- Author: Fatima A Alnaimat, MBBS; Chief Editor: Herbert S Diamond, MD more...
Behçet disease is a rare vasculitic disorder that is characterized by a triple-symptom complex of recurrent oral aphthous ulcers, genital ulcers, and uveitis. Hippocrates may have described Behçet disease in the fifth century BCE. In 1930, the Greek ophthalmologist Benediktos Adamantiades reported a patient with inflammatory arthritis, oral and genital ulcers, phlebitis, and iritis. The disease is named after the Turkish dermatologist Hulusi Behçet, who identified it in a patient in 1924 and published a description of the disease in 1937.
Theories behind the pathogenesis of Behçet disease currently suggest an autoimmune etiology.
Exposure to an infectious agent may trigger a cross-reactive immune response. Proposed infectious agents have included herpes simplex virus (HSV), Streptococcus species, Staphylococcus species, and Escherichia coli.
The International Study Group for Behçet's Disease has emphasized the presence of recurrent oral ulcers as a primary consideration in the diagnosis of Behçet disease. In response, the pathogens above have been targeted for study, with the hope of establishing a direct link between their presence and disease activity. Unfortunately so far, researchers have been unable to generalize results across geographic populations.
The study of heat shock proteins (HSPs) has provided some insight into possible mechanisms that contribute to the development of Behçet disease. Through discovery that human HSP-60 and HSP-65 share greater than 50% homology with mycobacterial HSP, enhanced T-cell response has been elicited with exposure to both bacterial and human homogenates in Behçet disease patients compared with controls in United Kingdom, Japanese, and Turkish populations. HSP-65, found in high concentrations in oral ulcers and active skin lesions in patients with Behçet disease, has also been demonstrated to stimulate production of antibodies that exhibit cross-reactivity with streptococcal species present in the mouth.[5, 6, 7]
Attempts at determining whether tissue antigens have a role in channeling the immune response have been unsuccessful. Elevated peripheral levels of gamma-delta T cells (γδ+ T cells) in patients with Behçet disease in response to exposure to mycobacterial HSPs compared with those in healthy subjects imply a role for their production. Antigen-driven expansion of oligoclonal Vβ+ T-cell receptor (TCR)–specific cell lines in Behçet disease patients has been demonstrated. However, generalization of these results is not applicable because of the high degree of interindividual variability in TCR expression.
T cells and neutrophils
Systemic involvement of multiple organs is observed in Behçet disease, rooted primarily in the development of vasculitic or vasculopathic lesions in the affected areas. These areas may demonstrate microscopic evidence of inflammatory tissue infiltration with both T cells and neutrophils.[10, 5, 11, 12]
Studies of T lymphocytes have suggested a T-helper type 1 (TH1)–predominant response. Both CD4+ and CD8+ lymphocytes demonstrate higher concentrations in peripheral blood, with characteristic and corresponding elevations of cytokines (interleukin [IL]–2] and interferon-γ [IFN-γ]). Serum levels of IL-12 have also been shown to be elevated in patients with Behçet disease, possibly helping drive the response. Decreased levels and impaired activity of natural killer cells were demonstrated in bronchoalveolar lavage specimens of Behçet disease patients with pulmonary manifestations.
Considering the degree of neutrophilic infiltration demonstrated in characteristic Behçet disease lesions, including hypopyon, pustular lesions, and pathergy reactions, activity and function of these cells has been explored extensively. Unfortunately, existing studies offer inconsistent results regarding cell adhesion and chemotactic behavior, superoxide production, and phagocytic properties. Thus, the specific role of neutrophils in Behçet disease has been difficult to characterize. Some studies have found that cytokine release in Behçet disease may, by an unknown mechanism, place neutrophils in a static pre-excitatory “primed” state, eventually triggered into hyperactivity by environmental stimuli at a lower threshold than in individuals who do not have Behçet disease.[14, 15, 16, 17]
Behçet disease is a sporadic disease, but a familial aggregation is well known. Carriers of HLA-B51/HLA-B5 have an increased risk of developing Behçet disease compared with noncarriers. HLA-B51 is the the strongest associated genetic factor and it has been shown to be more prevalent in Turkish, Middle Eastern, and Japanese populations, corresponding with a higher prevalence of Behçet disease in these populations. However, HLA-B51 has not been shown to affect the severity of symptoms.
