Extrahepatic Manifestations of Hepatitis C Infection.
Pr Patrice CACOUB, MD
Internal Medicine DepartmentLa 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) ?
53%
41%48%
28%
12%
0%
10%
20%
30%
40%
50%
60%
1972-79 1980-84 1985-89 1990-94 1995-99
FREQUENCY OF HBV-RELATED PAN: 1972-1999
Guillevin L
HCV and cryoglobulinemic vasculitis
asymptomaticOligosymptomaticarthralgias, 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%55 to 95% 30 to 55 %30 to 55 %
Hepatitis C Virus Chronic Infection : two main target cells
• Hepatitis • Cirrhosis• Hepatocarcinoma
• Cryoglobulinemia• B-NHL
HepatocyteChoo. Science 1989
LymphocyteZignego. J Hepatol 1992Ferri. Blood 1993
Cryoprecipitation
Endothelial cells
Pathogenesis
of
cryoglobulinae
mic 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
0
10
20
30
40
50
60
70
80
90
100
Ferri Disdier Casato Pechere Misiani Agnello Cacoub Dupin Monti
Clinical features of 231 MC Patients
end beginning
follow-up follow-up p°
Purpura 89% 81% .05Weakness 91% 80% .001Arthralgias 90% 72% .001Arthritis 6% 8% nsRaynaud's phen. 44% 36% nsSicca syndrome 48% 29% .001Skin ulcers 20% 11% .02Periph. neuropathy 73% 58% .001Liver involvement 70% 58% .02Renal involvement 27% 20% nsB-cell lymphoma 9% 0.4% .001Hepat. carcinoma 3% 0% .05
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
MononeuropathyMultiplex 20%
Cacoub P et al, AIDS 2005
MC and Neuropathy
Central Nervous System Involvement in HCV-Cryoglobulinemia Vasculitis
HCV-vasculitis HCVControls
(n=40) (n=11) (n=36)--------------------------------------------------------------------------------------Sex ratio F/M 23/17 6/5 20/16Age (yrs) 59 ± 13 56 ± 10
58 ± 12WMHS 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 HypersignalsNCFD: 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 expansionAutoantibodies
RF - ICMixed cryoglobulins
Cryoglobulinemic vasculitis
Monoclonal B-cellproliferation
Overt lymphoma
HCV eradication
Immunosuppressors
Chemotherapy
Plasma exchange
Steroids
Treatment Efficacy in HCV-Related Systemic Vasculitis
0
10
20
30
40
50
60
70
80
90
100
Skin Renal Nerve
IFN + RBV
PegIFN + RBV
Zuckerman, J Rheumatol 2000. Naarendorp, J Rheumatol 2001. Cacoub, Arthritis Rheum 2002, Zaja F, Blood 2003. Sansonno D, Blood 2003 , Cacoub, Arthritis Rheum 2005
%
imp
rovem
en
t
Predictive Factors of Clinical Response to HCV Therapy in Mixed Cryoglobulinemia
VasculitisMultivariate 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 cryoglobulinaemi
c 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
0
10
20
30
40
50
60
70
80
90
PegIFN-RBV (n=40) Rituximab (n=43)
%
imp
rovem
en
t
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 1011 24 36 48
10 (62.5)
6 (37.5)
Sansonno D et al, 2007
RITUXIMAB (375 mg/m²)
Time (months)0 1
RIBAVIRIN (600-1200 mg/d)
PEGYLATED INTERFERON 2b (1.5 μg/Kg/wk)
12
Rituximab plus Peg-IFNα2b-Ribavirin in Refractory HCV-Related Systemic
Vasculitis
2
Saadoun D et al, Ann Rheum Dis 2008
Response rate of HCV-cryoglobulinemia vasculitis during Rituximab & Peg-IFNα2b +
Ribavirin.
10
30
50
70
2 3 4 5 6 7 8 9 10 11 12 Months
18.7
20
37.5
1
50
62.5
Rituximab Peg-Interferon-ribavirin
% o
fco
mp
lete
resp
ond
ers
Figure 1
10
30
50
70
2 3 4 5 6 7 8 9 10 11 12 Months
18.7
20
37.5
1
50
62.5
Rituximab Peg-Interferon-ribavirin
% o
fco
mp
lete
resp
ond
ers
Figure 1
Immunologic parameters in HCV-MC patients during treatment with Rituximab & Peg-IFNα2b-
ribavirin.
