Introduction

Background
Behet disease (BD) was named in 1937 after the Turkish dermatologist Hulusi Behet, who first described the triplesymptom complex of recurrent oral aphthous ulcers, genital ulcers, anduveitis.1 Behet disease is a complex, multisystemic disease that includes involvement of the mucocutaneous, ocular, cardiovascular, renal, gastrointestinal, pulmonary, urologic, and central nervous systems and the joints, blood vessels, and lungs. Behet disease is characterized by oral aphthae and by at least 2 of the following: (1) genital aphthae, (2) synovitis, (3) posterior uveitis, (4) cutaneous pustular vasculitis, (5) meningoencephalitis, (6) recurrent genital ulcers, and (7) uveitis in the absence of inflammatory bowel disease or collagen-vascular disease.

Pathophysiology
The cause of Behet disease is not known; however, immunogenetics, immune regulation, vascular abnormalities, or bacterial and viral infection may have a role in its development.

Frequency
United States

Behet disease is not common in the United States, with a prevalence of 5 cases per 100,000 persons.
International

Behet disease is most prevalent (and more virulent) in the Mediterranean region, Middle East, and Far East, with an estimated prevalence of 1 case per 10,000 persons.

Mortality/Morbidity
Chronic morbidity is typical; the leading cause is ophthalmic involvement, which can result in blindness. The effects of the disease may be cumulative, especially with neurologic, vascular, and ocular involvement. The mortality rate is low, but death can occur from neurologic involvement, vascular disease, bowel perforation, cardiopulmonary disease, or as a complication of immunosuppressive therapy. 2

Sex
Men are affected more often, and with more severe disease, than women in some Mediterranean areas. In Iran, for example, the male-to-female ratio was 24:1 among 1712 patients. In Turkey, the ratio was 16:1 among 427 patients.

Age
Onset can occur at any age, but is it most common during the third decade of life. 3

Clinical
History
Signs and symptoms of Behet disease, which may be recurrent, may precede the onset of the mucosal membrane ulcerations by 6 months to 5 years.

Prior to the onset of Behet disease, patients may experience a variety of symptoms. o Malaise o Anorexia o Weight loss o Generalized weakness o Headache o Perspiration o Decreased or elevated temperature o Lymphadenopathy o Pain of the substernal and temporal regions A history of repeated sore throats, tonsillitis, myalgias, and migratory erythralgias without overt arthritis is common. A diagnosis of Behet disease is based on clinical criteria because of the absence of a pathognomonic laboratory test. The period between the appearance of an initial symptom and a major or minor secondary manifestation can be up to a decade in many cases. The number of different criteria or classification systems that have been introduced over the past 25 years reflects the failure of any single one to meet clinical demands. The revised 1987 criteria of the Japanese group (Mizushima) have been widely applied.4 More recently, the diagnostic criteria of the International Study Group for Behet Disease have been applied to establish a firmer diagnosis.5 The major limitation of these criteria is the fact that recurrent oral ulceration is the characteristic symptom for the diagnosis of Behet disease. For example, patients with uveitis and genital ulcers, without oral aphthosis, would not be considered to have Behet disease, although this is, in fact, a far-advanced form of the disease. Therefore, the authors recommend that both sets of criteria be applied concurrently until a more exact system is devised. Diagnostic criteria from the Behet syndrome research committee of Japan (1987 revision) are as follows 4 : o Major features Recurrent aphthous ulceration of the oral mucous membrane Skin lesions -Erythema nodosum like lesions, subcutaneous thrombophlebitis, folliculitis (acnelike lesions), cutaneous hypersensitivity Eye lesions - Iridocyclitis, chorioretinitis, retinouveitis, definite history of chorioretinitis or retinouveitis Genital ulcers o Minor features Arthritis without deformity and ankylosis Gastrointestinal lesions characterized by ileocecal ulcers Epididymitis Vascular lesions Central nervous system symptoms o Diagnosis Complete - Four major features Incomplete - (1) 3 major features, (2) 2 major and 2 minor features, or (3) typical ocular symptom and 1 major or 2 minor features Possible - (1) 2 major features or (2) 1 major and 2 minor features

