Cryoglobulinemia and Rheumatic Manifestations in a Patient with Hepatitis C Infection

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 1. NATIONAL CENTER OF RHEUMATIC DISEASES. UNIVERSITY HOSPITAL OF CARACAS. VENEZUELA 2. CENTER OFEXPERIMENTAL RHEUMATOLOGY. UNIVERSITY HOSPITAL, ZURICH, SWITZERLAND 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 CIS SCHOOL ON SYSTEMIC AUTOIMMUNE DISEASES Past medical history Non contributory Physical exam Purpuric lesions in fingertips of both hands CIS SCHOOL ON SYSTEMIC AUTOIMMUNE DISEASES Laboratory Anti-ANA (+) (-) Anti-DNA Genotype 1a Anti-ACA(-) 143.000 copies Anti-Sm Rheumatoid factor Anti-DNA (-) ↓ C3 RNA (+) VHC (+) cryocrit (+) Β-glycoprotein Lupus anticoagulant June, 2001 June, 2003 CIS SCHOOL ON SYSTEMIC AUTOIMMUNE DISEASES 3 IMMUNOSUPRESSIVE 52 WEEKS INTEFERON + RIBAVIRINE TREATMENT CORTICOSTEROID 1 LOW DOSES 2 CIS SCHOOL ON SYSTEMIC AUTOIMMUNE DISEASES CRYOGLOBULINEMIA AND RHEUMATIC MANIFESTATIONS IN A PATIENT WITH HEPATITIS C INFECTION. CIS SCHOOL ON SYSTEMIC AUTOIMMUNE DISEASES % 100 120 20 98 100 40 60 80 0 98 Pu rp ur a W ea kn es s A rth ra lg ia s A rth 6.7 Ra yn au d' s 48 53 22 80 77 30 1.9 Clinical features of 231 vasculitis cryoglobulinemic patients rit is ph en om Si en cc a a sy nd ro m e Sk Pe in rih ul er ce al rs ne ur op Li at ve hy ri nv ol ve m Re en na t li nv ol Lu m ng en t in vo lv em D if f en us t e va sc ul it i s 6.2 Ferri . Curr Opin Rheumatol. 2006 Jan;18(1):54-63 Clinical features of 231 vasculitis cryoglobulinemic patients 120 100 80 60 % 40 20 0.5 0 10 3.3 4.4 11 56 42 98 100 92 1 H at yp oi er d vis fa co ct sit or y sy nd ro Bm ce e H ll ep ly at m oc ph el om lu la a rc ar cin om Th a yr oi d ca nc er C ry oc rit % Rh eu m Ferri . Curr Opin Rheumatol. 2006 Jan;18(1):54-63 A ut o an t ib C 4 C 3 an t iH C V an t iH BV m g% m g% od ie s Hepatitis C virus-related autoimmune-lymphoproliferative disorder Mixed cryoglobulinemia syndrome /Cryoglobulinemia* Rheumatoid arthritis HIGH 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-Dec;21(6 Suppl 32):S78-84 Ramos-Casal. Lupus. 2000;9(2):83-91 Ramos-Casal. Curr Opin Rheumatol. 2005 Jul;17(4):447-55 Prevalence of autoantibodies with chronic HCV infection Study Fried Abauf Borotto Rolachon Pawlotsky Mcfarlane Richardet Clifford Czaja Cassani Buskila Rivera Cacoub Drygiannakis Stroffoloni Yee n 62 272 97 93 61 101 156 92 75 290 90 189 321 142 502 645 ANA 13 50 20 14 13 0 18 13 24 26 31 43 123 72 79 50 SMA 34 69 18 14 13 18 8 43 8 59 27 33 137 481 LKM 0 14 6 1 3 6 2 1 1 18 11 1 11 - DNA 0 4 8 16 ENA 0 1 10 - AMA 0 0 0 0 0 2 - CRY - RF - 21 - 43 - 9 - 35 21 36 39 107 - 64 110 - 1 1 - % 18.6 21.8 3.4 2.6 2.5 0.3 39.7 38.1 Ferri . Curr Opin Rheumatol. 2006 Jan;18(1):54-63 Hepatitis C virus and the immune system Innate inmune response Adaptative immune response Cellular immune response CD4+ CD8+ PAMPS TLR Humoral immune response Inteferon – α/β antibodies Gremion. Rev Med Virol. 2005 Jul-Aug;15(4):235-68. Lloyd. Immunol Cell Biol. 2007 Jan;85(1):24-32 Hepatitis C virus-related autoimmune-lymphoproliferative disorders HCV INFECTION HCV-E2CD81 LYMPHOCYTES Viral antigens autoantigens T(14;18) translocation Bcl2 activation Autorreactive cytotoxic T cells Inhibition of apoptosis Prolonged B-cell survival Benign B-cell expansion Autoantibodies, RF, CIC cryoglobulins Other genetic aberration Immunological disorders Cryoglobulinemic vasculitis B-cell Lymphomas Ferri . Curr Opin Rheumatol. 2006 Jan;18(1):54-63 Pathogenesis of cryoglobulinemic vasculitis HCV •Genotype • HCV protein: •E2 •Core •NS3,NS4, NS5A HOST •Autoantigens •CD81 •LDL receptors •HLA antigens •Sex hormones Lloyd. Immunol Cell Biol. 2007 Jan;85(1):24-32 Favre. Lipids Health Dis. 2005 Apr 19;4(1):9. Ferri . Curr Opin Rheumatol. 2006 Jan;18(1):54-63 Proposed functions of B cells in HCV infection High titer broadly reactive Extrahepatic HCV replication Neutralization ? CD81 BCR Clearance Ab B CELL CD21 CD19 Low titer restricted specificity Mutant selection Enhancement Low activation threshold B cell clonal expansion Persistance Lymphoproliferative diseases Mondelli. Antiviral Res. 2003 Oct;60(2):111-5 Leucocytoclastic vasculitis and organ involvement Cryo/noncryoprecipitable immune complexes Leucocytoclastic vasculitis Skin/diffusse vasculitis Nephritis Peripheral neuropathy Endocrine disorders Ferri . Curr Opin Rheumatol. 2006 Jan;18(1):54-63 Therapeutic interventions for hepatitis C virus (HCV) related cryoglobulinemia HCV eradication Inteferon-α + 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. 2005;:368-72 Lamprecht Arthritis Rheum. 1999 Dec;42(12):2507-16 Therapeutic interventions for hepatitis C virus (HCV) related cryoglobulinemia Possible sequential treatment Asymptomatic Mild Moderate Moderatesevere Monitoring Severe active manifestation Low-medium doses CS Rituximab ↓ IFN + RIBA IFN + RIBA ↓ Rituximab peg-IFN + Riba Active chronic hepatitis Severe Plasma exchange + CS + CFX or RIT Ferri . Curr Opin Rheumatol. 2006 Jan;18(1):54-63 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