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Franco Dammacco - One of the best experts on this subject based on the ideXlab platform.
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Clinical practice: hepatitis C virus infection, cryoglobulinemia and Cryoglobulinemic Vasculitis
Clinical and Experimental Medicine, 2019Co-Authors: Franco Dammacco, Sabino Russi, Gianfranco Lauletta, Patrizia Leone, Marco Tucci, Carlo Manno, Salvatore Monaco, Sergio Ferrari, Angelo Vacca, Vito RacanelliAbstract:Cryoglobulins are circulating immunoglobulins that reversibly precipitate at temperatures below 37 °C. Type-II cryoglobulins consist of monoclonal IgM/polyclonal IgG immune complexes (ICs), whereas in type-III cryoglobulins both IgM and IgG are polyclonal. The clinical condition resulting from the presence of cryoglobulins in the blood is called mixed cryoglobulinemia (MC), which can be asymptomatic or manifest as Cryoglobulinemic Vasculitis (CV). Type-I cryoglobulins, consisting of a single monoclonal isotype, are detected in patients with lymphoproliferative disorders. It is now established that > 90% of MCs are associated with HCV infection. Clinically, the spectrum of symptoms may range in severity from occasional purpuric eruptions to life-threatening features. In addition to the development of liver cirrhosis and hepatocellular carcinoma, the possible progression of HCV-positive CV patients to B-cell non-Hodgkin lymphoma (B-NHL) has been reported. The pathogenetic role played by HCV infection in the onset of B-NHL is suggested by regression of the latter following the achievement of a sustained virologic response (SVR). For several years, interferon-α alone or combined with ribavirin has been the standard of care. However, the rates of clinical, biochemical, and virologic responses have been low, and the occurrence of relapse frequent. The addition of rituximab has resulted in a higher rate of responses. With the advent of direct-acting antiviral agents, SVR has been achieved in ~ 95% of CV patients. However, in a minority of patients, despite SVR, CV may persist or reappear over variable lengths of time from the completion of therapy. The eventual appearance of B-NHL is also possible.
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The expanding spectrum of HCV-related Cryoglobulinemic Vasculitis: a narrative review
Clinical and Experimental Medicine, 2016Co-Authors: Franco Dammacco, Sabino Russi, Vito Racanelli, Domenico SansonnoAbstract:Cryoglobulinemic Vasculitis (CV) is a small-to-medium-vessel Vasculitis that appears in 10–15 % of patients chronically infected with hepatitis C virus (HCV). The classic symptom triad of CV, purpura/asthenia/arthralgia, is accompanied by clinical features that include glomerulonephritis, neuropathy, interstitial pneumonitis, and cardiomyopathy, ranging in their severity from mild to life threatening. The risk of developing non-Hodgkin lymphoma is also higher. The cumulative 10-year survival rate of CV patients is significantly lower than in the age- and sex-matched general population, with death typically caused by nephropathy, malignancies, liver involvement, and severe infections. Unfailing serological stigmata include both a cryoglobulin IgM fraction with rheumatoid factor activity and decreased complement C4 levels. On peripheral B cells, the expression of the CD81 B cell receptor is reduced while that of the CD19 receptor is increased. A monoclonal B cell lymphocytosis develops in almost one-third of patients. HCV-related proteins (but not HCV-RNA genomic sequences) can be detected on biopsy samples by immunofluorescence and immunohistochemistry and involve the vessel lumen, vessel walls, and the perivascular spaces of the skin, kidney, and peripheral nerves, supporting the pathogenetic role of HCV in the onset of a widespread microVasculitis. Based on the demonstration of HCV infection in the large majority of CV patients, a therapeutic regimen consisting of once-weekly pegylated interferon-α and the daily administration of ribavirin results in a sustained virologic response in ~50 % of patients. In those with refractory and relapsing disease, addition of the anti-CD20 monoclonal antibody rituximab has significantly increased the overall response rates. The extension to CV of latest-generation direct-acting antivirals, strikingly successful in non-CV HCV-positive patients, has yielded high complete response rates according to the few studies published thus far.
