Definition: Cryoglobulinemic vasculitis (CV) is an immune-complex-mediated systemic vasculitis; its histopathological hallmark is the leukocytoclastic vasculitis involving small-sized vessels.Clinical features: Besides the typical clinical triad - purpura, weakness, arthralgias -, the most frequent manifestations of CV are peripheral neuropathy, hepatitis, glomerulonephritis, Raynaud's phenomenon, sicca syndrome, and skin ulcers (Table). Moreover, in a limited but significant percentage of individuals (10-15%) the disease can be complicated by a malignancy, i.e. B-cell lymphoma, and less frequently hepatocellular carcinoma or thyroid cancer.CV and HCV infection: A striking association between CV and hepatitis C virus (HCV) infection has been established by means of clinico-epidemiological and laboratory studies. Due to its multiform clinico-pathological features (Table), CV can be regarded as a crossing road between autoimmune disorders and malignancies (B-cell lymphomas, liver and thyroid cancer). On these bases, a pathogenetic link among HCV and other autoimmune-lymphoproliferative disorders has been also investigated; namely, Sjogren's syndrome, polyarthritis, glomerulonephritis, endocrine disorders, B-cell lymphomas, etc. There is a great geographical etherogeneity in the prevalence of different HCV-related diseases, suggesting a possible contribution of other unknown environmental and/or genetic co-factors.Pathogenesis: HCV is a lymphotropic virus; the presence of active or latent viral replication in the peripheral lymphocytes may explain the B-lymphocyte proliferation observed in HCV-related CV. Given the biological properties of HCV, viral genomic sequences cannot be integrated into the host genome. HCV could trigger the immunological alterations only indirectly by exerting a chronic stimulus to the immune system through viral proteins (E2, core, NS3, NS4, and NS5A), HCV-induced autoantigens and/or molecular mimicry phenomena. In particular, 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. In this context the T(14;18) translocation, demonstrated in a significantly high percentage of HCV-related CV patients, leads to the activation of anti-apoptotic Bcl-2 protoncogene responsible for extended B-cell survival. Consequently, B-lymphocyte expansion may produce a variety of autoantibodies and immune-complexes, including mixed cryoglobulins.Prognosis: Patients with CV show a relatively benign clinical course in over 50% of cases; however, the cumulative 10th year survival is significantly worse if compared to general population (56.3 vs 93.4%; p<.001). In addition, significantly lower survival rates are observed in males and in subjects with renal involvement.Treatment: 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. Finally, a careful clinical monitoring of patients with CV is mandatory in all cases, with particular attention to neoplastic complications.References: 1. Gorevic PD, Frangione B. Mixed cryoglobulinemia cross-reactive idiotypes: implication for relationship of MC to rheumatic and lymphoproliferative diseases.