1. Extrahepatic Manifestations of
Hepatitis C Virus Infection
Pr. Patrice CACOUB
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

2. Manifestation Prevalence
certainly associated with HCV %
------------------------------------------------------
-
• Vasculitis (PAN, cryoglobulinemia) 5-40
• Fatigue 35-54
• Arthralgia-myalgia 25-35
• Sicca syndrome 10-25
• Autoantibodies 10-40
• Thrombocytopenia 20-40
• Lymphoma ?

3. Hepatitis C Virus Chronic Infection:
Two Main Target Cells
Hepatocyte Lymphocyte
Choo. Science 1989 Zignego. J Hepatol 1992
Ferri. Blood 1993
• Hepatitis • Cryoglobulinemia
• Cirrhosis
• Hepatocarcinoma • Auto-Ab
• B-NHL
3

4. Cryoglobulinémies mixtes
Infection VHC +++
Saadoun, Arch Intern Med, 2006

5. Cryoprecipitation
Endothelial cells
5

6. Pathogenesis of
cryoglobulinaemic
vasculitis
Roccatello, D. et al. Nephrol. Dial. Transplant. 2004 6

7. Skin Purpura Neuropathy
Cryoglobulinemia-Systemic Vasculitis
Membrano-proliferative
Glomerulonephritis CNS Vasculitis 7

9. Cutaneous Manifestations of HCV

10. HCV Mixed Cryoglobulinemia & Digestive Tract
Mesenteric artery stenosis Intestinal wall thickening
Terrier B et al, GUT 2011
10

11. Mixed Cryoglobulin and Neuropathy
Distal Polyneuropathy 80%
• Chronic progressive course,
• Distal, symetric, axonal PN, mainly
sensory and painful
• Few extra neurological signs : purpura
• Severe liver involvement
• Moderate inflammatory syndrome
Cacoub P et al, AIDS 2005

12. Mixed Cryoglobulin and Distal Polyneuropathy
Peripheral Nerve Biopsy
- important peri-vascular infiltrate of lymphocyte
- around small vessels i.e. venules, capillaries
- no PMN, no destruction of the vascular wall

13. Cryoglobulinemic Membrano-Proliferative
Glomerulonephritis
GNMP de type 1
Doubles Contours Pseudo-thrombi

14. HCV & glomerulonephritis
• Proteinuria (g/d) 3.1 ± 2.2
• Albumin (g/L)
29 ± 5
118 ± 41
• Creatinine (µmol/L)
16 / 2
• Cryoglobulin (II/III) 1.4 ± 1.8
• Cryoglobulin level (g/L) 1.5 ± 1
• ALT (IU x N/ml) 11/ 3/ 2/ 2
• Genotype 1/ 2/ 3/ 4
132 (66%)
8 (44%)
• Treatment of nephrotic sd 18 (100%)
plasmapheresis 12 (66%)
steroids
furosemide
ACE
Alric L. Am J K Dis, 2004

15. GNMP et VHC: Immunofluorescence
Dépôts immuns endomembraneux (pariéto-mésangiaux)
IgG/IgM ± IgA
Kappa/lambda
C3 ± C1q

16. Central Nervous System Involvement
in HCV-Cryoglobulinemia Vasculitis
HCV-vasculitis HCV Controls
(n=40) (n=11) (n=36)
-------------------------------------------------------------------------------------
-
Gender (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 * -
-------------------------------------------------------------------------------------
-
* P<0.01
WMHS: White Matter Hypersignals
PVHS: Periventricular Hypersignals
Casato M et al, J Hepatol 2004

17. Main Features of Mixed Cryoglobulinemia
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%
B-cell non-Hodgkin's lymphoma 11%
Hepatocellular carcinoma 3%
N = 250
Ferri C, Mascia MT, Saadoun D, Cacoub P. 2009
18