The specific etiology of Behçet disease remains elusive but, as described in Pathophysiology, the interplay between infectious-agent exposure and genetic factors may have a role. An environmentally triggered hyperactive primed state of autoimmunity ensues, resulting in two types of vascular damage. The first is vasculitic lesions that may be widespread. Sequelae depend on the various organ systems affected.
Some of the pathologic changes are not vasculitis but due to thrombosis and/or clot formation caused by the development of a hypercoagulable state. The mechanism is still undetermined; however, studies have demonstrated excessive thrombin formation and the potential role of impaired fibrinolytic kinetics in the generation of the hypercoagulable/prothrombotic state. Pathologic activation of the procoagulant cascade via endothelial injury has also been demonstrated in patients with Behçet disease.
The prevalence of Behçet disease in the United States is reported as 0.12-0.33 case per 100,000 population. However, data from the study of residents of Olmsted County, Minnesota over a 45-year period identified a prevalence of 5.2 cases per 100,000 population.
The incidence and prevalence of Behçet disease are highest along the old Silk Road, extending from the Middle East to China.
Turkey has the highest prevalence of Behçet disease, with 420 cases per 100,000 population. The prevalence in Japan, Korea, China, Iran, and Saudi Arabia ranges from 13.5-22 cases per 100,000 population. The prevalence in North America and Europe is much less, with 1 case per 15,000-500,000 population.[21, 16]
Mortality and morbidity data include the following:
The mortality rate in a cohort of 817 patients in France was 5% at a median follow-up of 7.7 years 
Coronary/pulmonary arterial aneurysm rupture in association with Behçet disease carries a high mortality rate
Neurologic involvement has been associated with mortality rates up to 20% at 7-year follow-up in one Turkish study 
Thrombosis may lead to death
CNS involvement can lead to permanent deficits or death
Eye involvement can result in blindness
In a study comparing 298 pregnancies in 94 Behçet disease patients with 219 pregnancies in 95 healthy controls, women with Behçet disease delivered smaller babies (3214 versus 3351 g, respectively; P= 0.028) and had higher miscarriage rates. The authors suggest vasculitis of the placenta as a possible cause.
Race-, Sex, and Age-related Variances
The prevalence of Behçet disease is highest in Middle Eastern and Japanese populations.
The sex prevalence varies by country. In the Middle East, Behçet disease is more common among males, with male-to-female ratios of 3.8:1 (Israel), 5.3:1 (Egypt), and 3.4:1 (Turkey). In Germany, Japan, and Brazil, the disease is slightly more common in females. In the United States, Behçet disease is more common in females (5:1 female-to-male ratio).[16, 21]
Males are more likely to develop severe presentations of Behçet disease. Pulmonary aneurysms, eye involvement, thrombophlebitis, and neurologic disease are all more common in males. However, females are more likely to develop erythema nodosum–like skin lesions.
Behçet disease is most common in persons aged 20-40 years. The mean age at onset is 25-30 years. Cases that develop before age 25 years are more likely to involve eye disease and active clinical disease.
Alpsoy E. Behçet's disease: A comprehensive review with a focus on epidemiology, etiology and clinical features, and management of mucocutaneous lesions. J Dermatol. 2016 Apr 14. [Medline].
Adamantiades B. A case of recurrent hypopyon iritis. Medical Society of Athens. 1930. 586-93.
Behcet H. Uber rezidiverendeaphthose durch ein virus verursachte Geschwure am Mund, am Auge, und an den Genitalien. Dermatol Wochenschr. 1937. 105:1152-7.
International Study Group for Behçet's Disease. Criteria for diagnosis of Behçet's disease. International Study Group for Behçet's Disease. Lancet. 1990 May 5. 335(8697):1078-80. [Medline].
