Medical Summary of Behcet's Disease

In 1937 the Turkish dermatologist Hulusi Behcet called attention to the association of oral and genital ulcerations with hypopyon-uveitis. Since then, Behcet’s Disease has become associated with a number of additional clinical manifestations, each attributed to an underlying vasculitis. Vessels of all sizes may be affected. The most typical clinical lesions are mucocutaneous, reflecting involvement of small vessels, but inflammation of the aorta and its branches and veins of all calibers is also possible. The disease is recognized worldwide, but there are significant differences in the epidemiological, genetic and clinical characteristics of the disorder between ethnic groups and in different geographic locations. As there are no specific manifestations nor specific diagnostic tests, the term "Behcet’s Syndrome" is preferred by some authors, especially for patients from low-prevalence areas whose disease manifestations are generally less severe and possibly due to other underlying conditions. The disease is associated with significant morbidity and mortality. Treatment is dependent on the site and severity of manifestations.

*(Findings applicable only in absence of other clinical explanations.)

Apthous oral ulcers are generally the first most persistent lesion. Lesions may be present 50% of the time in some individuals. Aphthae occur as 2mm to 12 mm discrete, painful, round or oval, red-rimmed lesions. (Figure 1). The non-keratinized mucosa of the cheeks, tongue, palate, and pharynx is mostly affected, whereas the well-keratinized hard palate is less involved. Oral ulcers are identical to the lesions of recurrent aphthous stomatitis, but six or more ulcers, variable in size, with surrounding erythema, and with involvement of the soft palate and oropharynx should increase the suspicion for Behcet's associated lesions. The severity and behavior of the oral ulcers in Behcet's Disease often fits the description of "complex aphthosis" in which multiple, recurrent, or persisting lesions result in a severe syndrome which may include perianal or genital ulceration. Complex aphthosis may be a forme fruste of Behcet's Disease when another cause is not found. The diagnosis of Behcet's Disease in these patients requires the presence of other characteristic lesions and exclusion of other systemic disorders, most notably sprue, hematologic disorders, herpes simplex infection, inflammatory bowel disease, cyclic neutropenia and acquired immune deficiency syndrome. Other disorders responsible for oral-genital ulcerative syndromes include the hypereosinophilic syndrome and myelodysplasia. Lesions in Stevens-Johnson syndrome, lichen planus, pemphigus, or cicatricial pemphigoid are not aphthous in character. The differential diagnosis can be clarified with the aid of an experienced dermatologist and biopsy.

Genital ulcers, resembling oral aphthae, occur on the vulva and vagina in females and on the scrotum or penis in males. Vulvar lesions are painful and may result in scarring, but vaginal ulcers may be asymptomatic or result in a discharge. Scrotal lesions may be superficial or deep, and may heal with scarring. Genital ulcers are single or multiple and typically occur two to four times a year. Perianal ulcers have been found in 7% of children with Behcet's disease.The frequency of skin lesions in Behcet’s Disease ranges from 41-97%. Skin lesions occurred in 64% of Behcet's patients from the United States and are often essential to meet diagnostic disease criteria. The ISG Criteria (Table 1) recognize erythema nodosum, pseudofolliculitis, papulopustular lesions, or acneiform nodules for the diagnosis. Histopathologic findings in lesions of erythema nodosum are those of a septal and lobular panniculitis and may include a lymphocytic vasculitis. These lesions are indistinguishable from erythema nodosum associated with other disorders. Nodose lesions should be distinguished from superficial thrombophlebitis. The distinction between acneiform and papulopustular lesions is unclear, but the term "pseudofolliculitis" separates these lesions from follicle-based eruptions. However, distinction of these lesions on clinical examination is not reliable, and biopsies are not often performed. A neutrophilic vascular reaction characterizes typical Behcet's lesions, but the pathology is not specific for the disease. Occasionally intense neutrophilic inflammation results in lesions of Sweet’s syndrome. Pyoderma gangrenosum-like lesions or cutaneous aphthosis may also occur, and more than one type of skin lesion may occur in the same patient.

