Behc¸et’s disease as a systemic disease M. Cem Mat MD, Ays¸eg¨ul Sevim MD, ˙Izzet Fresko MD, Yalc¸ın T¨uz¨un MD PII: DOI: Reference:
S0738-081X(13)00303-9 doi: 10.1016/j.clindermatol.2013.11.012 CID 6812
To appear in:
Clinics in Dermatology
˙ Please cite this article as: Mat M. Cem, Sevim Ay¸seg¨ ul, Fresko Izzet, T¨ uz¨ un Yal¸cın, Beh¸cet’s disease as a systemic disease, Clinics in Dermatology (2013), doi: 10.1016/j.clindermatol.2013.11.012
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ACCEPTED MANUSCRIPT Behçet’s disease as a systemic disease M. Cem Mat MD1, Ayşegül Sevim MD1, İzzet Fresko MD2, Yalçın Tüzün MD1*
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Istanbul University, Cerrahpasa Medical Faculty, Department of Dermatology, Division of Rheumatology, Istanbul, Turkey.
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* Corresponding Author: Yalçın Tüzün, MD, Department of Dermatology, Cerrahpaşa Medical Faculty, Istanbul University, 34098 Fatih, İstanbul. Turkey.
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E-mail: [email protected]
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Abstract
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Behçet’s disease usually begins with cutaneous manifestations such as recurrent aphthous stomatitis, genital ulcers, erythema nodosum-like lesions, papulopustular findings, and pathergy phenomenon. Recurrent aphthous stomatitis is generally the first ssign, and other findings may develop in the course of the disease. There is no specific diagnostic available for Behçet’s disease. It is most prevalent among patients along the ancient Silk Road. The high frequency of HLA-B51 among a wide range of ethnic populations favors the role of genetic factors. Behçet’s disease usually appears in the third to fourth decade of life, and is rarely seen in children and adults over 50 years of age. It affects both genders equally, but the course of the disease is more severe in men. Eye involvement leading to loss of vision, plus vascular, articular, and central nervous system involvemen,t are more commonly observed among the men. Behçet’s disease is a systemic inflammatory disorder. A complex genetic background, coupled with innate and adaptive immune system activation, causes the diverse clinical manifestations that characterize the clinical picture.
Behçet’s Disease: A multisystemic vasculitis diagnosed with cutaneous manifestations Behçet’s disease (BD) is a multi-systemic vasculitis, characterized by cutaneous lesions-like aphthous stomatitis, genital ulcers, erythema nodosum like lesions and papulopustular lesions, as well as uveitis, epididymitis, neurologic symptoms and involvement of vessels of all sizes, joints, and the gastrointestinal system. History Behçet’s disease was first described by Hulusi Behçet in 1937, as a trisymptom complex and today we still use these symptoms for diagnosis of the disease(1). Hulusi Behçet mentioned in his papers about patients having recurrent aphthous stomatitis, genital ulcers, and uveitis, together with erythema nodosum, papulopustular lesions, rheumatic pain, hemoptysis, and thrombophlebitis( 2). Today, there are many synonyms used for Behçet’s disease, including
ACCEPTED MANUSCRIPT Behçet’s syndrome, Behçet’s triad, Trisymptom Behçet, La maladie de Behçet, Morbus Behçet, Adamantiades Behçet disease. “Behçet’s disease” is the most frequently used synonym, which is also approved by the International Society of Behçet’s Disease (3, 4).
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Epidemiology
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There are sporadic cases of Behçet’s disease all around the world, but it is most frequently seen along the old Silk Road (5). According to epidemiological studies from different geographical regions of the world, the disease is most prevalent in the Middle East and the Far East regions. HLA-B5 and HLA-B51 genes are important in the pathogenesis of the disease, so this distribution may be attributed to the genetic background of these populations(6,7 ). According to the five large scale epidemiological studies conducted among the Turkish population, prevalence of Behçet’s disease is about 20-421/100000 (8-10 ). Prevalence of the disease is relatively lower in the Thracian region, when compared to Anatolia (11). It is also rarely seen in the pediatric population( 12). Prevelance of Behçet’s disease in Istanbul is 42/10000(10);however, among the Armenian population residing in Istanbul, Behçet’s disease is extremely rare. In addition to that, prevalence of the familial mediterranean fever is much higher(13). In the light of these researches, genetic factors are thought to play a stronger role than environmental factors in the pathogenesis of the disease.
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Behçet’s disease is commonly observed in Iran, Israel, China, North Korea, and Japan, whereas in Europe and the United States, the estimated prevalence of the disease is variable. Frequency of the diseases is higher in Southern Europe, when compared to tho Northern regions(5 ). In France, the total prevalence of the disease is higher among ethnic groups of Asian and North African origin (14).
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Patients with Behçet’s disease are usually in their third or fourth decades. It is very rare in children and adults over 50 years of age. The first sign is usually recurrent aphthous ulcers. The disease is diagnosed approximately 8.1 years after the presence of the first sign(15). Men and women are equally affected, but the course of the disease is more severe in men(16). Men have a greater tendency for eye involvement that may cause loss of vision,and for the central nervous system and pulmonary artery involvement(17). Skin Changes Mucocutaneous manifestations Recurrent aphthous stomatitis Recurrent aphthous stomatitis (RAS) is one of the most common clinical features of Behçet’s disease(2). In clinical practice, aphthous stomatitis is seen in approximately 97 to 100 percent of all Behçet patients(18,19). It usually presents as an initial sign of the disease, but it can also develop during the course of the disease, after the appearance of other signs and symptoms. In retrospective analysis, some signs of the disease become apparent many years after the development of aphthous stomatitis(15). Aphthae can be seen anywhere on the nonkeratinized mucosal membranes of the mouth, but the mucosal surface of the lips, the buccal mucosa, or on the lateral tongue are the most common locations. It begins as a painful papule and
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becomes rapidly ulcerated. White to yellowish pseudomembrane covers the surface of the ulcer and there is an erythematous halo surrounding the lesion. Minor aphthae with a diameter of less than 10 mm, are the most common type. They usually heal spontaneously within 7-10 days. Major aphthae consist of deep, painful ulcers, with diameter of more than 10 mm. They may cause scarring after the healing process. The third subgroup, herpetiform aphthae, are characterized by a convergence of multiple ulcers. According to the diagnostic criteria of ISG (International Study Group) for Behçet’s disease, aphthous lesions must recur more than 3 times a year(20) .
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Incidental trauma, such as tooth brushing,gum chewing, or sharp and rough particles can provoke the development of RAS(21). The application of a pathergy test to the oral mucosa showed a positivity rate of 47% whereas 15% of the patients with a positive oral pathergy test develop aphthous lesions( 22). Genital ulcers
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Nodular lesions
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Another cardinal sign of Behçet’s disease are genital ulcers. Men usually have ulcers on the scrotum, inguinal region, and penis, whereas women have femoro-inguinal and vulvar ulcers. The ulcer starts as a painful papule, pustule, or necrosis. It has a punched-out appearance with edematous borders and a fibrin layer on the floor. It usually resolves in 2-4 weeks. Prevalence of genital ulcer among Behçet’s patients is about 50-85 % (18,19). In Behçet patients, who are men 90% of ulcers larger than 1 cm in diameter heal with scar formation. Risk of scar tissue development in small ulcers is about 49%. In women, ulcers on the femoro-inguinal area and the major labia may leave scarring, whereas on the minor labia and vestibule no visible scar formation is seen( 23). Vaginal and cervical ulcers are extremely rare.
