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Cacoub Manif Extra HéPatiques

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  • 1. Extrahepatic Manifestations of Hepatitis C Virus Infection Pr. Patrice CACOUB, MD, PhD Service de Médecine Interne, et CNRS UMR 7087 Université Pierre et Marie Curie Hôpital La Pitié-Salpêtrière, Paris, FRANCE
  • 2. Manifestation Prevalences certainly associated with HCV % -------------------------------------------------- • Vasculitis (PAN, cryoglobulinemia) 4-40 • Fatigue 35-54 • Arthralgia-myalgia 25-35 • Sicca syndrome 10-25 • Autoantibodies 10-40 • Thrombocytopenia 20-40 • Lymphoma (SLVL) ?
  • 3. Cryoprecipitation Endothelial cells
  • 4. Pathogenesis of cryoglobulinaemic nephritis Roccatello, D. et al. Nephrol. Dial. Transplant. 2004
  • 5. Distal Polyneuropathy 80% Peripheral Nerve Biopsy - important peri-vascular infiltrate of lymphocyte - around small vessels i.e. venules, capillaries - no PMN, no destruction of the vascular wall
  • 6. Skin Purpura Neuropathy Cryoglobulinemia-Systemic Vasculitis Membrano-proliferative CNS Vasculitis Glomerulonephritis
  • 7. Prevalence of HCV infection in patients with essential cryoglobulinemia 100 90 80 70 60 50 40 30 20 10 0 Ferri Disdier Casato Pechere Misiani Agnello Cacoub Dupin Monti
  • 8. Hepatitis C Virus Chronic Infection : two main target cells Hepatocyte Lymphocyte Choo. Science 1989 Zignego. J Hepatol 1992 Ferri. Blood 1993 • Hepatitis • Cryoglobulinemia • Cirrhosis • B-NHL • Hepatocarcinoma
  • 9. FREQUENCY OF HBV-RELATED PAN: 1972-1999 60% 53% 50% 48% 40% 41% 30% 28% 20% 10% 12% 0% 1972-79 1980-84 1985-89 1990-94 1995-99 Guillevin L
  • 10. Clinical features of 231 MC Patients end beginning follow-up follow-up p° Purpura 89% 81% .05 Weakness 91% 80% .001 Arthralgias 90% 72% .001 Arthritis 6% 8% ns Raynaud's phen. 44% 36% ns Sicca syndrome 48% 29% .001 Skin ulcers 20% 11% .02 Periph. neuropathy 73% 58% .001 Liver involvement 70% 58% .02 Renal involvement 27% 20% ns B-cell lymphoma 9% 0.4% .001 Hepat. carcinoma 3% 0% .05 Ferri C, Sem Arthr Rheum 2004
  • 11. MC and Skin
  • 12. Cutaneous Manifestations of HCV
  • 13. HCV Core Protein in Skin Vascular Structures
  • 14. Systemic Vasculitis and Hepatitis C virus 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% insufficiency polyneurop. Severe HTA Livedo-ulcers- Purpura eight loss ultifoc. Sensory Neurop. Ery nod. Renal SM m W Cacoub P et al. Arthritis Rheum 2002
  • 15. MC and Neuropathy Distal Polyneuropathy 80% • First symptoms : 61 years • Chronic course, progressive • Distal, symetric, axonal polyneuropathy, mainly sensory and painful • Few extra neurological signs : purpura, Raynaud, kidney ... • Severe liver involvement • Moderate inflammatory syndrome Cacoub P et al, AIDS 2005
  • 16. MC and Neuropathy Mononeuropathy Multiplex 20% Cacoub P et al, AIDS 2005
  • 17. Mononeuropathy multiplex (20%) • Younger age at first symptoms (< 60 years) • Acute or subacute involvement • Severe, sensory-motor, mononeuritis multiplex • Weight loss, inflammatory syndrome • Extra-neurological manifestations • Moderate liver involvement
  • 18. Pathological data in HCV related vasculitis Cacoub P et al. Arthritis Rheum 2002 N % Membranoproliferative GN 5 - Leucocytoclastic vasculitis 6 - PAN-type vasculitis 7/23 30 % Mixed cryo-type vasculitis 14/23 61 % Both 2/23 9% Knodell score 6.5 (1-12) - Cirrhosis 3/26 12 %
  • 19. Central Nervous System Involvement in HCV-Infected Patients Stroke (ischemic or haemorraghic) - usually associated with numerous extra- neurologic manifestations, i.e. renal, PNS, skin, digestive tract - 4 cases with isolated CNS involvement Encephalopathy with coma or convulsions - multiple ischemic strokes, - in two cases, brain biopsy showed small vessel vasculitis -> Possible improvement under steroids, immunosuppressive and anti-viral treatment.