Emmi L, Brugnolo F, Salvati G, et al. Immunopathological aspects of Behçet's disease. Clin Exp Rheumatol. 1995 Nov-Dec. 13(6):687-91. [Medline].
Kaneko S, Suzuki N, Yamashita N, Nagafuchi H, Nakajima T, Wakisaka S, et al. Characterization of T cells specific for an epitope of human 60-kD heat shock protein (hsp) in patients with Behcet's disease (BD) in Japan. Clin Exp Immunol. 1997 May. 108(2):204-12. [Medline].
Hasan A, Fortune F, Wilson A, Warr K, Shinnick T, Mizushima Y, et al. Role of gamma delta T cells in pathogenesis and diagnosis of Behcet's disease. Lancet. 1996 Mar 23. 347(9004):789-94. [Medline].
Suzuki Y, Hoshi K, Matsuda T, et al. Increased peripheral blood gamma delta+ T cells and natural killer cells in Behçet's disease. J Rheumatol. 1992 Apr. 19(4):588-92. [Medline].
Direskeneli H, Eksioglu-Demiralp E, Kibaroglu A, Yavuz S, Ergun T, Akoglu T. Oligoclonal T cell expansions in patients with Behçet's disease. Clin Exp Immunol. 1999 Jul. 117(1):166-70. [Medline]. [Full Text].
Direskeneli H, Eksioglu-Demiralp E, Yavuz S, Ergun T, Shinnick T, Lehner T, et al. T cell responses to 60/65 kDa heat shock protein derived peptides in Turkish patients with Behçet's disease. J Rheumatol. 2000 Mar. 27(3):708-13. [Medline].
Frassanito MA, Dammacco R, Cafforio P, Dammacco F. Th1 polarization of the immune response in Behçet's disease: a putative pathogenetic role of interleukin-12. Arthritis Rheum. 1999 Sep. 42(9):1967-74. [Medline].
Sugi-Ikai N, Nakazawa M, Nakamura S, Ohno S, Minami M. Increased frequencies of interleukin-2- and interferon-gamma-producing T cells in patients with active Behçet's disease. Invest Ophthalmol Vis Sci. 1998 May. 39(6):996-1004. [Medline].
Hamzaoui K, Berraies A, Kaabachi W, Ammar J, Hamzaoui A. Pulmonary manifestations in Behcet disease: impaired natural killer cells activity. Multidiscip Respir Med. 2013 Apr 4. 8(1):29. [Medline].
Hallett MB, Lloyds D. Neutrophil priming: the cellular signals that say 'amber' but not 'green'. Immunol Today. 1995 Jun. 16(6):264-8. [Medline].
Sakane T, Takeno M, Suzuki N, Inaba G. Behçet's disease. N Engl J Med. 1999 Oct 21. 341(17):1284-91. [Medline].
Sakane T, Suzuki N, Takeno M. Innate and acquired immunity in Behçet’s disease. 8th International Congress on Behçet’s Disease. Reggio Emilia, Italy, 7-9 October 1998. Program and Abstracts: 56.
Takeno M, Shimayano Y, Suzuki N, Sakane T. Prolonged survival of autoprimed neutrophils from patients with Behçet ’s disease.: 8th International Congress on Behçet’s Disease. Reggio Emilia, Italy, 7-9 October 1998. Program and Abstracts: 57.
Koné-Paut I, Geisler I, Wechsler B, et al. Familial aggregation in Behçet's disease: high frequency in siblings and parents of pediatric probands. J Pediatr. 1999 Jul. 135(1):89-93. [Medline].
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 Oct 15. 61(10):1287-96. [Medline].
Kiraz S, Ertenli I, Oztürk MA, et al. Pathological haemostasis and "prothrombotic state" in Behçet's disease. Thromb Res. 2002 Jan 15. 105(2):125-33. [Medline].
Krause I, Yankevich A, Fraser A, Rosner I, Mader R, Zisman D, et al. Prevalence and clinical aspects of Behcet's disease in the north of Israel. Clin Rheumatol. 2007 Apr. 26(4):555-60. [Medline].
