Update on the diagnosis and management of Behçet’s disease
Authors Rokutanda R, Kishimoto M, Okada M
Received 3 July 2014
Accepted for publication 15 September 2014
Published 30 December 2014 Volume 2015:7 Pages 1—8
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 3
Editor who approved publication: Professor Chuan-Ju Liu
Ryo Rokutanda, Mitsumasa Kishimoto, Masato Okada
Immuno-Rheumatology Center, St Luke’s International Hospital, Tokyo, Japan
Abstract: Behçet’s disease is a multi-organ disorder that is more common in countries around the Silk Road, and manifests as mucosal ulcers and skin lesions, and with ocular involvement. As a systemic disease, it can also involve gastrointestinal organs and the central nervous or cardiovascular systems. Although the etiology of Behçet's disease is not clearly identified, the pathogenesis of the disease is most commonly hypothesized as a profound inflammatory response triggered by an infectious agent in a genetically susceptible host. As there are no single specific manifestations or specific diagnostic tests, various diagnostic criteria have been proposed around the world, and, among them, the International Study Group criteria have been most commonly used. As the clinical expression of Behçet's disease is heterogeneous, the treatment should be individualized based on involved organs, severity of the disease, and patient's background. The choice of therapeutic agents is limited by lack of clinical trials and is based largely on case reports, case series, and several open-label clinical trials. Corticosteroids, colchicine, and traditional immunosuppressive agents, including azathioprine and cyclosporine, have been used for the treatment of Behçet’s disease. Recently, tumor necrosis factor (TNF) inhibitors have become available for several rheumatic diseases, and considerable published data suggest that TNF inhibitors represent an important therapeutic advance for patients with severe and resistant disease, as well as for those with contraindications or intolerance to these treatments.
Keywords: Behçet’s disease, therapeutic agents, etiology, diagnosis
Behçet’s disease is a multi-organ disorder characterized by recurrent mucosal ulcers, ocular inflammation, skin lesions, gastrointestinal disease, and musculoskeletal involvement. It was first described by Hippocrates but was brought to attention in 1937 by Hulusi Behçet, a Turkish dermatologist from Istanbul, who reported three patients with recurrent oral and genital ulceration, hypopyon uveitis, and erythema nodosum.1 The etiology of Behçet’s disease remains unknown, but the most widely held hypothesis of disease pathogenesis is that a profound inflammatory response is triggered by an infectious agent in a genetically susceptible host.2
Behçet’s disease is commonly seen along the ancient Silk Road, which extends from Eastern Asia to the Mediterranean region; its prevalence is highest in Turkey, where it was first reported. The comparative prevalence in different countries is shown in several studies.3–13 The usual age of onset is between the second and fourth decades. Younger patients (age of onset ≤24 years) have a higher prevalence of eye disease and total clinical activity than older patients (age of onset ≥25 years).14 The disease is more common in females in Asian countries, while the opposite is true in the Mediterranean population.15
The etiology of Behçet’s disease is unknown, but both genetic background and environmental factors are thought to be associated with the development and progression of the disease. For instance, the presence of human leukocyte antigen (HLA) B51 increases the risk of developing Behçet’s disease in different ethnic groups 1.5- to 16-fold,16–18 and patients who have this allele have a higher incidence of posterior uveitis than those without it. On the other hand, some reports suggest a role of environmental factors in susceptibility to the disease. Infectious agents, such as Streptococcus sanguis,19 Herpes simplex virus,20 hepatitis viruses, and parvovirus B19 have been implicated as causes of Behçet’s disease.21 Interestingly, Turkish immigrants to Germany have a significantly lower risk of developing Behçet’s disease than those of Turkish origin still living in Turkey. Similarly, the disease is quite rare among Japanese immigrants in Hawaii and California, despite a high prevalence in Japan.22
Since there is no single test for diagnosing Behçet’s disease, several criteria sets existed for Behçet’s disease up to 1990. In 1990, the International Study Group (ISG) for Behçet’s disease proposed the first evidence-based criteria.23 According to the criteria, patients must have oral (aphthous) ulcers as well as two of the four other findings. It should be noted that this criteria was for research classification purposes. Clinicians should not rely on these criteria, since Behçet’s disease can start with serious manifestations such as pulmonary aneurysms or uveitis without meeting the classification criteria. The differential diagnosis comprises herpes simplex infection, HLA B-27-associated diseases, human immunodeficiency virus infection, inflammatory bowel disease, and other rheumatic diseases. In Japan, the criteria of the Behçet’s Disease Research Committee of Japan is most frequently used,24 and a recent large study has demonstrated high concordance rates for ISG and Japanese criteria fulfillment in US and Japanese patients with Behçet’s disease.25 In the Japanese criteria, arthritis, epididymitis, gastrointestinal lesions, vascular lesions, and genital ulcers are defined as additional symptoms, and patients with gastrointestinal, vascular, or neuronal lesions are classified as special types. The International Criteria for Behçet’s Disease (ICBD) is one of the latest proposed criteria sets, created with the participation of 27 countries from different parts of the world. In one study that compared the diagnostic performance of ICBD criteria with the ISG criteria in three independent cohorts, the ICBD criteria shows a higher sensitivity and accuracy than the ISG criteria in all three population groups.26