  • 20. Central Nervous System Involvement in HCV-Cryoglobulinemia Vasculitis HCV- 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 * P<0.01 2.2 ± 1.8 0.9 ± 0.8 * - --------------------------------------------------------- ----------------------------- WMHS: White Matter Hypersignals Casato M et al, J Hepatol 2004 PVHS: Periventricular Hypersignals
  • 21. HCV and membranoproliferative glomerulonephritis • Proteinuria (g/d) 3.1 ± 2.2 • Albumin (g/L) 29 ± 5 • Creatinine (µmol/L) 118 ± 41 • Cryoglobulin (II/III) 16 / 2 • Cryoglobulin level (g/L) 1.4 ± 1.8 • ALT (IU x N/ml) 1.5 ± 1 • Genotype 1/ 2/ 3/ 4 11/ 3/ 2/ 2 • Treatment of nephrotic sd plasmapheresis 132 (66%) steroids 8 (44%) furosemide 18 (100%) ACE 12 (66%) Alric L. Am J K Dis, 2004
  • 22. Therapeutic strategy in HCV+ Mixed Cryoglob. Chronic HCV infection HCV eradication Poly- oligoclonal Immunosuppressors B-cell expansion Autoantibodies Monoclonal B-cell RF - IC proliferation Chemotherapy Mixed cryoglobulins Overt lymphoma Plasma exchange Cryoglobulinemic vasculitis Steroids
  • 23. Treatment Efficacy in HCV-Related Systemic Vasculitis 100 90 80 % improvement 70 60 IFN + RBV 50 40 30 20 10 0 Skin Renal Nerve Zuckerman, J Rheumatol 2000. Naarendorp, J Rheumatol 2001. Cacoub, Arthritis Rheum 2002,
  • 24. Treatment Efficacy in HCV-Related Systemic Vasculitis 100 90 % improvement 80 70 60 50 IFN + RBV 40 PegIFN + RBV 30 20 10 0 Skin Renal Nerve Zuckerman, J Rheumatol 2000. Naarendorp, J Rheumatol 2001. Cacoub, Arthritis Rheum 2002, Zaja F, Blood 2003. Sansonno D, Blood 2003 , Cacoub, Arthritis Rheum 2005
  • 25. All MC patients α2b-Riba α2 IFNα2 α2b-Riba α2 PegIFNα2 Parameter (n=72) (n=32) (n=40) Treatment Duration of anti-HCV therapy (months) 16.63 ± 7.8 18.35 ± 10.0 13.25 ± 4.4 Ribavirin dosage (mg/day) 915.9 ± 182.8 875.9 ± 195.7 945 ± 169.3 Previous antiviral therapy (n,%) 20 (27.8) 7 (21.9) 13 (32.5) Corticosteroids use (n,%) 29 (40.3) 15 (46.9) 14 (35) Plasmapheresis (n,%) 9 (12.5) 8 (25) 1 (2.5) Immunosuppressors (n,%) 4 (5.6) 4 (12.5) 0 (0) All adverse events (n,%) 39 (54.2) 17 (53.1) 22 (55) Outcome Lower use of associated treatments in patients Deaths (n,%) 8 (11.1) 6 (18.8) 2 (5) Clinical CRreceived a combination of PegIFN + Ribavirin who † (n,%) 40 (55.5) 12 (37.5) 28 (70)* Virological CR † (n,%) 49 (68.0) 19 (59.3) 30 (75) Immunological CR † (n,%) 33 (45.8) 9 (28.1) 24 (60)*
  • 26. Predictive Factors of Clinical Response to HCV Therapy in Mixed Cryoglobulinemia Vasculitis Multivariate Analysis Odds ratio [95%CI] p ------------------------------------------------------------------ ------------------------------- • Renal involvement 0.27 [0.08-0.87] 0.02 Renal insufficiency (GFR<70) 0.18 [0.05-0.67] 0.01 • Renal insufficiency (GFR<70) 0.19 [0.04-0.69] 0.01 • Daily proteinuria > 1g 0.32 [0.09-1.11] 0.05 Early virological resp. (M3) 3.53 [1.18-10.59] 0.02 • Early virological response (M3) 2.86 [0.97-8.78] 0.05
