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  • 1. Patologie Immuni & Malattie Orfane Torino – 22-24 Gennaio 2009 22- Entero Behçet F. Rosina PRESIDIO SANITARIO GRADENIGO TORINO S.C. Gastroenterologia & Epatologia
  • 2. Behçet disease Epidemiology of a rare disease North America & North Europe 0,2 - 6,6 /100.000 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 3. Behçet disease Epidemiology of a not so rare disease North America & North Europe 0,2 - 6,6 /100.000 Far & Middle East 13,5 - 20/100.000 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 4. Behçet disease Epidemiology of a common disease North America & North Europe 0,2 - 6,6 /100.000 Far & Middle East 13,5 - 20/100.000 Turkey 80 - 370 / 100,000 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 5. Behçet disease Epidemiology of a common disease North America & North Europe 0,2-6,6/100.000 Far & Middle East 13,5-20/100.000 Turkey 80-370 / 100,000 Age 20-40 yrs Sex Men prevalence (Middle East) Female prevalence (Far East & North Europe) Severity More severe in Young Men Middle & Far East 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 6. Behçet disease Definition Behcet's disease is a chronic, relapsing vasculitis involving arterial and venous blood vessels of all sizes leading to several systemic manifestations…. 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 7. Behçet disease Clinical manifestations 100 100 90 80 75 75 75 70 60 50 50 40 33 30 20 20 10 10 1 1 1 0 ng l l al e n rs ac ar I is ita na G Ey i ur rit Sk lce ul Lu di en Re th Ne sc ar lU og Ar Va C ra Ur O 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 8. Behçet disease Large Vessels Disease Number of patients Arterial disease Pulmonary artery occlusion or aneurysm 36/728 (5%) Aortic aneurysm 17/728 (2%) Extremity arterial occlusion or aneurysm 45/728 (6%) Other arterial occlusion or aneurysm 42/728 (6%) Right ventricular thrombus 2/728 Review of 728 cases from Koc, Y, Gullu, I, Akpek, G, et al. J Rheumatol 1992; 19:402. 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 9. Behçet disease Enteral Arterial disease • Massive gastrointestinal bleeding due to aneurysmal rupture of ileo-colic artery. After the failure of hemostasis with arterial embolization, ileo-right colecctomy was performed. (Kim SU et al Korean J Gastroenterol. 2007) • Massive hemorrhage from ruptured small aneurysm on the right ileocolic artery successfully treated with superselective arterial embolization using microcoils (Hong YK, Yoo WH. Rheumatol Int 2008) 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 10. Behçet disease Large Vessels Disease Number of patients Venous disease Deep venous thrombosis 221/728 (30%) Subcutaneous thrombophlebitis 205/728 (28%) SVC occlusion 122/728 (17%) IVC occlusion 93/728 (13%) Cerebral sinus thrombosis 30/728 (4%) Budd-Chiari syndrome 17/728 (2%) Other venous occlusion 24/728 (3%) Review of 728 cases from Koc, Y, Gullu, I, Akpek, G, et al. J Rheumatol 1992; 19:402. 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 11. Behçet disease Large vessel Disease Number of patients Hepatic Vein Thrombosis 14/493 (3%) Hepatic Vein (HV) Thrombosis Alone 4/14 (29%) HV + Inferior Vena Cava (IVC) Thrombosis 8/14 (57%) HV + IVC + Portal Vein Thrombosis 2/14 (16%) Bayraktar Y et al.. Am J Gastroenterol 1997 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 12. Behçet disease Budd Chiari • Acute — 20 % (5% with fulminant hepatic failure) • Subacute — 40 % (signs or symptoms for less than six months and no evidence of liver cirrhosis) • Chronic — 40 % (signs or symptoms for more than six months with evidence of portal hypertension and cirrhosis) 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 13. Behçet Small Vessels Disease: Entero Behçet Symptoms • anorexia • nausea • abdominal pain • diarrhea Lesions • “punched out” or “flask shaped” ulcers involving both the submucosa and the muscularis propria, especially in the ileo-ciecal region, less frequenltly in the esophagus and rarely in the stomach and duodenum Griffin JW et al. South Med J 1982 Anti M et al. J Clin Gastroenterol 1986 Powderly WG et al. Ir J Med Sci 1987 Stringer DA et al. Pediatr Radiol 198 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 14. Behçet