One of the most characteristic signs of Behçet’s disease is recurrent stomatitis, which can be seen in 97%–100% of the patients.27 It is usually the initial symptom, and often precedes diagnosis by several years.28 Oral ulcers are similar to common mouth ulcers in appearance and localization. The typical lesion is round, well defined, and covered with a yellowish pseudomembrane. Lesions may occur singly or in crops, and subside within a few weeks. The most common sites of oral ulceration are the tongue, lips, and gingival and buccal mucosa, although involvement of the palate, pharynx, and tonsil can also occur. Oral ulcerations can be classified as minor, major, or herpetiform based on their characteristics. Minor ulcers are defined as isolated or multiple, shallow, and small (<10 mm), and usually heal without scarring. Major ulcers are larger (>10 mm), deeper, and more painful than minor ulcers. Herpetiform ulcers refer to numerous shallow, small, pinpoint (1–2 mm in diameter) lesions, occurring as clusters. Herpetiform ulcers sometimes enlarge and coalesce to form large ragged ulcers, which can heal with scarring.29 Incidental trauma such as tooth brushing, gum chewing, or eating foods with sharp and rough textures can trigger the formation of aphthous ulcers.30 Oral ulceration that recurs more than three times in 1 year is required to meet the diagnostic criteria for Behçet’s disease.
Genital ulcers occur in more than 70% of cases, and are morphologically similar to oral ulcers, but they are frequently larger, deeper, and heal with scarring.28 In males, they most commonly occur on the scrotum; penile lesions are uncommon. Epididymitis is also common, but urethritis is not a feature of Behçet’s disease, which may be useful in distinguishing it from Reiter’s syndrome. In female patients, ulcers occur on the vulva, vagina, and cervix and may cause dyspareunia. Groin, perianal, and perineal ulcers occur in both sexes.29
Eye involvement occurs in 30%–70% of patients with Behçet’s disease, and it is more common and more severe in men than in women. The typical form of ocular involvement is a relapsing–remitting uveitis. Chronic and recurrent anterior uveitis can result in hypopyon, which is characterized by accumulation of white blood cells in the anterior chambers of the eye. Less commonly, conjunctivitis, conjunctival ulcers, keratitis, episcleritis, scleritis, and extra-ocular muscle paralysis may occur as a result of the neurological activity of Behçet’s disease. Intraocular inflammation may involve the anterior or posterior segment, or, more commonly, both segments. The classification of uveitis as anterior or posterior type is important both therapeutically and prognostically because those lesions affecting the posterior segment are of a persistent nature, and correlate with significant visual loss.31 Other ocular lesions include vitreous hemorrhage, optic neuritis, retinal vein occlusion, and retinal neovascularization.32
Skin disease occurs in over 75% of patients with Behçet’s disease.33 Erythema nodosum usually occurs in the lower extremities and is characterized by red, painful nodules 1–5 cm in diameter. They are more commonly observed in female patients, and they heal with pigmentation in 1–6 weeks. Histopathology frequently shows septal panniculitis, although lobular panniculitis and vasculitis are also observed. Acneiform lesions are another common presentation of the disease. Although its appearance is similar to ordinary acne, and it appears on the usual acne sites, such as the face, back, and chest, it also occurs on unusual sites such as the arms and legs. The pustules are not usually sterile, and the microbiology is similar to that of acne vulgaris except that Staphylococcus aureus is more common and coagulase negative staphylococci is less common in patients with Behçet’s disease.34 Pathergy is skin hyper-reactivity to trauma such as needle puncture, and it manifests as an erythematous papular or pustular reaction to skin injury. Development of papules and pustules 48 hours after insertion of 20-gauge needles in hairless areas of the forearm is considered a positive test for pathergy. The rate of positivity is lower in North American and North European patients than in Middle Eastern patients.35 Interestingly, compared with 35 years ago, the sensitivity of the pathergy test has dropped to 35.8%, while the specificity has improved from 86.6% to 98.4%.36
Non-erosive arthritis is seen in about 50% of patients with Behçet’s disease. The arthritis is usually monoarthritis or oligoarthritis, affecting the medium and large joints such as knee, wrist, and ankle. The arthritis typically resolves within a few weeks. In contrast to HLA B-27-associated diseases, sacroiliitis is rare in patients with Behçet’s disease.37 Patients with Behçet’s disease who have arthritis tend to have more acne and enthesopathy,38 suggesting that these symptoms can be considered as one cluster. A recent study showed significant familial clustering of acne/arthritis/enthesitis, which supports a hypothesis that a common genetic pathway is involved in its clinical presentation.39,40
