Hépatite C & atteintes extra hépatiques. Patrice Cacoub, La Pitié-Salpêtrière, Paris

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2 Hépatite C & atteintes extra hépatiques Patrice Cacoub, La Pitié-Salpêtrière, Paris

3 HCV-related diseases pathogenesis Features of HCV Hepatotropic Choo et al. Science 1989 Lymphotropic Zignego et al. J Hepatol 1992 Ferri et al. Blood 1993

4 Chronic Infection with Hepatitis C Virus Hepatocytes B-Lymphocytes Hepatitis (acute/chronic) Cirrhosis Hepatocarcinoma Cryoglobulinemia Other extrahepatic manifestations

5 Prévalence Manifestation Prevalences certainly associated with HCV % Vasculitis (PAN, cryoglobulinemia) 4-40 Fatigue Arthralgia-myalgia-arthritis Sicca syndrome Autoantibodies Thrombocytopenia Lymphoma (SLVL) -

Vasculitis (PAN, cryoglobulinemia) 4-40 Fatigue 35-54

6 Systemic Vasculitis and Hepatitis C virus Cacoub P et al. Arthritis Rheum 2002 Mixed cryoglobulinemia Polyarteritis nodosa 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Weight loss Purpura Livedo-ulcers- Ery nod. SM multifoc. Neurop. Sensory polyneurop. Renal insufficiency Severe HTA

80% 70% 60% 50% 40% 30% 20% 10% 0% Weight loss Purpura Livedo-ulcers-

8 Distal Polyneuropathy Mononeuropathy Mononeuropathy Multiplex Brachial Plexopathy Inflammatory Demyelinating Polyneuropathy (GBS)

9 Polyneuropathie axonale distale (2/3) Installation subaiguë Mono-neuropathie multiple Début toujours sensitif Puis sensitivo-motrice Purpura membres inférieurs Périartérite Noueuse (1/3) Atteinte aiguë ou subaiguë Multinévrite sensitivo-motrice Sévère d emblée Signes extra-neurologiques +++ Atteinte hépatique peu sévère

inférieurs Périartérite Noueuse (1/3) Atteinte aiguë ou subaiguë Multinévrite

10 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.

11 HCV-vasculitis HCV Controls (n=40) (n=11) (n=36) Sex ratio F/M 23/17 6/5 20/16 Age (yrs) 59 ± ± ± 12 WMHS 7.0 ± ± 1.8 * 2.0 ± 3.1 PVHS 2.5 ± ± 0.5 * 0.8 ± 1.4 NCFD 2.2 ± ± 0.8 * * P<0.01 WMHS: White Matter Hypersignals PVHS: Periventricular Hypersignals NCFD: Number of Cognitive Function Deficiency Casato M et al, 2003 Central Nervous System Involvement in HCV- Cryoglobulinemia Vasculitis : a Multicenter Case- Control Study using MRI and Neuropsychological Tests.

8 * - -------------------------------------------------------------------------------------- * P<0.

12 Central Nervous System Involvement in HCV- Cryoglobulinemia Vasculitis : a Case-Control Study using MRI and Neuropsychological Tests. Function N (%) Attention Executive Function Visual Construction Function Visual Spatial Function Visual Memory Abstract Reasoning Visual Perceptual Function Comprehension Verbal Evocation AuralMemory Total ( 1 abnormal function) 32 94

6 Executive Function 16 47 Visual Construction Function 12 35.2 Visual Spatial Function 12 35.2 Visual Memory 11 32.3 Abstract Reasoning 8 23.

13 HCV and membranoproliferative glomerulonephritis Alric L et al. Am J K Dis, 2004 Proteinuria (g/d) Albumin (g/l) Creatinine (µmol/l) Cryoglobulin (II/III) Cryoglobulin level (g/l) ALT(IUx N/ml) Genotype 1/ 2/ 3/ 4 Treatment of nephrotic sd plasmapheresis steroids furosemide ACE 3.1 ± ± ± / ± ± 1 11/ 3/ 2/ (66%) 8 (44%) 18 (100%) 12 (66%)

Cryoglobulin level (g/l) ALT(IUx N/ml) Genotype 1/ 2/ 3/ 4 Treatment of nephrotic sd

14 Alric L. AJKD, 2004 * P < 0.05 Proteinuria (g/d) baseline EOF Viro. responders n= ± ± 0.8 * IFN-ribavirin Viro. non-respond. n= ± ± 0.5 Controls n= ± ± 3 Albumin (g/l) baseline EOF 29 ± 5 40 ± 6 33 ± 5 35 ± 5 33 ± 4 32 ± 7 Creatinine (µmol/l) baseline EOF 118 ± ± ± ± ± ± 37 Cryoglobulin (g/l) baseline EOF 1.38 ± ± 0.4 * 1.5 ± ± ± ± 0.7

3 ± 3 Albumin (g/l) baseline EOF 29 ± 5 40 ± 6 33 ± 5 35 ± 5 33 ± 4 32 ± 7 Creatinine (µmol/l) baseline EOF

15 Pathological data in patients with HCV related vasculitis 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 % Cacoub P et al. Arthritis Rheum 2002

vasculitis 7/23 30 % Mixed cryo-type vasculitis 14/23 61 % Both 2/23 9

16 Casato, 31 Mazzaro, 42 Adinolfi, 25 Dammaco, 52 Misiani, 53 Ferri, n = Treatment of HCV-related Systemic Vasculitis Alpha Interferon Skin Renal Nerve Death Improvement (%)

