Behçet's disease


Behçet's disease or Behçet's syndrome is a type of inflammatory disorder which affects multiple parts of the body. The most common symptoms include painful sores on the mucous membranes of the mouth and other parts of the body, inflammation of parts of the eye, and arthritis. The sores can last from a few days, up to a week or more. Less commonly there may be inflammation of the brain or spinal cord, blood clots, aneurysms, or blindness. Often, the symptoms come and go.
The cause is unknown. It is believed to be partly genetic. Behçet's is not contagious. Diagnosis is based on at least three episodes of mouth sores in a year, together with at least two of the following: genital sores, eye inflammation, skin sores, a positive skin prick test.
There is no cure. Treatments may include immunosuppressive medication such as corticosteroids and anti-TNFs as well as lifestyle changes. Lidocaine mouthwash may help with the pain. Colchicine may decrease the frequency of attacks.
While rare in the United States and Europe, it is more common in the Middle East and Asia. In Turkey, for example, about 2 per 1,000 are affected. Onset is usually in a person's twenties or forties. The disease was initially described by Turkish dermatologist Hulusi Behçet in 1937.

Signs and symptoms

Skin and mucosa

Nearly all people with Behçet's disease present with some form of painful ulcerations inside the mouth. They are a form of aphthous ulcers or non-scarring oral lesions. The oral lesions are similar to those found in inflammatory bowel disease and can be relapsing. Painful genital ulcerations usually develop around the anus, vulva, or scrotum and cause scarring in 75 percent of the patients. Additionally, patients may present with erythema nodosum, cutaneous pustular vasculitis, and lesions similar to pyoderma gangrenosum.

Eyes

Inflammatory eye disease can develop early in the disease course and lead to permanent vision loss in 20 percent of cases. Ocular involvement can be in the form of posterior uveitis, anterior uveitis, or retinal vasculitis. Anterior uveitis presents with painful eyes, conjuctival redness, hypopyon, and decreased visual acuity, while posterior uveitis presents with painless decreased visual acuity and visual field floaters. A rare form of ocular involvement in this syndrome is retinal vasculitis which presents with painless decrease of vision with the possibility of floaters or visual field defects.
Optic nerve involvement in Behçet's disease is rare, typically presenting as progressive optic atrophy and visual loss. However, cases of acute optic neuropathy have also been reported to occur. Optic nerve atrophy has been identified as the most common cause of visual impairment. Behçet's disease may result in primary or secondary optic nerve involvement. Papilledema as a result of dural sinus thrombosis and atrophy resulting from retinal disease, have been characterized as secondary causes of optic nerve atrophy in Behçet's disease.
Signs and symptoms of acute optic neuropathy include painless loss of vision which may affect either one or both eyes, reduced visual acuity, reduced color vision, relative afferent pupillary defect, central scotoma, swollen optic disc, macular edema, or retrobulbar pain. When these symptoms occur with concurrent mucocutaneous ulcerations, they raise suspicion of acute optic neuropathy in Behçet's Disease. Progressive optic atrophy may result in decreased visual acuity or color vision. Intracranial hypertension with papilledema may be present.
Episcleritis may occur, which causes eye redness and mild pain, without a significant impact on vision.

Bowels

Gastrointestinal manifestations include abdominal pain, nausea, and diarrhea with or without blood, and they often involve the terminal ileum and ileocecal valve. Some patients with BD experience abdominal tenderness, bloating, and general abdominal discomfort. When mild this can resemble irritable bowel syndrome; more severe cases bear similarities to inflammatory bowel diseases such as ulcerative colitis or Crohn's. Behçet's disease causes ulcers in the terminal ileum and ileocecal valve. The ulcers may be aphthous or have a classic punched out appearance with undermining. Linear and fissuring ulcers up to 5 cm may be present. Biopsies show vasculitis with a neutrophilic inflammatory infiltrate. Involvement of the oesophagus, stomach and large intestine is rare.

Lungs

Lung involvement is typically in the form of hemoptysis, pleuritis, cough, or fever, and in severe cases can be life-threatening if the outlet pulmonary artery develops an aneurysm which ruptures causing severe vascular collapse and death from bleeding in the lungs. Pulmonary artery thrombosis may occur.

Joints

Arthritis is seen in up to half of people, and is usually a non-erosive poly or oligoarthritis primarily of the large joints of the lower extremities.

Kidneys

Behçet's disease can rarely result in renal involvement. This can manifest in the following:
Small vessel vascular disease results in renal vasculitis, whereas large vessel involvement causes aneurysms and thrombosis. Serious kidney problems are more common in men typically with a history of large vessel involvement in other parts of the body. Bladder and urethral involvement is rare in Behçet's disease.

