AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

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

INTRODUCTION

Section 2 of 10  

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

Background

Behçet syndrome is a multisystem disease probably first described by Hippocrates in the 5th century. The syndrome carries the name of the Turkish dermatologist Hulusi Behçet, who, in 1937, described a syndrome of recurrent aphthous ulcers, genital ulcerations, and uveitis leading to blindness. Although the cause of the disease is still unknown, it has become recognized as a multisystemic inflammatory disease.

Pathophysiology

Behçet syndrome is characterized by recurrent aphthous ulcers, genital ulcers, and uveitis or retinal vasculitis. Other manifestations of the disease include skin lesions, arthritis, gastrointestinal lesions, central nervous system (CNS) involvement, and vascular lesions, including aneurysms and thrombosis. In Behçet syndrome, the basic lesion is vasculitis. Biopsies have shown vasculitis near lesions of Behçet syndrome, including the oral and genital ulcers and lesions of the CNS and the eyes; large vessels are affected by a vasculitis of the vasa vasorum. Vascular injuries may be superimposed on the hypercoagulability observed in some patients.

Neutrophilic hyperfunction is observed in patients with Behçet syndrome with neutrophilic infiltration of skin at the site of a prick with a sterile needle (the pathergy test). Lymphocyte function has also been reported as abnormal, with a clonal expansion of autoreactive T cells.

Frequency

United States

Frequency data for Behçet syndrome should be considered suspect because of problems with case ascertainment. This problem is inherent in any disease where no specific diagnostic test exists and only a set of clinical criteria is used for diagnosis. Figures available from Olmstead County, Minnesota reveal prevalence in this community to be 5 cases per 100,000 persons. Other estimates of prevalence vary from 0.12-0.33 cases per 100,000 persons.

International

Behçet syndrome is thought to be more common along the ancient Silk Road, extending from Asia to the Mediterranean. Estimates from Turkey vary from 80-370 cases per 100,000 population, while prevalence estimates from Japan, Korea, China, and the Middle East vary from 13-20 cases per 100,000 population. In northern Spain, prevalence has been reported as 0.66 cases per 100,000 population, while estimates from Germany are 2.26 cases per 100,000 population.

Mortality/Morbidity

• Ocular: Uveitis occurs in 60-80% of patients. Retinal arterial and venous lesions are prognostic indicators for blindness, which is a major complication of Behcet syndrome. In Middle Eastern populations, the mean time from onset of disease to blindness is 3-4 years in untreated patients or in those treated only with corticosteroids.
• CNS: Neurologic involvement is one of the most serious manifestations of Behçet syndrome, occurring in 10-30% of patients and carrying a poor prognosis. Manifestations include meningitis or meningoencephalitis; psychiatric symptoms, including personality changes; neurological deficits, including hemiparesis; and brainstem symptoms. Neurological deficits may be progressive, with 30% of those patients with neurologic manifestations eventually developing dementia.
• Vascular: Vascular involvement in Behçet syndrome is unique in that it is the only vasculitic disease that involves both the arterial and venous systems. Vascular complications, which occur in 7-40% of patients, include venous and arterial thromboses, vessel occlusions and stenoses, and aneurysm formation. Venous involvement typically includes superficial thrombophlebitis or deep venous thrombosis, usually of the lower extremities. Vena cava thrombosis can also occur, with extension to the hepatic vein, leading to Budd-Chiari syndrome and its associated morbidity and mortality. Patients with arterial manifestations may present with thrombosis or aneurysm formation with possible fatal rupture, especially if pulmonary arteries are involved.

Race

Behçet syndrome is thought to be more common in Turkish, Asian, and Middle Eastern populations. However, the severity of disease may be increased in these populations, with better case ascertainment as a result. An increased incidence of skin pathergy and HLA-B5 antigen is observed in Middle Eastern and Asian patients, compared to North American or northern European patients.

Sex

In Japan and Korea, Behçet syndrome is more common in females, with a male-to-female ratio of 1:2, but it is more common in males in the Middle East, with a male-to-female ratio of 2:1. In the literature, estimates of male-to-female ratios range from 11:1 to 0.2:1. Despite the variability of the reported sex ratios, the disease tends to run a more severe course in males.

Age

Onset typically occurs in patients in the late third and early fourth decades of life. Onset during the childhood years is well recognized, but Behçet syndrome rarely occurs before school age. Mean age of onset for pediatric patients in a large Turkish series was 11.7 years.