18. Cellular Infiltrate in HCV-Vasculitis
Who’s the culprit ?
HCV Core Protein in Skin Vascular
Structures
19

19. Detection of Genomic Viral RNA in
Ner ve
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
20

20. A Role for B Cell
Immunity
in HCV-Vasculitis
Rationale for
Rituximab treatment
in cryoglobulinemic
vasculitis
Roccatello, D. et al. Nephrol. Dial. Transplant. 2004
Rocatello D, Nephrol Dial Transplant, 2004 21

21. A Major Role for T Cell Immunity
in HCV-Vasculitis
 Abnormal T lymphocytes distribution
 Predominant T lymphocytes infiltration in vasculitis lesions
 Th1 cytokines profile in vasculitis lesions
 MHC-II polymorphism (DR11)
 Deficit in Treg lymphocytes
22

22. Quantitative Deficit in Treg Lymphocytes
(CD4+CD25+) in HCV-Vasculitis
Boyer O, Saadoun D et al, Blood 2004
23

23. Complete clinical response of HCV-vasculitis to anti-viral
treatment is associated with
an increase in CD4+CD25high Treg cells
A
66 -CR ** †
CD25high (% of CD4+)
-NR/PR ** †
55
4
44
3
Before treatment
On treatment arly F/u
E Late F/U †
On C
*
Before Early Late F/U. 40
Treat.
treat. F/U
/μl)
30
25high(cells
After Treat. 20
10
CD
0
Before
x
CR NR/PR
R
R
T
C
N
e
Treat. After Treat.
or
ef
B
Landau DA et al, Arthritis Rheum 2008 24

24. Correlation between Immune Response
and Treg Lymphocytes in HCV MC Vasculitis
3 0.4
R²-0.16 , p<0.005
R²-0.1, p< 0.005
Cryoglobulins ( g/l )
2
C 4 (g/l )
0.2
1
0 0.0
0 20 40 60 80 100 0 20 40 60 80 100
CD 25high (cells /μl) CD25 high (cells /μl)
Landau DA et al, Arthritis Rheum 2008 25

25. HCV Cr yoglobulinemic
Vasculitis
Tr eatments

26. 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
27

27. 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
28

28. n e m v or p m %
e i 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 29

29. * Clinical remission and SVR
30

30. Predictive Factor s of Response to HCV
T herapy in Cr yoglobulinemic 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
• Daily proteinuria > 1g 0.32 [0.09-1.11] 0.05
• Early virological response 3.53 [1.18-10.59] 0.02
Cacoub, Arthritis Rheum 2005, Saadoun, Arthritis Rheum 2007
31

31. Chronic HCV infection
Poly- oligoclonal Immunosuppressors
B-cell expansion
Autoantibodies Monoclonal B-cell
RF - IC proliferation Chemotherapy
Mixed cryoglobulins Overt lymphoma
Cryoglobulinemic vasculitis
32

32. Overall Survival of 151 HCV-Vasculitis Patients
32 deaths after a median
follow-up of 54 months (IQR
26-89)
Overall survivall
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
Terrier B et al. Arthritis Rheum 2010
33

33. Baseline Prognostic Factors
of HCV-Vasculitis Patients
34

34. Prognostic Factors
During follow-up
Use of Peg-IFN/riba had a positive prognostic impact
HR = 0.34 (0.16-0.67)
After adjustment on vasculitis severity,
immunosuppressants showed a negative impact
HR = 4.05 (1.75-9.36)
Terrier B et al. Arthritis Rheum 2010

35. Chronic HCV infection
Poly- oligoclonal Immuno-modulators
B-cell expansion Rituximab
Autoantibodies Monoclonal B-cell
RF - IC proliferation
Mixed cryoglobulins Overt lymphoma
Cryoglobulinemic vasculitis
36

36. Rationale for
Rituximab treatment
in cryoglobulinemic
vasculitis
Roccatello, D. et al. Nephrol. Dial. Transplant. 2004
Rocatello D, Nephrol Dial Transplant, 2004 37

