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.

Chikungunya virus (CHIKV), an arbovirus, is responsible for a two-stage disabling disease, consisting of an acute febrile polyarthritis for the first 10 days, frequently followed by chronic rheumatisms, sometimes lasting for years. Up to now, the pathophysiology of the chronic stage has been elusive. Considering the existence of occasional peripheral vascular disorders and some unexpected seronegativity during the chronic stage of the disease, we hypothesized the role of cryoglobulins.

Hepatitis B virus (HBV) infection is a rare etiology of cryoglobulinemia, and its clinical characteristics, virological features and treatment are poorly understood.

The clinical value of cryoglobulinemia (CG) in systemic lupus erythematosus (SLE) is largely unknown. The aim of this retrospective study was to describe the characteristics of CG in SLE, its impact on SLE phenotype, and the features associated with cryoglobulinemic vasculitis (CryoVas) in SLE patients.

Antibodies cross-reactive to pathogens and autoantigens are considered pivotal in both infection control and accompanying autoimmunity. However, the pathogenic roles of autoantibodies largely remain elusive without a priori knowledge of disease-specific autoantigens. Here, through a novel quantitative proteogenomics approach, we demonstrated a successful identification of immunoglobulin variable heavy chain (VH) sequences highly enriched in pathological immune complex from clinical specimens obtained from a patient with hepatitis C virus-induced cryoglobulinemia (HCV-CG). Reconstructed single-domain antibodies were reactive to both HCV antigens and potentially liver-derived human proteins. Moreover, over the course of antiviral therapy, a substantial "de-evolution" of a distinct sub-repertoire was discovered, to which proteomically identified cryoprecipitation-prone autoantibodies belonged. This sub-repertoire was characterized by IGHJ6*03-derived, long, hydrophobic complementarity determining region (CDR-H3). This study provides a proof-of-concept of de novo mining of autoantibodies and corresponding autoantigen candidates in a disease-specific context in human, thus facilitating future reverse-translational research for the discovery of novel biomarkers and the development of antigen-specific immunotherapy against various autoantibody-related disorders.

Hepatitis C virus (HCV) infection is associated with extrahepatic manifestations such as cryoglobulinemia and accounts for up to 90% of all cases of mixed cryoglobulinemia (MC). The present study aimed to evaluate the effect of sofosbuvir-daclatasvir therapy on symptomatic HCV-related MC and sustained virologic response (SVR) achievement.

Background and aim: Mixed cryoglobulinemia (MC) has been associated with several viral infections, and chronic hepatitis C is recognized as a major cause. MC associated with hepatitis E virus (HEV) has been described and little is known about this rare association. The aim of this study is to perform a systematic review of MC associated with HEV, and examine the presence of a causal relationship. Methods: An experienced librarian conducted a search of databases from each database's inception to 12 December 2016 based on a priori criteria. The risk of bias was assessed, and Hill's criteria were applied to determine causality. Results: Five publications met inclusion criteria, with a total of 15 cases. Three studies had low, one low to moderate and one moderate risk of bias. Median age was 43 years, and all patients came from Western Europe. Two patients were immunocompetent, while 13 were immunosuppressed, post solid organ transplant and had chronic hepatitis E. Renal involvement was observed in seven patients, mild to moderately severe cryoglobulinemic disease in one patient and severe cryoglobulinemic disease in three patients. One patient improved spontaneously, and another was treated with immunosuppressant reduction leading to viral clearance. Ten patients treated with peg-interferon or ribavirin for 3 months achieved loss of cryoglobulinemia and end-of-treatment response, but sustained virologic response was reported and achieved in two. Immunosuppressant achieved loss of cryoglobulinemia in three patients. One case of chronic renal failure, three cases of end-stage renal disease and one death were observed. Five of the nine Hill's criteria were fulfilled. Conclusion: MC has been described with HEV infection. A causal relationship between HEV infection and cryoglobulinemia is highly probable.

