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Behcet Disease Topology

Prepared by

Mo stafa Askar Askar

Mo lecular Bio lo gy Department

Introduction:

Behcet Disease: One of the largest types of autoimmune diseases.

Behçet's disease (beh-CHETS), sometimes called Behçet's syndrome, Morbus

Behçet, Adamantiades syndrome, or Silk Road disease. Behçet's 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.

As a systemic disease, it can also involve visceral organs such as the gastrointestinal

tract, pulmonary, musculoskeletal, cardiovascular and neurological systems. This

syndrome can be fatal due to ruptured vascular aneurysms or severe neurological

complications.

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History

Behçet disease is named after Hulusi Behçet (1889–1948), the Turkish

dermatologist and scientist who first recognized the syndrome in one of his patients

in 1924 and reported his research on the disease in Journal of Skin and Venereal

Diseases in 1936. The name (Morbus Behçet) was formally adopted at the

International Congress of Dermatology in Geneva in September 1947. Symptoms of

this disease may have been described by Hippocrates in the 5th century BC, in his 3rd

Epidemion-book. Its first modern formal description was published in 1922.

Epidemiology

The syndrome is rare in the United States, but is common in the Middle East and

Asia. It is not associated with cancer. One study has revealed a possible connection to

food allergies, particularly to dairy products. An estimated 15,000 to 20,000

Americans have been diagnosed with this disease. In the UK, it is estimated to have

about 1 case for every 100,000 people. Globally, males are affected more frequently

than females. In the United States, more females are affected than males. In an

epidemiologic study, 56% of patients with Behçet's disease developed ocular

involvement at a mean age of 30.

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Signs and symptoms

Oral Lesions

Oral ulceration is usually an initial symptom

Oral aphthae which are grossly

Lesions heal within about 10 days without scarring.

Uro-genital Lesions

Genital ulceration occurs in 75 percent or more of patients with Behcet's

disease.

The ulcers are similar in appearance to the oral aphthae.

Genital ulcers are most commonly found on the scrotum in men and the vulva

in women

Recurrence is typically less frequent than with oral ulcerations.

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Cutaneous Lesions

Cutaneous lesions also occur in over 75 percent of patients with Behcet's

disease.

May include acneiform lesions, erythema nodosum, pyoderma gangrenosum-

type lesions, and palpable purpura.

Arthritis

Nonerosive, asymmetric, usually nondeforming arthritis occurs in about one-

half of patients with Behcet's disease, particularly during exacerbations.

Most commonly affects the medium and large joints, including the knee,

ankle, and wrist.

Ocular

Ocular disease occurs in 25 to 75 percent of patients with Behcet's disease,

and may progress to blindness.

Symptoms, including blurred vision, eye pain, photophobia, lacrimation,

floaters

Uveitis is often the dominant feature of Behcet's disease. It is typically

bilateral and episodic.

Hypopyon, a visible layer of pus in the anterior ocular chamber, is

characteristic of Behçet's disease

The most serious ocular problem in patients with Behçet's disease is retinal

disease, as a result of vaso-occlusive lesions.

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Gastrointestinal

Symptoms include abdominal pain, diarrhea, melena, and sometimes

perforation.

Gastrointestinal ulcerations occur most often in the terminal ileum, cecum,

and ascending colon.

Histologically, the intestinal ulcers of Behçet's disease are indistinguishable

from those of ulcerative colitis.

It is often difficult to distinguish between Behçet's disease and inflammatory

bowel diseases, because of the similarity in extraintestinal symptoms

Neurologic

Neurologic disease occurs in less than one-fifth of patients with Behcet's

disease, more frequently in men than women.

Classically, meningitis or meningoencephalitis, neurologic deficits such as

motor disturbances and brain-stem symptoms, and psychiatric symptoms

including personality changes develop more than five years after Behçet's

disease is diagnosed.

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Vascular

Small-vessel vasculitis is common and accounts for much of the pathologic

process in Behçet's disease.

Large vessel vascular involvement occurs in approximately one-third of

patients with Behcet's disease.

Superficial and deep venous thrombosis is common.

Cause

The cause is not well-defined, but it is primarily characterized by auto-inflammation

of the blood vessels.

In fact, no one knows yet why the immune system starts to behave this way in

Behçet's disease.