The frequency of gastrointestinal involvement varies depending on geographic location and ranges from 3% to 50%. Gastrointestinal involvement causes anorexia, abdominal pain, diarrhea, melena, and perforation. Ulceration is seen usually in the terminal ileum, cecum, and ascending colon, but virtually any part of the gastrointestinal tract can be affected. Clinically, ulceration associated with inflammatory bowel disease is often indistinguishable from that of Behçet’s disease. In addition, these diseases share features such as oral ulceration, arthritis, uveitis, and erythema nodosum. Thus, special consideration is required before making the diagnosis of Behçet’s disease in patients with gastrointestinal involvement.41–45
Central nervous system (CNS) involvement in Behçet’s disease, usually called neuro-Behçet’s disease, is one of the most serious manifestations, occurring in less than 20% of cases. Male predominance was reported in patients with CNS involvement.46 Of patients with CNS disease, 70%–80% have parenchymal involvement, and the brain stem is the most commonly affected site.47 Typically, neurologic symptoms such as meningoencephalitis, neurologic deficits, and psychiatric symptoms (including personality changes) develop several years after diagnosis. Non-parenchymal involvement may be observed as intracranial hypertension due to dural sinus thrombosis and presents with headaches and papilledema. The symptoms recur many times and gradually result in irreversible neural injury. Neuroimaging has a significant role in the diagnosis of CNS involvement. Abnormalities detected by magnetic resonance imaging (MRI) have been well described in CNS disease.48 Cerebrospinal fluid (CSF) may show increased protein and increased cells, usually neutrophil predominant.
Vascular involvement occurs in about 25% of patients with Behçet’s disease, with a predilection for veins.49 Superficial thrombophlebitis and deep venous thrombosis are the most common venous complications. Occlusion of vena cava superior or inferior, dural sinus, and Budd–Chiari syndrome have also been reported.50 The coagulation system is usually intact; therefore, the formation of thrombi may occur due to endothelial cell injury rather than increased thrombin generation.51–53 The frequency of arterial lesions is relatively low, ranging from 1% to 33.5% of all vascular involvement,54 and the mortality rate in patients with arterial involvement is reported to be higher than in those without it.55 Involvement of the aorta and pulmonary artery can cause serious aneurysm formation or occlusion, and pulmonary aneurysm is one of the most significant causes of death due to life-threatening hemorrhage in patients with Behçet’s disease.56
Treatment options depend on the affected organ and its severity. It is important to prioritize therapeutic options according to the disease type, severity, age, and sex of each patient. Special attention should be paid to ocular, vascular, and neurologic disease, because they are the most serious manifestations and require more aggressive treatment.
Topical corticosteroids are beneficial for oral and genital ulcerations, and can be the first-line treatment, especially for patients with mild disease, while systemic corticosteroids are the recommended treatment for patients with moderate to severe disease with ocular, vascular, gastrointestinal, or neurological involvement.57 Although corticosteroids are widely used for patients with Behçet’s disease, there has been only one placebo-controlled trial, in which 86 patients who had active disease with genital ulcer were randomized for administration of either intramuscular methylprednisolone 40 mg or placebo every 3 weeks for 27 weeks. The result showed no significant differences in the mean number of genital and oral ulcers or folliculitis between the groups. However, the mean number of erythema nodosum lesions was less in the corticosteroid group as a whole; subgroup analyses revealed that this was significant for female patients but not for male patients.58 Although corticosteroids are effective in decreasing acute inflammation, systemic corticosteroids alone often fail to prevent recurrences in cases with ocular involvement. They are generally used in combination with other immunosuppressive drugs.59 Intravitreal triamcinolone acetonide injection may be used as adjunct therapy for the treatment of refractory panuveitis or in patients who were intolerant to systemic corticosteroids.60
Colchicine has been used for the treatment of Behçet’s disease, particularly for mucocutaneous disease. The anti-inflammatory effect of colchicine has been attributed to its disruption of microtubules in neutrophils, thereby inhibiting their migration toward chemotactic factors. In one randomized controlled trial, use of colchicine significantly reduced the rate of genital ulcers, erythema nodosum, and arthritis associated with Behçet’s disease, especially among female patients.61 A more recent double-blinded, placebo-controlled crossover trial concluded that colchicine significantly improved the overall Disease Activity Index score.62 However, patients may develop significant gastrointestinal intolerance if the medication is taken at doses higher than 1.5 mg/day.