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hcv related Cryoglobulinemic Vasculitis an overview
2016Co-Authors: Franco Dammacco, Sabino Russi, Domenico SansonnoAbstract:Cryoglobulinemic Vasculitis (CV) is a small and medium-size Vasculitis characterized by the occurrence in the serum of reversibly precipitating proteins, named cryoglobulins and immunochemically formed by an IgM component (monoclonal or polyclonal) with rheumatoid factor activity and a polyclonal IgG component (mixed cryoglobulins). CV is almost invariably associated to chronic HCV infection. In addition to the typical purpura/asthenia/arthralgia syndrome, the pleomorphic clinical picture often includes membrano-proliferative glomerulonephritis and motor-sensory axonopathy. Hemorrhagic alveolitis, gastrointestinal Vasculitis, heart failure and hyperviscosity syndrome are less frequently observed. The amount of cryoprecipitate, named cryocrit, is not strictly related to the clinical severity of CV and to the viral load. Rheumatoid factor activity and low levels of the complement C4 (sometimes also of C3 and CH50) are unfailing serological abnormalities. The pathogenetic mechanism of CV is still incompletely defined, but it can be essentially ascribed to the formation of HCV particles/IgG/IgM macromolecular complexes that are good acceptors of C1q and can therefore bind to the C1q receptors on the endothelial cells. This would eventually trigger the onset of a leukocytoclastic Vasculitis. Although with wide geographic variations, CV can progress to non-Hodgkin lymphoma (NHL), possibly through an impaired regulatory control of B-cell growth. In Italy, approximately 5 % of B-cell NHLs seem to be HCV-related. Therapy of CV should be adapted to each patient’s condition. Low daily doses of corticosteroids can mitigate arthralgias and possibly prevent flares, but their long-term administration should be avoided for their inevitable side effects. Pulsed intravenous infusions of corticosteroids can prevent organ damage in the course of severe Vasculitis flares. High rates of sustained virologic responses can be achieved with the use of the new interferon-free, all-oral direct acting antiviral agents. In patients with refractory/relapsing or with severely active CV, characterized by B-cell clonal expansion, a B-cell depleting therapy with rituximab often results in a satisfactory control of clinical features, although the viral load may sometimes transiently increase. Low-grade and indolent HCV-related NHLs have been found to undergo complete or partial remission following anti-HCV therapy. Finally, double filtration plasmapheresis can contribute to the improvement and possibly healing of chronic ulcers on the legs.
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thymic stromal lymphopoietin in hepatitis c virus related Cryoglobulinemic Vasculitis gene expression level and protein distribution
Arthritis Research & Therapy, 2015Co-Authors: Domenico Sansonno, Sabino Russi, Silvia Sansonno, Fabio Pavone, Franco DammaccoAbstract:Introduction: Hepatitis C virus (HCV) infection can be detected in virtually all patients with Cryoglobulinemic Vasculitis (CV). Among its many effects, the virus is able to stimulate the production of thymic stromal lymphopoietin (TSLP) by infected hepatocytes. In this study, we assessed the systemic levels and tissue distribution of TSLP in 60 chronically HCV-infected patients, 36 with and 24 without CV. Methods: Serum TSLP levels were measured by an enzyme-linked immunosorbent assay (ELISA) method. TSLP mRNA was assessed in patient samples by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). TSLP protein in liver and skin biopsy samples was revealed by indirect immunofluorescence. All other methods were carried out according to standardized procedures. Results: Serum TSLP levels were significantly higher in patients with than in those without CV and in healthy individuals. Higher TSLP levels paralleled specific mRNA expression and the up-regulation of TSLP protein in liver tissue. Compared with non-CV patients, higher TSLP levels in CV were accompanied by a higher frequency of circulating mono/oligoclonal B-cell expansions (8% vs. 92%, p < 0.0001) and a higher number of peripheral CD20 + B-cells (10.3% vs. 15.5% p = 0.04). In addition, TSLP mRNA expression in the liver of CV patients was lower than in their correspondent skin tissue and paralleled specific immune deposits of TSLP protein in keratinocytes. Conclusion: Overall, this study shows that TSLP secreted by hepatocytes and keratinocytes of HCV-infected patients with CV is involved in the pathogenesis of Vasculitis and may possibly support the therapeutic use of TSLP-targeted monoclonal antibodies.
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thymic stromal lymphopoietin in hepatitis c virus related Cryoglobulinemic Vasculitis gene expression level and protein distribution
Arthritis Research & Therapy, 2015Co-Authors: Domenico Sansonno, Sabino Russi, Silvia Sansonno, Fabio Pavone, Franco DammaccoAbstract:Hepatitis C virus (HCV) infection can be detected in virtually all patients with Cryoglobulinemic Vasculitis (CV). Among its many effects, the virus is able to stimulate the production of thymic stromal lymphopoietin (TSLP) by infected hepatocytes. In this study, we assessed the systemic levels and tissue distribution of TSLP in 60 chronically HCV-infected patients, 36 with and 24 without CV. Serum TSLP levels were measured by an enzyme-linked immunosorbent assay (ELISA) method. TSLP mRNA was assessed in patient samples by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). TSLP protein in liver and skin biopsy samples was revealed by indirect immunofluorescence. All other methods were carried out according to standardized procedures. Serum TSLP levels were significantly higher in patients with than in those without CV and in healthy individuals. Higher TSLP levels paralleled specific mRNA expression and the up-regulation of TSLP protein in liver tissue. Compared with non-CV patients, higher TSLP levels in CV were accompanied by a higher frequency of circulating mono/oligoclonal B-cell expansions (8% vs. 92%, p < 0.0001) and a higher number of peripheral CD20+ B-cells (10.3% vs. 15.5% p = 0.04). In addition, TSLP mRNA expression in the liver of CV patients was lower than in their correspondent skin tissue and paralleled specific immune deposits of TSLP protein in keratinocytes. Overall, this study shows that TSLP secreted by hepatocytes and keratinocytes of HCV-infected patients with CV is involved in the pathogenesis of Vasculitis and may possibly support the therapeutic use of TSLP-targeted monoclonal antibodies.