International criteria for the classification of Behet disease (1990) are as follows 5 : o Recurrent oral ulceration - Minor aphthous or major aphthous or herpetiform ulceration observed by a physician or reported reliably by a patient that recurs at least 3 times in one 12-month period plus 2 of the following: Recurrent genital ulceration - Recurrent genital aphthous ulceration or scarring, especially males, observed by a physician or reliably reported by a patient Eye lesions - (1) Anterior uveitis, posterior uveitis, and cells in vitreous upon slit-lamp examination or (2) retinal vasculitis observed by physician (ophthalmologist) Skin lesions - (1) Erythema nodosumlike lesions observed by physician or reliably reported by a patient, pseudofolliculitis, and papulopustular lesions or (2) acneiform nodules consistent with Behet disease, observed by a physician, and in postadolescent patients not receiving corticosteroids Positive pathergy test - An erythematous papule larger than 2 mm at the prick site 48 hours after the application of a 20- to 22-gauge sterile needle, which obliquely penetrated avascular skin to a depth of 5 mm as read by a physician at 48 hours Findings are applicable if no other clinical explanation is present.

Physical
Oral ulcers Oral aphthae that occur in patients with Behet disease are indistinguishable from common aphthae (canker sores). Aphthae may be more extensive, more painful, more frequent, and evolve quickly from a pinpoint flat ulcer to a large sore. Lesions can be shallow or deep (2-30 mm in diameter) and usually have a central, yellowish, necrotic base and a punched-out, clean margin. They can appear singly or in crops, are located anywhere in the oral cavity, persist for 1-2 weeks, and subside without leaving scars. The most common sites are the tongue, lips, buccal mucosa, and gingiva; the tonsils, palate, and pharynx are less common sites. The interval between recurrences ranges from weeks to months. Oral ulcers can be classified into the following 3 types: Minor ulcer: This consists of 1-5 small, moderately painful ulcers persisting for 4-14 days (see the image below).

Minor aphthous ulcer.

Major ulcer: This is 1-10 very painful ulcers, measuring 10-30 mm, persisting up to 6 weeks, and possibly leaving a scar upon healing (see the image below).

Major aphthous ulcer.

Herpetiform ulcer: This is a recurrent crop of as many as 1000 small and painful ulcers (see the image below).

Herpetiform oral ulcer.

Genital manifestations Genital ulcers resemble their oral counterparts but may cause greater scarring. They have been found in 56.7-97% of cases, but their appearance is mostly a secondary symptom that accompanies oral ulcers. In males, the ulcers usually occur on the scrotum (see the image below), penis, and groin.

A characteristic genital ulcer on scrotum.

In females, they occur on the vulva (see the image below), vagina, groin, and cervix.

A single ulcer on vulva.

Ulcers have also been found in the urethral orifice and perianal area. Epididymitis may arise and is a minor diagnostic criterion for the disease according to the Behet Disease Research Committee of Japan. An additional genital symptom is orchiepididymitis, observed in 10.8% of men.

Cutaneous manifestations A variety of skin lesions may appear in patients with Behet disease (58.6-97%), including the following:

Erythema nodosum like lesions, which are most common (see the image below)

Erythema nodosumlike lesions on skin.

Papulopustular eruptions (see the image below)

Papulopustular eruptions.

Erythema multiformelike lesions Thrombophlebitis Ulcers Lesions resembling Sweet syndrome (see the image below)

Sweet syndromelike lesion.

Bullous necrotizing vasculitis Pyoderma gangrenosum

Nonspecific skin inflammatory reactivity to any scratches or intradermal saline injection is a common and specific manifestation of these lesions, ie, pathergy (see the image below).

Typical positive pathergy reaction at injection site.

Lesions often occur in combination (eg, erythema nodosumlike lesions and papulopustular eruptions). Follicle-based

pustules or acne lesions are not considered specific lesions of Behet disease. Ocular manifestations Ocular involvement is the major cause of morbidity and the most dreaded complication because it occasionally progresses rapidly to blindness. It is reported in 47-65% of patients with Behet disease. Childhood-onset Behet uveitis is more common in males.6 The most diagnostically relevant lesion is posterior uveitis, ie, retinal vasculitis (see the image below). Other lesions include anterior uveitis, iridocyclitis, chorioretinitis, scleritis, keratitis, vitreous hemorrhage, optic neuritis, conjunctivitis, retinal vein occlusion, and retinal neovascularization. Hypopyon, which was considered the hallmark of Behet disease, is now uncommon.

Ocular involvement showing posterior uveitis.

