AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Hippocrates may have described Behçet disease in the fifth century BC; however, the first description of the syndrome was attributed to the Turkish dermatologist Hulusi Behçet in 1924. In 1930, the Greek physician Adamantiades presented reports of a patient with inflammatory arthritis, oral and genital ulcers, phlebitis, and iritis. Since then, the syndrome has been referred to as Behçet disease.

Pathophysiology

Behçet disease is presumed to be an autoimmune disease. As with many other autoimmune diseases, aspects suggest an infectious disease but no organism has ever been isolated.

Microscopically, the primary lesion is vasculitic. Depending on the organ system involved, various signs and symptoms are possible, including internal organ failure.

Perturbations in T-cell populations have been found in the circulation and inflammatory lesions in Behçet disease. CD4⁺ T lymphocytes are found in the inflammatory infiltrates. Interleukin (IL)-1, IL-8, IL-10, IL-12, soluble tumor necrosis factor receptor (sTNFR), and some growth factors are present in higher concentrations in the blood of patients with active Behçet disease. Increases in blood g/d T cells and natural killer cells have been reported. This all supports an inflammatory etiopathogenesis, although whether this is T_H1 or T_H2 mediated is uncertain.

Evidence also includes enhanced adherence of neutrophils to endothelial cells in the presence of serum from patients with Behçet disease. Increased expression of adhesion molecules on the neutrophils also has been observed. Immune complexes are increased in the serum and in some lesions.

Recurrent thrombosis occurs and may resemble antiphospholipid syndrome (APS). Antiphospholipid antibodies correlate with retinal vascular lesions. Elevated levels of the von Willebrand factor also are detected, but this is likely the result of vessel damage.

Genetically, human leukocyte antigen B5 (HLA-B5) is found in higher prevalence in Middle Eastern and Far Eastern populations and is associated with a more severe disease, especially in men. A higher prevalence of HLA-B51 is found in Israeli patients.

Frequency

United States

Prevalence is 0.3-6.6 cases per 100,000 population.

International

The incidence and prevalence are highest along the old Silk Road, extending from the Middle East to China. International incidences are as follows:

International Incidence of Behçet Disease

*Number of cases per 100,000 population each year

Mortality/Morbidity

Rupture of aneurysms can lead to a 60% mortality rate. Pulmonary arterial involvement has led to death in about 50% of patients with hemoptysis in less than a year. Neurologic involvement has been associated with a mortality rate as high as 20% after 7 years of follow-up in one study, but this is was not borne out by others. An overall mortality rate of up to 16% at 5 years has been reported in previous epidemiology studies.

• The rupture of aneurysms of large vessels may lead to death, as can thrombosis.
• Central nervous system involvement can lead to permanent deficits or death.
• Eye involvement can result in blindness.

Race

The highest prevalence is in the Middle East and Japan.

Sex

Sexual prevalence may be variable.

• In the Middle East, cases involving males predominate, with male-to-female ratios of 3.8:1 (Israel), 5.3:1 (Egypt), and 3.4:1 (Turkey). In Germany, Japan, and Brazil, a slight female predominance exists. In the United States, females are affected more frequently than males (5:1 female-to-male ratio).
• Males may have more severe disease. They are more likely to develop aneurysms, eye involvement, thrombophlebitis, and, perhaps, neurologic disease. Females are more likely to develop erythema nodosum.

Age

• This syndrome is most common among patients aged 15-45 years. An age of onset younger than 25 years is associated with a higher prevalence of eye disease and active clinical disease.
• Cases are reported in newborns of mothers with genital ulcerations.
• The mean age at onset is 27 years in males and 24.5 years in females.

CLINICAL

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History

The diagnosis of Behçet disease was clarified by an international study group (ISG) that compared the clinical findings of 914 patients with controls who had aphthous ulcers. This group developed ISG criteria, which currently are used to define the illness.

At least 3 episodes of oral ulceration must occur in a 12-month period. They must be observed by a physician or the patient and may be herpetiform or aphthous in nature. At least 2 of the following must occur: (1) recurrent, painful genital ulcers that heal with scarring; (2) ophthalmic lesions, including anterior or posterior uveitis, hypopyon, or retinal vasculitis; (3) skin lesions, including erythema nodosum, pseudofolliculitis, or papulopustular lesions (may also include atypical acne); and (4) pathergy, which is defined as a sterile erythematous papule larger than 2 mm in size appearing 48 hours after skin pricks with a sharp, sterile needle (a dull needle may be used as a control).