Hepatocellular carcinoma (HCC) is ranked the fifth-most common cancer in men and ninth most common cancer in women. Immunotherapy has been shown effective in malignancies refractory to chemotherapy and has been used as a second-line therapies in many advanced cancers, including HCC. The advent of immunotherapy has resulted in a brand-new set of side effects, and it has been proposed that it was related to over activated immune system. Herein, we presented the case of 59-year-old African American gentlemen who was diagnosed with HCC caused by Hepatitis C virus, for which he was started on chemotherapy and immunotherapy. However, the patient developed cryoglobulinemia that prompted stopping both therapies and giving rituximab and steroids. We believe that the mixed cryoglobulinemia was unmasked by immunotherapy in our patient. To our knowledge, this is one of the few first cases to describe such adverse effect from immune checkpoint inhibitors.

Twenty-nine patients with HCV infection (HCV+) and mixed cryoglobulinemia (MC+) were retrospectively selected and matched for age and sex with 31 HCV+ MC- patients. Biomarkers of cholestasis (direct bilirubin, alkaline phosphatase, and gamma-glutamyl transferase), HCV-RNA and genotype, and plasma cryoprecipitates were measured before and after virus eradication; liver histology and plasma cells (aggregation and distribution), observed blinded by two pathologists, were analyzed. Sixty participants (mean age: 56.5; range: 35-77, males: 50%) with HCV infection were enrolled. Cholestasis (≥2 pathologically increased cholestasis biomarkers) was significantly higher in the MC group (p = 0.02) and correlated with cryoglobulinemia (OR 6.52; p = 0.02). At liver histological assessment, plasma cells were significantly increased in the MC+ group (p = 0.004) and tended to form aggregates more than the control group (p = 0.05). At multivariate analysis with MC, age, HCV-RNA, HBV diabetes, and cirrhosis, cholestasis was only significantly correlated to MC (OR 8.30; p < 0.05). In 25% patients, MC persisted after virus eradication with new antiviral treatment. Our study identified for the first time an association between MC, cholestasis, and an increased number of intrahepatic plasma cells in chronic hepatitis C (CHC) patients before virus eradication. Future studies are required to understand how MC contributes to liver damage and how its persistence affects the patients' follow-up after antiviral therapies.

Correlation of C-C chemokine receptor type 5 (CCR5) and NACHT, LRR and PYD domain-containing protein 3 (NLRP3) gene polymorphisms with renal damage due to hepatitis C virus (HCV)-related cryoglobulinemia were investigated. The 1:1 matched case-control study design was adopted, 171 patients with renal damage due to HCV-related cryoglobulinemia were selected as the case group, and 171 patients without renal damage were selected as the control group. Polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis was used to detect the polymorphisms of locus rs1799987A/G in CCR5 gene and locus rs35829419A/C in NLRP3 gene of 171 pairs of HCV patients. SPSS 20.0 software was used for logistic regression analysis, and genetics package of the R programming language for Hardy-Weinberg equilibrium test. The frequencies of locus rs1799987A/G in CCR5 gene in the case group were 48.0 and 52.0%, while those in the control group were 47.9 and 52.1%; the frequencies of locus rs35829419A/C in NLRP3 gene were 55.8 and 44.2%, while those in the control group were 55.3 and 44.7%. The results of logistic regression analysis showed that the distribution of CCR5 gene polymorphism in the case group was statistically different from that in the control group (P<0.05), which had a statistical correlation with the renal damage due to HCV-related cryoglobulinemia (P<0.05). At rs1799987, GG genotype was compared with AA genotype, and AG genotype was compared with AA genotype; the results showed that the renal damage due to HCV-related cryoglobulinemia was not decreased [odds ratio (OR) = 0.91, 95% confidence interval (95% CI): 0.47-1.54; OR = 0.89, 95% CI: 0.49-1.31]. The negative analysis model of the GG genotype reduced the risk of renal damage due to HCV-related cryoglobulinemia remarkably (OR = 0.62, 95% CI: 0.39-0.98). Rs1799987A/G and gene polymorphism of CCR5 may be associated with renal damage due to HCV-related cryoglobulinemia, and the carriage of G allele may lower the incidence rate of the disease, while rs35829419A/C in NLRP3 has no correlation with renal damage due to HCV-related cryoglobulinemia.

