MEDICAL SUMMARY OF BEHCET'S DISEASE
Hoffman/Weyand: Inflammatory Disease of Blood Vessels Marcel Dekker, Inc., NY (2001)
Written by Dr. Kenneth Calamia, ABDA Medical Board Member
In 1937, the Turkish dermatologist H. Behcet called attention to the association of oral and genital ulceration with hypopyon-uveitis.1 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.2 The disease is associated with significant morbidity and mortality. Treatment is dependent on the site and severity of manifestations.3
The prevalence of Behcet's Disease is highest in countries of the eastern Mediterranean, the Middle East and the eastern Asian rim. This geographic distribution coincides with the historic "silk road" of commerce and travel between Europe and the Orient. It is postulated that either agents responsible for the disease or the necessary genetic susceptibility traveled with the ancients along this path. Prevalence rates of up to 300 per 100,000 are reported from Turkey4 and are in the range of 13-17 per 100,000 in Japan, Korea, and China. In Europe, rates of 0.5-3 per 100,000 are reported.5,6 The prevalence is much higher in Germans who have Turkish origins,6 but is still only about one-fourth of the rate reported in Turkey. Coupled with very low prevalence rates for Behcet’s Disease in Japanese-Americans, a role for environmental contributions to the disease is suggested. Recent data from Olmsted County, Minnesota, reveal a prevalence rate of 6.6 per 100,0007 suggesting that the disease may be more common in the United States than previously suspected. Prevalence rates in all areas of the world are increasing, likely due to improved disease recognition and reporting.
The disease occurs primarily in young adults. The mean age of onset is between 25 and 30 years.6,8,9 Less than 10% of cases are reported in juveniles.3,6,10 Earlier reports from eastern countries have shown a male predominance in patients with Behcet's disease, but recent reports reflect a male:female ratio much closer to one. In western countries, females predominate.
In high prevalence areas, Behcet's Disease is associated with the HLA-B*5101 allele of HLA-B51, a split product of HLA-B5.11 Clinical features of patients from these areas are more similar than when compared to western patients whose disease has no strong association with HLA antigens.4 Familial Behcet's Disease is uncommon, and no clear pattern of inheritance can be determined in most cases but familial disease was noted in 15% of affected children.10
The International Study Group (ISG) criteria for the diagnosis of Behcet’s disease (Table 1) are weighted heavily in favor of mucocutaneous manifestations.12 The mucocutaneous lesions as well as the pathergy lesion may be varied presentations of the same pathologic process.13 Vasculitis is thought to underlie these lesions, and has been demonstrated in a high percentage of ulcers and skin lesions.14 Vasculitis or the perivascular inflammation seen in Behcet's lesions may be either neutrophilic or lymphocytic, and is thought to reflect the age of the lesions.13 The vasculitis seen in some skin biopsy specimens may be secondary to intense perivascular inflammation.15
| Table I: International Study Group criteria for Behcet's disease12
| Recurrent oral ulceration
||Minor aphthous, major aphthous, or herpetiform ulceration observed by physician or patient, which recurred at least 3 times in one 12-month period*
| Plus 2 of:
| Recurrent genital ulceration
||Aphthous ulceration or scarring, observed by physician or patient*
| Eye lesions
||Anterior uveitis, posterior uveitis, or cells in vitreous on slit lamp examination; or retinal vasculitis observed by ophthalmologist
| Skin lesions
||Erythema nodosum observed by physician or patient, pseudofolliculitis, or papulopustular lesions; or acneiform nodules observed by physician in post-adolescent patients not on corticosteroid treatment*
| Positive pathergy test
||Read by physician at 24-48 h
*(Findings applicable only in absence of other clinical explanations.)