Cryoglobulin
0
0,4
0,8
1,2
1,6
2
0 3 6 9 12 EOF
g/l
Months
C4
0
0,03
0,06
0,09
0,12
0,15
0,18
0 3 6 9 12 EOFMonths
g/l
RF
0
40
80
120
160
200
240
0 3 6 9 12 EOF
IU/lIgM
0
0,4
0,8
1,2
1,6
2
2,4
2,8
0 3 6 9 12 EOF
g/l
A B
C D
Months Months
Figure 4
Cryoglobulin
0
0,4
0,8
1,2
1,6
2
0 3 6 9 12 EOF
g/l
Months
C4
0
0,03
0,06
0,09
0,12
0,15
0,18
0 3 6 9 12 EOFMonths
g/l
RF
0
40
80
120
160
200
240
0 3 6 9 12 EOF
IU/lIgM
0
0,4
0,8
1,2
1,6
2
2,4
2,8
0 3 6 9 12 EOF
g/l
A B
C D
Months Months
Figure 4
HCV RNA viral load during treatment with Rituximab & Peg-IFNα2b + Ribavirin in HCV-
cryoglobulinemia vasculitis.
0
1
2
3
4
5
6
7
Peg-Interferon-ribavirin
0 3 6 9 12 EOF
Rituximab
Lo
g c
op
ies
/ml
Months
Figure 3
0
1
2
3
4
5
6
7
Peg-Interferon-ribavirin
0 3 6 9 12 EOF
Rituximab
Lo
g c
op
ies
/ml
Months
Figure 3
Dynamics of CD19+ B cell depletion and recovery during treatment with rituximab
combined with Peg-IFNα2b-ribavirin in HCV-MC patients.
0
10
30
50
70
90
110
130
150
170
0 1 2 3 4 5 6 7 8 9 10 11 12 15
Months
CD19+/mm3
Figure 2
0
10
30
50
70
90
110
130
150
170
0 1 2 3 4 5 6 7 8 9 10 11 12 15
Months
CD19+/mm3
Figure 2
Saadoun D et al, Ann Rheum Dis 2008
Maintenance of Complete Remission of HCV-Cryoglobulinemia Vasculitis after Rituximab & Peg-IFNα2b + Ribavirin.
0 30 60 90 120 150 1800
20
40
60
80
100
Jours
Main
tien
de la R
C (
%)
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
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007
ManifestationManifestation Prevalences Prevalences
certainly associated with HCV certainly associated with HCV %%
------------------------------------------------------------------------------------------------------------------------------ Vasculitis (PAN, cryoglobulinemia) Vasculitis (PAN, cryoglobulinemia) 4-40 4-40 Fatigue 35-54 Arthralgia-myalgia-arthritisArthralgia-myalgia-arthritis 25-3525-35 Sicca syndromeSicca syndrome 10-2510-25 AutoantibodiesAutoantibodies 10-4010-40 ThrombocytopeniaThrombocytopenia 20-4020-40 Lymphoma (SLVL)Lymphoma (SLVL) --
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007
% of patients
n = 1614
% of controls
n = 412
Fatigue without depression
Fatigue with depression
Depression without fatigue
No fatigue and no depression
Total
48
5
2
45
100
0.7
0
0
99.3
100
Fatigue without EM
Fatigue with EM
EM without fatigue
No fatigue and no EM
Total
19
35
21
25
100
0.5
0.2
3.4
96
100
Association between fatigue, depression and clinical extrahepatic manifestations (EM)
Poynard T et al. J Viral Hep, 2002
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007Multivariate analysisMultivariate 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, 2002Poynard T et al. J Viral Hep, 2002
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007Prevalence of fatigue at baseline and at 18 months follow-up in treated
and untreated patients
Baseline 18 months 18 months vsbaseline
Non treated (n=72) No fatigue Moderate Severe
39 %35 %26 %
42 %39 %19 %
P = 0.74
Sustained responders(n=82) No fatigue Moderate Severe
41 %37 %22 %
69 %24 %7 %
P < 0.001
Relapsers (n= 47) No fatigue Moderate Severe
45 %43 %13 %
40 %45 %15 %
P = 0.68
Non responders (n= 224) No fatigue Moderate Severe
40 %42 %18 %
46 %40 %14 %
P = 0.18
Poynard T et al. J Viral Hep, 2002
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007
ManifestationManifestation Prevalences Prevalences
certainly associated with HCV certainly associated with HCV %%
------------------------------------------------------------------------------------------------------------------------------ Vasculitis (PAN, cryoglobulinemia) Vasculitis (PAN, cryoglobulinemia) 4-40 4-40 FatigueFatigue 35-5435-54 Arthralgia-myalgia-arthritis 25-35 Sicca syndromeSicca syndrome 10-2510-25 AutoantibodiesAutoantibodies 10-4010-40 ThrombocytopeniaThrombocytopenia 20-4020-40 Lymphoma (SLVL)Lymphoma (SLVL) --
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007
0%5%
10%
15%20%25%30%
35%40%
Sustained responders (n = 83)
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
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007
0%5%
10%15%20%25%30%35%40%
Sustained responders (n = 83) Non responders - RNA + (n = 348)
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.