37. Treatment of Mixed Cryoglobulinemia Resistant
to Interferonα with Rituximab
38
Sansonno D et al, Zaja F et al, Blood 2003

38. Cryoglobulinemia Vasculitis: Poor Response
Maintenance after Discontinuation of Rituximab
100 15 (93.7)
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
39
Sansonno D et al, 2007

39. Rituximab for the Treatment of Severe
Cryoglobulinemic Vasculitis
RTX
non-RTX
De Vita S, Arthritis Rheum 2012 40

40. Rituximab for the Treatment of Severe
Cryoglobulinemic Vasculitis
De Vita S, Arthritis Rheum 2012
41

41. PegIFN plus Ribavirin
Rituximab
HCV Vasculitis: a Two-
Faces Disease
…
Needs a Two Faces
Treatment Strategy
42

42. 43

43. Outcome of HCV-MC according to treatment
Parameters All PegIFNα-ribavirin RTX-PegIFNα-
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
Death 5 (5.4) 2 (3.6) 3 (7.9) 0.70
44

44. Outcome of HCV-MC according to treatment
Parameters All PegIFNα-ribavirin RTX-PegIFNα-
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
Death 5 (5.4) 2 (3.6) 3 (7.9) 0.70
45

45. Outcome of HCV-MC according to treatment
Parameters All PegIFNα-ribavirin RTX-PegIFNα-
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
Death 5 (5.4) 2 (3.6) 3 (7.9) 0.70
46

46. Outcome of HCV-MC according to treatment
Parameters All PegIFNα-ribavirin RTX-PegIFNα-
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
Death 5 (5.4) 2 (3.6) 3 (7.9) 0.70
47

47. Course of kidney parameters in HCV-MC
according to the type of treatment
PegIFNα-ribavirin RTX-PegIFNα-
ribavirin
n=10 p n=21 p
Kidney inv. CR 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
48

48. Course of kidney parameters in HCV-MC
according to the type of treatment
PegIFNα-ribavirin RTX-PegIFNα-
ribavirin
n=10 p n=21 p
Kidney inv. CR 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
49

49. RTX/Peg-IFNα-Ribavirin vs. Peg-IFNα-Ribavirin in
HCV Systemic Vasculitis
Maintenance of Complete Response
50
Dammacco F et al, Blood 2010

50. 51

51. Time Course of HCV Viral Load
Terrier B et al. Arthritis Rheum 2009
52

52. 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)
• If failure or CI of PegINF/riba: RTX alone
• Place to be defined for PegIFN/Riba/Previr

53. Chronic HCV infection
Poly- oligoclonal Immuno-modulators
B-cell expansion Low dose IL2
Autoantibodies Monoclonal B-cell
RF - IC proliferation
Mixed cryoglobulins Overt lymphoma
Cryoglobulinemic vasculitis
54

54. Reversible Quantitative Deficit in Treg Lymphocytes
(CD4+CD25+) in HCV-Systemic Vasculitis
Boyer, Blood 2004. Landau Arthritis Rheum 2008
A
66 -CR ** †
CD25high (% of CD4+)
-NR/PR ** †
55
44
3
Before treatment
On treatment arly F/u
On E Late F/U
3 Before Early Late F/U.
Treat.
treat. F/U
R²-0.1, p< 0.005 After Treat.
Cryoglobulins ( g/l )
2 0.4
R²-0.16, p<0.005
C4 (g/l)
1 0.2
0
0 20 40 60 80 100 0.0
0 20 40 60 80 100
CD 25high (cells /μl) CD25 high (cells /μl)
55

55. 56

56. Effects of Low-Dose Interleukin-2 on Levels of CD4-
Treg in Patients with HCV-Vasculitis, According to
Treatment Course (C).
Saadoun D et al, NEJM 2012
57