Domenico Sansonno - One of the best experts on this subject based on the ideXlab platform.
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The expanding spectrum of HCV-related Cryoglobulinemic Vasculitis: a narrative review
Clinical and Experimental Medicine, 2016Co-Authors: Franco Dammacco, Sabino Russi, Vito Racanelli, Domenico SansonnoAbstract:Cryoglobulinemic Vasculitis (CV) is a small-to-medium-vessel Vasculitis that appears in 10–15 % of patients chronically infected with hepatitis C virus (HCV). The classic symptom triad of CV, purpura/asthenia/arthralgia, is accompanied by clinical features that include glomerulonephritis, neuropathy, interstitial pneumonitis, and cardiomyopathy, ranging in their severity from mild to life threatening. The risk of developing non-Hodgkin lymphoma is also higher. The cumulative 10-year survival rate of CV patients is significantly lower than in the age- and sex-matched general population, with death typically caused by nephropathy, malignancies, liver involvement, and severe infections. Unfailing serological stigmata include both a cryoglobulin IgM fraction with rheumatoid factor activity and decreased complement C4 levels. On peripheral B cells, the expression of the CD81 B cell receptor is reduced while that of the CD19 receptor is increased. A monoclonal B cell lymphocytosis develops in almost one-third of patients. HCV-related proteins (but not HCV-RNA genomic sequences) can be detected on biopsy samples by immunofluorescence and immunohistochemistry and involve the vessel lumen, vessel walls, and the perivascular spaces of the skin, kidney, and peripheral nerves, supporting the pathogenetic role of HCV in the onset of a widespread microVasculitis. Based on the demonstration of HCV infection in the large majority of CV patients, a therapeutic regimen consisting of once-weekly pegylated interferon-α and the daily administration of ribavirin results in a sustained virologic response in ~50 % of patients. In those with refractory and relapsing disease, addition of the anti-CD20 monoclonal antibody rituximab has significantly increased the overall response rates. The extension to CV of latest-generation direct-acting antivirals, strikingly successful in non-CV HCV-positive patients, has yielded high complete response rates according to the few studies published thus far.
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hcv related Cryoglobulinemic Vasculitis an overview
2016Co-Authors: Franco Dammacco, Sabino Russi, Domenico SansonnoAbstract:Cryoglobulinemic Vasculitis (CV) is a small and medium-size Vasculitis characterized by the occurrence in the serum of reversibly precipitating proteins, named cryoglobulins and immunochemically formed by an IgM component (monoclonal or polyclonal) with rheumatoid factor activity and a polyclonal IgG component (mixed cryoglobulins). CV is almost invariably associated to chronic HCV infection. In addition to the typical purpura/asthenia/arthralgia syndrome, the pleomorphic clinical picture often includes membrano-proliferative glomerulonephritis and motor-sensory axonopathy. Hemorrhagic alveolitis, gastrointestinal Vasculitis, heart failure and hyperviscosity syndrome are less frequently observed. The amount of cryoprecipitate, named cryocrit, is not strictly related to the clinical severity of CV and to the viral load. Rheumatoid factor activity and low levels of the complement C4 (sometimes also of C3 and CH50) are unfailing serological abnormalities. The pathogenetic mechanism of CV is still incompletely defined, but it can be essentially ascribed to the formation of HCV particles/IgG/IgM macromolecular complexes that are good acceptors of C1q and can therefore bind to the C1q receptors on the endothelial cells. This would eventually trigger the onset of a leukocytoclastic Vasculitis. Although with wide geographic variations, CV can progress to non-Hodgkin lymphoma (NHL), possibly through an impaired regulatory control of B-cell growth. In Italy, approximately 5 % of B-cell NHLs seem to be HCV-related. Therapy of CV should be adapted to each patient’s condition. Low daily doses of corticosteroids can mitigate arthralgias and possibly prevent flares, but their long-term administration should be avoided for their inevitable side effects. Pulsed intravenous infusions of corticosteroids can prevent organ damage in the course of severe Vasculitis flares. High rates of sustained virologic responses can be achieved with the use of the new interferon-free, all-oral direct acting antiviral agents. In patients with refractory/relapsing or with severely active CV, characterized by B-cell clonal expansion, a B-cell depleting therapy with rituximab often results in a satisfactory control of clinical features, although the viral load may sometimes transiently increase. Low-grade and indolent HCV-related NHLs have been found to undergo complete or partial remission following anti-HCV therapy. Finally, double filtration plasmapheresis can contribute to the improvement and possibly healing of chronic ulcers on the legs.