Azathioprine is a purine synthesis inhibitor and one of the most widely used immunosuppressive medications for Behçet’s disease. In the only placebo-controlled trial, 73 patients who had Behçet’s disease with or without ocular involvement, were randomly assigned for treatment with either azathioprine (2.5 mg/kg/day), or placebo. After 2 years of follow-up, the patients taking azathioprine developed less ocular disease and experienced less frequent ocular complications, oral ulcers, genital ulcers, and arthritis.63 A long-term follow-up further confirmed the beneficial effects of azathioprine in these patients.64 Recently, a retrospective analysis of 157 consecutive patients with severe uveitis (active posterior uveitis or panuveitis) treated with corticosteroids (0.5–1 mg/kg/day) and azathioprine (2.5 mg/kg/day) revealed that posterior uveitis was controlled in 92.9% of patients, of whom 51.6% were complete responders and 41.4% were partial responders.65
Cyclosporine, a calcineurin inhibitor that affects both T-cell and B-cell proliferation,66 is commonly used for uveitis associated with Behçet’s disease. Three controlled trials have evaluated the efficacy of cyclosporine in patients with Behçet’s disease. A single-masked trial of cyclosporine 5 mg/kg/day versus a monthly 1 g intravenous bolus of cyclophosphamide was conducted among 23 patients with Behçet’s disease who had active potentially reversible uveitis. During the initial 6 months, patients in the cyclosporine group showed a significant improvement in visual acuity. However, the subsequent follow-up of patients up to 24 months suggested that this effect was not sustained.67 In a randomized, double-masked trial, 96 patients with active ocular disease were treated with either cyclosporine (10 mg/kg/day) or colchicine (1 mg/day). After 16 weeks, cyclosporine was more beneficial than colchicine in reducing the frequency of ocular attacks, alleviation of such attacks, and improvement of visual acuity as well as extra-ocular manifestation such as oral aphthous ulcer, dermal lesions, and genital ulceration.68
Despite its efficacy in treating many manifestations of Behçet’s disease, cyclosporine appears to cause neurotoxicity or accelerates the development of CNS symptoms.69 In these cases, there may be some selection bias because there is an association between neurologic and eye involvement – the main indication for the use of cyclosporine in Behçet’s disease.70 However, in a large retrospective analysis that compared patients treated with cyclosporine, other immunosuppressive drugs, and colchicine, parenchymal neurologic involvement was observed more frequently in the cyclosporine-treated group, even after adjusting for disease severity.71
Thalidomide was developed in the 1950s as a sedative drug and was withdrawn in 1961 because of its teratogenic effects. However, it has been rediscovered recently as an immunomodulatory drug that suppresses tumor necrosis factor (TNF)-α-induced nuclear factor (NF)-κB activation and adenosine triphosphate (ATP)-induced interleukin (IL)-1β secretion.72 By modulating the activity of NF-κB, thalidomide can up-regulate the expression of downstream genes involved in the pathophysiology of Behçet’s disease. Thalidomide has been reported to be effective in treating patients with mucocutaneous lesions.73,74
Although a systematic review of the Cochrane database concluded that there was not enough evidence to support the use of cyclophosphamide in the treatment of Behçet’s disease, particularly the ocular manifestations,75 it still can be a choice for life-threatening manifestations. According to The European League Against Rheumatism (EULAR) recommendations, use of cyclophosphamide is advocated for major vessel disease, pulmonary artery disease, and CNS disease.
Although the mechanism of action of interferon (IFN)-α in Behçet’s disease remains elusive, it has been administered for various manifestations of Behçet’s disease, first by Tsambaos et al,76 because of its antiviral and anti-proliferative properties. One large literature review, which included data on IFNα treatment published between 1986 and 2002, revealed that IFNα treatment was effective in 86% of patients with mucocutaneous disease, 96% with arthritis, and 94% with ocular uveitis.76 Higher IFNα doses were more effective than low-dose regimens, and led to up to 56% long-term remissions even after discontinuation of the IFNα. Side effects were dose-dependent and similar to those noted in patients with hepatitis C.77
Tumor necrosis factor-α inhibitors
Evidence is emerging that anti-TNFα agents are highly effective for patients with Behçet’s disease. Among them, infliximab has been most frequently used, mainly for refractory ocular Behçet’s disease. Although there have been no controlled trials, a considerable number of observational studies have reported that infliximab reduces the frequency of uveitis attacks, successfully treats refractory macular edema, and improves visual acuity.78–83 Only one prospective study from Japan has evaluated the efficacy of infliximab, using 3–5 mg/kg body weight every 8 weeks in patients with gastrointestinal disease. In this study, all patients showed improvement of gastrointestinal symptoms and disease-associated complications within 4 weeks. Furthermore, the rate of disappearance of ileocecal ulcerations was 90% after 1 year.84 Although there have been no prospective studies, some case reports or case series suggest the efficacy of infliximab for treating vascular and neurologic disease.85–87
Etanercept is the only TNF inhibitor evaluated in a randomized trial. In the trial, 40 patients with mucocutaneous disease and/or arthritis were assigned to either etanercept (25 mg subcutaneously twice a week) or placebo injections for 4 weeks. The mean numbers of oral ulcers, nodular lesions, and papulopustular lesions were lower in the etanercept group than in the placebo group at almost all weekly evaluations.88
The management of Behçet’s disease has markedly improved, with better use of conventional medications and the development of newer agents such as biologics. This is especially beneficial for patients with severe or life-threatening disease. Indeed, the morbidity and mortality of Behçet’s disease have dramatically changed during the last 2 decades.89–91 However, large, well designed trials and more advanced translational research are still needed to develop better diagnostic and management strategies for this complex disease.
