HCV_Manifestations extra hépatiques.ppt

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, MD, PhD

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) ?

Hepatitis C Virus Chronic Infection : Two Main Target Cells

• Hepatitis • Cirrhosis• Hepatocarcinoma

• Cryoglobulinemia• Auto-Ab• B-NHL

HepatocyteChoo. Science 1989

LymphocyteZignego. J Hepatol 1992Ferri. Blood 1993

Cryoprecipitation

Endothelial cells

Pathogenesis of cryoglobulinaemi

c nephritis

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

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%

Skin Purpura

Membrano-proliferative Glomerulonephritis CNS Vasculitis

Neuropathy

Cryoglobulinemia-Systemic Vasculitis

HCV Mixed Cryoglobulinemia & Digestive Tract

Mesenteric artery stenosis Intestinal wall thickening

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% Liver involvement 73% B-cell non-Hodgkin's lymphoma 11% Hepatocellular carcinoma 3%

Demographic & Clinical Features of 250 Mixed Cryoglobulinemic Patients.

Ferri C, Mascia MT, Saadoun D, Cacoub P. 2009

Cellular Infiltrate in HCV-Vasculitis

HCV Core Protein in Skin Vascular Structures

Who’s the culprit ?

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

A Major Role for T Cell Immunity in HCV-Vasculitis

• Abnormal T lymphocytes distribution

• Predominant T lymphocytes infiltration in vasculitis lesions

• MHC-II polymorphism (DR11)

• Th1 cytokines profile in vasculitis lesions

• Deficit in Treg lymphocytes

Boyer O, Saadoun D et al, Blood 2004

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

Before treatmentOn treatmentEarly F/u Late F/U3

4

5

6

CD

25h

igh

(%

of

CD

4+)

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-MC vasculitis to anti-viral treatment is associated

with an increase in CD4+CD25high levels.

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

0

10

20

30

40*

10

20

30

Before Treat.

After Treat.

CD

25h

igh

(ce

lls/

μl)

SVR No-SVRbefore on early late3

4

5

6

4

5

6

Before Treat.

On Treat.

Early F/U. Late F/U.

After Treat.

** *

*

CD

25h

igh

(%

of

CD

4+)

MC-vasculitis patientsMC-vasculitis patients

-SVR

-no-SVR

Sustained virological response is associated with an increase in lymphocytes Treg frequency

and concentration in HCV-MC vasculitis.

ANRS HC 21 VASCU-IL2

Phase II pilot study evaluating the impact of IL2 on cellular immune response, and clinical efficacy and safety in HCV

cryoglobulinemia vasculitis refractory to conventional treatments.

Investigateur Coordonnateur Pr Patrice CACOUB Hôpital de la Pitié, 83 Bd de l’Hôpital75651 Paris cedex 13FranceTél. : 01 42 17 80 09 - Fax : 01 42 17 80 [email protected]

mailto:[email protected]

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

Anti-HCV Treatment Efficacy in HCV-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, Saadoun, Arthritis Rheum 2007

%

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

cryoglobulinaemic

nephritis

and

rationale for

Rituximab

treatment

Rocatello D, Nephrol Dial Transplant, 2004

Treatment of Mixed Cryoglobulinemia Resistant to Interferon-alfa with

Rituximab* (anti-CD 20 Ab)

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

0

10

20

30

40

50

60

70

80

90

PegIFN-RBV (n=40) Rituximab (n=43)

% im

pro

vem

en

t

HCV-Vasculitis Treatment : PegIFN-Ribavirin vs. Rituximab

Cacoub P, Ann Rheum Dis 2008

Personal series

Literature review

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

Lymphocyte Infiltrate in HCV-Vasculitis

HCV Core Protein in Skin Vascular Structures

HCV Vasculitis: a Two-Faces

Disease


HCV Vasculitis: a Two-Faces

Disease…

Needs a Two Faces Treatment

Strategy

Rituximab

PegIFN plus Ribavirin

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

73

27

304

3729

MC pre-Rx

MC post-Rx

VH1-69+ B CellsTotal B Cells

0

10

20

30

40

%V

H1-

69+/

CD

19+

97

3

912

51

p=0.01

A B

Effects of rituximab on VH1-69 clonal B cells.