Eye disease is usually present from the outset but also may develop within the first few years. Decreased visual acuity is a result of secondary glaucoma, cataracts, or vitreous hemorrhage. Blindness has been reported to occur within 4-5 years from the onset of ocular symptoms. Retinal vein thrombosis leading to sudden blindness is not rare. Saadoun et al found that cerebral venous thrombosis (CVT) was present in 7.8% of a large cohort of patients with Behet disease. The main complication of CVT was severe visual loss from optic atrophy. Papilledema and concurrent prothrombotic risk factors were independently associated with the occurrence of sequelae; peripheral venous thrombosis and concurrent prothrombotic risk factors were associated with relapse of thrombosis. Anticoagulant therapy proved safe and effective in up to 90% of patients. 7 Vascular involvement Vascular involvement8 occurs in 7-29% of patients, mostly men. Histologic findings include media thickening, elastic fiber splitting, and perivascular round cell infiltration. The 4 types of vascular lesions recognized in persons with Behet disease are arterial occlusions, venous occlusions, aneurysms, and varices. Venous involvement is usually limited to occlusion, with the varices rarely affected. Affected sites of the venous system are the superior vena cava, inferior vena cava, deep femoral vein, and subclavian vein. Arterial complications account for 7% of cases. Aneurysm and occlusion are most common. The subclavian artery and pulmonary artery are the most common arteries occluded. Depending on the site, arterial occlusions can have different clinical presentations. Pulseless disease is due to subclavian artery occlusion. Hypertension can originate from renal artery stenosis. Femoral artery stenosis and intermittent claudication cause avascular necrosis of the femoral head. Pulmonary vasculitis can produce dyspnea, chest pain, cough, or hemoptysis. Aneurysm formation accounts for most vascular deaths. Common sites of aneurysms are the abdominal aorta, femoral artery, and thoracic artery. Because the vascular involvement of Behet disease can be significant and life-threatening, diagnosing and treating vascular involvement early is vital.

Gastrointestinal involvement The clinical spectrum of gastrointestinal effects9 is enormously varied and occurs in more than 10% of patients with Behet disease. Anorexia, vomiting, dyspepsia, diarrhea, abdominal distention, and abdominal pain all may occur. Joint manifestations More than half the patients develop signs or symptoms of synovitis, arthritis, and/or arthralgia during the course of the disease.10 The most frequent minor feature in childhood-onset Behet disease is reported to be arthritis, occurring in 11 of 40 patients. Multiple-joint involvement is common. Clinical features have been reported as pain, tenderness, swelling, limitation of joint movement, warmth, and morning stiffness. Neurologic manifestations The rate of neurologic involvement in persons with Behet disease varies from 3.2-49% according to the reports of different populations. Neurologic involvement may present (in various combinations) as meningoencephalitis, a multiple sclerosislike illness, acute myelitis, stroke, or pseudotumor cerebri. Three categories of neurologic involvement are (1) brain stem syndrome, (2) meningomyelitis syndrome, and (3) organic confusional syndrome. Neurologic involvement is one of the most serious complications, leading to severe disability and a high fatality rate. Neurologic manifestations usually occur within 5 years of disease onset. Severe headache is the most frequent initial neurological symptom. Pregnancy-associated manifestations Pregnant women with Behet disease may experience more severe symptoms during the course of the pregnancy, especially in the first trimester. Overall, pregnancy does not seem to markedly affect the course of Behet disease.11 Close follow-up is necessary to monitor the health of the mother and baby. Other organ manifestations Myocarditis and cardiac vessel disease may occur. Major hemoptysis may result from pulmonary vascular thrombosis, aneurysms, or vasculitis. Cases with renal involvement, such as mild asymptomatic glomerulonephritis, have also been reported. However, most patients have been asymptomatic. 12 Pathergy (skin hyperreactivity) The presence of pathergy strongly suggests the diagnosis of Behet disease. Following a needle prick or intradermal injection with saline or dilute histamine, the puncture site becomes inflamed and develops a small sterile pustule from hyperactivity of the skin to any intracutaneous insult. The pustular reaction of the skin is thought to denote increased neutrophil chemotaxis. Higher positivity (84-98%) is found in Mediterranean areas and the Middle East than in the Far East (40-70%), with Western countries having significantly lower positivity than the other regions.

Causes

Immunogenetics13 o HLA-B51 or its B101 allele is significantly associated with Behet disease in Japan, Korea, Turkey, and France and with ocular manifestations in Britain. Although HLA-B51 transgenic mice do not develop any manifestations of Behet disease, their neutrophils show excessive function.

