Assessment of liver stiffness in patients with HCV and mixed cryoglobulinemia undergoing rituximab treatment.

INTRODUCTION: Mixed cryoglobulinemia (MC) is a HCV-related lymphoproliferative disorder generally associated with advanced liver disease. Liver stiffness has been significantly correlated with histopathological stage of fibrosis. Moreover, it was influenced by necroinflammatory activity. Rituximab (RTX) is a chimeric anti-CD20 monoclonal antibody inducing transient B lymphocytes depletion that was shown to be useful and safe in the majority of HCV MC patients, leading also to improvement of cirrhotic syndrome. Aim of this study was to evaluate the modifications of liver stiffness following RTX treatment in HCV-related MC patients. MATERIALS AND METHODS: Fourteen consecutive patients (10 F, 4 M; mean age 60.43 ± 43) with HCV-related chronic hepatitis (n = 10) or cirrhosis (n = 4) and MC, eligible for RTX treatment, were prospectively enrolled. Intravenous injection of 1 g of RTX was performed at day 0 and at day 15. Assessment of stiffness was carried out by Fibroscan(®) (Echosens, Paris-France) at baseline, 15 days after the first infusion, and at month 1, 3 and 6 after therapy. RESULTS: MC symptoms significantly improved during the study, especially during the first 3 months. Liver stiffness observed 3 months after treatment was significantly reduced when compared with pre-treatment values (p = 0.01). This difference disappeared after 6 months of follow-up. Cytofluorimetric analysis showed a decrease of CD19+ peripheral blood cells, with the nadir at month 3 after therapy and B cell compartment reconstitution after 6 months. CONCLUSION: This study, for the first time showed that RTX-treatment in HCV-related MC induces a reduction of liver stiffness that is strictly associated with the B-cell depletion

Long-term effect of HCV eradication in patients with mixed cryoglobulinemia: A prospective, controlled, open-label, cohort study

Limited data are available about the efficacy of antiviral treatment in hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC), especially concerning the long-term effects of HCV eradication. The aim of this study was to evaluate the influence of MC on the virological response and the long-term effects of viral eradication on MC. We prospectively enrolled 424 HCV+ patients belonging to the following groups: MCS-HCV (121 patients with symptomatic MC); MC-HCV (132 patients with asymptomatic MC); HCV group (158 patients without MC). Peg-IFN+RBV treatment was administered according to standard protocols. Post-treatment follow-up ranged from 35 to 124 months (mean: 92.5 months). A significant difference was observed in the rate of sustained virological response (SVR) between HCV and both MC-HCV (p=0.009) and MC-HCV+MCS-HCV (p=0.014) groups. Multivariate logistic regression analysis identified cryoglobulinemia as an independent prognostic factor of non-response. The clinical-immunological response in MCS-HCV correlated with the virological one. All patients with SVR also experienced a sustained clinical response, either complete or partial. In the majority of SVR patients all MCS symptoms persistently disappeared (36 patients, 57%); in only 2 (3%) did definite MCS persist. All virological non-responders were also clinical non-responders, in spite of a transient improvement in some cases. No evolution to lymphoma was observed. For the first time we have evaluated both the effects of IFN-based therapy on HCV patients with or without MC, and with or without symptoms, and the long-term effects of viral eradication on MC. MC was shown to be a negative prognostic factor of virological response. HCV clearance led to persistent resolution or improvement of MC syndrome, strongly suggesting the need for a next generation of highly effective antiviral drugs

Role of MicroRNA Profile Modifications in Hepatitis C Virus-Related Mixed Cryoglobulinemia

Hepatitis C virus infection is closely related to lymphoproliferative disorders (LPDs), including mixed cryoglobulinemia (MC) and some lymphomas. Modification of the expression of specific microRNAs (miRNAs) has been associated with different autoimmune diseases and/or LPDs. No data exist about the modifications in miRNA expression in HCV-associated LPDs. The aim of this study was to analyze the expression levels of a panel of miRNAs previously associated with autoimmune/LPDs in a large population of HCV patients with and without MC or non-Hodgkin’s lymphoma (NHL), to identify potential markers of evolution of HCV infection. PBMC expression of miR-Let-7d, miR-16, miR-21, miR-26b, miR-146a and miR-155 was evaluated by real-time PCR in 167 HCV patients (75 with MC [MC-HCV], 11 with HCV-associated NHL [NHL-HCV], 81 without LPD [HCV]) and in 35 healthy subjects (HS). A significant increase in miR-21 (p<0.001), miR-16 (p<0.01) and miR-155 (p<0.01) expression was detected in PBMCs from only NHL patients whereas a significant decrease in miR-26b was detected in both MC and NHL subjects (p<0.01) when compared to HS and HCV groups. A restoration of miR-26b levels was observed in the post-treatment PBMCs of 35 HCV-MC patients experiencing complete virological and clinical response following antiviral therapy. This study, for the first time, shows that specific microRNAs in PBMC from HCV patients who developed MC and/or NHL are modulated differently. The specific, reversible downregulation of miR-26b strongly suggests the key role it plays in the pathogenesis of HCV-related LPDs and its usefulness as a biomarker of the evolution of HCV infection to these disorders

Combined Treatment with Antiviral Therapy and Rituximab in Patients with Mixed Cryoglobulinemia: Review of the Literature and Report of a Case Using Direct Antiviral Agents-Based Antihepatitis C Virus Therapy

