CIS SCHOOL ON SYSTEMIC AUTOIMMUNE DISEASES

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CIS SCHOOL ON SYSTEMIC AUTOIMMUNE DISEASES
SANTA FE, NM MARCH 14TH-18 TH, 2007
CRYOGLOBULINEMIA AND RHEUMATIC MANIFESTATIONS IN
A PATIENT WITH HEPATITIS C INFECTION.

• Yvonne Rengel MD 1,2
• Martin Rodriguez MD PhD 1
• Renata Gay MD 2
• NATIONAL CENTER OF RHEUMATIC DISEASES. UNIVERSITY
  HOSPITAL OF CARACAS. VENEZUELA
• CENTER OFEXPERIMENTAL RHEUMATOLOGY. UNIVERSITY
  HOSPITAL, ZURICH, SWITZERLAND

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CASE PRESENTATION
42 years old female
Headache Photophobia Phonobia Paresthesias
Fever Fatigue Malaise Blurred vision
Arthralgias Purpuric lesion
Hepatitis C Cryoglobulinemia
June, 2001
February, 2002
May, 2002
3
Past medical history Non contributory
Physical exam Purpuric lesions in fingertips of
both hands
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Laboratory
Anti-ANA ()
(-)
Anti-DNA
Genotype 1a
Anti-Sm
Anti-ACA(-)
143.000 copies
Rheumatoid factor
Anti-DNA (-)
RNA ()
?-glycoprotein
? C3
VHC ()
cryocrit ()
Lupus anticoagulant
June, 2001
June, 2003
5
3
IMMUNOSUPRESSIVE
52 WEEKS
TREATMENT
CORTICOSTEROID
INTEFERON RIBAVIRINE
1
LOW DOSES
2
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CRYOGLOBULINEMIA AND RHEUMATIC MANIFESTATIONS IN
A PATIENT WITH HEPATITIS C INFECTION.
DISCUSION
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Clinical features of 231 vasculitis
cryoglobulinemic patients
Ferri . Curr Opin Rheumatol. 2006 Jan18(1)54-63
8
Clinical features of 231 vasculitis
cryoglobulinemic patients
Ferri . Curr Opin Rheumatol. 2006 Jan18(1)54-63
9
Hepatitis C virus-related autoimmune-lymphoprolife
rative disorder
Mixed cryoglobulinemia syndrome /Cryoglobulinemia
HIGH
Rheumatoid arthritis
Sjögren syndrome
SLE
Autoimmune hepatitis
INTERMEDIATE
Monoclonal gammopathies
B Cells NHL
Polymyalgia rheumatica
LOW
Systemic sclerosis
Fibromyalgia
Ferri et al. Clin Exp Rheumatol. 2003
Nov-Dec21(6 Suppl 32)S78-84 Ramos-Casal.
Lupus. 20009(2)83-91 Ramos-Casal. Curr Opin
Rheumatol. 2005 Jul17(4)447-55
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Prevalence of autoantibodies with chronic HCV
infection
Ferri . Curr Opin Rheumatol. 2006 Jan18(1)54-63
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Hepatitis C virus and the immune system
Innate inmune response
Adaptative immune response
Humoral immune response
Cellular immune response
TLR
CD4
CD8
Inteferon a/ß
antibodies
Gremion. Rev Med Virol. 2005 Jul-Aug15(4)235-68.
Lloyd. Immunol Cell Biol. 2007 Jan85(1)24-32
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Hepatitis C virus-related autoimmune-lymphoprolife
rative disorders
HCV INFECTION HCV-E2?CD81 LYMPHOCYTES
Viral antigens autoantigens
T(1418) translocation Bcl2 activation
Autorreactive cytotoxic T cells
Inhibition of apoptosis Prolonged B-cell survival
Benign B-cell expansion
Other genetic aberration
Autoantibodies, RF, CIC cryoglobulins

Immunological disorders
B-cell Lymphomas
Cryoglobulinemic vasculitis
Ferri . Curr Opin Rheumatol. 2006 Jan18(1)54-63
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Pathogenesis of cryoglobulinemic vasculitis

• HOST
• Autoantigens
• CD81
• LDL receptors
• HLA antigens
• Sex hormones

• HCV
• Genotype
• HCV protein
• E2
• Core
• NS3,NS4, NS5A

Lloyd. Immunol Cell Biol. 2007 Jan85(1)24-32
Favre. Lipids Health Dis. 2005 Apr
194(1)9. Ferri . Curr Opin Rheumatol. 2006
Jan18(1)54-63
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Proposed functions of B cells in HCV infection
Extrahepatic replication
High titer broadly reactive
HCV
Neutralization
?
CD81
BCR
Clearance
Ab
B CELL
CD21
Low titer restricted specificity
CD19
Low activation threshold
Mutant selection
B cell clonal expansion
Enhancement
Lymphoproliferative diseases
Persistance
Mondelli. Antiviral Res. 2003 Oct60(2)111-5
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Leucocytoclastic vasculitis and organ involvement
Cryo/noncryoprecipitable immune complexes
Leucocytoclastic vasculitis
Endocrine disorders
Nephritis Peripheral neuropathy
Skin/diffusse vasculitis
Ferri . Curr Opin Rheumatol. 2006 Jan18(1)54-63
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Therapeutic interventions for hepatitis C virus
(HCV) related cryoglobulinemia
HCV eradication Inteferon-a ribavirin
HCV infection
Immunosuppressors cyclophosphamide
Benign B-cell expansion
CIC reduction Plasma exchange
Steroid
Cryoglobulinemic vasculitis
Chemotherapy
B-cell- Lymphoma
Morra. Hematology Am Soc Hematol Educ Program.
2005368-72 Lamprecht Arthritis Rheum. 1999
Dec42(12)2507-16
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Therapeutic interventions for hepatitis C virus
(HCV) related cryoglobulinemia
Possible sequential treatment
Monitoring
Asymptomatic
Severe active manifestation
Rituximab ? IFN RIBA
Mild Moderate
Low-medium doses CS
IFN RIBA ? Rituximab
Active chronic hepatitis
Moderate- severe
peg-IFN Riba
Plasma exchange CS CFX or RIT
Severe
Ferri . Curr Opin Rheumatol. 2006 Jan18(1)54-63
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CONCLUSION
Hepatitis C virus infection represent an example
of the relationship between infections and
autoimmunity, which must be considered for the
precise diagnose and treatment of conditions
like cryoglobulinemic vasculitis