Behçet's disease

Skin and mucosa Nearly all people with Behçet's disease present with some form of painful ulcerations inside the mouth. 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 (eye) 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 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 Episcleritis may occur, which causes eye redness and mild pain, without a significant impact on vision. Bowels Gastrointestinal (GI) manifestations include abdominal pain, nausea, and diarrhea with or without blood, and they often involve the terminal ileum and ileocecal valve. Although infrequent, myocardial infarction (heart attack) 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 (Th17) 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 (HSPs) 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 (including S. sanguinis and S. pyogenes) 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 ("GTPase of the immunity-associated protein") family of genes on the long arm of chromosome 7 (7q36.1) has been reported. Gene locations of single-nucleotide polymorphisms associated with Behçet's disease included GIMAP1, GIMAP2 and GIMAP4. == Pathophysiology ==

is strongly associated with Behçet's disease 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. No infectious origin has been confirmed to lead to Behçet's disease, but certain strains of S. sanguinis have 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 (MRI) in some patients with acute optic neuropathy. However, a normal study does not rule out optic neuropathy. Cerebrospinal fluid (CSF) 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. Diagnostic guidelines According to the International Study Group guidelines, for a patient to be diagnosed with Behçet's disease, • arthritis/arthralgia • cardio-vascular problems of an inflammatory origin • changes of personality, psychoses • deep vein thrombosis • epididymitis • extreme exhaustion – chronic fatigue • inflammatory problems in chest and lungs • mouth ulcers • nervous system symptoms • problems with hearing or balance • stomach or bowel inflammation • superficial thrombophlebitis • any other members of the family with a diagnosis of Behçet's disease. == Treatment ==

Current treatment is aimed at easing the symptoms, reducing inflammation, and controlling the immune system. The quality of the evidence for treating the oral ulcers associated with Behçet's disease, however, is poor. High-dose corticosteroid therapy is often used for severe disease manifestations. Anti-TNF therapy such as infliximab has shown promise in treating the uveitis associated with the disease. Infliximab as well as other anti-TNF therapies including etanercept and adalimumab may be useful in treating mucocutaneous disease according to several case reports and prospective studies, as well as one randomized trial for etanercept. Apremilast may also be used to treat oral ulcers associated with Behçet's disease. Interferon alpha-2a may also be an effective alternative treatment, particularly for the genital and oral ulcers as well as ocular lesions. Azathioprine, when used in combination with interferon alpha-2b also shows promise, and colchicine can be useful for treating some genital ulcers, erythema nodosum, and arthritis. Benzathine-penicillin may also reduce new arthritic attacks. Thalidomide has also been used due to its immune-modifying effect. Dapsone and rebamipide have been shown, in small studies, to have beneficial results for mucocutaneous lesions. Given its rarity, the optimal treatment for acute optic neuropathy in Behçet's disease has not been established. Early identification and treatment are essential. Response to ciclosporin, periocular triamcinolone, and IV methylprednisolone followed by oral prednisone has been reported although relapses leading to irreversible visual loss may occur even with treatment. or complicated cases. A recent 2024 reports that infliximab improved the likelihood of achieving a complete response at 22 weeks for patients with severe Behçet's syndrome compared to cyclophosphamide, according to head-to-head trial data. Mild to moderate adverse events, primarily infections, were reported in 29.6% of patients on infliximab and 64% on cyclophosphamide. Serious adverse events occurred in 15% and 12% of patients, respectively. Surgery Surgical treatment of arterial manifestations of BD bears many pitfalls since the obliterative endarteritis of vasa vasorum causes thickening of the medial layer and splitting of elastin fibers. Therefore, anastomotic pseudoaneurysms are likely to form, as well as pseudoaneurysms at the site of the puncture in case of angiography or endovascular treatment; furthermore, early graft occlusion may occur. For these reasons, invasive treatment should not be performed in the acute and active phases of the disease when inflammation is at its peak. The evaluation of disease's activity is usually based on relapsing symptoms, ESR (erythrocyte sedimentation rate), and serum levels of CRP (C-reactive protein). Endovascular treatment can be an effective and safe alternative to open surgery, with less postoperative complications, faster recovery time, and reduced need for intensive care, while offering patency rates and procedural success rates comparable with those of surgery. This notwithstanding, long-term results of endovascular treatment in BD are still to be determined. == Epidemiology ==

The syndrome is rare in the United States, Africa and South America, but is common in Asia, suggesting a possible cause endemic to those areas. A theory suggested that past exposure to lethal infectious agents might have fixed the genetic susceptibility factors to Behçet's disease in those areas. 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. In an epidemiologic study, 56 percent of patients with Behçet's disease developed ocular involvement at a mean age of 30. Ocular involvement was the first manifestation of Behçet's disease in 8.6 percent of patients. Ocular Behçet's disease with involvement of the optic nerve is rarely reported. Among patients with ocular Behçet's disease funduscopic findings of optic atrophy, and optic disc paleness have been identified with a frequency of 17.9 percent and 7.4 percent, respectively. Other fundoscopic findings include vascular sheathing (23.7%), retinal hemorrhage (9%), macular edema (11.3%), branch retinal vein occlusion (5.8%), and retinal edema (6.6%). However, optic atrophy was the most significant cause of visual impairment identified in 54 percent of patients with ocular Behçet's disease and permanent visual impairment. == Pregnancy ==

With Behçet's disease as a pre-existing disease in pregnancy or acquired, the pregnancy does not have an adverse effect on the course of Behçet's disease and may possibly ameliorate its course. Still, there is a substantial variability in clinical course between patients and even for different pregnancies in the same patient. == History ==

The first modern formal description of the symptoms was made by H.Planner and F.Remenovsky and published in 1922 in the Archiv für Dermatologie und Syphilis. 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 Epidemion (book 3, case 7). Some sources use the term "Adamantiades's syndrome" or "Adamantiades–Behçet syndrome", for the work done by Benediktos Adamantiades. However, the current World Health Organization/ICD-10 standard is "Behçet's disease". In 1991, Saudi Arabian medical researchers described neuro-Behçet's disease, a neurological involvement in Behçet's disease, considered one of the most devastating manifestations of the disease. The mechanism can be immune-mediated or thrombotic. The term dates back to at least 1990. == References ==