eMedicine Specialties > Dermatology > Reactive & Inflammatory Dermatoses
Behcet Disease
Updated: Jun 19, 2009
Introduction
Background
Behçet disease (BD) was named in 1937 after the Turkish dermatologist Hulusi Behçet, who first described the triple-symptom complex of recurrent oral aphthous ulcers, genital ulcers, and uveitis.1
Behçet disease is a complex, multisystemic disease that includes involvement of the mucocutaneous, ocular, cardiovascular, renal, gastrointestinal, pulmonary, urologic, and central nervous systems and the joints, blood vessels, and lungs.
Behçet disease is characterized by oral aphthae and by at least 2 of the following: (1) genital aphthae, (2) synovitis, (3) posterior uveitis, (4) cutaneous pustular vasculitis, (5) meningoencephalitis, (6) recurrent genital ulcers, and (7) uveitis in the absence of inflammatory bowel disease or collagen-vascular disease.
Pathophysiology
The cause of Behçet disease is not known; however, immunogenetics, immune regulation, vascular abnormalities, or bacterial and viral infection may have a role in its development.
Frequency
United States
Behçet disease is not common in the United States, with a prevalence of 5 cases per 100,000 persons.
International
Behçet disease is most prevalent (and more virulent) in the Mediterranean region, Middle East, and Far East, with an estimated prevalence of 1 case per 10,000 persons.
Mortality/Morbidity
- Chronic morbidity is typical; the leading cause is ophthalmic involvement, which can result in blindness. The effects of the disease may be cumulative, especially with neurologic, vascular, and ocular involvement.
- The mortality rate is low, but death can occur from neurologic involvement, vascular disease, bowel perforation, cardiopulmonary disease, or as a complication of immunosuppressive therapy.2
Sex
- Men are affected more often, and with more severe disease, than women in some Mediterranean areas. In Iran, for example, the male-to-female ratio was 24:1 among 1712 patients. In Turkey, the ratio was 16:1 among 427 patients.
Age
- Onset can occur at any age, but is it most common during the third decade of life.3
Clinical
History
Signs and symptoms of Behçet disease, which may be recurrent, may precede the onset of the mucosal membrane ulcerations by 6 months to 5 years.
- Prior to the onset of Behçet disease, patients may experience a variety of symptoms.
- Malaise
- Anorexia
- Weight loss
- Generalized weakness
- Headache
- Perspiration
- Decreased or elevated temperature
- Lymphadenopathy
- Pain of the substernal and temporal regions
- A history of repeated sore throats, tonsillitis, myalgias, and migratory erythralgias without overt arthritis is common.
- A diagnosis of Behçet disease is based on clinical criteria because of the absence of a pathognomonic laboratory test. The period between the appearance of an initial symptom and a major or minor secondary manifestation can be up to a decade in many cases.
- The number of different criteria or classification systems that have been introduced over the past 25 years reflects the failure of any single one to meet clinical demands. The revised 1987 criteria of the Japanese group (Mizushima) have been widely applied.4
- More recently, the diagnostic criteria of the International Study Group for Behçet Disease have been applied to establish a firmer diagnosis.5
- The major limitation of these criteria is the fact that recurrent oral ulceration is the characteristic symptom for the diagnosis of Behçet disease. For example, patients with uveitis and genital ulcers, without oral aphthosis, would not be considered to have Behçet disease, although this is, in fact, a far-advanced form of the disease.
- Therefore, the authors recommend that both sets of criteria be applied concurrently until a more exact system is devised.