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Eryhema nodosum
Erythema nodosum-like lesions are localized symmetrically on the lower extremities, as well as the thighs and sacral region. These painful nodules are about 1-5 cm in diameter. Females are more prone to develop erythema nodosum-like lesions. They usually heal in 1-6 weeks, with postlesional hyperpigmentation(18,19). Histology of the lesions shows characteristics of septal panniculitis. In some cases, lobular panniculitis with vasculitis can also be seen and is regarded as nodular vasculitis. Signs of vascular inflammation and infiltration of neutrophiles are common accompanying features. Granuloma formation is rarely seen(24). Superficial Thrombophlebitis Superficial thrombophlebitis migrans is another kind of nodular lesion seen in Behçet’s disease. They are more frequent in men. Dusky, red nodules are usually located on the medial side of the legs. Superficial thrombosis can present itself as palpable masses along the course of the veins. As old lesions heal with hyperpigmentation, new ones appear. Superficial thrombophlebitis migrans is also thought to be related to deep vein thrombosis(25).
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Histopathologic examination is the gold standard method of differentiating superficial thrombophlebitis migrans lesions from erythema nodosum. High resolution ultrasound imaging is also helpful. Hypoechoic nodules and the presence of thrombus in the lumen and negative compression are the cardinal findings of sonography in cases of superficial thrombophlebitis. Erythema nosodum lesions are hyperechogenic with regular contours(26).
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Papulopustular Lesions
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Papulopustular lesions are one of the most common findings in Behçet’s disease. They are seen in 30-96% of patients with this disease.
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Acneiform lesions are polymorphous in nature. Inflammatory papules, pustules and cysts can accompany noninflammatory lesions like comedons. These acneiform lesions are mostly located on the back, chest and shoulder area, and less commonly on face. Acne vulgaris, on the other hand, is seen particularly on the facial area( 27). According to ISG, post-adolescent acne in patients who are not on systemic corticosteroid treatment, can be regarded as one of the diagnostic criteria. However, acne vulgaris can persist in 5 % of males, and 20 % of females who are over 25 years of age.
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Papulopustular lesions are mostly follicular. They were once regarded as non-infectious, sterile pustules, but recent studies have shown the colonization of coagulase negative staphylococcus and provotella species(28). Biopsy specimens of papulopustular lesions, obtained from 89 Bheçet patients ,were blindly analysed. 87% of the specimens showed features of folliculitis and perfolliculitis, whereas 9 % had vascular pathologies. Thus, histological examination of papulopustular lesions are not diagnostic. Clinical differentiation of both follicular and nonfollicular lesions is also difficult(29).
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There are many studies that reveal a strong relationship between papulopustular skin lesions and arthritis( 30,31). Other Skin Lesions
Sweet syndrome can be seen during the course of the disease in Behçet patients, in approximately 4% of cases. Painful, erythematous nodules and papules emerges on the facial areas and extremities. Aphthous ulcers, arthritis and uveitis can also be components of Sweet syndrome(32). Extragenital ulcers are very rare in Behçet’s disease, and they are located on the inframammarian folds, axillary region and interdigital area of the feet(33). Patients with a history of deep vein thrombosis are more prone to develop ulcus cruris and vasculitis. Pathergy Phenomenon The pathergy reaction is a nonspecific hyperreactivity to a needle prick, but it is indeed very specific in the diagnosis of Behçet’s disease(34 ). The test is applied to the hairless site of theforearm skin. After cleaning with alcohol, 20 G needles are inserted in an oblique or perpendicular angle. 48 hours after insertion of the needles, a papule or pustule formation on
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the area shows a positive result. We usually insert 6 needles at a time, three on one arm and three on the other, to increase the positivity rate. The frequency of pathergy positivity and intensity of the reaction is higher in men(35,36 ). Pathergy positivity is also one of the diagnostic criteria of ISG. Pathergy positivity rates show geographical variations. In the United Kingdom, pathergy positivity is rarely observed in Behçet patients(36), whereas the positivity rate among Japanese and Turkish Behçet patients is approximately 60-70%. Blunt tip needles, when compared to disposable or sharp tip needles, cause more local injury to the area, which increases the positivity rate of the test (37).
Systemic involvement
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Eye Involvement
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Many organ systems may be affected by Behçet’s disease, but the most commonly involved organ is the eye. About half of the patients have eye involvement. The prevelance can be as high as 70 % among young men, whereas in the older woman population, eye involvement is seen in about 30% of cases. In hospital-based studies, eye involvement begins within the first few years of the disease(17,38). Uveitis generally starts unilaterally but eventually most patients develop bilateral uveitis. Among patients with uveitis, 80% of men and 64% of women have bilateral uveitis during their first visits(17).
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Ocular inflammation mostly presents itself as panuveitis or retinitis. Isolated anterior uveitis can be rarely seen but still most of them transform into panuveitis. When the anterior uveal tract is affected, the main symptom is photophobia. Depending on the extensity of the retinal vasculitis, scar formation on the vascular arch, and optic nerve damage may cause irreversible loss of vision. Topical treatments are used for anterior segment involvement, but frequent attacks may lead to the development of secondary glaucoma and cataract. In cases of posterior segment involvement, systemic treatment with corticosteroids or immunosuppressive agents is mandatory. Loss of vision is inevitable in some patients, despite intensive treatment, (39).
Joint Involvement: Up to 50% of Behçet patients have either arthritis or arhtralgia. Arthritis of Behçet’s disease can be monoarticular or oligoarticular. Symptoms usually heal within a few weeks, without leaving a deformity. Knee, ankle, wrist, and elbow joints are the most frequently affected (40). Back pain and sacroiliac joint involvement is not seen(41). Examination of the synovial fluid reveals inflammatory findings and the formation of mucin clots. Histology of the synovial fluid shows features of nonspecific synovitis(40). Entesopathy usually accompanies arhtritis. Acneiform lesions are also common findings of Behçet patients with arthritis. Papulopustular lesions and arthritis are together regarded as cluster of disease expression. This cluster is frequently found in familial cases. These observations lead to the hypothesis that co-existence papulopustular lesions and arthritis in
ACCEPTED MANUSCRIPT Behçet’s disease may have a similar pathogenetic basis with acne-associated reactive arthritis(31). Vascular Involvement:
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Behçet’s disease involves both arteries and veins. According to the studies conducted in Turkey, more than 40% of Behçet patients have vascular involvement(17 ). The frequency of large-vessel involvement in Japan was 6% in a 412 patients series. Venous involvement was more common than arterial (42). Vascular involvement is more commonly seen in with with Behçet. The most frequent manifestation of vascular involvement is venous thrombosis in the lower extremities. These thrombotic symptoms become evident two to three years after the diagnosis of the disease(43). In the case of superficial thrombophlebitis, erythema nodosumlike lesions present on the medial side of the leg, along the course of the veins. These patients may have accompanying deep femoral vein thrombosis or inferior vena cava syndrome. Recurrent thrombosis may lead to chronic venous insufficiency and venous claudication (Fig 1)(43).
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Vena cava thrombosis has variable clinical signs and symptoms, according to the level of obliteration. In cases of superior vena cava syndrome, there is an edema in the head and neck region, together with jugular venous distention, whereas inferior vena cava syndrome causes edema in the lower extremities, with stasis dermatitis and leg ulcers. The dilatation of collateral veins in the abdominal area and thoracic wall is also another finding.