Pathergy, an excessive skin response to trauma, has been considered a unique manifestation of Behcet's Disease, reflecting neutrophil hyperreactivity. The phenomenon can also be demonstrated in patients with chronic myelogenous leukemia. Pathergy testing is performed by inserting a sterile 20-gauge needle at a 45-degree angle into the skin and subcutaneous tissue of the volar forearm to a depth of 1 cm. An erythematous papule or pustule (>2 mm in diameter) at the puncture site after 48 hours constitutes a positive test. Pathergy equivalents in the form of sterile abscesses or pustules after therapeutic injections or skin trauma may occur. The pathergy test is less likely to be positive in Behcet's patients from North America and European countries than in Turkish patients. Nonetheless, a positive pathergy test was found in 6 of 18 patients tested from the United States, suggesting that the test may be underutilized in western countries. However, positivity of the test may wax and wane and standardization of the test procedure has been lacking. The outcome of testing is influenced by the diameter of the needle, the use of sharp, disposable needles as compared to blunted reusable needles, the number of puncture sites, and the use of cleansing antiseptic.

aneurysms
occlusions

aneurysms
occlusions

superficial venous thromboses
deep venous thromboses
vena cava thromboses
cerebral venous thromboses
Budd-Chiari syndrome
portal vein thrombosis
right ventricular thrombi
pulmonary emboli

Superficial thrombophlebitis often precedes deep venous disease, and both conditions appear to increase risk for caval thrombosis, as well as for arterial disease. Thromboses of superficial veins may occur following venipuncture and have been reported at sites of heparin infusions. Deep venous thrombosis is the most common large vascular lesion. It occurs primarily in the lower extremities, but involvement is possible at any site. Vena cava occlusion is a commonly recognized thrombotic complication in Behcet's Disease, and is associated with a high risk of mortality. Additional thrombotic complications include the Budd-Chiari syndrome, and cavernous transformation of the portal vein. Chest wall, abdominal, and esophageal varices may occur as a consequence of deep-seated venous thrombosis. Right ventricular thrombi have been reported in Behcet's Disease, usually associated with pulmonary vasculitis. With cerebral venous thrombosis, patients usually present with symptoms associated with elevated intracranial pressure, including headache and visual obscurations with papilledema. Focal deficits, seizures, and altered consciousness may also occur. Magnetic resonance (MR) imaging may be used to demonstrate acute or recent clot in the larger dural sinuses (Figure 2). Magnetic resonance angiography (MRA) provides more reliable imaging of the cerebral venous system, especially of the smaller veins and if thromboses are older. Two-dimensional (Figure 3) and three-dimensional phase contrast MRAs allow imaging of the cerebral veins without administration of contrast.

In spite of the frequency of venous thrombosis, there is a conspicuous rarity of pulmonary emboli in patients within Behcet's Disease. This supports histologic evidence that the vascular wall itself is a major factor in the process of thrombosis in Behcet's Disease, resulting in an adherent thrombus. In some cases, however, venous thrombosis may be recurrent and progressive, in spite of treatment with anticoagulants and can result in life threatening emboli. All of the factors contributing to venous thrombosis in Behcet's Disease are not known. Inflammation of the venous endothelium is present. There have been no consistent primary abnormalities of the coagulation, anticoagulation, or fibrinolytic systems yet identified, although some evidence exists for impaired fibrinolysis. Thrombophilia has been implicated in some patients with thrombosis. Antiphospholipid antibodies have been reported in some patients, but these do not correlate with thrombosis.