- Diagnostic criteria from the Behçet syndrome research committee of Japan (1987 revision) are as follows4 :
- Major features
- Recurrent aphthous ulceration of the oral mucous membrane
- Skin lesions -Erythema nodosum –like lesions, subcutaneous thrombophlebitis, folliculitis (acnelike lesions), cutaneous hypersensitivity
- Eye lesions - Iridocyclitis, chorioretinitis, retinouveitis, definite history of chorioretinitis or retinouveitis
- Genital ulcers
- Minor features
- Arthritis without deformity and ankylosis
- Gastrointestinal lesions characterized by ileocecal ulcers
- Epididymitis
- Vascular lesions
- Central nervous system symptoms
- Diagnosis
- Complete - Four major features
- Incomplete - (1) 3 major features, (2) 2 major and 2 minor features, or (3) typical ocular symptom and 1 major or 2 minor features
- Possible - (1) 2 major features or (2) 1 major and 2 minor features
- Major features
- International criteria for the classification of Behçet disease (1990) are as follows5 :
- Recurrent oral ulceration - Minor aphthous or major aphthous or herpetiform ulceration observed by a physician or reported reliably by a patient that recurs at least 3 times in one 12-month period plus 2 of the following:
- Recurrent genital ulceration - Recurrent genital aphthous ulceration or scarring, especially males, observed by a physician or reliably reported by a patient
- Eye lesions - (1) Anterior uveitis, posterior uveitis, and cells in vitreous upon slit-lamp examination or (2) retinal vasculitis observed by physician (ophthalmologist)
- Skin lesions - (1) Erythema nodosum–like lesions observed by physician or reliably reported by a patient, pseudofolliculitis, and papulopustular lesions or (2) acneiform nodules consistent with Behçet disease, observed by a physician, and in postadolescent patients not receiving corticosteroids
- Positive pathergy test - An erythematous papule larger than 2 mm at the prick site 48 hours after the application of a 20- to 22-gauge sterile needle, which obliquely penetrated avascular skin to a depth of 5 mm as read by a physician at 48 hours
- Recurrent oral ulceration - Minor aphthous or major aphthous or herpetiform ulceration observed by a physician or reported reliably by a patient that recurs at least 3 times in one 12-month period plus 2 of the following:
- Findings are applicable if no other clinical explanation is present.
Physical
Oral ulcers
Oral aphthae that occur in patients with Behçet disease are indistinguishable from common aphthae (canker sores). Aphthae may be more extensive, more painful, more frequent, and evolve quickly from a pinpoint flat ulcer to a large sore. Lesions can be shallow or deep (2-30 mm in diameter) and usually have a central, yellowish, necrotic base and a punched-out, clean margin. They can appear singly or in crops, are located anywhere in the oral cavity, persist for 1-2 weeks, and subside without leaving scars. The most common sites are the tongue, lips, buccal mucosa, and gingiva; the tonsils, palate, and pharynx are less common sites. The interval between recurrences ranges from weeks to months.
Oral ulcers can be classified into the following 3 types:
- Minor ulcer: This consists of 1-5 small, moderately painful ulcers persisting for 4-14 days (see Media File 1).
Minor aphthous ulcer.
- Major ulcer: This is 1-10 very painful ulcers, measuring 10-30 mm, persisting up to 6 weeks, and possibly leaving a scar upon healing (see Media File 2).
Major aphthous ulcer.
- Herpetiform ulcer: This is a recurrent crop of as many as 1000 small and painful ulcers (see Media File 3).
Herpetiform oral ulcer.
Genital manifestations
Genital ulcers resemble their oral counterparts but may cause greater scarring. They have been found in 56.7-97% of cases, but their appearance is mostly a secondary symptom that accompanies oral ulcers. In males, the ulcers usually occur on the scrotum (see Media File 4), penis, and groin.
A characteristic genital ulcer on scrotum.
In females, they occur on the vulva (see Media File 5), vagina, groin, and cervix.
A single ulcer on vulva.
Ulcers have also been found in the urethral orifice and perianal area. Epididymitis may arise and is a minor diagnostic criterion for the disease according to the Behçet Disease Research Committee of Japan. An additional genital symptom is orchiepididymitis, observed in 10.8% of men.
Cutaneous manifestations
A variety of skin lesions may appear in patients with Behçet disease (58.6-97%), including the following:
- Erythema nodosum –like lesions, which are most common (see Media File 6)
Erythema nodosum–like lesions on skin.
- Papulopustular eruptions (see Media File 7)
Papulopustular eruptions.
- Erythema multiforme–like lesions
- Thrombophlebitis
- Ulcers
- Lesions resembling Sweet syndrome (see Media File 8)
Sweet syndrome–like lesion.
- Bullous necrotizing vasculitis
- Pyoderma gangrenosum
Nonspecific skin inflammatory reactivity to any scratches or intradermal saline injection is a common and specific manifestation of these lesions, ie, pathergy (see Media File 9).
Typical positive pathergy reaction at injection site.
Lesions often occur in combination (eg, erythema nodosum–like lesions and papulopustular eruptions). Follicle-based pustules or acne lesions are not considered specific lesions of Behçet disease.
Ocular manifestations
Ocular involvement is the major cause of morbidity and the most dreaded complication because it occasionally progresses rapidly to blindness. It is reported in 47-65% of patients with Behçet disease. Childhood-onset Behçet uveitis is more common in males.6
The most diagnostically relevant lesion is posterior uveitis, ie, retinal vasculitis (see Media File 10). Other lesions include anterior uveitis, iridocyclitis, chorioretinitis, scleritis, keratitis, vitreous hemorrhage, optic neuritis, conjunctivitis, retinal vein occlusion, and retinal neovascularization. Hypopyon, which was considered the hallmark of Behçet disease, is now uncommon.