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thymic stromal lymphopoietin in hepatitis c virus related Cryoglobulinemic Vasculitis gene expression level and protein distribution
Arthritis Research & Therapy, 2015Co-Authors: Domenico Sansonno, Sabino Russi, Silvia Sansonno, Fabio Pavone, Franco DammaccoAbstract:Introduction: Hepatitis C virus (HCV) infection can be detected in virtually all patients with Cryoglobulinemic Vasculitis (CV). Among its many effects, the virus is able to stimulate the production of thymic stromal lymphopoietin (TSLP) by infected hepatocytes. In this study, we assessed the systemic levels and tissue distribution of TSLP in 60 chronically HCV-infected patients, 36 with and 24 without CV. Methods: Serum TSLP levels were measured by an enzyme-linked immunosorbent assay (ELISA) method. TSLP mRNA was assessed in patient samples by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). TSLP protein in liver and skin biopsy samples was revealed by indirect immunofluorescence. All other methods were carried out according to standardized procedures. Results: Serum TSLP levels were significantly higher in patients with than in those without CV and in healthy individuals. Higher TSLP levels paralleled specific mRNA expression and the up-regulation of TSLP protein in liver tissue. Compared with non-CV patients, higher TSLP levels in CV were accompanied by a higher frequency of circulating mono/oligoclonal B-cell expansions (8% vs. 92%, p < 0.0001) and a higher number of peripheral CD20 + B-cells (10.3% vs. 15.5% p = 0.04). In addition, TSLP mRNA expression in the liver of CV patients was lower than in their correspondent skin tissue and paralleled specific immune deposits of TSLP protein in keratinocytes. Conclusion: Overall, this study shows that TSLP secreted by hepatocytes and keratinocytes of HCV-infected patients with CV is involved in the pathogenesis of Vasculitis and may possibly support the therapeutic use of TSLP-targeted monoclonal antibodies.
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thymic stromal lymphopoietin in hepatitis c virus related Cryoglobulinemic Vasculitis gene expression level and protein distribution
Arthritis Research & Therapy, 2015Co-Authors: Domenico Sansonno, Sabino Russi, Silvia Sansonno, Fabio Pavone, Franco DammaccoAbstract:Hepatitis C virus (HCV) infection can be detected in virtually all patients with Cryoglobulinemic Vasculitis (CV). Among its many effects, the virus is able to stimulate the production of thymic stromal lymphopoietin (TSLP) by infected hepatocytes. In this study, we assessed the systemic levels and tissue distribution of TSLP in 60 chronically HCV-infected patients, 36 with and 24 without CV. Serum TSLP levels were measured by an enzyme-linked immunosorbent assay (ELISA) method. TSLP mRNA was assessed in patient samples by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). TSLP protein in liver and skin biopsy samples was revealed by indirect immunofluorescence. All other methods were carried out according to standardized procedures. Serum TSLP levels were significantly higher in patients with than in those without CV and in healthy individuals. Higher TSLP levels paralleled specific mRNA expression and the up-regulation of TSLP protein in liver tissue. Compared with non-CV patients, higher TSLP levels in CV were accompanied by a higher frequency of circulating mono/oligoclonal B-cell expansions (8% vs. 92%, p < 0.0001) and a higher number of peripheral CD20+ B-cells (10.3% vs. 15.5% p = 0.04). In addition, TSLP mRNA expression in the liver of CV patients was lower than in their correspondent skin tissue and paralleled specific immune deposits of TSLP protein in keratinocytes. Overall, this study shows that TSLP secreted by hepatocytes and keratinocytes of HCV-infected patients with CV is involved in the pathogenesis of Vasculitis and may possibly support the therapeutic use of TSLP-targeted monoclonal antibodies.
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Interleukin 28B gene polymorphisms in hepatitis C virus-related Cryoglobulinemic Vasculitis.