Arterial complications occur in up to 7% of patients with Behcet's Disease. Arterial lesions may be seen in the systemic circulation as well as in the pulmonary arterial bed (Figure 4). In either location stenoses, occlusions, and aneurysms may result and frequently coexist. Isolated occlusions or stenosis may be asymptomatic or associated with ischemic symptoms, depending upon the adequacy of the collateral circulation. Arterial aneurysms, due to vasculitis of the vasa vasorum, primarily involve the aorta, but any large vessel may be affected, and the risk of rupture is high. Pulmonary artery vasculitis (Figure 5) with aneurysm formation was found in about 1% of Behcet’s patients in Turkey. Patients usually present with hemoptysis due to pulmonary artery-bronchial fistula. Hemoptysis may be massive and threaten life. As venous thrombosis often coexists with pulmonary artery-bronchial fistulae, it is extremely important to distinguish these patients from those with hemoptysis due to pulmonary emboli so that anticoagulant treatment is not initiated.

Clinically apparent cardiac vascular involvement is unusual, but may result in myocardial infarction. However, subclinical cardiac and vascular abnormalities are common if patients are systematically evaluated.

Certainty in the treatment of Behcet's disease is limited by the lack of controlled studies. Treatment practices may reflect the experience and biases of clinicians from different geographic areas. Aphthous lesions are treated with topical or intralesional corticosteriods but results are frequently disappointing. Dapsone can also be used to suppress mucocutaneous lesions. A controlled study, limited to male patients, demonstrated the value of thalidomide for the prevention and treatment of mucosal and follicular lesions. Colchicine is widely used in the treatment of mucocutaneous manifestations and as an adjunct in the treatment of more serious manifestations but proof of its effectiveness in one controlled study was limited to improvement in erythema nodosum. The addition of penicillin to colchicine was found to be beneficial in reducing the number of arthritis attacks. Interferon has been used in open studies of Behcet's patients and found to be useful in mucocutaneous lesions and arthritis. Methotrexate has been effective in the treatment of mucocutaneous disease in a small series.

In general, younger male patients are at greatest risk for severe disease, especially uveitis, warranting expectant and aggressive treatment. A controlled study has demonstrated the value of azathioprine at a dose of 2.5 mg / kilogram / day in limiting the progression of ocular disease and preventing new eye disease in male patients. Treatment also had benefits on mucosal ulcers, arthritis, deep-vein thrombosis, and on long-term prognosis. Cyclosporin A has been recognized as an effective agent for the control of uveitis, but the long-term benefits of the drug is less certain. Combination treatment with Cyclosporin A and azathioprine has been used when single agents fail. In an open trial, interferon- was highly effective in the control of eye disease in seven patients with early ocular disease or with limited damage.

Corticosteriods are useful in suppression of inflammation in acute phases of the disease but these agents do not consistently suppress mucosal ulcers or central nervous system disease, and do not appear to prevent blindness in Behcet's patients with posterior uveitis or retinal vasculitis. Immunosuppression with cyclophosphamide or chlorambucil is used for uncontrolled ocular disease, central nervous system disease, and large vessel vasculitis including recurrent deep venous thrombosis. The mucocutaneous disease also improves. We favor the use of chlorambucil in these settings based on our positive experience with the use of this agent. The toxicity of chlorambucil includes infertility and an increased risk of malignancy. Chlorambucil is more lipophilic than cyclophosphamide, giving it a theoretical advantage in the treatment of central nervous system disease.

Surgery is usually indicated for the treatment of systemic arterial aneurysms because of the risk of rupture, but isolated arterial occlusions may be asymptomatic and not require operation. Pulmonary arterial aneurysms with uncontrolled bleeding require surgery. Percutaneous embolization techniques have been reported to thrombose these lesions. Arterial vasculitis resulting in aneurysms of the systemic or pulmonary circulations should be treated with alkalating agents. If surgery is required, these agents are also necessary to minimize the high risk of anastomotic recurrences or continued disease.

