eMedicine Specialties > Ophthalmology > Unclassified Disorders

Behcet Disease

Author: Mounir Bashour, MD, CM, FRCS(C), PhD, FACS, Assistant Professor of Ophthalmology, McGill University; Clinical Assistant Professor of Ophthalmology, Sherbrooke University; Medical Director, Cornea Laser and Lasik MD
Contributor Information and Disclosures

Updated: Oct 12, 2007

Introduction

Background

Behçet disease is a systemic disorder characterized by recurrent aphthous ulcers and intraocular inflammation. The clinical triad of uveitis with recurrent oral and genital ulcers bears the name of Hulusi Behçet, a Turkish dermatologist who described 3 patients who had this triad.

The Behçet's Disease Research Committee of the Ministry of Health and Welfare of Japan first proposed formal diagnostic criteria in 1972. This set of criteria, which has been used throughout the world, classifies disease findings into 4 major criteria and 5 minor criteria. When all 4 major criteria are met, the disease is said to be of the complete type, whereas the incomplete type consists of various combinations of major and minor criteria, with added weight given to ocular disease.

In 1990, The International Study Group for Behçet's Disease proposed a separate set of diagnostic criteria for Behçet disease. Based upon these criteria, a diagnosis of Behçet disease requires recurrent oral ulceration and at least 2 additional criteria, including recurrent genital ulcers, ocular lesions, skin lesions, and a positive pathergy test.

Pathophysiology

The cause and the pathogenesis of Behçet disease remain unknown, but the tumor necrosis factor alpha (TNF-alpha) pathway is likely involved in the pathophysiology of Behçet disease. The frequency of the R92Q TNFRSF1A mutation in patients with Behçet disease is significantly higher than that in control subjects (P=0.006 by the Fisher exact test) and is associated with an increased risk of extracranial venous thrombosis.

Frequency

United States

Prevalence of Behçet disease is estimated to be only 1 case per 300,000 per year.

In a university hospital setting, Behçet disease was responsible for 12-20% of cases of uveitis in Japan compared with only 0.2-0.4% in the United States.

International

Behçet disease occurs worldwide, with predominance among Asians, North Africans, and Europeans who live between the latitudes of 30-45°N.

It is one of the main causes of endogenous uveitis in Japan and Turkey, with prevalence rates of 1 case per 10,000 and 8-30 cases per 10,000, respectively.

Race

The prevalence of Behçet disease exhibits a strong geographic variation and has a unique geographic distribution, being most prevalent along the ancient Silk Road linking Rome with China, which was used for centuries as a trade passage.¹

The prevalence of Behçet disease is highest in Turkey, in the countries bordering the Mediterranean, in the Mideast, in the Far East, and in Japan, where it is 1 case per 1000.

Behçet disease occurs less frequently in northern Europe, the United States, and the United Kingdom.

The prevalence of Behçet disease in African Americans is 1 case per 100,000.

Sex

The male-to-female ratio varies with ethnic origin; androtropism is still observed in Arabian countries with a ratio of 2.3:1, whereas female predominance is seen in some European countries and in the United States.¹

Age

• Mean age of onset is in the third decade of life.
• When Behçet disease occurs in young men aged 15-25 years, it takes a more serious form.

Clinical

History

• Ocular
  • Ocular involvement is seen in about 70% of patients who have Behçet disease.
  • In most cases, the ocular symptoms follow the oral and genital ulcers by 3-4 years, although ocular disease is the initial manifestation in about 20% of cases.
  • Behçet disease is characterized by severe recurrent attacks of intraocular inflammation. In one series, anterior uveitis was present in 59% of cases; posterior uveitis was present in 76% of cases; and panuveitis was present in 88.1% of cases.
  • Symptoms include periorbital pain, redness, photophobia, and blurred vision.
• Oral aphthous ulcers - Recurrent painful oral aphthous ulcers are the most common lesions associated with Behçet disease and occur in 99.3% of cases.
• Skin - Cutaneous hypersensitivity is relatively common, occurring in 81.8% of cases. Acnelike lesions or folliculitis occur frequently. Migratory thrombophlebitis also can develop.
• Genital ulcers - Recurrent painful genital ulcers occur in 62.8% of cases.

Physical

Initial ocular involvement may be unilateral but progresses to bilateral disease in at least two thirds of cases.

