Serological profile of asymptomatic HCV positive patients with low level of cryoglobulins

Basile, Umberto; Napodano, Cecilia; Pocino, Krizia; Gulli, Francesca; Santini, Stefano Angelo; Todi, Laura; Marino, Mariapaola; Rapaccini, Gian Ludovico

doi:10.1002/biof.1485

Cited by 12 publications

(19 citation statements)

References 49 publications

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“…The characterization of mixed cryoglobulins, even at low concentrations, and autoimmune profile in HCV‐positive patients is important, because they are markers of additional immune dysfunction. In particular, the presence of monoclonal cryoglobulins must be considered as a predictive marker of further immune pathologies (clinical autoimmunity, monoclonal B cell proliferation leading to lymphoma) . The detection of autoantibodies in HCV‐positive patients with mixed cryoglobulins associated with other biomarkers may be of interest for the treatment of patients at risk for autoimmune dysfunction disease development .…”

Section: Discussionmentioning

confidence: 99%

Cryoglobulins Today: Detection and Immunologic Characteristics of 1,675 Positive Samples From 13,439 Patients Obtained Over Six Years

Kolopp‐Sarda

Nombel

Miossec

2019

Arthritis & Rheumatology

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Objective Cryoglobulins are cold‐precipitating immunoglobulins. Through progress in techniques, we undertook this study to update information on the biologic characteristics of cryoglobulins in a very large population. Methods A cohort of 13,439 patients was tested for cryoglobulins from January 2010 to December 2016. The analysis included cryoglobulin isotype, clonality, concentration, and IgM rheumatoid factor (IgM‐RF) in cryoprecipitate, as well as serum complement and RF. Markers of gammopathy, viral infection, and autoimmunity were also investigated. Results Of the 13,439 patients, 1,675 (12.5%) tested positive for cryoglobulins: 155 patients (9.3%) with type I, 788 (47%) with type II, and 732 (43.7%) with type III cryoglobulins. Nine percent of patients who were retested after initially testing negative for cryoglobulins showed a positive result on a follow‐up test (196 of the 2,213 retested patients). In type I cryoglobulins, IgM was more frequent but occurred at lower concentrations than IgG. Mixed cryoglobulins were found in 34.8% of the tested patients who were positive for hepatitis C virus and <5% of those who were positive for hepatitis B virus or HIV. Of the patients with anti–double‐stranded DNA, anti‐SSA, or anti–cyclic citrullinated peptide autoantibodies, 25.4% tested positive for mixed cryoglobulins, with type III occurring more frequently than type II. Both cryoprecipitate and serum were RF‐positive in 21.6% of type II and 10.1% of type III cryoglobulins. A decrease of C4, with or without accompanying decreases of C3 and CH50, was found in 23.6% of cryoglobulin samples. Conclusion Obtained with the use of modern assays, our findings from this very large collection of cryoglobulins provide an update on cryoglobulin distribution and characteristics, with minimal selection bias. Despite strict preanalytical conditions, a negative finding for the presence of cryoglobulin must be confirmed in a second sample. RF activity and complement decreases were rarely detected.

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Section: Discussionmentioning

confidence: 99%

Cryoglobulins Today: Detection and Immunologic Characteristics of 1,675 Positive Samples From 13,439 Patients Obtained Over Six Years

Kolopp‐Sarda

Nombel

Miossec

2019

Arthritis & Rheumatology

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“…In HCV-related MC, the antigenic stimulus represented by HCV as well as the occurrence of RFs with dual specificity for viral polypeptides and IgG3 could play a role. Nevertheless, the occurrence of oligoclonal IgM in CGs at low concentrations has been previously reported [46] . IgM oligoclonality represents a transitional stage from polyclonal to monoclonal, and its production may be induced by the persistence of IgG-HCV immune complexes.…”

Section: Introductionmentioning

confidence: 94%

“…A high prevalence of low cryoglobulin levels (≤ 0.05 g/L) in non-HCV patients may account for renal and neurological complications, leading to high morbidity and mortality [45] . Clinical manifestations and autoantibody presence in chronic HCV infection can easily be misdiagnosed as classic autoimmune diseases, and the possibility of early serological biomarkers of MC could be crucial for the effective control of extrahepatic manifestations [46] . Here, we review the most reliable biomarkers for CGs according to the literature (also summarized in Table 2 ).…”