The MICA allele is a polymorphic MHC class Irelated A gene (MICA) family. The MICA6 allele has recently been shown to be significantly associated with Behet disease (74%), compared with controls (45.6%) in Japan. The relationship between MICA6 and Behet disease was confirmed in France. The MICA6allele is thought to be in linkage disequilibrium with HLA-B51; consequently, the search for genes related to Behet disease continues. A recent study of 23 Japanese patients showed that the MICA6 allele had no significant association with Behet disease, but it showed a strong association with HLA-B51; therefore, the association between MICA6 and Behet disease may be a secondary phenomenon related to HLAB5114 o MEFV gene mutations, seen in persons with Mediterranean fever, are increased in persons with Behet disease. This mutation has been associated with vascular Behet disease.15,16 o Levels of tumor necrosis factor-alpha (TNF-alpha) have been reported to be significantly elevated in Behet disease patients; thus, reports of TNF-alpha blockers having therapeutic benefits have been reported. Park et al analyzed TNF-alpha haplotypes in the promoter response element that affect the binding affinity of certain transcription factors. Their study showed that TNF-alpha 1031*C, -863*A, -857*C, and -308*G alleles were significantly associated with Behet disease. TNF-alpha haplotypes in the promoter response elements may be useful in identifying those more susceptible to Behet disease.17 o Single nucleotide polymorphism (SNP) of the gene encoding protein tyrosine phosphatase type 22 (PTPN22 620W) has been strongly genetically linked to human autoimmune diseases; however, an inverse relationship exists between Behet disease and this gene.18 Viral and bacterial infection o Investigations of the etiology of Behet disease have focused predominantly on herpes simplex virus infection, streptococcal infection, and autoimmunity or cross-reactivity between microbial and oral mucosal antigens. o Behet suggested the herpes simplex virus as a causative agent in his first report. Polymerase chain reaction studies have remarkably improved the diagnostic significance of viral infections, especially herpes simplex virus. Herpes simplex virus DNA has been detected in saliva, genital ulcers, and intestinal ulcers of patients with Behet disease. Behet disease like symptoms have been induced in an Institute for Cancer Research mouse after inoculation of herpes simplex virus into its earlobe.19 o Acquired hypersensitivity to streptococcal antigens plays an important role in the etiopathology of Behet disease. o The multiplicity of etiologic factors may have a common denominator in the 65-kd microbial heat shock protein (HSP), which shows significant homology with the human 60-kd mitochondrial HSP. Indeed, the uncommon serotypes of Streptococcus sanguis found in Behet disease cross-react with the 65-kd HSP, which also shares antigenicity with an oral mucosal antigen. o T-cell epitope mapping has identified 4 peptides derived from the sequence of the 65-kd HSP that specifically stimulates T-cell receptor (TCR+) lymphocytes from patients with Behet disease. These peptides (111-125, 154-172, 219-233, and 311-325) show significant homology with the corresponding peptides (136-150, 179-197, 244-258, 336-351) derived from the human 60-kd HSP. B-cell epitopes within mycobacterial HSP65 or human HSP60 overlap with the T-cell epitopes, and both immunoglobulin G and immunoglobulin A antibodies have been identified. Among the 4 T- and B-cell epitopes, peptide 336-351 of the 60-kd HSP is significantly associated with Behet disease in Britain, Japan, and Turkey. HSP60/65 was also found to be significantly increased in the epidermal cells of Behet disease skin lesions, and antibody levels to HSP65 were significantly elevated in the cerebrospinal fluid from patients with neurological manifestations of Behet disease.

An experimental model of Behet disease uveitis was established in rats, in which subcutaneous immunization with peptide 336-351 and adjuvants elicited uveitis in approximately 80% of Lewis rats. Furthermore, a mucosal model of induction of uveitis was developed in rats by oral or nasal administration of peptide 336-351 without an adjuvant, and this is consistent with the oral onset of ulceration in more than 90% of patients with Behet disease.

