Cacoub hcv meh

75
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 Pr. Patrice CACOUB

Transcript of Cacoub hcv meh

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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

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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 ?

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• Hepatitis • Cirrhosis• Hepatocarcinoma

• Cryoglobulinemia• Auto-Ab• B-NHL

HepatocyteChoo. Science 1989

LymphocyteZignego. J Hepatol 1992Ferri. Blood 1993

Hepatitis C Virus Chronic Infection:

Two Main Target Cells

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Cryoglobulinémies mixtes

Saadoun, Arch Intern Med, 2006

Infection VHC +++

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Endothelial cells

Cryoprecipitation

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Pathogenesis of

cryoglobulinae

mic vasculitis

Roccatello, D. et al. Nephrol. Dial. Transplant. 2004

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Skin Purpura

Membrano-proliferative Glomerulonephritis CNS Vasculitis

Neuropathy

Cryoglobulinemia-Systemic Vasculitis

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Cutaneous Manifestations of HCV

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HCV Mixed Cryoglobulinemia & Digestive Tract

Mesenteric artery stenosis

Intestinal wall thickening

Terrier B et al, GUT 2011

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Distal Polyneuropathy 80%

Cacoub P et al, AIDS 2005

Mixed Cryoglobulin and Neuropathy

• Chronic progressive course,

• Distal, symetric, axonal PN, mainly

sensory and painful

• Few extra neurological signs :

purpura

• Severe liver involvement

• Moderate inflammatory syndrome

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- important peri-vascular infiltrate of lymphocyte- around small vessels i.e. venules, capillaries- no PMN, no destruction of the vascular wall

Mixed Cryoglobulin and Distal Polyneuropathy

Peripheral Nerve Biopsy

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Cryoglobulinemic Membrano-Proliferative Glomerulonephritis

Doubles Contours Pseudo-thrombi

GNMP de type 1

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• 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 ± 4116 / 2

1.4 ± 1.8

1.5 ± 1

11/ 3/ 2/ 2

132 (66%)8 (44%)

18 (100%)12 (66%)

HCV & glomerulonephritis

Alric L. Am J K Dis, 2004

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IgG/IgM ± IgA

Kappa/lambda

C3 ± C1q

GNMP et VHC: ImmunofluorescenceDépôts immuns endomembraneux (pariéto-mésangiaux)

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Central Nervous System Involvement in HCV-

Cryoglobulinemia Vasculitis 

HCV-vasculitis HCVControls

(n=40) (n=11) (n=36)--------------------------------------------------------------------------------------Gender (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 * -

--------------------------------------------------------------------------------------* P<0.01WMHS: White Matter Hypersignals PVHS: Periventricular HypersignalsNCFD: Number of Cognitive Function Deficiency

Casato M et al, J Hepatol 2004

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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%

Main Features of Mixed Cryoglobulinemia

Ferri C, Mascia MT, Saadoun D, Cacoub P. 2009N = 250

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HCV Core Protein in Skin Vascular Structures

Who’s the culprit ?

Cellular Infiltrate in HCV-Vasculitis

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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

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Rationale for Rituximab treatment in cryoglobulinemic vasculitis

Rocatello D, Nephrol Dial Transplant, 2004Roccatello, D. et al. Nephrol. Dial. Transplant. 2004

A Role for B Cell Immunity in HCV-Vasculitis

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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

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Quantitative Deficit in Treg Lymphocytes (CD4+CD25+) in HCV-Vasculitis

Boyer O, Saadoun D et al, Blood 2004

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Before treatmentOn treatmentEarly F/u Late F/U3

4

5

6

CD

25

hig

h (

% o

f C

D4

+)

44

5

6

Before treat.

On Treat.

Early F/U

Late F/U.

**†

**†

-CR

-NR/PR

0

10

20

30

40

CD25h

igh

(ce

lls/μl)

†*

BeforeTreat.

CR NR/PRAfter Treat.

C

After Treat.

A

Complete clinical response of HCV-vasculitis to anti-viral treatment is associated with an increase in CD4+CD25high Treg cells

Landau DA et al, Arthritis Rheum 2008

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25

0 20 40 60 80 1000.0

0.2

0.4

CD25high (cells /μl)C

4 (

g/l

)

R²-0.16, p<0.005

0 20 40 60 80 1000

1

2

3

CD25high (cells /μl)

Cry

og

lob

uli

ns

(g

/l)

R²-0.1, p<0.005

Correlation between Immune Response and Treg Lymphocytes in HCV MC Vasculitis

Landau DA et al, Arthritis Rheum 2008

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HCV Cryoglobulinemic Vasculitis Treatments