Section: Introductionmentioning

confidence: 99%

“… Presence of C1q into cryoprecipitates of the patients with lupus nephritis. C1q mRNA levels are much higher in HCV patients with MC compared to HCV patients without MC or healthy controls Positive correlation between circulating C1q with RF activity and C1q concentrations in HCV patients with MC Presence of C1q in the cryoprecipitates of patients with CG associated with HCV infection C4 levels progressively decreased among HCV patients’ groups: naïve > asymptomatic > symptomatic [71] [77] [73] [74] [74] [74] [86] Free light chains FLCs could represent the signature of “dormant” B cell clones’ activity indicative of possible relapse or worsening outcome in patients HCV positive with MC after rituximab treatment HCV-related MC is strongly associated with high levels of FLCs FLC levels could be used as a diagnostic marker of vasculitis and MC syndrome FLC levels could be used as a new tool to identify patients requiring urgent access to antiviral treatment k/λ ratio can be useful to monitor therapy Serum levels of kFLC have been used to monitor extrahepatic manifestations caused by HCV Relevance of serological FLC levels in the diagnosis and prognosis pathway of diseases caused by deposition of immunocomplexes and immune-proliferative disorders In positive HCV patients, the determination of serum FLC can be clinically useful as a predictive index of MC for the diagnostic and prognostic value of the k/λ ratio High concentrations of monoclonal component k sFLC have been found in HCV patients with type II MC The alteration of the κ/λ ratio correlates with the clinical conditions of the lymphoproliferative disorder that accompanies the HCV infection [43] [46] [55] [55] [55] [77] [88] [88] [88] [88] Heavy chain Post-treatment HLC values could be useful for recognizing those patients that could benefit from additional anti-CD20 therapy, with an improvement in patient-tailored treatments Serum biomarker panel with HLC identifies patients with overt B-NHL associated with MC vasculitis in chronic HCV infection [43] …”

Section: Introductionmentioning

confidence: 99%

“…This is related both to the complement system activation, with C4 binding to immune complexes, and to the genetic polymorphisms of C4 in these patients [29] . Recently, Basile et al, who studied different HCV-positive populations (naïve without CGs; MC asymptomatic patients with low levels of CGs; and MC symptomatic patients with high levels of type II CGs), observed that the C4 levels progressively decreased among patient groups (naïve > asymptomatic > symptomatic) [46] . The detection of low C4 levels together with the assessment of low levels of CGs may represent a biomarker of this activation.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cryoglobulins: Identification, classification, and novel biomarkers of mysterious proteins

Napodano

Gulli²,

Rapaccini

et al. 2021

Advances in Clinical Chemistry

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Cryoglobulins consist of serum immunoglobulins that precipitate below 37°C and resolubilize upon warming. The clinical triad of cryoglobulinemia usually includes purpura, weakness, and arthralgia. Cryoglobulinemic syndrome, clinically defined as a systemic vasculitis, is associated with chronic infection with hepatitis C virus (HCV) and autoimmune disorders and can evolve into B-cell malignancies. While the current literature about HCV-associated cryoglobulinemia is not very limited, little is known about the immunologic and serologic profiles of affected patients. Therefore, comprehension of the pathogenetic mechanisms underlying cryoprecipitation could be very helpful. Due to the persistence of viral antigenic stimulation, biomarkers to use after the worsening progression of HCV infection to lymphoproliferative and/or autoimmune diseases are widely needed. Laboratory methods used to detect and characterize low concentrations of cryoprecipitates and immunotyping patterns could improve patient management. The most critical factor affecting cryoglobulin testing is that the pre-analytical phase is not fully completed at 37°C.

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Biomarkers of minimal residual disease in rituximab‐treated patients with mixed cryoglobulinemia

Basile

Gulli

Napodano

et al. 2020

Biotech and App Biochem

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Hepatitis C virus (HCV) represents the major risk factor for mixed cryoglobulinemia (MC), a small‐vessel vasculitis that may evolve into an overt B‐cell non‐Hodgkin's lymphoma. Here, we aimed to identify a biomarker signature for the early diagnosis of minimal residual disease (MRD). We assessed free light chains (FLCs), IgM k,and IgM λ heavy/light chain (HLC) pairs, and vascular endothelial growth factor (VEGF) in sera from 34 patients with MC vasculitis (32 HCV‐ and 2 HBV‐related), treated with low‐dose rituximab (RTX). FLCs and IgM HLCs were measured by turbidimetric assay; VEGF by an enzyme‐linked immunosorbent assay. After RTX, the positive (complete + partial) clinical and laboratory responses were of 85.29% and 50%, respectively; in contrast, the mean levels of FLCs, IgM HLCs, and VEGF were substantially unaffected in most patients and still above the normal range. In those achieving a reduction of FLCs and IgM k and λ chains values within the range of normality, we found that post‐treatment free λ chains and IgM k values correlated with clinical and laboratory response. Our results suggest that high levels of FLCs, IgM HLCs, and VEGF could represent the signature of “dormant” B cell clones’ activity that could be very useful to identify MRD indicative of possible relapse or worsening outcome.

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Serological profile of asymptomatic HCV positive patients with low level of cryoglobulins

Cited by 12 publications

References 49 publications

Cryoglobulins Today: Detection and Immunologic Characteristics of 1,675 Positive Samples From 13,439 Patients Obtained Over Six Years

Cryoglobulins Today: Detection and Immunologic Characteristics of 1,675 Positive Samples From 13,439 Patients Obtained Over Six Years

Cryoglobulins: Identification, classification, and novel biomarkers of mysterious proteins

Biomarkers of minimal residual disease in rituximab‐treated patients with mixed cryoglobulinemia

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