The authors received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The authors report no conflicts of interest in this work.
Behçet H. Über rezidivierende aphthöse, durch ein Virus verursachte Geschwüre am Mund, am Auge und an den Genitalien. Dermatol Wochenschr. 1937;36:1152–1157.
Marshall SE. Behçet’s disease. Best Pract Res Clin Rheumatol. 2004; 18(3):291–311.
Crespo J, Ribeiro J, Jesus E, Moura A, Reis C, Porto A. Behçet’s disease: particular features at the central zone of Portugal. In: Wechsler B, Godeau P, editors. Behçet’s Disease. International Congress series 1037. Amsterdam: Excerpta Medica; 1993:207–210.
Al-Dalaan A, Al Ballaa S, Al Sukati M, Mousa M, Bahabri S, Biyari T, et al. The prevalence of Behçet’s disease in Al-Qassim region of Saudi Arabia. In: Hamza M, editor. Behçet’s Disease. Tunis: Pub Adhoua; 1997:170–172.
Assaad-Khalil SH, Kamel FA, Ismail EA. Starting a regional registry for patients with Behçet’s disease in North West Nile Delta region in Egypt. In: Hamza M, editor. Behçet’s Disease. Tunis: Pub Adhoua; 1997:173–176.
González-Gay MA, García-Porrúa C, Brañas F, López-Lázaro L, Olivieri I. Epidemiologic and clinical aspects of Behçet’s disease in a defined area of Northwestern Spain, 1988–1997. J Rheumatol. 2000;27(3):703–707.
Azizlerli G, Köse AA, Sarica R, et al. Prevalence of Behçet’s disease in Istanbul, Turkey. Int J Dermatol. 2003;42(10):803–806.
Al-Rawi ZS, Neda AH. Prevalence of Behçet’s disease among Iraqis. Adv Exp Med Biol. 2003;528:37–41.
Kurosawa M, Inaba Y, Nishibu A, et al. Nationwide epidemiological survey of Behçet’s disease in 2003 in Japanese. Clin Exp Rheumatol. 2004;22(4 Suppl 34):S84.
Krause I, Yankevich A, Fraser A, et al. Prevalence and clinical aspects of Behcet’s disease in the north of Israel. Clin Rheumatol. 2007;26(4):555–560.
Salvarani C, Pipitone N, Catanoso MG, et al. Epidemiology and clinical course of Behçet’s disease in the Reggio Emilia area of Northern Italy: a seventeen-year population-based study. Arthritis Rheum. 2007;57(1):171–178.
Davatchi F, Jamshidi AR, Banihashemi AT, et al. WHO-ILAR COPCORD Study (Stage 1, Urban Study) in Iran. J Rheumatol. 2008;35(7):1384.
Zhang Z, He F, Shi Y. Behcet’s disease seen in China: analysis of 334 cases. Rheumatol Int. Mar 2013;33(3):645–648.
Yazici H, Tüzün Y, Pazarli H, et al. Influence of age of onset and patient’s sex on the prevalence and severity of manifestations of Behçet’s syndrome. Ann Rheum Dis. 1984;43(6):783–789.
Kaklamani VG, Vaiopoulos G, Kaklamanis PG. Behçet’s disease. Semin Arthritis Rheum. 1998;27(4):197–217.
Mizuki N, Inoko H, Ohno S. Pathogenic gene responsible for the predisposition of Behçet’s disease. Int Rev Immunol. 1997;14(1):33–48.
Yazici H, Akokan G, Yalçin B, Müftüoğlu A. The high prevalence of HLA-B5 in Behçet’s disease. Clin Exp Immunol. 1977;30(2):259–261.
De Menthon M, Lavalley MP, Maldini C, Guillevin L, Mahr A. HLA-B51/B5 and the risk of Behçet’s disease: a systematic review and meta-analysis of case-control genetic association studies. Arthritis Rheum. 2009;61(10):1287–1296.
Lehner T. The role of heat shock protein, microbial and autoimmune agents in the aetiology of Behçet’s disease. Int Rev Immunol. 1997;14(1):21–32.
