What is Behcet?

Behcet Disease is also known by the following names

• Adamantiades-Behcet's Syndrome
• BD or BS
• Behcet's Disease
• Behcet's Syndrome
• Halushi-Behcet's Syndrome
• Oculo-Bucco-Genital Syndrome
• Silk-Road Disease
• Touraine's Aphthosis
• Triple Symptom Complex of Behcet

The etiology and pathogenesis of Behcet disease remain obscure. Currently it is considered an autoimmune disease, because of the common denominator of vasculitis in most patients. Biopsies have shown vasculitis near lesions of Behcet disease, including the oral and genital ulcers and lesions of the CNS and in the eyes; large vessels are affected by a vasculitis of the vasa vasorum. Vascular injuries may be superimposed on the hypercoagulability seen in some patients. Circulatory autoantibodies to human oral mucous membranes and immune complexes are found in 50% of the cases. Familial occurrence has been reported, and in patients from eastern Mediterranean countries (including Israel) and Japan the disease appeared to be linked to HLA-B51 (see causes).

Background: The Turkish dermatologist Hulusi Behcet first described the triple symptom-complex of recurrent oral aphthous ulcers, genital ulcers and uveitis in 1924. The Greek physician Adamantiades presented reports of a patient with inflammatory arthritis, oral and genital ulcers, phlebitis, and iritis in 1930. Since then more symptoms were added, and in 1937 it was named Behcet disease. However, it had been described before by the physicians Zong-Zing-Zang of China in 200A.D., and by Hyppocrates in Greece in the fifth century B.C. 

Behcet's disease is not infectious, contagious, nor sexually transmitted. This complex multisystemic disease with its spontaneous remissions and relapses (similar to other autoimmune diseases) includes involvement of the mucocutaneous, ocular, cardiovascular, renal, gastrointestinal, pulmonary, urologic and central nervous systems as well as the joints and blood vessels. Therefore it is often characterised by some of the following conditions, although not all of them have to occur at the same time or at all.

There is, however, controversy over the diagnostic criteria. Please refer to the relevant sections for more information.

Because Behcet's disease is rare and the symptoms of this disease overlap symptoms of other diseases, it can be very difficult to diagnose. Spontaneous remission is common for patients with Behcet's disease, which can add to the difficulty in diagnosis.

The clinical course of Behcet disease is variable even in early stages, making it difficult to determine the patient's long-term prognosis.

The disease usually runs a protracted course with attacks generally lasting for days or weeks but sometimes longer, and recurring more frequently early in the course of the disease. Mucocutaneous and arthritic involvement usually occur early.

Pathophysiology: The exact cause of Behcet disease is not known; however immunogenetics, bacterial and viral infection, immune regulation, or vascular abnormalities may play a role. As with many other autoimmune diseases, aspects suggest an infectious disease but no organism has ever been isolated, although bacterial antigens that have cross-reactivity with human peptides possibly can initiate an immune reaction based on molecular mimicry (see causes).

The basic lesion seems to be vasculitis. Biopsies have shown vasculitis near lesions of Behcet patients, including the oral and genital ulcers and lesions of the CNS and in the eyes; large vessels are affected by a vasculitis of the vasa vasorum. Vascular injuries may be superimposed on the hypercoagulability observed in some patients.

Neutrophilic hyperfunction is observed in patients with neutrophilic infiltration of skin at the site of a prick with a sterile needle (the pathergy test). Lymphocyte function has also been reported as abnormal, with a clonal expansion of autoreactive T cells.

 

Geography: Frequency data for Behcet disease should be considered suspect due to problems with case ascertainment. This problem is inherent in any disease where there is no specific diagnostic test, but only a set of clinical criteria for diagnosis. However, it is generally agreed that the disease shows almost exclusively in lattidudes 30-45 degrees north. An environmental factor is thought to be involved, based on such information as higher frequency and worse prognosis in the north of Japan relatively to its other areas.

Behcet disease is more prevalent (and more virulent) in countries along the old silk-road (in the Mediterranean, Middle and Far East) with an estimated 1 in 10,000 people affected. In Israel there are at least 500 BD eye patients, but there are no figures for the total number of BD patients in this country. The frequency of some manifestations may differ from region to region.

Heredity: Familial occurance has been reported, and more frequently so in some countries, including Israel. Studies point out to some genetic links, such as HLA-B51 (particularly in  Israel). More research should be done to address this issue (see causes).

Patients who have a parent with Behcet disease have disease onset at a younger age (genetic anticipation). In addition, pediatric patients are more likely to have a family history of Behcet disease, compared to patients with disease onset as an adult.

Sex: Recent data seems to indicate less sexual differences than previously thought. Nevertheless, men are considered to be affected more often in some countries, particularly in the Middle East . In Israel the ratio is 3:1 men:women (more so in the Arab population), with men often having a worse prognosis. In the Far East there is not much difference in prevalence between the sexes, while in the US there seems to be a much higher ratio of female patients. Despite the variability of the reported sex ratios, it is agreed that the disease runs a more severe course in males.

Age: Onset can occur at any age, but diagnosis is most common during the third decade of life (also see geography).

