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HCV-related cryoglobulinemic vasculitis: An update on its etiopathogenesis and therapeutic strategies

C. Ferri, D. Giuggioli, M. Cazzato¹, M. Sebastiani¹, M.T. Mascia, A.L. Zignego²

Rheumatology Unit, Department of Internal Medicine, Medical School, University of Modena and Reggio Emilia, Modena; ¹Rheumatology Unit, Department of Internal Medicine, University of Pisa, Medical School, Pisa; ²Department of Internal Medicine, University of Florence, Medical School, Florence, Italy.

ABSTRACT
Cryoglobulinemic vasculitis (CV) is an immune-complex-mediated systemic vasculitis involving small-medium sized vessels. A causative role of hepatitis C virus (HCV) in over 4/5 patients has been definitely established on the basis of epidemiological, pathological, and laboratory studies. There is great geographical heterogeneity in the prevalence of CV as well as other HCV-related immuno-lymphoproliferative disorders. Thus, unknown environmental and/or genetic co-factors should contribute to the pathogenesis of these conditions. Due to its biological properties, HCV genomic sequences cannot be integrated into the host genome; the virus could trigger the immunological alterations only indirectly by exerting a chronic stimulus to the immune system.
Recent laboratory observations gave us new important insights on the complex pathogenetic mechanism(s) of HCV-related CV. Firstly, the HCV envelop protein E2, able to bind CD81 molecule expressed on B-lymphocytes, might be involved in the first steps of HCV-driven autoimmune and lymphoproliferative phenomena. The interaction between HCV-E2 and CD81 may increase the frequency of VDJ rearrangement in antigen-reactive B-cell. One possible consequence may be the activation of anti-apoptotic Bcl-2 protoncogene that leads to extended B-cell survival. Interestingly, t(14, 18) translocation along with Bcl-2 activation have been demonstrated in B-lymphocytes of 80% HCV-related CV. The B-lymphocyte expansion is responsible for a wide autoantibody and immune-complex production, including mixed cryoglobulins.
CV shows a relatively benign clinical course; however, its cumulative survival is significantly worse if compared to general population. For a correct therapeutic approach to HCV-related CV we must deal with conflicting conditions: HCV infection, autoimmune, and lymphoproliferative alterations. Therapeutic strategy of CV includes etiologic, pathogenetic, and/or symptomatic therapies, which should be tailored for the single patient according to the severity of clinical symptoms. A careful clinical monitoring of patients with HCV-related CV is mandatory in all cases, with particular attention to neoplastic complications.

Key words
Cryoglobulinemia, cryoglobulinemic vasculitis, hepatitis C virus.

Please address correspondence to: Prof. Clodoveo Ferri, MD, Reumatologia, Universitá di Modena e Reggio Emilia, Policlinico di Modena, Via del Pozzo no. 71, 41100 Modena, Italy.
E-mail: clferri@unimo.it