AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Background

Behçet disease (BD) was named in 1937 after the Turkish dermatologist Hulusi Behçet, who first described the triple-symptom complex of recurrent oral aphthous ulcers, genital ulcers, and uveitis.

This complex, multisystemic disease includes involvement of the mucocutaneous, ocular, cardiovascular, renal, gastrointestinal, pulmonary, urologic, and central nervous systems and the joints, blood vessels, and lungs.

It 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 BD is not known; however, immunogenetics, immune regulation, vascular abnormalities, or bacterial and viral infection may have a role in its development.

Frequency

United States

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

International

BD 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.

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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

History

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

• Prior to the onset of BD, patients may experience a variety of symptoms.
• • Malaise
  • Anorexia
  • Weight loss
  • Generalized weakness
  • Headache
  • Perspiration
  • Decreased or elevated temperature
  • Lymphadenopathy
  • 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 BD 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.
• More recently, the diagnostic criteria of the International Study Group for Behçet Disease have been applied to establish a firmer diagnosis.
• The major limitation of these criteria is the fact that recurrent oral ulceration is the characteristic symptom for the diagnosis of BD. For example, patients with uveitis and genital ulcers, without oral aphthosis, would not be considered to have BD, 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 Behçet syndrome research committee of Japan (1987 revision) are as follows:
• • 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
  • Minor features
    • Arthritis without deformity and ankylosis
    • Gastrointestinal lesions characterized by ileocecal ulcers
    • Epididymitis
    • Vascular lesions
    • Central nervous system symptoms
  • 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 BD (1990) are as follows:
• • 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 nodosum–like lesions observed by physician or reliably reported by a patient, pseudofolliculitis, and papulopustular lesions or (2) acneiform nodules consistent with BD, 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 BD 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 3 types.
    • Minor ulcer: This consists of 1-5 small, moderately painful ulcers persisting for 4-14 days (see Image 1).
    • 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 Image 2).
    • Herpetiform ulcer: This is a recurrent crop of as many as 1000 small and painful ulcers (see Image 3).
• 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 Image 4), penis, and groin.
  • In females, they occur on the vulva (see Image 5), vagina, groin, and cervix.
  • 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 Behçet 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 BD (58.6-97%), including the following:
    • Erythema nodosum–like lesions, which are most common (see Image 6)
    • Papulopustular eruptions (see Image 7)
    • Erythema multiforme–like lesions
    • Thrombophlebitis
    • Ulcers
    • Lesions resembling Sweet syndrome (see Image 8)
    • 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 Image 9).
  • Lesions often occur in combination (eg, erythema nodosum–like lesions and papulopustular eruptions).
  • Follicle-based pustules or acne lesions are not considered specific lesions of BD.
• 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 BD. Childhood-onset Behçet uveitis is more common in males (Tugal, 2003).
  • The most diagnostically relevant lesion is posterior uveitis, ie, retinal vasculitis (see Image 10). 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 BD, is now uncommon.
  • 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.
• Vascular involvement
• • This 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 BD 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 BD can be significant and life-threatening, diagnosing and treating vascular involvement early is vital.
• Gastrointestinal involvement
• • The clinical spectrum of gastrointestinal effects is enormously varied and occurs in more than 10% of patients with BD.
  • 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.
  • The most frequent minor feature in childhood-onset BD 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 BD varies from 3.2-49% according to the reports of different populations.
  • Neurologic involvement may present (in various combinations) as meningoencephalitis, a multiple sclerosis–like 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 BD 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 BD (Uzun, 2003).
  • 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.
• Pathergy (skin hyperreactivity)
  • The presence of pathergy strongly suggests the diagnosis of BD.
  • 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