Ocular involvement showing posterior uveitis.
Eye disease is usually present from the outset but also may develop within the first few years. Decreased visual acuity is a result of secondary glaucoma, cataracts, or vitreous hemorrhage. Blindness has been reported to occur within 4-5 years from the onset of ocular symptoms. Retinal vein thrombosis leading to sudden blindness is not rare.
Saadoun et al found that cerebral venous thrombosis (CVT) was present in 7.8% of a large cohort of patients with Behçet disease. The main complication of CVT was severe visual loss from optic atrophy. Papilledema and concurrent prothrombotic risk factors were independently associated with the occurrence of sequelae; peripheral venous thrombosis and concurrent prothrombotic risk factors were associated with relapse of thrombosis. Anticoagulant therapy proved safe and effective in up to 90% of patients.7
Vascular involvement8
This occurs in 7-29% of patients, mostly men. Histologic findings include media thickening, elastic fiber splitting, and perivascular round cell infiltration. The 4 types of vascular lesions recognized in persons with Behçet disease are arterial occlusions, venous occlusions, aneurysms, and varices. Venous involvement is usually limited to occlusion, with the varices rarely affected. Affected sites of the venous system are the superior vena cava, inferior vena cava, deep femoral vein, and subclavian vein.
Arterial complications account for 7% of cases. Aneurysm and occlusion are most common. The subclavian artery and pulmonary artery are the most common arteries occluded. Depending on the site, arterial occlusions can have different clinical presentations. Pulseless disease is due to subclavian artery occlusion. Hypertension can originate from renal artery stenosis. Femoral artery stenosis and intermittent claudication cause avascular necrosis of the femoral head.
Pulmonary vasculitis can produce dyspnea, chest pain, cough, or hemoptysis. Aneurysm formation accounts for most vascular deaths. Common sites of aneurysms are the abdominal aorta, femoral artery, and thoracic artery. Because the vascular involvement of Behçet disease can be significant and life-threatening, diagnosing and treating vascular involvement early is vital.
Gastrointestinal involvement9
The clinical spectrum of gastrointestinal effects is enormously varied and occurs in more than 10% of patients with Behçet disease. Anorexia, vomiting, dyspepsia, diarrhea, abdominal distention, and abdominal pain all may occur.
Joint manifestations10
More than half the patients develop signs or symptoms of synovitis, arthritis, and/or arthralgia during the course of the disease. The most frequent minor feature in childhood-onset Behçet disease is reported to be arthritis, occurring in 11 of 40 patients. Multiple-joint involvement is common. Clinical features have been reported as pain, tenderness, swelling, limitation of joint movement, warmth, and morning stiffness.
Neurologic manifestations
The rate of neurologic involvement in persons with Behçet disease varies from 3.2-49% according to the reports of different populations. Neurologic involvement may present (in various combinations) as meningoencephalitis, a multiple sclerosis–like illness, acute myelitis, stroke, or pseudotumor cerebri.
Three categories of neurologic involvement are (1) brain stem syndrome, (2) meningomyelitis syndrome, and (3) organic confusional syndrome. Neurologic involvement is one of the most serious complications, leading to severe disability and a high fatality rate. Neurologic manifestations usually occur within 5 years of disease onset. Severe headache is the most frequent initial neurological symptom.
Pregnancy-associated manifestations
Pregnant women with Behçet disease may experience more severe symptoms during the course of the pregnancy, especially in the first trimester. Overall, pregnancy does not seem to markedly affect the course of Behçet disease.11 Close follow-up is necessary to monitor the health of the mother and baby.
Other organ manifestations
Myocarditis and cardiac vessel disease may occur. Major hemoptysis may result from pulmonary vascular thrombosis, aneurysms, or vasculitis. Cases with renal involvement, such as mild asymptomatic glomerulonephritis, have also been reported. However, most patients have been asymptomatic.12
Pathergy (skin hyperreactivity)
The presence of pathergy strongly suggests the diagnosis of Behçet disease. Following a needle prick or intradermal injection with saline or dilute histamine, the puncture site becomes inflamed and develops a small sterile pustule from hyperactivity of the skin to any intracutaneous insult. The pustular reaction of the skin is thought to denote increased neutrophil chemotaxis. Higher positivity (84-98%) is found in Mediterranean areas and the Middle East than in the Far East (40-70%), with Western countries having significantly lower positivity than the other regions.