17 Treatment of HCV-Related Systemic Vasculitis Alpha Interferon + Ribavirin Improvement (%) Skin Renal Nerve Death 20 0 Zuckerman, 9 Naarendrop, 11 Cacoub, 28 Zuckerman E, J Rheumatol Naarendrop M, J Rheumatol Cacoub P, Arthritis Rheum 2002

120 100 Improvement (%) 80 60 40 Skin Renal Nerve Death 20 0

18 Correlation Between HCV Viremia and Clinical Response in Patients with HCV Systemic Vasculitis Receiving IFN plus Ribavirin. Negative viremia at the end of follow up HCV RNA level at the end of follow up (millions copies/ml) Complete clin. Non or partial p-value response (n=20) response (n=8) 16 (80%) 1 (13%) ± ± Cacoub P et al. Arthritis Rheum 2002

Negative viremia at the end of follow up HCV RNA level at the end of follow up (millions

19 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 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 Anti-CD20

In combination with anti-hcv treatments. Prednisone 0.

20 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

21 TREATMENT OF MIXED CRYOGLOBULINEMIA After HCV era Cytotoxic drugs Colchicine None Pegylated Interferon α + Ribavirin + Anti-CD20? Steroids NSAIDs Plasma exchanges

22 HCV Systemic Vasculitis Treatment MILD SEVERE CATASTROPHIC - Mild skin - Arthralgias - Mild renal - Severe skin - Motor neuropathy - Severe renal - RPGN - Necrotic digits BEST ANTIVIRAL THERAPY BEST ANTIVIRAL THERAPY Steroids ± Cyclophosphamide Above plus apheresis

23 Facteurs associés au caractère symptomatique des Cryoglobulinémies Mixtes-VHC chez 125 patients suivis 45 ± 20 mois Sene D et al, J Rheumatol 2004 Symptômes Non symptomatiques Analyse univariée p Analyse multi-variée p OR (IC95%) N (%) 60 (48) 65 (52) ns Sex Ratio 28/32 35/30 ns Age Dg CM 55,6 ± 13,6 48,5 ± 11,8 0,002 0,03 Ancienneté (ans) CM II: n (%) 20,6 ± 10,9 41 (68,3) 16,1 ± 7,7 19 (29,2) 0,07 <10-4 0,04 < (2-11) CM III : n (%) 16 (26,7) 37 (56,9) <10-3 CM Oligo : n (%) 3 (5) 9 (13,8) 0,09 Taux (g/l) 0,58 ± 1,1 0,22 ± 0,15 0,001 <10-2

24 Evolution des types immunochimiques des Cryoglobulinémies Mixtes-VHC entre 2 typages (45 ± 20 mois), chez 125 patients VHC+. Sene D et al, J Rheumatol % de patients Evolution vers CM II CMIII CM Oligo CM II (n=60) CM III (n=53) CM Oligo (n=12) Variation isotypique : CM Oligo (83,3 %); CM III (41,5 %) vs CM II (21,7 %) P=0,0001

25 HCV E2 Polyclonal RF T(14; 18) translocation Bcl-2 overexpression Oligo-monoclonal RF Other genetic aberration (c-myc, etc.) CD81 B B B MC type III other autoimmune disorders MC type III-II MC type II (MLDUS) B-cell NHL Unknown genetic and/or environmental factors Ferri C et al. Clin Exp Rheumatol 2003

26 Detection of Genomic Viral RNA in Nerve and Muscle of Patients with HCV Neuropathy Authier JF et al, Neurology, 2003 Inflammatory vascular lesions in 26/30 (87%) patients: - distal axonal polyneuropathy (25) - mononeuropathy multiplex (3), demyelinating np. (2) 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 virustriggered immune-mediated mechanisms rather than direct nerve infection and in situ replication

27 VCAM & ICAM expression in nerve biopsies of HCV-MC patients VCAM-1 ICAM-1 Patient # 1 Patient # 2 Kaplanski G et al., 2003

28 HUVEC stimulated with cryoprecitate purified from an HCV-MC vasculitis patient ELAM Control Medium Cryoprecipitate ICAM-1 Control Medium Cryoprecipitate VCAM-1 Control Medium Cryoprecipitate Kaplanski G et al., 2003

29 Lymphocytes T régulateurs (Treg) Marqueurs : CD4+, CD25hi CD62Lhi, CTLA-4+, Fox P3 CD25 Thymo-dépendants, auto-réactifs CD4 Inhibent l activation des LyT Régulation physiologique de l auto immunité

30 Déficit quantitatif en LyTreg dans les CM symptomatiques Boyer O, Saadoun D et al, Blood 2004

31 Conclusion Systemic vasculitis in patients with chronic active HCV infection : may be of cryoglobulinemia- or PAN-type are mainly due to virus-triggered immunemediated mechanisms. represent a good model of infection-related vasculitis. usually respond to anti-hcv treatment with IFN and Ribavirin ± steroids.

Anti-HCV therapy in HCV-related NHL

Gabriele Pozzato M.D. University of Trieste Anti-HCV therapy in HCV-related NHL Questions about HCV+ in NHL Is the NHL related with HCV infection? Which is the best therapeutic strategy? Is the antiviral