Mixed cryoglobulinemia (MC) is an autoimmune/B-cell lymphoproliferative disorder associated with Hepatitis C Virus (HCV) infection, manifesting as a systemic vasculitis. In the last decade, antiviral treatment (AT) with pegylated interferon (Peg-IFN) plus ribavirin (RBV) was considered the first therapeutic option for HCV-MC. In MC patients ineligible or not responsive to antivirals, the anti-CD20 monoclonal antibody rituximab (RTX) is effective. A combined AT plus RTX was also suggested. Since the introduction of direct acting antivirals (DAAs), few data were published about MC and no data about a combined schedule. Here, we report a complete remission of MC after a sustained virological response following a combined RTX/Peg-IFN+RBV+DAA (boceprevir) treatment and review the literature about the combined RTX/AT

Computed tomography densitometric study of anti-angiogenic effect of regorafenib in colorectal cancer liver metastasis

Regorafenib induces radiological changes in liver metastasis among patients with metastatic colorectal cancer (mCRC). The standard criteria used to evaluate solid tumor response (Response Evaluation Criteria in Solid Tumors) may be limited in assessing response to biologic agents with anti-angiogenic action

Hepatitis B virus related cryoglobulinemic vasculitis: A multicentre open label study from the Gruppo Italiano di Studio delle Crioglobulinemie - GISC

Background: Cryoglobulinemic vasculitis (CV) related to Hepatitis-B Virus (HBV) is rare and its treatmentis ill-defined.Aims: To describe clinical and treatment characteristics of HBV-related CV patients. In addition, the effi-cacy of treatment with antiviral agent nucleotide (NUC), including Entecavir, Adefovir, and Lamivudine,was explored.Methods: In four Italian centres, 17 HBV-positive CV patients (median age 56 years, range 45\u201370) wereenrolled.Results: The extrahepatic manifestations were: purpura (100%), arthralgias (71%), peripheral neuropathy(29%), chronic hepatitis (47%), liver cirrhosis (29%), and glomerulonephritis (18%). Mixed cryoglobuline-mias were type II (88%) and type III (12%). The median cryocrit was 3% (range 1\u201314), rheumatoid factor was200 U/L (range 20\u20135850), C4 was 12 mg/dl (range 2\u201331), ALT 71 U/L (range 36\u2013114). All patients wereHBsAg-positive and 80% anti-HbeAg-positive. At enrollment, they were treated with steroids (eight),Entecavir (five), Alpha-IFN (two), Adefovir and Lamivudine (one each). After NUC treatment, no diseaseprogression was observed and, in all patients, HBV-DNA became undetectable. Moreover, a regressionof purpura and a reduction of cryocrit were observed. Four patients died during therapy, two of kidneyfailure and two of liver cirrhosis.Conclusion: NUC therapy appeared to be safe and effective in CV-related HBV

HCV-related lymphatic and hepatic malignancies are associated with different microRNA expression patterns in PBMCs

HCV infection leads to chronic liver damage often evolving to Hepatocellular Carcinoma (HCC), but also promotes lymphoproliferative disorders (LPDs) such as mixed cryoglobulinemia (MC) and Non Hodgkin Lymphomas (NHL). Modified expression levels of specific microRNAs have been associated with different autoimmune/lymphoproliferative or neoplastic disorders. We previously showed a downregulation of miR-26b in HCV-related MC and NHL. In this study we analyzed the expression of a panel of microRNAs in peripheral blood mononuclear cells (PBMCs) from a large population of HCV patients with or without LPDs or HCC, in order to identify non-invasive markers of such evolutions of HCV infection. PBMCs levels of miR-Let7d, miR-16, miR-21, miR-26b, miR-146a and miR-155 were evaluated by Real Time PCR in 187 HCV patients (75 with MC [HCV-MC], 11 with HCV-related NHL [HCV-NHL], 20 with HCV-related HCC [HCV-HCC], 81 without LPD or HCC [HCV]) and in 35 healthy blood donors (HS). A significant increase of miR-21 (p&lt; 0.001) expression was detected in PBMCs from only NHL patients, while miR-155 and miR-16 were upregulated both in NHL (p&lt; 0.05) and HCC subjects (p&lt;0.001), when compared to the other groups. A similar level for miR-146a was observed in all groups, except for the HCV-HCC patients, where miR-146a resulted upregulated (p&lt;0.001). A significant decrease of miR-26b was observed in both MC and NHL subjects (p&lt;0.05) when compared to HS and HCV groups. The upregulation of miR-16 and miR-155 is consistent with their reported role as “oncogenic microRNAs” in both HCC and lymphomas, while the upregulation of miR-21 only in the HCV-NHL group confirms its specific role in hematological malignancy. Interestingly, the downregulation of miR-26b in HCV-related LPDs, but not in HCC, suggests its pathogenetic relevance and its potential use as biomarker for evolution into LPDs. Furthermore, the upregulation of miR-146a in PBMC was shown as peculiar profile of HCC patients, suggesting that this could identify an evolution to a hepatic malignancy. In conclusion, this study shows that microRNAs are differently modulated in PBMCs from HCV patients who developed LPDs, NHL or HCC and thus, they could represent clinically relevant tools, useful to discriminate between the two major HCV-related malignancies