Knowledge on rare diseases and orphan drugs

Behçet disease (BD) is most often reported in populations along the Silk Road, with highest prevalence reported in Turkey at >1/1,000, versus 1/10,000 in Japan. European cases are more often described in Mediterranean countries.

Onset most commonly occurs in adults (mean 30 years of age), but pediatric cases have been reported. Relapsing episodes of round oral aphthae with sharp erythematous and elevated borders (1-3 cm diameter) may be accompanied by genital aphthae (>50% of cases); cutaneous features may include pseudo-folliculitis and erythema nodosum. Ocular disorders (posterior uveitis, retinal vasculitis) occur in over 50% of BD patients. Arthralgia and/or non-erosive, asymmetric, arthritis affecting mainly large articulation (knees, ankles ect.) are frequent (45%) and can occur as an initial symptom. Vasculitis in BD is more frequent in the venous system where thromboses in femoro-iliac, superior and inferior vena cava and cerebral territories may occur. Rarer arterial thromboses and aneurysms primarily affect the pulmonary and aorta vessels. Neurological manifestations (neuro-BD) are frequent (>20%), and may include headache, fever, pyramidal signs with hemiparesis, cranial nerve damage, meningitis, behavioral changes and sphincter dysfunction. Aphthoid and/or ulcerative lesions may affect the whole digestive tract but mainly the ileo-caecum and ascending colon, potentially leading to hemorrhages and perforations.

Of unknown origin, genetic predisposition in BD may allow certain infectious (in particular Streptococcus sanguis) and/or environmental insults to trigger symptoms involving sporadic inflammatory attacks reminiscent of auto-inflammatory disorders due to cross reactions with oral mucosa antigens. HLAB5101 antigen is associated to BD in 50-60% of patients. NF-kB activation and aberrant cytokine levels (eg- IL-6, TNF-a, IL-8, IL-12, IL-17 and IL-21) have been implicated in the pathogenesis of BD. A familial, autosomal dominant form of BD, A20 haploinsufficiency, is linked to mutations in TNFAIP3(6q23.3).

The diagnosis of BD is essentially clinical and is based on the international classification criteria, which are sensitive and specific. The presence of recurrent oral ulceration (at least 3 times over 12 months; 2 points), genital ulceration (2 points), uveitis (2 points), skin lesions (1 point), cardiovascular (1 point), neurologic (1 point) and/or pathergy reaction (1 point). Behçet disease is retained with 4 or more points. Other elements may contribute to the diagnosis. Isolated severe visceral involvement (e.g. vena cava, cerebral and/or subhepatic vein thrombosis, pulmonary aneurysms, neurological involvement and/or retinal vasculitis) can be inaugural and should evoke BD; therefore, systematic request of an expert opinion is recommended. A family history of BD also increases the probability of diagnosis. Searching for the HLA-B51 haplotype is not a strong diagnostic element, but can be useful in situations of diagnostic uncertainty.

Differential diagnosis depends on upon the manifestations, herpes ulcerations, spondylo-arthropathies, infectious uveitis, relapsing polychondritis, sarcoidosis, antiphospholipid syndrome, Takayasu arteritis, Crohn's disease, infectious meningo-encephalitis or multiple sclerosis may be considered.

Anti-inflammatory steroids are the basis of treatment; however, corticodependance and relapses may occur upon discontinuation. Concurrent administration of immunosuppresive drugs (e.g. azathioprine, cyclophosphamide, methotrexate or mycophenolate mofetil), are also prescribed but their action is delayed. Anti-TNF and alpha-interferon (2a or 2b) are efficient, particularly in severe uveitis, and antiplatelet or anticoagulation treatments are discussed in case of vascular thrombosis. Colchicine relieves mucocutaneous symptoms. Apremilast has been recently approved in refractory oral ulceration of BD. Efficacy is dependent upon rapid initiation and patient compliance.

In the absence of treatment, the prognosis is severe due to ocular involvement leading potentially to blindness, the risk of lethal arterial rupture, large vessel thrombosis and neurological symptoms potentially causing encephalopathy or cerebral hypertension that may lead to a loss of autonomy. Intensive care coupled with close multidisciplinary follow-up, and adapted immunosuppressive treatment has been shown to reduce morbidity and mortality.

Last update: June 2020 - Expert reviewer(s): Pr David SAADOUN