HCV Infection and Cryoglobulinemia
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2 HCV Infection and Cryoglobulinemia
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4 Franco Dammacco Editor HCV Infection and Cryoglobulinemia Foreword by Jay H. Hoofnagle
5 Editor Franco Dammacco Department of Internal Medicine and Clinical Oncology University of Bari Medical School Bari, Italy ISBN e-isbn DOI / Springer Milan Heidelberg Dordrecht London New York Library of Congress Control Number: Springer-Verlag Italia 2012 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the Italian Copyright Law in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the Italian Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Printed on acid-free paper Springer is part of Springer Science+Business Media (
6 To my wife Tecla, lifetime partner. Without her unfailing inspiration, I would have been unable to read even a single page of the endless, puzzling and fascinating Book of Nature.
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8 Foreword Major breakthroughs in biomedical research are often followed by paradigm shifts in our understanding of diseases. This was particularly true after the landmark discovery of hepatitis C virus (HCV). The identification of a small but viral-specific RNA sequence in the serum of patients with non-a, non-b hepatitis led directly to the development of tests for antibody and viral RNA. Moreover, it fostered recognition of several facts: (1) that hepatitis C is the most common cause of chronic liver disease, cirrhosis, and liver cancer in most countries of the world; (2) that post-transfusion hepatitis can be prevented by screening for antibody; (3) that the implementation of simple public health measures would markedly decrease the rate of new infections with this virus; and (4) that a therapy with beneficial effects on the disease could actually cure the infection and permanently eradicate the virus. Another paradigm shift, perhaps less well known but just as ground-breaking, was the recognition of hepatitis C as the major cause of the uncommon and poorly understood autoimmune disease known as essential mixed cryoglobulinemia. Immediately obvious was that the name essential mixed cryoglobulinemia was no longer appropriate. The syndrome was not essential but instead due to hepatitis C, and it was not always mixed. Importantly, cryogloblins were detectable in low amounts in a large proportion of patients with chronic hepatitis C, not all of whom had vasculitis. Perhaps a better term for the condition is HCV-related cryoglobulinemic vasculitis. This change in terminology points out that the mere presence of cryoglobulins is not adequate; rather, the diagnosis also requires clinical signs and symptoms of vasculitis. What is the nature of the cryoglobulins found in HCV-related vasculitis? They appear to be circulating immune complexes and to consist of intact hepatitis C virions bound by IgG anti-hcv. These immune complexes are then aggregated into large macromolecular complexes by pentameric rheumatoid factor, that is, IgM antibody to IgG. The ability of the large viral-igg-igm complexes to precipitate in the cold (thus cryo globulins) is well known but they can also precipitate in tissues, such as skin, joints, kidneys, lung, intestine and nerves, in response to cold or to other, less well defined stresses (perhaps including mechanical pressure, hypoxia, minor tissue damage, local immune activation, or immunoglobulin receptors). Precipitation of these viral-antibody complexes gives rise to the clinical signs and symptoms of the disease, which most commonly presents as an episodic cutaneous vasculitis over the lower extremities that is often painful and pruritic and may be accompanied by local edema, joint or muscle aches, and fatigue. More serious forms of cryoglobulinemia result in injury to the lungs (interstitial pneumonitis), intestine (intestinal infarction or perforation), kidney (glomerulonephritis), and peripheral nerves (neuropathy), probably as a result of local vascular injury. These complications can be severe, vii
