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Behçet Disease

(Behçet's Disease)

By

Alexandra Villa-Forte

, MD, MPH, Cleveland Clinic

Last full review/revision Jul 2020| Content last modified Jul 2020
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Behçet disease is a multisystem, relapsing, chronic vasculitic disorder with mucosal inflammation. Common manifestations include recurrent oral ulcers, ocular inflammation, genital ulcers, and skin lesions. The most serious manifestations are blindness, neurologic or gastrointestinal manifestations, venous thromboses, and arterial aneurysms. Diagnosis is clinical, using international criteria. Treatment is mainly symptomatic but may involve corticosteroids with or without other immunosuppressants for more severe manifestations.

Behçet disease is an inflammatory disorder that can include a vasculitis of small and large arteries and/or veins. Arterial and venous thrombosis may occur as well.

The disease occurs nearly equally in men and women but tends to be more severe in men, typically beginning during their 20s. Occasionally, the disease develops in children. Incidence varies by location. Behçet disease is most common along the silk route from the Mediterranean to China; it is uncommon in the US.

The cause of Behçet disease is unknown. Immunologic (including autoimmune) and viral or bacterial triggers have been suggested, and HLA-B51 is a major risk factor. Prevalence of an HLA-B51 allele is > 15% among people from Europe, the Middle East, and the Far East but is low or absent among people from Africa, Oceania, and South America.

Neutrophil infiltration is detected in biopsy specimens from oral aphthous ulcers and erythema nodosum and pathergy lesions, but no histologic changes are pathognomonic.

Symptoms and Signs

Mucocutaneous

Almost all patients have recurrent, painful oral ulcers resembling those of aphthous stomatitis; in most, these ulcers are the first manifestations. The ulcers are round or oval, 2 to 10 mm in diameter, and shallow or deep with a central yellowish necrotic center; they can occur anywhere in the oral cavity, often in clusters. Ulcers last 1 to 2 weeks. Similar ulcers occur on the penis and scrotum, on the vulva where they are painful, or in the vagina where they may cause little or no pain.

Cutaneous lesions are common and may include acneiform lesions, nodules, erythema nodosum, superficial thrombophlebitis, pyoderma gangrenosum–type lesions, and palpable purpura.

Pathergy (an erythematous papular or pustular response to local skin injury) is defined as a papule > 2 mm that appears 24 to 48 hours after oblique insertion of a 20- to 25-gauge needle into the skin.

Ocular

The eyes are affected in 25 to 75% of patients. Eye manifestations may be associated with neurologic manifestations. The following may occur:

  • Relapsing uveitis or iridocyclitis (most common) often manifests as pain, photophobia, and red eye.

  • Hypopyon (a layer of pus visible in the anterior chamber) may occur.

  • Uveitis is typically bilateral and episodic, often involves the entire uveal tract (panuveitis), and may not resolve completely between episodes.

  • Choroiditis, retinal vasculitis, vascular occlusion, and optic neuritis may irreversibly impair vision and even progress to blindness.

Musculoskeletal

Relatively mild, self-limiting, and nondestructive arthralgias or frank arthritis, especially in the knees and other large joints, occur in 50% of patients. Sacroiliac inflammation can occur.

Vascular

Perivascular and endovascular inflammation may develop in arteries and veins. In arteries, thrombosis, aneurysm, pseudoaneurysm, hemorrhage, and stenosis can develop. Large-vessel arterial involvement is recognized during life in 3 to 5% of patients; however, at autopsy, one third of patients have evidence of large-vessel involvement that was asymptomatic during life. Aortic and pulmonary artery aneurysms can rupture. In situ thrombosis can cause pulmonary artery occlusion. Hemoptysis may occur if fistulas develop between the pulmonary artery and bronchus.

Venous involvement can cause superficial and deep venous thromboses. More than one vein may be affected, including the inferior and superior vena cava, the hepatic veins (causing Budd-Chiari syndrome), and the dural venous sinuses.

In situ arterial or venous thromboses, aneurysms, and pseudoaneurysms are more common than stenoses and occlusions.

Neurologic and psychiatric

Central nervous system involvement is less common but is serious. Onset may be sudden or gradual. The first manifestations may be parenchymal involvement with pyramidal signs, small-vessel disease with a multiple sclerosis–like pattern, or nonparenchymal with aseptic meningitis or meningoencephalitis, or dural sinus thrombosis. Aseptic meningitis, in the characteristic clinical setting, can suggest the diagnosis.

Psychiatric disorders including personality changes and dementia may develop years later. Peripheral neuropathy, common in other vasculitic disorders, is uncommon in Behçet disease.

Gastrointestinal (GI)

Abdominal discomfort, abdominal pain, and diarrhea with intestinal ulcers, occurring primarily in the ileum and colon and closely resembling Crohn disease, may occur.

Constitutional

Fever and malaise may occur.

Diagnosis

  • Clinical criteria

Behçet disease should be suspected in young adults with recurrent oral aphthous ulcers, unexplained ocular findings, or genital ulcers. Diagnosis of Behçet disease is clinical and often delayed because many of the manifestations are nonspecific and can be insidious.

International criteria for diagnosis include recurrent oral ulcers (3 times in 1 year) and 2 of the following:

  • Recurrent genital ulcers

  • Eye lesions

  • Skin lesions

  • Positive pathergy test with no other clinical explanation

Laboratory tests (eg, complete blood count, erythrocyte sedimentation rate or C-reactive protein, serum albumin and total protein levels) are done. Results are nonspecific but characteristic of inflammatory disease (elevated erythrocyte sedimentation rate, C-reactive protein, and alpha2-globulins and gamma-globulins; mild leukocytosis).

