2. Definition Inflammatory multisystem disease : –Recurrent oral aphthous ulcers –Genital ulcers –Uveitis –Skin lesions BD is a vasculitis

3. History of Behcet’s disease in the world Recurrent ocular inflammation, oral ulcers, and genital ulcerations Hippocrates Recurrent ocular inflammation, oral ulcers, and genital ulcerations Hulusi Behcet 1937 HLA B51 role 1975 Cytotoxic drugs 1980 International criteria 1990

5. Idiopathic multisystem disease More common in men Occurs in 3 rd - 4 th decade Highest incidence in Mediterranean region and Japan Associated with HLA-B5 Rare in black

6. History of Behcet’s disease in Iran 1975: Diagnosis of the first BD case in IRAN 1993: Iranian criteria of BD Male/female = 3 Incidence = 16/7/100000 Mean age = 26/3 Prevalence: 1.67/10000 or 1 in 6000 Familial prevalence: %6

7. R R R R C C

8. Distribution 1/100000

9. Mongoloids CaucasiansSemites 14.4 6.6 2.4 Epidemiology of Behcet’s disease in Iran Ethnic groups in Iran

10. Azari Turkoman 14.3 0.6 Epidemiology of Behcet’s disease in Iran Ethnic groups in Iran - Mongoloids

11. Kurd 11.4 Lor Fars Armenian Belouch Zoroastrian 7.9 6.4 0.4 3.5 0 Epidemiology of Behcet’s disease in Iran Ethnic groups in Iran - Caucasians

12. ArabJews Assyrian 2.8 1.4 0 Epidemiology of Behcet’s disease in Iran Ethnic groups in Iran - Semites

13. BEHCET’ DISEASE Unknown etiology Genetic predisposition Different causes –Infection Viral Bacterial –Environmental factors –Autoimmune mechanism

14. Trigger factors Altering immune system Inflammatory response Genetic susceptibility Neuroendocrine dysfunction

15. Trigger factors Altering immune system Inflammatory response Genetic susceptibility Neuroendocrine dysfunction

16. Trigger factors Altering immune system Inflammatory response Genetic susceptibility Neuroendocrine dysfunction

17. Genetic factors HLA B5: relationship with disease frequency Iran %52.5 Japan %58 USA %10-15 HLA B51 Iran % 33.9

18. Environmental factors Virus : – Parvovirus – Cytomegalovirus – Herpes simplex virus I Bacteria : – Streptococci : s.pyogenes S.sanginus – Mycobacterium

19. Trigger factors Altering immune system Inflammatory response Genetic susceptibility Neuroendocrine dysfunction

20. Pathogenesis Hypercoagulability 1. Low Factor V leiden in %40 of patients with thrombosis 2. low protein C and S level 3.High Von Willebrand factor level

21. Pathogenesis Endothelium Pathology 1.High VIII related Ag in patients with thrombosis 2.AECA in %30-60 of patients 3.Low prostacyclin production by endothelial cells

22. Pathogenesis Immunologic factors 1.Oligoclonal T cell expansion 2.Increased Tγδ 3.Increased NK cells 4.Increased IL1, IL2, IL6, IL8, TNFα, IFNγ 5.Increased IgA, IgG

23. SCENARIO OF PATHOGENESIS HSP

24. B51 Genetic Background SCENARIO OF PATHOGENESIS

25. HSP B51 Genetic Background Macrophage T-Cell Super Antigen SCENARIO OF PATHOGENESIS

26. Macrophage T-Cell SCENARIO OF PATHOGENESIS

27. Macrophage T-Cell TNF-  IL-1 B-Cell SCENARIO OF PATHOGENESIS TNF- 

28. Macrophage T-Cell Tissue B-Cell Anti.Endot.Cell.Ab Vessel Wall SCENARIO OF PATHOGENESIS

29. Vessel Wall PMN T-Cell IL-8 THROMBOSIS SCENARIO OF PATHOGENESIS

30. PMN T-Cell TISSUE Superoxide TNF

31. HSP Tissue SCENARIO OF PATHOGENESIS

32. HSP Tissue Macrophage T-Cell B-Cell AECA Vessel Wall PMN T-Cell IL-8 THROMBOSIS SCENARIO OF PATHOGENESIS

33. Clinical findings Major Oral ulcer Genital ulcer Eye lesions Skin lesions Minor Arthritis GI lesions Vascular lesions CNS lesions

34. Oral ulcers aphthous ulcer (%85) Superficial round to oval ulcers with erythematous halo which covered by a yellow membrane Painful Size<1cm Number: single or numerous Location: anywhere Heal without scar Recurrent

35. Aphtus of mouth & Lip

37. Genital ulcers Morphology like oral ulcer but larger and deeper Location In men: scrotum and penis In women: vulva and vagina Rare in cervix and perianal Heal in 1-3 weeks Frequently infected Recurrent

38. Skin lesions (80%) Major 1. Erythema nodosum

39. Skin lesions Major 1. Erythema nodosum 2. Pseudofoliculitis

40. Skin lesions Cutaneous aphthus ulcer

41. Skin reaction

42. Pathergy phenomenon

43. Severe Pathergy phenomenon

44. Pathology of pathergy

45. Eye lesions Frequency: %5o More common and sever in Iranian and Japanese More frequent in men Often begin in the first 2-3 years of disease onset Often bilateral Cause blindness in %6.2

47. Eye lesions

48. Anterior uveitis Decrease in visual acuity Red eye Periorbital pain Photophobia Discoloration of iris

49. Eye lesions Anterior uveitis Decrease in visual acuity Red eye Periorbital pain Photophobia Discoloration of iris Flare and KP in anterior chamber