  • 27. Is there a place for other treatments in HCV- systemic vasculitis ? • Steroids – at the initial phase, multivisceral lifethreatening disease, i.e. kidney, CNS, digestive tract involvement. – in combination with anti-HCV treatments. – prednisone 0.5-1 mg/kg/d, rapidly tapered to 10 mg/d • Immunosuppressive – cyclophosphamide: if no response with CT + IFN + ribavirin – azathioprine, methotrexate: cautious with liver disease • Plasmapheresis – if multivisceral involvement, particularly kidney. – if no response with CT + IFN + ribavirin
  • 28. Pathogenesis of cryoglobulinaemic nephritis and rationale for Rituximab treatment Roccatello, D. et al. Nephrol. Dial. Transplant. 2004
  • 29. 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
  • 30. HCV-Vasculitis Treatment : PegIFN-Ribavirin vs. Rituximab 90 80 % improvement 70 60 50 40 30 20 10 0 ia e s ura alg er v ney ryo pse P urp rth r N Kid C Re la A PegIFN-RBV (n=40) Rituximab (n=43)
  • 31. Cryoglobulinemia Vasculitis : Response Maintenance after Discontinuation of Rituximab 100 15 (93.7) RESPONSE MAINTENANCE (%) 90 13 (81.2) 80 12 (75) 70 60 10 (62.5) 50 40 6 (37.5) 30 20 10 1 2 3 4 5 6 7 8 9 10 11 12 24 36 48 MONTHS Sansonno D et al, 2007
  • 32. Rituximab plus Peg-IFNα2b-Ribavirin in Refractory Peg-IFNα2b- HCV- HCV-Related Systemic Vasculitis PEGYLATED INTERFERON α2b (1.5 μg/Kg/wk) RIBAVIRIN (600-1200 mg/d) RITUXIMAB (375 mg/m²) 0 1 2 12 Time (months) Cacoub P, 2007
  • 33. Figure 1 Response rate of HCV-cryoglobulinemia vasculitis during Rituximab & Peg-IFNα2b + Ribavirin. Rituximab Peg-Interferon-ribavirin 70 % of complete responders 62.5 50 50 37.5 30 20 18.7 10 1 2 3 4 5 6 7 8 9 10 11 12 Months
  • 34. Immunologic parameters in HCV-MC patients during treatment with Rituximab & Peg-IFNα2b-ribavirin. Figure 4 A B Cryoglobulin C4 g/l g/l 2 0,18 1,6 0,15 0,12 1,2 0,09 0,8 0,06 0,4 0,03 0 0 0 3 6 9 12 EOF 0 3 6 9 12 EOF Months Months C D g/l IgM RF IU/l 2,8 240 2,4 200 2 160 1,6 120 1,2 80 0,8 0,4 40 0 0 0 3 6 9 12 EOF 0 3 6 9 12 EOF Months Months
  • 35. HCV RNA viral load during treatment with Rituximab & Peg-IFNα2b + Ribavirin in HCV-cryoglobulinemia vasculitis. 7 6 Log copies/ml 5 4 3 2 1 0 Months 0 3 6 9 12 EOF Rituximab Peg-Interferon-ribavirin