• Skin and mucous membranes
• • Painful oral lesions are one of the criteria for diagnosis and may be the first manifestation (70%). They occur in any part of the mouth and may last as long as 3 weeks.
  • Skin lesions occur in the genital region of both sexes. In males, this includes the scrotum and penis, and, in females, the vulvar and vaginal areas are involved. The ulcerations tend to be more painful in men and often heal with scarring.
  • Painful nodules from erythema nodosum are common in Behçet disease. Patients commonly present with acnelike or pustular lesions.
• Ocular lesions
• • These may vary but can be found in 50-79% of affected patients.
  • Complaints may include blurred vision, periorbital pain, photophobia, scleral injection, or excessive lacrimation.
  • Men tend to have more severe eye involvement, which is especially prevalent in Iranian and Japanese patients.
  • Posterior uveitis and blindness occurs an average of 4 years after disease onset.
• Neurologic manifestations: The mortality rate is up to 41% in patients with CNS disease. This tends to be an unusual late manifestation 1-7 years after disease onset.
• • Headache - 50%
  • Meningoencephalitis - 28%
  • Seizures - 13%
  • Cranial nerve abnormalities - 16%
  • Instability
  • Cerebellar ataxia
  • Extrapyramidal signs
  • Pseudobulbar palsy
  • Hemiplegia or paralysis
  • Personality changes
  • Incontinence
  • Cranial nerve abnormalities
  • Dementia (no more than 10% of patients, in which progression is not unusual)
• Vasculopathy
• • Behçet disease is a cause of aneurysms of the pulmonary tree that may be fatal.
  • Vasculitis of the small and large vessels can cause a panoply of symptoms.
  • Deep venous thrombophlebitis has been described in about 10% of patients, and superficial thrombophlebitis occurred in 24% of patients in the same study. Noninflammatory vascular lesions include arterial and venous occlusions, varices, and aneurysms.
  • Symptoms correlate with the vessel involved and may be devastating. For example, Budd-Chiari syndrome is reported in these patients, and as many as 32% of the patients with vascular involvement in one series had occlusion of the vena cava.
  • Esophageal varices also have been described.
• Arthritis
• • Arthritis and arthralgias occur in any pattern in as many as 60% of patients.
  • A predilection exists for the lower extremities, especially the knee. Ankles, wrist, and elbows can also be primarily involved.
  • The arthritis usually is not deforming or chronic and may be the presenting symptom and rarely involves erosions.
  • The arthritis is inflammatory, with warmth, redness, and swelling around the affected joint.
  • Back pain due to sacroiliitis may occur.
• Gastrointestinal manifestations
• • Symptoms suggestive of inflammatory bowel disease
  • Diarrhea or gastrointestinal bleeding
  • Ulcerative lesions (described in almost any part of the gastrointestinal tract)
  • Flatulence
  • Abdominal pain
  • Vomiting
  • Dysphagia (higher prevalence in Japanese patients compared to Turkish patients)
• Other manifestations
• • Cardiac lesions include arrhythmias, pericarditis, vasculitis of the coronary arteries, endomyocardial fibrosis, and granulomas in the endocardium.
  • Epididymitis
  • Glomerulonephritis
  • Lymphadenopathy
  • Myositis
  • Polychondritis
  • Amyloidosis (uncommon, 2%)

