Knowledge on rare diseases and orphan drugs

Exact prevalence is unknown. From a Danish registry, the annual incidence was estimated to be 1/1,670,000/ year for children <5 years of age.

Skin rash (of tiny red/tan dots) is usually the first manifestation and appears as early as the age of 1 month on the face and then spreads to the trunk. Patients can have intermittent episodes of skin lesions that resolve without treatment. Joint manifestations usually begin before the age of 10 with painless cyst-like swellings on the back of feet and wrists. Symmetric arthritis (with boggy inflammatory synovitis and tenosynovitis) of the wrists, ankles, knees and sometimes elbows follows. Camptodactyly due to hypertrophic tenosynovitis is often described as the disease progresses. Severe handicap is not usually experienced until the age of 40-50. An insidious granulomatous iridocyclitis and posterior uveitis can evolve into a severe destructive panuveitis. Over time, characteristic iris nodules, focal synechiae, cataract, increased intraocular pressure and characteristic clumpy keratic precipitates at the limbus ensue. Posterior involvement includes vitritis, multifocal choroiditis, retinal vasculopathy and optic nerve edema. Significant visual loss is observed in 20-30% of the affected individuals. The spectrum of clinical manifestations includes fever, malignant systemic and pulmonary hypertension, granulomatous large-vessel vasculitis and granulomatous inflammation of the liver, kidneys and lung.

BS is due to an inherited or de novo mutation in the NOD2 gene (16q12), responsible for alterations in the innate immune response, inflammation and cell death. From transfection studies, it has been proposed that NOD2 mutations cause activation of nuclear factor kappa B which is in turn an up-regulator of pro-inflammatory cytokine transcription.

Diagnosis relies greatly on the demonstration of noncaseating granulomatous inflammation with epithelioid cells and multinucleated giant cells on a skin, synovial or conjunctival biopsy, and genetic testing for mutations in the NOD2 gene.

Differential diagnoses include polyarthritis and systemic juvenile idiopathic arthritis (JIA), granulomatous inflammation associated with primary immunodeficiencies, and systemic granulomatous vasculitis. In patients with granulomatous inflammation, chronic infections especially with mycobacteria and fungi must be excluded.

Antenatal diagnosis and prenatal genetic testing is rarely performed.

BS is an autosomal dominant disorder in the familial form and genetic counseling is advised.

There is no evidence-based data on the optimal treatment of BS. Moderate to low-dose daily corticosteroid therapy is effective in controlling uveitis and joint disease but the side effects of prolonged use may become unacceptable. Methotrexate at a dosage of 10-15 mg/m² once weekly is effective in suppressing disease activity and allowing corticosteroid tapering. The introduction of anti-TNF monoclonal antibody agents (infliximab and adalimumab) may constitute a major therapeutic advance in the treatment of BS; however, the effect on uveitis activity may be less convincing.

BS is a chronic and progressive disease with a variable and often unpredictable spectrum of severity. In cases with expanded manifestations, life expectancy may be reduced. Uveitis has a poor prognosis.

Last update: December 2012 - Expert reviewer(s): Dr Carlos ROSE - Pr Carine WOUTERS