Aphthous oral ulcers are usually the first and most persistent clinical feature (Figure 1). Lesions may be present 50% of the time in some individuals.16 Aphthae occur as 2- to 12-mm discrete, painful, round or oval, red-rimmed lesions. 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.17,18 Complex aphthosis may be a forme fruste of Behcet's disease when another cause is not found.19 The diagnosis of Behcet's disease in these patients requires the presence of other characteristic lesions and exclusion of other systemic disorders,18 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.18 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.20 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.10
The frequency of skin lesions in Behcet’s disease ranges from 41-97%.21 Skin lesions occurred in 64% of Behcet's patients from the United States22 and are often essential to meet diagnostic disease criteria. The ISG criteria12 (Table 1) recognize erythema nodosum, pseudofolliculitis, papulopustular lesions, or acneform 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.23 These lesions are indistinguishable from erythema nodosum associated with other disorders. Nodose lesions should be distinguished from superficial thrombophlebitis. The distinction between acneform 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,13 and biopsies are not often performed. A neutrophilic vascular reaction19 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,21 and more than one type of skin lesion may occur in the same patient.21,24
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.25 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.26 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.22 However, positivity of the test may wax and wane27 and standardization of the test procedure has been lacking.28,29 The outcome of testing is influenced by the diameter of the needle,30 the use of sharp, disposable needles as compared to blunted reusable needles,31 the number of puncture sites, and the use of cleansing antiseptic.32
The ocular finding in Behcet's original patients was that of hypopyon-uveitis1 which may still be found in up to one-third of patients with eye disease.33 While eye disease limited to the anterior chamber does not usually threaten vision,34 hypopyon suggests severe ocular inflammation and a poor visual prognosis. In fully developed Behcet's eye disease, a panuveitis, including posterior uveitis and retinal vasculitis, is usually associated with anterior uveitis and is responsible for the visual loss in these patients. Younger patients and males are at higher risk for ocular involvement.35 Severe eye disease is less common in western countries than in the Middle East or Japan. In Japanese patients, ocular disease is found in about 90% of men, and results in blindness in up to 25% of affected individuals.33 Ocular inflammation in Behcet's typically follows mucocutaneous symptoms by a few years and progresses with a chronic, relapsing course affecting both eyes. Vasculitis leads to episodes of retinal occlusion and areas of ischemia and may be followed by neovascularization, vitreous hemorrhage and contraction, glaucoma, and retinal detachment. The earliest findings of retinal vasculitis may be detected with fluoroscein angiography. It is essential for patients with ocular involvement to be monitored very carefully by an experienced ophthalmologist. Isolated optic disc edema in Behcet's disease suggests cerebral venous thrombosis rather than ocular disease,36 but papillitis may occur with ocular inflammation and central nervous system disease. Occasionally, cranial nerve palsies resulting from brain stem lesions are present and visual field defects may occur with intracranial lesions.37 Rarely, conjunctival aphthous lesions are found.
Major Vessel Involvement
Large vessel involvement in Behcet's disease affects about one-fourth to one-third of patients. The types of major vessel lesions seen are shown in Table 2. Sixty-eight percent of patients with vascular disease in one report had involvement of both arterial and venous systems.38 Major vessel problems and their complications are a significant cause of morbidity and mortality in Behcet's disease and are a major determinant of disease prognosis.39-41
Vascular involvement in Behcet's Disease Systemic arterial vasculitis
Pulmonary arterial vasculitis
- superficial venous thromboses
- deep venous thromboses
- vena cava thromboses
- cerebral venous thromboses
- Budd-Chiari syndrome
- portal vein thrombosis
- right ventricular thrombi
- right ventricular thrombi
- pulmonary emboli
Superficial thrombophlebitis often precedes deep venous disease, and both conditions appear to increase risk for caval thrombosis,38,42,43 as well as for arterial disease.44 Thromboses of superficial veins may occur following venipuncture and have been reported at sites of heparin infusions.45 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,46 and is associated with a high risk of mortality.46,47 Additional thrombotic complications include the Budd-Chiari syndrome,48 and cavernous transformation of the portal vein.49 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.50 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.51 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.44 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.52 Thrombophilia has been implicated in some patients with thrombosis.53 Antiphospholipid antibodies have been reported in some patients, but these do not correlate with thrombosis.54
