Hcv Meh Cacoub

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) --


% 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.

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




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


Chronic infection withHepatitis C Virus

HepatocytesB-Lymphocytes

Hepatitis (acute/chronic)CirrhosisHepatocarcinoma

Mixed cryoglobulinemia

B-cell lymphoma ?


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)


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


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

Hcv Meh Cacoub

Health & Medicine

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