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Nature Reviews. Disease Primers Aug 2018Cryoglobulinaemia refers to the serum presence of cryoglobulins, which are defined as immunoglobulins that precipitate at temperatures <37 °C. Type I... (Review)
Review
Cryoglobulinaemia refers to the serum presence of cryoglobulins, which are defined as immunoglobulins that precipitate at temperatures <37 °C. Type I cryoglobulinaemia consists of only one isotype or subclass of monoclonal immunoglobulin, whereas type II and type III are classified as mixed cryoglobulinaemia because they include immunoglobulin G (IgG) and IgM. Many lymphoproliferative, infectious and autoimmune disorders have been associated with mixed cryoglobulinaemia; however, hepatitis C virus (HCV) is the aetiologic agent in most patients. The underlying mechanism of the disorder is B cell lymphoproliferation and autoantibody production. Mixed cryoglobulinaemia can cause systemic vasculitis, with manifestations ranging from purpura, arthralgia and weakness to more serious lesions with skin ulcers, neurological and renal involvement. This Primer focuses on mixed cryoglobulinaemia, which has a variable course and a prognosis that is primarily influenced by vasculitis-associated multiorgan damage. In addition, the underlying associated disease in itself may cause considerable mortality and morbidity. Treatment of cryoglobulinaemic vasculitis should be modulated according to the underlying associated disease and the severity of organ involvement and relies on antiviral treatment (for HCV infection), immunosuppression and immunotherapy, particularly anti-CD20 B cell depletion therapies.
Topics: Antiviral Agents; Cryoglobulinemia; Hepacivirus; Hepatitis C; Humans; Immunoglobulins; Interleukin-4; Rituximab
PubMed: 30072738
DOI: 10.1038/s41572-018-0009-4 -
Blood Jan 2017Cryoglobulinemia is a distinct entity characterized by the presence of cryoglobulins in the serum. Cryoglobulins differ in their composition, which has an impact on the... (Review)
Review
Cryoglobulinemia is a distinct entity characterized by the presence of cryoglobulins in the serum. Cryoglobulins differ in their composition, which has an impact on the clinical presentation and the underlying disease that triggers cryoglobulin formation. Cryoglobulinemia is categorized into two main subgroups: type I, which is seen exclusively in clonal hematologic diseases, and type II/III, which is called mixed cryoglobulinemia and is seen in hepatitis C virus infection and systemic diseases such as B-cell lineage hematologic malignancies and connective tissue disorders. Clinical presentation is broad and varies between types but includes arthralgia, purpura, skin ulcers, glomerulonephritis, and peripheral neuropathy. Life-threatening manifestations can develop in a small proportion of patients. A full evaluation for the underlying cause is required, because each type requires a different kind of treatment, which should be tailored on the basis of disease severity, underlying disease, and prior therapies. Relapses can be frequent and can result in significant morbidity and cumulative organ impairment. We explore the spectrum of this heterogeneous disease by discussing the disease characteristics of 5 different patients.
Topics: Adult; Connective Tissue Diseases; Cryoglobulinemia; Cryoglobulins; Female; Hepatitis C; Humans; Leukemia, B-Cell; Lymphoma, B-Cell; Male; Middle Aged; Recurrence
PubMed: 27799164
DOI: 10.1182/blood-2016-09-719773 -
Blood Sep 2018Plasma hyperviscosity is a rare complication of both monoclonal and polyclonal disorders associated with elevation of immunoglobulins. Asymptomatic patients with an... (Review)
Review
Plasma hyperviscosity is a rare complication of both monoclonal and polyclonal disorders associated with elevation of immunoglobulins. Asymptomatic patients with an elevation in the serum viscosity do not require plasma exchange, and the majority will have other indications for therapeutic intervention. For patients with hemorrhagic or central nervous system manifestations, plasma exchange is the therapy of choice and is relatively safe. Viscosity measurements are not required to initiate therapy if the index of suspicion is high and the clinical presentation is typical. However, patients should have a sample sent for confirmation of the diagnosis. Whole-blood hyperviscosity is seen in patients with extreme elevation of the red cell and white cell count. Phlebotomy of patients with primary and secondary elevation of the red cell count is a well-established therapy.
