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Hepatitis C virus (HCV) infection affects about 70 million people worldwide. HCV is responsible for both hepatitis and extra-hepatic manifestations. Chronic infection has been shown to develop in about 70% of cases and can progress to cirrhosis or hepatocellular carcinoma. Ten percent of HCV patients may develop extra-hepatic manifestations, including mixed cryoglobulinemia (MC) and non-Hodgkin lymphomas. Many studies have demonstrated that, after antiviral therapy, MC can disappear along with HCV eradication. After the introduction of the new direct antiviral agents (DAAs), the combination of pegylated interferon and ribavirin has been abandoned. Several studies on new DAAs have reported remarkable 90% to 100% eradication rates, regardless of HCV genotype. Treatment with DAAs has comparable efficacy on viral eradication in patients with MC, but definite clinical improvements of vasculitis can be observed only in half the patients. On the contrary, the regression of renal disease and lympho-proliferative disorders, induced by HCV, appears to have a lower remission rate after viral eradication with DAAs and most cases need immunosuppressive treatments. In HCV related CV, the main clinical goal must be early eradication of HCV, to avoid organ complication and manifestation of lympho-proliferative diseases. This review focuses on the role of DAAs in treatment of HCV-related cryoglobulinemic vasculitis., Competing Interests: Declaration of Competing Interest The authors have no conflict of interests to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: Some of the manifestations of mixed cryoglobulinemia syndrome (MCS) can be severe or life-threatening, and should be rapidly contained but, as the therapeutic approaches to such conditions are largely based on anecdotal data, a consensus conference was organised by the Italian Group for the Study of Cryoglobulinemia (GISC) with the aim of providing a set of recommendations based on an in-depth survey of the available data and expert opinion., Methods: The consensus panel, which included specialists working in different medical fields involved in the management of MCS patients, was first asked to divide the manifestations of MCS into severe or life-threatening conditions on the basis of their own experience, after which a complete literature review was carried out in accordance with the Cochrane guidelines for systematic reviews., Results: Therapeutic plasma exchange (TPE) was considered the elective first-line treatment in the case of life-threatening manifestations of MCS (LT-MCS) and patients with severe clinical symptoms (S-MCS) who fail to respond to (or who are ineligible for) other treatments. The data supporting the combined use of cyclophosphamide and TPE were considered limited and inconclusive. High-dose pulsed glucocorticoid (GCS) therapy can be considered the first-line treatment of severe MCS, generally in association with TPE. Rituximab (RTX)-based treatments should be considered in patients with skin ulcers, peripheral neuropathy or glomerulonephritis, and in patients with persistent LT-MCS after TPE. In patients with hepatitis C virus-related MCS with S-MCS, viral eradication should be attempted as soon as a patient's condition allows the use of direct-acting antivirals., (Copyright © 2019. Published by Elsevier B.V.)

Objective: The objective of this review was to define a core set of recommendations for the treatment of HCV-associated mixed cryoglobulinemia syndrome (MCS) by combining current evidence from clinical trials and expert opinion., Methods: Expert physicians involved in studying and treating patients with MCS formulated statements after discussing the published data. Their attitudes to treatment approaches (particularly those insufficiently supported by published data) were collected before the consensus conference by means of a questionnaire, and were considered when formulating the statements., Results: An attempt at viral eradication using pegylated interferon plus ribavirin should be considered the first-line therapeutic option in patients with mild-moderate HCV-related MCS. Prolonged treatment (up to 72 weeks) may be considered in the case of virological non-responders showing clinical and laboratory improvements. Rituximab (RTX) should be considered in patients with severe vasculitis and/or skin ulcers, peripheral neuropathy or glomerulonephritis. High-dose pulsed glucocorticoid (GC) therapy is useful in severe conditions and, when necessary, can be considered in combination with RTX; on the contrary, the majority of conference participants discouraged the chronic use of low-medium GC doses. Apheresis remains the elective treatment for severe, life-threatening hyper-viscosity syndrome; its use should be limited to patients who do not respond to (or who are ineligible for) other treatments, and emergency situations. Cyclophosphamide can be considered in combination with apheresis, but the data supporting its use are scarce. Despite the limited available data, colchicine is used by many of the conference participants, particularly in patients with mild-moderate MCS refractory to other therapies. Careful monitoring of the side effects of each drug, and its effects on HCV replication and liver function tests is essential. A low-antigen-content diet can be considered as supportive treatment in all symptomatic MCS patients. Although there are no data from controlled trials, controlling pain should always be attempted by tailoring the treatment to individual patients on the basis of the guidelines used in other vasculitides., Conclusion: Although there are few controlled randomised trials of MCS treatment, increasing knowledge of its pathogenesis is opening up new frontiers. The recommendations provided may be useful as provisional guidelines for the management of MCS., (Copyright © 2011. Published by Elsevier B.V.)