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Budd-Chiari syndrome is a rare, but a potentially fatal complication, of Behçet’s disease. Hepatic vein thrombosis results in ascite formation together with abdominal pain, edema of the lower extremities and scrotal area, and even hepatic failure in severe cases. Behçet’s disease is the single most frequent cause of Budd-Chiari syndrome (44).
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Arterial involvement can also be seen in forms of aneurysms, mostly on the pulmonary artery, peripheral arteries or abdominal aorta. In a study of 101 patients with Behçet’s disease, Sadoun and colleagues(45) found that arterial lesions develop approximately 4 years after the initial diagnosis, with an average age of 38 and a male predominance. Pulmonary artery involvement is rather rare (5%), presenting with either an aneurysm or thrombosis. Vasculitis causes endothelial injury, leading to formation of thrombosis. Main symptoms of pulmonary artery aneurysm are fever, chest pain, cough, dispnea and hemoptysis. On initial evaluation, unilateral or bilateral hilar opacities can be observed on a chest X-ray (Figures 2 and 3) (46) . Arterial aneurysms can also be observed in the peripheral arteries such as the femoral, iliac, popliteal, or carotid artery, together with abdominal aorta. The rupture of these aneurysms is a major cause of mortality (43 ). Cardiac involvement is rare in Behçet patients. Intracardiac thrombosis is very rarely seen ( 47). Young male patients with a concomitant pulmonary artery involvement, are candidates for intracardiac thrombosis. The thrombus is mostly located on the right ventricle, firmly attached to the underlying myocardium( 48).
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Gastrointestinal Involvement:
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Gastrointestinal involvement shows geographical variations. In Japan almost half of the patients with Behçet’s disease have gastrointestinal involvement, whereas in the Mediterranean region it is relatively rare. Patients usually have mild symptoms such as abdominal pain, diarrhea, nausea or vomiting. Gastrointestinal bleeding or inflammatory bowel disease-like symptoms are also rarely seen. Ulcers of the gastrointestinal tract are mostly located in the terminal ileum, cecum and colon region, whereas the rectum is usually spared. Perianal ulcers are also rare. Esophageal involvement is more common in men, and ulcers are usually lcated at the mid-esophageal level. The main symptoms of these patients are substernal pain and dysphagia(49). Neurological Involvement:
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According to large-scale studies 5-10% of Behçet patients have central nervous system involvement. These patients are usually young men, with a mean age of 26,27. Neurologic manifestations are recognized approximately 5 years after the initial diagnosis. In 80% of neuro-Behçet patients, the brain parenchyma is affected. The second most common presentation is cerebral venous thrombosis, seen in about 20% of the patients. Both parenchymal disease and venous thrombosis can have accompanying vasculitis. The parenchymal form is characterised by small vessel involvement, with pyramidal symptoms such as hemiparesis, cognitive changes, sphincter dysfunction, and impotence. In cases of cerebral venous thrombosis, the clinical picture is comprised of dural sinus thrombosis, severe headaches, papilledema ,and motor or ocular nerve paralysis due to elevated intracranial pressure. Dural sinus thrombosis has a benign course. Neuro-psycho Behçet is an organic psychotic syndrome, and a rare variant of neuro-Behçet. Peripheric neuropathy is not seen in Behçet patients (50,51,52). In a large study of 728 patients, pediatric neuro-Behçet has a frequency of 3%, with a male predominance, and unlike adult patients, dural venous thrombosis is the most common presenting symptom (53 ).
Pathophysiology Behçet’s disease is a systemic inflammatory disorder. A complex genetic background coupled to an innate and adaptive immune system activation causes the diverse clinical manifestations that characterises the clinical picture. The presence of familial cases in around 10% of the patients, its geographic predilection (a high frequency along the so-called Silk Road from Japan to the Mediterranean basin) and the high frequency of HLA-B51 among a wide range of ethnic populations favors the role of genetic factors in the pathogenesis (6).
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HLA-B51 is a split antigen of HLA-B5. A recent meta-analysis has shown that the pooled odds ratio of HLA-B51/B5 carriers developing Behçet’s disease compared to non-carriers was 5,78 (95% CI 5.00-6.67). The risk was consistent across different populations with varying frequencies of Behçet’s disease (54). The role of HLA-B51 in the pathogenesis is not clear. The presentation of a specific peptide to CD 8+ T cells (55) and interactions between KIR (killer immunoglobulin like) receptors of natural killer (NK) cells, CD 8+ T cells and gamma delta T cells (56) are possible mechanisms.
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The possibility of a linkage disequilibrium with HLA-B51 has also been discussed. MICA 009 allele, and its transmembrane microsatellite polymorphism A6, was the main candidate; however, fine mapping among different ethnic groups showed that HLA-B51 still had the strongest association. The only exception to this was the HLA-A*26-F*010101-G*010102 haplotype, which is associated with Behçet’s disease independently of HLA-B51 (57). A recent meta-analysis explored the relationship of HLA-B51 with different clinical manifestations of the disease in 72 studies representing 74 populations. The results showed that the main associations were between genital ulcers, eye and skin involvement , and with the male gender (58).
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Non HLA genes also contribute to the pathogenesis of Behçet’s disease. Case control studies have shown various associations; however, these studies are usually carried out on a small number of patients and they lack statistical power.
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Two genome wide association studies (GWAS) have demonstrated results with important functional consequences (59,60). The first was the reduced production of IL-10; an inhibitory cytokine that regulates both innate and adaptive immune responses. The second one concerned polymorphisms in the IL-23R gene, frequently associated with ankylosing spondylitis, inflammatory bowel disease and psoriasis. Recent data presented in the 15th International Conference of Behçet’s disease, also reported associations with CCR1, STAT4 and KLRC4 encoding a chemokine receptor, a transcription factor implicated in IL-12 and IL23 signalling and a natural killer receptor, and with ERAP1 which is an endoplasmic reticulum expressed aminopeptidase that trims peptides, and loads them on to MHC Class I. An epistatic interaction between HLA B51 and ERAP was demonstrated and MEVF, NOD2 and TLR4, and loci pertinent to innate immunity were also implicated (61). A Th1 predominance in the peripheral blood and tissue specimens of Behçet patients was reported in several studies (62). Recent evidence also showed the preponderance of Th17 cells in the pathogenetic process (63). A study that evaluated T cell profiles and their related cytokines in patients with neurological involvement demonstrated that IL-21 induced IL-17 proliferation and a resultant suppression of regulatory T cells was prominent (64). Another study which explored the roles of Th1, Th2 and Th17 cells in patients with Behçet’s disease showed that peripheral blood Th17/Th1 ratio of Behçet patients was higher than those of the healthy controls, whereas the Th1/Th2 and Th17/Th2 ratios were similar among the two groups. Patients with uveitis or folliculitis had higher Th17/Th1 ratios, when compared to patients without these manifestations (65).
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Another study demonstrated a predominance of Th1 cells compared to Th17 in patients with gastrointestinal manifestations. They also compared cytokine profiles of Behçet patients who have gastrointestinal involvement with those of ankylosing spondylitis, Crohn’s disease and healthy controls. IL-23 MRNA levels were normal in ileal biopsies of Behçet patients in contrast to ankylosing spondylitis and Crohn’s patients. STAT-3 and IL-17A mRNA were also normal in Behçet patients whereas TNF-alfa, IFN-gamma and IL-12p35 mRNA levels were significantly similar to Crohn’s and higher than healthy controls (66). It was interesting to note that although the clinical and histological pictures of Behçet’s disease and Crohn’s disease are very similar, the cytokine profiles of the patients were quite different.