Immunological abnormalities o In persons with Behet disease, the Th1 cytokine interferon (IFN) level is elevated in serum, in skin T cells, and cerebrospinal fluid, and interleukin (IL) 12 is generated by the stimulation of CD4+ T cells with the HSP peptide 336-351, although IL-12 can also be secreted by neutrophils in persons with Behet disease. However, the concentration of the Th2 cytokine IL-6 is also increased in the serum of patients with Behet disease, especially in the active stage, as was also found with IL-10 upon stimulation of the peripheral blood mononuclear cell. o Stimulation with S sanguis (KTH-1) of T-cell lines generated from patients with Behet disease suggests that Th1-type mRNA is induced (IL-2 and IFN). o Investigations of intracellular IFN and IL-4 suggest that polarization toward the Th1 type of cells occurs in patients with active Behet disease because of a significant increase in the intracellular IFN that was not observed with IL-4. However, the converse was found in another investigation by stimulating peripheral blood mononuclear cells, with increased Th2 cytokines (IL-10 and decreased IL-2 or IFN) in active Behet disease. o The intracellular adhesion molecule 1 was enhanced in human dermal microvascular endothelial cells after treatment with serum from patients with Behet disease, and this may have induced increased adhesion of T cells to the endothelial cells. o Levels of the proinflammatory cytokines tumor necrosis factor (TNF)alpha, TNF receptor 1, IL-1, and IL-8 are elevated in the serum of persons with Behet disease and remain unregulated in peripheral blood mononuclear cells and neutrophils of patients with Behet disease. 20 Levels of IL10 and IL-13 may also be elevated.21 o IL-23 p19 mRNA has been detected in erythema nodosum-like lesions of Behet's disease. This finding suggests that anti IL-23 therapy may be an option for treatment.22 o Plasma levels of vascular endothelial growth factor, a proinflammatory cytokine, is significantly higher in persons with active Behet disease. 23 o Neopterin is produced by human monocytes and macrophages in response to interferon-gamma (IFN-gamma) released from activated T cells; thus, it serves as a marker for cellular immune activation. Kose et al showed that serum levels of neopterin were significantly higher in active and inactive Behet disease patients than in controls. Those with active disease had higher levels than those with inactive disease.24 o Polymorphisms in toll-like receptor 4 have been associated with Behet disease.25

Endothelial and vascular dysfunctions o Vascular changes leading to vasculitis and thrombosis are important pathological features of Behet disease. o A recent study proposes that immunoglobulin to carboxy-terminal subunit of Sip1 (Sip1 C-ter) may be a useful novel autoantigen in Behet disease. Interestingly, this autoantigen level was not only elevated in 41% of Behet disease patients, but also in 45% of those patients with primary vasculitis, thus this marker may also point at endothelial dysfunction in vasculitis. 26

o o o o o o o o

Antiendothelial cell antibodies are detected in diseases with immune-mediated vascular damage and show significantly increased prevalence in Behet disease. T cells (mostly CD4 cells), B cells, and neutrophils are infiltrated perivascularly. Esmat et al showed much higher serum lipoprotein(a) levels in patients with vascular complications and lower levels of serum nitrites during disease activity. 27 Another study demonstrated an association of factor V Leiden and G20210A prothrombin mutation with thrombosis in Behet disease patients.28 Prostanoid synthesis in endothelial cells or vessel walls is impaired, whereas von Willebrand factor, thromboxane, and thrombomodulin are increased. The level of endothelin 1 and 2 is increased in patients with Behet disease vascular involvement. Endothelial celldependent vasodilator function is significantly impaired in patients with Behet disease and is demonstrated by high-resolution ultrasound imaging. Thrombomodulin is a receptor on vascular endothelial cells, which, when down-regulated, leads to a procoagulation state. Most of the high levels of thrombomodulin are observed in persons with skin pathergy reactions. This may help explain vasculitis and vascular symptoms associated with Behet disease.29 Thrombin activatable fibrinolysis inhibitor levels are higher in Behet disease patients than in those without the disease, possibly contributing to the increased thrombosis observed in these patients.

Differential Diagnoses
Lupus Erythematosus, Acute Pyoderma Gangrenosum Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Acute Febrile Neutrophilic Dermatosis Herpes Simplex Aphthous Stomatitis Erythema Multiforme Erythema Nodosum

Other Problems to Be Considered

Inflammatory bowel disease (Crohn disease)

Workup

Laboratory Studies

Behet disease cannot be confirmed through clinical laboratory results. Mild anemia and leukocytosis are observed in some patients with chronic disease. The erythrocyte sedimentation rate, C-reactive protein value, and other acute phase reactants may be elevated during the active stage of Behet disease, but they do not correlate well with the clinical activity. An increase in alpha-2 globulins is often observed. Serum immunoglobulin levels, especially immunoglobulin A, may be elevated. Circulating immune complexes are often present. Rheumatoid factor and antinuclear antibodies are absent. Antineutrophil cytoplasmic antibody and antiphospholipid antibody test results are usually negative.

Histologic Findings

The etiology and pathogenesis of Behet disease remain obscure, although many reviews describe a lymphocytic vasculitis. Vasculitis is thought to affect vessels of all sizes; the various skin lesions are thought to be secondary to small vessel vasculitis.

