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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
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Hepatitis C Virus Chronic Infection : Two Main Target Cells  ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Hepatocyte Choo. Science 1989 Lymphocyte Zignego. J Hepatol 1992 Ferri. Blood 1993
Cryoprecipitation Endothelial cells
Pathogenesis of cryoglobulinaemic nephritis Roccatello, D. et al. Nephrol. Dial. Transplant. 2004
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%
Skin Purpura   Membrano-proliferative Glomerulonephritis CNS Vasculitis   Neuropathy Cryoglobulinemia-Systemic Vasculitis
HCV Mixed Cryoglobulinemia & Digestive Tract Mesenteric artery stenosis Intestinal wall thickening
Demographic & Clinical Features of 250 Mixed Cryoglobulinemic Patients. Ferri C, Mascia MT, Saadoun D, Cacoub P. 2009 Age at disease onset 54 ± 13 (29-72) Female/Male ratio 3 Purpura 98% Weakness 98% Arthralgias 91% Arthritis (non-erosive) 8% Raynaud's phenomenon 32% Sicca syndrome 51% Peripheral neuropathy 81% Renal involvement 31% Liver involvement 73% B-cell non-Hodgkin's lymphoma 11% Hepatocellular carcinoma 3%
Cellular Infiltrate in HCV-Vasculitis  HCV Core Protein in Skin Vascular Structures Who’s the culprit ?
Detection of Genomic Viral RNA in Nerve and Muscle of  Patients with HCV Neuropathy ,[object Object],[object Object],[object Object],[object Object],Authier JF et al, Neurology, 2003
A Major Role for T Cell Immunity in HCV-Vasculitis ,[object Object],[object Object],[object Object],[object Object],[object Object]
Boyer O, Saadoun D et al, Blood 2004 Quantitative Deficit in Treg Lymphocytes ( CD4 + CD25 + )  in HCV-Systemic Vasculitis
 
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.
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
* 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.
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]
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
Anti-HCV Treatment Efficacy in HCV-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, Saadoun, Arthritis Rheum 2007  % improvement
Predictive Factors of Clinical Response to  HCV Therapy in Mixed Cryoglobulinemia Vasculitis Multivariate Analysis ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Renal insufficiency  (GFR<70)   0.18    [0.05-0.67]  0.01 Early virological resp.  (M3) 3.53   [1.18-10.59]  0.02
Roccatello, D. et al. Nephrol. Dial. Transplant. 2004 Pathogenesis of cryoglobulinaemic nephritis  and  rationale for Rituximab treatment Rocatello D, Nephrol Dial Transplant, 2004
Treatment of Mixed Cryoglobulinemia Resistant to Interferon-alfa with Rituximab* (anti-CD 20 Ab) Sansonno D et al, Zaja F et al, Blood 2003
% improvement HCV-Vasculitis Treatment  :  PegIFN-Ribavirin vs. Rituximab Cacoub P, Ann Rheum Dis  2008 Personal series Literature review
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
Lymphocyte Infiltrate in HCV-Vasculitis  HCV Core Protein in Skin Vascular Structures HCV Vasculitis: a Two-Faces Disease
Roccatello, D. et al. Nephrol. Dial. Transplant. 2004 HCV Vasculitis: a Two-Faces Disease … Needs a Two Faces Treatment Strategy Rituximab PegIFN plus Ribavirin
 