Calamia KT, Wilson FC, Icen M, Crowson CS, Gabriel SE, Kremers HM. Epidemiology and clinical characteristics of Behçet's disease in the US: a population-based study. Arthritis Rheum. 2009 May 15. 61(5):600-4. [Medline]. [Full Text].
Saadoun D, Wechsler B, Desseaux K, et al. Mortality in Behçet's disease. Arthritis Rheum. 2010 Sep. 62(9):2806-12. [Medline].
Akman-Demir G, Serdaroglu P, Tasçi B. Clinical patterns of neurological involvement in Behçet's disease: evaluation of 200 patients. The Neuro-Behçet Study Group. Brain. 1999 Nov. 122 ( Pt 11):2171-82. [Medline].
Gungor AN, Kalkan G, Oguz S, Sen B, Ozoguz P, Takci Z, et al. Behcet disease and pregnancy. Clin Exp Obstet Gynecol. 2014. 41 (6):617-9. [Medline].
Alpsoy E, Zouboulis CC, Ehrlich GE. Mucocutaneous lesions of Behcet's disease. Yonsei Med J. 2007 Aug 31. 48(4):573-85. [Medline].
Calamia KT, Schirmer M, Melikoglu M. Major vessel involvement in Behçet disease. Curr Opin Rheumatol. 2005 Jan. 17(1):1-8. [Medline].
Kobayashi K, Ueno F, Bito S, et al. Development of consensus statements for the diagnosis and management of intestinal Behçet's disease using a modified Delphi approach. J Gastroenterol. 2007 Sep. 42(9):737-45. [Medline].
Hemmen T, Perez-Canto A, Distler A, et al. IgA nephropathy in a patient with Behçet's syndrome--case report and review of literature. Br J Rheumatol. 1997 Jun. 36(6):696-9. [Medline].
Hashimoto T, Toya Y, Kihara M, Yabana M, Inayama Y, Tanaka K, et al. Behçet's disease complicated by IgA nephropathy with nephrotic syndrome. Clin Exp Nephrol. 2008 Jun. 12(3):224-7. [Medline].
Akpolat T, Akkoyunlu M, Akpolat I, et al. Renal Behçet's disease: a cumulative analysis. Semin Arthritis Rheum. 2002 Apr. 31(5):317-37. [Medline].
Arevalo JF, Lasave AF, Al Jindan MY, Al Sabaani NA, Al-Mahmood AM, Al-Zahrani YA, et al. Uveitis in Behçet Disease in a Tertiary Center Over 25 Years: The KKESH Uveitis Survey Study Group. Am J Ophthalmol. 2015 Jan. 159(1):177-184.e2. [Medline].
Saadoun D, Wechsler B, Resche-Rigon M, Trad S, Le Thi Huong D, Sbai A, et al. Cerebral venous thrombosis in Behçet's disease. Arthritis Rheum. 2009 Apr 15. 61(4):518-26. [Medline].
Seyahi E, Cakmak OS, Tutar B, Arslan C, Dikici AS, Sut N, et al. Clinical and Ultrasonographic Evaluation of Lower-extremity Vein Thrombosis in Behcet Syndrome: An Observational Study. Medicine (Baltimore). 2015 Nov. 94 (44):e1899. [Medline].
Oktayoglu P, Mete N, Caglayan M, Bozkurt M, Bozan T, Em S, et al. Elevated serum levels of calprotectin (MRP8/MRP14) in patients with Behçet's disease and its association with disease activity and quality of life. Scand J Clin Lab Invest. 2014 Dec 4. 1-7. [Medline].
Hatemi G, Silman A, Bang D, et al. EULAR recommendations for the management of Behçet disease. Ann Rheum Dis. 2008 Dec. 67(12):1656-62. [Medline].
Aktulga E, Altac M, Muftüoglu A, et al. A double blind study of colchicine in Behçet's disease. Haematologica. 1980 Jun. 65(3):399-402. [Medline].
Calis M, Ates F, Yazici C, Kose K, Kirnap M, Demir M, et al. Adenosine deaminase enzyme levels, their relation with disease activity, and the effect of colchicine on adenosine deaminase levels in patients with Behçet's disease. Rheumatol Int. 2005 Aug. 25(6):452-6. [Medline].