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The variation of cytokine profiles in Behçet patients with different clinical manifestations suggest that the disease may not be a homogenous entity. A cluster analysis performed demonstrated four different patterns of clinical involvement (67,68). The first consisted of mucocutaneous manifestations, the second superficial and deep vein thrombosis, the third eye disease, and the fourth, papulopustular skin disease and arthritis. The last group also showed a familial occurrence, (69) and an increased prevalence of enthesopathy on ultrasonography (31).
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Some authors have attempted to classify Behçet’s disease among autoinflammatory diseases: a group of inherited disorders characterised by episodes of seemingly unprovoked, recurrent inflammatory attacks of innate-nature, mainly mediated by neutrophils (70). Levels of autoantibodies or antigen-specific T cells are not significantly elevated in these diseases. Recurrent lesions of Behçet’s disease, enhanced pro inflammatory cytokine responses such as IL-1 and IL-18 (71) and the occasional presence of MEVF mutations (72) are features suggesting autoinflammation; however, the complex genetical nature of Behçet’s disease, compared to the usual monogenic inheritance observed in the classical autoinflammatory disorders, the presence of panuveitis, hypercoagulability, a clinical course that gets milder in older age, pathergy tests, and the abscence of a childhood onset, paroxysmal attacks of serosal inflammation and fever strengthen the case against autoinflammation (73).
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21. Wray D, Graykowski EA, Notkins AL. Role of mucosal injury in initiating recurrent aphthous stomatitis. Br Med J (Clin Res Ed) 1981; 283: 1569-1570. 22. Sharquie KE, Al-Araji A, Hatem A. Oral pathergy test in Behçet's disease. Br J Dermatol. 2002; 146: 168-169. 23. Mat C, Goksugur N, Ergin B, Yurdakul S, Yazıcı H. The frequency of scarring after genital ulcers in Behçet’s syndrome: a prospective study. Int J Dermatol 2006; 45: 554-556. 24. Demirkesen C, Tüzüner N, Mat C, Senocak M, Büyükbabani N, Tüzün Y, Yazici H. Clinicopathologic evaluation of nodular cutaneous lesions of Behcet syndrome. Am J Clin Pathol 2001; 116: 341-346. 25. Tunç R, Saip S, Siva A, Yazıcı H. Cerebral venous thrombosis is associated with major vessel disease in Behçet’s syndrome. Ann Rheum Dis 2004; 63: 1693-1694. 26. Kucukoglu S, Tunc R, Cetinkaya F, Demirkesen C, Mat C, Yazici H. The importance of cutaneous ultrasonography on the differentiation of nodular skin lesions seen in patients with Behcet’s disease. Yonsei Med J 2000; 41: 40. 27. Alpsoy E, Aktekin M, Er H, Durusoy C, Yilmaz E. A randomized, controlled and blinded study of papulopustular lesions in Turkish Behçet’s patients. Int J Dermatol 1998; 37: 839-842. 28. Hatemi G, Bahar H, Uysal S, Mat C, Gogus F, Masatlioglu S. The pustular skin lesions in Behcet's syndrome are not sterile. Ann Rheum Dis 2004; 63: 1450-1452. 29. Ergun T, Gürbüz O, Doğusoy G, Mat C. Histopathologic features of the spontaneous pustular lesions of Behçet’s syndrome. Int J Dermatol 1998; 37: 194-196. 30. Diri E, Mat C, Hamuryudan V, Yurdakul S, Hizli N, Yazici H. Papulopustular skin lesions are seen more frequently in patients with Behçet's syndrome who have arthritis: a controlled and masked study. Ann Rheum Dis 2001; 60: 1074-1076. 31. Hatemi G, Fresko I, Taşcılar K, Yazıcı H. Entesopathy is increased among Behçet’s syndrome patients with acne and arthritis: an ultrasonographic study. Arthritis Rheum 2008; 58: 1539-1545. 32. Oğuz O, Serdaroğlu S, Tüzün Y, Erdoğan N, Yazici H, Savaşkan H. Acute febrile neutrophilic dermatosis associated with Behcet’s syndrome. Int J Dermatol 1992; 31: 645-646. 33. Azizlerli G, Ozarmağan G, Ovül C, Sarica R, Mustafa SO. A new kind of skin lesion in Behçet’s disease: extragenital ulcers. Acta Derm Venereol 1992; 72: 286. 34. Altaç M, Tüzün Y, Yurdakul S, Binyildiz P, Yazici H. The validity of the pathergy test (non-specific skin hyperreactivity) in Behçet's disease: a double-blind study by independent observers. Acta Derm Venereol 1982; 62: 158-159. 35. Yazici H, Tüzün Y, Tanman AB, Yurdakul S, Serdaroglu S, Pazarli H, Müftüoglu A. Male patients with Behçet's syndrome have stronger pathergy reactions. Clin Exp Rheumatol 1985; 3: 137-141. 36. Yazici H, Chamberlain MA, Tüzün Y, Yurdakul S, Müftüoglu A. A comparative study of the pathergy reaction among Turkish and British patients with Behçet's disease. Ann Rheum Dis 1984; 43: 74-75. 37. Dilşen N, Koniçe M, Aral O, Ocal L, Inanç M, Gül A. Comparative study of the skin pathergy test with blunt and sharp needles in Behçet's disease: confirmed specificity but decreased sensitivity with sharp needles. Ann Rheum Dis 1993; 52: 823-825. 38. Tugal-Tutkun I, Onal S, Altan-Yaycioglu R, Huseyin Altunbas H, Urgancioglu M. Uveitis in Behçet disease: an analysis of 880 patients. Am J Ophthalmol 2004; 138: 373-380. 39. Özyazgan Y, Bodaghi B. Eye disease in Behçet’s syndrome. In Behçet’s Syndrome. Ed. Yazici Y, Yazici H. 1. Edition. New York, Springer, 2010; 73-94.