Physical

• Oral ulcers
• • Oral lesions are one of the most common, and often the first, manifestations of the disease. They eventually occur in most patients, and, not surprisingly, they are a primary criterion.
  • The ulcers are aphthous and may occur almost anywhere in the oral cavity. They may be very painful, last for as long as 3 weeks, and occasionally heal with scarring. Pseudomembranes over ulcerations are described. Ulcerations are 2-10 mm in diameter.
• Genital ulcers
• • In females, these lesions may appear on the vulva and vagina.
  • In males, they appear at the perianal region, penis, and scrotum.
  • The lesions are deeper and more likely to scar than the oral ulcerations, and they last longer.
  • Ulcerations in women may be related to menstruation.
• Skin
• • Pseudofolliculitis, which is found more often in men, is the most common lesion associated with Behçet disease.
  • Erythema nodosum is found more commonly in women and may ulcerate, which is not common in most cases of erythema nodosum.
  • Pustular, acnelike, and comedones lesions appear on the upper parts of the body.
• Ocular manifestations
• • Anterior uveitis
  • Posterior uveitis that causes blindness
  • Hypopyon and its sequelae
  • Cataracts
  • Glaucoma
  • Synechiae
  • Retinal vasculitis
  • Infarctions
  • Hemorrhage
  • Disc may appear edematous with retinal detachment.
  • Fluorescein angiography may show leaky retinal vessels. Atrophy and fibrosis may be the ultimate outcome.
• Neurologic manifestations
• • Central nervous system involvement may occur in 10-30% of cases. It usually occurs later in the course of disease and includes meningoencephalitis, pyramidal tract lesions with spastic paralysis, cranial nerve lesions, behavioral changes, and dementia.
  • The pathologic changes include vasculitis, perivascular white matter inflammation, and demyelinating lesions.
  • Signs may include mental status changes; seizures; clonus; positive Babinski sign; difficulty with speech, swallowing, and emotional lability; and acute deafness.
  • Peripheral nerve involvement is rare.
• Vascular manifestations
• • Both vasculitis and thrombotic disease can occur. This can occur on both the venous and arterial sides, and it can lead to ischemia or aneurysms. Venous thrombosis is the most common. It can vary from subcutaneous veins to almost any other vein, including the vena cava, hepatic veins, and cerebral venous sinuses.
  • A major risk of morbidity is arterial involvement that may lead to ischemic problems, including claudication, transient ischemic attacks, myocardial infarction, and aseptic necrosis. If the aneurysms rupture, mortality is significant.
  • Interestingly, pulmonary thromboemboli are rare, but pulmonary aneurysms are not. Patients may present with hemoptysis.
• Arthritis
• • Inflammatory peripheral arthritis is common, occurring in about half of the patients. The arthritis has a predominance for the lower extremities but may occur in any pattern. Arthralgias also are common. Monoarthritis, especially in the knee, is the most common manifestation, but symmetric involvement may predominate. Overall, the large joints are involved most frequently. The arthritis usually is not destructive or deforming.
  • Joint fluid content varies, with white blood cell counts from 300-36,200/mm³ and variable viscosity.
  • Rare manifestations include aseptic necrosis, enthesopathies, and sacroiliitis.
• Gastrointestinal manifestations
• • First and foremost, common causes of mouth or genital ulcers, such as inflammatory bowel disease (IBD), should be excluded.
  • Ulcerative lesions predominate, resulting in abdominal pain, bloody diarrhea, and occasional intestinal perforation.
  • Lesions are indistinguishable from inflammatory bowel disease and may occur anywhere in the gastrointestinal tract.
• Renal manifestations
• • Glomerulonephritis and epididymitis are the 2 most common lesions; however, they only occur in about 10% of the patients.
  • Cases are described with renal vein thrombosis and immunoglobulin A (IgA) nephropathy.
• Other lesions
• • Cardiac manifestations include coronary vasculitis and thrombosis, pericarditis, myocarditis, endocarditis with granulomatous changes or fibrosis, regurgitation, and diastolic dysfunction (5-17% of the patients).
  • Lung involvement may occur in as many as 18% of patients. Pulmonary vasculitis, hypertension, and pleural effusions are described. Aneurysms are a more feared complication of Behçet disease that may result in massive hemoptysis.
  • Overlaps with myositis and polychondritis (mouth and genital ulcers with inflamed cartilage [MAGIC]) also have been described.
  • Amyloidosis is an uncommon complication and may be related to the duration of disease.

Causes

• Infectious causes: The epidemiologic information available suggests that an infectious agent such as streptococci could play a role in the pathogenesis of the disease.
• Genetic causes
• • The role of genetics is confusing, but about 5-12% of the cases have some familial association.
  • HLA-B5 and HLA-B51 confer an increased risk of developing the syndrome and are more common in persons of Japanese and Mediterranean descent, with an incidence 3-6 times that of the regular population. Patients with sacroiliitis have an increased frequency of HLA-B27.
• Risk factors
• • Multiple risk factors likely are necessary for the genetically susceptible host to contact the right environmental factor, either before or at the onset of disease or repeatedly during it.
  • One reference reports an exacerbation of Behçet syndrome after ingestion of English walnuts.