Causes
- Immunogenetics13
- HLA-B51 or its B101 allele is significantly associated with Behçet disease in Japan, Korea, Turkey, and France and with ocular manifestations in Britain. Although HLA-B51 transgenic mice do not develop any manifestations of Behçet disease, their neutrophils show excessive function.
- The MICA allele is a polymorphic MHC class I–related A gene (MICA) family.
- The MICA6 allele has recently been shown to be significantly associated with Behçet disease (74%), compared with controls (45.6%) in Japan.
- The relationship between MICA6 and Behçet disease was confirmed in France. The MICA6 allele is thought to be in linkage disequilibrium with HLA-B51; consequently, the search for genes related to Behçet disease continues. A recent study of 23 Japanese patients showed that the MICA6 allele had no significant association with Behçet disease, but it showed a strong association with HLA-B51; therefore, the association between MICA6 and Behçet disease may be a secondary phenomenon related to HLA-B5114
- MEFV gene mutations, seen in persons with Mediterranean fever, are increased in persons with Behçet disease. This mutation has been associated with vascular Behçet disease.15,16
- Levels of tumor necrosis factor-alpha (TNF-alpha) have been reported to be significantly elevated in Behçet disease patients; thus, reports of TNF-alpha blockers having therapeutic benefits have been reported. Park et al analyzed TNF-alpha haplotypes in the promoter response element that affect the binding affinity of certain transcription factors. Their study showed that TNF-alpha -1031*C, -863*A, -857*C, and -308*G alleles were significantly associated with Behçet disease. TNF-alpha haplotypes in the promoter response elements may be useful in identifying those more susceptible to Behçet disease.17
- Single nucleotide polymorphism (SNP) of the gene encoding protein tyrosine phosphatase type 22 (PTPN22 620W) has been strongly genetically linked to human autoimmune diseases; however, an inverse relationship exists between Behçet disease and this gene.18
- HLA-B51 or its B101 allele is significantly associated with Behçet disease in Japan, Korea, Turkey, and France and with ocular manifestations in Britain. Although HLA-B51 transgenic mice do not develop any manifestations of Behçet disease, their neutrophils show excessive function.
- Viral and bacterial infection
- Investigations of the etiology of Behçet disease have focused predominantly on herpes simplex virus infection, streptococcal infection, and autoimmunity or cross-reactivity between microbial and oral mucosal antigens.
- Behçet suggested the herpes simplex virus as a causative agent in his first report. Polymerase chain reaction studies have remarkably improved the diagnostic significance of viral infections, especially herpes simplex virus. Herpes simplex virus DNA has been detected in saliva, genital ulcers, and intestinal ulcers of patients with Behçet disease. Behçet disease–like symptoms have been induced in an Institute for Cancer Research mouse after inoculation of herpes simplex virus into its earlobe.19
- Acquired hypersensitivity to streptococcal antigens plays an important role in the etiopathology of Behçet disease.
- The multiplicity of etiologic factors may have a common denominator in the 65-kd microbial heat shock protein (HSP), which shows significant homology with the human 60-kd mitochondrial HSP. Indeed, the uncommon serotypes of Streptococcus sanguis found in Behçet disease cross-react with the 65-kd HSP, which also shares antigenicity with an oral mucosal antigen.
- T-cell epitope mapping has identified 4 peptides derived from the sequence of the 65-kd HSP that specifically stimulates T-cell receptor (TCR+) lymphocytes from patients with Behçet disease.
- These peptides (111-125, 154-172, 219-233, and 311-325) show significant homology with the corresponding peptides (136-150, 179-197, 244-258, 336-351) derived from the human 60-kd HSP.
- B-cell epitopes within mycobacterial HSP65 or human HSP60 overlap with the T-cell epitopes, and both immunoglobulin G and immunoglobulin A antibodies have been identified.
- Among the 4 T- and B-cell epitopes, peptide 336-351 of the 60-kd HSP is significantly associated with Behçet disease in Britain, Japan, and Turkey. HSP60/65 was also found to be significantly increased in the epidermal cells of Behçet disease skin lesions, and antibody levels to HSP65 were significantly elevated in the cerebrospinal fluid from patients with neurological manifestations of Behçet disease.
- An experimental model of Behçet disease uveitis was established in rats, in which subcutaneous immunization with peptide 336-351 and adjuvants elicited uveitis in approximately 80% of Lewis rats. Furthermore, a mucosal model of induction of uveitis was developed in rats by oral or nasal administration of peptide 336-351 without an adjuvant, and this is consistent with the oral onset of ulceration in more than 90% of patients with Behçet disease.