The histopathology is variable, dependent upon the type of lesion. Pathergic lesions are characterized by a heavy neutrophilic infiltrate without fibrin within the vessel walls. Folliculitis, acneiform lesions, and dermal abscesses have been described in Behet disease. The erythema nodosumlike lesions show a perivascular lymphocytic infiltrate of lymphocytes in the deep dermis and septa with a lymphocytic vasculitis but lack the histiocytic granulomas of typical erythema nodosum. The aphthous ulcers have a nonspecific pathology with a variable infiltrate of lymphocytes, macrophages, and neutrophils at the base of the ulcer. T-cell subsets with a preponderance of helper-inducer cells over T suppressor-cytotoxic cells have been observed in lesions. Electron microscopic observations Examination of erythema nodosumlike lesions shows microvascular changes and lymphocyte-mediated fat cell lysis. Additionally, small dermal blood vessels embolized by thrombi are observed at the sites of the needle prick reaction (pathergy) and at the erythema nodosum like lesions. The early changes in fat cells may be caused by vascular changes brought about by the specific degeneration of endothelial cells and vascular stenosis associated with the delayed-type hypersensitivity reaction.

Treatment
Medical Care
Although multiple therapeutic modalities have been used, treatment is far from satisfactory. Treatment of Behet disease seems to be symptomatic and empiric. Therapeutic efficacy has been difficult to evaluate because of the variable course of the disease and the limited number of cases for clinical investigation.

Local therapy o Tetracycline remains the drug of choice for aphthous stomatitis and oral ulcers of Behet disease. o The patient dissolves the contents of a 250-mg tetracycline capsule in 5 mL of water or flavored syrup and holds the solution in the mouth for approximately 2 minutes before swallowing. This is repeated 4 times daily. o Topical corticosteroids are effective for oral or genital ulcerations if they are applied during the prodromal stage of ulceration. o Other useful drugs include lidocaine gel (2%), sucralfate suspension, and 5% amlexanox. o Twice daily usage of topical 0.2% hyaluronic acid gel improved inflammation and healing periods and reduced oral ulcers.31 Systemic therapy o No single drug has proven effective. o Corticosteroids are the mainstay of treatment for all the various clinical manifestations. Although they have a beneficial effect on acute manifestations, no definite evidence indicates they are effective for controlling progression. o The adverse effects of long-term steroid therapy must be considered. o Mucocutaneous lesions and arthritis have been treated with nonsteroidal anti-inflammatory drugs, zinc sulfate, levamisole, colchicine, dapsone, or sulfapyridine and thalidomide (use is strictly limited because of its teratogenicity). Immunosuppressive therapy with azathioprine, chlorambucil, or cyclophosphamide has been used. o Uveitis and central nervous system involvement is treated with systemic corticosteroids, azathioprine, or cyclosporine. However, in patients with central nervous system involvement, risks and benefits of cyclosporine need to be considered given the medication may have neurological side effects.32,33,34,35 o Anticoagulants are given to patients with thromboses.

o o

o o

Other therapeutic approaches have included cyclosporine, IFN alfa, IFN gamma, acyclovir, highdose corticosteroids or cyclophosphamide pulse therapy, and FK506 (tacrolimus, an immunosuppressive agent similar to cyclosporine). FK506 (tacrolimus) has been particularly noteworthy. The Japanese FK506 study group reported that FK506 was effective in treating refractory uveitis in a dosage-dependent manner. Adverse effects were renal impairment (28.3%), neurologic symptoms (20.8%), gastrointestinal symptoms (18.9%), and hyperglycemia (13.2%). The study group also noted the need for further clinical investigations on FK506 before more widespread application. Subcutaneous IFN alfa-2a therapy has resulted in reduced ulcers and eye disease. Flulike symptoms were the most common adverse effect. Leukopenia, hair loss, and development of antinuclear and antithyroid antibodies were reported less commonly. 36,37 A patient with Behet disease presenting with oral ulcers resistant to prednisone, azathioprine, colchicine, dapsone, and cyclosporin responded well to lenalidomide. 38 In a single patient previously diagnosed with Behcet syndrome with recurrent oral aphthous ulcers, quadruple therapy (proton pump inhibitor, bismuth, tetracycline, and metronidazole), for histologically positive H pylori determined by upper gastrointestinal endoscopy, reduced the development of new ulcers and frequency of recurrent attacks for less than one month. Evaluation of breath test for H pylori was negative in the first month after discontinuation of therapy. 39 A case of Behet disease resistant to prednisone, cyclosporin, azathioprine, infliximab with methotrexate, and colchicine has been successfully treated with anakinra. 40 With the possible role of TNF-alpha in the pathogenesis of Behet disease, infliximab, a chimeric monoclonal immunoglobulin G antibody that inhibits TNF-alpha, and etanercept, a TNF receptor blocker, have steroid-sparing effects and have decreased the frequency of attacks in patients with Behet disease.41 Case reports describe treatment of patients with recalcitrant disease or those in whom conventional immunosuppressive agents have failed. 42,43,44,45 Pediatric case responding to infliximab has been reported.46 Infliximab has resulted in responses after etanercept failed. 47 Infliximab infusions of 5-10 mg/kg have been used with variable dosing schedules. Tuberculosis was a reported adverse effect of infliximab infusion in one Behet disease patient.43 Several patients not responding to infliximab have been treated with adalimumab. 48 Etanercept has been used at 25 mg twice a week.49