Markomichelakis N, Delicha E, Masselos S, Sfikakis PP. Intravitreal infliximab for sight-threatening relapsing uveitis in Behçet disease: a pilot study in 15 patients. Am J Ophthalmol. 2012 Sep. 154(3):534-541.e1. [Medline].
Keino H, Okada AA, Watanabe T, Taki W. Decreased ocular inflammatory attacks and background retinal and disc vascular leakage in patients with Behcet's disease on infliximab therapy. Br J Ophthalmol. 2011 Sep. 95(9):1245-50. [Medline].
Deuter CM, Zierhut M, Mohle A, et al. Long-term remission after cessation of interferon-a treatment in patients with severe uveitis due to Behçet's disease. Arthritis Rheum. 2010 Sep. 62(9):2796-805. [Medline].
Nuñez-Sotelo CM, Gutiérrez-Gonzalez LA, Rodriguez MA. Rapid, complete and sustained response to corticosteroids and pulse cyclophosphamide therapy in a patient with behçet and central nervous disease. Maedica (Buchar). 2012 Dec. 7(4):348-51. [Medline]. [Full Text].
Borhani Haghighi A, Pourmand R, Nikseresht AR. Neuro-Behçet disease. A review. Neurologist. 2005 Mar. 11(2):80-9. [Medline].
Ueda A, Takeno M, Ishigatsubo Y. Adalimumab in the management of Behçet's disease. Ther Clin Risk Manag. 2015. 11:611-9. [Medline].
Melikoglu M, Fresko I, Mat C, Ozyazgan Y, Gogus F, Yurdakul S, et al. Short-term trial of etanercept in Behçet's disease: a double blind, placebo controlled study. J Rheumatol. 2005 Jan. 32 (1):98-105. [Medline].
Vallet H, et al; French Behçet Network. Efficacy of anti-TNF alpha in severe and/or refractory Behçet's disease: Multicenter study of 124 patients. J Autoimmun. 2015 Aug. 62:67-74. [Medline].
Takayama K, Ishikawa S, Enoki T, Kojima T, Takeuchi M. Successful Treatment with Infliximab for Behçet Disease during Pregnancy. Ocul Immunol Inflamm. 2013 Apr 25. [Medline].
Davatchi F, Shams H, Rezaipoor M, Sadeghi-Abdollahi B, Shahram F, Nadji A, et al. Rituximab in intractable ocular lesions of Behcet's disease; randomized single-blind control study (pilot study). Int J Rheum Dis. 2010 Aug. 13 (3):246-52. [Medline].
Sadreddini S, Noshad H, Molaeefard M, Noshad R. Treatment of retinal vasculitis in Behçet's disease with rituximab. Mod Rheumatol. 2008. 18 (3):306-8. [Medline].
Perez-Pampin E, Campos-Franco J, Blanco J, Mera A. Remission induction in a case of refractory Behçet disease with alemtuzumab. J Clin Rheumatol. 2013 Mar. 19(2):101-3. [Medline].
Mesquida M, Victoria Hernández M, Llorenç V, et al. Behçet disease-associated uveitis successfully treated with golimumab. Ocul Immunol Inflamm. 2013 Apr. 21(2):160-2. [Medline].
Hatemi G, Melikoglu M, Tunc R, Korkmaz C, Turgut Ozturk B, Mat C, et al. Apremilast for Behçet's syndrome--a phase 2, placebo-controlled study. N Engl J Med. 2015 Apr 16. 372 (16):1510-8. [Medline].
Estrach C, Mpofu S, Moots RJ. Behçet's syndrome: response to infliximab after failure of etanercept. Rheumatology (Oxford). 2002 Oct. 41(10):1213-4. [Medline].
Sfikakis PP, Markomichelakis N, Alpsoy E, et al. Anti-TNF therapy in the management of Behcet's disease--review and basis for recommendations. Rheumatology (Oxford). 2007 May. 46(5):736-41. [Medline].