1. Extrahepatic Manifestations of Hepatitis C Virus Infection Service de Médecine Interne, et CNRS UMR 7087 Université Pierre et Marie Curie Centre National de Référence Maladies Autoimmunes Hôpital La Pitié-Salpêtrière, Paris, FRANCE Pr. Patrice CACOUB, MD, PhD
6. Peripheral Nerve Biopsy - important peri-vascular infiltrate of lymphocyte - around small vessels i.e. venules, capillaries - no PMN, no destruction of the vascular wall Distal Polyneuropathy 80%
10. Cellular Infiltrate in HCV-Vasculitis HCV Core Protein in Skin Vascular Structures Who’s the culprit ?
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13. Boyer O, Saadoun D et al, Blood 2004 Quantitative Deficit in Treg Lymphocytes ( CD4 + CD25 + ) in HCV-Systemic Vasculitis
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15. CD25high (% of CD4+) 4 4 5 6 Before treat. On Treat. Early F/U Late F/U . ** † ** † -CR -NR/PR After Treat . A Complete clinical response of HCV-MC vasculitis to anti-viral treatment is associated with an increase in CD4 + CD25 high levels.
16. 0 20 40 60 80 100 0 1 2 3 CD 25 high ( cells / μ l) Cryoglobulins ( g/l ) R ² - 0 . 1 , p< 0 . 005 Correlation between Immune Response and Treg Lymphocytes in HCV MC Vasculitis 0 20 40 60 80 100 0.0 0.2 0.4 CD 25 high ( cells / μ l) C 4 ( g/l ) R ² - 0 . 16 , p< 0 . 005
17. * 10 20 30 Before Treat . After Treat . CD25high (cells/ μ l) SVR No-SVR 4 5 6 Before Treat . On Treat . Early F/U . Late F/U . After Treat . ** ** CD25high (% of CD4+) MC-vasculitis patients MC-vasculitis patients -SVR -no-SVR Sustained virological response is associated with an increase in lymphocytes Treg frequency and concentration in HCV-MC vasculitis.
18. ANRS HC 21 VASCU-IL2 Phase II pilot study evaluating the impact of IL2 on cellular immune response, and clinical efficacy and safety in HCV cryoglobulinemia vasculitis refractory to conventional treatments. Investigateur Coordonnateur Pr Patrice CACOUB Hôpital de la Pitié , 83 Bd de l’Hôpital 75651 Paris cedex 13 France Tél. : 01 42 17 80 09 - Fax : 01 42 17 80 33 [email_address]
22. Roccatello, D. et al. Nephrol. Dial. Transplant. 2004 Pathogenesis of cryoglobulinaemic nephritis and rationale for Rituximab treatment Rocatello D, Nephrol Dial Transplant, 2004
23. Treatment of Mixed Cryoglobulinemia Resistant to Interferon-alfa with Rituximab* (anti-CD 20 Ab) Sansonno D et al, Zaja F et al, Blood 2003
24. % improvement HCV-Vasculitis Treatment : PegIFN-Ribavirin vs. Rituximab Cacoub P, Ann Rheum Dis 2008 Personal series Literature review
26. Lymphocyte Infiltrate in HCV-Vasculitis HCV Core Protein in Skin Vascular Structures HCV Vasculitis: a Two-Faces Disease
27. Roccatello, D. et al. Nephrol. Dial. Transplant. 2004 HCV Vasculitis: a Two-Faces Disease … Needs a Two Faces Treatment Strategy Rituximab PegIFN plus Ribavirin
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29. R ituximab plus Peg-IFNα2b-Ribavirin in Refractory HCV-Related Systemic Vasculitis RITUXIMAB (375 mg/m²) Time (months) 0 1 RIBAVIRIN (600-1200 mg/d) PEGYLATED INTERFERON 2b (1.5 μ g/Kg/wk) 12 2 Saadoun D et al, Ann Rheum Dis 2008
30. Response rate of HCV-cryoglobulinemia vasculitis during Rituximab & Peg-IFNα2b + Ribavirin.
31. MC pre-Rx MC post-Rx VH1-69+ B Cells Total B Cells p=0.01 A B Effects of rituximab on VH1-69 clonal B cells. A patient with HCV-MC-vasculitis demonstrating staining with anti-Vh1-69 gene product mAb (MC pre-Rx) and disappearance of VH1-69+ B cells following rituximab (MC post-Rx). VH1-69+ cells among CD19+ B cells in patients with HCV-MC vasculitis (n=11) before and after rituximab 73 27 30 4 37 29 97 3 91 2 5 1
40. Course of cryoglobulinemia & HCV RNA in HCV-MC patients according to the type of treatment Saadoun D et al, Blood 2010
41. Time Course of HCV Viral Load Terrier B et al. Arthritis Rheum 2009
42. Long term follow up of HCV vasculitis patients treated with Rituximab ( 23 ± 12 months, 6-44) Tolerance Good 25/32 (78%) Serum sickness 3 Neutropenia 2 Herpès zooster 1 Out of vein RTX 1 Terrier B et al. Arthritis Rheum 2009
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46. Overall Survival of 151 HCV-Vasculitis Patients Terrier B et al. Arthritis Rheum 2010 Years Overall survivall
52. Prognostic Factors During follow-up Use of Peg-IFN/riba had a positive prognostic impact HR = 0.34 (0.16-0.67)
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55. Association between fatigue, depression and clinical extrahepatic manifestations (EM) Poynard T et al. J Viral Hep, 2002
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57. Prevalence of fatigue at baseline and at 18 months follow-up in treated and untreated patients Poynard T et al. J Viral Hep, 2002
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59. Impact of Treatment on Extra hepatic Manifestations in HCVpatients. At Baseline and 18 months Follow-up in Responders. Cacoub P et al. J Hepatol 2002
60. Impact of Treatment on Extra hepatic Manifestations in HCVpatients. At Baseline and 18 months Follow-up in Responders. Cacoub P et al. J Hepatol 2002
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62. Auto-antibody production in chronic HCV infection. Pawlotsky JM, Hepatology 1994. Pawlotsky JM, Ann Intern Med 1994. Prieto J, Hepatology 1996. Cacoub P, J Rheumatol 1997. Cacoub P, Medicine 2000.