-year follow-up of neurologic involvement in Behet syndrome. Arch Neural 53:691-694.
Akoglu TF, Direskeneli H, Yazici H, Lawrence R (1990). TNF, soluble IL-2R and soluble CD-8 in Behet’s disease. J Rheumatol 17:1107-1108.
Akpolat T, Akkoyunlu M, Akpolat I, Dilek M, Odabas AR, Ozen S (2002). Renal Behet’s disease: a cumulative analysis. Semin Arthritis Rheum 31:317-337.
Aksu K, Kabasakal Y, Sayiner A, Keser G, Oksel F, Bilgic A, et al. (1999). Prevalences of hepatitis A, B, C and E viruses in Behet’s disease. Rheumatology (Oxford) 38:1279-1281.
Aktulga E, Altac M, Muftuoglu A, Ozyazgan Y, Pazarli H, Tuzun Y, et al. (1980). A double blind study of colchicine in Behet’s disease. Haematologica 65:399-402.
Akyol M, Dogan S, Kaptanoglu E, Ozcelik S (2002). Systemic isotrelinoin in the treatment of Behet’s patients with arthritic symptoms and acne lesions. Clin Exp Rheumatol 20(4 Suppl):S-55.
al Aboosi MM, al Salem M, Saadeh A, al Jamal M, Hijawi M, Khammash M, et al. (1996). Behet’s disease: clinical study of Jordanian patients. Int J Dermatol 35:623-625.
al Dalaan AN, al Balaa SR, el Ramahi K, al Kawi Z, Bohlega S, Bahabri S, et al. (1994). Behet’s disease in Saudi Arabia. J Rheumalol 21:658-661.
Al Fahad SA, Al Araji AH (1999). Neuro-Behet’s disease in Iraq: a study of 40 patients. J Neural Sci 170:105-111.
Al Rawi ZS, Neda AH (2003). Prevalence of Behet’s disease among Iraqis. Adv Exp Med Biol 528:37-41.
Alpsoy E, Aktekin M, Er H, Durusoy C, Yilmaz E (1998). A randomized, controlled and blinded study of papulopustular lesions in Turkish Behet’s patients. Int J Dermatol 37:839-842.
Alpsoy E, Durusoy C, Yilmaz E, Ozgurel Y, Ermis O, Yazar S, et al. (2002). Interferon alfa-2a in the treatment of Behet disease: a randomized placebo-controlled and double-blind study. Arch Dermatol 138:467-471.
Aral O, Dilsen N, Konice M (1986). Positive skin pathergy reactivity as a genetic marker of Behet’s disease. In: Recent advances in Behet’s disease. Lehner T, Barnes CG, editors. London: Royal Society of Medical Services, pp. 173-175.
Aridogan BC, Yildirim M, Baysal V, Inaloz HS, Baz K, Kaya S (2003). Serum levels of IL-4, IE-10, IE-12, IE-13 and IFN-gamma in Behet’s disease. J Dermatol 30:602-607.
Ayata EM, Celik AF, Melikoglu M, Hamuryudan V, Yazici H (2002). The effect of smoking on oral ulcers (OU) of Behet’s syndrome (BS) (abstract). Berlin: 10th International Congress on Behet’s Disease.
Aykutlu E, Baykan B, Serdaroglu P, Gokyigit A, Akman-Demir G (2002). Epileptic seizures in Behet disease. Epilepsia 43:832-835.
Bahram S, Spies T (1996). The MIC gene family. Res Immunol 147:328-333.
Bahram S, Bresnahan M, Geraghty DE, Spies T (1994). A second lineage of mammalian major histocompatibility complex class I genes. Proc Natl Acad Sci USA 91:6259-6263.
Baixauli A, Calvo J, Tamarit JJ, Campos C, Garcia S, Herrera A (2001). Behet’s disease: retrospective study. Ann Med Interna 18:405- 410.
Bang D, Yoon KH, Chung HG, Choi EH, Lee ES, Lee S (1997a). Epi\demiological and clinical features of Behet’s disease in Korea. Yonsei Med J 38:428-436.
Bang D, Chun YS, Haam IB, Lee ES, Lee S (1997b). The influence of pregnancy on Behet’s disease. Yonsei Med J 38:437-443.
Bang D, Lee JH, Lee ES, Lee S, Choi JS, Kim YK, et al. (2001). Epidemiologic and clinical survey of Behet’s disease in Korea: the first multicenter study. J Korean Med Sci 16:615-618.
Bang DS, Oh SH, Lee KH, Lee ES, Lee SN (2003). Influence of sex on patients with Behet’s disease in Korea. J Korean Med Sci 18:231- 235.
