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HCV_Manifestations extra hépatiques.ppt HCV_Manifestations extra hépatiques.ppt Presentation Transcript

  • 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
    • 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) ?
  • Hepatitis C Virus Chronic Infection : Two Main Target Cells
    • Hepatitis
    • Cirrhosis
    • Hepatocarcinoma
    • Cryoglobulinemia
    • Auto-Ab
    • B-NHL
    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
    • Inflammatory vascular lesions in 26/30 (87%) patients.
    • Positive-strand genomic HCV RNA detected in 10/30 patients (muscle 9, nerve 3).
    • Negative-strand replicative HCV RNA never detected.
    • --> HCV neuropathy probably results from virus-triggered immune-mediated mechanisms rather than direct nerve infection and in situ replication.
    Authier JF et al, Neurology, 2003
  • A Major Role for T Cell Immunity in HCV-Vasculitis
    • Abnormal T lymphocytes distribution
    • Predominant T lymphocytes infiltration in vasculitis lesions
    • MHC-II polymorphism (DR11)
    • Th1 cytokines profile in vasculitis lesions
    • Deficit in Treg lymphocytes
  • 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
    • Odds ratio [95%CI] p
      • -------------------------------------------------------------------------------------------------
    • Renal involvement 0.27 [0.08-0.87] 0.02
    • 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 response (M3) 2.86 [0.97-8.78] 0.05
    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
    • 32 deaths after a median follow-up of 54 months (IQR 26-89)
    • Causes of death:
    • - Infection (n=10)
    • Cirrhosis (n=10; 4 HCC)
    • Non-HCC neoplasia (n=4)
    • Cardiovascular (n=4)
    • Renal failure (n=2)
    • Vasculitis (n=2)
    • Unknown (n=2)
    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)
    • Metavir fibrosis score:
    • HR = 10.8 (3.63-32.14), P<0.0001
    • Five Factor Score:
    • HR = 2.49 (1.29-4.8), P=0.007
    • Multivariate analysis
    • Metavir fibrosis score:
    • HR 10.8 (3.63-32.14), P<0.0001
    • FFS:
    • HR 2.49 (1.29-4.8), P=0.007
    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
    • Multivariate analysis
    • Metavir fibrosis score:
    • HR 10.8 (3.63-32.14), P<0.0001
    • FFS:
    • HR 2.49 (1.29-4.8), P=0.007
    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
    • After adjustment on vasculitis severity
    • Negative impact of immunosuppressants
    • HR = 4.05 (1.75-9.36), P=0.001
    • … but not of corticosteroids
    • HR = 1.79 (0.77-4.16), P=0.17
    Use of Peg-IFN/riba had a positive prognostic impact HR = 0.34 (0.16-0.67)
    • 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) -
  • Association between fatigue, depression and clinical extrahepatic manifestations (EM) Poynard T et al. J Viral Hep, 2002
  • Multivariate analysis
    • 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
  • Prevalence of fatigue at baseline and at 18 months follow-up in treated and untreated patients Poynard T et al. J Viral Hep, 2002
    • 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) -
  • 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
    • 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) -
  • 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)
    • 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
    • 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) -
  •  
    • B-cell-Non Hodgin’s Lymphoma
    Hepatitis C virus
    • 2462 tested
    • 13.5 % positive
    • vs 0-5 % in controls
    • vs 5 % in other malignant
    • hemopathy
    469 tested 0 - 39 %
  • Effects of alpha-interferon on HCV+/SLVL course
    • 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
    • HCV antibodies : B-NHL (< 3%) vs SLVL (15%)
    • ----> Splenic lymphoma with villous lymphocytes may be associated with HCV infection
    • 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
    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
    • 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
  • Conclusion
    • Extrahepatic manifestations of HCV infection are frequent, and may be cured by HCV treatment :
    • Systemic vasculitis (cryoglobulinemia, PAN)
    • Fatigue
    • Arthralgia - myalgia - arthritis (±)
    • Auto-antibodies (?)
    • Splenic lymphoma with villous lymphocytes
    • Thrombocytopenia
    • O. Boyer, Paris
    • S. Caillat-Zucman, Paris
    • F. Charlotte, Paris
    • P. Ghilani, Paris
    • G. Kaplanski, Marseille
    • D. Klatzman, Paris
    • L. Musset, Paris
    • D. Sene, Paris
    • D. Saadoun, Paris
    • B. Terrier, Paris
    • P. Hausfater, Paris
    • O. Lidove, Paris
    • A. Gatel, St Brieuc
    • J-M. Léger, Paris
    • N. Limal, Paris
    • T. Maisonobe, Paris
    • G. Perlemuter, Paris
    • JC Piette, Paris
    Thanks
    • L. Alric, Toulouse
    • M. Bourlière, Marseille
    • P. Halfon, Marseille
    • S. Pol, Paris
    • T. Poynard, Paris
    • V. Thibault, Paris
    • Membres du GERMIVIC
    • L. Calabrese, Cleveland
    • M. Casato, Roma
    • C. Ferri, Modena
    • G. Kerr, Washington
    • E. Sasso, Seattle
    • JA. Schifferli, Basel
    • V. Soriano, Madrid