9 viii Foreword disabling, or indeed fatal. Fortunately, the clinical syndrome of cryoglobulinemic vasculitis is rare; but its infrequency does not help the unfortunate affected individuals. Therapies directed at HCV eradication can result in remission of the clinical syndrome, but not all patients respond to the current antiviral regimens, and others respond but have an incomplete remission of the vasculitis and its complications. HCV-related cryoglobulinemic vasculitis itself represents a special paradigm for understanding complex diseases. It is basically an uncommon complication of a common disease. What do we know of its pathogenesis? It is more frequently seen in women than men with hepatitis C and it arises during the chronic phase of the illness, after years if not decades of infection. The severity of injury correlates only roughly with the levels of serum cryoglobulins and rheumatoid factor and with the degree of complement activation. The production of cryoglobulins apparently derives from an overactivation of B cells, resulting in the production of clones that secrete anti-hcv and rheumatoid factor. The prolonged stimulation and activation of B cells can give rise to genetic alterations that may cause unregulated, self-sustaining clonal B cell proliferation and even B cell lymphoma. Thus, a common chronic viral infection of the liver appears to be a cause of both an autoimmune disease and cancer. Further elucidation of the pathogenesis of HCV-related cryoglobulinemic vasculitis may thus also lead to fundamental discoveries regarding the pathogenesis of other autoimmune diseases (rare complications of common infections?) and cancer (unregulated cell growth caused by chronic stimulation by microbial antigens or toxins?). Recently, important inroads have been made in understanding the natural history of HCV-related cryoglobulinemic vasculitis as well as its treatment. Antiviral therapies that reduce or eradicate HCV also improve the vasculitis, with sustained viral clearance usually followed by long-term remission of the cryoglobulinemia and the disappearance of serum cryoglobulins. As new therapies for hepatitis C become available (particularly the new direct-acting antiviral agents), those for cryoglobulinemia will likely become more effective. In patients in whom eradication of hepatitis C is not possible, therapies directed at B cell overactivity (particularly rituximab) may nonetheless be effective, at least in the short-term. Combined approaches of anti-b cell followed by potent antiviral therapy may represent the best therapeutic strategy for patients with advanced or resistant disease. The current monograph, Hepatitis C Virus Infection and Cryoglobulinemia, brings together an international group of investigators from the fields of basic virology, clinical medicine, rheumatology, hematology, nephrology, oncology, immunology, and genetics to focus on perhaps the most unusual manifestation of this chronic viral infection. The editor and authors should be congratulated for this most welcomed and combined effort at understanding and improving the management of HCV-related cryoglobulinemic vasculitis. A broader and more complete understanding of this complex disease is likely to bring further paradigm shifts in our understanding of how the intricate interactions between an infectious agent and susceptible host are responsible for clinical disease. Bethesda, MD, USA Jay H. Hoofnagle Director, Liver Disease Research Branch National Institutes of Health
10 Contents 1 Introductory Remarks Franco Dammacco and Domenico Sansonno Part I Hepatitis C Virus Infection and the Role of the Immune System 2 Natural History, Pathogenesis, and Prevention of HCV Infection Edgar D. Charles, Lynn B. Dustin, and Charles M. Rice 3 Immune Control of HCV Infection Lynn B. Dustin 4 B Cell Activation: General to HCV-Specific Considerations Vito Racanelli and Claudia Brunetti 5 Organ-Specific Autoimmunity in HCV-Positive Patients Corrado Betterle and Fabio Presotto Part II Cellular Compartments of HCV Infection (and Replication) 6 HCV and Blood Cells: How Can We Distinguish Infection from Association? Lynn B. Dustin and Charles M. Rice 7 Mechanisms of Cell Entry of Hepatitis C Virus Franco Dammacco and Vito Racanelli 8 HCV Infection of Hematopoietic and Immune Cell Subsets Tram N.Q. Pham and Tomasz I. Michalak Part III Cryoglobulinemia and the Complement System 9 Cryoglobulinemia and Chronic HCV Infection: An Evolving Story Jürg A. Schifferli and Marten Trendelenburg 10 The Complement System in Cryoglobulinemia Marten Trendelenburg ix
