Hcv Meh Cacoub

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  • Hcv Meh Cacoub

    1. 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
    2. 2. <ul><li>Manifestation Prevalences </li></ul><ul><li>certainly associated with HCV % </li></ul><ul><li>-------------------------------------------------- </li></ul><ul><li>Vasculitis (PAN, cryoglobulinemia) 4-40 </li></ul><ul><li>Fatigue 35-54 </li></ul><ul><li>Arthralgia-myalgia 25-35 </li></ul><ul><li>Sicca syndrome 10-25 </li></ul><ul><li>Autoantibodies 10-40 </li></ul><ul><li>Thrombocytopenia 20-40 </li></ul><ul><li>Lymphoma (SLVL) ? </li></ul>
    3. 3. FREQUENCY OF HBV-RELATED PAN: 1972-1999 Guillevin L
    4. 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. 5. > 250 million infected individuals worldwide > 3,0 in USA; > 0,5 in France
    6. 6. <ul><li>« Essential » mixed cryoglobulinemia </li></ul>Hepatitis C virus 55 to 95% 30 to 55 %
    7. 7. Hepatitis C Virus Chronic Infection : two main target cells <ul><li>Hepatitis </li></ul><ul><li>Cirrhosis </li></ul><ul><li>Hepatocarcinoma </li></ul><ul><li>Cryoglobulinemia </li></ul><ul><li>B-NHL </li></ul>Hepatocyte Choo. Science 1989 Lymphocyte Zignego. J Hepatol 1992 Ferri. Blood 1993
    8. 8. Cryoprecipitation Endothelial cells
    9. 9. Pathogenesis of cryoglobulinaemic nephritis Roccatello, D. et al. Nephrol. Dial. Transplant. 2004 hlkjhjhkhuhhh
    10. 10. Skin Purpura Membrano-proliferative Glomerulonephritis CNS Vasculitis Cryoglobulinemia-Systemic Vasculitis Neuropathy
    11. 11. Cryoglobulins are immune complexes Type III Mixed cryoglobulins Type I m Ig <ul><li>Myeloma </li></ul><ul><li>Lymphoproliferative disorders </li></ul>Type II m Ig + polyclonal Ig polyclonal Igs <ul><li>Chronic infections </li></ul><ul><li>Connective tissue diseases </li></ul><ul><li>Lymphoproliferative disorders </li></ul><ul><li>Essential </li></ul>
    12. 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. 13. Prevalence of HCV infection in patients with essential cryoglobulinemia
    14. 14. Ferri C, Sem Arthr Rheum 2004
    15. 15. MC and Skin
    16. 16. Severe necrotizing leukocytoclastic vasculitis: extensive fibrinoid necrosis of the vessel wall with permeation of the wall by disintegrating neutrophils
    17. 17. HCV Core Protein in Skin Vascular Structures
    18. 18. Distal Polyneuropathy 80% Cacoub P et al, AIDS 2005 MC and Neuropathy <ul><li>First symptoms : 61 years </li></ul><ul><li>Chronic course, progressive </li></ul><ul><li>Distal, symetric, axonal polyneuropathy, mainly sensory and painful </li></ul><ul><li>Few extra neurological signs : purpura, Raynaud, kidney ... </li></ul><ul><li>Severe liver involvement </li></ul><ul><li>Moderate inflammatory syndrome </li></ul>
    19. 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%