In a large retrospective study, the mean age at onset of uveitis was 28.5 years in male patients and 30 years in female patients. Ocular involvement was bilateral in 78.1% of patients and unilateral in 21.9% of patients. Panuveitis was the most common form in both sexes. Fundus lesions as well as sight-threatening complications were more common in male patients than in female patients. At the beginning of follow-up, potential visual acuity was 0.1 or less in 30.9% of eyes in male patients and 24.2% of eyes in female patients. The Kaplan-Meier survival analysis estimated the risks of losing useful vision (>0.1) at 5 and 10 years for male patients and female patients as 21% versus 10% and 30% versus 17%, respectively.

• Ocular
• Described in 75% of patients, either anterior segment iridocyclitis or posterior segment involvement. Panuveitis and posterior uveitis/retinitis occurred more frequently in males than in females (28.9% vs 11.5% and 57.9% vs 36.1%, respectively; p <0.05).
• The classic finding of this disease, iridocyclitis with hypopyon, is present in about one third of cases.
• Gonioscopy may reveal an occult hypopyon in many cases. One characteristic feature of the hypopyon in Behçet disease is that it may change position with head movement, and it may form and disappear rapidly without sequelae.
• Recurrent attacks may result in posterior synechiae, peripheral anterior synechiae, iris atrophy, and secondary glaucoma.
• Retinal disease is the most serious complication of Behçet disease. The classic fundus finding is retinal vasculitis, which affects both arteries and veins in the posterior pole.
• Ophthalmoscopy shows venous engorgement, retinal hemorrhages, yellow-white exudates deep in the retina, white focal retinal infiltrates, retinal edema, and optic disc edema with hyperemia.
• Severe vasculitis may lead to thrombosis of vessels and secondary ischemic retinal changes. Optic disc edema may be secondary to inflammation and may be seen during the acute phase in at least one fourth of cases.
• Vitreous cellular infiltration almost always is present during the acute phase.
• Retinal neovascularization, secondary to either retinal vein occlusion or chronic inflammation, may result in retinal or vitreous hemorrhage.
• Neovascular glaucoma occurs in as many as 6% of patients and often results in phthisis bulbi.
• Repeated episodes of posterior segment inflammation cause sheathing of retinal vessels, chorioretinal scars, and retinal and optic nerve atrophy.
• Oral aphthous ulcers
• Recurrent aphthous ulceration of the oral mucosa is the most common nonocular manifestation of Behçet disease.
• They are the first symptoms in 50-70% of patients and develop in as many as 98% of patients.
• The lesions are located on the gingiva, lips, tongue, buccal mucosa, hard palate, uvula, and posterior pharynx.
• A nationwide study in Japan revealed that 97.7% of patients who have Behçet disease have recurrent aphthous ulcers. Ulcers tend to develop in crops, which recur at various frequencies.
• White or yellowish pseudomembrane usually covers the surface of the ulcer.
• They usually heal within 7-10 days with no scarring.
• However, fusion of several small ulcers may produce a large ulcer that leads to scar formation.
• Skin involvement
• Skin involvement appears in 70% of patients. Behçet disease may produce a variety of skin lesions in affected individuals.
• Erythema nodosum, acneiform lesions, thrombophlebitis, and cutaneous hypersensitivity are most common.
• Erythema nodosum lesions, which occur in more than two thirds of patients with Behçet disease, usually are found on the anterior surface of the legs but also may be seen on the face, arms, and buttocks. These lesions appear as slightly raised, red nodules with subcutaneous induration and tenderness. They tend to involute in 10-14 days without ulceration.
• Acneiform lesions occur in almost 60% of patients and may occur in patients who receive corticosteroid treatment; therefore, their presence is of questionable diagnostic usefulness.
• A peculiar feature of Behçet disease is cutaneous hypersensitivity, which results in small pustules that form on skin after it has been scratched, shaved, or pricked with a needle.
• Genital ulcers
• Genital ulcers occur in 80% of patients. They are painful punched-out lesions similar to those that occur in mouth and usually are located in the scrotum or vulva.
• These genital ulcers may be deep and, in many cases, result in scarring. These scars are indicators of old disease and may help in diagnosis.
• Musculoskeletal
• Painful swelling with redness of joints occurs in as many as 50% of patients.
• Transient, recurrent, nondestructive, and nonmigratory arthritis commonly affects large joints such as the knee, ankle, elbow, and wrist. The knee joint is most commonly affected.
• Gastrointestinal
• At least 50% of patients who have Behçet disease develop gastrointestinal symptoms.
• Intestinal erosions and ulcers may cause abdominal pain, melena, and perforation.
• This constellation of intestinal signs and symptoms may simulate Crohn disease and other inflammatory bowel disorders.
• Vascular
• Thrombophlebitis is found in 15% of these patients.
• Obliterating thrombophlebitis, arterial occlusion, and aneurysm may occur in vessels of all sizes.
• Neurologic
• Multiple neurologic disorders that involve pyramidal and extrapyramidal tracts, the cerebellum, the cranial nerves, and rarely the peripheral nerves occur more commonly in male patients and in 5-30% of cases.
• Both the central nervous system and the peripheral nervous system can be involved. Central nervous system manifestations can be divided into 2 main groups: (1) parenchymal involvement, which includes brainstem involvement, hemispheric manifestations, spinal cord lesions, and meningoencephalitic presentations; and (2) nonparenchymal involvement, including dural sinus thrombosis, arterial occlusion, and/or aneurysms. Peripheral neuropathy and myopathy are relatively rare.

