Epidemiology

The disease is reported commonly in the Mediterranean basin and Asia along the trading route, the so-called Silk Road, and is relatively rare in Europe and the USA. Among the populations of these areas, the estimated prevalence in adults ranges between 20 and 421/ 100,000, although in Europe the prevalence range is 0.6-6.4/100,000. The condition is uncommon in children, who account for an estimated 5% of cases. Most of the pediatric cases are diagnosed in late childhood, although disease symptoms may begin much earlier. On the basis of case reports and the later few series in children, the mean age of onset is 7.5 yr, and the mean age at which patients meet the diagnostic criteria for the diagnosis is 12 yr. The male : female ratio ranges from 1 : 1.2 to 1 : 1.4. No sex predominance is seen in adult-onset Behçet disease.

Etiology and Pathogenesis

The etiology of Behçet disease is unknown, although both genetic and environmental factors may play a significant role in triggering the inflammatory process. Excessive T helper type 1 (Th1) cell activity and increased expression of heat shock proteins (especially HSP60) occur in patients with Behçet disease.

In areas of the world with a high prevalence of disease (along the old Silk Road), HLA-B51 allele located on chromosome 6p has been the most strongly associated risk factor. HLA-B51 may serve as an immunogenetic marker for a subgroup of patients with enhanced neutrophil function and eye involvement. A few cases of transient neonatal Behçet disease in offspring of mothers with the disease have been reported, suggesting that an antibody-mediated immune process may also have a role in the pathogenesis. The basic pathologic lesion is vasculitis of small and medium-sized arteries, with cellular infiltration leading to fibrinoid necrosis and narrowing and obliteration of the vessel lumens. Necrotizing and granulomatous inflammation of large vessels such as the aorta and pulmonary artery may also occur. There is speculation that Behçet disease is an autoinflammatory disease similar to sarcoidosis and inflammatory bowel disease and is caused by dysregulation of the innate immune system.

Clinical Manifestations

The clinical course is highly variable, with recurrent exacerbations and disease-free intervals of uncertain duration. The most consistent symptom is painful, shallow oral ulcers, usually 2-10 mm in diameter with surrounding erythema, that develop on the buccal mucosa, gingiva, lips, and tongue, persist for days to weeks, and then heal without scarring in 1-3 wk. These oral necrotic ulcers may occur singly or in crops, with a mean of 13 attacks per year. Genital (labia, scrotum, penis) ulcers occur in most patients and follow a parallel course but may heal with scars. Skin manifestations occur in most patients and include erythema nodosum, papulopustular lesions, pseudofolliculitis, and acneiform nodules. Cutaneous pathergy is often present, manifesting as an erythematous sterile pustule that develops 24-48 hr after a needle prick. Ocular manifestations, including anterior or posterior uveitis and retinal vasculitis, occur less frequently in children than in adults but are more severe in the pediatric population and may progress to blindness. Arthritis is common and is usually acute, recurrent, asymmetric, and polyarticular, involving the large joints. Gastrointestinal involvement is variable in different populations and is seen more frequently in Japan. Clinical features include abdominal pain, dyspepsia, and intestinal mucosal ulcerations, especially in the ileocecal region. Central nervous system abnormalities, such as meningoencephalitis, cranial nerve palsies, and psychosis, usually occur later in the course of the disease and indicate a poor prognosis. Fever, orchitis, myositis, pericarditis, nephritis, splenomegaly, and amyloidosis are rare manifestations. There is an increased risk for thrombophlebitis and large vessel thrombosis, including involvement of the superior or inferior vena cava and hepatic veins (Budd-Chiari syndrome).

Diagnosis

The diagnosis of Behçet disease is not usually confirmed until the patient is 20-30 yr of age. The International Study Group criteria for diagnosis of Behçet disease are oral aphthae that recur at least 3 times within 12 mo accompanied by 2 of the following: recurrent genital ulcerations, eye lesions (anterior or posterior uveitis, or retinal vasculitis), skin lesions (erythema nodosum, pseudofolliculitis, or acneiforme nodules), and a positive pathergy test result. These criteria have 91% sensitivity and 96% specificity in adults. Laboratory tests are not diagnostic, although the finding of HLA-B51 supports the diagnosis.

Differential Diagnosis

The differential diagnosis of Behçet disease includes herpes simplex virus infection, inflammatory bowel disease, recurrent aphthous stomatitis, and complex aphthosis (recurrent oral and genital aphthous ulcers or ≥3 persistent oral aphthae). In addition, Stevens-Johnson syndrome and familial Mediterranean fever (in some areas) need to be considered.

Treatment

Treatment is based on anecdotal reports. Many drugs, including corticosteroids, colchicine, chlorambucil, azathioprine, cyclosporine, and tacrolimus, have been used. Colchicine is effective against of Behçet disease and shows higher efficacy in children than in adults, especially for oral ulcers, skin rash, joint symptoms, and, occasionally, eye disease. Thalidomide has been reported to be a highly effective and useful therapeutic option for severe oral, genital, and intestinal ulcerations that are unresponsive to other therapies. The successful use of anti–tumor necrosis factor-α (TNF-α) therapy in severe or intractable cases of Behçet disease suggests that these agents may also have a role in its management. The most commonly used anti–TNF-α agent has been infliximab, especially in childhood cases associated with refractory uveitis. In the only placebo-controlled trial, etanercept significantly decreased the mean number of oral ulcers and nodular and papulopustular lesions. Interferon alpha-2a has been used successfully to treat adult patients with Behçet disease. This agent is efficacious and safe in children with corticosteroid-dependent uveitis, allowing tapering of corticosteroid doses. Symptomatic treatment of oral ulcerations may include oral rinses with solutions containing tetracycline, topical anesthetics, and chlorhexidine gluconate.

Complications and Prognosis

Behçet disease has a variable clinical course with exacerbations and remissions, with the serious complications occurring many years after diagnosis. Blindness may result from posterior uveitis. Gastrointestinal lesions resembling orogenital aphthae occur most commonly in the ileocecal region and rarely lead to perforation. Central nervous system complications include venous sinus thrombosis and parenchymal involvement. Mortality is low and is usually attributable to bowel perforation, thrombosis, or central nervous system involvement.