- Immunological abnormalities
- In persons with Behçet disease, the Th1 cytokine interferon (IFN) level is elevated in serum, in skin T cells, and cerebrospinal fluid, and interleukin (IL)–12 is generated by the stimulation of CD4+ T cells with the HSP peptide 336-351, although IL-12 can also be secreted by neutrophils in persons with Behçet disease. However, the concentration of the Th2 cytokine IL-6 is also increased in the serum of patients with Behçet disease, especially in the active stage, as was also found with IL-10 upon stimulation of the peripheral blood mononuclear cell.
- Stimulation with S sanguis (KTH-1) of T-cell lines generated from patients with Behçet disease suggests that Th1-type mRNA is induced (IL-2 and IFN).
- Investigations of intracellular IFN and IL-4 suggest that polarization toward the Th1 type of cells occurs in patients with active Behçet disease because of a significant increase in the intracellular IFN that was not observed with IL-4. However, the converse was found in another investigation by stimulating peripheral blood mononuclear cells, with increased Th2 cytokines (IL-10 and decreased IL-2 or IFN) in active Behçet disease.
- The intracellular adhesion molecule 1 was enhanced in human dermal microvascular endothelial cells after treatment with serum from patients with Behçet disease, and this may have induced increased adhesion of T cells to the endothelial cells.
- Levels of the proinflammatory cytokines tumor necrosis factor (TNF)–alpha, TNF receptor 1, IL-1, and IL-8 are elevated in the serum of persons with Behçet disease and remain unregulated in peripheral blood mononuclear cells and neutrophils of patients with Behçet disease.20 Levels of IL-10 and IL-13 may also be elevated.21
- IL-23 p19 mRNA has been detected in erythema nodosum-like lesions of Beh ç et's disease. This finding suggests that anti – IL-23 therapy may be an option for treatment.22
- Plasma levels of vascular endothelial growth factor, a proinflammatory cytokine, is significantly higher in persons with active Behçet disease.23
- Neopterin is produced by human monocytes and macrophages in response to interferon-gamma (IFN-gamma) released from activated T cells; thus, it serves as a marker for cellular immune activation. Kose et al showed that serum levels of neopterin were significantly higher in active and inactive Behçet disease patients than in controls. Those with active disease had higher levels than those with inactive disease.24
- Polymorphisms in toll-like receptor 4 have been associated with Beh ç et disease.25
- Endothelial and vascular dysfunctions
- Vascular changes leading to vasculitis and thrombosis are important pathological features of Behçet disease.
- A recent study proposes that immunoglobulin to carboxy-terminal subunit of Sip1 (Sip1 C-ter) may be a useful novel autoantigen in Behçet disease. Interestingly, this autoantigen level was not only elevated in 41% of Behçet disease patients, but also in 45% of those patients with primary vasculitis, thus this marker may also point at endothelial dysfunction in vasculitis.26
- Antiendothelial cell antibodies are detected in diseases with immune-mediated vascular damage and show significantly increased prevalence in Behçet disease.
- T cells (mostly CD4 cells), B cells, and neutrophils are infiltrated perivascularly.
- Esmat et al showed much higher serum lipoprotein(a) levels in patients with vascular complications and lower levels of serum nitrites during disease activity.27
- Another study demonstrated an association of factor V Leiden and G20210A prothrombin mutation with thrombosis in Behçet disease patients.28
- Prostanoid synthesis in endothelial cells or vessel walls is impaired, whereas von Willebrand factor, thromboxane, and thrombomodulin are increased.
- The level of endothelin 1 and 2 is increased in patients with Behçet disease vascular involvement.
- Endothelial cell–dependent vasodilator function is significantly impaired in patients with Behçet disease and is demonstrated by high-resolution ultrasound imaging.
- Thrombomodulin is a receptor on vascular endothelial cells, which, when down-regulated, leads to a procoagulation state. Most of the high levels of thrombomodulin are observed in persons with skin pathergy reactions. This may help explain vasculitis and vascular symptoms associated with Beh ç et disease.29
- Thrombin activatable fibrinolysis inhibitor levels are higher in Beh ç et disease patients than in those without the disease, possibly contributing to the increased thrombosis observed in these patients.30
More on Behcet Disease |
 Overview: Behcet Disease |
| Differential Diagnoses & Workup: Behcet Disease |
| Treatment & Medication: Behcet Disease |
| Follow-up: Behcet Disease |
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| References |
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Keywords
Behcet disease, Behcet's disease, Behçet disease, Behcet's disease, Behcet syndrome, Behcet's syndrome, oral aphthous ulcer, genital ulcer, uveitis, oral aphthae, oral ulcers, canker sores