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40. Yurdakul S, Yazici H, Tüzün Y, Pazarli H, Yalçin B, Altaç M. The arthritis of Behçet’s disease: a prospective study. Ann Rheum Dis 1983; 42: 505-515. 41. Yazici H, Tuzlaci M, Yurdakul S. A controlled survey of sacroiliitis in Behçet’s disease. Ann Rheum Dis 1981; 40: 558-559. 42. Ideguchi H, Suda A, Takeno M, Ueda A, Ohno S, Ishigatsubo Y. Characteristics of vascular involvement in Behçet’s disease in Japan: A retrospectif cohort study. Clin Exp Rheumatol 2011; 29: 47-53. 43. Seyahi E, Yurdakul S. Behçet’s syndrome and thrombosis. Mediterr J Hematol Infect Dis 2011; 3: e2011026. 44. Bayraktar Y, Balkanci F, Bayraktar M, Calguneri M. Budd-Chiari syndrome: a common complication of Behçet’s disease. Am J Gastroenterol 1997; 92: 858-862. 45. Saadoun D, Asli B, Wechsler B, Houman H, Geri G, Desseaux K et al. Long-term outcome of arterial lesions in Behçet disease: a series of 101 patients. Medicine (Baltimore) 2012; 91: 18-24. 46. Hamuryudan V, Er T, Seyahi E, Akman C, Tüzün H, Fresko I et al. Pulmonary artery aneurysms in Behçet syndrome. Am J Med 2004; 117: 867-870. 47. Ozkan M, Emel O, Ozdemir M, Yurdakul S, Koçak H, Ozdoğan H et al: M-mode, 2-D and Doppler echocardiographic study in 65 patients with Behçet’s syndrome. Eur Heart J 1992; 13: 638-641. 48. Geri G, Wechsler B, Thi Huong du L, Isnard R, Piette JC, Amoura Z et al. Spectrum of cardiac lesions in Behçet disease: a series of 52 patients and review of literature. Medicine (Baltimore) 2012; 91: 25-34. 49. Cheon JH, Çelik AF, Kim WH. Behçet’s disease: Gastrointestinal involvement. In Behçet’s Syndrome. Ed. Yazici Y, Yazici H. 1. Edition. New York, Springer, 2010; 165-188. 50. Akman-Demir G, Serdaroğlu P, Tascı B. Clinical patterns of neurological involvement in Behçet’s disease: evaluation of 200 patients. Brain 1999; 122: 2171-2182. 51. Siva A, Kantarci OH, Saip S, Altintas A, Hamuryudan V, Islak C et al. Behçet’s disease; diagnostic and prognostic aspects of neurological involvement J Neurology 2001; 248: 95-103. 52. Ideguchi H, Suda A, Takeno M, Kirino Y, Ihata A, Ueda A et al. Neurological manifestations of Behçet’s disease in Japan: a study of 54 patients. J Neurol 2010; 257: 1012-1020. 53. Uluduz D, Kürtüncü M, Yapıcı Z, Seyahi E, Kasapçopur Ö, Özdoğan H et al. Clinical characteristics of pediatric onset neuro-Behçet’s disease. Neurology. 2011; 77: 19001905. 54. de Menthon M, Lavalley MP, Maldini C, Guillevin L, Mahr A. HLAB51/B5 and the risk of Behçet’s disease: a systematic review and meta-analysis of case control genetic association studies. Arthritis Rheum 2009; 61: 1287-1296. 55. Sakaguchi T, Ibe M, Miwa K, Yokota S, Tanaka K, Schönbach C, Takiguchi M. Predominant role of N-terminal residue of nonamer peptides in their binding to HLAB*5101 molecules. Immunogenetics 1997; 46: 245-248. 56. Duymaz-Tozkır J, Uyar AF, Norman PJ, Parham P, Direskeneli GS, Gül A. Distribution of killer immunoglobulin like receptor 3DL1/3DS1 alleles in Behçet’s disease. Arthritis Rheum 2008; 58(Suppl): S855. 57. Meguro A, Inoko H, Ota M, Katsuyama Y, Oka A, Okada E et al. Genetics of Behçet’s Disease inside and outside the MHC. Ann Rheum Dis 2012; 69: 747-754. 58. Maldini C, Lavalley MP, Cheminant M, de Menthon M, Mahr A. Relationships of HLA-B51 or B5 genotype with Behçet’s disease clinical characteristics: systematic
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review and meta-analyses of observational studies. Rheumatology (Oxford) 2012; 51: 887-900. 59. Remmers EF, Cosan F, Kirino Y, Ombrello MJ, Abaci N, Satorius C et al. Genomewide association study identifies variants in the MHC class I, IL10 and IL-23RIL12RB2 regions associated with Behçet’s disease. Nat Genet 2010; 42: 698-702. 60. Mizuki N, Meguro A, Ota M, Ohno S, Shiota T, Kawagoe T. Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behçet’s disease susceptibility loci. Nat Genet 2010; 42: 703-706. 61. Fresko I. 15th International Congress on Behçet’s Disease 13-15 July 2012, Yokohama, Japan. Clin Exp Rheumatol 2012; 30(Suppl.72): S118-S128. 62. Direskeneli H, Fujita H, Akdis CA. Regulation of Th17 and regulatory T cells in patients with Behçet’s disease. J Allergy Clin Immunol 2011; 128: 665-666. 63. Hamzaoui K. Th17 cells in Behçet’s disease: a new immunoregulatory axis. Clin Exp Rheumatol 2011; 29(Suppl.67): S71-6. 64. Geri G, Terrier B, Rosenzwajg M, Wechsler B, Touzot M, Seilhean D et al. Critical role of IL-21 in modulating Th17 and regulatory T cells in Behçet’s disease. J Allergy Clin Immunol 2011; 128: 655-664. 65. Kim J, Park JA, Lee EY, Lee YJ, Song YW, Lee EB. Imbalance of Th17 to Th1 cells in Behçet’s disease. Clin Exp Rheumatol 2010; 28(Suppl. 60): S16-9. 66. Ferrante A, Ciccia F, Principato A, Giardina AR, Impastato R, Peralta S, Triolo G. A Th1 but not a Th17 response is present in the gastrointestinal involvement of Behçet’s disease. Clin Exp Rheumatol 2010; 28(Suppl. 60): S27-30. 67. Tunc R, Keyman E, Melikoglu M, Fresko I, Yazici H. Target organ associations in Turkish patients with Behçet’s disease: a cross sectional exploratory factor analysis. J Rheumatol 2002; 29: 2393-2396. 68. Yazici H, Ugurlu S, Seyahi E.Behçet’s Syndrome: Is It One Condition? Clin Rev Allergy Immunol 2012; 43: 275-280. 69. Karaca M, Hatemi G, Sut N, Yazici H. The papulopustular lesion/arthritis cluster in Behçet’s syndrome also clusters in families. Rheumatology (Oxford) 2012; 51: 10531060. 70. Stojanov S, Kastner DL. Familial autoinflammatory diseases: genetics, pathogenesis and treatment. Curr Opin Rheumatol 2005; 17: 586-599. 71. Musabak U, Pay S, Erdem H, Simsek I, Pekel A, Dinc A, Sengul A. Serum interleukin-18 levels in patients with Behçet’s disease. Is its expression associated with disease activity or clinical presentations? Rheumatology Int 2006; 26: 545-550. 72. Rabinovich E, Shinar Y, Leiba M, Ehrenfeld M, Langevitz P, Livneh A. Common FMF alleles may predispose to development of Behçet’s disease with increased risk for venous thrombosis. Scand J Rheumatol 2007; 36: 48-52. 73. Yazici H, Fresko I. Behçet’s disease and other autoinflammatory conditions: what’s in a name? Clin Exp Rheumatol 2005; 23(4Suppl38):S1-2.
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Figure 1. Ulcers due to vasculitis and venous insufficiency
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Figure 2. Chest x-ray unilateral hilar opacity
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Figure 3. Right pulmonary artery aneurysm in CT scan
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S0738-081X(13)00303-9 doi: 10.1016/j.clindermatol.2013.11.012 CID 6812
To appear in:
Clinics in Dermatology
˙ Please cite this article as: Mat M. Cem, Sevim Ay¸seg¨ ul, Fresko Izzet, T¨ uz¨ un Yal¸cın, Beh¸cet’s disease as a systemic disease, Clinics in Dermatology (2013), doi: 10.1016/j.clindermatol.2013.11.012
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ACCEPTED MANUSCRIPT Behçet’s disease as a systemic disease M. Cem Mat MD1, Ayşegül Sevim MD1, İzzet Fresko MD2, Yalçın Tüzün MD1*
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Istanbul University, Cerrahpasa Medical Faculty, Department of Dermatology, Division of Rheumatology, Istanbul, Turkey.
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* Corresponding Author: Yalçın Tüzün, MD, Department of Dermatology, Cerrahpaşa Medical Faculty, Istanbul University, 34098 Fatih, İstanbul. Turkey.
