Overview Of Pathogenesis & Management Of Behcet’s Disease.


Abstract: Genetic Background: Behcet’s Disease (BD) is known t0 be associated with the HLA-B5 gene. The association is with the B51subtype, the B*5101allele. The tryptophan amino acid in position 167 and histidine in position 171 seems to determine the susceptibility of B51 for BD. However all persons with B51 do not have BD and all BD patients do not have B51. Some particularity in the TNFβ gene region in BD patients may suggest another susceptibility gene around the TNT region having a desequilibrium linkage with B51. ANTIGEN: Microbial agents and herpes simplex virus (HSV) were found to be involved in BD. There are some evidences that streptococcal strains, mainly the S. Sanguis and the S. Pyogenes, are involved in the pathogenesis of Behcet's Diseases. Streptococcus Sanguis related antigens (RRE KTH-1 antigens) can act as superantigen on T cells to produce more IL-6. The 65 kilo Dalton (65-kDa) heat shock protein (HSP) of Mycobacterium Tuberculosis has a corresponding 65-kDa band with 6 different strains of S. Sanguis and S. Pyogenes and may act as the antigen for BD. The responsible amino-acid seems to be the sequence 111-125, 154-172, 311-325, and 219-233. While in the homologous human HSP the sequences were 135-I50, 179-197, 244-258, and 336-351. The mycobacterial peptide (111-125, and 311-326) and the human homologous peptide (136-150 and 336-351) could produce a uveitis in the Lewis rat. T-CELL: The study of T cell receptors in BD shows an increased rate of T cells with gamma-delta receptors. The gamma-delta T cells in BD produced large amounts of interferon gamma (INF-ү ), TNF-, and TNF-β than the alpha-beta T cells (30). ADHESION MOLECULES: The main pathologic lesion of BD is the invasion of tissues by polymorphonuclear cells (PMN). Cell adhesion molecules (CAM) are essential for PMN to reach the involved tissue. The percentage of PMN expressing LEC-CAM-1 and CD44 in the peripheral blood was highly decreased in active BD, moderately decreased in the recovery stage and the same as in healthy subjects in inactive stage of the disease. The percentage of PMN expressing MAC-1 was identical in healthy subjects and BD patients. PMN cells are hyperactive in BD with enhanced chemotactic response and overproduction of oxygen free radicals. The hyperfunction of neutrophils seems to be mediated by HLA-B51. The PMN from patients and controls with B51 produced higher amounts of superoxide than those without B51. PMN from B51 transgenic mice produced more H2O2 than the B35 transgenic mice or the non transgenic mice. A very simplified scheme for the pathogenesis for BD may be: On a special genetic background a 65-kDa HSP will act as a superantigen and be recognized directly by T-cells with ү-∂ receptors. The overproduction of cytokines, mainly IL-6, by these T-Cells will activate PMN which will produce high amounts of H202 in the presence of B51 and induce the tissue injury. THE MANAGEMENT of BD is still empirical but may be explained by the pathogenesis. Colchicine is by excellence the anti chemotactic drug for PMN. It has been used for every lesion of BD, even for ophthalmological manifestations. However the main indication is the mucocutaneous lesions and sometimes joint manifestations. It is used as 1 to 2 milligrams per day. levamisole is an immunomodalator drug. It is classically used in mucocutaneous lesions, mild uveitis, and joint manifestations. The usual dosage is 150 mg daily, 3 consecutive days per week. Thalidomide is mainly used in resistant mucous membrane manifestations. The usual dose is around 200 mg daily at the beginning, to be reduced to 100 or even 50 mg after achievement of the therapeutic response. The main side effects are peripherai neuropathy and drowsiness. Dapson may be used in mtractable mucocutaneous lesions. Corticosteroids are usually used as an anti-inflammatory drugs in association with immunosuppressor drugs. However in moderate to high dose, they may become an immunodepressant drug. The main cytotoxic drugs used in BD are chlurambucil, azathioprine, cyclophosphamide, pulse cyclophosphamide, and Methotrexate. They are used in sever forms of the disease specially in ophthalmological manifestations, Neuro Behcet, sever Entero Behcet, pulmonary vasculitis, and severe vessel involvement such as arterial and large vein thrombosis. The dosage and monitoring are the same as in use for other autoimmune diseases. Cyclosporine A acts principally on interleukin-2. Side effects are important specially the nephrotoxicity. It is used as 5 mg/kg by oral root in ocular lesions and should be reserved for non responder cases.