Cerebral venous thrombosis responds well to treatment with heparin and corticosteroids. Venous thrombosis may be progressive or recurrent in spite of warfarin treatment. As inflammation underlies the thrombosis, corticosteroids and immunosuppressive agents should be considered in these cases. The treatment of the Budd-Chiari syndrome has included anticoagulants, colchicine and corticosteriods but others prefer a combination of antiaggregants. Portocaval shunting is recommended if the inferior vena cava is patent. Successful treatment of right ventricular thrombi has been reported with anticoagulants, corticosteroids, and immunosuppressive agents.

Clues to the pathogenesis of Behcet's disease come from analysis of the cellular infiltrates from inflammatory lesions as well as from circulating immune cell types and cytokine patterns. While neutrophilic vascular lesions are characteristic on biopsies of established lesions at mucocutaneous sites, perivascular mononuclear cells dominate in early lesions. in mucocutaneous sites, ocular lesions, gastrointestinal lesions, and in vascular lesions, CD4+T cells are the predominant type. Reversal in the ratio of CD4+ / CD8+ cells in the circulation has been found. Oligoclonal expansion of T cells with specific V T cell receptors has been found. Elevated numbers of T cells have been found in Behcet's patients, and are found in mucosal lesions. These cells possess activation markers and produce inflammatory cytokines during disease exacerbation, but the exact role of T cells in the pathogenesis of Behcet’s disease remains uncertain.

Interleukin-8, a chemokine responsible for neutrophilic activation, is elevated in the serum of Behcet's patients. Elevated levels of other proinflammatory cytokines, including IL-1, IL-6, INF-, IL-12, TNF, as well as sIL-2R, have been reported in Behcet's patients, consistent with systemic immune system activation. Mononuclear cells from these patients produce greater amounts of these cytokines ex vivo, when compared to normals. However, cytokine studies have not yet led to clinically useful measures of disease activity.

Cytokine analysis and cellular characterization suggest a Th1 response by lymphocytes in Behcet's disease. Other studies have shown participation of both Th1 and Th2 cells. Although circulating immune complexes and anti-endothelial antibodies have been found in Behcet’s patients, there is little evidence for a contribution of B cell hyperactivity in Behcet's disease.

Extrinsic agents have been suspected to trigger autoimmunity in Behcet's disease. Molecular techniques have identified Herpes Simplex viral RNA and DNA in cells from Behcet's patients. Streptococcal antigens are suspected to trigger disease activity. The use of minocycline reduced symptoms in affected patients.

Peptides from mycobacterial heat shock protein (HSP) and homologous human peptides have been found to specifically stimulate T cells from Behcet's patients. It is postulated that cross reactivity and molecular mimicry between peptides from streptococcal and/or viral HSP, homologous human HSP, and mucosal antigens result in selection of autoreactive T cells.

Neutrophilic hyperfunction is recognized in Behcet's disease, in normals with HLA-B51, and in HLA-B51 transgenic mice. It remains uncertain if this association is due to antigen interaction with HLA, another effect of the molecule, or to genes in linkage disequilibrium with HLA-B51. The disease associated HLA-B*51 and the closely related but disease-unassociated HLA-B52 molecules differ in two amino acid positions located in an antigen-binding pocket of the HLA groove. This suggests a direct role of the HLA-molecule itself in the susceptibility to Behcet's disease, and implies a role for extrinsic agents. However, microsatellite data have also suggested a pathogenic role for genes located between the HLA-B and TNF regions on chromosome number 6. This region contains the MICA gene (Major Histocompatibility Complex Class I chain-related gene A), whose cell surface product is preferentially expressed on fibroblasts and endothelial cells. These gene products may have a role in the presentation of antigen to NK cells or to T cells. Analysis of triplet repeat polymorphisms of the MICA gene revealed an association of the A6 allele with Behcet's disease in Japanese patients which is greater than that of HLA-B5.11 These findings were also demonstrated in Caucasian patients, making MICA, or a closely related gene, a leading candidate gene for the disease.

Medical Summary of Behcet's Disease

Clinial Features of Behcet's Disease

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