Arterial complications occur in up to 7% of patients with Behcet's disease.55 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.56 Arterial aneurysms, due to vasculitis of the vasa vasorum,57 primarily involve the aorta, but any large vessel may be affected, and the risk of rupture is high.58 Pulmonary artery vasculitis (Figure 5) with aneurysm formation was found in about 1% of Behcet’s patients in Turkey.44 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.59 However, subclinical cardiac and vascular abnormalities are common if patients are systematically evaluated.60,61
Central Nervous System Disease
In addition to cerebral venous thrombosis, central nervous system symptoms in Behcet's disease may be due to aseptic meningitis or parenchymal lesions, resulting in focal or diffuse brain dysfunction. Aseptic meningitis presents with headache, stiff neck and fever, and is associated with elevated protein and a lymphocytic pleocytosis in the cerebrospinal fluid.62 Focal or multifocal nervous system involvement reflects the predilection of the disease for brain stem and periventricular white matter involvement.63 Diffuse or recurrent disease may result in dementia. Magnetic resonance imaging is more sensitive than computed tomography in demonstrating focal lesions. Although the findings are non-specific, the clinical combination of stroke, aseptic meningitis with CSF pleocytosis, and the presence of mucocutaneous lesions can be diagnostic. Cerebral angiography is usually negative because small vessels are involved, but findings consistent with vasculitis can occasionally be seen.64 MR venography is warranted in patients with papilledema or other symptoms suggesting increased intracranial pressure to rule out venous sinus thrombosis.
Central nervous system disease in Behcet's patients may be more common in European and United States patients, affecting about 30%.65 Involvement was found in about 5% of patients from Turkey,66 and in 3.2% from Iran.4 Isolated headaches in Behet’s patients are common but may represent secondary migraine or be unrelated to the disease. Follow up of a group of headache patients, however, revealed neurologic abnormalities in one-fourth.67
Gastrointestinal disease in Behcet's is much more common in Japanese patients than in patients from other geographic areas.39 Gastrointestinal symptoms include melena or abdominal pain. Lesions consist of single or multiple ulcerative lesions which primarily involve the distal ileum and cecum, but any region can be affected. Gastrointestinal lesions have a tendency to perforate or bleed and may recur after surgery.68,69 Vasculitis has been demonstrated in surgical specimens of operated patients. Lesions should be distinguished from those of Crohn’s disease or those due to the use of non-steroidal antiinflammatory drugs.
Arthritis and Spondylitis
An intermittent, symmetric oligoarthritis of the knees, ankles, hands, and/or wrists, affects 40-70% of patients with Behcet's disease.70-72 Episodes often persist for a few weeks and may not be associated with other clinical manifestations. Synovial fluid analysis reveals inflammatory range white blood cell counts, consisting primarily of polymorphonuclear leukocytes.73 Synovial biopsies reveal superficial neutrophilic infiltration,74 distinct from the lymphocytic synovitis seen in rheumatoid arthritis. A destructive arthropathy is unusual.
Some studies have found an increased frequency of ankylosing spondylitis or radiographic sacroiliitis in patients with Behcet's disease, but others have shown no association.75 HLA-B27 is present in those Behcet's patients with spondyloarthropathy and patients may have inflammatory bowel disease as well.75 Despite the occasional association with spondylitis, Behcet's disease should not be classified as a seronegative spondyloarthropathy.
There have been sporadic reports of glomerulonephritis in Behcet's disease, but renal involvement is seen much less frequently than one might expect in a systemic vasculitis. Peripheral neuropathy is unusual in Behcet's disease.20 Epididymitis occurs in about 5% of affected patients. Amyloidosis of the AA-type can accompany Behcet's disease, usually presenting as nephrotic syndrome. This complication has occurred primarily in Mediterranean patients.76-78 The MAGIC (Mouth And Genital Ulcers with Inflamed Cartilage) syndrome is diagnosed in patients who have features of both Behcet's disease and relapsing polychondritis.79 A generalized myositis can rarely be associated with Behcet's disease.80
There are no laboratory abnormalities that are diagnostic of Behcet's disease. Acute phase reactants may be elevated, especially in patients with large vessel vasculitis, but may be normal with active eye disease. Levels of immune complexes may be elevated in Behet’s disease, but measurements of rheumatoid factor, cryoglobulins, and complement components are usually normal or negative. The histocompatibility antigen HLA-B51 is more common in Behcet's disease patients, than in control subjects, especially in high-prevalence areas and in patients with ocular disease. The absence of an HLA-B51 association in northern caucasoid patients, 49% of whom were found to have HLA-DRB1*04,81 makes HLA testing in these patients unnecessary. Measurement of the T-cell proliferative response to heat shock proteins (HSP) has been proposed for the diagnosis of Behcet's disease82 as was measurement of impaired fibrinolytic activity,52 but the value of testing has not been confirmed.