The Journal of rheumatology, 2013Co-Authors: Domenico Sansonno, Sabino Russi, Fabio Pavone, Gaetano Serviddio, Vincenza Conteduca, Giovanna D'andrea, Loredana Sansonno, Gianfranco Lauletta, Maria Addolorata Mariggiò, Franco DammaccoAbstract:Objective. Single-nucleotide polymorphisms (SNP) in the interleukin 28B (IL-28B) gene region are strongly predictive of the response of infected patients to antiviral therapy for hepatitis C virus (HCV). We sought to determine the prevalence of SNP IL-28B rs12979860 C/C and non-C/C (C/T plus T/T) genotypes in HCV-related Cryoglobulinemic Vasculitis (CV), as compared with HCV-positive patients without CV. We also searched for their association with peculiar clinical manifestations of CV and potential influence on the complete response (virological, molecular, and immunological) to the therapy. Methods. The study cohort comprised 159 and 172 HCV-infected patients with and without CV, respectively, prospectively followed starting from 1990. SNP rs12979860 genotyping was performed by Taq-Man allelic discrimination. In 106 patients (66.6%) with CV, the profile of circulating B cell clonalities was determined as well. All patients with CV were treated with pegylated interferon-α/ribavirin-based antiviral therapy. Results. The T/T IL-28B genotype was more common in patients with CV than in those without (17% vs 8.1%, p = 0.02). In patients with CV, compared with non-C/C variants, the IL-28B C/C genotype was associated with a higher rate of complete response (52.6% vs 39.2%, p = 0.13), whereas a treatment response of 61.4% was demonstrated when solely virological response was considered (p = 0.008). A higher frequency of expanded B cell clonalities in the circulation (84.2% vs 55.9%; p = 0.005), kidney involvement (21% vs 2.9%; p = 0.003), and B cell non-Hodgkin lymphoma (17.5% vs 6.8%; p = 0.048), were also observed. Conclusion. In HCV-positive patients with CV, the IL-28B C/C genotype is distinguished biologically by a higher frequency of restriction of B cell response and clinically by a higher risk of Cryoglobulinemic nephropathy and B cell malignancies, while acting as an independent predictor of a sustained virological response to antiviral therapy. In addition, we found that IL-28B T/T variant was more prevalent in patients with CV than in those without.
Sabino Russi - One of the best experts on this subject based on the ideXlab platform.
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Clinical practice: hepatitis C virus infection, cryoglobulinemia and Cryoglobulinemic Vasculitis
Clinical and Experimental Medicine, 2019Co-Authors: Franco Dammacco, Sabino Russi, Gianfranco Lauletta, Patrizia Leone, Marco Tucci, Carlo Manno, Salvatore Monaco, Sergio Ferrari, Angelo Vacca, Vito RacanelliAbstract:Cryoglobulins are circulating immunoglobulins that reversibly precipitate at temperatures below 37 °C. Type-II cryoglobulins consist of monoclonal IgM/polyclonal IgG immune complexes (ICs), whereas in type-III cryoglobulins both IgM and IgG are polyclonal. The clinical condition resulting from the presence of cryoglobulins in the blood is called mixed cryoglobulinemia (MC), which can be asymptomatic or manifest as Cryoglobulinemic Vasculitis (CV). Type-I cryoglobulins, consisting of a single monoclonal isotype, are detected in patients with lymphoproliferative disorders. It is now established that > 90% of MCs are associated with HCV infection. Clinically, the spectrum of symptoms may range in severity from occasional purpuric eruptions to life-threatening features. In addition to the development of liver cirrhosis and hepatocellular carcinoma, the possible progression of HCV-positive CV patients to B-cell non-Hodgkin lymphoma (B-NHL) has been reported. The pathogenetic role played by HCV infection in the onset of B-NHL is suggested by regression of the latter following the achievement of a sustained virologic response (SVR). For several years, interferon-α alone or combined with ribavirin has been the standard of care. However, the rates of clinical, biochemical, and virologic responses have been low, and the occurrence of relapse frequent. The addition of rituximab has resulted in a higher rate of responses. With the advent of direct-acting antiviral agents, SVR has been achieved in ~ 95% of CV patients. However, in a minority of patients, despite SVR, CV may persist or reappear over variable lengths of time from the completion of therapy. The eventual appearance of B-NHL is also possible.