• Immunogenetics
• • HLA-B51 or its B101 allele is significantly associated with BD in Japan, Korea, Turkey, and France and with ocular manifestations in Britain. Although HLA-B51 transgenic mice do not develop any manifestations of BD, their neutrophils show excessive function.
  • The MICA allele is a polymorphic MHC class I–related A gene (MICA) family. The MICA6 allele has recently been shown to be significantly associated with BD (74%), compared with controls (45.6%) in Japan. The relationship between MICA6 and BD was confirmed in France. The MICA6 allele is thought to be in linkage disequilibrium with HLA-B51; consequently, the search for genes related to BD continues. A recent study of 23 Japanese patients showed that the MICA6 allele had no significant association with BD, but it showed a strong association with HLA-B51; therefore, the association between MICA6and BD may be a secondary phenomenon related to HLA-B51 (Nishiyama, 2006).
  • MEFV gene mutations, seen in persons with Mediterranean fever, are increased in persons with BD. This mutation has been associated with vascular BD (Atagunduz, 2003).
  • Levels of tumor necrosis factor-alpha (TNF-alpha) have been reported to be significantly elevated in BD 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 BD. TNF-alpha haplotypes in the promoter response elements may be useful in identifying those more susceptible to BD (Park, 2006).
• Viral and bacterial infection
• • Investigations of the etiology of BD have focused predominantly on herpes simplex virus infection, streptococcal infection, and autoimmunity or cross-reactivity between microbial and oral mucosal antigens.
  • Behçet 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 BD. BD-like symptoms have been induced in an Institute for Cancer Research mouse after inoculation of herpes simplex virus into its earlobe.
  • Acquired hypersensitivity to streptococcal antigens plays an important role in the etiopathology of BD.
  • 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 BD cross-react with the 65-kd HSP, which also shares antigenicity with an oral mucosal antigen.
  • 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 BD.
    • 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 BD in Britain, Japan, and Turkey. HSP60/65 was also found to be significantly increased in the epidermal cells of BD skin lesions, and antibody levels to HSP65 were significantly elevated in the cerebrospinal fluid from patients with neurological manifestations of BD.
    • An experimental model of BD 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 BD.
• Immunological abnormalities
• • In persons with BD, 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 BD. However, the concentration of the Th2 cytokine IL-6 is also increased in the serum of patients with BD, especially in the active stage, as was also found with IL-10 upon stimulation of the peripheral blood mononuclear cell.
  • Stimulation with S sanguis (KTH-1) of T-cell lines generated from patients with BD suggests that Th1-type mRNA is induced (IL-2 and IFN).
  • Investigations of intracellular IFN and IL-4 suggest that polarization toward the Th1 type of cells occurs in patients with active BD 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 BD.
  • The intracellular adhesion molecule 1 was enhanced in human dermal microvascular endothelial cells after treatment with serum from patients with BD, and this may have induced increased adhesion of T cells to the endothelial cells.
  • 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 BD and remain unregulated in peripheral blood mononuclear cells and neutrophils of patients with BD (Duzgun, 2005). Levels of IL-10 and IL-13 may also be elevated (Aridogan, 2003).
  • Plasma levels of vascular endothelial growth factor, a proinflammatory cytokine, is significantly higher in persons with active BD (Cekmen, 2003).
  • 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 BD patients than in controls. Those with active disease had higher levels than those with inactive disease (Kose, 2006).
• Endothelial and vascular dysfunctions
• • Vascular changes leading to vasculitis and thrombosis are important pathological features of BD.
  • A recent study proposes that immunoglobulin to carboxy-terminal subunit of Sip1 (Sip1 C-ter) may be a useful novel autoantigen in BD. Interestingly, this autoantigen level was not only elevated in 41% of BD patients, but also in 45% of those patients with primary vasculitis, thus this marker may also point at endothelial dysfunction in vasculitis (Delunardo, 2006).
  • Antiendothelial cell antibodies are detected in diseases with immune-mediated vascular damage and show significantly increased prevalence in BD.
  • 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 (Esmat, 2006).
  • Another study demonstrated an association of factor V Leiden and G20210A prothrombin mutation with thrombosis in BD patients (Ricart, 2006).
  • 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 BD vascular involvement.
  • Endothelial cell–dependent vasodilator function is significantly impaired in patients with BD and is demonstrated by high-resolution ultrasound imaging.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Other Problems to be Considered

Inflammatory bowel disease (Crohn disease)

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Lab Studies

• BD 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 BD, 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 BD 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 BD.