11 x Contents 11 The Pivotal Role of C1qR in Mixed Cryoglobulinemia Domenico Sansonno, Loredana Sansonno, and Franco Dammacco Part IV Structural and Genetic Features, Cytokines and Chemokines in Cryoglobulinemia 12 Mixed Cryoglobulinemia (MC) Cross-Reactive Idiotypes (CRI): Structural and Clinical Significance Peter D. Gorevic 13 Molecular Insights into the Disease Mechanisms of Type II Mixed Cryoglobulinemia Valli De Re and Marica Garziera 14 The Role of VCAM-1 in the Pathogenesis of Hepatitis-C-Associated Mixed Cryoglobulinemia Vasculitis Gilles Kaplanski 15 Up-Regulation of B-Lymphocyte Stimulator (BLyS) in Patients with Mixed Cryoglobulinemia Martina Fabris and Salvatore De Vita 16 Role of B-Cell-Attracting Chemokine-1 in HCV-Related Cryoglobulinemic Vasculitis Sabino Russi, Silvia Sansonno, Gianfranco Lauletta, Domenico E. Sansonno, and Franco Dammacco 17 Serum a-chemokine CXCL10 and b-chemokine CCL2 Levels in HCV-Positive Cryoglobulinemia Alessandro Antonelli, Clodoveo Ferri, Silvia Martina Ferrari, Michele Colaci, IIaria Ruffilli, Caterina Mancusi, Ele Ferrannini, and Poupak Fallahi Part V Clinical Manifestations of Cryoglobulinemia 18 Experimental Models of Mixed Cryoglobulinemia Charles E. Alpers, Tomasz A. Wietecha, and Kelly L. Hudkins 19 The Expanding Spectrum of Clinical Features in HCV-Related Mixed Cryoglobulinemia Clodoveo Ferri, Alessandro Antonelli, Marco Sebastiani, Michele Colaci, and Anna Linda Zignego 20 Classification of Cryoglobulinemic Vasculitis Salvatore De Vita and Luca Quartuccio 21 Demographic and Survival Studies of Cryoglobulinemic Patients Giuseppe Monti, Francesco Saccardo, and Laura Castelnovo 22 HCV-Associated Membranoproliferative Glomerulonephritis Christos P. Argyropoulos, Sheldon Bastacky, and John Prentiss Johnson
12 Contents xi 23 Rheumatologic Symptoms in Patients with Mixed Cryoglobulinemia Gianfranco Ferraccioli, Francesca Faustini, and Elisa Gremese 24 Endocrine Manifestations of HCV-Positive Cryoglobulinemia Alessandro Antonelli, Clodoveo Ferri, Silvia Martina Ferrari, Michele Colaci, Alda Corrado, Andrea Di Domenicantonio, and Poupak Fallahi 25 Cutaneous Cryoglobulinemic Vasculitis Konstantinos Linos, Bernard Cribier, and J. Andrew Carlson 26 Peripheral Neuropathy and Central Nervous System Involvement in Cryoglobulinemia Salvatore Monaco, Sara Mariotto, and Sergio Ferrari 27 Long-Term Course of Patients with Mixed Cryoglobulinemia Damien Sene and Patrice P. Cacoub 28 HBV/HCV Co-infection and Mixed Cryoglobulinemia Massimo Galli and Salvatore Sollima 29 Clinical and Immunological Features of HCV/HIV Co-infected Patients with Mixed Cryoglobulinemia David Saadoun and Patrice P. Cacoub 30 HCV-Negative Mixed Cryoglobulinemia: Facts and Fancies Massimo Galli, Salvatore Sollima, and Giuseppe Monti 31 Cryoglobulinemia in HCV-Positive Renal Transplant and Liver Transplant Patients Lionel Rostaing, Hugo Weclawiak, and Nassim Kamar Part VI HCV Infection, Cryoglobulinemia and Non-Hodgkin s Lymphomas 32 Chromosome Abnormalities in HCV-Related Lymphoproliferation Cristina Mecucci, Gianluca Barba, and Caterina Matteucci 33 Molecular Features of Lymphoproliferation in Mixed Cryoglobulinemia Valli De Re and Maria Paola Simula 34 The Higher Prevalence of B-Cell Non-Hodgkin s Lymphoma in HCV-Positive Patients with and Without Cryoglobulinemia Franco Dammacco and Domenico Sansonno 35 Incidence and Characteristics of Non-Hodgkin s Lymphomas in HCV-Positive Patients with Mixed Cryoglobulinemia Pietro Enrico Pioltelli, Giuseppe Monti, Maurizio Pietrogrande, and Massimo Galli
13 xii Contents 36 Waldenström s Macroglobulinemia Associated with Cryoglobulinemia: Pathogenetic, Clinical, and Therapeutic Aspects Meletios A. Dimopoulos and Efstathios Kastritis Part VII Therapy of Cryoglobulinemia 37 Should HCV-Positive Asymptomatic Patients with Mixed Cryoglobulinemia Be Treated with Combined Antiviral Therapy? José Luis Calleja Panero, Juan de la Revilla Negro, and Fernando Pons Renedo 38 The Role of Rituximab in the Therapy of Mixed Cryoglobulinemia Francesco Zaja, Stefano Volpetti, Stefano De Luca, and Renato Fanin 39 Rituximab in Cryoglobulinemic Vasculitis: First- or Second-Line Therapy? Peter Lamprecht and Paul Klenerman 40 PIRR Therapy in HCV-Related Mixed Cryoglobulinemia Franco Dammacco and Domenico Sansonno 41 Antiviral Therapy in HCV-Positive Non-Hodgkin s Lymphoma: Pathogenetic Implications Franco Dammacco, Cinzia Conteduca, and Domenico Sansonno 42 Active or Indolent Cutaneous Ulcers in Cryoglobulinemia: How Should They Be Treated? Maurizio Pietrogrande 43 Double Filtration Plasmapheresis: An Effective Treatment of Cryoglobulinemia Alfonso Ramunni and Paola Brescia 44 Emergency in Cryoglobulinemia: Clinical and Therapeutic Approach Francesco Saccardo, Laura Castelnovo, and Giuseppe Monti 45 Novel Therapeutic Approaches to Cryoglobulinemia: Imatinib, Infliximab, Bortezomib, and Beyond Giampaolo Talamo and Maurizio Zangari Index