  • 36. HCV- Outcome of 93 HCV-MC patients according to the type of treatment Parameters All α PegIFNα-ribavirin RTX-PegIFNα-α ribavirin n=93 n=55 n=38 p Time of clinical response (months) 6.8 ± 4.7 8.4 ± 4.7 5.4 ± 4.0 0.004 Clinical response CR 68 (73.1) 40 (72.7) 28 (73.7) 0.98 PR 22 (23.6) 13 (23.6) 9 (23.7) NR 3 (3.2) 2 (3.6) 1 (2.6) Relapse 17 (18.3) 10 (18.1) 7 (18.4) Immunological response CR 49 (52.7) 24 (43.6) 26 (68.4) 0.001 PR 35 (37.6) 25 (45.4) 10 (26.3) NR 8 (8.6) 6 (10.9) 2 (5.2) Relapse 17 (18.3) 10 (18.1) 7 (18.4) Virological response SVR 55 (59.1) 33 (60) 22 (57.9) 0.94 NR 38 (40.8) 22 (40) 16 (42.1) Death 5 (5.4) 2 (3.6) 3 (7.9) 0.70 Cirrhosis 1 (1.1) _ 1 (2.6) Liver carcinoma 3 (3.2) 2 (3.6) 1 (2.6) Unknown 1 (1.1) _ 1 (2.6)
  • 37. HCV- Course of kidney parameters in HCV-MC patients according to the type of treatment α PegIFNα-ribavirin RTX-PegIFNα-α ribavirin n=10 p n=21 p - CR of kidney involv. 4 (40) 17 (80.9) 0.04 - Creatininemia (µmol/l) Baseline 150.0 ± 30.6 217.5 ± 47.4 EOF 169.2 ± 44.2 0.28 136.9 ± 27.1 0.03 - GFR (ml/min) Baseline 58.0 ± 7.4 42.8 ± 5.8 EOF 59.5 ± 9.9 0.41 57.6 ± 4.5 0.01 - Daily Proteinuria (g) Baseline 3.1 ± 0.9 3.5 ± 0.9 EOF 1.2 ± 0.5 0.046 0.35 ± 0.1 <0.001 - Hematuria (n,%) Baseline 10 (100) 19 (90.5) EOF 2 (20) 2 (10.5) <0.001
  • 38. HCV- Course of B lymphocytes in HCV-MC patients according to the type of treatment n=38 n=55
  • 39. Antiviral therapy alone decreases the memory B cells HCV- in HCV-MC patients n=38 n=55
  • 40. Antiviral therapy in association with Rituximab B- HCV- decreases naive B-cells in HCV-MC patients : n=38 n=55
  • 41. Time Course of HCV Viral Load
  • 42. Therapeutic Strategies in HCV-related Cryoglobulinemic Vasculitis Mild to Moderate Severe disease Life threatening disease (Progressive renal disease, (Rapidly progressive nephritis, (Purpura, arthralgia, mononeuritis multiplex, skin CNS, digestive and/or pulmonary polyneuropathy) ulcer) involvement) Peg IFN-α + Ribavirin Rituximab Steroids, plasma exchange, Peg IFN-α + Ribavirin cyclophosphamide and/or rituximab. Peg IFN-α + Ribavirin (differed)
  • 43. Hepatitis C virus : extrahepatic manifestations, an update 2007 Manifestation Prevalences certainly associated with HCV % --------------------------------------------------------------- Vasculitis (PAN, cryoglobulinemia) 4-40 Fatigue 35-54 Arthralgia-myalgia-arthritis 25-35 Sicca syndrome 10-25 Autoantibodies 10-40 Thrombocytopenia 20-40 Lymphoma (SLVL) -
  • 44. Association between fatigue, extrahepatic manifestations, an update 2007 Hepatitis C virus : depression and clinical extrahepatic manifestations (EM) % of patients % of controls n = 1614 n = 412 Fatigue without depression 48 0.7 Fatigue with depression 5 0 Depression without fatigue 2 0 No fatigue and no depression 45 99.3 Total 100 100 Fatigue without EM 19 0.5 Fatigue with EM 35 0.2 EM without fatigue 21 3.4 No fatigue and no EM 25 96 Total 100 100 Poynard T et al. J Viral Hep, 2002