CLINICAL

Section 3 of 10  

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

History

Two sets of criteria are commonly used for diagnosis of Behçet syndrome: an international criteria for Behçet syndrome, derived in 1990, and the O'Duffy criteria. Both sets of criteria may be too stringent for application in children who have lower risk for oral or genital ulcerations from other causes.

• The international criteria include recurrent oral ulcerations, plus 2 of the following:
• • Recurrent genital ulcerations
  • Eye lesions
    • Anterior uveitis
    • Posterior uveitis
  • Cells in the vitreous
  • Retinal vasculitis
  • Skin lesions
    • Erythema nodosum
    • Pseudo folliculitis
    • Papulopustular lesions
    • Acneiform nodules (in a postadolescent patient not taking corticosteroids)
  • Positive pathergy test
• The O'Duffy criteria require the presence of recurrent aphthous ulcerations, plus any 2 of following:
  • Genital ulcers
  • Uveitis
  • Cutaneous pustular vasculitis
  • Synovitis
  • Meningoencephalitis
  • Exclusion of inflammatory bowel disease, systemic lupus erythematosus (SLE), Reiter syndrome, and herpetic infections
• Oral ulceration, the hallmark of this disease, is usually the initial clinical symptom and can precede other manifestations by years. Ulcers are typically painful, appear in crops, and are nonscarring. For diagnostic purposes, at least 3 episodes in a 12-month period are required. In one study of pediatric Behçet syndrome, the average time interval between the initial oral ulceration and the second manifestation was 8.8 years.
• Genital ulcers appear in the vulva and vagina in females and scrotum and penis in men. Ulcers are painful, recurring, and scarring.
• Ocular manifestations may be asymptomatic initially, or may present quite dramatically with hypopyon uveitis. Patients may report blurred vision, eye pain, photophobia, increased lacrimation, and erythematous conjunctiva.
• Skin manifestations are nonspecific and include erythema nodosum, folliculitis, and pustular rash.
• Arthralgias and arthritis can occur in small or large joints. Sacroiliitis has been described in HLA-B27–positive patients.
• Gastrointestinal symptoms are common and include abdominal pain, diarrhea, and melena. Perforation may occur.
• CNS involvement may occur in up to 25% of children and is the most severe manifestation of the disease. Patients with meningoencephalitis present with headache and stiff neck; focal neurological abnormalities can also be observed. Neuropsychiatric symptoms include hallucinations and personality changes. Other features that have been described include brainstem lesions; pseudotumor cerebri; cranial nerve palsies; and pyramidal, extrapyramidal, and cerebellar symptoms.
• Vascular manifestations are varied and depend on the type and location of the vessel involved. The most common vascular complaints are secondary to venous thrombosis, often of the superficial veins. This can occur after venipuncture. Patients who develop superficial thrombophlebitis are more at risk than other patients with Behçet syndrome for the development of deep vein thrombosis and arterial disease. Well-known syndromes of large venous occlusions, such as Budd-Chiari syndrome or superior vena-caval syndrome, may occur. Patients with cerebral venous thrombosis develop signs and symptoms of increased intracranial pressure, such as headache and visual blurring. Arterial occlusions may present with symptoms related to ischemia. Cigarette smoking may be a risk factor for arterial disease in Behçet syndrome.
• Pulmonary manifestations include pulmonary vasculitis and pulmonary arterial aneurysm formation; patients may present with hemoptysis, dyspnea, chest pain, or cough.