    20. 20. Detection of Genomic Viral RNA in Nerve and Muscle of Patients with HCV Neuropathy <ul><li>Inflammatory vascular lesions in 26/30 (87%) patients. </li></ul><ul><li>Positive-strand genomic HCV RNA detected in 10/30 patients (muscle 9, nerve 3). </li></ul><ul><li>Negative-strand replicative HCV RNA never detected. </li></ul><ul><li>--> HCV neuropathy probably results from virus-triggered immune-mediated mechanisms rather than direct nerve infection and in situ replication. </li></ul>Authier JF et al, Neurology, 2003
    21. 21. Mononeuropathy Multiplex 20% Cacoub P et al, AIDS 2005 MC and Neuropathy
    22. 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
    23. 23. <ul><li>Proteinuria (g/d) </li></ul><ul><li>Albumin (g/L) </li></ul><ul><li>Creatinine (  mol/L) </li></ul><ul><li>Cryoglobulin (II/III) </li></ul><ul><li>Cryoglobulin level (g/L) </li></ul><ul><li>ALT (IU x N/ml) </li></ul><ul><li>Genotype 1/ 2/ 3/ 4 </li></ul><ul><li>Treatment of nephrotic sd </li></ul><ul><li>plasmapheresis </li></ul><ul><li>steroids </li></ul><ul><li>furosemide </li></ul><ul><li>ACE </li></ul>3.1 ± 2.2 29 ± 5 118 ± 41 16 / 2 1.4 ± 1.8 1.5 ± 1 11/ 3/ 2/ 2 132 (66%) 8 (44%) 18 (100%) 12 (66%) HCV and membranoproliferative glomerulonephritis Alric L. Am J K Dis, 2004
    24. 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. 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
    26. 26. Predictive Factors of Clinical Response to HCV Therapy in Mixed Cryoglobulinemia Vasculitis Multivariate Analysis <ul><li> Odds ratio [95%CI] p </li></ul><ul><ul><li>------------------------------------------------------------------------------------------------- </li></ul></ul><ul><li>Renal involvement 0.27 [0.08-0.87] 0.02 </li></ul><ul><li>Renal insufficiency (GFR<70) 0.19 [0.04-0.69] 0.01 </li></ul><ul><li>Daily proteinuria > 1g 0.32 [0.09-1.11] 0.05 </li></ul><ul><li>Early virological response (M3) 2.86 [0.97-8.78] 0.05 </li></ul>Renal insufficiency (GFR<70) 0.18 [0.05-0.67] 0.01 Early virological resp. (M3) 3.53 [1.18-10.59] 0.02
    27. 27. Pathogenesis of cryoglobulinaemic nephritis and rationale for Rituximab treatment Roccatello, D. et al. Nephrol. Dial. Transplant. 2004
    28. 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. 29. Main Course of Cryoglobulinemia Vasculitis Features after Rituximab Treatment. HCV+ 43 patients, HCV- 14 patients Cacoub P, Ann Rheum Dis 2007
    30. 30. % improvement HCV-Vasculitis Treatment : PegIFN-Ribavirin vs. Rituximab
    31. 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. 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. 33. Response rate of HCV-cryoglobulinemia vasculitis during Rituximab & Peg-IFNα2b + Ribavirin.
    34. 34. Immunologic parameters in HCV-MC patients during treatment with Rituximab & Peg-IFNα2b-ribavirin.
    35. 35. HCV RNA viral load during treatment with Rituximab & Peg-IFNα2b + Ribavirin in HCV-cryoglobulinemia vasculitis.
    36. 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. 37. Maintenance of Complete Remission of HCV-Cryoglobulinemia Vasculitis after Rituximab & Peg-IFNα2b + Ribavirin.
