Hcv Meh Cacoub
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Hcv Meh Cacoub Hcv Meh Cacoub Presentation Transcript

  • 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
    • 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) ?
  • FREQUENCY OF HBV-RELATED PAN: 1972-1999 Guillevin L
  • 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
  • > 250 million infected individuals worldwide > 3,0 in USA; > 0,5 in France
    • « Essential » mixed cryoglobulinemia
    Hepatitis C virus 55 to 95% 30 to 55 %
  • Hepatitis C Virus Chronic Infection : two main target cells
    • Hepatitis
    • Cirrhosis
    • Hepatocarcinoma
    • Cryoglobulinemia
    • 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 hlkjhjhkhuhhh
  • Skin Purpura Membrano-proliferative Glomerulonephritis CNS Vasculitis Cryoglobulinemia-Systemic Vasculitis Neuropathy
  • Cryoglobulins are immune complexes Type III Mixed cryoglobulins Type I m Ig
    • Myeloma
    • Lymphoproliferative disorders
    Type II m Ig + polyclonal Ig polyclonal Igs
    • Chronic infections
    • Connective tissue diseases
    • Lymphoproliferative disorders
    • Essential
  • 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
  • Prevalence of HCV infection in patients with essential cryoglobulinemia
  • Ferri C, Sem Arthr Rheum 2004
  • MC and Skin
  • Severe necrotizing leukocytoclastic vasculitis: extensive fibrinoid necrosis of the vessel wall with permeation of the wall by disintegrating neutrophils
  • HCV Core Protein in Skin Vascular Structures
  • Distal Polyneuropathy 80% Cacoub P et al, AIDS 2005 MC and Neuropathy
    • 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
  • 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%
  • 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
  • Mononeuropathy Multiplex 20% Cacoub P et al, AIDS 2005 MC and Neuropathy
  • 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
    • Proteinuria (g/d)
    • Albumin (g/L)
    • Creatinine (  mol/L)
    • Cryoglobulin (II/III)
    • Cryoglobulin level (g/L)
    • ALT (IU x N/ml)
    • Genotype 1/ 2/ 3/ 4
    • Treatment of nephrotic sd
    • plasmapheresis
    • steroids
    • furosemide
    • ACE
    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
  • 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
  • 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
  • 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
  • Pathogenesis of cryoglobulinaemic nephritis and rationale for Rituximab treatment Roccatello, D. et al. Nephrol. Dial. Transplant. 2004
  • 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
  • Main Course of Cryoglobulinemia Vasculitis Features after Rituximab Treatment. HCV+ 43 patients, HCV- 14 patients Cacoub P, Ann Rheum Dis 2007
  • % improvement HCV-Vasculitis Treatment : PegIFN-Ribavirin vs. Rituximab
  • 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
  • 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.
  • Immunologic parameters in HCV-MC patients during treatment with Rituximab & Peg-IFNα2b-ribavirin.
  • HCV RNA viral load during treatment with Rituximab & Peg-IFNα2b + Ribavirin in HCV-cryoglobulinemia vasculitis.
  • 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
  • Maintenance of Complete Remission of HCV-Cryoglobulinemia Vasculitis after Rituximab & Peg-IFNα2b + Ribavirin.
  • San Francisco, ACR 2008
  • 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
  •  
    • 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.
  • Auto-antibody production in chronic HCV infection.
    • Most patients were negative for all other autoAbs :
      • neutrophil cytoplasmic,  2 GP1
      • Langherans islet, insulin, GAD
      • liver-kidney microsome, mitochondria
    • There was no correlation between :
      • Clinical or immunological abnormalities
      •  -IFN & clinical/immunological abnormalities
  • 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) -
  • Chronic infection with Hepatitis C Virus Hepatocytes B-Lymphocytes Hepatitis (acute/chronic) Cirrhosis Hepatocarcinoma Mixed cryoglobulinemia B-cell lymphoma ?
  • 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)
    • 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
    • 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