The erythema nodosum–like 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 nodosum–like 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

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Medical Care

Although multiple therapeutic modalities have been used, treatment is far from satisfactory. Treatment of BD 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
• • Tetracycline remains the drug of choice for aphthous stomatitis and oral ulcers of BD.
  • 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.
  • Topical corticosteroids are effective for oral or genital ulcerations if they are applied during the prodromal stage of ulceration.
  • Other useful drugs include lidocaine gel (2%), sucralfate suspension, and 5% amlexanox.
• Systemic therapy
• • No single drug has proven effective.
  • 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.
  • The adverse effects of long-term steroid therapy must be considered.
  • 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.
  • Uveitis and central nervous system involvement is treated with systemic corticosteroids, azathioprine, or cyclosporine.
  • Anticoagulants are given to patients with thromboses.
  • Recent therapeutic approaches have included cyclosporine, IFN alfa, IFN gamma, acyclovir, high-dose 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 (Alpsoy, 2003; Kotter, 2003).
  • With the possible role of TNF-alpha in the pathogenesis of BD, 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 BD (Sfikakis, 2002). Case reports describe treatment of patients with recalcitrant disease or those in whom conventional immunosuppressive agents have failed (Katsiari, 2003; Ohno, 2004; Tugal-Tutkun, 2005. Etanercept has been used at 25 mg twice a week (Melikoglu, 2005). Infliximab has resulted in responses after etanercept failed (Estrach, 2002). 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 BD patient (Ohno, 2004).

Surgical Care

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

• Gastrointestinal perforation
• • Enterocutaneous fistula formation
  • Spontaneous arterial aneurysm formation
  • Thrombotic obstruction in large-caliber vessels
  • 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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

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

Drug Category: 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.

Drug Category: 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.

Drug Category: Antibiotics

May be immunomodulatory.

Drug Category: Antiulcer agents

Topical treatment for aphthae.

Drug Category: Immunosuppressive agents

Indicated to treat autoimmune diseases.

Drug Category: Immunomodulators

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

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Prognosis

• The clinical course of BD 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.

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Media file 1:  Minor aphthous ulcer.
	View Full Size Image
Media type:  Photo

Media file 2:  Major aphthous ulcer.
	View Full Size Image
Media type:  Photo

Media file 3:  Herpetiform oral ulcer.
	View Full Size Image
Media type:  Photo

Media file 4:  A characteristic genital ulcer on scrotum.
	View Full Size Image
Media type:  Photo

Media file 5:  A single ulcer on vulva.
	View Full Size Image
Media type:  Photo

Media file 6:  Erythema nodosum–like lesions on skin.
	View Full Size Image
Media type:  Photo

Media file 7:  Papulopustular eruptions.
	View Full Size Image
Media type:  Photo

Media file 8:  Sweet syndrome–like lesion.
	View Full Size Image
Media type:  Photo

Media file 9:  Typical positive pathergy reaction at injection site.
	View Full Size Image
Media type:  Photo

Media file 10:  Ocular involvement showing posterior uveitis.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