disease Clinical manifestations Italy Turkey China Taiwan Korea Thai Number of studied pts 137 2313 28 125 1527 23 • Oral ulcerations 99% 100% 95% NR 99% 100% • Uro-genital lesions Uro- 63% 85% 50% NR 83% 70% • Cutaneous lesions 82% 80% 95% NR 84% 61% • Ocular disease 61% 38% 50% NR 51% 52% • Neurologic disease NR 3% NR NR NR 9% • Vascular disease NR 25% NR NR NR 9% • Arthritis NR 11% 45% NR NR NR • Renal disease NR NR NR NR NR NR • Cardiac disease NR NR NR NR NR NR • Pulmonary disease NR 0,03% NR NR NR NR Salvarani C et al. Arthritis Rheum 2007 Pipitone N et al. Clin Exp Rheumatol 2004 Tursen U et al. Int J Dermatol 2003 Ning Sheng L et al. Clin Rheumatol 2005 Chou SJ et al J Gastrointest Surg 2007 Ling J et al Yan Ke Xue Bao 2005 Bang D et al. J Korean Med Sci 2001 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 15. Behçet disease Gastrointestinal 100 * 43% HP/NSAIDs neg.ve 90 Peptic ulcers 80 70 66 60 50 40 35 30 20 9 9 10 1,5 Salvarani C et al. Arthritis Rheum 2007 0 0 Pipitone N et al. Clin Exp Rheumatol 2004 Tursen U et al. Int J Dermatol 2003 Ning Sheng L et al. Clin Rheumatol 2005 ey a ly an ai a* re Ita Th rk Chou SJ et al J Gastrointest Surg 2007 iw in Ko Tu Ch Ta Ling J et al Yan Ke Xue Bao 2005 Bang D et al. J Korean Med Sci 2001 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 16. Entero Behçet Natural History Remitting relapsing disease complicated by Intestinal perforation Taiwan 125 Behçet’s disease cases Follow-up 25 yrs 82/125 (66%) intestinal Behçet’s disease 22/82 (27%) intestinal perforation Male/female 14/8 - Age 22-65 yrs Surgery: • Hemicolectomy 11 • Partial Ileum Resection 8 • Ileocecal Resection 3 Reperforation:3 Chou SJ et al J Gastrointest Surg 2007 Choi IJ et al. Dis Colon Rectum 2000 Kin Js et al. Endoscopy 2000 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 17. Entero Behçet Treatment Glucocorticoids plus Azathiopine / 6-mercaptopurine • Prednisone 0.5 to 1.0 mg/kg daily • Azathioprine 2.5 – 2.5 mg/k / daily Infliximab 3 to 5 mg/kg at 0, 2, and 6 weeks, followed by 5 mg/kg every 8 weeks (Travis SP et al , Gut 2001; Kram MT et al, Dis Colon Rectum. 2003; Naganuma M et al, Inflamm Bowel Dis 2008; Lee JH et al Korean J Intern Med 2007)) Thalidomide 2 mg/kg per day, (Yasui K et al, J Pediatr 2003; Yasui K et al Inflamm Bowel Dis 2008) Cyclosporin Surgery 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 18. Entero Behçet Diagnosis ……the problem is not to assess the presence of GI involvement in a patient with a known Behçet disease, but …… to make a diagnosis of Behçet syndrome in a patient with GI ulcers 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 19. Entero Behçet Diagnosis • Radiology • Endoscopy • Upper GI Endoscopy • Colonoscopy • Wireless Capsule Endoscopy • Histology • Serology but …… 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 20. Entero Behçet Diagnosis Small Bowel & Colon Barium Studies • mucosal fold thickening • discrete ulcers • poor sensitivity and specificity CT scans • bowel wall thickening • perienteric infiltration • polipoid bowel involvement • polipod mass-like lesions Chung SY et alRadiographics 2001 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 21. Entero Behçet Diagnosis Crohn’s • Endoscopy • Upper GI Endoscopy • Colonoscopy • Small Bowel Capsule Endoscopy Behçet’s 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 22. Entero Behçet Wireless Capsule Endoscopy Barium-CT pos.ve / suspected Behçet (0/11 - 0%) WCE pos.ve / suspected Behçet (10/11 - 91%) Thomson M et al. J Pediatr Gastroenterol Nutr 2007 Hamdulay SS et al Rheumatology Oxford 2008 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 23. Entero Behçet Diagnosis • Endoscopy • Upper GI Endoscopy • Colonoscopy • Small Bowel Capsule Endoscopy • Histology does not discriminate between Behçet and other Gastrointestinal Vasculitis, specific for IBD only when early lesions are present • Serology 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 24. Entero Behçet Diagnosis Serology ASCA IgA & IgG Crohn Disease 42% Behçet Disease 4% Ulcerative Colitis 4% Ankilosing Spondilitis 15% Fresko I et al. Clin Exper Rheumatol 2005 Choi CH et al. Dis Colon Rectum 2006 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 25. Entero Behçet Diagnosis