The ISG criteria for the diagnosis of Behcet's disease (Table 1)12 have been proposed and validated,83 but these criteria were not meant to replace clinical judgement regarding the diagnosis in individual cases. The criteria require the presence of oral ulcerations which may be absent in about 3% of Behcet's patients. In Japan, Korea, and Iran, alternative criteria are applied concurrently by investigators.21,84 For patients in western countries, substitution of large vessel disease or acute central nervous system infarction for missing ISG criteria is acceptable.85 The multiple manifestations of Behcet's disease may not occur simultaneously but may be separated in time, occasionally by several years. For a definitive diagnosis, manifestations must be documented or witnessed by a physician. Acneform lesions should not be attributed to Behcet's disease in an adolescent or in patients taking corticosteriods.12
The differential diagnosis of Behcet's disease includes those conditions which result in complex aphthosis. The prevalence of recurrent aphthous stomatitis is much greater than Behcet's and the diagnosis of "possible Behcet’s" in patients who only have aphthae is inappropriate. In Reiter’s disease, mucocutaneous lesions are nonulcerative and painless. The uveitis is usually limited to the anterior chamber. In addition to gastrointestinal lesions, similarities between Behcet's and Crohn’s disease include fever, anemia, oral ulcers, uveitis, arthritis, thrombophlebitis and erythema nodosum.86 However, granuloma formation in intestinal lesions is not seen in Behcet’s, and in Crohn’s the iritis is typically anterior. Genital ulcerations and central nervous system disease are extremely rare in Crohn’s disease.
For mucocutaneous manifestations, disease activity is recognized and monitored by recording the number, size and location of lesions, and the percentage of time that lesions have been present since the patient’s last visit. Frequent ophthalmologic examinations are necessary for patients with ocular disease and periodic monitoring of the eyes is recommended for patients at risk. A careful history and examination with attention to vascular and neurologic systems should be part of the physician’s assessment. Standardized tools for recording and scoring disease activity have been developed for use in clinical trials as well as for the care of individual patients.87 Validation efforts continue for the Behcet's Disease Current Activity Form88 and for the Iran Behcet's Disease Dynamic Activity Measure,89 both currently in use. Similar assessment tools for ocular disease activity have been devised.87,90
For individual patients in whom systemic symptoms or a particular disease manifestation is paralleled by a nonspecific acute phase response, sequential measurements may be of value. A number of cytokines and markers of vascular inflammation are under investigation as tools for monitoring disease activity.
