1. Extrahepatic Manifestations of Hepatitis C Infection. Pr Patrice CACOUB, MD Internal Medicine Department La Pitié-Salpêtrière Hospital CNRS UMR 7087, Université Pierre et Marie Curie PARIS, FRANCE

3. FREQUENCY OF HBV-RELATED PAN: 1972-1999 Guillevin L

4. HCV and cryoglobulinemic vasculitis asymptomatic Oligosymptomatic arthralgias, Raynaud’s, Sjögren, RF+ symptomatic chronic peripheral hepatitis purpura MPGN neuropathy lymphoma Rheumatology Hepatology Nephrology Hematology Dermatology Neurology Prevalence unknown

5. > 250 million infected individuals worldwide > 3,0 in USA; > 0,5 in France

8. Cryoprecipitation Endothelial cells

9. Pathogenesis of cryoglobulinaemic nephritis Roccatello, D. et al. Nephrol. Dial. Transplant. 2004 hlkjhjhkhuhhh

10. Skin Purpura Membrano-proliferative Glomerulonephritis CNS Vasculitis Cryoglobulinemia-Systemic Vasculitis Neuropathy

12. 17,035 MC testing between 1989 and 2003 in a single university hospital 1,434 cryoglobulin level >0.05g/L on  2 occasions (during >6 months) 1301 (91%) Persistent MC with HCV infection 133 Persistent MC without HCV infection 15,601 MC negative Saadoun D, Arch Intern Med 2006

13. Prevalence of HCV infection in patients with essential cryoglobulinemia

14. Ferri C, Sem Arthr Rheum 2004

15. MC and Skin

16. Severe necrotizing leukocytoclastic vasculitis: extensive fibrinoid necrosis of the vessel wall with permeation of the wall by disintegrating neutrophils

17. HCV Core Protein in Skin Vascular Structures

19. 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%

21. Mononeuropathy Multiplex 20% Cacoub P et al, AIDS 2005 MC and Neuropathy

22. Central Nervous System Involvement in HCV-Cryoglobulinemia Vasculitis HCV-vasculitis HCV Controls (n=40) (n=11) (n=36) -------------------------------------------------------------------------------------- Sex ratio F/M 23/17 6/5 20/16 Age (yrs) 59 ± 13 56 ± 10 58 ± 12 WMHS 7.0 ± 9.9 0.9 ± 1.8 * 2.0 ± 3.1 PVHS 2.5 ± 3.1 0.4 ± 0.5 * 0.8 ± 1.4 NCFD 2.2 ± 1.8 0.9 ± 0.8 * - -------------------------------------------------------------------------------------- WMHS: White Matter Hypersignals PVHS: Periventricular Hypersignals NCFD: Number of Cognitive Function Deficiency Casato M et al, J Hepatol 2004 * P<0.01

24. Therapeutic strategy in HCV+ Mixed Cryoglob. Chronic HCV infection Poly- oligoclonal B-cell expansion Autoantibodies RF - IC Mixed cryoglobulins Cryoglobulinemic vasculitis Monoclonal B-cell proliferation Overt lymphoma HCV eradication Immunosuppressors Chemotherapy Plasma exchange Steroids

25. Treatment Efficacy in HCV-Related Systemic Vasculitis Zuckerman, J Rheumatol 2000. Naarendorp, J Rheumatol 2001. Cacoub, Arthritis Rheum 2002, Zaja F, Blood 2003. Sansonno D, Blood 2003 , Cacoub, Arthritis Rheum 2005 % improvement

27. Pathogenesis of cryoglobulinaemic nephritis and rationale for Rituximab treatment Roccatello, D. et al. Nephrol. Dial. Transplant. 2004

28. Treatment of Mixed Cryoglobulinemia Resistant to Interferon-alfa with an Anti-CD 20 Monoclonal Antibody (Rituximab*) Sansonno D et al, Zaja F et al, Blood 2003

29. Main Course of Cryoglobulinemia Vasculitis Features after Rituximab Treatment. HCV+ 43 patients, HCV- 14 patients Cacoub P, Ann Rheum Dis 2007

30. % improvement HCV-Vasculitis Treatment : PegIFN-Ribavirin vs. Rituximab

31. Cryoglobulinemia Vasculitis : Response Maintenance after Discontinuation of Rituximab RESPONSE MAINTENANCE (%) 10 20 30 40 50 60 70 80 90 MONTHS 100 6 12 15 (93.7) 13 (81.2) 12 (75) 1 2 3 4 5 7 8 9 10 11 24 36 48 10 (62.5) 6 (37.5) Sansonno D et al, 2007

32. 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

33. Response rate of HCV-cryoglobulinemia vasculitis during Rituximab & Peg-IFNα2b + Ribavirin.

34. Immunologic parameters in HCV-MC patients during treatment with Rituximab & Peg-IFNα2b-ribavirin.

35. HCV RNA viral load during treatment with Rituximab & Peg-IFNα2b + Ribavirin in HCV-cryoglobulinemia vasculitis.

36. Dynamics of CD19+ B cell depletion and recovery during treatment with rituximab combined with Peg-IFNα2b-ribavirin in HCV-MC patients. Saadoun D et al, Ann Rheum Dis 2008

37. Maintenance of Complete Remission of HCV-Cryoglobulinemia Vasculitis after Rituximab & Peg-IFNα2b + Ribavirin.

38. San Francisco, ACR 2008

42. Association between fatigue, depression and clinical extrahepatic manifestations (EM) Poynard T et al. J Viral Hep, 2002

44. Prevalence of fatigue at baseline and at 18 months follow-up in treated and untreated patients Poynard T et al. J Viral Hep, 2002

46. 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

47. 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

49. 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.

53. Chronic infection with Hepatitis C Virus Hepatocytes B-Lymphocytes Hepatitis (acute/chronic) Cirrhosis Hepatocarcinoma Mixed cryoglobulinemia B-cell lymphoma ?

54. Chronic viral replication Mixed cryoglobulinemia Large B-cell lymphoma SLVL/Marginal zone NHL Other low grade B-cell NHL dependance on antigenic stimulation polyclonal monoclonal Progression of B-cell proliferation induced by HCV direct transformation (no cryo)