Bank I, Duvdevani M, Livneh A (2003). Expansion of gammadelta T- cells in Behet’s disease: role of disease activity and microbial flora in oral ulcers. J Lab Clin Med 141:33-40.
Bardak Y (1999). Effects of age and sex on Behet’s disease. J Rheumatol 26:1008-1009.
Bayraktar Y, Balkanci F, Bayraktar M, Calguneri M (1997). Budd- Chiari syndrome: a common complication of Behet’s disease. Am J Gastroenterol 92:858-862.
Behet’s Disease Research Committee of Japan (1974). Behet’s disease: guide to diagnosis of Behet’s disease. Jpn J Ophthalmol 18:291-294.
Bhakta BB, Brennan P, James TE, Chamberlain MA, Noble BA, Silman AJ (1999). Behet’s disease: evaluation of a new instrument to measure clinical activity. Rheumatology (Oxford) 38:728-733.
Binder AI, Graham EM, Sanders MD, Dinning W, James DG, Denman AM (1987). Cyclosporin A in the treatment of severe Behet’s uveitis. Br J Rheumatol 26:285-291.
Bird Stewart JA (1986). Genetic analysis of families of patients with Behet’s syndrome: data incompatible with autosomal recessive inheritance. Ann Rheum Dis 45:265-268.
Blobner F (1937). Zur rezidivierenden Hypopyoniritis. Z Augenheilkunde 91:129-139.
Bonass W, Bird-Stewart J, Chamberlain MA (1986). Molecular studies in Behet’s syndrome. In: Recent advances in Behet’s disease. Lehner T, Barnes CG, editors. London: Royal Society of Medical Services, pp. 37-41.
Cakir N, Yazici H, Chamberlain MA, Barnes CG, Yurdakul S, Atasoy S, et al. (1991). Response to intradermal injection of monosodium urate crystals in Behet’s syndrome. Ann Rheum Dis 50:634-636.
Carletto A, Pacor ML, Biasi D, Caramaschi P, Zeminian S, Bellavite P, et al. (1997). Changes of neutrophil migration without modification of in vitro metabolism and adhesion in Behet’s disease. J Rheumatol 24:1332-1336.
Celenligil-Nazliel H, Kansu E, Ebersole JL (1999). Periodontal findings and systemic antibody responses to oral microorganisms in Behet’s disease. J Periodontol 70:1449-1456.
Cengiz M, Altundag MK, Zorlu AF, Gullu IH, Ozyar E, Atahan IL (2001). Malignancy in Behet’s disease: a report of 13 cases and a review of the literature. Clin Rheumatol 20:239-244.
Cetinel B, Obek C, Solok V, Yaycioglu O, Yazici H (1998). Urologic screening for men with Behet’s syndrome. Urology 52:863- 865.
Chen YC, Chang HW (2001). Clinical characteristics of Behet’s disease in southern Taiwan. J Microbiol Immunol Infect 34:207-210.
Chikamori T, Doi YL, Yonezawa Y, Takata J, Kawamura M, Ozawa T (1990). Aortic regurgitation secondary to Behet’s disease. A case report and review of the literature. Eur Heart J 11:572-576.
Cho YH, Jung J, Lee KH, Bang D, Lee ES, Lee S (2003). Clinical features of patients with Behet’s disease and epididymitis. J Urol 170:1231-1233.
Choukri F, Chakib A, Himmich H, Hue S, Caillat-Zucman S (2001). HLA-B*51 and B*15 alleles confer predisposition to Behet’s disease in Moroccan patients. Hum Immunol 62:180-185.
Chun SI, Su WP, Lee S, Rogers RS III (1989). Erythema nodosum- like lesions in Behet’s syndrome: a histopathologic study of 30 cases. J Cutan Pathol 16:259-265.
Cohen R, Metzger S, Nahir M, Chajek-Shaul T (2002). Association of the MlC-A gene and HLA-B51 with Behet’s disease in Arabs and non- Ashkenazi Jews in Israel. Ann Rheum Dis 61:157-160.
Davatchi F, Shahram F, Akbarian M (1992). Epidemiology of Behet’s disease Iran. In: Rheumatology APPLAR 1992. Nasution AR, Darmawan J, Isbagio H, editors. Tokyo: Churchill Livingstone, pp. 95-98.
Davatchi F, Shahram F, Akbarian M (1997). Behet’s disease: analysis of 3443 cases. APLAR J Rheumatol 1:2-5.