• Cases of Behcet disease have been described among newborns born to mothers with the disease, usually those who flared during pregnancy. The sevserity of neonatal disease apparently varies. The transmission of disease from mother to newborn might be caused by a specific antibody entering the fetus through the placenta. In a different case, it was suggested that the fetus may be able to transfer the disease to the mother as well.
• Although Behcet's syndrome is rarely diagnosed in children, it must be considered in the differential diagnosis of multi- systemic inflammatory disorder. A review of the English language literature suggests that the clinical picture of Behcet's syndrome in children differs from that in adults, in that there is a lower frequency of ocular disease and unusual manifestations appear to be more common. Those included neutropenia (low white blood cell count) , splenomegaly (enlarged spleen), Budd-Chiari syndrome, pulmonary infiltrate and rupture of pulmonary artery aneurysm.
• When Behcet disease occurs in young men aged 15-25 years, it takes a more serious form.
• A survey of pediatric rheumatology clinics in Israel concluded that the disease was not rare in the under-16 Isreali population.

Mortality/Morbidity:

• Chronic morbidity is usual; the leading cause is ophthalmic involvement, which can result in blindness. Reduced mobility can also be seen.The effects of the disease may be cumulative, especially with neurologic, vascular, and ocular involvement. Internal organ failure can also occur. 

• Mortality is low but can occur from neurologic involvement, vascular disease, bowel perforation, cardiopulmonary disease, or as a complication of immunosuppressive therapy. 

(see also symptoms and outcomes)

Causes:

It is generally believed that the potentential for the disease is inheritted, while it is only activated in response to environmental or other stimuli (stress). However, more concrete evidence is still needed.

Immunogenetics:

• Although familial occurrences have been reported, no consistent inheritance pattern has been established. Most commonly the disease occurs in siblings rather than different generations within the same family. Patients who have a parent with Behcet have disease onset at a younger age (genetic anticipation). In addition, pediatric patients are more likely to have a family history of Behcet, compared to patients with disease onset as an adult. In Isreal there seems to be a stronger familial pattern than some other countries, and the search in this direction continues, notably in the medical centres of Sheba and Rambam. (If you and at least one of your family members have been diagnosed with Behcet, and you wish to take part in this study, please click here and state so clearly).

Viral and Bacterial Infection:  Investigations of the etiology of Behcet disease have focused predominantly on: (a) viral infections, in particular Herpes Simplex Virus; (b) bacterial agents, in particular Streptococci (acquired hyper-sensitivity to streptococcal antigens); (c) autoimmunity or cross-reactivity between microbial and oral mucosal antigens.

Behcet patients tend to have a higher incidence of antibodies to herpes simplex virus, hepatitis C virus, and parvovirus B19. 

Behcet suggested the herpes simplex virus as a causative agent in his first report. The new method called polymerase chain reaction (PCR) improved remarkably the diagnostic significance of viral infections, especially herpes simplex virus (HSV). HSV DNA was detected in saliva, genital ulcer, and intestinal ulcers of patients with BD. Behcet disease-like symptoms were induced in an ICR mouse (originally designed for studying cancer) after inoculation of HSV into the earlobe. 

 

Streptococcal antigens also have been implicated, in particular rare varieties of Streptococcus sanguis. Acquired hypersensitivity to streptococcal antigens plays an important role in the etiopathology of BD. It has been the subject of extensive research in Japan for many years.

The multiplicity of etiologic factors may have a common denominator in the 65kD microbial HSP (Heat Shock Protein), which shows significant homology with the human 60kD mitochondrial HSP. Indeed, the uncommon serotypes of Streptococcus sanguis found in BD cross-react with the 65kD HSP, which also shares antigenicity with an oral mucosal antigen. HSP60/65 was also found to be significantly increased in the epidermal cells of skin lesions in Behcet disease, and antibodies to HSP65 were significantly raised in the cerebrospinal fluid from patients with neurological manifestations of Behcet disease. Peptide 336-351 of the 60kD HSP is significantly associated with Behcet disease in Britain, Japan and Turkey, and is the only agent thus far to induce symptoms consistent with Behcet disease in Lewis rats (used for studying autoimmune diseases).

A trial of prophylactic penicillin treatment decreased the number of acute arthritis episodes in studied patients. 

Immunological Abnormalities: 

T-cells from Behcet's patients show that TH cytokines such as IFN (interferone) as well as immunoleukocytes (IL-1, IL-2, IL-4, IL-6, IL-8, IL-10 and IL-12) are increased, especially in the active stage, or when stimulated with Streptococcus sanguis. However, some research produced contradicting results (decreased IL-2 or INF).

Endothelial and Vascular Dysfunction:

The main lesion in Behcet patients appears to be vasculitis. Vascular changes leading to vasculitis and thrombosis are one of the important pathological features of Behcet disease.

Anti-endothelial (against endothelium- the lining membrane of the blood vessels) cell antibodies are prevalent; T cells, B cells and neutrophils are infiltrated perivascularly (around the blood vessels); various other endothelial functions are impaired, and inflammatory factors are increased.

Prostanoid synthesis in endothelial cells or vessel walls is impaired, whereas von Willebrand factor, thromboxane and thrombomodulin are increased; The level of endothelin (ET)-1,2 is increased in patients with vascular involvement, while endothelial cell dependent vasodilator function is significantly impaired in all patients and is demonstrated by high-resolution ultrasound imaging. 

Treatment of Behcet's Disease is symptomatic and empirical (see medicine & treatment). Currently there is no cure.

(The above material has been amended by the author and does not necessarily reflect the views of the sources)

Sources

e-medicine - Behcet Disease - Sungnack Lee, M.D. et al (March 2003)   

e-medicine - Behcet Disease - Jeffrey R Lisse, M.D. et al (March 2003)   

e-medicine - Behcet Disease - C Egla Rabinovich, M.D. et al (March 2003)   

e-medicine - Behcet Disease - Mounir Bashour, M.D. et al (March 2003)   

Vanderbilt University Medical Center - Allergy/Immunology - Behcet Disease (June 1998)