The standard-of-care treatment of patients with hepatitis C virus (HCV)-mixed cryoglobulinemia (MC) vasculitis includes pegylated interferon α (PegIFN)-α plus ribavirin and/or rituximab. About 30-40% of patients are non-responders or relapsers to such combination.

Mixed cryoglobulinemia (MC) in hepatitis C virus (HCV) infection is associated with abnormal immune responses mediated by T cells and B cells, while the relationships of different subsets of CD4 + T helper (Th) cells, B cells and associated cytokines with type III asymptomatic MC in HCV infection are poorly understood.

Several studies have provided conflicting results regarding the immune responses in chronic hepatitis C (CHC) patients with mixed cryoglobulinemia (MC). The importance of B-cell activating factor (BAFF) in MC has been described, but the role of interleukin (IL)-17A is less clear.

Chronic infection by pathogens such as hepatitis C virus induces monoclonal or oligoclonal proliferation of B cells, which produce IgM rheumatoid factor, leading to the development of mixed cryoglobulinemia (MC). Antigen-driven lymphoproliferation is essential to the onset of MC; however, the underlying mechanism is largely unknown. Herein, we show that type II MC is induced by Capillaria hepatica infection through a mechanism in which splenic B-1a cells reacting to C. hepatica-specific antigen selectively proliferate, producing IgM rheumatoid factor under co-stimulation of the specific worm antigen and IL-5. In vitro assays using B-1a cells from infected mice showed that stimulation by C. hepatica soluble fraction promoted the proliferation of B-1a cells and the secretion of IgM, which reacted with the 75-kDa antigen in the soluble fraction. The severity of MC was correlated with the increase in serum IL-5 levels in the infected mice. Furthermore, i.p. injection of the soluble worm fraction caused MC without an inflammatory response in IL-5 transgenic mice, indicating that IL-5 is critical for the development of MC. These results indicate that the selective proliferation of IgM rheumatoid factor-secreting B-1a cells is induced by co-stimulation by the specific pathogen antigen and IL-5 in the development of MC in C. hepatica-infected mice.

(1) Background. Hepatitis C infection often leads to extrahepatic manifestations, including cryoglobulinemic vasculitis. This systematic review aimed to assess the efficacy and safety of rituximab in treating hepatitis C-associated cryoglobulinemic vasculitis. (2) Methods. Following PRISMA guidelines, databases were searched for relevant studies. Eligibility criteria included studies on hepatitis C-associated cryoglobulinemic vasculitis treated with rituximab. (3) Results. Nine studies met the eligibility criteria and were included in this analysis. Rituximab was commonly administered at 375 mg/m2 weekly for one month. The results consistently demonstrated the efficacy of rituximab, whether as a standalone treatment or as part of a therapeutic regimen. The combination of rituximab with Peg-IFN-α and ribavirin significantly increased the complete response rate compared to Peg-IFN-α and ribavirin alone (54.5% vs. 33.3%, p < 0.05). The 3-year sustained response rate was notably higher in the rituximab combination group (83.3% vs. 40%). In another trial, rituximab achieved remission in 83.3% of patients at 6 months, compared to only 8.3% in the control group. The efficacy of rituximab was supported by long-term experience, with clinical benefits in patients with severe cryoglobulinemic vasculitis, including those resistant to standard therapies. Mild adverse events were generally reported, with rare severe reactions in some studies. (4) Conclusions: In conclusion, rituximab appeared to be effective and safe in managing hepatitis C-associated cryoglobulinemic vasculitis, either alone or with antiviral therapy.