Causes

• The etiology and the pathogenesis of Behçet disease are not clear but are presumed to be multifactorial, involving genetic, infectious, and immunological factors. There is increasing evidence that antigens derived from infectious agents (eg, Streptococcus sanguis, herpes simplex virus, heat shock proteins) are implicated in the pathogenesis of the disease, and it has also become increasingly apparent that these events, once triggered, may be influenced by numerous interdependent and independent genetic regions.
• Despite 20 years of intense efforts to identify other associated genetic regions in chromosome 6 and elsewhere, human leukocyte antigen B51 (HLA-B51) remains foremost among candidate risk factors for the disease. MICA alleles in the major histocompatibility complex (MHC) have also been implicated, but their close linkage with HLA-B51 has made their independent contribution to the disease less easy to define.¹
• Since the disease is characterized by a vasculitis, the underlying mechanism is believed to be an autoimmune process.
• Although familial occurrences have been reported, no consistent inheritance pattern has been established; however, human leukocyte antigen B5 (HLA-B5) is associated with Behçet disease and poor visual prognosis.
• Considerable evidence now points toward a more specific association with HLA-B51, a split antigen of HLA-B5.
• The frequency of HLA-B51 is 57% in Japanese patients who have Behçet disease compared to only 14% in the control group, which equates to a relative risk of 7.9 for this marker.
• Restriction fragment link polymorphism studies showed linkage disequilibrium between the HLA-B51 locus and the tumor necrosis factor beta (TNF-beta) gene. This finding may imply that lower levels of TNF-beta may contribute to activation of inflammatory cascade in Behçet disease.
• In Japan, an association has been found between human leukocyte antigen A26 (HLA-A26) and Behçet disease.
• The disease occurs more frequently in temperate northern parts of Japan than in subtropical southern parts, a distribution that suggests that environmental factor influences the prevalence of disease.
• With regard to the immunology of Behçet disease, several data suggest a direct role of Th1 lymphocytes in the pathogenesis of the disease lesions. Th1 cytokines, including interleukin 2 (IL-2), TNF-alpha, interferon gamma (IFN-gamma), interleukin 12 (IL-12), and interleukin 18 (IL-18), are elevated and probably contribute to neutrophil and endothelial cell activation.¹
• Other diagnostic considerations
• It is important to consider other forms of uveitis in the differential diagnosis, especially in those patients who have a mild or atypical presentation of Behçet disease.
• Human leukocyte antigen B27 (HLA-B27)-related anterior uveitis also may give recurrent iridocyclitis with hypopyon, but it is typically unilateral.
• Since Behçet disease is a bilateral panuveitis, other inflammatory processes that affect both eyes must be considered. Syphilis causes a retinitis with vitreitis rather than a strict vasculitis. The diagnosis for syphilis is confirmed by serology.
• Sarcoidosis, another bilateral inflammatory process, may have posterior pole findings similar to those in Behçet disease but is generally more indolent, in contrast to the explosive recurrent attacks of Behçet disease. Furthermore, the vasculitis seen in sarcoidosis usually is not occlusive in nature and typically involves only veins compared with the involvement of both arteries and veins in Behçet disease.
• Other conditions that may mimic the ocular changes of Behçet disease include collagen vascular diseases and viral retinitis.

• Search for CME/CE on This Topic »

• Behcet Disease (Dermatology)
• Behcet Disease (Rheumatology)
• Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy (Rheumatology)
• Urticaria (Pediatrics: General Medicine)

• Systemic and Ophthalmic Manifestations of West Nile Virus Infection
• Current Concepts in the Treatment of Recurrent Aphthous Stomatitis
• Accuracy and Limitations of Equations for Predicting the Glomerular Filtration Rate during Follow-up of Patients with Non-diabetic Nephropathies