Physical

• Physical findings vary, reflecting the disease manifestations in a particular patient.
• • Oral ulcerations: Ulcers are typically 2-15 mm in diameter, with a necrotic center and surrounding red rim. A white or yellow pseudomembrane covers the surface of the ulcer. The ulcers are typically painful, nonscarring, and found on the lips, buccal mucosa, tongue, tonsils, and larynx. Most last 7-14 days and occur in crops.
• • Genital ulcerations: These typically occur less often than the oral ulcerations. The ulcers occur on the scrotum and vulva, are painful and heal with scarring, especially on the scrotum. Genital ulcerations tend to be deeper and larger than the oral lesions. Females can have asymptomatic ulcers, especially in the vagina.
  • Ocular manifestations: Uveitis can occur in both the anterior and posterior chambers of the eye. Frank pus (hypopyon) may be observed in the anterior chamber. Retinal vasculitis is the most serious ocular finding. Vaso-occlusive lesions of the retinal vessels may cause a progressive decreased visual acuity. A slit lamp examination is necessary for diagnosis of uveitis, and fluorescein angiography is useful to identify retinal lesions.
  • Skin manifestations: Erythema nodosum lesions typically occur on the extremities, especially the lower legs, but they can also be observed on the face, neck, and buttocks. The lesions are painful and resolve spontaneously, although some may ulcerate. Lesions may leave a hyperpigmented area on the skin. A folliculitislike rash, resembling acne vulgaris, appears on the face, neck, chest, back, and hairline of patients. Some lesions become more pustular. Twenty-four to 48 hours after a sterile needle prick, some patients develop erythema with a nodule or pustule at the prick site. This pathergy response is commonly observed in patients from Asia and the Middle East and is uncommon in northern European and North American patients.
  • Skeletal involvement: Monoarthritis or polyarthritis occurs in at least 50% of patients. Knees are the most commonly affected joints, followed by wrists, ankles, and elbows. The arthritis is typically nonerosive.
  • Gastrointestinal manifestations: In addition to the oral mucosa, ulcerative lesions may occur anywhere in the gastrointestinal tract. Most commonly, ulcers occur in the ileocecal region. Other involved areas include the transverse and ascending colon and the esophagus. Anticoagulation is controversial in patients with Behçet syndrome because of the risk of bleeding from one of these ulcers.
  • CNS involvement: CNS involvement occurs in up to 25% of patients and may be the most serious manifestation of disease. Findings may include meningitis, encephalitis, focal neurological deficits, and psychiatric symptoms. The CNS lesions may have exacerbations and remissions. In some patients, irreversible dementia ultimately results.
• Vascular involvement
• • Venous involvement includes migratory superficial thrombophlebitis of the skin and deep venous thrombosis. Patients with lower extremity deep vein thrombosis may have distal edema. With chronic venous occlusion, collateral circulation may develop.
  • Arteritis may involve the aorta or its branches and lead to aneurysm formation. Rupture of aneurysms may be fatal. Pulmonary artery involvement may result in aneurysm formation with pulmonary artery–to–bronchus fistula formation and resultant hemoptysis. Aneurysm formation carries a worse prognosis than occlusive disease. Patients with pulmonary aneurysms often have extrapulmonary vascular complications, such as superficial or deep vein thrombosis.
  • Cardiac valves may develop vegetations with subsequent emboli. Clinically, these lesions are similar to bacterial endocarditis, but cultures are negative, and round cell infiltration is most typically observed on histology. Right ventricular thrombi may also develop, and are frequently found in patients with pulmonary aneurysms.
  • Nephrotic syndrome and kidney amyloidosis have rarely been described in patients with Behçet syndrome.
• Muscular involvement: Myositis has been described in pediatric Behçet syndrome.

Causes

The etiology of Behçet syndrome is unknown. Behçet syndrome is thought to be caused by a combination of hereditary and environmental factors. The HLA-B51 allele (one of the split antigens of B5) is commonly found in patients from Asia and the Middle East, yet it is rarely found in northern European and North American patients. Infections may play a pathogenic role, as patients who have Behçet syndrome have a higher incidence of antibodies to herpes simplex virus, hepatitis C virus, and parvovirus B19. Streptococcal antigens have also been implicated; a trial of prophylactic penicillin treatment decreased the number of acute arthritis episodes in patients with Behçet syndrome.

Patients who have a parent with Behçet syndrome have disease onset at a younger age (genetic anticipation). In addition, pediatric patients are more likely to have a family history of Behçet syndrome, compared to patients with disease onset as an adult.

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to be Considered

Primary antiphospholipid antibody syndrome
Multiple sclerosis
Stevens-Johnson syndrome
Familial Mediterranean fever
PFAPA- Syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis

WORKUP

Section 5 of 10  

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

Lab Studies

• No specific laboratory test result is diagnostic of Behçet syndrome.
• • Serum complement levels are within the reference range, except for just prior to eye or mucous membrane involvement, at which time they may be decreased.
  • Sedimentation rate or C-reactive protein may be elevated. Anemia of chronic disease is common, and a neutrophil leukocytosis is seen in about 15% of patients.
  • HLA-B51 may be present in patients of Asian, Mexican, or Middle Eastern descent.
  • Anticardiolipin antibodies are present in up to 30% of patients.
• Systemic lupus erythematosus and other vasculitic syndromes must be ruled out. Patients with Behcet syndrome have negative antinuclear and antineutrophilic cytoplasmic antibodies.
• In patients with CNS findings, cerebral spinal fluid pleocytosis may be present.
• In addition to thrombosis associated with antiphospholipid antibodies, reports exist of thrombosis in Behçet syndrome associated with factor V Leiden mutations and with prothrombin G20210A mutations.

