What are the causes of Behçet’s disease?

Causes of Behçet's Disease

Behçet's disease is primarily caused by a complex interplay between genetic predisposition (particularly HLA-B*51) and environmental triggers that lead to dysregulated immune responses, resulting in systemic vasculitis. 1, 2

Genetic Factors

• The strongest genetic susceptibility factor is HLA-B*51, which significantly increases disease risk and influences the typical phenotype 2
• Non-HLA genetic associations have been identified, including variations in:
  • Endoplasmic reticulum aminopeptidase 1 (ERAP1) - particularly in HLA-B*51 positive patients 3
  • Interleukin-23 receptor (IL-23R) and IL-12RB2 genes 4
  • Interleukin-10 (IL-10) gene polymorphisms 4
• These genetic variations suggest Behçet's disease shares susceptibility genes and inflammatory pathways with spondyloarthritis 3

Environmental Triggers

• Infectious agents are believed to be important environmental triggers in genetically predisposed individuals 2
• Streptococcus sanguinis has been implicated as a potential triggering agent 2
• Alterations in salivary or gut microbiome composition may trigger innate-derived inflammation 2
• These environmental factors likely initiate the inflammatory cascade that is then sustained by adaptive immune responses 2

Immunological Mechanisms

• Behçet's disease sits at the crossroad between autoimmune and autoinflammatory syndromes 4
• Altered peptide processing by ERAP1 may lead to abnormal peptide presentation by HLA-B*51, disrupting T cell balance 2
• Immune dysregulation includes:
  • Downregulation of regulatory T cells (Tregs) 4
  • Expansion of Th1 and Th17 cell populations 4, 2
  • Increased IL-17 response that enhances neutrophil activity 2
  • Increased neutrophil infiltration in early inflammatory stages 2
• Both innate and adaptive immune systems are involved in the pathogenesis 5

Disease Characteristics

• Behçet's disease is characterized by recurrent episodes of inflammation affecting multiple organ systems 6
• It is more common in Turkey, with a prevalence of 80-370 cases per 100,000 persons, compared to only 1-3 cases per million in the United States 7
• The disease is characterized by oral ulceration plus at least two of: recurrent genital ulceration, uveitis/retinal vasculitis, or specific skin lesions 7
• Vascular involvement occurs in approximately one-third of patients, affecting both arteries and veins 7

Clinical Implications

• Understanding the genetic and immunological basis of Behçet's disease has led to targeted therapeutic approaches 5
• Treatment should be individualized based on organ involvement and disease severity 1
• Biologic therapies targeting specific inflammatory pathways (TNF-α, IL-1, IL-6) have shown promising results in refractory cases 5
• Early and aggressive immunomodulatory treatment is crucial for preventing recurrences and improving prognosis, especially in ocular disease 6

Common Pitfalls and Considerations

• Avoid cyclosporine A in patients with central nervous system involvement due to potential neurotoxicity 1
• Anticoagulants should generally be avoided in Behçet's disease with venous thrombosis due to bleeding risk, especially with coexisting pulmonary arterial aneurysms 1
• Young men with early disease onset have higher risk of severe disease and may benefit from early systemic immunosuppression 1
• Post-thrombotic syndrome is frequent with recurrent deep vein thrombosis and may result in difficult-to-treat leg ulcers 1