• Alpsoy E, Durusoy C, Yilmaz E, et al. Interferon alfa-2a in the treatment of Behçet disease: a randomized placebo-controlled and double-blind study. Arch Dermatol. Apr 2002;138(4):467-71. [Medline].
• Aridogan BC, Yildirim M, Baysal V, et al. Serum Levels of IL-4, IL-10, IL-12, IL-13 and IFN-gamma in Behçet''s disease. J Dermatol. Aug 2003;30(8):602-7. [Medline].
• Atagunduz P, Ergun T, Direskeneli H. MEFV mutations are increased in Behçet''s disease (BD) and are associated with vascular involvement. Clin Exp Rheumatol. Jul-Aug 2003;21(4 Suppl 30):S35-7. [Medline].
• Behçet H. Uber rezidivierende, aphthose, durchein Virus verursachte Geschwure am Mund, am Auge und anden Genitalien. Dermatol Wochenschr. 1937;36:1152-7.
• Boe J, Dalgaard JB, Scott D. Mucocutaneous-ocular syndrome with intestinal involvement; a clinical and pathological study of four fatal cases. Am J Med. Dec 1958;25(6):857-67. [Medline].
• Cekmen M, Evereklioglu C, Er H, et al. Vascular endothelial growth factor levels are increased and associated with disease activity in patients with Behçet''s syndrome. Int J Dermatol. Nov 2003;42(11):870-5. [Medline].
• Cho MY, Lee SH, Bang D, Lee S. Epidemiologic findings of Behcet's syndrome. Korean J Dermatol. 1988;26:320-9.
• Düzgün N, Ayaslioglu E, Tutkak H, Aydintug OT. Cytokine inhibitors: soluble tumor necrosis factor receptor 1 and interleukin-1 receptor antagonist in Behçet's disease. Rheumatol Int. Jan 2005;25(1):1-5. [Medline].
• Delunardo F, Conti F, Margutti P, et al. Identification and characterization of the carboxy-terminal region of Sip-1, a novel autoantigen in Behcet's disease. Arthritis Res Ther. 2006;8(3):R71. [Medline].
• Esmat S, El Sherif H, Anwar S, et al. Lipoprotein (a) and nitrites in Behcet's disease: relationship with disease activity and vascular complications. Eur J Dermatol. Jan-Feb 2006;16(1):67-71. [Medline].
• Estrach C, Mpofu S, Moots RJ. Behçet''s syndrome: response to infliximab after failure of etanercept. Rheumatology (Oxford). Oct 2002;41(10):1213-4. [Medline].
• Gharibdoost F, Davatchi F, Shahram F, et al. Clinical manifestations of Behcet's disease in Iran. Analysis of 2176 cases. In: Godeau P, Wechsler B, eds. Proceedings of the 6th International Conference on Behcet's Disease. Amsterdam, The Netherlands: Elsevier Science; 1993:. 153-8.
• Ghate JV, Jorizzo JL. Behcet''s disease and complex aphthosis. J Am Acad Dermatol. Jan 1999;40(1):1-18; quiz 19-20. [Medline].
• Imirzalioglu N, Dursun A, Tastan B, et al. MEFV gene is a probable susceptibility gene for Behçet''s disease. Scand J Rheumatol. 2005;34(1):56-8. [Medline].
• International Study Group for Behcet''s Disease. Criteria for diagnosis of Behcet''s disease. International Study Group for Behcet''s Disease. Lancet. May 5 1990;335(8697):1078-80. [Medline].
• Kötter I, Zierhut M, Eckstein AK, et al. Human recombinant interferon alfa-2a for the treatment of Behçet''s disease with sight threatening posterior or panuveitis. Br J Ophthalmol. Apr 2003;87(4):423-31. [Medline].
• Kaklamani VG, Vaiopoulos G, Kaklamanis PG. Behcet''s Disease. Semin Arthritis Rheum. Feb 1998;27(4):197-217. [Medline].
• Kansu E, Deglin S, Cantor RI, et al. The expanding spectrum of Behcet syndrome: a case with renal involvement. JAMA. Apr 25 1977;237(17):1855-6. [Medline].
• Katsiari CG, Theodossiadis PG, Kaklamanis PG, et al. Successful long-term treatment of refractory Adamantiades-Behçet''s disease (ABD) with infliximab: report of two patients. Adv Exp Med Biol. 2003;528:551-5. [Medline].