Topics: Blood Component Removal; Blood Viscosity; Cryoglobulinemia; Disease Management; Humans; Hypergammaglobulinemia; Male; Middle Aged; Plasma Exchange; Sjogren's Syndrome
PubMed: 30104220
DOI: 10.1182/blood-2018-06-846816 -
Viruses Nov 2021Extrahepatic manifestations are a feature of chronic hepatitis C virus (HCV) infection. In the course of chronic HCV infection, about 70% of patients have one or more... (Review)
Review
Extrahepatic manifestations are a feature of chronic hepatitis C virus (HCV) infection. In the course of chronic HCV infection, about 70% of patients have one or more extrahepatic manifestations. The latter are often the first and only clinical sign of infection. Experimental and clinical data support a causal association for many extrahepatic manifestations and HCV infection, which include mixed cryoglobulinemia, non-Hodgkin lymphomas (NHL), cardiovascular disease, insulin resistance, type 2 diabetes, neurological and psychiatric disease and other rheumatic diseases. All these extrahepatic conditions influence the morbidity, quality of life and mortality of HCV-infected patients. Currently, interferon-free therapeutic regimens with direct-acting antiviral agents (DAA) offer the possibility of treatment to almost the entire infected population, irrespective of stage of cirrhosis and associated serious comorbidities, always maintaining a high efficacy and tolerability. Several studies have shown a close association between HCV clearance by DAAs and an improvement or reduction in the risk of extrahepatic manifestations. Patients with HCV after a sustained virologic response (SVR) by DAA treatment have a lower risk than non-responders of developing cryoglobulinemic vasculitis and B-cell non-Hodgkin's lymphomas. Furthermore, the SVR by DAA also reduces the risk of acute coronary syndrome, cardiovascular disease, insulin resistance and type 2 diabetes, and it improves atherosclerosis. HCV clearance by DAA also improves the quality of life and survival of patients with chronic HCV infection with associated extrahepatic diseases. Thus, DAAs should be initiated as early as possible in HCV patients with extrahepatic manifestations.
Topics: Antiviral Agents; Cardiovascular Diseases; Cryoglobulinemia; Diabetes Mellitus, Type 2; Hepacivirus; Hepatitis C, Chronic; Humans; Kidney Diseases; Lymphoma, Non-Hodgkin; Mental Disorders; Nervous System Diseases; Rheumatic Diseases
PubMed: 34835054
DOI: 10.3390/v13112249 -
Oncology (Williston Park, N.Y.) Nov 2013"Cryoglobulinemia" refers to the presence of cryoglobulins (immunoglobulins that precipitate at variable temperatures < 37 degrees C [98.6 degrees F]) in serum.... (Review)
Review
"Cryoglobulinemia" refers to the presence of cryoglobulins (immunoglobulins that precipitate at variable temperatures < 37 degrees C [98.6 degrees F]) in serum. Monoclonal cryoglobulinemia (type I) involves a single type of monoclonal immunoglobulin, while mixed cryoglobulinemia involves a mixture either of polyclonal immunoglobulin (Ig) G and monoclonal IgM (type II), or of polyclonal IgG and polyclonal IgM (type Ill); both monoclonal and polyclonal IgM have rheumatoid factor activity. Cryoglobulinemia is a unique model of human disease for several reasons: (1) cryoglobulins are detected using a simple technical approach that is based on in vitro laboratory observation of cold precipitation in serum; (2) cryoglobulinemic organ damage may be produced by two different etiopathogenic mechanisms (accumulation of cryoglobulins and autoimmune-mediated vasculitic damage); and (3) cryoglobulinemia is associated with a wide range of etiologies, symptoms, and outcomes, and is considered a disease that combines elements of autoimmune and lymphoproliferative diseases. There are three main broad treatment strategies in cryoglobulinemia-conventional immunosuppression, antiviral treatment, and biologic therapy. Some agents, such as corticosteroids and rituximab, have been successfully used in all types of cryoglobulinemia; however, treatment should be modulated according to the underlying associated disease (chronic viral infections, autoimmune diseases, or cancer), the predominant etiopathogenic damage (vasculitis vs. hyperviscosity), and the severity of internal organ involvement.