Hamzaoui K, Ayed K, Slim A, Hamza M, Touraine J. Natural killer cell activity, interferon-gamma and antibodies to herpes viruses in patients with Behçet’s disease. Clin Exp Immunol. 1990;79(1):28–34.
Nussenblatt RB. Uveitis in Behçet’s disease. Int Rev Immunol. 1997;14(1):67–79.
Hirohata T, Kuratsune M, Nomura A, Jimi S. Prevalence of Behçet’s syndrome in Hawaii. With particular reference to the comparison of the Japanese in Hawaii and Japan. Hawaii Med J. 1975;34(7):244–246.
No authors listed. Criteria for diagnosis of Behcet’s disease. International Study Group for Behcet’s Disease. Lancet. 1990;335(8697):1078–1080.
Suzuki Kurokawa M, Suzuki N. Behcet’s disease. Clin Exp Med. 2004;4(1):10–20.
Kobayashi T, Kishimoto M, Swearingen CJ, et al. Differences in clinical manifestations, treatment, and concordance rates with two major sets of criteria for Behçet’s syndrome for patients in the US and Japan: data from a large, three-center cohort study. Mod Rheumatol. 2013;23(3):547–553.
Davatchi F. Diagnosis/classification criteria for Behcet’s disease. Patholog Res Int. 2012;2012:607921.
Yurdakul S, Yazici H. Behçet’s syndrome. Best Pract Res Clin Rheumatol. 2008;22(5):793–809.
Ideguchi H, Suda A, Takeno M, Ueda A, Ohno S, Ishigatsubo Y. Behçet disease: evolution of clinical manifestations. Medicine (Baltimore). 2011;90(2):125–132.
Alpsoy E, Zouboulis CC, Ehrlich GE. Mucocutaneous lesions of Behcet’s disease. Yonsei Med J. 2007;48(4):573–585.
Sharquie KE, Al-Araji A, Hatem A. Oral pathergy test in Behçet’s disease. Br J Dermatol. 2002;146(1):168–169.
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(3):373–380.
Verity DH, Wallace GR, Vaughan RW, Stanford MR. Behçet’s disease: from Hippocrates to the third millennium. Br J Ophthalmol. 2003;87(9):1175–1183.
Sakane T, Takeno M, Suzuki N, Inaba G. Behçet’s disease. N Engl J Med. 1999;341(17):1284–1291.
Hatemi G1, Bahar H, Uysal S, et al. The pustular skin lesions in Behcet’s syndrome are not sterile. Ann Rheum Dis. 2004;63(11):1450–1452.
Yazici H, Tüzün Y, Pazarli H, et al. Influence of age of onset and patient’s sex on the prevalence and severity of manifestations of Behçet’s syndrome. Ann Rheum Dis. 1984;43(6):783–789.
Davatchi F, Chams-Davatchi C, Ghodsi Z, et al. Diagnostic value of pathergy test in Behcet’s disease according to the change of incidence over the time. Clin Rheumatol. 2011;30(9):1151–1155.
Yazici H, Tuzlaci M, Yurdakul S. A controlled survey of sacroiliitis in Behcet’s disease. Ann Rheum Dis. 1981;40(6):558–559.
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(11):1074–1076.
Karaca M, Hatemi G, Sut N, Yazici H. The papulopustular lesion/arthritis cluster of Behçet’s syndrome also clusters in families. Rheumatology (Oxford). 2012;51(6):1053–1060.
Hatemi G, Fresko I, Tascilar K, Yazici H. Increased enthesopathy among Behçet’s syndrome patients with acne and arthritis: an ultrasonography study. Arthritis Rheum. 2008;58(5):1539–1545.
Cheon JH, Çelik AF, Kim WH. Behçet’s disease: gastrointestinal involvement. In: Yazici Y, Yazici H, editors. Behçet’s syndrome. New York: Springer; 2010:165–188.
Shimizu T, Ehrlich GE, Inaba G, Hayashi K. Behçet disease (Behçet syndrome). Semin Arthritis Rheum. 1979;8(4):223–260.
Lakhanpal S, Tani K, Lie JT, Katoh K, Ishigatsubo Y, Ohokubo T. Pathologic features of Behçet’s syndrome: a review of Japanese autopsy registry data. Hum Pathol. 1985;16(8):790–795.
Gürler A, Boyvat A, Türsen U. Clinical manifestations of Behçet’s disease: an analysis of 2147 patients. Yonsei Med J. 1997;38(6):423–427.
Ebert EC. Gastrointestinal manifestations of Behçet’s disease. Dig Dis Sci. 2009;54(2):201–207.
Tursen U, Gurler A, Boyvat A. Evaluation of clinical findings according to sex in 2313 Turkish patients with Behcet’s disease. Int J Dermatol. 2003;42(5):346–351.
Ideguchi H, Suda A, Takeno M, et al. Neurological manifestations of Behçet’s disease in Japan: a study of 54 patients. J Neurol. 2010;257(6):1012–1020.