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The expanding spectrum of HCV-related Cryoglobulinemic Vasculitis: a narrative review
Clinical and Experimental Medicine, 2016Co-Authors: Franco Dammacco, Sabino Russi, Vito Racanelli, Domenico SansonnoAbstract:Cryoglobulinemic Vasculitis (CV) is a small-to-medium-vessel Vasculitis that appears in 10–15 % of patients chronically infected with hepatitis C virus (HCV). The classic symptom triad of CV, purpura/asthenia/arthralgia, is accompanied by clinical features that include glomerulonephritis, neuropathy, interstitial pneumonitis, and cardiomyopathy, ranging in their severity from mild to life threatening. The risk of developing non-Hodgkin lymphoma is also higher. The cumulative 10-year survival rate of CV patients is significantly lower than in the age- and sex-matched general population, with death typically caused by nephropathy, malignancies, liver involvement, and severe infections. Unfailing serological stigmata include both a cryoglobulin IgM fraction with rheumatoid factor activity and decreased complement C4 levels. On peripheral B cells, the expression of the CD81 B cell receptor is reduced while that of the CD19 receptor is increased. A monoclonal B cell lymphocytosis develops in almost one-third of patients. HCV-related proteins (but not HCV-RNA genomic sequences) can be detected on biopsy samples by immunofluorescence and immunohistochemistry and involve the vessel lumen, vessel walls, and the perivascular spaces of the skin, kidney, and peripheral nerves, supporting the pathogenetic role of HCV in the onset of a widespread microVasculitis. Based on the demonstration of HCV infection in the large majority of CV patients, a therapeutic regimen consisting of once-weekly pegylated interferon-α and the daily administration of ribavirin results in a sustained virologic response in ~50 % of patients. In those with refractory and relapsing disease, addition of the anti-CD20 monoclonal antibody rituximab has significantly increased the overall response rates. The extension to CV of latest-generation direct-acting antivirals, strikingly successful in non-CV HCV-positive patients, has yielded high complete response rates according to the few studies published thus far.
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hcv related Cryoglobulinemic Vasculitis an overview
2016Co-Authors: Franco Dammacco, Sabino Russi, Domenico SansonnoAbstract:Cryoglobulinemic Vasculitis (CV) is a small and medium-size Vasculitis characterized by the occurrence in the serum of reversibly precipitating proteins, named cryoglobulins and immunochemically formed by an IgM component (monoclonal or polyclonal) with rheumatoid factor activity and a polyclonal IgG component (mixed cryoglobulins). CV is almost invariably associated to chronic HCV infection. In addition to the typical purpura/asthenia/arthralgia syndrome, the pleomorphic clinical picture often includes membrano-proliferative glomerulonephritis and motor-sensory axonopathy. Hemorrhagic alveolitis, gastrointestinal Vasculitis, heart failure and hyperviscosity syndrome are less frequently observed. The amount of cryoprecipitate, named cryocrit, is not strictly related to the clinical severity of CV and to the viral load. Rheumatoid factor activity and low levels of the complement C4 (sometimes also of C3 and CH50) are unfailing serological abnormalities. The pathogenetic mechanism of CV is still incompletely defined, but it can be essentially ascribed to the formation of HCV particles/IgG/IgM macromolecular complexes that are good acceptors of C1q and can therefore bind to the C1q receptors on the endothelial cells. This would eventually trigger the onset of a leukocytoclastic Vasculitis. Although with wide geographic variations, CV can progress to non-Hodgkin lymphoma (NHL), possibly through an impaired regulatory control of B-cell growth. In Italy, approximately 5 % of B-cell NHLs seem to be HCV-related. Therapy of CV should be adapted to each patient’s condition. Low daily doses of corticosteroids can mitigate arthralgias and possibly prevent flares, but their long-term administration should be avoided for their inevitable side effects. Pulsed intravenous infusions of corticosteroids can prevent organ damage in the course of severe Vasculitis flares. High rates of sustained virologic responses can be achieved with the use of the new interferon-free, all-oral direct acting antiviral agents. In patients with refractory/relapsing or with severely active CV, characterized by B-cell clonal expansion, a B-cell depleting therapy with rituximab often results in a satisfactory control of clinical features, although the viral load may sometimes transiently increase. Low-grade and indolent HCV-related NHLs have been found to undergo complete or partial remission following anti-HCV therapy. Finally, double filtration plasmapheresis can contribute to the improvement and possibly healing of chronic ulcers on the legs.