Topics: Antiviral Agents; Cryoglobulinemia; Humans; Lymphocyte Depletion
PubMed: 24575538
DOI: No ID Found -
European Review For Medical and... Sep 2018Mixed Cryoglobulinemia is the most well-known Hepatitis C Virus (HCV)-associated extrahepatic manifestation. MC is both an autoimmune and B-lymphoproliferative disorder.... (Observational Study)
Observational Study
OBJECTIVE
Mixed Cryoglobulinemia is the most well-known Hepatitis C Virus (HCV)-associated extrahepatic manifestation. MC is both an autoimmune and B-lymphoproliferative disorder. Cryoglobulins (CGs) are classified into three groups according to immunoglobulin (Ig) composition: type I is composed of one isotype or Ig class. Type II and type III mixed CGs are immune complexes composed of polyclonal IgGs acting as autoantigens and mono, polyclonal or oligoclonal IgM with rheumatoid factor activity. IgG1 and IgG3 are the predominant subclasses involved. This study shows the simultaneous presence of IgG-RF and IgG3, supporting the hypothesis of an involvement of this subclass in the initiation of early stages of CGs.
PATIENTS AND METHODS
We describe a case series of six HCV-positive patients, all of whom had peripheral neuropathy and transient ischemic attacks, presenting cryoprecipitates formed by IgG3 and IgG1. Cryoprecipitate IgG subclass research was carried out by immunofixation electrophoresis by using antisera against IgG1, IgG2, IgG3, and IgG4.
RESULTS
Our six patients presented with an immunochemical pattern characterized by the mere presence of IgG1 and IgG3 subclasses with probable RF activity and one of these six patients exhibited monoclonal IgG3 in his cerebrospinal fluid.
CONCLUSIONS
We can hypothesize that the IgG passage through the blood-brain barrier could have contributed to the cause of TIAs, through a mechanism involving the precipitation of circulating immune complexes formed by the two subclasses in the intrathecal vessels.
Topics: Aged; Blood-Brain Barrier; Cryoglobulinemia; Female; Hepatitis C; Humans; Immunoglobulin G; Male; Middle Aged; Peripheral Nervous System Diseases; Rheumatoid Factor
PubMed: 30280791
DOI: 10.26355/eurrev_201809_15943 -
Therapeutic Apheresis and Dialysis :... Feb 2023Cryoglobulinemia is defined as the presence of an abnormal immunoglobulin that may be responsible for vasculitis of small-caliber vessels. Apheresis can be used in order... (Review)
Review
BACKGROUND
Cryoglobulinemia is defined as the presence of an abnormal immunoglobulin that may be responsible for vasculitis of small-caliber vessels. Apheresis can be used in order to temporarily eliminate circulating cryoglobulins. The aim of this study was to assess the effectiveness of apheresis (double-filtration plasmapheresis-DFPP-) in symptomatic and/or severe cryoglobulinemias.
METHODS
Four male patients presenting cryoglobulinemic vasculitis and who received DFPP sessions were included.
RESULTS
Their mean age was 57 ± 15 years. One patient had hepatitis-C virus (HCV)-related cryoglobulinemia and the other three patients were carriers of an IgM Kappa monoclonal gammopathy. Mean duration of follow-up was 15 ± 2 months. DFPP allowed healing of ulcerative skin lesions in the first patient and remission of nephrotic syndrome in the other patients after a median of 6(5-10) sessions.
CONCLUSION
DFPP can be used safely in cryoglobulinemic-vasculitis and can be considered early to achieve a faster and sustained clinical-biological response.
Topics: Humans; Male; Adult; Middle Aged; Aged; Cryoglobulinemia; Plasmapheresis; Blood Component Removal; Vasculitis; Hepacivirus
PubMed: 35583180
DOI: 10.1111/1744-9987.13885 -
Frontiers in Immunology 2022We aimed to explore and identify candidate protein biomarkers of cryoglobulinemia (CGE) in disease control patients with negative cryoglobulin (DC) or healthy controls...
OBJECTIVE
We aimed to explore and identify candidate protein biomarkers of cryoglobulinemia (CGE) in disease control patients with negative cryoglobulin (DC) or healthy controls (HCs).
METHODS
The tandem mass tag (TMT)-labeled serum quantitative proteomics approach was used to identify differentially expressed proteins between the CGE and DC groups. Ingenuity pathway analysis was used for functional annotation of differentially expressed proteins. Biomarker candidates were validated in another cohort using the parallel reaction monitoring (PRM) method. Apolipoprotein A1 (APOA1), apolipoprotein CIII (APOC3), adiponectin, and proprotein convertase subtilisin/kexin type-9 (PCSK9), which represent key proteins involved in the cholesterol metabolism pathway, were further verified in an increased number of samples by enzyme-linked immunosorbent assay (ELISA).