DIFFERENTIALS

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Other Problems to be Considered

AIDS

WORKUP

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Lab Studies

• Laboratory findings
• • Laboratory findings are nonspecific and reflect the inflammatory state.
  • C-reactive protein, erythrocyte sedimentation rate (ESR), leukocyte count, and complement components and acute-phase reactants all may be elevated during an acute attack.
  • Elevations are occasionally found in IgA, immunoglobulin G (IgG), alpha-2 globulin, immunoglobulin M (IgM) levels and immune complexes.
  • None of these findings is specific for the diagnosis of Behçet disease, but they can corroborate active disease.
• Antiphospholipid antibodies: These include lupus anticoagulant and anticardiolipin antibodies. Although uncommon in Behçet disease, they are worth pursuing, especially in cases of thrombosis. The best correlation occurs with retinal vascular lesions.
• Up to one third of patients with Behçet disease who have thrombosis are found to have factor V Leiden deficiency mutations. Other causes of hypercoagulability should be ruled out.
• Antineutrophil cytoplasmic antibody: Occasionally, patients are found with positive test results for perinuclear antineutrophil cytoplasmic (p-ANCA) antibody, although positive or negative results on this test do not change prognosis or therapy.
• Synovial fluid: Synovial fluid usually is cloudy with variable viscosity, and the WBC counts are 300-36,000/µL (either noninflammatory or inflammatory). Polymorphonuclear leukocytes and protein elevation are the predominant findings, and glucose levels are near normal.
• Cerebrospinal fluid: These findings show local inflammation with increased WBC counts, with lymphocyte predominance and elevated protein, immunoglobulin (Ig) levels, and Ig index, reflecting local production of Ig. Opening pressures may be very high in some patients.

Imaging Studies

• Radiograph, magnetic resonance imaging, or computed tomography (CT) scan
• • Sacroiliitis may be present and observed on either a radiograph, magnetic resonance imaging, or CT scan.
  • Aseptic necrosis also is described.
• Brain CT scan
• Brain magnetic resonance imaging (MRI)
• Single-photon emission computed tomography (SPECT)
• Angiography for aneurysms

Other Tests

• Pathergy test: Minor skin trauma induces an inflammatory papule/pustule after 24-48 hours.

Histologic Findings

Though these findings are not specific for Behçet disease, vasculitis of the affected organ is the most important finding. It may be accompanied by perivascular infiltrates, which are an even less specific finding. Central nervous system lesions include meningeal and cerebral inflammation, cerebral atrophy, and encephalomalacia. Evidence of thrombosis is common and must be distinguished from vasculitis. Other organ system findings include the following:

• Skin - Erythema nodosum lesions with characteristic findings and occasional granulomas; folliculitis; leukocytoclastic vasculitis; dermal inflammation and perivascular infiltrates; fibrosis; and mucosal lesions, including aggregated intravascular conglomerates of neutrophils, endothelial cell swelling, fibrinoid necrosis, and a mixed perivascular infiltrate (Pathergy test reveals mononuclear cell infiltrates and keratinocytes.)
• Eye - Cataracts, posterior and anterior uveitis, retinal vasculitis and thrombosis, cytoid macular degeneration, retinal detachment, and lymphocytic infiltrates in the iris (even during clinical remissions)
• Brain - Infarctions from vasculitis or thrombosis, meningoencephalitis, lymphocytic meningeal infiltration, or demyelinization
• Joint - Superficial inflammatory synovial infiltrates, mainly polymorphonuclear lymphocytes, and deposition of IgG in the synovium
• Gastrointestinal tract - Ulcerations from the buccal mucosa to the anus, intestinal perforation, peritonitis, infiltration with polymorphonuclear leukocytes and lymphocytes, hepatitis, cholecystitis, and pancreatitis
• Heart - Pericarditis, myocarditis, endocarditis, coronary arteritis, and myocardial fibrosis
• Lung - Serositis and vasculitis
• Kidneys - Glomerulonephritis