Imaging Studies

• Brain MRI and/or computed tomography (CT) scanning for visualization of the neurological lesions is often helpful in patients with CNS involvement. Focal lesions may be observed anywhere in the CNS on the MRI, appearing as high signal on the T2-weighted images and low signal on the T1-weighted images. Flare images may be especially helpful. Enlargement of ventricles or subarachnoid spaces may be observed. However, the MRI findings of the brain may be normal even in the presence of neurologic involvement. Neuropsychologic testing results may be abnormal prior to any detectable lesions on neuro-imaging.
• Angiography shows areas of aneurysm formation and thrombosis.
• Echocardiography is useful in patients with murmurs because it is useful for diagnosing the valve vegetations and ventricular thrombi, which can occur in Behçet syndrome.

Other Tests

• Endoscopy of the gastrointestinal (GI) tract is useful for detecting gastrointestinal ulcerations.
• A thorough eye examination by an experienced ophthalmologist is essential. Consider fluorescein angiography for evaluation of retinal vessels. Follow-up visits with an ophthalmologist should be scheduled at least every 6-12 months.
• Neuropsychologic testing may be useful with CNS involvement, revealing memory impairment or personality changes, and can be useful in monitoring neuropsychologic status.

Histologic Findings

Behçet syndrome is diagnosed clinically, not by means of tissue evaluation. However, round cell infiltration may be found in cardiac valve lesions. Biopsy of the buccal and genital ulcers reveals lymphocytic and plasma cell invasion in the prickle cell layer of the epidermis. Dermal vessels are infiltrated with lymphocytes and plasma cells with immune deposits of immunoglobulin M (IgM) and C3. Occasionally, necrotizing vasculitis is observed.

TREATMENT

Section 6 of 10  

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

Medical Care

Treatment must be tailored to each patient's clinical manifestations. Corticosteroids are considered palliative; they are useful in controlling acute manifestations, but progression of CNS and ocular disease may occur in patients treated with corticosteroids alone. Cytotoxic medications are usually indicated in patients with ocular, CNS, and vascular disease. Biologic medications are also being used in patients with these complications. Decreasing morbidity and mortality is the goal of treatment for children with Behçet syndrome.

Surgical Care

Surgical resection of aneurysms with graft placement should be considered if feasible because of the high risk of aneurysmal rupture. However, complications of arterial surgery, such as aneurysms at the surgical site (similar to a pathergylike effect) and local thrombus formation, commonly occur.

Consultations

A rheumatologist should be consulted for all patients with Behçet syndrome. For children, a pediatric rheumatologist is preferable. Consider other consultations depending on patient signs and symptoms.

• All patients should have regular eye examinations by an ophthalmologist experienced with vasculitis.
• Consultation with a neurologist should be considered for patients with CNS symptoms.
• A consultation with a gastroenterologist is appropriate for evaluation and management of abdominal symptoms.
• Consultation with a vascular surgeon is important for patients with aneurysm formation.

Diet

No specific dietary recommendations are needed for patients with Behçet syndrome. However, patients on long-term corticosteroid treatment should avoid excessive weight gain and follow a low-salt, low-fat diet.

Activity

Restriction of activity should be tailored to a patient's clinical manifestations.

MEDICATION

Section 7 of 10  

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

Choice of medications depends on a patient's clinical manifestations. Ocular, CNS, and large vessel involvement requires aggressive medical treatment. Corticosteroids have a suppressive effect on most manifestations of Behçet syndrome, but they do not prevent dementia or blindness. Cytoxic therapies have been shown to be more effective. Close communication between subspecialists, such as ophthalmologists and neurologists, is important for patient care.

Drug Category: Antigout medications

These agents are useful in decreasing frequency of mucosal ulcerations, the skin findings of pseudofolliculitis and erythema nodosum, and can be useful in the management of uveitis and retinal vasculitis.

Drug Category: Corticosteroids

This agent decreases acute inflammatory manifestations of Behçet syndrome. Depending on patient needs, this agent may be administered topically, orally, parenterally, or by intraocular injection.

Drug Category: Immunosuppressant agents

These agents are used for the more serious long-term effects of Behçet syndrome, ie, ocular and CNS involvement, severe vasculitis.

Drug Category: Immunomodulatory agent

Thalidomide has a broad range of immunomodulatory properties. Use of this drug is limited by well-documented teratogenicity and potentially irreversible peripheral neuropathy.