    38. 38. San Francisco, ACR 2008
    39. 39. Is there a place for other treatments in HCV-systemic vasculitis ? <ul><li>Steroids </li></ul><ul><ul><li>at the initial phase, multivisceral lifethreatening disease, i.e. kidney, CNS, digestive tract involvement. </li></ul></ul><ul><ul><li>in combination with anti-HCV treatments. </li></ul></ul><ul><ul><li>prednisone 0.5-1 mg/kg/d, rapidly tapered to 10 mg/d </li></ul></ul><ul><li>Immunosuppressive </li></ul><ul><ul><li>cyclophosphamide: if no response with CT + IFN + ribavirin </li></ul></ul><ul><ul><li>azathioprine, methotrexate: cautious with liver disease </li></ul></ul><ul><li>Plasmapheresis </li></ul><ul><ul><li>if multivisceral involvement, particularly kidney. </li></ul></ul><ul><ul><li>if no response with CT + IFN + ribavirin </li></ul></ul>
    40. 41. <ul><li>Manifestation Prevalences </li></ul><ul><li>certainly associated with HCV % </li></ul><ul><li>--------------------------------------------------------------- </li></ul><ul><li>Vasculitis (PAN, cryoglobulinemia) 4-40 </li></ul><ul><li>Fatigue 35-54 </li></ul><ul><li>Arthralgia-myalgia-arthritis 25-35 </li></ul><ul><li>Sicca syndrome 10-25 </li></ul><ul><li>Autoantibodies 10-40 </li></ul><ul><li>Thrombocytopenia 20-40 </li></ul><ul><li>Lymphoma (SLVL) - </li></ul>
    41. 42. Association between fatigue, depression and clinical extrahepatic manifestations (EM) Poynard T et al. J Viral Hep, 2002
    42. 43. Multivariate analysis <ul><li>Fatigue (moderate or severe) in comparison to absence of fatigue was associated with : </li></ul><ul><ul><li>female gender, </li></ul></ul><ul><ul><li>age > 50 years, </li></ul></ul><ul><ul><li>cirrhosis or many septa, </li></ul></ul><ul><ul><li>purpura. </li></ul></ul><ul><li>Independently of these associations, fatigue (moderate-severe) was associated with : arthralgia, myalgia, paresthesia, sicca sd & pruritus. </li></ul>Poynard T et al. J Viral Hep, 2002
    43. 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
    44. 45. <ul><li>Manifestation Prevalences </li></ul><ul><li>certainly associated with HCV % </li></ul><ul><li>--------------------------------------------------------------- </li></ul><ul><li>Vasculitis (PAN, cryoglobulinemia) 4-40 </li></ul><ul><li>Fatigue 35-54 </li></ul><ul><li>Arthralgia-myalgia-arthritis 25-35 </li></ul><ul><li>Sicca syndrome 10-25 </li></ul><ul><li>Autoantibodies 10-40 </li></ul><ul><li>Thrombocytopenia 20-40 </li></ul><ul><li>Lymphoma (SLVL) - </li></ul>
    45. 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
    46. 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
    47. 48. <ul><li>Manifestation Prevalences </li></ul><ul><li>certainly associated with HCV % </li></ul><ul><li>--------------------------------------------------------------- </li></ul><ul><li>Vasculitis (PAN, cryoglobulinemia) 4-40 </li></ul><ul><li>Fatigue 35-54 </li></ul><ul><li>Arthralgia-myalgia-arthritis 25-35 </li></ul><ul><li>Sicca syndrome 10-25 </li></ul><ul><li>Autoantibodies 10-40 </li></ul><ul><li>Thrombocytopenia 20-40 </li></ul><ul><li>Lymphoma (SLVL) - </li></ul>
    48. 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.
    49. 50. Auto-antibody production in chronic HCV infection. <ul><li>Most patients were negative for all other autoAbs : </li></ul><ul><ul><li>neutrophil cytoplasmic,  2 GP1 </li></ul></ul><ul><ul><li>Langherans islet, insulin, GAD </li></ul></ul><ul><ul><li>liver-kidney microsome, mitochondria </li></ul></ul><ul><li>There was no correlation between : </li></ul><ul><ul><li>Clinical or immunological abnormalities </li></ul></ul><ul><ul><li> -IFN & clinical/immunological abnormalities </li></ul></ul>
    50. 51. Extrahepatic manifestations associated with HCV infection. (Prospective study in 321 HCV patients) <ul><li>Autoantibody Number % </li></ul><ul><li>----------------------------------------------------- </li></ul><ul><li>Antinuclear 124 41 </li></ul><ul><ul><li>A-nucleosome 6 2 </li></ul></ul><ul><ul><li>A-DNA 8 3 </li></ul></ul><ul><ul><li>A-histone 9 3 </li></ul></ul><ul><ul><li>A-ENA 10 3 </li></ul></ul>Cacoub P et al. Medicine 2000; 79: 47-56
    51. 52. <ul><li>Manifestation Prevalences </li></ul><ul><li>certainly associated with HCV % </li></ul><ul><li>--------------------------------------------------------------- </li></ul><ul><li>Vasculitis (PAN, cryoglobulinemia) 4-40 </li></ul><ul><li>Fatigue 35-54 </li></ul><ul><li>Arthralgia-myalgia-arthritis 25-35 </li></ul><ul><li>Sicca syndrome 10-25 </li></ul><ul><li>Autoantibodies 10-40 </li></ul><ul><li>Thrombocytopenia 20-40 </li></ul><ul><li>Lymphoma (SLVL) - </li></ul>
    52. 53. Chronic infection with Hepatitis C Virus Hepatocytes B-Lymphocytes Hepatitis (acute/chronic) Cirrhosis Hepatocarcinoma Mixed cryoglobulinemia B-cell lymphoma ?