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thymic stromal lymphopoietin in hepatitis c virus related Cryoglobulinemic Vasculitis gene expression level and protein distribution
Arthritis Research & Therapy, 2015Co-Authors: Domenico Sansonno, Sabino Russi, Silvia Sansonno, Fabio Pavone, Franco DammaccoAbstract:Introduction: Hepatitis C virus (HCV) infection can be detected in virtually all patients with Cryoglobulinemic Vasculitis (CV). Among its many effects, the virus is able to stimulate the production of thymic stromal lymphopoietin (TSLP) by infected hepatocytes. In this study, we assessed the systemic levels and tissue distribution of TSLP in 60 chronically HCV-infected patients, 36 with and 24 without CV. Methods: Serum TSLP levels were measured by an enzyme-linked immunosorbent assay (ELISA) method. TSLP mRNA was assessed in patient samples by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). TSLP protein in liver and skin biopsy samples was revealed by indirect immunofluorescence. All other methods were carried out according to standardized procedures. Results: Serum TSLP levels were significantly higher in patients with than in those without CV and in healthy individuals. Higher TSLP levels paralleled specific mRNA expression and the up-regulation of TSLP protein in liver tissue. Compared with non-CV patients, higher TSLP levels in CV were accompanied by a higher frequency of circulating mono/oligoclonal B-cell expansions (8% vs. 92%, p < 0.0001) and a higher number of peripheral CD20 + B-cells (10.3% vs. 15.5% p = 0.04). In addition, TSLP mRNA expression in the liver of CV patients was lower than in their correspondent skin tissue and paralleled specific immune deposits of TSLP protein in keratinocytes. Conclusion: Overall, this study shows that TSLP secreted by hepatocytes and keratinocytes of HCV-infected patients with CV is involved in the pathogenesis of Vasculitis and may possibly support the therapeutic use of TSLP-targeted monoclonal antibodies.
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thymic stromal lymphopoietin in hepatitis c virus related Cryoglobulinemic Vasculitis gene expression level and protein distribution
Arthritis Research & Therapy, 2015Co-Authors: Domenico Sansonno, Sabino Russi, Silvia Sansonno, Fabio Pavone, Franco DammaccoAbstract:Hepatitis C virus (HCV) infection can be detected in virtually all patients with Cryoglobulinemic Vasculitis (CV). Among its many effects, the virus is able to stimulate the production of thymic stromal lymphopoietin (TSLP) by infected hepatocytes. In this study, we assessed the systemic levels and tissue distribution of TSLP in 60 chronically HCV-infected patients, 36 with and 24 without CV. Serum TSLP levels were measured by an enzyme-linked immunosorbent assay (ELISA) method. TSLP mRNA was assessed in patient samples by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). TSLP protein in liver and skin biopsy samples was revealed by indirect immunofluorescence. All other methods were carried out according to standardized procedures. Serum TSLP levels were significantly higher in patients with than in those without CV and in healthy individuals. Higher TSLP levels paralleled specific mRNA expression and the up-regulation of TSLP protein in liver tissue. Compared with non-CV patients, higher TSLP levels in CV were accompanied by a higher frequency of circulating mono/oligoclonal B-cell expansions (8% vs. 92%, p < 0.0001) and a higher number of peripheral CD20+ B-cells (10.3% vs. 15.5% p = 0.04). In addition, TSLP mRNA expression in the liver of CV patients was lower than in their correspondent skin tissue and paralleled specific immune deposits of TSLP protein in keratinocytes. Overall, this study shows that TSLP secreted by hepatocytes and keratinocytes of HCV-infected patients with CV is involved in the pathogenesis of Vasculitis and may possibly support the therapeutic use of TSLP-targeted monoclonal antibodies.
Clodoveo Ferri - One of the best experts on this subject based on the ideXlab platform.
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Cryoglobulinemic Vasculitis and skin ulcers our therapeutic strategy and review of the literature
Seminars in Arthritis and Rheumatism, 2015Co-Authors: Dilia Giuggioli, Andreina Teresa Manfredi, Marco Sebastiani, Federica Lumetti, Clodoveo FerriAbstract:Abstract Objective Cryoglobulinemic Vasculitis (CV) involving small- and medium-sized vessels is very frequently associated with hepatitis C virus and may be responsible for multiple organ involvement and skin ulcers (SU). Skin ulcers are often non-healing cutaneous lesions, possibly complicated by local infection and gangrene; they may severely affect the patients׳ quality of life and the overall prognosis. Therefore, the treatment of Cryoglobulinemic SU is particularly challenging in the clinical practice. The present work evaluated the prevalence and correlations of Cryoglobulinemic SU with other clinico-epidemiological features of CV; moreover, our long-term experience with the management strategies of these cutaneous lesions was compared with the world literature on this topic. Methods The study included 126 CV patients (24 male and 102 female, aged 69 ± 11.2 SD years, disease duration 7 ± 6.9 SD years), followed at our Rheumatology Unit during the past decade. All patients were carefully evaluated regarding the entire Cryoglobulinemic syndrome with particular concern for clinical characteristics and treatment of SU. Results Among 126 CV patients, 36 individuals (29%) experienced at least one episode of SU, more commonly localized at the lower limbs. Patients with complicating SU showed significantly higher percentage of purpuric manifestations ( p p p p = 0.019). Therapeutic approach to SU included both systemic (immunosuppressors, corticosteroids, and/or plasma exchange) and local treatments. Local treatments consisted of sharp or surgical debridement as well as interactive dressing according to the condition of wound bed, perilesional skin, and the possible presence of infection, detected in 29 of 36 (81%) individuals in our Rheumatology unit. All patients underwent analgesic treatment for SU-related background pain as well as procedural pain, which was critical for an effective local SU management. The large majority of patients with SU healed at a variable time interval according to the severity of the single lesion; only five patients with very severe, non-healing SU needed amputation. The updated review of the literature revealed the presence of SU in around a quarter of CV patients. Among systemic treatments, the anti-CD20 monoclonal antibody rituximab represents one of the most effective and frequently employed therapies; however, the available data focusing on local therapeutic approach are generally limited to anecdotal observations. Conclusions Overall, the treatment of Cryoglobulinemic SU should be tailored to the single patient׳s conditions using combined systemic and local treatments; lesional sharp debridement and interactive dressing as well as procedural pain management were decisive, particularly for more severe, non-healing cutaneous lesions.