Drug Category: Tumor necrosis factor antagonists

Blockade of TNF-alpha by biologics have been shown in uncontrolled reports to be beneficial in uveitis, severe GI disease, severe ulcerations, and CNS vasculitis. Long-term efficacy is unknown.

Drug Category: Rheostatic agents

These agents are used to improve peripheral blood flow and to improve delivery of oxygen to tissue suffering from vascular disease.

FOLLOW-UP

Section 8 of 10  

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

Further Inpatient Care

• Patients may need to be admitted during acute flares for IV therapy or for diagnostic testing or surgical intervention.

Further Outpatient Care

• Close follow-up care is warranted to monitor clinical status, including routine eye examinations.

In/Out Patient Meds

• Medications (see Medication) vary depending on the clinical manifestations. Monitor drug side effects and efficacy closely.

Transfer

• Transfer to a tertiary care center for diagnosis and intervention may be warranted, depending on the clinical symptomatology.

Deterrence/Prevention

• No preventative measures are known for Behçet syndrome.

Complications

• Complications include those caused by medications and the primary disease, and they vary depending on clinical presentation and disease manifestations.

Prognosis

• Prognosis depends on clinical manifestations. The worst prognoses are associated with retinal vasculitis, leading to blindness; vascular aneurysm formation, with possible rupture; and neuro–Behçet syndrome, which may lead to dementia despite appropriate aggressive treatment.

Patient Education

• Patients must be educated in disease manifestations, long-term prognosis, and medication side effects.

MISCELLANEOUS

Section 9 of 10  

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

Medical/Legal Pitfalls

• Most of the drugs used to treat Behçet syndrome are immunosuppressive, with associated risk of serious life-threatening infections that patients should be warned about. In addition, cytotoxics increase the risk of malignancy, and communication of these risks should be clearly delineated and documented in the medical record.

REFERENCES

Section 10 of 10

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

• Alpsoy E. Behcet's disease: treatment of mucocutaneous lesions. Clin Exp Rheumatol. Jul-Aug 2005;23(4):532-9. [Medline].
• Fresko I, Soy M, Hamuryudan B, et al. Genetic anticipation in Behcet''s syndrome. Ann Rheum Dis. 1998;57:45-8. [Medline].
• Gerber S, Biondi A, Dormont D, et al. Long-term MR follow-up of cerebral lesions in neuro-Behcet''s disease. Neuroradiology. Nov 1996;38(8):761-8. [Medline].
• Ihle J, Kummerle-Deschner J, Orlikowsky T, et al. Factor V Leiden and venous thrombosis in a 4-yr-old girl with Behcet''s syndrome. Rheumatology (Oxford). Feb 2000;39(2):209-10. [Medline]. [Full Text].
• Kone-Paut I, Geisler I, Wechsler B, et al. Familial aggregation in Behcet''s disease: high frequency in siblings and parents of pediatric probands. J Pediatr. Jul 1999;135(1):89-93. [Medline].
• Lanthier N, Parc C, Scavennec R, et al. Infliximab in the treatment of posterior uveitis in Behçet's disease. Long term follow up in four patients. Presse Med. Jul 23 2005;34(13):916-8. [Medline].
• Marshall SE. Behcet's disease. Best Pract Res Clin Rheumatol. Jun 2004;18(3):291-311. [Medline].
• Martini A. Behcet''s disease and Takayasu''s disease in children. Curr Opin Rheumatol. Sep 1995;7(5):449-54. [Medline].
• 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].
• Nakamura S, Ohno S. Anti-tumor necrosis factor alpha antibody in the treatment of Behcet's disease. Int Ophthalmol Clin. 2005;45(2):179-89. [Medline].
• Oktem-Tanor O, Baykan-Kurt B, Gurvit IH, et al. Neuropsychological follow-up of 12 patients with neuro-Behcet disease. J Neurol. Feb 1999;246(2):113-9. [Medline].
• Rakavor Y, Adar H, Tal I, et al. Behcet Disease: Long-term follow-up of three children and review of the literature. Pediatrics. 1989;83:986-92. [Medline].
• Sakane T, Takeno M, Suzuki N, Inaba G. Behcet''s disease. N Engl J Med. Oct 21 1999;341(17):1284-91. [Medline].
• Yazici H, Pazarli H, Barnes CG, et al. A controlled trial of azathioprine in Behcet''s syndrome. N Engl J Med. Feb 1 1990;322(5):281-5. [Medline].

Article Last Updated: Jun 14, 2006