Behcet Disease

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.

This complex, multisystemic disease includes involvement of the mucocutaneous, ocular, cardiovascular, renal, gastrointestinal, pulmonary, urologic, and central nervous systems and the joints, blood vessels, and lungs.

It 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 BD is not known; however, immunogenetics, immune regulation, vascular abnormalities, or bacterial and viral infection may have a role in its development.

Frequency:

In the US: BD is not common in the United States, with a prevalence of 5 cases per 100,000 persons.

Internationally: BD 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.

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.

History: Signs and symptoms, which may be recurrent, may precede the onset of the mucosal membrane ulcerations by 6 months to 5 years.

Prior to the onset of BD, 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 BD 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.

More recently, the diagnostic criteria of the International Study Group for Behçet Disease have been applied to establish a firmer diagnosis.
The major limitation of these criteria is the fact that recurrent oral ulceration is the characteristic symptom for the diagnosis of BD. For example, patients with uveitis and genital ulcers, without oral aphthosis, would not be considered to have BD, 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 follows:

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

International criteria for the classification of BD (1990) are as follows:

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 BD, 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

Findings are applicable if no other clinical explanation is present.

Physical:

Oral ulcers

Oral aphthae that occur in patients with BD 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 3 types.

Minor ulcer: This consists of 1-5 small, moderately painful ulcers persisting for 4-14 days (see Image 1).
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 Image 2).
Herpetiform ulcer: This is a recurrent crop of as many as 1000 small and painful ulcers (see Image 3).

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 Image 4), penis, and groin.
In females, they occur on the vulva (see Image 5), vagina, groin, and cervix.
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 BD (58.6-97%), including the following:

Erythema nodosum–like lesions, which are most common (see Image 6)
Papulopustular eruptions (see Image 7)
Erythema multiforme–like lesions
Thrombophlebitis
Ulcers
Lesions resembling Sweet syndrome (see Image 8)
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 Image 9).
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 BD.

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 BD. Childhood-onset Behçet uveitis is more common in males (Tugal, 2003).
The most diagnostically relevant lesion is posterior uveitis, ie, retinal vasculitis (see Image 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 BD, is now uncommon.
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.

Vascular involvement

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 BD 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 BD can be significant and life-threatening, diagnosing and treating vascular involvement early is vital.

Gastrointestinal involvement

The clinical spectrum of gastrointestinal effects is enormously varied and occurs in more than 10% of patients with BD.
Anorexia, vomiting, dyspepsia, diarrhea, abdominal distention, and abdominal pain all may occur.

Joint manifestations

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 BD 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 BD 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 BD 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 BD (Uzun, 2003).
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.

Pathergy (skin hyperreactivity)

The presence of pathergy strongly suggests the diagnosis of BD.
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:

Immunogenetics

HLA-B51 or its B101 allele is significantly associated with BD in Japan, Korea, Turkey, and France and with ocular manifestations in Britain. Although HLA-B51 transgenic mice do not develop any manifestations of BD, 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 BD (74%), compared with controls (45.6%) in Japan. The relationship between MICA6 and BD was confirmed in France. The MICA6 allele is thought to be in linkage disequilibrium with HLA-B51; consequently, the search for genes related to BD continues. A recent study of 23 Japanese patients showed that the MICA6 allele had no significant association with BD, but it showed a strong association with HLA-B51; therefore, the association between MICA6and BD may be a secondary phenomenon related to HLA-B51 (Nishiyama, 2006).
MEFV gene mutations, seen in persons with Mediterranean fever, are increased in persons with BD. This mutation has been associated with vascular BD (Atagunduz, 2003).
Levels of tumor necrosis factor-alpha (TNF-alpha) have been reported to be significantly elevated in BD 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 BD. TNF-alpha haplotypes in the promoter response elements may be useful in identifying those more susceptible to BD (Park, 2006).

Viral and bacterial infection

Investigations of the etiology of BD 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 BD. BD-like symptoms have been induced in an Institute for Cancer Research mouse after inoculation of herpes simplex virus into its earlobe.
Acquired hypersensitivity to streptococcal antigens plays an important role in the etiopathology of BD.
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 BD 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 BD.

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 BD in Britain, Japan, and Turkey. HSP60/65 was also found to be significantly increased in the epidermal cells of BD skin lesions, and antibody levels to HSP65 were significantly elevated in the cerebrospinal fluid from patients with neurological manifestations of BD.
An experimental model of BD 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 BD.

Immunological abnormalities

In persons with BD, 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 BD. However, the concentration of the Th2 cytokine IL-6 is also increased in the serum of patients with BD, 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 BD suggests that Th1-type mRNA is induced (IL-2 and IFN).