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
Response rate of HCV-cryoglobulinemia vasculitis during Rituximab & Peg-IFNα2b + Ribavirin.
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
Blood, 2010
Outcome of HCV-MC pts according to treatment Parameters All  PegIFN  -ribavirin RTX-PegIFN  -ribavirin n=93 n=55 n=38 p Time 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)
Course of kidney parameters in HCV-MC patients according to the type of treatment  PegIFN  -ribavirin RTX-PegIFN  -ribavirin n=10 p n=21 p CR of kidney involv. 4 (40) 17 (80.9) 0.04 Creatininemia (µmol/l) Baseline 150 ± 30 217 ± 47 EOF 169 ± 44 0.28 136 ± 27 0.03 GFR (ml/min) Baseline 58 ± 7 42 ± 5 EOF 59 ± 9 0.41 57 ± 4 0.01 Daily Proteinuria (gr/d) Baseline 3.1 ± 0.9 3 ± 1 EOF 1.2 ± 0.5 0.046 0.4 ± 0.1 <0.001 Hematuria (n,%) Baseline 10 (100) 19 (90.5) EOF 2 (20) 2 (10.5) <0.001
Antiviral therapy alone decreases the memory B cells n=38  n=55 Saadoun D et al, Blood 2010
Antiviral therapy alone decreases the memory B cells Antiviral therapy plus Rituximab decrease naive B-cells  Saadoun D et al, Blood 2010
Blood 2010
Dammacco F et al, Blood 2010
Dammacco F et al, Blood 2010
Course of cryoglobulinemia & HCV RNA in HCV-MC patients according to the type of treatment Saadoun D et al, Blood 2010
Time Course of HCV Viral Load Terrier B et al. Arthritis Rheum 2009
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
 
 
 
Overall Survival of 151 HCV-Vasculitis Patients Terrier B et al. Arthritis Rheum 2010 Years Overall survivall
Overall Survival of 151 HCV-Vasculitis Patients ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Years Overall survivall
Baseline Prognostic Factors of HCV-Vasculitis Patients
Liver Fibrosis and Five Factor Score are Associated with a Poor Prognosis in  HCV vasculitis Patients  ( Multivariate Analysis) ,[object Object],[object Object],[object Object],[object Object]
[object Object],[object Object],[object Object],[object Object],[object Object],FFS is a good predictor of outcome Interaction Between Liver Fibrosis and Five Factor Score in  HCV-Vasculitis Patients Metavir Fibrosis FFS F0-F2 F3-F4 0 1.0 1 2.49 > 1 6.2
FFS=good predictor of outcome No more prognostic value of FFS Interaction Between Liver Fibrosis and Five Factor Score in  HCV -Vasculitis Patients ,[object Object],[object Object],[object Object],[object Object],[object Object],Metavir Fibrosis FFS F0-F2 F3-F4 0 1.0 10.8 1 2.49 10.25 > 1 6.2 9.74
Prognostic Factors During follow-up Use of Peg-IFN/riba had a positive prognostic impact  HR = 0.34 (0.16-0.67)
Prognostic Factors During follow-up ,[object Object],[object Object],[object Object],[object Object],[object Object],Use of Peg-IFN/riba had a positive prognostic impact  HR = 0.34 (0.16-0.67)
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Association between fatigue, depression and clinical  extrahepatic manifestations (EM) Poynard T et al. J Viral Hep, 2002
Multivariate analysis ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Poynard T et al. J Viral Hep, 2002
Prevalence of fatigue at baseline and at 18 months follow-up in treated and untreated patients Poynard T et al. J Viral Hep, 2002
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
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
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
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
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.
Extrahepatic manifestations associated with HCV infection. (Prospective study in  321 HCV patients) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Cacoub P et al. Medicine 2000; 79: 47-56
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
 
[object Object],Hepatitis C virus ,[object Object],[object Object],[object Object],[object Object],[object Object],469 tested 0 - 39 %
Effects of alpha-interferon on  HCV+/SLVL  course ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Hermine O. et al, N Engl J Med 2002; 347: 89-94 ,[object Object],[object Object]
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Effects of alpha-interferon on  HCV+/SLVL  course Hermine O. et al, N Engl J Med 2002; 347: 89-94
HCV negative / SLVL  Patients Treated with Alpha-Interferon ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],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
Conclusion ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Thanks ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

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HCV_Manifestations extra hépatiques.ppt