57. Temporal Effects of Low-Dose Interleukin-2 on
Clinical Features & Levels of Regulatory T Cells
for Each Study Patient
30 30 30 30
CD4+Treg (%)
20 20 20 20
10 10 10 10
0 0 0 0
Baseline C1 C2 C3 C4 Post IL-2 Baseline C1 C2 C3 C4 Post IL-2 Baseline C1 C2 C3 C4 Post IL-2 Baseline C1 C2 C3 C4 Post IL-2
Arthralgia
Fatigue
RESPONSE
Kidney Involvement
CLINICAL
Neuropathy
Purpura
Baseline C1 C2 C3 C4 Post IL-2 Baseline C1 C2 C3 C4 Post IL-2 Baseline C1 C2 C3 C4 Post IL-2 Baseline C1 C2 C3 C4 Post IL-2
Saadoun D et al, NEJM 2012

58. Effects of Low-Dose Interleukin-2 on Levels on the
Ratio of Treg Cells to the sum of Effector T Cells CD4
+ CD8 in Patients with HCV-Vasculitis
Saadoun D et al, NEJM 2012
59

59. Saadoun D et al, NEJM 2012 60

60. Manifestation Prevalence
certainly associated with HCV %
------------------------------------------------------
-
• Vasculitis (PAN, cryoglobulinemia) 5-40
• Fatigue 35-54
• Arthralgia-myalgia 25-35
• Sicca syndrome 10-25
• Autoantibodies 10-40
• Thrombocytopenia 20-40
• Lymphoma ?

61. 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

62. 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

63. Prevalence of fatigue at baseline and at 18 months follow-up in treated
Hepatitis C virus : 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

64. Manifestation Prevalence
certainly associated with HCV %
------------------------------------------------------
-
• Vasculitis (PAN, cryoglobulinemia) 5-40
• Fatigue 35-54
• Arthralgia-myalgia 25-35
• Sicca syndrome 10-25
• Autoantibodies 10-40
• Thrombocytopenia 20-40
• Lymphoma ?

65. 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
a
ia
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

66. 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%
8
8
8
8
M1
M1
M1
M1
M0
0
M0
M0
dM
ia
ia
ia
as
alg
alg
es
cc
My
sth
thr
Si
Ar
re
Pa
Sustained responders (n = 83) Non responders - RNA + (n = 348)
Cacoub P et al. J Hepatol

67. Manifestation Prevalence
certainly associated with HCV %
------------------------------------------------------
-
• Vasculitis (PAN, cryoglobulinemia) 5-40
• Fatigue 35-54
• Arthralgia-myalgia 25-35
• Sicca syndrome 10-25
• Autoantibodies 10-40
• Thrombocytopenia 20-40
• Lymphoma ?

68. 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.

69. 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

70. Manifestation Prevalence
certainly associated with HCV %
------------------------------------------------------
-
• Vasculitis (PAN, cryoglobulinemia) 5-40
• Fatigue 35-54
• Arthralgia-myalgia 25-35
• Sicca syndrome 10-25
• Autoantibodies 10-40
• Thrombocytopenia 20-40
• Lymphoma ?

72. 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

73. 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

74. Hepatitis C virus : extrahepatic manifestations, an update 2007
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

75. 

D. Saadoun, Paris
D. Sene, Paris Merci
 B. Terrier, Paris
 G. Géri, Paris  L. Calabrese, Cleveland
 P. Hausfater, Paris  M. Casato, Roma
 O. Lidove, Paris  C. Ferri, Modena
 A. Gatel, St Brieuc  G. Kerr, Washington
 J-M. Léger, Paris  E. Sasso, Seattle
 N. Limal, Paris  JA. Schifferli, Basel
 T. Maisonobe, Paris  V. Soriano, Madrid
 JC Piette, Paris
 L. Alric, Toulouse
 S. Caillat-Zucman, Paris  M. Bourlière, Marseille
 P. Ghillani, Paris  P. Halfon, Marseille
 D. Klatzmann, Paris  S. Pol, Paris
 L. Musset, Paris  T. Poynard, Paris
 M. Rosenzwajg, Paris  V. Thibault, Paris
 Les membres du GERMIVIC
76