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E-mail: [email protected]
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Abstract
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Behçet’s disease usually begins with cutaneous manifestations such as recurrent aphthous stomatitis, genital ulcers, erythema nodosum-like lesions, papulopustular findings, and pathergy phenomenon. Recurrent aphthous stomatitis is generally the first ssign, and other findings may develop in the course of the disease. There is no specific diagnostic available for Behçet’s disease. It is most prevalent among patients along the ancient Silk Road. The high frequency of HLA-B51 among a wide range of ethnic populations favors the role of genetic factors. Behçet’s disease usually appears in the third to fourth decade of life, and is rarely seen in children and adults over 50 years of age. It affects both genders equally, but the course of the disease is more severe in men. Eye involvement leading to loss of vision, plus vascular, articular, and central nervous system involvemen,t are more commonly observed among the men. Behçet’s disease is a systemic inflammatory disorder. A complex genetic background, coupled with innate and adaptive immune system activation, causes the diverse clinical manifestations that characterize the clinical picture.
Behçet’s Disease: A multisystemic vasculitis diagnosed with cutaneous manifestations Behçet’s disease (BD) is a multi-systemic vasculitis, characterized by cutaneous lesions-like aphthous stomatitis, genital ulcers, erythema nodosum like lesions and papulopustular lesions, as well as uveitis, epididymitis, neurologic symptoms and involvement of vessels of all sizes, joints, and the gastrointestinal system. History Behçet’s disease was first described by Hulusi Behçet in 1937, as a trisymptom complex and today we still use these symptoms for diagnosis of the disease(1). Hulusi Behçet mentioned in his papers about patients having recurrent aphthous stomatitis, genital ulcers, and uveitis, together with erythema nodosum, papulopustular lesions, rheumatic pain, hemoptysis, and thrombophlebitis( 2). Today, there are many synonyms used for Behçet’s disease, including
ACCEPTED MANUSCRIPT Behçet’s syndrome, Behçet’s triad, Trisymptom Behçet, La maladie de Behçet, Morbus Behçet, Adamantiades Behçet disease. “Behçet’s disease” is the most frequently used synonym, which is also approved by the International Society of Behçet’s Disease (3, 4).
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Epidemiology
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There are sporadic cases of Behçet’s disease all around the world, but it is most frequently seen along the old Silk Road (5). According to epidemiological studies from different geographical regions of the world, the disease is most prevalent in the Middle East and the Far East regions. HLA-B5 and HLA-B51 genes are important in the pathogenesis of the disease, so this distribution may be attributed to the genetic background of these populations(6,7 ). According to the five large scale epidemiological studies conducted among the Turkish population, prevalence of Behçet’s disease is about 20-421/100000 (8-10 ). Prevalence of the disease is relatively lower in the Thracian region, when compared to Anatolia (11). It is also rarely seen in the pediatric population( 12). Prevelance of Behçet’s disease in Istanbul is 42/10000(10);however, among the Armenian population residing in Istanbul, Behçet’s disease is extremely rare. In addition to that, prevalence of the familial mediterranean fever is much higher(13). In the light of these researches, genetic factors are thought to play a stronger role than environmental factors in the pathogenesis of the disease.
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Behçet’s disease is commonly observed in Iran, Israel, China, North Korea, and Japan, whereas in Europe and the United States, the estimated prevalence of the disease is variable. Frequency of the diseases is higher in Southern Europe, when compared to tho Northern regions(5 ). In France, the total prevalence of the disease is higher among ethnic groups of Asian and North African origin (14).
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Patients with Behçet’s disease are usually in their third or fourth decades. It is very rare in children and adults over 50 years of age. The first sign is usually recurrent aphthous ulcers. The disease is diagnosed approximately 8.1 years after the presence of the first sign(15). Men and women are equally affected, but the course of the disease is more severe in men(16). Men have a greater tendency for eye involvement that may cause loss of vision,and for the central nervous system and pulmonary artery involvement(17). Skin Changes Mucocutaneous manifestations Recurrent aphthous stomatitis Recurrent aphthous stomatitis (RAS) is one of the most common clinical features of Behçet’s disease(2). In clinical practice, aphthous stomatitis is seen in approximately 97 to 100 percent of all Behçet patients(18,19). It usually presents as an initial sign of the disease, but it can also develop during the course of the disease, after the appearance of other signs and symptoms. In retrospective analysis, some signs of the disease become apparent many years after the development of aphthous stomatitis(15). Aphthae can be seen anywhere on the nonkeratinized mucosal membranes of the mouth, but the mucosal surface of the lips, the buccal mucosa, or on the lateral tongue are the most common locations. It begins as a painful papule and
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becomes rapidly ulcerated. White to yellowish pseudomembrane covers the surface of the ulcer and there is an erythematous halo surrounding the lesion. Minor aphthae with a diameter of less than 10 mm, are the most common type. They usually heal spontaneously within 7-10 days. Major aphthae consist of deep, painful ulcers, with diameter of more than 10 mm. They may cause scarring after the healing process. The third subgroup, herpetiform aphthae, are characterized by a convergence of multiple ulcers. According to the diagnostic criteria of ISG (International Study Group) for Behçet’s disease, aphthous lesions must recur more than 3 times a year(20) .
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Incidental trauma, such as tooth brushing,gum chewing, or sharp and rough particles can provoke the development of RAS(21). The application of a pathergy test to the oral mucosa showed a positivity rate of 47% whereas 15% of the patients with a positive oral pathergy test develop aphthous lesions( 22). Genital ulcers
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Nodular lesions
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Another cardinal sign of Behçet’s disease are genital ulcers. Men usually have ulcers on the scrotum, inguinal region, and penis, whereas women have femoro-inguinal and vulvar ulcers. The ulcer starts as a painful papule, pustule, or necrosis. It has a punched-out appearance with edematous borders and a fibrin layer on the floor. It usually resolves in 2-4 weeks. Prevalence of genital ulcer among Behçet’s patients is about 50-85 % (18,19). In Behçet patients, who are men 90% of ulcers larger than 1 cm in diameter heal with scar formation. Risk of scar tissue development in small ulcers is about 49%. In women, ulcers on the femoro-inguinal area and the major labia may leave scarring, whereas on the minor labia and vestibule no visible scar formation is seen( 23). Vaginal and cervical ulcers are extremely rare.
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Eryhema nodosum
Erythema nodosum-like lesions are localized symmetrically on the lower extremities, as well as the thighs and sacral region. These painful nodules are about 1-5 cm in diameter. Females are more prone to develop erythema nodosum-like lesions. They usually heal in 1-6 weeks, with postlesional hyperpigmentation(18,19). Histology of the lesions shows characteristics of septal panniculitis. In some cases, lobular panniculitis with vasculitis can also be seen and is regarded as nodular vasculitis. Signs of vascular inflammation and infiltration of neutrophiles are common accompanying features. Granuloma formation is rarely seen(24). Superficial Thrombophlebitis Superficial thrombophlebitis migrans is another kind of nodular lesion seen in Behçet’s disease. They are more frequent in men. Dusky, red nodules are usually located on the medial side of the legs. Superficial thrombosis can present itself as palpable masses along the course of the veins. As old lesions heal with hyperpigmentation, new ones appear. Superficial thrombophlebitis migrans is also thought to be related to deep vein thrombosis(25).
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Histopathologic examination is the gold standard method of differentiating superficial thrombophlebitis migrans lesions from erythema nodosum. High resolution ultrasound imaging is also helpful. Hypoechoic nodules and the presence of thrombus in the lumen and negative compression are the cardinal findings of sonography in cases of superficial thrombophlebitis. Erythema nosodum lesions are hyperechogenic with regular contours(26).
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Papulopustular Lesions
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Papulopustular lesions are one of the most common findings in Behçet’s disease. They are seen in 30-96% of patients with this disease.