  • 45. Multivariate analysis Hepatitis C virus : extrahepatic manifestations, an update 2007 Fatigue (moderate or severe) in comparison to absence of fatigue was associated with: • female gender, • age > 50 years, • cirrhosis or many septa, • purpura. Independently of these associations, fatigue (moderate-severe) was associated with : arthralgia, myalgia, paresthesia, sicca sd & pruritus. Poynard T et al. J Viral Hep, 2002
  • 46. Prevalence of fatigue at Hepatitis C virus :at 18 months follow-up in treated baseline and extrahepatic manifestations, an update 2007 and untreated patients Baseline 18 months 18 months vs baseline Non treated (n=72) No fatigue 39 % 42 % P = 0.74 Moderate 35 % 39 % Severe 26 % 19 % Sustained responders (n=82) P < 0.001 No fatigue 41 % 69 % Moderate 37 % 24 % Severe 22 % 7% Relapsers (n= 47) No fatigue 45 % 40 % P = 0.68 Moderate 43 % 45 % Severe 13 % 15 % Non responders (n= 224) No fatigue 40 % 46 % P = 0.18 Moderate 42 % 40 % Severe 18 % 14 % Poynard T et al. J Viral Hep, 2002
  • 47. Hepatitis C virus : extrahepatic manifestations, an update 2007 Manifestation Prevalences certainly associated with HCV % --------------------------------------------------------------- Vasculitis (PAN, cryoglobulinemia) 4-40 Fatigue 35-54 Arthralgia-myalgia-arthritis 25-35 Sicca syndrome 10-25 Autoantibodies 10-40 Thrombocytopenia 20-40 Lymphoma (SLVL) -
  • 48. Impact of Treatment on Extra hepatic Manifestations in HCVpatients. Hepatitis C virus : extrahepatic manifestations, an update 2007 At Baseline and 18 months Follow-up in Responders. 40% 35% 30% 25% 20% 15% 10% 5% 0% 0 0 0 0 18 18 18 18 M M M M M M M M ia a ia sd si lg lg he a ya ra cc st th M Si re Ar Pa Sustained responders (n = 83) Cacoub P et al. J Hepatol 2002
  • 49. Impact of Treatment on Extra hepatic Manifestations in HCVpatients. Hepatitis C virus : extrahepatic manifestations, an update 2007 At Baseline and 18 months Follow-up in Responders. 40% 35% 30% 25% 20% 15% 10% 5% 0% 18 18 18 18 0 0 0 0 M M M M M M M M ia sd a ia lgi lg es a ya ra cc sth th M Si re Ar Pa Sustained responders (n = 83) Non responders - RNA + (n = 348) Cacoub P et al. J Hepatol 2002
  • 50. Hepatitis C virus : extrahepatic manifestations, an update 2007 Manifestation Prevalences certainly associated with HCV % --------------------------------------------------------------- Vasculitis (PAN, cryoglobulinemia) 4-40 Fatigue 35-54 Arthralgia-myalgia-arthritis 25-35 Sicca syndrome 10-25 Autoantibodies 10-40 Thrombocytopenia 20-40 Lymphoma (SLVL) -
  • 51. Auto-antibody production in chronic HCV infection. 70 60 50 A-nuclear A-phospholipid 40 A-thyroglobulin 30 A-smooth muscle 20 ≥ one auto-Ab ≥ three auto-Ab 10 0 % Pawlotsky JM, Hepatology 1994. Pawlotsky JM, Ann Intern Med 1994. Prieto J, Hepatology 1996. Cacoub P, J Rheumatol 1997. Cacoub P, Medicine 2000.