Differential diagnosis

Differential diagnosis includes

Behçet disease has no single pathognomonic finding but may be distinguished by its combinations of relapsing symptoms with spontaneous remissions and multiple organ involvement, particularly in patients with recurrent, deep mucosal ulcers.

Prognosis

Behçet disease typically has a waxing and waning course characterized by exacerbations and remissions. Prognosis tends to be worse if patients are young men. Risk also appears to be higher if patients have an HLA-B51 allele. Mucocutaneous and ocular lesions and arthralgias are often worse early in the disease. Central nervous system and large-vessel manifestations, if they develop, typically occur later. Occasionally, the disease results in death, usually due to neurologic, vascular (eg, aneurysms), or gastrointestinal manifestations. Risk of death is highest for young men and patients with arterial disease or a high number of flare-ups. Many patients eventually go into remission.

Treatment

  • Colchicine, dapsone, azathioprine, apremilast, thalidomide, anti-tumor necrosis factor (TNF) drugs, and/or interferon for mucosal disease

  • Azathioprine, methotrexate, cyclosporine, or anti-TNF drugs for eye disease

  • Anti-TNF drugs, cyclophosphamide, and chlorambucil for refractory, severe central nervous system, or life-threatening disease

Treatment of Behçet disease depends on the clinical manifestations. Treatment recommendations are limited by incomplete data from clinical studies (eg, cross-sectional studies, usually not prospective, limited statistical power).

Topical corticosteroids may temporarily relieve ocular manifestations and most oral lesions. However, topical or systemic corticosteroids do not alter the frequency of relapses. A few patients with severe uveitis or central nervous system manifestations respond to high-dose systemic corticosteroids (eg, prednisone 60 to 80 mg orally once a day).

Anti-TNF drugs appear to be effective for a wide range of manifestations, including gastrointestinal manifestations and ocular disease (eg, severe refractory uveitis), and decrease the number of attacks. In severe cases of gastrointestinal and ocular attacks, an anti-TNF drug can be used in combination with another drug such as azathioprine. Infliximab, in particular, has the advantage of rapid onset of action.

Immunosuppressants, including anti-TNF drugs, improve the prognosis for patients with vascular involvement. Immunosuppressants help prevent recurrence of venous thrombosis, but it is unclear whether anticoagulation does. Anticoagulation is contraindicated in patients with pulmonary arterial aneurysms.

Mucosal disease

Mucosal disease can be managed symptomatically. Topical corticosteroids, local anesthetics, and sucralfate are helpful.

Colchicine 0.6 mg orally twice a day may decrease the frequency and severity of oral or genital ulcers and may be effective for erythema nodosum and arthralgias. Colchicine, which was hypothesized to decrease the need for later immunosuppressive therapy when used early in the disease course, has not been shown to do so.

Dapsone 50 to 100 mg orally once a day may decrease the number, duration, and frequency of oral and genital lesions. Patients should first be tested for glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Azathioprine 2.5 mg/kg orally once a day has been shown to improve oral and genital ulcers.

Apremilast, an oral phosphodiesterase type 4 inhibitor, has been shown to decrease the number of oral ulcers and pain.

Thalidomide 100 to 300 mg orally once a day may be used to treat oral, genital, and skin lesions, but lesions may recur when treatment is stopped.

The anti-TNF drug etanercept, 50 mg subcutaneously once a week or 25 mg subcutaneously twice a week, may suppress mucocutaneous lesions. Etanercept can be given if colchicine is ineffective. Sometimes another anti-TNF drug (infliximab or adalimumab) is used instead of etanercept.

Interferon alfa-2a 6 million units 3 times a week can also be given if colchicine is ineffective.

Ocular disease

Azathioprine 2.5 mg/kg orally once a day helps preserve visual acuity and prevent new eye lesions. Azathioprine is also useful for mucocutaneous lesions and arthralgia.

Methotrexate 15 to 25 mg orally once a week has been useful in reducing eye inflammation.

Cyclosporine 5 to 10 mg/kg orally once a day may be reserved for patients with severe ocular manifestations and may be used with azathioprine to treat refractory uveitis.

Interferon alfa-2a 6 million units subcutaneously 3 times a week and infliximab (a TNF inhibitor) 3 to 10 mg/kg IV at 0, 2, and 4 weeks and then every 8 weeks show promise for patients with ocular manifestations.

Refractory or life-threatening disease

Cyclophosphamide, chlorambucil, and anti-TNF drugs are used in patients with refractory disease, life-threatening conditions (eg, pulmonary aneurysms), or central nervous system manifestations. A trend toward longer event-free survival has been observed in patients with severe neurologic manifestations after treatment with IV cyclophosphamide than with azathioprine.

Key Points

  • Behçet disease is a relapsing inflammatory disorder characterized by prominent mucosal inflammation often with vasculitis of large and small vessels.

  • Among the many organ systems involved, oral and genital ulcers, skin lesions, aseptic meningitis, and ocular findings, particularly in combination, are very characteristic.

  • Diagnose based on specific clinical criteria.

  • Risk factors for early death are male sex, frequent disease flare-ups, and arterial complications (eg, thrombosis, aneurysms, pseudoaneurysms).

  • Treat with cyclophosphamide, chlorambucil, or anti-TNF drugs (for life-threatening disease), azathioprine, methotrexate, cyclosporine, or anti-TNF drugs (for eye disease), and colchicine, dapsone, azathioprine, apremilast, thalidomide, anti-TNF drugs, and/or interferon (for mucosal disease).

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