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Acneiform lesions are polymorphous in nature. Inflammatory papules, pustules and cysts can accompany noninflammatory lesions like comedons. These acneiform lesions are mostly located on the back, chest and shoulder area, and less commonly on face. Acne vulgaris, on the other hand, is seen particularly on the facial area( 27). According to ISG, post-adolescent acne in patients who are not on systemic corticosteroid treatment, can be regarded as one of the diagnostic criteria. However, acne vulgaris can persist in 5 % of males, and 20 % of females who are over 25 years of age.
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Papulopustular lesions are mostly follicular. They were once regarded as non-infectious, sterile pustules, but recent studies have shown the colonization of coagulase negative staphylococcus and provotella species(28). Biopsy specimens of papulopustular lesions, obtained from 89 Bheçet patients ,were blindly analysed. 87% of the specimens showed features of folliculitis and perfolliculitis, whereas 9 % had vascular pathologies. Thus, histological examination of papulopustular lesions are not diagnostic. Clinical differentiation of both follicular and nonfollicular lesions is also difficult(29).
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There are many studies that reveal a strong relationship between papulopustular skin lesions and arthritis( 30,31). Other Skin Lesions
Sweet syndrome can be seen during the course of the disease in Behçet patients, in approximately 4% of cases. Painful, erythematous nodules and papules emerges on the facial areas and extremities. Aphthous ulcers, arthritis and uveitis can also be components of Sweet syndrome(32). Extragenital ulcers are very rare in Behçet’s disease, and they are located on the inframammarian folds, axillary region and interdigital area of the feet(33). Patients with a history of deep vein thrombosis are more prone to develop ulcus cruris and vasculitis. Pathergy Phenomenon The pathergy reaction is a nonspecific hyperreactivity to a needle prick, but it is indeed very specific in the diagnosis of Behçet’s disease(34 ). The test is applied to the hairless site of theforearm skin. After cleaning with alcohol, 20 G needles are inserted in an oblique or perpendicular angle. 48 hours after insertion of the needles, a papule or pustule formation on
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the area shows a positive result. We usually insert 6 needles at a time, three on one arm and three on the other, to increase the positivity rate. The frequency of pathergy positivity and intensity of the reaction is higher in men(35,36 ). Pathergy positivity is also one of the diagnostic criteria of ISG. Pathergy positivity rates show geographical variations. In the United Kingdom, pathergy positivity is rarely observed in Behçet patients(36), whereas the positivity rate among Japanese and Turkish Behçet patients is approximately 60-70%. Blunt tip needles, when compared to disposable or sharp tip needles, cause more local injury to the area, which increases the positivity rate of the test (37).
Systemic involvement
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Eye Involvement
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Many organ systems may be affected by Behçet’s disease, but the most commonly involved organ is the eye. About half of the patients have eye involvement. The prevelance can be as high as 70 % among young men, whereas in the older woman population, eye involvement is seen in about 30% of cases. In hospital-based studies, eye involvement begins within the first few years of the disease(17,38). Uveitis generally starts unilaterally but eventually most patients develop bilateral uveitis. Among patients with uveitis, 80% of men and 64% of women have bilateral uveitis during their first visits(17).
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Ocular inflammation mostly presents itself as panuveitis or retinitis. Isolated anterior uveitis can be rarely seen but still most of them transform into panuveitis. When the anterior uveal tract is affected, the main symptom is photophobia. Depending on the extensity of the retinal vasculitis, scar formation on the vascular arch, and optic nerve damage may cause irreversible loss of vision. Topical treatments are used for anterior segment involvement, but frequent attacks may lead to the development of secondary glaucoma and cataract. In cases of posterior segment involvement, systemic treatment with corticosteroids or immunosuppressive agents is mandatory. Loss of vision is inevitable in some patients, despite intensive treatment, (39).
Joint Involvement: Up to 50% of Behçet patients have either arthritis or arhtralgia. Arthritis of Behçet’s disease can be monoarticular or oligoarticular. Symptoms usually heal within a few weeks, without leaving a deformity. Knee, ankle, wrist, and elbow joints are the most frequently affected (40). Back pain and sacroiliac joint involvement is not seen(41). Examination of the synovial fluid reveals inflammatory findings and the formation of mucin clots. Histology of the synovial fluid shows features of nonspecific synovitis(40). Entesopathy usually accompanies arhtritis. Acneiform lesions are also common findings of Behçet patients with arthritis. Papulopustular lesions and arthritis are together regarded as cluster of disease expression. This cluster is frequently found in familial cases. These observations lead to the hypothesis that co-existence papulopustular lesions and arthritis in
ACCEPTED MANUSCRIPT Behçet’s disease may have a similar pathogenetic basis with acne-associated reactive arthritis(31). Vascular Involvement:
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Behçet’s disease involves both arteries and veins. According to the studies conducted in Turkey, more than 40% of Behçet patients have vascular involvement(17 ). The frequency of large-vessel involvement in Japan was 6% in a 412 patients series. Venous involvement was more common than arterial (42). Vascular involvement is more commonly seen in with with Behçet. The most frequent manifestation of vascular involvement is venous thrombosis in the lower extremities. These thrombotic symptoms become evident two to three years after the diagnosis of the disease(43). In the case of superficial thrombophlebitis, erythema nodosumlike lesions present on the medial side of the leg, along the course of the veins. These patients may have accompanying deep femoral vein thrombosis or inferior vena cava syndrome. Recurrent thrombosis may lead to chronic venous insufficiency and venous claudication (Fig 1)(43).
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Vena cava thrombosis has variable clinical signs and symptoms, according to the level of obliteration. In cases of superior vena cava syndrome, there is an edema in the head and neck region, together with jugular venous distention, whereas inferior vena cava syndrome causes edema in the lower extremities, with stasis dermatitis and leg ulcers. The dilatation of collateral veins in the abdominal area and thoracic wall is also another finding.
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Budd-Chiari syndrome is a rare, but a potentially fatal complication, of Behçet’s disease. Hepatic vein thrombosis results in ascite formation together with abdominal pain, edema of the lower extremities and scrotal area, and even hepatic failure in severe cases. Behçet’s disease is the single most frequent cause of Budd-Chiari syndrome (44).
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Arterial involvement can also be seen in forms of aneurysms, mostly on the pulmonary artery, peripheral arteries or abdominal aorta. In a study of 101 patients with Behçet’s disease, Sadoun and colleagues(45) found that arterial lesions develop approximately 4 years after the initial diagnosis, with an average age of 38 and a male predominance. Pulmonary artery involvement is rather rare (5%), presenting with either an aneurysm or thrombosis. Vasculitis causes endothelial injury, leading to formation of thrombosis. Main symptoms of pulmonary artery aneurysm are fever, chest pain, cough, dispnea and hemoptysis. On initial evaluation, unilateral or bilateral hilar opacities can be observed on a chest X-ray (Figures 2 and 3) (46) . Arterial aneurysms can also be observed in the peripheral arteries such as the femoral, iliac, popliteal, or carotid artery, together with abdominal aorta. The rupture of these aneurysms is a major cause of mortality (43 ). Cardiac involvement is rare in Behçet patients. Intracardiac thrombosis is very rarely seen ( 47). Young male patients with a concomitant pulmonary artery involvement, are candidates for intracardiac thrombosis. The thrombus is mostly located on the right ventricle, firmly attached to the underlying myocardium( 48).