Kalra S, Silman A, Akman-Demir G, et al. Diagnosis and management of Neuro-Behçet’s disease: international consensus recommendations. J Neurol. 2014;261(9):1662–1676.
Yazici H. Behçet’s syndrome: where do we stand? Am J Med. 2002; 112(1):75–76.
Tohmé A1, Aoun N, El-Rassi B, Ghayad E. Vascular manifestations of Behçet’s disease. Eighteen cases among 140 patients. Joint Bone Spine. 2003;70(5):384–389.
Mader R, Ziv M, Adawi M, Mader R, Lavi I. Thrombophilic factors and their relation to thromboembolic and other clinical manifestations in Behçet’s disease. J Rheumatol. 1999;26(11):2404–2408.
Leiba M, Seligsohn U, Sidi Y, et al. Thrombophilic factors are not the leading cause of thrombosis in Behçet’s disease. Ann Rheum Dis. 2004;63(11):1445–1449.
Espinosa G, Font J, Tàssies D, et al. Vascular involvement in Behçet’s disease: relation with thrombophilic factors, coagulation activation, and thrombomodulin. Am J Med. 2002;112(1):37–43.
Lakhanpal S, Tani K, Lie JT, Katoh K, Ishigatsubo Y, Ohokubo T. Pathologic features of Behcet’s syndrome: a review of Japanese autopsy registry data. Hum Pathol. 1985;16(8):790–795.
Saadoun D, Asli B, Wechsler B, et al. Long-term outcome of arterial lesions in Behçet disease: a series of 101 patients. Medicine (Baltimore). 2012;91(1):18–24.
Seyahi E, Melikoglu M, Akman C, et al. Pulmonary artery involvement and associated lung disease in Behçet disease; a series of 47 patients. Medicine (Baltimore). 2012;91(1):35–48.
Hatemi G, Silman A, Bang D, et al; EULAR Expert Committee. EULAR recommendations for the management of Behçet disease. Ann Rheum Dis. 2008;67(12):1656–1662.
Mat C, Yurdakul S, Uysal S, et al. A double-blind trial of depot corticosteroids in Behçet’s syndrome. Rheumatology (Oxford). 2006;45(3):348–352.
Okada AA. Drug therapy in Behçet’s disease. Ocul Immunol Inflamm. 2000;8(2):85–91.
Tuncer S, Yilmaz S, Urgancioglu M, Tugal-Tutkun I. Results of intravitreal triamcinolone acetonide (IVTA) injection for the treatment of panuveitis attacks in patients with Behçet disease. J Ocul Pharmacol Ther. 2007;23(4):395–401.
Yurdakul S, Mat C, Tüzün Y, et al. A double-blind trial of colchicine in Behçet’s syndrome. Arthritis Rheum. 2001;44(11):2686.
Davatchi F, Sadeghi Abdollahi B, Tehrani Banihashemi A, et al. Colchicine versus placebo in Behçet’s disease; randomized, double-blind, controlled crossover trial. Mod Rheumatol. 2009;19(5):542–549.
Yazici H, Pazarli H, Barnes CG, et al. A controlled trial of azathioprine in Behçet’s syndrome. N Engl J Med. 1990;322(5):281–285.
Hamuryudan V, Ozyazgan Y, Hizli N, et al. Azathioprine in Behcet’s syndrome: effects on long-term prognosis. Arthritis Rheum. 1997;40(4):769–774.
Saadoun D, Wechsler B, Terrada C, et al. Azathioprine in severe uveitis of Behçet’s disease. Arthritis Care Res (Hoboken). 2010;62(12):1733–1738.
Ho S, Clipstone N, Timmermann L, et al. The mechanism of action of cyclosporin A and FK506. Clin Immunol Immunopathol. 1996;80(3 Pt 2):S40–S45.
Ozyazgan Y, Yurdakul S, Yazici H, et al. Low dose cyclosporin A versus pulsed cyclophosphamide in Behçet’s syndrome: a single masked trial. Br J Ophthalmol. 1992;76(4):241–243.
Masuda K, Nakajima A, Urayama A, Nakae K, Kogure M, Inaba G. Double-masked trial of cyclosporin versus colchicine and long-term open study of cyclosporin in Behçet’s disease. Lancet. 1989;1(8647):1093–1096.
Kotake S, Higashi K, Yoshikawa K, Sasamoto Y, Okamoto T, Matsuda H. Central nervous system symptoms in patients with Behçet disease receiving cyclosporine therapy. Ophthalmology. 1999;106(3):586–589.
Hatemi G, Yazici Y, Yazici H. Behçet’s syndrome. Rheum Dis Clin North Am. 2013;39(2):245–261.
