A 38-year-old Middle Eastern man presented to the emergency department complaining of sudden onset of chest pain associated with hemoptysis. Physical examination was notable for swelling in his right lower extremity. A provisional diagnosis of right leg DVT and secondary pulmonary embolism was suspected, and the patient underwent a computed tomography (CT) scan of the chest that revealed a 3-cm arterial aneurysm involving the right pulmonary artery (Figure 84-1). Further questioning revealed the patient had been suffering from recurrent painful oral aphthous ulcers for the past 5 years. He reported that the ulcers recurred around 6 times yearly. He also complained of two scrotal ulcers in the past 2 years. Moreover, the patient reported recurrent bilateral eye redness and pain over the past couple of years that were treated as conjunctivitis; no evaluation by an ophthalmologist was performed. This constellation of clinical symptoms, venous thrombosis, as well as the pulmonary aneurysms lead to the diagnosis of Behçet syndrome (BS)—a relapsing systemic vasculitis syndrome that can be as benign as isolated mucocutaneous lesions or be associated with significant morbidity and mortality as in this case.
BS is a systemic inflammatory vasculitis characterized by recurrent oral aphthous ulcerations, genital ulcers, and skin and ocular lesions.1
It is a heterogeneous disease with systemic involvement of cardiovascular, gastrointestinal, renal, and nervous systems.
BS is also known as the “Old Silk Route” disease, as the first description of the disease is attributed to Hippocrates in the fifth century BC in the Third Book of Endemic Diseases where he describes a disease characterized by aphthous ulcers endemic in Asia Minor.
Hulusi Behçet, a Turkish dermatologist, identified the major manifestations of oral aphthous ulcers, genital ulcers, and recurrent hypopyon uveitis (Figure 84-2) and clumped them into a clinical entity that he called the “triple symptom complex” in 1937.
BS is most commonly encountered in Mediterranean countries and countries of the far east along the old “Silk Route”—an ancient commercial line stretching between the Mediterranean, Middle East, and the Far East.
Prevalence is between 20 and 421 per 100,000 adults in Turkey; Japan follows with reported prevalence between 13.5 and 20 cases per 100,000 adults. Prevalence is much lower in Western countries ranging from 0.12 to 0.64 cases per 100,000 adults.
A recent epidemiologic study revealed an 18-fold increase in the prevalence of this syndrome in the United States. The causes of this increase are not exactly known, but it is in part due to migration of population but could also be due to better recognition and awareness of this disorder.
Environmental components influence the prevalence of BS. Migrant studies suggest that immigration might be associated with an alteration of BS risk.
Typical age of onset is the third or fourth decade of life.
BS has a more aggressive and severe course in young male adults in Eastern Mediterranean cohorts, Turkey, the Middle and Far East, and Japan than in Western populations.
Genetics of BS are mostly uncertain; however, it is a polygenic disorder.
Genetic factors are suggested by the fact that immigrants of endemic areas to areas of low prevalence show higher disease prevalence than the general population of the area.
Human leukocyte antigen (HLA)-B51 allele expression signifies an increased risk of developing BS. HLA-B51 phenotype appears to be more prevalent in the familial cases of BS, and its contribution is actually limited to 20% of BS cases.
Other non-HLA genes have also been reported in the pathogenicity of the disease including intracellular adhesion molecule (ICAM)-1 gene, in-terleukin (IL)-1 gene, endothelin nitric oxide synthase (eNOS) gene, vascular endothelial growth factor (VEGF) gene, manganese superoxide dismutase gene, and cytochrome P450. Mutations in the Mediterranean fever gene (MEFV) encoding the protein pyrin have been implicated as well.
Many studies point to a possible role for an infectious process in the pathogenicity of BS.
It is theorized that bacterial or viral antigens share some homology in terms of sequences and thus cross-react with the heat shock family of proteins (HSP), resulting in a cell-mediated and humoral immune response.
Specific pathogens studied include Streptococcus species, Helicobacter pylori, herpes simplex virus, and parvovirus B19.
Immune system dysfunction is the hallmark of BS; this includes both the innate as well as the acquired immune systems, both the cell-mediated and the humoral components.2
As noted earlier, HSP and bacterial or viral antigens lead to stimulation of T lymphocytes and oligoclonal expansion; these autoreactive T cells appear to have a critical role in the pathogenic cascade of the disease.
T helper 1 (Th1) polarization of the immune response occurs in BS; this seems to be integral to the mechanistic cascade that leads to the inflammatory state of BS. These TH1-primed cells overproduce IL-2,-6,-8, -12, and -18; tumor necrosis factor-alpha (TNF-α); and interferon-gamma (IFN-γ).
Neutrophils in BS patients also demonstrate an activated phenotype with increased chemotaxis, phagocytosis, superoxide production, and mye-loperoxidase expression.
Higher numbers of circulating B lymphocytes have been reported in BS patients.
Many autoantibodies have been reported in BS patients. The pathogenicity and the clinical significance of these antibodies are yet to be determined. Targets include oral mucosal antigens, endothelial cells, T-cell costimulatory molecule, cytotoxic T lymphocyte antigen-4 (CTLA-4), and oxidized low-density lipoprotein, among others.
Anti-Saccharomyces cerevisiae antibodies have also been reported in BS patients, particularly in patients with intestinal involvement.
Endothelial dysfunction is a hallmark of BS with reduced flow-mediated dilation. This promotes vascular inflammation and provides a prothrombotic milieu in BS.
Nitric oxide (NO) evokes endothelial dysfunction, with increased NO concentrations reported in the serum of BS patients as well as their synovium and aqueous humor.
Thrombotic events can occur in up to 25% of BS patients; although some evidence exists for defects in the hemostasis or coagulation or fibrinolysis cascade, it is currently believed that the thrombotic manifestations of BS are secondary to vascular damage resulting from inflammation and endothelial dysfunction rather than a generalized hypercoagulable state.
Table 84-1 summarizes the major disturbances in the immune or hemostatic or coagulation and fibrinolytic systems in BS patients.
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The diagnosis of BS remains a challenge given the protean manifestations, and the multiple diseases, which mimic this syndrome as well as the lack of specific diagnostic tests.
The diagnosis of BS should be based on collective information from the pattern of clinical involvement, laboratory findings, tissue histology, and imaging.