The study of the incidence of cryoglobulinemia is relevant in patients with an intestinal anastomotic leak. This study aims to determine a laboratory marker of the risk of small intestine anastomotic leak. The study was based on 96 patients who were subjected to resections of segments of the small intestine with the formation of intestinal anastomoses at the State Institution "Zaytsev V.T. Institute of General and Urgent Surgery of National Academy of Medical Sciences of Ukraine". Of all the operated patients, there were 55.2% women and 44.8% men. Of the 96 patients examined, cryoglobulinemia was detected in the majority - 62.5% of patients, of which 4 were later proved to have inactive hepatitis C; the remaining 38.5% had no cryoglobulinemia. According to the existing theory of the autoimmune mechanism of postoperative surgical complications formation, the revealed decrease in the level of cryoglobulins on the second day could be related to their fixation in the microcirculatory bed and the development of immunocomplex inflammation. While the increase in the content of cryoglobulins in serum on the third day can be caused by their entry into the circulatory bed from deposition or fixation sites and the development of a secondary immune response. In patients with intestinal anastomosis failure after resection of intestinal segments, cryoglobulinemia rates increased more than 80 mg/l; this indicator could be used as a marker of postoperative complications.

Extrahepatic manifestations of Hepatitis E, though rare, are being increasingly reported in the medical literature. In this review article, we will discuss the extrahepatic manifestations of hepatitis E, such as Guillain-Barre syndrome, pancreatitis, and cryoglobulinemia, their clinical association with hepatitis E, and their management.

In this paper we review the clinical manifestations in cutaneous necrotizing vasculitis. Palpable purpura is the most common clinical pattern, while urticarial vasculitis, erythema elevatum diutinum and nodular vasculitis have found less commonly. Clinicopathological lesions may occur in internal locations also, presumably due to circulating immune complex-mediated vessel damage at those sites. In the setting of the disease, it is possible to observe serum sickness-like reactions, distinct clinical patterns, such as Henoch-Schönlein purpura, essential mixed cryoglobulinemia, vasculitis associated with connective tissue diseases and with malignancies.

Hepatitis C virus (HCV) has been identified as one of the major risk factors for type II mixed cryoglobulinemia (MC), during the clinical evolution of chronic hepatitis, which may lead to development of B cell non-Hodgkin's lymphoma (NHL). We have previously shown that the candidate idiotype vaccine, based on the IGKV3-20 light chain protein, is able to induce activation and maturation of circulating antigen presenting cells (APCs) in both HCV-positive and HCV-negative healthy control subjects, with production of Th2-type cytokines. Here, the effect of the recombinant IGKV3-20 protein on human peripheral blood mononuclear cells (PBMCs) from HCV-positive subjects, with known blood levels of cryoglobulins, is shown via gene expression profiling analysis combined to multiparameter flow cytometry and multiplex analyses of cytokines.

A subset of patients with immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) develop IgM-related disorders (IgM-RD) including peripheral neuropathy, cryoglobulinemia and/or cold agglutinin disease (CAD). We examined the clinical and bone marrow pathologic findings in 191 IgM MGUS patients (2016 World Health Oragnization criteria). Clonal plasma cells were identified in 41 of 171 (24%) cases by immunohistochemistry (IHC) and clonal B cells in 43 of 157 (27%). IgM-RD was identified in 82 (43%) cases, including peripheral neuropathy (n=67, 35%), cryoglobulinemia (n=21, 11%), and CAD (n=10, 5%). Cases of CAD showed distinctive features including lack of MYD88 mutations (P=0.048), supporting the concept of primary CAD as a distinct clinicopathologic disorder. Following exclusion of CAD, comparison of the remaining cases with (n=72) or without (n=109) IgM-RD showed IgM-RD to be more frequent in men than women (P=0.02) and to be more highly associated with MYD88 L265P (P=0.011). Cases with and without IgM-RD otherwise showed similar features including serum IgM concentrations, presence of lymphoid aggregates, clonal B cells by flow cytometry or clonal plasma cells by IHC. No differences were observed in overall survival between cases with and without IgM-RD. No cases in this series met criteria for plasma cell type IgM MGUS as defined in the 2022 International Consensus Classification of lymphoid neoplasms. These results show IgM-RD to be common in patients with IgM MGUS. While CAD shows distinctive features, the remaining cases of IgM-RD largely show pathologic findings similar to IgM MGUS without IgM-RD.