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Gastrointestinal Involvement:
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Gastrointestinal involvement shows geographical variations. In Japan almost half of the patients with Behçet’s disease have gastrointestinal involvement, whereas in the Mediterranean region it is relatively rare. Patients usually have mild symptoms such as abdominal pain, diarrhea, nausea or vomiting. Gastrointestinal bleeding or inflammatory bowel disease-like symptoms are also rarely seen. Ulcers of the gastrointestinal tract are mostly located in the terminal ileum, cecum and colon region, whereas the rectum is usually spared. Perianal ulcers are also rare. Esophageal involvement is more common in men, and ulcers are usually lcated at the mid-esophageal level. The main symptoms of these patients are substernal pain and dysphagia(49). Neurological Involvement:
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According to large-scale studies 5-10% of Behçet patients have central nervous system involvement. These patients are usually young men, with a mean age of 26,27. Neurologic manifestations are recognized approximately 5 years after the initial diagnosis. In 80% of neuro-Behçet patients, the brain parenchyma is affected. The second most common presentation is cerebral venous thrombosis, seen in about 20% of the patients. Both parenchymal disease and venous thrombosis can have accompanying vasculitis. The parenchymal form is characterised by small vessel involvement, with pyramidal symptoms such as hemiparesis, cognitive changes, sphincter dysfunction, and impotence. In cases of cerebral venous thrombosis, the clinical picture is comprised of dural sinus thrombosis, severe headaches, papilledema ,and motor or ocular nerve paralysis due to elevated intracranial pressure. Dural sinus thrombosis has a benign course. Neuro-psycho Behçet is an organic psychotic syndrome, and a rare variant of neuro-Behçet. Peripheric neuropathy is not seen in Behçet patients (50,51,52). In a large study of 728 patients, pediatric neuro-Behçet has a frequency of 3%, with a male predominance, and unlike adult patients, dural venous thrombosis is the most common presenting symptom (53 ).
Pathophysiology Behçet’s disease is a systemic inflammatory disorder. A complex genetic background coupled to an innate and adaptive immune system activation causes the diverse clinical manifestations that characterises the clinical picture. The presence of familial cases in around 10% of the patients, its geographic predilection (a high frequency along the so-called Silk Road from Japan to the Mediterranean basin) and the high frequency of HLA-B51 among a wide range of ethnic populations favors the role of genetic factors in the pathogenesis (6).
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HLA-B51 is a split antigen of HLA-B5. A recent meta-analysis has shown that the pooled odds ratio of HLA-B51/B5 carriers developing Behçet’s disease compared to non-carriers was 5,78 (95% CI 5.00-6.67). The risk was consistent across different populations with varying frequencies of Behçet’s disease (54). The role of HLA-B51 in the pathogenesis is not clear. The presentation of a specific peptide to CD 8+ T cells (55) and interactions between KIR (killer immunoglobulin like) receptors of natural killer (NK) cells, CD 8+ T cells and gamma delta T cells (56) are possible mechanisms.
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The possibility of a linkage disequilibrium with HLA-B51 has also been discussed. MICA 009 allele, and its transmembrane microsatellite polymorphism A6, was the main candidate; however, fine mapping among different ethnic groups showed that HLA-B51 still had the strongest association. The only exception to this was the HLA-A*26-F*010101-G*010102 haplotype, which is associated with Behçet’s disease independently of HLA-B51 (57). A recent meta-analysis explored the relationship of HLA-B51 with different clinical manifestations of the disease in 72 studies representing 74 populations. The results showed that the main associations were between genital ulcers, eye and skin involvement , and with the male gender (58).
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Non HLA genes also contribute to the pathogenesis of Behçet’s disease. Case control studies have shown various associations; however, these studies are usually carried out on a small number of patients and they lack statistical power.
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Two genome wide association studies (GWAS) have demonstrated results with important functional consequences (59,60). The first was the reduced production of IL-10; an inhibitory cytokine that regulates both innate and adaptive immune responses. The second one concerned polymorphisms in the IL-23R gene, frequently associated with ankylosing spondylitis, inflammatory bowel disease and psoriasis. Recent data presented in the 15th International Conference of Behçet’s disease, also reported associations with CCR1, STAT4 and KLRC4 encoding a chemokine receptor, a transcription factor implicated in IL-12 and IL23 signalling and a natural killer receptor, and with ERAP1 which is an endoplasmic reticulum expressed aminopeptidase that trims peptides, and loads them on to MHC Class I. An epistatic interaction between HLA B51 and ERAP was demonstrated and MEVF, NOD2 and TLR4, and loci pertinent to innate immunity were also implicated (61). A Th1 predominance in the peripheral blood and tissue specimens of Behçet patients was reported in several studies (62). Recent evidence also showed the preponderance of Th17 cells in the pathogenetic process (63). A study that evaluated T cell profiles and their related cytokines in patients with neurological involvement demonstrated that IL-21 induced IL-17 proliferation and a resultant suppression of regulatory T cells was prominent (64). Another study which explored the roles of Th1, Th2 and Th17 cells in patients with Behçet’s disease showed that peripheral blood Th17/Th1 ratio of Behçet patients was higher than those of the healthy controls, whereas the Th1/Th2 and Th17/Th2 ratios were similar among the two groups. Patients with uveitis or folliculitis had higher Th17/Th1 ratios, when compared to patients without these manifestations (65).
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Another study demonstrated a predominance of Th1 cells compared to Th17 in patients with gastrointestinal manifestations. They also compared cytokine profiles of Behçet patients who have gastrointestinal involvement with those of ankylosing spondylitis, Crohn’s disease and healthy controls. IL-23 MRNA levels were normal in ileal biopsies of Behçet patients in contrast to ankylosing spondylitis and Crohn’s patients. STAT-3 and IL-17A mRNA were also normal in Behçet patients whereas TNF-alfa, IFN-gamma and IL-12p35 mRNA levels were significantly similar to Crohn’s and higher than healthy controls (66). It was interesting to note that although the clinical and histological pictures of Behçet’s disease and Crohn’s disease are very similar, the cytokine profiles of the patients were quite different.
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The variation of cytokine profiles in Behçet patients with different clinical manifestations suggest that the disease may not be a homogenous entity. A cluster analysis performed demonstrated four different patterns of clinical involvement (67,68). The first consisted of mucocutaneous manifestations, the second superficial and deep vein thrombosis, the third eye disease, and the fourth, papulopustular skin disease and arthritis. The last group also showed a familial occurrence, (69) and an increased prevalence of enthesopathy on ultrasonography (31).
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Some authors have attempted to classify Behçet’s disease among autoinflammatory diseases: a group of inherited disorders characterised by episodes of seemingly unprovoked, recurrent inflammatory attacks of innate-nature, mainly mediated by neutrophils (70). Levels of autoantibodies or antigen-specific T cells are not significantly elevated in these diseases. Recurrent lesions of Behçet’s disease, enhanced pro inflammatory cytokine responses such as IL-1 and IL-18 (71) and the occasional presence of MEVF mutations (72) are features suggesting autoinflammation; however, the complex genetical nature of Behçet’s disease, compared to the usual monogenic inheritance observed in the classical autoinflammatory disorders, the presence of panuveitis, hypercoagulability, a clinical course that gets milder in older age, pathergy tests, and the abscence of a childhood onset, paroxysmal attacks of serosal inflammation and fever strengthen the case against autoinflammation (73).
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Figure 1. Ulcers due to vasculitis and venous insufficiency
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Figure 2. Chest x-ray unilateral hilar opacity
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Figure 3. Right pulmonary artery aneurysm in CT scan
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