50. Eye lesions Anterior uveitis Decrease in visual acuity Red eye Periorbital pain Photophobia Discoloration of iris Flare and KP ( keratic precipitate )in anterior chamber Hypopion (%8.7)

52. Eye lesions Anterior uveitis Posterior uveitis Vitreitis Macular edema Papillaitis

53. Eye lesions Anterior uveitis Posterior uveitis Retinal vasculitis Perivascular sheeting Retinal hemorrhage Retinal infarction Optic atrophy Retinal detachment

54. Retinal vasculitis

55. Eye lesions Panuveitis (%34.3) Panophthalmitis (%22) Anterior uveitis (%6.7) Posterior uveitis (%5.1) Retinal vasculitis (%1.8)

56. Musculoskeletal involvement(50%) Arthritis (%34.2) Arthralgia (%15.2) Enthesopathy and sacroileitis (%1.5) Myositis Mono (%7.6) or oligoarticular (%16.6) More common in knee, ankle, elbow, and wrist Non erosive and non deforming Episodic and self limiting

57. Vascular lesions Characteristics of vasculitis Involvement of large, medium, and small vessels Involvement of arteries and veins Inflammation is diffuse, not patchy IC deposition is not seen Neuropathy and glomerulonephritis is rare

58. Vascular lesions Venous thrombosis (30%) Arterial lesions

59. Vascular lesions Venous thrombosis (30%) Deep vein thrombosis in lower limb ( more common ) Arterial lesions

60. Vascular lesions Thrombosis in femoral vein

61. Vascular lesions Venous thrombosis (30%) Deep vein thrombosis in lower limb ( more common ) Superficial phlebitis Arterial lesions(5%)

62. Vascular lesions Superficial phlebitis

63. Vascular lesions Venous thrombosis (30%) Deep vein thrombosis in lower limb ( more common ) Superficial phlebitis Large vein thrombosis Arterial lesions

64. Vascular lesions

65. Venous thrombosis Deep vein thrombosis in lower limb ( more common ) Superficial phlebitis Large vein thrombosis Arterial lesions Aneurysm (%0.4) Aortitis Arterial thrombosis (%0.1) pulmonary artery vasculitis

66. Arterial lesions Aneurysm Aorta is the most common site

67. Arterial lesions Aneurysm Infrarenal aorta pseudoaneurysm

68. Aneurysm in bifurcation of Aorta

69. Arterial lesions Aneurysm Aorta is the most common site Pulmonary artery aneurysm

70. Arterial lesions Aneurysm Pulmonary artery aneurysm

71. Behcet’s disease: aneurysms, popliteal and femoral arteries (angiogram)

72. Arterial lesions Aneurysm Aorta is the most common site Pulmonary artery aneurysm Other arteries

73. Vascular lesions Aneurysm multiple fusiform aneurysms of the iliac arteries Aneurysm of carotid artery

74. Arterial lesions Arterial occlusion

75. Gastrointestinal lesions Ulcer Involve all parts of the GI tracts from the esophagus to the anus The most common site is the terminal ileum Numerous, deep, and punched out They cause colitis like symptoms Anal ulcer and fistula is rare

76. Gastrointestinal lesions Ulcer Bowel perforation due to. intestinal ulceration Diffusely scattered punched-out. ulcers in the ascending colon

77. Colonoscopy

78. Gastrointestinal lesions Ulcer A large, discrete ulcer with thickened mucosal folds at the terminal ileum Diffuse ulcers in the midesophagus along with fold thickening and luminal narrowing of the esophagus

79. Nervous system involvement More common in western countries, rare in Iran Rarely it is the first symptom Symptoms are episodic It is a poor prognostic sign Peripheral neuropathy is rare

80. Nervous system involvement(5%- 10%) It is two type: 1. Parenchymal lesions (%80) Cerebrospinal tract demyelination Encephalomalacia Cerebellar atrophy Perivascular cellular infiltration 2. Venous sinus thrombosis (%20)

81. Nervous system involvement Hemiplegia, paraplegia (%82) Headaches (%65) Cerebellar symptoms (%24) Sensory symptoms (%24) Meningitis(%12) Hemianopsia(%12) Dementia(%6)

82. Nervous system involvement Parenchymal lesions Two intramedullary hyperintense discrete nodular lesion areas at the level of C4 and C6 White matter changes. in the pons Hyperintense lesion in the right thalamus

83. Transverse sinus thrombosis

84. Diagnosis International criteria (1990)

85. international criteria, the ICBD(2004) Oral aphtus 1 Genital aphtus 2 Eye 2 Skin ( Erythema nodosum, Pseudofuliculitis ) 1 Pathergy 1 Vascular 1 =, > 3 = Behcet diseases

86. Treatment No major organ involvement Local treatment : corticosteroid Systemic treatment : Aphtus: –colchicin1-2mg/d,levamizol150- 300 mg/w,MTX, prednisolone, thalidomide Arthritis: NSAID,Colchicin, Prednisolone, MTX, SSZ Erhytema nodosum : NSAIDs, Colchicin

87. Treatment major organ involvement Glucorticoid in high dose Ctotoxics Anti TNFα ( Panuveitis resistant to treatment) Pulmonary or arterial aneurysm, CNS involvement, deep thrombophlebitis )

88. Treatment major organ involvement Ant.uveitis : local steroid, mydriatic Post.uveitus : AZT,MTX,Cyclosporine Vasculitis : Endoxan, AZT, MTX, cyclosporine GI:SSZ, Prednisolone CNS: Prednisolone + endoxan Aneurism : Prednisolone + endoxan + surgery anticoagulant if trombosis present Large vein thrombosis :prednosolone, cyclophosphamide, anticoagulant Thanks for your kind attention