Serology ASCA IgA & IgG Crohn Disease 42% Behçet Disease 4% Ulcerative Colitis 4% Ankilosing Spondilitis 15% Enteral Behçet 44% ……..severity and relapse rates of intestinal Behçet's disease not associated with ASCA expression. ASCA pos.ve pts more likely to receive surgical treatment. Fresko I et al. Clin Exper Rheumatol 2005 Choi CH et al. Dis Colon Rectum 2006 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 26. Entero Behçet Diagnosis • Barium Studies • Endoscopy • Upper GI Endoscopy • Colonoscopy • Small Bowel Capsule Endoscopy • Biopsy • Serology • International Diagnostic Criteria 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 27. Entero Behçet International Diagnostic Criteria Recurrent Oral Aphthae (three times in one year) plus two of the following in the absence of other systemic diseases: • Recurrent genital aphthae • Eye lesions (including anterior or posterior uveitis, cells in vitreous on slit lamp examination, or retinal vasculitis, observed by an ophthalmologist) • Skin lesions (including erythema nodosum, pseudo vasculitis, papulopustular lesions, or acneiform nodules consistent with Behcet's) • A positive pathergy test (a papule 2 mm or more in size developing 24 to 48 hours after oblique insertion of a 20 to 25 gauge needle 5mm into the skin, generally performed on the forearm) International Study Group for Behcet's Disease. Lancet 1990 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 28. Entero Behçet Sensitivity & specificity of Behçet Diagnostic criteria Sensitivity Specificity International 95% 100% Japanese 100% 95% Mason & Barnes 100% 94% International Study Group for Behcet's Disease. Lancet 199 Tunc R etr al. Clin Exp Rheumatol 2001 Chang HK et al Clin Exp Rheumatol 2004 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 29. Entero Behçet International Diagnostic Criteria Recurrent Oral Aphthae (three times in one year) plus two of the following in the absence of other systemic diseases: • Recurrent genital aphthae • Eye lesions (including anterior or posterior Uveitis, cells in vitreous on slit lamp examination, or retinal vasculitis, observed by an ophthalmologist) • Skin lesions (including Erythema Nodosum, pseudo vasculitis, papulopustular lesions, or acneiform nodules consistent with Behcet's) • A positive pathergy test (a papule 2 mm or more in size developing 24 to 48 hours after oblique insertion of a 20 to 25 gauge needle 5mm into the skin, generally performed on the forearm) International Study Group for Behcet's Disease. Lancet 1990 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 30. Entero Behçet Sensitivity & specificity of Behçet Diagnostic criteria Sensitivity Specificity International 95% 100% Japanese 100% 95% Mason & Barnes 100% 94% … inclusion of pts with Crohn disease and Ulcerative Colitis did not substantially change sensitivity & specificity of ISG (International Study Group) diagnostic score International Study Group for Behcet's Disease. Lancet 199 Tunc R etr al. Clin Exp Rheumatol 2001 Chang HK et al Clin Exp Rheumatol 2004 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 31. Entero Behçet Conclusions .....if you have still some doubt on your diagnosis……. …. just rule out infective colitis and feel comfortable since ……. 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 32. Entero Behçet Conclusions Steroids Azathioprine Infliximab 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 33. Entero Behçet Conclusions Steroids Azathioprine Infliximab …… are perfectly fitting with both Behçet’ and Crohn’s diseases 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 34. Entero Behçet Conclusions Crohn’s Behçet’s Steroids OK OK Azathioprine OK OK Infliximab OK OK 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 35. …if you still have some doubt on the diagnosis, Just rule out infective colitis and fell confortable since ……. Crohn’s Behçet’s Steroids OK OK Azathioprine OK OK Infliximab OK OK ….. Perfectly fitting for both Behçet’s and Crohn’s disease. 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 36. The Mason–Barnes Criteria Major Symptoms Minor Symptoms Buccal ulcerations Gastrointestinal lesions Genital ulcerations Thrombophlebitis Ocular lesions Cardiovascular lesions Arthritis Skin lesions Neurologic lesions Family history Three major or two major and two minor criteria are required to establish the diagnosis of Behçet’s disease