14 Contributors Charles E. Alpers Department of Pathology, University of Washington, Seattle, WA, USA Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA, USA Alessandro Antonelli Metabolism Unit, Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy Christos P. Argyropoulos Renal and Electrolyte Division, Department of Internal Medicine, University of Pittsburgh, Pittsburgh, PA, USA Gianluca Barba Hematology and Clinical Immunology Unit, Clinical and Experimental Medicine, University of Perugia, Perugia, Italy Sheldon Bastacky Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA Corrado Betterle Unit of Endocrinology, Department of Medical and Surgical Sciences, University of Padua, Padua, Italy Paola Brescia Division of Nephrology, Department of Internal and Public Medicine, University of Bari, Bari, Italy Claudia Brunetti Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy Patrice P. Cacoub UMR 7211 (UPMC/CNRS), U 959 (INSERM), Université Pierre Marie Curie, Paris, France Department of Internal Medicine, Hôpital La Pitié-Salpêtrière, Paris, France José Luis Calleja Panero Gastroenterology and Hepatology Department, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Madrid, Spain J. Andrew Carlson Division of Dermatology and Dermatopathology, Department of Pathology, Albany Medical College, Albany, NY, USA Laura Castelnovo Internal Medicine Unit, Ospedale di Saronno, Saronno, Italy Edgar D. Charles Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA Michele Colaci Rheumatology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, Medical School, Modena, Italy xiii
15 xiv Contributors Cinzia Conteduca Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy Alda Corrado Metabolism Unit, Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy Bernard Cribier Dermatologique Clinique, Les Hopitaux Universtaires de Strasbourg, Strasbourg, France Franco Dammacco Department of Biomedical Sciences and Clinical Oncology, University of Bari Medical School, Bari, Italy Stefano De Luca Clinica Ematologica, DISM, Azienda Ospedaliero Universitaria S. Maria Misericordia, Udine, Italy Valli De Re Clinical and Experimental Pharmacology, Department of Molecular Oncology and Translational Medicine (DOMERT), Centro di Riferimento Oncologico, IRCCS, National Cancer Institute, Aviano, Italy Salvatore De Vita Clinic of Rheumatology, Department of Medical and Biological Sciences, Azienda Ospedaliero Universitaria of Udine, Udine, Italy Andrea Di Domenicantonio Metabolism Unit, Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy Meletios A. Dimopoulos Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece Lynn B. Dustin Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA Martina Fabris Clinical Pathology and Clinic of Rheumatology, Azienda Ospedaliero Universitaria of Udine, Udine, Italy Poupak Fallahi Metabolism Unit, Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy Renato Fanin Clinica Ematologica, DISM, Azienda Ospedaliero Universitaria S. Maria Misericordia, Udine, Italy Francesca Faustini Division of Rheumatology, Institute of Rheumatology and Affine Sciences(IRSA), CIC Catholic University of the Sacred Heart, Rome, Italy Gianfranco Ferraccioli Division of Rheumatology, Institute of Rheumatology and Affine Sciences(IRSA), CIC Catholic University of the Sacred Heart, Rome, Italy Ele Ferrannini Metabolism Unit, Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy Silvia Martina Ferrari Metabolism Unit, Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy Sergio Ferrari Department of Neuroscience, University of Verona, Verona, Italy Clodoveo Ferri Rheumatology Unit, Department of Internal Medicine, University of Modena and Reggio Emilia, Medical School, Modena, Italy
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