Brain

Central nervous system involvement most often occurs as a chronic meningoencephalitis. Lesions tend to occur in the brainstem, the basal ganglia and deep hemispheric white matter and may resemble those of multiple sclerosis. Brainstem atrophy is seen in chronic cases.
Neurological involvements range from aseptic meningitis to vascular thrombosis such as dural sinus thrombosis and organic brain syndrome manifesting with confusion, seizures, and memory loss. Sudden hearing loss is often associated with it. They often appear late in the progression of the disease but are associated with a poor prognosis.

Heart

Chronic aortic regurgitation due to aortic root disease may also be seen. Although infrequent, myocardial infarction with angiographically identified acute coronary artery thrombosis has been reported, including one case with a pathologically demonstrable lesion due to arteritis found at autopsy.

Blood vessels

Blood vessel problems are observed in 7–29% of people with arterial lesions representing 15% of vascular lesions. Arterial lesions pose a greater risk. Most common arterial lesions are occlusions or stenosis and aneurysms or pseudoaneurysms.

Cause

The cause is not well-defined, but it is primarily characterized by auto-inflammation of the blood vessels. Although sometimes erroneously referred to as a diagnosis of exclusion, the diagnosis can sometimes be reached by pathologic examination of the affected areas.
The primary mechanism of the damage is autoimmune, which by definition is an overactive immune system that targets the patient's own body. The involvement of a subset of T cells seems to be important. The primary cause is not well known. In fact, no one knows yet why the immune system starts to behave this way in Behçet's disease. There does however seem to be a genetic component involved, as first degree relatives of the affected patients are often affected in more than the expected proportion for the general population.
Research suggests that previous infections may provoke the autoimmune responses present in Behçet's disease. Heat shock proteins are present in some bacteria and serve as a "danger signal" to the immune system. However, some HSPs share a similarity in bacteria and humans. The anti-HSP60 and anti-HSP65 antibodies that target HSPs produced by Streptococci and Mycobacterium tuberculosis can also target human HSPs, leading to immune responses linked to uveitis and various symptoms shown in parenchymal neuro-Behçet's disease.
An association with the GIMAP family of genes on the long arm of chromosome 7 has been reported. Gene locations of single-nucleotide polymorphisms associated with Behçet's disease included GIMAP1, GIMAP2 and GIMAP4.

Pathophysiology

Behçet's disease is considered more prevalent in the areas surrounding the old silk trading routes in the Middle East and in Central Asia. Thus, it is sometimes known as Silk Road disease. However, this disease is not restricted to people from these regions. A large number of serological studies show a linkage between the disease and 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 when a certain SUMO4 gene variant is involved, and symptoms appear to be milder when HLA-B27 is present. At the current time, a similar infectious origin has not yet been confirmed that leads to Behçet's disease, but certain strains of S. sanguinis has been found to have a homologous antigenicity.
Vasculitis resulting in occlusion of the vessels supplying the optic nerve may be the cause of acute optic neuropathy and progressive optic atrophy in Behçet's disease. Histological evaluation in a reported case of acute optic neuropathy demonstrated substitution of the axonal portion of the optic nerve with fibrous astrocytes without retinal changes. CNS involvement in Behçet's disease may lead to intracranial hypertension most commonly due to dural venous sinus thrombosis and subsequent secondary optic atrophy.

Diagnosis

There is no specific pathological testing or technique available for the diagnosis of the disease, although the International Study Group criteria for the disease are highly sensitive and specific, involving clinical criteria and a pathergy test. Behçet's disease has a high degree of resemblance to diseases that cause mucocutaneous lesions such as Herpes simplex labialis, and therefore clinical suspicion should be maintained until all the common causes of oral lesions are ruled out from the differential diagnosis.
Visual acuity, or color vision loss with concurrent mucocutaneous lesions or systemic Behçet's disease symptoms should raise suspicion of optic nerve involvement in Behçet's disease and prompt a work-up for Behçet's disease if not previously diagnosed in addition to an ocular work-up. Diagnosis of Behçet's disease is based on clinical findings including oral and genital ulcers, skin lesions such as erythema nodosum, acne, or folliculitis, ocular inflammatory findings and a pathergy reaction. Inflammatory markers such ESR, and CRP may be elevated. A complete ophthalmic examination may include a slit lamp examination, optical coherence tomography to detect nerve loss, visual field examinations, fundoscopic examination to assess optic disc atrophy and retinal disease, fundoscopic angiography, and visual evoked potentials, which may demonstrate increased latency. Optic nerve enhancement may be identified on Magnetic Resonance Imaging in some patients with acute optic neuropathy. However, a normal study does not rule out optic neuropathy. Cerebrospinal fluid analysis may demonstrate elevated protein level with or without pleocytosis. Imaging including angiography may be indicated to identify dural venous sinus thrombosis as a cause of intracranial hypertension and optic atrophy.