  • 37. Entero Behçet Sensitivity & specificity of Behçet Diagnostic criteria Sensitivity Specificity International 95% 100% Japanese (Suzuki) 100% 95% Mason & Barnes 100% 94% International Study Group for Behcet's Disease. Lancet 199 Tunc R etr al. Clin Exp Rheumatol 2001 Chang HK et al Clin Exp Rheumatol 2004 12° Convegno Patologie Immuni & Malattie Orfane , Torino 22-24 gennaio 2009
  • 38. XIII Congresso Nazionale delle Malattie Digestive Corso AIGO-SIGE AIGO- “Hot topics in Gastroenterologia” Palermo – 3 ottobre 2007 “Up date” su …. Colangite Sclerosante Primitiva F. Rosina Presidio Sanitario Gradenigo Torino
  • 39. Behçet disease • Oral ulcerations (95-100%) • Uro-genital lesions (75%) Clinical manifestations • Cutaneous lesions (>75%) • Ocular disease (25-75%) • Neurologic disease ( < 20%) • Vascular disease (33%) • Arthritis (75%) • Renal disease (uncommon) • Cardiac disease (uncommon) • Pulmonary diasease (uncommon) • Gastrointestinal Symptoms (common) • Gastrointestinal disease (more or less frequent depending on the geographical area: unfrequent in in Italy and middle east – common in far east (Japan, Korea) • Severity is generally greater in men. The greatest morbidity and mortality occurs with ocular disease (affecting up to two-thirds of patients), vascular disease (affecting up to one-third of patients), and central nervous system disease (affecting 10 to 20 percent of patients). Cutaneous and articular manifestations are common. Renal disease and peripheral nervous system involvement are less common than in other vasculitides 20° Congresso Regionale ACOI , 31 ottobre 2008
  • 40. Behçet disease Epidemiology Behcet's disease is more common (and often more severe) along the ancient silk road, which extends from eastern Asia to the Mediterranean [4]. It is most common in Turkey (80 to 370 cases per 100,000) while the prevalence ranges from 13.5 to 20 per 100,000 in Japan, Korea, China, Iran, Iraq, and Saudi Arabia [4]. By comparison, the prevalence is from 1:15,000 to 1:500,000 in Northern American (Olmsted County, Minnesota) and Northern European countries. It is somewhat more common in men in the eastern Mediterranean area and in women in north European countries, and typically affects young adults 20 to 40 years of age. The disease appears to be more severe in young, male, and Middle Eastern or Far Eastern patients FARE TABELLA IMPOSTANDOLA TUTTA SU UN RAPPORTO …./100.000 clinical manifestations vary among different patients and populations. Men and women have different propensities to develop the disease, but this varies among populations. As an example, Behcet's is more common in men in the Middle East and in women in Japan and Korea [6]. 20° Congresso Regionale ACOI , 31 ottobre 2008
  • 41. Behçet disease Vascular disease Most clinical manifestations of Behcet's disease are due to vasculitis involving: • blood vessels of all sizes • arterial and venous 20° Congresso Regionale ACOI , 31 ottobre 2008
  • 42. Behçet disease Budd Chiari etiology Myeloproliferative diseases Malignancy Hepatocellular carcinoma Infections and benign lesions of the liver Oral contraceptives Pregnancy Hypercoagulable states (Factor V Leiden mutation, Prothrombin gene mutation, Antiphospholipid antibody syndrome, Antithrombin III deficiency, Protein C deficiency, Protein S deficiency ) Paroxysmal nocturnal hemoglobinuria JAK2 mutations Behcet's disease Membranous webs of the inferior vena cava and/or the hepatic veins Miscellaneous conditions Idiopathic 20° Congresso Regionale ACOI , 31 ottobre 2008
  • 43. Behçet disease Clinical manifestations • Oral ulcerations (95-100%) (95- • Uro-genital lesions (75%) Uro- • Cutaneous lesions (>75%) • Ocular disease (25-75%) (25- • Neurologic disease ( < 20%) • large Vessel Vascular disease (33%) • Arthritis (75%) • Renal disease (uncommon) • Cardiac disease (uncommon) • Pulmonary disease (uncommon) • Gastrointestinal Symptoms (common) • Gastrointestinal Disease (more or less frequent depending on the geographical area: infrequent in in Italy and middle east – common in far east) 20° Congresso Regionale ACOI , 31 ottobre 2008