TREATMENT

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Medical Care

• Colchicine or azathioprine can be used for systemic manifestations, such as severe ulcers or skin disease. Antileprosy drugs, dapsone and thalidomide, and the immune modulator levamisole may be useful.
• Joint involvement may respond to prednisone, local corticosteroid injections, and nonsteroidal anti-inflammatory drugs (NSAIDs). Colchicine, sulfasalazine, and interferon-alpha also are used. Levamisole and azathioprine may be alternatives.
• Ocular disease is a feared complication. Treatment involves topical drops (ie, both mydriatic and corticosteroid drops). Successful immunosuppression is achieved with azathioprine, systemic corticosteroids, cyclosporine, chlorambucil, tacrolimus, or cyclophosphamide.
• Erythema nodosum is a special circumstance and may be treated with colchicine or dapsone.
• Central nervous system disease usually is treated with prednisone (or prednisolone), chlorambucil, or cyclophosphamide.
• Gastrointestinal lesions usually are treated with corticosteroids, sulfasalazine, or thalidomide.
• Thrombotic events are treated with anticoagulants.
• Vasculitis is treated with immunosuppressive medication, such as cyclophosphamide. Anticoagulants may increase the mortality in patients with pulmonary vasculitis.
• Tumor necrosis factor (TNF) antagonists, such as etanercept or infliximab may be effective.

Surgical Care

• Gastrointestinal perforations and subsequent peritonitis need surgical treatment.
• Aneurysms may require resection, as may ischemic tissues affected by vasculitis or thrombosis.
• Surgical excision has been performed for endocardial fibrosis.
• Ventricular aneurysms and coronary thrombosis may be amenable to surgery.
• Glaucoma, cataracts, or retinal detachment may require surgery, and neurosurgery may correct some central nervous system aneurysms or clots.

Consultations

• Rheumatology consultation
• Specialist consultations as needed
• • Urologist consultation for genital and urologic lesions
  • Neurologist for central nervous system involvement
  • Ophthalmologist for ocular disease
  • Gastroenterologist for intestinal disease
  • Dermatologist for possible help with recurrent skin lesions
  • Surgeon when indicated

Diet

• No general dietary recommendations exist.
• Patients with severe bowel involvement are advised to follow the recommendations of gastroenterologists for patients with inflammatory bowel disease.

Activity

Activity is suggested as tolerated and may be limited due to systemic symptoms or arthritis.

MEDICATION

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The drugs used generally are immunosuppressive. Because the cause of Behçet disease is unknown, therapy is directed at diminishing symptoms by suppressing the immune system. These medications may increase the risk of infection due to the nonspecific nature of immunosuppression. Symptomatic therapy is directed at specific complaints; for example, oral ulcers or arthritis.

Drug Category: Corticosteroids

May be used orally or parenterally for systemic symptoms, topically for ulcers or ocular involvement, or intra-articularly for arthritis.

Drug Category: Immunosuppressive agents

Decrease immune response that cause signs and symptoms of Behçet disease.

Drug Category: Immunomodulators

Affect the immune system in various ways, thus decreasing the autoimmune symptoms characteristic of Behçet disease. Immunomodulators do not, however, cause the generalized immunosuppression characteristic of immunosuppressive drugs.

FOLLOW-UP

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Further Inpatient Care

• Inpatient care is based on individual organ system involvement.
• In general, no further care is needed.

Further Outpatient Care

• As disease activity subsides, taper medications to the lowest dose that effectively controls the symptoms and disease activity.

In/Out Patient Meds

• These medications essentially are the same as those found empirically effective in controlling the manifestations of Behçet disease.

Transfer

• Individualize the transfer situation for each patient based on the particular organ system involvement.

Deterrence/Prevention

• Continual use of immunosuppressive medications may be required to suppress disease. Use the lowest dose required to control the manifestations of illness.

Complications

• Aneurysms are especially feared, and thrombotic events and vasculitis may lead to ischemia distal to the lesion.

Prognosis

• Prognosis is related to the site and severity of involvement.

Patient Education

• For excellent patient education resources, visit eMedicine's Arthritis Center, Eye and Vision Center, and Teeth and Mouth Center. Also, see eMedicine's patient education articles Canker Sores, Inflammatory Bowel Disease, and Iritis.

MISCELLANEOUS

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Medical/Legal Pitfalls

• No medical/legal issues exist other than the risk of misdiagnosis or failure to ascertain the extent of organ involvement.

MULTIMEDIA

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Media file 1:  Oral aphthous ulcers secondary to Behçet disease.
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REFERENCES

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Article Last Updated: Jul 5, 2006