    53. 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)
    54. 55. <ul><li>B-cell-Non Hodgin’s Lymphoma </li></ul>Hepatitis C virus <ul><li>2462 tested </li></ul><ul><li>13.5 % positive </li></ul><ul><li>vs 0-5 % in controls </li></ul><ul><li>vs 5 % in other malignant </li></ul><ul><li>hemopathy </li></ul>469 tested 0 - 39 %
    55. 56. Effects of alpha-interferon on HCV+/SLVL course <ul><li>After 6 months of IFN alpha treatment in SLVL/HCV+: </li></ul><ul><li>Complete clinical hematologic response (spleen size < 12 cm, lymphocytosis <4500/mm3, No cytopenia ): </li></ul><ul><li>---> 7/9 HCV RNA negative </li></ul><ul><li>Partial clinical hematologic response </li></ul><ul><li>(spleen size or lymphocytosis decrease >50%) : </li></ul><ul><li>---> 2/9 HCV RNA + </li></ul>Hermine O. et al, N Engl J Med 2002; 347: 89-94 <ul><li>HCV antibodies : B-NHL (< 3%) vs SLVL (15%) </li></ul><ul><li>----> Splenic lymphoma with villous lymphocytes may be associated with HCV infection </li></ul>
    56. 57. <ul><li>Median Follow-up of 3 years (2-5) </li></ul><ul><li>6 Complete Responses ---> HCV RNA still negative </li></ul><ul><li>1 relapse off therapy at 1 year, </li></ul><ul><ul><li>associated with positivity of HCV RNA. </li></ul></ul><ul><ul><li>second CR following IFN & negativity HCV RNA </li></ul></ul><ul><li>2 Partial Responses </li></ul><ul><ul><li>CR after Combination of Interferon and Ribavirin </li></ul></ul><ul><ul><li>PR after Interferon and Ribavirin </li></ul></ul>Effects of alpha-interferon on HCV+/SLVL course Hermine O. et al, N Engl J Med 2002; 347: 89-94
    57. 58. HCV negative / SLVL Patients Treated with Alpha-Interferon <ul><li>Median age 65 (54-72) </li></ul><ul><li>Prior therapy (2/6), chemotherapy (1), splenectomy(1) </li></ul><ul><li>Splenomegaly (4/6) </li></ul><ul><li>Hyperlymphocytosis Median 25,000 (500-100.000) </li></ul><ul><li>Cytopenia (2/6) </li></ul><ul><li>Cryoglobulinemia or rheumatoid factor (0/6) </li></ul>Alpha-Interferon 3 M IU x 3/W during 6 months No response Hermine O. et al, N Engl J Med 2002; 347: 89-94
    58. 59. Conclusion <ul><li>Extra hepatic manifestations of HCV infection are frequent, & may be curred by HCV treatment : </li></ul><ul><li>Systemic vasculitis (cryoglobulinemia, PAN) </li></ul><ul><li>Fatigue </li></ul><ul><li>Arthralgia - myalgia - arthritis (±) </li></ul><ul><li>Auto-antibodies (?) </li></ul><ul><li>Splenic lymphoma with villous lymphocytes </li></ul><ul><li>Thrombocytopenia </li></ul>

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