Hepatitis B virus-infection related cryoglobulinemic vasculitis. Clinical manifestations and the effect of antiviral therapy: A review of the literature

Objective: Hepatitis B virus (HBV) infection causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Furthermore, about 20% of the patients develop extrahepatic manifestations such as cryoglobulinemic vasculitis (CV), polyarteritis nodosa, non-rheumatoid arthritis, glomerulonephritis and non-Hodgkin lymphoma. This review analyzed literature data on clinical manifestations of HBV-related CV and the impact of antiviral therapy with analoques nucleotide. Methods: A PubMed search was performed to select eligible studies in the literature, up to July 2022. Results: Some studies have analyzed clinical manifestations in HBV-related CV and have investigated the role of antiviral therapy with nucleotides analogues (NAs). Clinical manifestations of CV vary from mild to moderate (purpura, asthenia and arthralgias) to severe (leg ulcers, peripheral neuropathy, glomerulonephritis, and non-Hodking lymphoma). NAs therapy leads to suppression of HBV-DNA; therefore, it is capable of producing clinical response in the majority of patients with mild to moderate symptoms. Conclusion: Antiviral therapy with NAs is the first choice for HBV suppression and control of mild to moderate disease. In severe vasculitis (glomerulonephritis, progressive peripheral neuropathy and leg ulcers), rituximab alone or with plasma-exchange is always indicated in combination with antiviral therapy

Management of mixed cryoglobulinemia with rituximab: evidence and consensus-based recommendations from the Italian Study Group of Cryoglobulinemia (GISC)

Cryoglobulinemic vasculitis (CV) or mixed cryoglobulinemic syndrome (MCS) is a systemic small-vessel vasculitis characterized by the proliferation of B-cell clones producing pathogenic immune complexes, called cryoglobulins. It is often secondary to hepatitis C virus (HCV), autoimmune diseases, and hematological malignancies. CV usually has a mild benign clinical course, but severe organ damage and life-threatening manifestations can occur. Recently, evidence in favor of rituximab (RTX), an anti-CD 20 monoclonal antibody, is emerging in CV: nevertheless, questions upon the safety of this therapeutic approach, especially in HCV patients, are still being issued and universally accepted recommendations that can help physicians in MCS treatment are lacking. A Consensus Committee provided a prioritized list of research questions to perform a systematic literature review (SLR). A search was made in Medline, Embase, and Cochrane library, updated to August 2021. Of 1227 article abstracts evaluated, 27 studies were included in the SLR, of which one SLR, 4 RCTs, and 22 observational studies. Seventeen recommendations for the management of mixed cryoglobulinemia with rituximab from the Italian Study Group of Cryoglobulinemia (GISC) were developed to give a valuable tool to the physician approaching RTX treatment in CV

Detection and quantitation of HCV core protein in single hepatocytes by means of laser capture microdissection and enzyme-linked immunosorbent assay

Immunohistochemistry provides valuable information concerning the localization and distribution of hepatitis C virus (HCV)-related proteins in histological sections of liver tissue, but does not readily permit their quantitation in individual cells and the staining intensity of cell immunodeposits cannot be calibrated with the current number of antigen molecules. We specifically detected and quantitated HCV core protein in single hepatocytes by coupling laser capture microdissection (LCM) with a sensitive enzyme-linked immunosorbent assay (ELISA). Quantitation of HCV core protein per cell was carried out on liver tissue cells obtained by LCM from fixed and stained frozen sections of 10 HCV-positive patients with chronic active hepatitis (CAH). Macromolecules from captured cells were solubilized in an extraction buffer and directly assayed for core protein using a sandwich ELISA. Calibration was achieved by developing a standard curve based on known concentrations of HCV core protein. Precision, linearity and sensitivity were verified for known numbers of microdissected tissue cells. In this study, the concentration of HCV core protein in single hepatocytes ranged from 7 to 56 pg/ cell. Specificity was verified on 10 replicates of 10 HCVnegative liver tissues. Immunohistochemical staining of HCV core protein was compared with the results of the soluble immunoassay for the adjacent liver tissue sections. Independent scoring of HCV immunostaining failed to parallel the LCM quantitative immunoassay. LCM-based immunoassay significantly expands our ability to investigate function- related antigens in apparently pure cell populations in HCV infection

Hepatitis C virus infection and mixed cryoglobulinemia

Hepatitis C virus (HCV) chronic infection is recognized as the major cause of mixed cryoglobulinemia (MC). Its persistence represents a continuous stimulus for host immune system with production of circulating immune complexes (ICs), one-third of them with cryoprecipitate property. Several factors contribute to the biological activities of ICs, many of which are not completely known. Among them, complement factors play a crucial role in the cold-insoluble ICs-mediated vasculitis, involving primarily small blood vessels in different tissues including skin, kidney, peripheral, and central nervous system. Liver represents the major target of HCV infection with inflammatory infiltrates, resembling secondary lymphoid follicles. Cytokine like CXCL13 contribute to B-cell homing in intraportal lymphoid aggregates, in which B-cell clonal selection may arise. B-cell clonal expansion starts as an antigen-driven event and expands towards indolent and malignant B-cell proliferation. Occurrence of intrahepatic Bcell clonalities correlates with extrahepatic clinical manifestations of HCV infection. In this context, cryoglobulinemic patients should be considered a peculiar HCV-infected population that needs a clinical multidisciplinary approach and more articulated therapeutic measures

MIXED CRYOGLOBULINEMIA: A MODEL OF VIRUS-RELATED DISEASE IN INTERNAL MEDICINE

Like other hepatotropic viruses, hepatitis C virus (HCV) exhibits the property of inducing hepatocellular damage, possibly through induction of immune mechanisms that lead to hepatocellular necrosis. The early activated mechanisms include production of non-specific and specific antibodies, which represent the first line of defence against invading foreign pathogens. As a consequence, circulating immune complexes are promptly formed and antigen uptake and processing by specialized cells are enhanced. A major fraction of circulating immunoglobulins (Igs) are part of the spectrum of so-called "natural" antibodies, which include anti-idiotypic antibodies and molecules with rheumatoid factor (RF) activity. They mainly belong to the IgM class, are polyclonal and have no intrinsic pathogenetic potential. In 20 30% of HCV-infected patients, RFs share characteristics of high affinity molecules, are monoclonal in nature, and result in the production of cold-precipitating immune complexes and mixed cryoglobulinemia (MC). The persistent production of monoclonal RF molecules implies the existence of a further mechanism capable of restricting the reactivity and reflects a distinct selection of a cell population that can be maintained throughout life because it is continuously exposed to antigen pressure. Either polyclonal or monoclonal profiles of B-cell expansion are demonstrable in the liver of the majority of HCV-infected patients. The frequent detection of oligoclonal B cell expansion may, indeed, represent a key pathobiologic feature which sustains non-malignant B-cell lymphoproliferation. The preferential expansion of one clone would in turn lead to a monoclonal pattern, which could favor stochastic oncogenic events. Thus, it can be postulated that HCV is the stimulus not only for the apparent benign lymphoproliferative process underlying a wide spectrum of clinical features, but also for the progression to frank lymphoid malignancy in a subgroup of patients