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Chronic HCV infection

Poly- oligoclonal B-cell expansion

AutoantibodiesRF - ICMixed cryoglobulins

Cryoglobulinemic vasculitis

Monoclonal B-cellproliferationOvert lymphoma

HCV eradication

Immunosuppressors

Chemotherapy

Plasma exchange

Steroids

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Chronic HCV infection

Poly- oligoclonal B-cell expansion

AutoantibodiesRF - ICMixed cryoglobulins

Cryoglobulinemic vasculitis

Monoclonal B-cellproliferationOvert lymphoma

HCV eradication

Immunosuppressors

Chemotherapy

Plasma exchange

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HCV Treatment Efficacy in HCV-Vasculitis%

im

pro

vem

en

t

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

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* Clinical remission and SVR

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Predictive Factors of Response to HCV Therapy in Cryoglobulinemic 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

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Chronic HCV infection

Poly- oligoclonal B-cell expansion

AutoantibodiesRF - ICMixed cryoglobulins

Cryoglobulinemic vasculitis

Monoclonal B-cellproliferationOvert lymphoma

Immunosuppressors

Chemotherapy

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Years

Overa

ll su

rviv

all

Overall Survival of 151 HCV-Vasculitis Patients

Terrier B et al. Arthritis Rheum 2010

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)

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Baseline Prognostic Factors of HCV-Vasculitis Patients

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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, immunosuppressants showed a negative

impact

HR = 4.05 (1.75-9.36)

Terrier B et al. Arthritis Rheum 2010

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Chronic HCV infection

Poly- oligoclonal B-cell expansion

AutoantibodiesRF - ICMixed cryoglobulins

Cryoglobulinemic vasculitis

Monoclonal B-cellproliferationOvert lymphoma

Immuno-modulatorsRituximab

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Rationale for Rituximab treatment in cryoglobulinemic vasculitis

Rocatello D, Nephrol Dial Transplant, 2004Roccatello, D. et al. Nephrol. Dial. Transplant. 2004

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Treatment of Mixed Cryoglobulinemia Resistant

to Interferon with Rituximab

Sansonno D et al, Zaja F et al, Blood 2003

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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)

Cryoglobulinemia Vasculitis: Poor Response Maintenance after Discontinuation of

Rituximab

Sansonno D et al, 2007

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40De Vita S, Arthritis Rheum 2012

RTX

non-RTX

Rituximab for the Treatment of Severe Cryoglobulinemic Vasculitis

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41De Vita S, Arthritis Rheum 2012

Rituximab for the Treatment of Severe Cryoglobulinemic Vasculitis

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HCV Vasculitis: a Two-Faces Disease…Needs a Two Faces Treatment Strategy

Rituximab

PegIFN plus Ribavirin

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Outcome of HCV-MC according to treatment

Parameters All PegIFN-ribavirin RTX-PegIFN-

ribavirinn=93 n=55 n=38 P

Time clinical response, months

6.8 ± 4.7

8.4 ± 4.75.4 ± 4.0

0.004

Clinical response

CR68

(73.1) 40 (72.7) 28 (73.7) 0.98PR 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

CR49

(52.7) 24 (43.6) 26 (68.4) 0.001PR 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

SVR55

(59.1) 33 (60) 22 (57.9) 0.94Death 5 (5.4) 2 (3.6) 3 (7.9) 0.70

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Outcome of HCV-MC according to treatment

Parameters All PegIFN-ribavirin RTX-PegIFN-

ribavirinn=93 n=55 n=38 P

Time clinical response, months

6.8 ± 4.7

8.4 ± 4.75.4 ± 4.0

0.004

Clinical response

CR68

(73.1) 40 (72.7) 28 (73.7) 0.98PR 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

CR49

(52.7) 24 (43.6) 26 (68.4) 0.001PR 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

SVR55

(59.1) 33 (60) 22 (57.9) 0.94Death 5 (5.4) 2 (3.6) 3 (7.9) 0.70

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Outcome of HCV-MC according to treatment

Parameters All PegIFN-ribavirin RTX-PegIFN-

ribavirinn=93 n=55 n=38 P

Time clinical response, months

6.8 ± 4.7

8.4 ± 4.75.4 ± 4.0

0.004

Clinical response

CR68

(73.1) 40 (72.7) 28 (73.7) 0.98PR 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

CR49

(52.7) 24 (43.6) 26 (68.4) 0.001PR 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

SVR55

(59.1) 33 (60) 22 (57.9) 0.94Death 5 (5.4) 2 (3.6) 3 (7.9) 0.70

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Outcome of HCV-MC according to treatment

Parameters All PegIFN-ribavirin RTX-PegIFN-

ribavirinn=93 n=55 n=38 P

Time clinical response, months

6.8 ± 4.7

8.4 ± 4.75.4 ± 4.0

0.004

Clinical response

CR68

(73.1) 40 (72.7) 28 (73.7) 0.98PR 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

CR49

(52.7) 24 (43.6) 26 (68.4) 0.001PR 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