Davatchi F, Shahram F, Nadji A, Jamshidi AR, Chams C, Chams H, et al. (2003). Influence of pathergy test on the accuracy of different diagnosis criteria for Behcet’s disease. Adv Exp Med Biol 528:109- 112.
Davies PG, Fordham JN, Kirwan JR, Barnes CG, Dinning WJ (1984). The pathergy test and Behet’s syndrome in Britain. Ann Rheum Dis 43:70-73.
Davies UM, Palmer RG, Denman AM (1988). Treatment with acyclovir does not affect orogenital ulcers in Behet’s syndrome: a randomized double-blind trial. Br J Rheumatol 27:300-302.
Demiroglu H, Dundar S (1997). Inflects of age, sex, and initial presentation on the clinical course of Behet’s syndrome (letter). South Med J 90:567.
Demiroglu H, Ozcebe OI, Barista I, Dundar S, Eldem B (2000). Interferon alfa-2b, colchicine, and benzathine penicillin versus colchicine and benzathine penicillin in Behet’s disease: a randomised trial. Lancet 355:605-609.
Dilsen N, Konice M, Aral O (1986). Our diagnostic criteria of Behet’s disease-an overview. In: Recent advances in Behet’s disease. Lehner T, Barnes CG, editors. London: Academic Press, pp. 177-180.
Direskeneli H, Saruhan-Direskeneli G (2003). The role of heat shock proteins in Behcet’s disease. Clin Exp Rheumatol 21:S44-S48.
Dunlop E (1979). Genital and other manifestations of Behet’s disease seen in venereological clinical practice. In: Behet’s syndrome: clinical and immunological features. Lehner T, Barnes G, editors. London: Academic Press, pp. 159-175.
Eglin RP, Lehner T, Subak-Sharpe JH (1982). Detection of RNA complementary to herpes-simplex virus in mononuclear cells from patients with Behet’s syndrome and recurrent oral ulcers. Lancet 2:1356-1361.
Ekmekci P, Boyvat A, Ozdemir E, Gurler A, Gurgey E (2003). Is long term observation of patients with recurrent aphthous stomatitis necessary? Clinical follow-up of 1238 cases. Adv Exp Med Biol 528:127-130.
Eldem B, Onur C, Ozen S (1998). Clinical features of pediatric Behet’s disease. J Pediatr Ophthalmol Strabismus 35:159-161.
Ergun T, Ince U, Eksioglu-Demiralp E, Direskeneli H, Gurbuz O, Gurses L, et al. (2001). HSP 60 expression in mucocutaneous lesions of Behet’s disease. J Am Acact Dermatol 45:904-909.
Estrach C, Mpofu S, Moots RJ (2002). Behet’s syndrome: response to infliximab after failure of etanercept. Rheumatology (Oxford) 41:1213-1214.
Fam AG, Siminovitch KA, Carette S, From L (1981). Neonatal Behet’s syndrome in an infant of a mother with the disease. Ann Rheum Dis 40:509-512.
Fresko I, Yazici H, Bayramicli M, Yurdakul S, Mat C (1993). Effect of surgical cleaning of the skin on the pathergy phenomenon in Behet’s syndrome. Ann Rheum Dis 52:619-620.
Freysdottir J, Lau S, Fortune F (1999). Gammadelta T cells in Behet’s disease (BD) and recurrent aphthous stomatitis (RAS). Clin Exp Immunol 118:451-457.
Ghayad E, Tohme A (1995). Bchcet’s disease in Lebanon: report of 100 cases. J Med Liban 43:2-7.
Gonzalez-Gay MA, Garcia-Porrua C, Branas F, Lopez-Lazaro E, Olivieri I (2000). Epidemiologic and clinical aspects of Behet’s disease in a defined area of Northwestern Spain, 1988-1997. J Rheumatol 27:703-707.
Goossens PH, Verburg RJ, Breedveld FC (2001). Remission of Behet’s syndrome with tumour necrosis factor alpha blocking therapy (case report). Ann Rheum Dis 60:637.
Groh V, Bahram S, Bauer S, Herman A, Beauchamp M, Spies T (1996). Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc Natl Acad Sci USA 93:12445-12450.
Gul A, Ozbek U, Ozturk C, Inanc M, Konice M, Ozcelik T (1996). Coagulation factor V gene mutation increases the risk of venous thrombosis in Behet’s disease. Br J Rheumatol 35:1178-1180.
Gul A, Inane M, Ocal L, Aral O, Konice M (2000). Familial aggregation of Behet’s disease in Turkey. Ann Rheum Dis 59:622-625.
Gurler A, Boyvat A, Tursen U (1997). Clinical manifestations of Behet’s disease: an analysis of 2147 patients. Yonsei Med J 38:423- 427.