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007
ManifestationManifestation Prevalences Prevalences
certainly associated with HCV certainly associated with HCV %%
------------------------------------------------------------------------------------------------------------------------------ Vasculitis (PAN, cryoglobulinemia) Vasculitis (PAN, cryoglobulinemia) 4-40 4-40 FatigueFatigue 35-5435-54 Arthralgia-myalgia-arthritisArthralgia-myalgia-arthritis 25-3525-35 Sicca syndromeSicca syndrome 10-2510-25 Autoantibodies 10-40 ThrombocytopeniaThrombocytopenia 20-4020-40 Lymphoma (SLVL)Lymphoma (SLVL) --
Auto-antibody production in chronic HCV infection.
0
10
20
30
40
50
60
70
%
A-nuclearA-phospholipidA-thyroglobulinA-smooth muscle≥ one auto-Ab≥ three auto-Ab
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
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007
ManifestationManifestation Prevalences Prevalences
certainly associated with HCV certainly associated with HCV %%
------------------------------------------------------------------------------------------------------------------------------ Vasculitis (PAN, cryoglobulinemia) Vasculitis (PAN, cryoglobulinemia) 4-40 4-40 FatigueFatigue 35-5435-54 Arthralgia-myalgia-arthritisArthralgia-myalgia-arthritis 25-3525-35 Sicca syndromeSicca syndrome 10-2510-25 AutoantibodiesAutoantibodies 10-4010-40 ThrombocytopeniaThrombocytopenia 20-4020-40 Lymphoma (SLVL) -
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007
Chronic infection withHepatitis C Virus
HepatocytesB-Lymphocytes
Hepatitis (acute/chronic)CirrhosisHepatocarcinoma
Mixed cryoglobulinemia
B-cell lymphoma ?
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007
Chronic viral replication
Mixed cryoglobulinemia
Large B-cell lymphoma
SLVL/Marginal zone NHLOther low grade B-cell NHL
dependance on antigenic stimulationpolyclonal
mon
oclo
nal
Progression of B-cell proliferation induced by HCVdirect transform
ation (no cryo)
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007
B-cell-Non Hodgin’s LymphomaB-cell-Non Hodgin’s Lymphoma
Hepatitis C virusHepatitis C virus
2462 tested2462 tested
13.5 % positive • vs 0-5 % in controlsvs 0-5 % in controls
• vs 5 % in other malignant vs 5 % in other malignant hemopathyhemopathy
469 tested469 tested
0 - 39 %
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007Effects 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%)HCV antibodies : B-NHL (< 3%) vs SLVL (15%)
----> Splenic lymphoma with villous lymphocytes may be associated with HCV infection
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007
Median Follow-up of 3 years (2-5)
6 Complete Responses ---> HCV RNA still negative6 Complete Responses ---> HCV RNA still negative
1 relapse off therapy at 1 year,1 relapse off therapy at 1 year,
• associated with positivity of HCV RNA. associated with positivity of HCV RNA.
• second CR following IFN & negativity HCV RNAsecond CR following IFN & negativity HCV RNA
2 Partial Responses 2 Partial Responses
• CR after Combination of Interferon and Ribavirin CR after Combination of Interferon and Ribavirin
• PR after Interferon and Ribavirin PR after Interferon and Ribavirin
Hermine O. et al, N Engl J Med 2002; 347: 89-94
Effects of alpha-interferon on HCV+/SLVL course
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007HCV negative / SLVL Patients Treated with Alpha-Interferon
Median age 65 (54-72)Median age 65 (54-72)
Prior therapy (2/6), chemotherapy (1), splenectomy(1)Prior therapy (2/6), chemotherapy (1), splenectomy(1)
Splenomegaly (4/6)Splenomegaly (4/6)
Hyperlymphocytosis Median 25,000 (500-100.000)Hyperlymphocytosis Median 25,000 (500-100.000)
Cytopenia (2/6)Cytopenia (2/6)
Cryoglobulinemia or rheumatoid factor (0/6)Cryoglobulinemia or rheumatoid factor (0/6)
Alpha-Interferon 3 M IU x 3/W during 6 monthsNo response
Hermine O. et al, N Engl J Med 2002; 347: 89-94
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007Conclusion
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
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