SVR55

(59.1) 33 (60) 22 (57.9) 0.94Death 5 (5.4) 2 (3.6) 3 (7.9) 0.70

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Course of kidney parameters in HCV-MC according to the type of treatment

PegIFN-ribavirin RTX-PegIFN-

ribavirinn=10 p n=21 p

Kidney inv. CR 4 (40) 17 (80.9) 0.04Creatininemia (µmol/l)Baseline 150 ± 30 217 ± 47EOF 169 ± 44 0.28 136 ± 27 0.03GFR (ml/min)Baseline 58 ± 7 42 ± 5EOF 59 ± 9 0.41 57 ± 4 0.01Daily Proteinuria (gr/d)Baseline 3.1 ± 0.9 3 ± 1EOF 1.2 ± 0.5 0.046 0.4 ± 0.1 <0.001Hematuria (n,%)Baseline 10 (100) 19 (90.5)EOF 2 (20) 2 (10.5) <0.001

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Course of kidney parameters in HCV-MC according to the type of treatment

PegIFN-ribavirin RTX-PegIFN-

ribavirinn=10 p n=21 p

Kidney inv. CR 4 (40) 17 (80.9) 0.04Creatininemia (µmol/l)Baseline 150 ± 30 217 ± 47EOF 169 ± 44 0.28 136 ± 27 0.03GFR (ml/min)Baseline 58 ± 7 42 ± 5EOF 59 ± 9 0.41 57 ± 4 0.01Daily Proteinuria (gr/d)Baseline 3.1 ± 0.9 3 ± 1EOF 1.2 ± 0.5 0.046 0.4 ± 0.1 <0.001Hematuria (n,%)Baseline 10 (100) 19 (90.5)EOF 2 (20) 2 (10.5) <0.001

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50Dammacco F et al, Blood 2010

RTX/Peg-IFNα-Ribavirin vs. Peg-IFNα-Ribavirin in HCV Systemic VasculitisMaintenance of Complete Response

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Time Course of HCV Viral Load

Terrier B et al. Arthritis Rheum 2009

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

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Chronic HCV infection

Poly- oligoclonal B-cell expansion

AutoantibodiesRF - ICMixed cryoglobulins

Cryoglobulinemic vasculitis

Monoclonal B-cellproliferationOvert lymphoma

Immuno-modulatorsLow dose IL2

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Reversible Quantitative Deficit in Treg Lymphocytes (CD4+CD25+) in HCV-Systemic

Vasculitis

Before treatmentOn treatmentEarly F/u Late F/U3

4

5

6

CD

25

hig

h (

% o

f C

D4

+)

44

5

6

Before treat.

On Treat.

Early F/U

Late F/U.

**†

**†

-CR

-NR/PR

After Treat.

A

0 20 40 60 80 1000

1

2

3

CD25high (cells /μl)

Cry

og

lob

uli

ns

(g

/l)

R²-0.1, p<0.005

0 20 40 60 80 1000.0

0.2

0.4

CD25high (cells /μl)

C4

(g/l )

R²-0.16, p<0.005

Boyer, Blood 2004. Landau Arthritis Rheum 2008

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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

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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

Baseline C1 C2 C3 C4 Post IL-20

10

20

30

Baseline C1 C2 C3 C4 Post IL-20

10

20

30

Baseline C1 C2 C3 C4 Post IL-20

10

20

30

Baseline C1 C2 C3 C4 Post IL-20

10

20

30

PurpuraNeuropathy

ArthralgiaFatigueKidney Involvement

CD

4+Tr

eg

(%

)C

LIN

ICA

LR

ES

PO

NS

ETemporal Effects of Low-Dose Interleukin-2 on

Clinical Features & Levels of Regulatory T Cells for Each Study Patient

Saadoun D et al, NEJM 2012

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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

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60Saadoun D et al, NEJM 2012

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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 ?

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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

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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

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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

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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 ?

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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

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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.

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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 ?

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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.

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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

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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 ?

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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 %

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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

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Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis 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

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S. Caillat-Zucman, Paris

P. Ghillani, Paris D. Klatzmann, Paris L. Musset, Paris M. Rosenzwajg, Paris

D. Saadoun, Paris D. Sene, Paris B. Terrier, Paris G. Géri, Paris P. Hausfater, Paris O. Lidove, Paris A. Gatel, St Brieuc J-M. Léger, Paris N. Limal, Paris T. Maisonobe, Paris JC Piette, Paris

Merci

L. Alric, Toulouse M. Bourlière, Marseille P. Halfon, Marseille S. Pol, Paris T. Poynard, Paris V. Thibault, Paris Les membres du GERMIVIC

L. Calabrese, Cleveland M. Casato, Roma C. Ferri, Modena G. Kerr, Washington E. Sasso, Seattle JA. Schifferli, Basel V. Soriano, Madrid