Hamuryudan V, Moral F, Yurdakul S, Mat C, Tuzun Y, Ozyazgan Y, et al. (1994). Systemic interferon alpha 2b treatment in Behet’s syndrome. J Rheumatol 21:1098-1100.
Hamuryudan V, Sonsuz A, Yurdakul S (1995). More on hepatitis C virus and Behet’s syndrome. N Engl J Med 333:322-323.
Hamuryudan V, Ozyazgan Y, Hizli N, Mat C, Yurdakul S, Tuzun Y, et al. (1997). Azathioprine in Behet’s syndrome: effects on long-term prognosis. Arthritis Rheum 40:769-774.
Hasan A, Childerstone A, Pervin K, Shinnick T, Mizushima Y, van der Zee R, et al. (1995). Recognition of a unique peptide epitope of the mycobacterial and human heat shock protein 65-60 antigen by T cells of patients with recurrent oral ulcers. Clin Exp Immunol 99:392-397.
Hasan A, Fortune F, Wilson A, Warr K, Shinnick T, Mizushima Y, et al. (1996). Role of gamma delta T cells in pathogenesis and diagnosis of Behet’s disease. Lancet 347:789-794.
Haugeberg G, Velken M, Johnsen V (2004). Successful treatment of genital ulcers with infliximab in Behet’s disease. Ann Rheum Dis 63:744-745.
Hirohata S, Oka H, Mizushima Y (1992). Streptococcal-related antigens stimulate production of IL6 and interferon-gamma by T cells from patients with Behet’s disease. Cell Immunol 140:410-419.
Hirohata S, Suda H, Hashimoto T (1998). Low-dose weekly methotrexate for progressive neuropsychiatric manifestations in Behet’s disease. J Neurol Sci 159:181-185.
Huong DL, Wechsler B, Papo T, de Zuttere D, Bletry O, Hernigou A, et al. (1997). Endomyocardial fibrosis in Behet’s disease. Ann Rheum Dis 56:205-208.
Imai H, Motegi M, Mizuki N, Ohtani H, Komatsuda A, Hamai K, et al. (1997). Mouth and genital ulcers with inflamed cartilage (MAGIC syndrome): a case report and literature review. Am J Med Sci 314:330- 332.
Imai Y (1971). Studies on prognosis and symptoms of Behet’s disease in long term observation. Jpn J Clin Ophthaimol 25:661-694.
Inaloz \HS, Evereklioglu C, Unal B, Kirtak N, Eralp A, Inaloz SS (2004). The significance of immunohistochemistry in the skin pathergy reaction of patients with Behet’s syndrome. J Eur Acad Dermatol Venereol 18:56-61.
International Study Group for Behet’s Disease (1990). Criteria for diagnosis of Behet’s disease. Lancet 335:1078-1080.
Ioakimidis D, Georganas C, Panagoulis C, Gournizakis A, Iliopoulos A, Kremastinos D, et al. (1993). A case of Adamantiadis- Behet’s syndrome presenting as myocardial infarction. Clin Exp Rheumatol 11:183-186.
Isogai E, Ohno S, Kotake S, Isogai H, Tsurumizu T, Fujii N, et al. (1990a). Chemiluminescence of neutrophils from patients with Behet’s disease and its correlation with an increased proportion of uncommon serotypes of Streptococcus sanguis in the oral flora. Arch Oral Biol 35:43-48.
Isogai E, Ohno S, Takeshi K, Yoshikawa K, Tsurumizu T, Isogai H, et al. (1990b). Close association of Streptococcus sanguis uncommon serotypes with Behet’s disease. Bifidobacteria Microflora 9:27-41.
Jaber L, Milo G, Halpern GJ, Krause I, Weinberger A (2002). Prevalence of Behet’s disease in an Arab community in Israel. Ann Rheum Dis 61:365-366.
Jankowski J, Crombie I, Jankowski R (1992). Behet’s syndrome in Scotland. Postgrad Med J 68:566-570.
Kaklamani VG, Vaiopoulos G, Markomichelakis N, Kaklamanis P (2000). Recurrent epididymo-orchitis in patients with Behet’s disease. J Urol 163:487-489.
Kaklamani VG, Tzonou A, Markomichelakis N, Papazoglou S, Kaklamanis PG (2003). The effect of smoking on the clinical features of Adamantiades-Behet’s disease. Adv Exp Med Biol 528:323-327.
Kaneko F, Oyama N, Nishibu A (1997). Streptococcal infection in the pathogenesis of Behet’s disease and clinical effects of minocycline on the disease symptoms. Yonsei Med J 38:444-454.