An association with the GIMAP family of genes on the long arm of chromosome

7 (7q36.1) has been reported. The genes implicated

were GIMAP1, GIMAP2 and GIMAP4.

(GIMAP) This gene encodes a protein belonging to the GTP-binding superfamily and

to the immuno-associated nucleotide (IAN) subfamily of nucleotide-binding proteins.

The encoded protein of this gene may be negatively regulated by T-cell acute

lymphocytic leukemia 1 (TAL1). In humans, the IAN subfamily genes are located in

a cluster at 7q36.1.

Pathophysiology

A large number of serological studies show a linkage between the disease and human

leucocytes antigen HLA-B51. HLA-B51 is more frequently found from the Middle

East to South Eastern Siberia, but the incidence of B51 in some studies was 3 fold

higher than the normal population. However, B51 tends not to be found in disease

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when a certain SUMO4 gene variant is involved, and symptoms appear to be milder

when HLA-B27 is present. (Small ubiquitin-related modifier 4 is a protein that in

humans is encoded by the SUMO4 gene.

(This gene is a member of the SUMO gene family. This family of genes encodes small ubiquitin-related modifiers that are attached to proteins and control the target proteins' subcellular localization, stability, or activity. The protein described in this record is located in the cytoplasm and specifically modifies IKBA, leading to negative regulation of NF-kappa-B-dependent transcription of the IL12B gene. A specific polymorphism in this SUMO gene, which leads to the M55V substitution, has been associated with type I diabetes) At the current time, a similar infectious origin has not yet been confirmed that leads

to Behçet's disease, but certain strains of Streptococcus sanguinis has been found to

have a homologous antigenicity.

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Finally

Both innate and adaptive immune systems are activated in BD, with a

proinflammatory and Th1-type of cytokine profile. BD may be linked to a specific,

primary immune abnormality with a genetic mutation aVecting an adhesion molecule

or a proinflammatory cytokine, which predisposes to early or more intense neutrophil

and T cell responses. Alternatively, a broad intracellular signaling abnormality of a

transcription factor, which lowers the threshold of inflammatory responses to external

stimuli, as proposed for familial Mediterranean fever with decreased pyrine

expression of neutrophils, may be present (hyperreactivity model). However, an

adaptive immune system is also crucial in BD, with possibly both external

(streptococcal, superantigens) and internal (heat shock or organ-specific proteins)

antigens driving the pathogenic tissue T cell infiltrations. Better characterisation of

pathogenic immune cell subsets, systemic and local antigens, and abnormal cell-

activation mechanisms may help in the future to develop more specific and less toxic

immunotherapeutic approaches to the still unsatisfactorily treated BD.

Diagnosis

4 "hallmark" symptoms:

genital ulcers (including anal ulcers and spots in the genital region and

swollen testicles or epididymitis in men)

skin lesions (papulo-pustules, folliculitis, erythema nodosum, acne in post-

adolescents not on corticosteroids)

eye inflammation (iritis, uveitis, retinal vasculitis, cells in the vitreous)

pathergy reaction (papule >2 mm dia. 24-48 hrs or more after needle-prick). Positive

pathergy test. In a pathergy test, your doctor inserts a sterile needle into your skin and then examines the

area one to two days later. If the pathergy test is positive, a small red bump forms under your skin where the

needle was inserted. This indicates your immune system is overreacting to a minor injury.

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Another clinical manifestations

mouth ulcers

arthritis/arthralgia

nervous system symptoms

stomach and/or bowel inflammation

deep vein thrombosis

superficial thrombophlebitis

epididymitis

cardio-vascular problems of an inflammatory origin

inflammatory problems in chest and lungs

problems with hearing and/or balance

extreme exhaustion

changes of personality, psychoses

any other members of the family with a diagnosis of Behçet disease.

Treatment

Current treatment is aimed at easing the symptoms, reducing inflammation, and

controlling the immune system. High dose Corticosteroid therapy (1 mg/kg/d oral

prednisone) is indicated for severe disease manifestations.

Anti-TNF therapy such as infliximab has shown promise in treating

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References

http://ard.bmj.com/content/60/11/996.full.html#related-urls Article cited in:

http://ard.bmj.com/content/60/11/996.full.html#ref-list-1