A patient with HCV-MC-vasculitis demonstrating staining with anti-Vh1-69 gene product mAb (MC pre-Rx) and disappearance of VH1-69+ B cells following rituximab (MC post-Rx).

VH1-69+ cells among CD19+ B cells in patients with HCV-MC vasculitis (n=11) before and after rituximab

Blood, 2010

Outcome of HCV-MC pts according to treatment

Parameters All PegIFN-ribavirin RTX-PegIFN-ribavirin

n=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

CR 68 (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

CR 49 (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

SVR 55 (59.1) 33 (60) 22 (57.9) 0.94NR 38 (40.8) 22 (40) 16 (42.1)

Death 5 (5.4) 2 (3.6) 3 (7.9) 0.70Cirrhosis 1 (1.1) _ 1 (2.6)Liver carcinoma 3 (3.2) 2 (3.6) 1 (2.6)Unknown 1 (1.1) _ 1 (2.6)

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

treatment PegIFN-ribavirin RTX-PegIFN-

ribavirinn=10 p n=21 p

CR of kidney involv. 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

Antiviral therapy alone decreases the memory B

cells

n=38 n=55

Saadoun D et al, Blood 2010

Antiviral therapy alone decreases the memory B

cells

Antiviral therapy plus

Rituximab decrease

naive B-cells


Blood 2010

Dammacco F et al, Blood 2010

Course of cryoglobulinemia & HCV RNA in HCV-MC patients according to the type of

treatment


Time Course of HCV Viral Load

Terrier B et al. Arthritis Rheum 2009

Long term follow up of HCV vasculitis patients treated with Rituximab (23 ± 12 months, 6-44)

Tolerance

Good 25/32 (78%)

Serum sickness 3Neutropenia 2Herpès zooster 1Out of vein RTX 1


Overall Survival of 151 HCV-Vasculitis Patients

Years

Ove

rall

surv

ival

l


Overall Survival of 151 HCV-Vasculitis Patients

Years

Ove

rall

surv

ival

l

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)

Baseline Prognostic Factors of HCV-Vasculitis Patients

Liver Fibrosis and Five Factor Score are Associated with a Poor Prognosis in HCV vasculitis Patients

(Multivariate Analysis)

- Metavir fibrosis score:HR = 10.8 (3.63-32.14), P<0.0001

-Five Factor Score:HR = 2.49 (1.29-4.8), P=0.007

Multivariate analysis

- Metavir fibrosis score:HR 10.8 (3.63-32.14), P<0.0001-FFS:HR 2.49 (1.29-4.8), P=0.007

Metavir Fibrosis

FFS F0-F2 F3-F4

0 1.0

1 2.49

> 1 6.2

FFS is a good predictorof outcome

Interaction Between Liver Fibrosis and Five Factor Score in HCV-Vasculitis Patients

FFS=good predictorof outcome

No more prognostic value of FFS

Interaction Between Liver Fibrosis and Five Factor Score in HCV -Vasculitis Patients

Metavir Fibrosis

FFS F0-F2 F3-F4

0 1.0 10.8

1 2.49 10.25

> 1 6.2 9.74

Multivariate analysis

- Metavir fibrosis score:HR 10.8 (3.63-32.14), P<0.0001-FFS:HR 2.49 (1.29-4.8), P=0.007

Prognostic Factors

During follow-up

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

• Negative impact of immunosuppressantsHR = 4.05 (1.75-9.36), P=0.001

• … but not of corticosteroidsHR = 1.79 (0.77-4.16), P=0.17

Use of Peg-IFN/riba had a positive prognostic impact

HR = 0.34 (0.16-0.67)

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) --


% 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




------------------------------------------------------------------------------------------------------------------------------ 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) --


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


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.




------------------------------------------------------------------------------------------------------------------------------ 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.

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




------------------------------------------------------------------------------------------------------------------------------ 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) -


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


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


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



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

• O. Boyer, Paris• S. Caillat-Zucman,

Paris• F. Charlotte, Paris• P. Ghilani, Paris• G. Kaplanski, Marseille• D. Klatzman, Paris• L. Musset, Paris

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

Thanks

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

• L. Calabrese, Cleveland

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

HCV_Manifestations extra hépatiques.ppt

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