RESULTS
A total of 1004 proteins were identified, of which 109 proteins were differentially expressed between the CGE and DC groups. These differentially expressed proteins were primarily involved in hepatic fibrosis/hepatic stellate cell activation and immune/inflammation-related pathways. In the disease and biofunction analysis, these proteins were mainly associated with the adhesion of blood cells, leukocyte migration, cholesterol transport, and transport of lipids. Twelve candidate biomarkers were validated by PRM-based proteomics, and proteins involved in the cholesterol metabolism pathway were further verified. APOA1, APOC3, adiponectin and PCSK9 concentrations were increased in CGE patients compared with healthy controls (P=0.0123, 0.1136, 0.5760, and 0.0019, respectively).
CONCLUSION
This report describes the first application of a TMT-PRM-ELISA workflow to identify and validate CGE-specific biomarkers in serum. APOA1 and PCSK9 have been confirmed to be increased in CGE patients, demonstrating that proteins involved in cholesterol metabolism are also implicated in the development of CGE. These findings contribute to pathogenesis research and biomarker discovery in CGE.
Topics: Adiponectin; Apolipoproteins; Biomarkers; Cryoglobulinemia; Humans; Proprotein Convertase 9; Proteome; Proteomics
PubMed: 35677050
DOI: 10.3389/fimmu.2022.855513 -
Kidney International Oct 2009In this review we discuss the clinical manifestations, pathogenesis, and treatment of hepatitis C virus (HCV)-related cryoglobulinemia. HCV is a major cause of... (Review)
Review
In this review we discuss the clinical manifestations, pathogenesis, and treatment of hepatitis C virus (HCV)-related cryoglobulinemia. HCV is a major cause of liver-related morbidity and is increasingly recognized as an instigator of B-cell lymphoproliferative disorders such as mixed cryoglobulinemia and non-Hodgkin lymphoma. Cryoglobulinemia is characterized by the clonal expansion of rheumatoid factor-expressing B cells in the liver, lymph nodes, and peripheral blood, resulting in the presence of cryoglobulins in the circulation. Cryoglobulins are cold-insoluble immune complexes containing rheumatoid factor, polyclonal IgG, and HCV RNA that precipitate and deposit on vascular endothelium, causing vasculitis in organs such as the skin, kidneys, and peripheral nerves. A subset of patients develops a low-grade lymphoma composed of B cells that are immunophenotypically similar to the expanded B cells seen in cryoglobulinemia. HCV-related B-cell lymphoproliferative disorders likely comprise a spectrum of disease, ranging from asymptomatic clonal B-cell expansions to pathogenic cryoglobulinemia and lymphoma. It is unclear how B cells become dysregulated during the course of chronic HCV infection, and continued patient-centered research is necessary to elucidate the pathogenesis of HCV-related B-cell dysregulation.
Topics: Antiviral Agents; B-Lymphocytes; Cryoglobulinemia; Hepatitis C; Humans; Immunosuppressive Agents; Lymphatic Diseases; Plasmapheresis; Treatment Outcome
PubMed: 19606079
DOI: 10.1038/ki.2009.247 -
Journal of Clinical Pathology Jan 2002Serum cryoglobulins are found in a wide spectrum of disorders but are often transient and without clinical implications. Monoclonal cryoglobulins are usually associated... (Review)
Review
Serum cryoglobulins are found in a wide spectrum of disorders but are often transient and without clinical implications. Monoclonal cryoglobulins are usually associated with haematological disorders, whereas mixed cryoglobulins are found in many infectious and systemic disorders. So called essential mixed cryoglobulinaemia shows a striking association with hepatitis C virus (HCV) infection (> 90%). It is a systemic vasculitis (leucocytoclastic vasculitis) with cutaneous and multiple visceral organ involvement. Chronic HCV infection can lead to a constellation of autoimmune and neoplastic disorders. In this review, the aetiology, diagnosis, disease heterogeneity, and treatment of cryoglobulinaemia are discussed.
Topics: Autoimmunity; Cryoglobulinemia; Hepatitis C, Chronic; Humans; Lymphoproliferative Disorders
PubMed: 11825916
DOI: 10.1136/jcp.55.1.4