Elevated levels of von-Willebrand factor91 and thrombomodulin in the serum of Behcet's patients reflect vascular cell injury.92,93 As in other vasculitides, levels of soluble intercellular adhesion molecule-1 (sICAM-1), reflecting endothelial activation, were higher in active Behcet's patients but were not different in patients with and without clinical vascular disease.94
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.95 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.78 The addition of penicillin to colchicine was found to be beneficial in reducing the number of arthritis attacks.96 Interferon- has been used in open studies of Behcet's patients and found to be useful in mucocutaneous lesions and arthritis.97,98 Methotrexate has been effective in the treatment of mucocutaneous disease in a small series.99
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.100 Treatment also had benefits on mucosal ulcers, arthritis, deep-vein thrombosis, and on long-term prognosis.101 Cyclosporin A has been recognized as an effective agent for the control of uveitis,102,103 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.104 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.105
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.62 The toxicity of chlorambucil includes infertility and an increased risk of malignancy.106 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,58 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.107,108 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.55,56
Cerebral venous thrombosis responds well to treatment with heparin and corticosteroids.51 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 corticosteriods109 but others prefer a combination of antiaggregants.48 Portocaval shunting is recommended if the inferior vena cava is patent.109 Successful treatment of right ventricular thrombi has been reported with anticoagulants, corticosteroids, and immunosuppressive agents.110
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.111,112 In mucocutaneous sites, ocular lesions,113 gastrointestinal lesions,114 and in vascular lesions,111 CD4+T cells are the predominant type. Reversal in the ratio of CD4+ / CD8+ cells in the circulation has been found.115 Oligoclonal expansion of T cells with specific V T cell receptors has been found.116 Elevated numbers of T cells have been found in Behcet's patients,117,118 and are found in mucosal lesions.119 These cells possess activation markers and produce inflammatory cytokines during disease exacerbation, but the exact role of T cells in the pathogenesis of Behet’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,120-123 consistent with systemic immune system activation. Mononuclear cells from these patients produce greater amounts of these cytokines ex vivo, when compared to normals.124-127 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.128 Other studies have shown participation of both Th1 and Th2 cells.129 Although circulating immune complexes130 and anti-endothelial antibodies131,132 have been found in Behet’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.133 The use of minocycline reduced symptoms in affected patients.134
Peptides from mycobacterial heat shock protein (HSP)135 and homologous human peptides have been found to specifically stimulate T cells from Behcet's patients.82 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.136
Neutrophilic hyperfunction is recognized in Behcet's disease, in normals with HLA-B51, and in HLA-B51 transgenic mice.137 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.138 However, microsatellite data have also suggested a pathogenic role for genes located between the HLA-B and TNF regions on chromosome number 6.139 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.139 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,140 making MICA, or a closely related gene, a leading candidate gene for the disease.
The clinical manifestations of Behcet's disease are due to a vasculitis which can involve arteries of all sizes and the venous system as well. The disease has a predilection for the small vessels in mucocutaneous sites and in the eyes, but any organ system may be involved. The diagnosis is made on clinical grounds as there are no specific tests for the disease. Clinical, epidemologic and genetic differences exist between patients of varied ethnic backgrounds and from different geographic areas. The morbidity of Behcet's disease comes primarily from ocular involvement and mortality relates primarily to large vessel involvement and central nervous system disease.
In recent years, the development of dedicated Behcet's disease treatment units, collaborative efforts between investigators, biennial international symposia on the disorder, and controlled studies have led to new information on the treatments for the disorder and its pathogenesis. Genetic studies have revealed a strong association with HLA-B51, but the role of this gene in the development of the disease remains uncertain. Evidence exists for neutrophil hyper-reactivity as well as for antigen-driven immune mechanisms in the pathogenesis of the disease.
ARTICLE CONTRIBUTED BY: KENNETH T. CALAMIA, MD, FACP
Kenneth T. Calamia, MD, FACP is board-certified in Internal Medicine and Rheumatology. He is a Consultant in Internal Medicine and Rheumatology at Mayo Clinic, Jacksonville, Florida, with a joint appointment to the Department of Applied Informatics, and is an Associate Professor of Medicine at Mayo Medical School
Dr Calamia is a native of New Orleans, LA. He graduated from medical school from Loyola University in Chicago and did his internship, residency, and fellowship in rheumatology at Mayo Clinic in Rochester, MN. He spent 10 years in private practice in Lafayette, LA before joining the staff of Mayo Clinic, Jacksonville, FL in 1990. Dr. Calamia's research interests include vasculitis, especially Behcet's disease and giant cell arteritis. He has traveled extensively along the silk road to gain experience in the treatment of Behcet’s disease in the middle east. He has contributed numerous original articles, abstracts, and textbook chapters to the medical literature. Dr. Calamia has presented his work at national and international symposia and he has been a reviewer for several peer-reviewed journals.