  • 52. Auto-antibody production in chronic HCV infection. Most patients were negative for all other autoAbs : • neutrophil cytoplasmic, β2 GP1 • Langherans islet, insulin, GAD • liver-kidney microsome, mitochondria There was no correlation between : • Clinical or immunological abnormalities • α-IFN & clinical/immunological abnormalities
  • 53. Extrahepatic manifestations associated with HCV infection. (Prospective study in 321 HCV patients) Autoantibody Number % ----------------------------------------------------- Antinuclear 124 41 • A-nucleosome 6 2 • A-DNA 8 3 • A-histone 9 3 • A-ENA 10 3 Cacoub P et al. Medicine 2000; 79: 47-56
  • 54. Hepatitis C virus : extrahepatic manifestations, an update 2007 Manifestation Prevalences certainly associated with HCV % --------------------------------------------------------------- Vasculitis (PAN, cryoglobulinemia) 4-40 Fatigue 35-54 Arthralgia-myalgia-arthritis 25-35 Sicca syndrome 10-25 Autoantibodies 10-40 Thrombocytopenia 20-40 Lymphoma (SLVL) -
  • 55. Hepatitis C Virus Chronic Infection : two main target cells Hepatocyte Lymphocyte Choo. Science 1989 Zignego. J Hepatol 1992 Ferri. Blood 1993 • Hepatitis • Cryoglobulinemia • Cirrhosis • B-NHL • Hepatocarcinoma
  • 56. Hepatitis C virus : extrahepatic manifestations, an update 2007 B-cell-Non Hodgin’s Lymphoma 2462 tested 13.5 % positive 469 tested • vs 0-5 % in controls • vs 5 % in other malignant 0 - 39 % hemopathy Hepatitis C virus
  • 57. Effects of alpha-interferon on HCV+/SLVL course update 2007 Hepatitis C virus : extrahepatic manifestations, an HCV antibodies : B-NHL (< 3%) vs SLVL (15%) ----> Splenic lymphoma with villous lymphocytes may be associated with HCV infection After 6 months of IFN alpha treatment in SLVL/HCV+: Complete clinical hematologic response (spleen size < 12 cm, lymphocytosis <4500/mm3, No cytopenia ): ---> 7/9 HCV RNA negative Partial clinical hematologic response (spleen size or lymphocytosis decrease >50%) : ---> 2/9 HCV RNA + Hermine O. et al, N Engl J Med 2002; 347: 89-94
  • 58. Effects of alpha-interferon on HCV+/SLVL course update 2007 Hepatitis C virus : extrahepatic manifestations, an Median Follow-up of 3 years (2-5) 6 Complete Responses ---> HCV RNA still negative 1 relapse off therapy at 1 year, • associated with positivity of HCV RNA. • second CR following IFN & negativity HCV RNA 2 Partial Responses • CR after Combination of Interferon and Ribavirin • PR after Interferon and Ribavirin Hermine O. et al, N Engl J Med 2002; 347: 89-94
  • 59. HCV negative / SLVL Patients Treated with Alpha-Interferon 2007 Hepatitis C virus : extrahepatic manifestations, an update Median age 65 (54-72) Prior therapy (2/6), chemotherapy (1), splenectomy(1) Splenomegaly (4/6) Hyperlymphocytosis Median 25,000 (500-100.000) Cytopenia (2/6) Cryoglobulinemia or rheumatoid factor (0/6) 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
  • 60. Conclusion Hepatitis C virus : extrahepatic manifestations, an update 2007 Extra hepatic manifestations of HCV infection are frequent, & may be curred by HCV treatment : • Systemic vasculitis (cryoglobulinemia, PAN) • Fatigue • Arthralgia - myalgia - arthritis (±) • Auto-antibodies (?) • Splenic lymphoma with villous lymphocytes • Thrombocytopenia