• Kim DK, Chang SN, Bang D, et al. Clinical analysis of 40 cases of childhood-onset Behcet''s disease. Pediatr Dermatol. Jun 1994;11(2):95-101. [Medline].
• Kim NH, Yang IH, Kim SM, Bang D. Behcet's arthritis. J Korean Orthop Surg. 1993;28:1890-7.
• Kose O, Arca E, Akgul O, Erbil K. The levels of serum neopterin in Behçet's disease--objective marker of disease activity. J Dermatol Sci. May 2006;42(2):128-30. [Medline].
• Lee YP, Cho CH, Chi HS, et al. Intestinal Behcet's disease. J Korean Surg Soc. 1988;35:310-5.
• Melikoglu M, Fresko I, Mat C, et al. Short-term trial of etanercept in Behçet's disease: a double blind, placebo controlled study. J Rheumatol. Jan 2005;32(1):98-105. [Medline].
• Mizuki N, Inoko H, Ohno S. Molecular genetics (HLA) of Behcet''s disease. Yonsei Med J. Dec 1997;38(6):333-49. [Medline].
• Mizushima Y. [Revised diagnostic criteria for Behcet''s disease in 1987]. Ryumachi. Feb 1988;28(1):66-70. [Medline].
• Nishiyama M, Takahashi M, Manaka K, et al. Microsatellite polymorphisms of the MICA gene among Japanese patients with Behcet's disease. Can J Ophthalmol. Apr 2006;41(2):210-5. [Medline].
• Ohno S, Nakamura S, Hori S, et al. Efficacy, safety, and pharmacokinetics of multiple administration of infliximab in Behçet's disease with refractory uveoretinitis. J Rheumatol. Jul 2004;31(7):1362-8. [Medline].
• Park K, Kim N, Nam J, et al. Association of TNFA promoter region haplotype in Behçet's Disease. J Korean Med Sci. Aug 2006;21(4):596-601. [Medline].
• Ricart JM, Vaya A, Todoli J, et al. Thrombophilic risk factors and homocysteine levels in Behcet's disease in eastern Spain and their association with thrombotic events. Thromb Haemost. Apr 2006;95(4):618-24. [Medline].
• Sakane T, Suzuki N, Nagafuchi H. Etiopathology of Behcet''s disease: immunological aspects. Yonsei Med J. 1997;38:350-8. [Medline].
• Saylan T, Mat C, Fresko I, Melikoglu M. Behcet''s disease in the Middle East. Clin Dermatol. Mar-Apr 1999;17(2):209-23; discussion 105-6. [Medline].
• Saylan T, Urgancioglu M, Akarcay K, Bozan G. General data of the patients with Behcet's disease. In: Dilsen N, Konice M, Ovul C, eds. Proceedings of the 2nd International Symposium on Behcet's Disease. Amsterdam, The Netherlands: Elsevier Science; 1977:. 130-2.
• Sechas MN, Liapis CD, Gougoulakis AG, et al. Vascular manifestations of Behcet''s disease. Int Angiol. 1989;8(3):145-50. [Medline].
• Sfikakis PP. Behçet''s disease: a new target for anti-tumour necrosis factor treatment. Ann Rheum Dis. Nov 2002;61 Suppl 2:ii51-3. [Medline].
• Sohn S. Etiopathology of Behcet''s disease: herpes simplex virus infection and animal model. Yonsei Med J. 1997;38:359-64. [Medline].
• Tugal-Tutkun I, Urgancioglu M. Childhood-onset uveitis in Behçet disease:a descriptive study of 36 cases. Am J Ophthalmol. Dec 2003;136(6):1114-9. [Medline].
• Tugal-Tutkun I, Mudun A, Urgancioglu M, et al. Efficacy of infliximab in the treatment of uveitis that is resistant to treatment with the combination of azathioprine, cyclosporine, and corticosteroids in Behçet's disease: an open-label trial. Arthritis Rheum. Aug 2005;52(8):2478-84. [Medline].
• Uzun S, Alpsoy E, Durdu M, Akman A. The clinical course of Behçet''s disease in pregnancy: a retrospective analysis and review of the literature. J Dermatol. Jul 2003;30(7):499-502. [Medline].
• Wong RC, Ellis CN, Diaz LA. Behcet''s disease. Int J Dermatol. 1984;23:25-32. [Medline].
• Yazici H, Yurdakul S, Hamuryudan V. Behcet''s syndrome. Curr Opin Rheumatol. Jan 1999;11(1):53-7. [Medline].

Article Last Updated: Feb 26, 2007