Surgical Care
Surgical therapy becomes necessary in serious conditions, including the following:

Gastrointestinal perforation o Enterocutaneous fistula formation o Spontaneous arterial aneurysm formation o Thrombotic obstruction in large-caliber vessels o Cardiac involvement Proper timing for surgical treatment is important. Delayed wound healing or inflammation at operative sites may be related to pathergy.

Consultations

Dermatologist - For evaluation of mucocutaneous lesions (ie, oral ulcer, genital ulcer, skin lesions) Ophthalmologist - For evaluation of eye involvement Rheumatologist or orthopedic surgeon - For evaluation of joint involvement Neurologist or psychiatrist - For evaluation of CNS involvement

Internal medicine specialist - For evaluation of gastrointestinal, pulmonary, renal, or endocrine involvement General surgeon - For evaluation of gastrointestinal involvement Chest surgeon or cardiologist - For evaluation of cardiovascular involvement Ear, nose, and throat specialist or dentist - For evaluation of oral cavity

Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Corticosteroids have been used for all of the various clinical manifestations of Behet disease. Anti-inflammatory and immunosuppressive agents are used to treat mucocutaneous lesions and arthritis associated with this disease. Anticoagulants are administered to patients with thromboses.

Corticosteroids
These agents modify the body's immune response to diverse stimuli and therefore have anti-inflammatory properties. In addition, they cause profound and varied metabolic effects. Corticosteroids are immunosuppressive and affect the replication, movement, and activity of virtually all cells involved with inflammation.

Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

Dosing Interactions Contraindications Precautions

Adult

0.05-2 mg/kg/d PO divided bid/qid; not to exceed 80 mg/d; taper as condition improves; single morning dose is safer for long-term use, but divided doses have more anti-inflammatory effect
Pediatric

4-5 mg/m2/d PO; alternatively, 0.05-2 mg/kg PO divided bid/qid; if used > 3 wk, taper over 2 wk as symptoms resolve

Hydrocortisone (Solu-Cortef)

Decreases inflammation by suppressing migration of PMN leukocytes and reversing increased capillary permeability.

Dosing Interactions Contraindications Precautions

Adult

15-240 mg IV/IM q12h

Pediatric

1-5 mg/kg/d or 75-300 mg/m2/d PO divided q12-24h

Nonsteroidal anti-inflammatory drugs

Although most NSAIDs are used primarily for their anti-inflammatory effects, they are effective analgesics and used to treat mild to moderate pain.

Ibuprofen (Ibuprin, Advil, Motrin)

DOC for mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Dosing Interactions Contraindications Precautions

Adult

400 mg PO q4-6h, 600 mg q6h, or 800 mg PO q8h while symptoms persist; not to exceed 3.2 g/d
Pediatric

6 months to 12 years: 4-10 mg/kg/dose PO tid/qid >12 years: Administer as in adults

Antibiotics
May be immunomodulatory.

Tetracycline (Sumycin)

Inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunit(s). Has anti-inflammatory activity.

Dosing Interactions Contraindications Precautions

Adult

Dissolve the contents of a 250-mg cap in 5 mL water or flavored syrup and hold solution in mouth for 2 min before swallowing; repeat qid
Pediatric

<8 years: Not recommended >8 years: 25-50 mg/kg/d (10-20 mg/lb) PO qid

Antiulcer agents
Topical treatment for aphthae.

Amlexanox (Aphthasol)

Paste at 5% concentration. Topical mucosal anti-inflammatory agent. Exact mechanism of action remains unknown. Begin treatment as soon as patient notices symptoms.

Dosing Interactions Contraindications Precautions

Adult

Apply topically to each mouth ulcer qid

Pediatric

Not established

Sucralfate (Carafate, Sulcrate)

Forms viscous adhesive substance that protects GI lining against pepsin, peptic acid, and bile salts. Use for shortterm management of ulcers.