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systemic sclerosis and cryoglobulinemia our experience with overlapping syndrome of scleroderma and severe Cryoglobulinemic Vasculitis and review of the literature
Autoimmunity Reviews, 2013Co-Authors: Dilia Giuggioli, Andreina Teresa Manfredi, Michele Colaci, Carlo Umberto Manzini, Alessandro Antonelli, Clodoveo FerriAbstract:Abstract Objective Systemic sclerosis (SSc) is an immune-mediated disorder characterized by multiple organ fibrotic alterations and diffuse microangiopathy. The SSc can be associated with other connective tissue diseases and less frequently with systemic vasculitides, including Cryoglobulinemic Vasculitis (CV). The aim of the present study was to investigate the prevalence of CV in a large series of SSc patients. Methods The presence of serum cryoglobulins was detected in 246 SSc patients (24 M and 222 F, age 61 ± 13.5 SD years, disease duration 9.3 ± 6.7 SD years); the observed clinico-serological findings, in particular the presence of SSc–CV overlapping syndrome, were carefully analyzed and compared with previous data reported in the literature. Results The presence of circulating cryoglobulins was found in 7/246 (2.8%) of SSc patients; namely, 2 subjects only trace amounts of cryoglobulins, while 5 (2%) showed mixed cryoglobulinemia (type II, IgG-IgMk), low C4, rheumatoid factor seropositivity, and hepatitis C virus infection. Among SSc patients with serum mixed cryoglobulins, 4 (1.6%) developed a clinically overt CV, while the other one was totally asymptomatic with regard to typical vasculitic manifestations. Patients with SSc–CV overlapping syndrome had limited cutaneous SSc with serum anticentromere antibodies, pulmonary hypertension, clinico-serological features of HCV-related CV, and non-healing skin ulcers of the lower limbs. In all cases, the diagnosis of SSc preceded the clinical onset of CV, from 3 to 17 years. The treatment with rituximab was useful on skin ulcers of lower limb in 2/3 patients; however, the overall clinical outcome of the four SSc–CV patients was unusually severe: one with very severe skin ulcers complicated by gangrene required bilateral through-the knee amputation, the other three subjects died because of severe heart failure, and in two cases because of untreatable pulmonary hypertension. In the literature, the prevalence of mixed cryoglobulinemia in scleroderma patients is quite rare (range 0.3–2%); while, the association of SSc with clinically overt CV is only anecdotally described, always in the absence of HCV infection. Conclusion The SSc–CV overlapping syndrome described here is characterized by markedly severe vascular manifestations responsible for very poor prognosis; these peculiar clinical manifestations suggest a synergic activity of typical scleroderma microangiopathy and Cryoglobulinemic Vasculitis.
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hcv related Cryoglobulinemic Vasculitis an update on its etiopathogenesis and therapeutic strategies
Clinical and Experimental Rheumatology, 2003Co-Authors: Clodoveo Ferri, Dilia Giuggioli, Marco Sebastiani, Maria Teresa Mascia, M Cazzato, A L ZignegoAbstract:Cryaglobulinemic 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-lymphoproloiferative 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.
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successful treatment of type 1 Cryoglobulinemic Vasculitis with cardiac involvement
Canadian Journal of Cardiology, 2017Co-Authors: Xinxin Cao, Zhuang Tian, Lu Lin, Jian Sun, Daobin ZhouAbstract:Cryoglobulinemic Vasculitis is a rare and frequently fatal type of myocarditis. Cardiac manifestations in type 1 Cryoglobulinemic Vasculitis have never been reported to our knowledge. We report a rare case of type 1 Cryoglobulinemic Vasculitis with cardiac involvement in a patient who experienced progressive heart failure during the diagnosis. The diagnosis was made by the presence of cryoglobulins and endomyocardial biopsy results. After bortezomib-containing treatments, plasma cryoglobulin levels returned to normal, and the patient's clinical condition gradually improved.