  • 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
  • 2.
  • 3.
  • 5. Pathogenesis of cryoglobulinaemic nephritis Roccatello, D. et al. Nephrol. Dial. Transplant. 2004
  • 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%
  • 7. Skin Purpura Membrano-proliferative Glomerulonephritis CNS Vasculitis Neuropathy Cryoglobulinemia-Systemic Vasculitis
  • 8. HCV Mixed Cryoglobulinemia & Digestive Tract Mesenteric artery stenosis Intestinal wall thickening
  • 9. Demographic & Clinical Features of 250 Mixed Cryoglobulinemic Patients. Ferri C, Mascia MT, Saadoun D, Cacoub P. 2009 Age at disease onset 54 ± 13 (29-72) Female/Male ratio 3 Purpura 98% Weakness 98% Arthralgias 91% Arthritis (non-erosive) 8% Raynaud's phenomenon 32% Sicca syndrome 51% Peripheral neuropathy 81% Renal involvement 31% Liver involvement 73% B-cell non-Hodgkin's lymphoma 11% Hepatocellular carcinoma 3%
  • 10. Cellular Infiltrate in HCV-Vasculitis HCV Core Protein in Skin Vascular Structures Who’s the culprit ?
  • 11.
  • 12.
  • 13. Boyer O, Saadoun D et al, Blood 2004 Quantitative Deficit in Treg Lymphocytes ( CD4 + CD25 + ) in HCV-Systemic Vasculitis
  • 14.  
  • 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]
  • 19. 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
  • 20. Anti-HCV Treatment Efficacy in HCV-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, Saadoun, Arthritis Rheum 2007 % improvement
  • 21.
  • 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
  • 25. 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
  • 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
  • 28.  
  • 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
  • 33. Outcome of HCV-MC pts according to treatment Parameters All PegIFN  -ribavirin RTX-PegIFN  -ribavirin n=93 n=55 n=38 p Time 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)
  • 34. Course of kidney parameters in HCV-MC patients according to the type of treatment PegIFN  -ribavirin RTX-PegIFN  -ribavirin n=10 p n=21 p CR of kidney involv. 4 (40) 17 (80.9) 0.04 Creatininemia (µmol/l) Baseline 150 ± 30 217 ± 47 EOF 169 ± 44 0.28 136 ± 27 0.03 GFR (ml/min) Baseline 58 ± 7 42 ± 5 EOF 59 ± 9 0.41 57 ± 4 0.01 Daily Proteinuria (gr/d) Baseline 3.1 ± 0.9 3 ± 1 EOF 1.2 ± 0.5 0.046 0.4 ± 0.1 <0.001 Hematuria (n,%) Baseline 10 (100) 19 (90.5) EOF 2 (20) 2 (10.5) <0.001
  • 35. Antiviral therapy alone decreases the memory B cells n=38 n=55 Saadoun D et al, Blood 2010
  • 36. Antiviral therapy alone decreases the memory B cells Antiviral therapy plus Rituximab decrease naive B-cells Saadoun D et al, Blood 2010
  • 38. Dammacco F et al, Blood 2010
  • 39. Dammacco F et al, Blood 2010
  • 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
  • 43.  
  • 44.  
  • 45.  
  • 46. Overall Survival of 151 HCV-Vasculitis Patients Terrier B et al. Arthritis Rheum 2010 Years Overall survivall
  • 47.
  • 48. Baseline Prognostic Factors of HCV-Vasculitis Patients
  • 49.
  • 50.
  • 51.
  • 52. Prognostic Factors During follow-up Use of Peg-IFN/riba had a positive prognostic impact HR = 0.34 (0.16-0.67)
  • 53.
  • 54.
  • 55. Association between fatigue, depression and clinical extrahepatic manifestations (EM) Poynard T et al. J Viral Hep, 2002
  • 56.
  • 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
  • 58.
  • 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
  • 61.
  • 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.
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  • 64.
  • 65.  
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  • 67.
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  • 69.
  • 70.
  • 71.