Dosing Interactions Contraindications Precautions

Adult

1 g PO qid
Pediatric

Not established; suggested dose, 40-80 mg/kg/d PO divided q6h

Immunosuppressive agents
Indicated to treat autoimmune diseases.

Azathioprine (Imuran)

Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.

Dosing Interactions Contraindications Precautions

Adult

1 mg/kg/d PO for 6-8 wk; increase by 0.5 mg/kg q4wk until response or dose reaches 2.5 mg/kg/d
Pediatric

Initial dose: 2-5 mg/kg/d PO/IV Maintenance dose: 1-2 mg/kg/d PO/IV

Chlorambucil (Leukeran)

Alkylates and cross-links strands of DNA, inhibiting DNA replication and RNA transcription.

Dosing Interactions Contraindications Precautions

Adult

0.1-0.2 mg/kg/d PO or 3-6 mg/m2/d PO for 3-6 wk; adjust dose depending on blood counts
Pediatric

0.1-0.2 mg/kg/d PO for 5-15 wk

Tacrolimus (Prograf, Tacrine, FK506)

Suppresses humoral immunity (T lymphocyte) activity.

Dosing Interactions Contraindications Precautions

Adult

0.05 mg/kg/d IV or 0.15-0.3 mg/kg/d PO divided bid

Pediatric

0.1 mg/kg/d IV or 0.3 mg/kg/d PO

Cyclosporine (Sandimmune, Neoral)

Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease for a variety of organs. For children and adults, base dosing on ideal body weight.

Dosing Interactions Contraindications Precautions

Adult

2-10 mg/kg/d IV divided q8-12h

Pediatric

Administer as in adults

Immunomodulators
Anti-inflammatory agents that modulate the immune system through a variety of mechanisms.

Thalidomide (Thalomid)

Immunomodulatory agent that may suppress excessive production of TNF-alpha and may down-regulate selected cell-surface adhesion molecules involved in leukocyte migration.

Dosing Interactions Contraindications Precautions

Adult

100-300 mg/d PO qd with water, preferably hs and at least 1 h pc <50 kg (110 lb): Start at low end of dose regimen
Pediatric

Not established

Infliximab (Remicade)

Neutralizes cytokine TNF-alpha and inhibits its binding to TNF-alpha receptor. Mix in 250 mL NS for infusion over 2 h. Must use with low protein-binding filter ( 1.2 m) Has been used off label for treating BD.

Dosing Interactions Contraindications Precautions

Adult

5-10 mg/kg IV infusion at 0, 2, and 6 wk as induction regimen; then, 5 mg/kg q8wk for maintenance IV infusion must be administered over at least 2 h; must use infusion set with inline, sterile, nonpyrogenic, low protein-binding filter ( 1.2 m); regimen approved for psoriatic arthritis; case reports describe slightly different intervals; one reported administration day 1, day 30, and then every 8 wk for total of 20 mo and 16 mo of continuous treatment in 2 different patients
Pediatric

Not available

Etanercept (Enbrel)

Soluble p75 TNF receptor fusion protein (sTNFR-Ig). Inhibits TNF binding to cell surface receptors, which, in turn, decreases inflammatory and immune responses. Off label use for Behet disease.

Dosing Interactions Contraindications Precautions

Adult

25 mg SC 2 times/wk or 50 mg SC 2 times/wk for 3 mo; then maintenance dose of 50 mg/wk (administration is for psoriatic arthritis)
Pediatric

0.8 mg/kg SC; maximum single dose 25 mg

Follow-up
Prognosis
The clinical course of Behet disease is variable, even in the early stages, making determinations of the long-term prognosis difficult. Men appear to have a poorer prognosis. The disease usually runs a protracted course, with attacks generally lasting for several weeks and recurring more frequently early in the disease. Mucocutaneous and arthritic involvement usually occur early. Chronic morbidity is usual; the leading cause is ophthalmic involvement, which can result in blindness. The effects of the disease may be cumulative, especially for neurologic, vascular, and ocular involvement. Mortality is low, but patients may die from neurologic involvement, vascular disease, bowel perforation, cardiopulmonary disease, or as a complication of immunosuppressive therapy.

Patient Education
For excellent patient education resources, visit eMedicine's Teeth and Mouth Center. Also, see eMedicine's patient education article Canker Sores.
Acknowledgments The authors and editors of eMedicine gratefully acknowledge the contributions of previous Chief Editor, William D. James, MD, and previous author, Eun-So Lee, MD, PhD, to the development and writing of this article.