Akman-Demir G, Ayranci O, Kurtuncu M, Vanli EN, Mutlu M, Tugal-Tutkun I. Cyclosporine for Behçet’s uveitis: is it associated with an increased risk of neurological involvement? Clin Exp Rheumatol. 2008;26(4 Suppl 50):S84–S90.
Yasui K, Kobayashi N, Yamazaki T, Agematsu K. Thalidomide as an immunotherapeutic agent: the effects on neutrophil-mediated inflammation. Curr Pharm Des. 2005;11(3):395–401.
Hamuryudan V, Mat C, Saip S, et al. Thalidomide in the treatment of the mucocutaneous lesions of the Behçet syndrome. A randomized, double-blind, placebocontrolled trial. Ann Intern Med. 1998;128(6):443–450.
Hello M, Barbarot S, Bastuji-Garin S, Revuz J, Chosidow O. Use of thalidomide for severe recurrent aphthous stomatitis: a multicenter cohort analysis. Medicine (Baltimore). 2010;89(3):176–182.
Saenz A, Ausejo M, Shea B, Wells G, Welch V, Tugwell P. Pharmacotherapy for Behcet’s syndrome. Cochrane Database Syst Rev. 2000;(2):CD001084.
Tsambaos D, Eichelberg D, Goos M. Behçet’s syndrome: treatment with recombinant leukocyte alpha-interferon. Arch Dermatol Res. 1986;278(4):335–336.
Kötter I, Günaydin I, Zierhut M, Stübiger N. The use of interferon alpha in Behçet disease: review of the literature. Semin Arthritis Rheum. 2004;33(5):320–335.
Tugal-Tutkun I, Mudun A, Urgancioglu M, et al. Efficacy of infliximab in the treatment of uveitis that is resistant to treatment with the combination of azathioprine, cyclosporine, and corticosteroids in Behçet’s disease: an open-label trial. Arthritis Rheum. 2005;52(8):2478–2484.
Sfikakis PP. Behçet’s disease: a new target for anti-tumour necrosis factor treatment. Ann Rheum Dis. 2002;61 Suppl 2:ii51–ii53.
Triolo G, Vadalà M, Accardo-Palumbo A, et al. Anti-tumour necrosis factor monoclonal antibody treatment for ocular Behçet’s disease. Ann Rheum Dis. 2002;61(6):560–561.
Niccoli L, Nannini C, Benucci M, et al. Long-term efficacy of infliximab in refractory posterior uveitis of Behcet’s disease: a 24-month follow-up study. Rheumatology. 2007;46(7):1161–1164.
Sfikakis PP, Theodossiadis PG, Katsiari CG, Kaklamanis P, Markomichelakis NN. Effect of infliximab on sight-threatening panuveitis in Behçet’s disease. Lancet. 2001;358(9278):295–296.
Sfikakis PP, Kaklamanis PH, Elezoglou A, et al. Infliximab for recurrent, sight-threatening ocular inflammation in Adamantiades-Behçet disease. Ann Intern Med. 2004;140(5):404–406.
Iwata S, Saito K, Yamaoka K, et al. Efficacy of combination therapy of anti-TNF-α antibody infliximab and methotrexate in refractory entero-Behçet’s disease. Mod Rheumatol. 2011;21(2):184–191.
Adler S, Baumgartner I, Villiger PM. Behçet’s disease: successful treatment with infliximab in 7 patients with severe vascular manifestations. A retrospective analysis. Arthritis Care Res (Hoboken). 2012;64(4):607–611.
Giardina A1, Ferrante A, Ciccia F, Vadalà M, Giardina E, Triolo G. One year study of efficacy and safety of infliximab in the treatment of patients with ocular and neurological Behçet’s disease refractory to standard immunosuppressive drugs. Rheumatol Int. 2011;31(1):33–37.
Fasano A, D’Agostino M, Caldarola G, Feliciani C, De Simone C. Infliximab monotherapy in neuro-Behçet’s disease: four year follow-up in a long-standing case resistant to conventional therapies. J Neuroimmunol. 2011;239(1–2):105–107.
Melikoglu M, Fresko I, Mat C, et al. Short-term trial of etanercept in Behçet’s disease: a double blind, placebo controlled study. J Rheumatol. 2005;32(1):98–105.
Kump LI, Moeller KL, Reed GF, Kurup SK, Nussenblatt RB, Levy-Clarke GA. Behçet’s disease: comparing 3 decades of treatment response at the National Eye Institute. Can J Ophthalmol. 2008;43(4):468–472.
Ando K, Fujino Y, Hijikata K, Izawa Y, Masuda K. Epidemiological features and visual prognosis of Behçet’s disease. Jpn J Ophthalmol. 1999;43(4):312–317.
Yoshida A, Kawashima H, Motoyama Y, et al. Comparison of patients with Behçet’s disease in the 1980s and 1990s. Ophthalmology. 2004; 111(4):810–815.
This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.Download Article [PDF]