Kaneko F, Takahashi Y, Muramatsu Y, Miura Y (1985). Immunological studies on aphthous ulcer and erythema nodosum-like eruptions in Behet’s disease. Br J Dermatol 113:303-312.
Kaneko S, Suzuki N, Yamashita N, Nagafuchi H, Nakajima T, Wakisaka S, et al. (1997). Characterization of T cells specific for an epitope of human 60-kD heat shock protein (hsp) in patients with Behet’s disease (BD) in Japan. Clin Exp Immunol 108:204-212.
Kari JA, Shah V, Dillon MJ (2001). Behet’s disease in UK children: clinical features and treatment including thalidomide. Rheumatology (Oxford) 40:933-938.
Katzenellenbogen I, Feuerman EJ (1965). Beitrag zum Morbus Behet Die Bedeutung der spezifschen. Hauthyperraktivitt und der Behetin Reaktion Hautarzt 16:13-18.
Kaya TI, Dur H, Tursen U, Gurler A (2002). Association of class I HLA antigens with the clinical manifestations of Turkish patients with Behet’s disease. Clin Exp Dermatol 27:498-501.
Kilbourne ED, Horsefall FL (1951). Primary herpes simplex virus infection of the adult. Arch Intern Med 88:495-502.
Kilmartin DJ, Forrester JV, Dick AD (1998). Tacrolimus (FK506) in failed cyclosporin A therapy in endogenous posterior uveitis. Ocul Immunol Inflamm 6:101-109.
Kim DK, Chang SN, Bang D, Lee ES, Lee S (1994). Clinical analysis of 40 cases of childhood-onset Behet’s disease. Pediatr Dermatol 11:95-101.
Koc Y, Gullu I, Akpek G, Akpolat T, Kansu E, Kiraz S, et al. (1992). Vascular involvement in Behet’s disease. J Rheumatol 19:402- 410.
Kone-Paut I, Yurdakul S, Bahabri SA, Shafae N, Ozen S, Ozdogan H, et al. (1998). Clinical features of Behet’s disease in children: an international collaborative study of 86 cases. J Pediatr 132:721- 725.
Kone-Paut I, Gorchakoff-Molinas A, Weschler B, Touitou I (2002). Paediatric Behet’s disease in France. Ann Rheum Dis 61:655-656.
Kontogiannis V, Powell RJ (2000). Behet’s disease. Postgrad Med J 76:629-637.
Kotter I, Gunaydin I, Stubiger N, Yazici H, Fresko I, Zouboulis CC, et al. (2001). Comparative analysis of the association of HLA- B*51 suballeles with Behet’s disease in patients of German and Turkish origin. Tissue Antigens 58:166-170.
Krause I, Uziel Y, Guedj D, Mukamel M, Molad Y, Amit M, et al (1998). Mode of presentation and multisystem involvement in Behet’s disease: the influence of sex and age of disease onset. J Rheuatol 25:1566-1569.
Krause I, Uziel Y, Guedj D, Mukamel M, Harel L, Molad Y, et al. ( 1999). Childhood Behet’s disease: clinical features and comparison with adult-onset disease. Rheumatology (Oxford) 38:457-462.
Krause I, Mader R, Sulkes J, Paul M, Uziel Y, Adawi M, et al. (2001). Behet’s disease in Israel: the influence of ethnic origin on disease expression and severity. J Rheumatol 28:1033-1036.
Kural-Seyahi E, Fresko I, Seyahi N, Ozyazgan Y, Mat C, Hamuryudan V, et al. (2003). The long-term mortality and morbidity of Behet syndrome: a 2-decade outcome survey of 387 patients followed at a dedicated center. Medicine (Baltimore) 82:60-76.
Lakhanpal S, O’Duffy JD, Lie J (1988). Pathology. In: Behet’s disease: a contemporary synopsis. Plotkin G, Calabro J, O’Duffy J, editors. New York: Futura Publishing Company, pp. 102-142.
Lamb JR, Young DB (1990). T cell recognition of stress proteins. A link between infectious and autoimmune disease. Mol Biol Med 7:311- 321.
Lannuzel A, Lamaury I, Charpentier D, Caparros-Lefebvre D (2002). Neurological manifestations of Behet’s disease in a Caribbean population: clinical and imaging findings. J Neurol 249:410-418.
Larkin G, Lightman S (1999). Mycophenolate mofetil. A useful immunosuppressive in inflammatory eye disease. Ophthalmology 106:370- 374.
Lehner T (1997). The role of heat shock protein, microbial and autoimmune agen
