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Mixed cryoglobulinemia vasculitis (MCV) is caused in ~90% of cases by chronic hepatitis C virus (HCV pos MCV) and more rarely by hepatitis B virus (HBV) infection, or apparently noninfectious. HCV pos MCV develops in only ~5% of patients with chronic hepatitis C (CHC), but risk factors other than female gender have not been identified so far. We conducted a retrospective case control study investigating whether past active HBV infection, defined by hepatitis B surface antigen (HBsAg) seroclearance and anti-core antibody (HBcAb) positivity, could be a risk factor for developing HCV pos MCV. The prevalence of HBsAg seroclearance was 48% within 123 HCV pos MCV patients and 29% within 257 CHC patients (p=0.0003). Multiple logistic regression including as variables gender, birth year, age at HBV testing, cirrhosis, and hepatocellular carcinoma, confirmed an association of HBsAg seroclearance with HCV pos MCV [adjusted odds ratio (OR) 2.82, 95% confidence interval (95% CI) 1.73-4.59, p<0.0001]. Stratification by gender, however, showed that HBsAg seroclearance was associated with HCV pos MCV in male [OR 4.63, 95% CI 2.27-9.48, p<0.0001] and not in female patients [OR 1.85, 95% 95% CI 0.94-3.66, p=0.076]. HBsAg seroclearance, and more likely occult HBV infection, is an independent risk factor for HCV pos MCV in male CHC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Morrone, Fiorilli, Cinti, Roberto, Ferri, Visentini, Pulsoni, Spinelli, De Santis, Antonelli, Basili, Tosti, Conti and Casato.)

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., (© 2022. The Author(s).)

Introduction: Direct-acting antiviral agents (DAAs) have modified the management of chronic hepatitis C virus (HCV) infection, including HCV-related cryoglobulinemic vasculitis (CryoVas). However, patients might experience vasculitis relapse, and no reliable predictors of CryoVas relapse after sustained virologic response (SVR) have been established. We aimed to describe HCV-CryoVas relapse rates and factors associated with it., Methods: An international multicenter cohort where patients with HCV-CryoVas from Egypt, France, and Italy treated with DAA were analyzed retrospectively. Factors associated with relapse-free survival were evaluated in a multivariate-adjusted model., Results: Of 913 patients, 911 (99.8%) obtained SVR. After 35 months of the median follow-up, 798 patients (87.4%) had sustained remission of vasculitis, while 115 (12.6%) experienced CryoVas relapse. By the time of relapse, skin involvement was present in 100%, renal involvement in 85.2%, and peripheral neuropathy in 81.7%. Relapses were treated with glucocorticoids in 90.9%, associated with plasma exchange, cyclophosphamide, or rituximab in 50%, 37.3%, and 6.4%, respectively. The cumulative incidence of CryoVas relapse was 0.7% (95% CI 0.3-1.4), 12.3% (95% CI 10.2-14.6), and 13.1% (95% CI 11.0-15.5) at 12, 24, and 36 months after DAA treatment, respectively. Independent baseline risk factors associated with CryoVas relapse were male sex, skin ulcers, kidney involvement at baseline, and peripheral neuropathy at the end of DAA treatment. Death occurred in 11 relapsers, mainly due to infections., Discussion: A substantial proportion of patients with CryoVas experience relapse after DAA-induced SVR. Relapses are moderate-to-severe and affect survival after 24 months, mainly due to infections. Independent risk factors for relapse or death were found., (Copyright © 2022 by The American College of Gastroenterology.)

Background: Glucocorticoids (GCs) plus rituximab (RTX) represent the first-line treatment of nonviral mixed cryoglobulinemia vasculitis (CryoVas). However, data on therapeutic management and outcome of patients refractory to RTX are lacking., Methods: We conducted a European collaborative retrospective multicenter study of patients with nonviral mixed CryoVas refractory to RTX and performed a literature review., Results: Twenty-six original cases and 7 additional patients from the literature were included. All patients but one had type 2 cryoglobulinemia, and causes were autoimmune disease (51%), malignant hemopathy (12%) or essential CryoVas (42%). CryoVas was primary refractory to RTX in 42%, while 58% had an initial response to RTX before immune escape. After RTX failure, patients received a median of 1 (IQR, 1-3) line of treatment, representing 65 treatment periods during follow-up. Main treatments used were GCs in 92%, alkylating agents in 43%, RTX in combination with other treatments in 46%, and belimumab in 17%. Combination of anti-CD20 plus belimumab, alkylating agents alone and anti-CD20 plus alkylating agents provided the highest rates of clinical response in 100% 82% and 73%, respectively, but showed poor immunological response, in 50%, 30% and 38%, respectively. Rates of severe infection were 57%, 9% and 0% in patients receiving anti-CD20 plus belimumab, alkylating agents alone and anti-CD20 plus alkylating agents, respectively., Conclusion: In patients with nonviral mixed CryoVas refractory to RTX, anti-CD20 plus belimumab, and alkylating agents associated or not with anti-CD20, provide the highest rates of clinical response. However, anti-CD20 plus belimumab was frequently associated with severe infections., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Hepatitis C virus (HCV) causes neuropsychiatric disorders and quality of life impairment, especially in patients with cryoglobulinemic vasculitis (CV). Direct acting antivirals (DAAs) are effective in most extrahepatic HCV diseases, but limited information exists regarding the outcome of psychiatric disorders in patients with and without CV, after therapy. We aimed to evaluate psychiatric outcomes, in HCV-patients with and without CV, before and after successful DAA therapy., Methods: We prospectively studied DAA-treated HCV-patients, stratified into presence (CV) or absence of CV (NON-CV). Four psychometric scales were administered to assess depression (HAM-D and MADRS), anxiety (HAM-A), and mania (MRS). Short-Form-36 questionnaires evaluated quality of life., Results: Seventy-six patients were recruited, and 47 CV and 29 NON-CV were treated with antivirals. At baseline, depression and anxiety, from mild to severe, were frequently shown, with the most advanced cases in thee CV group; no patients achieved the scores for mania. A significant improvement emerged for all the psychometric scales in the entire population and in the subgroups, after viral eradication even in the short-term outcome. The Short-Form-36 summary components showed benefits., Conclusions: After HCV eradication, the depression and anxiety scores significantly improved and severity grade generally lowered. DAA-positive effects on mental disorders should be considered part of the therapy outcome, being beneficial especially in CV patients who usually have worse baseline mental scores. Key Points • HCV frequently causes psychiatric disorders and an often-invalidating autoimmune/lymphoproliferative disease called cryoglobulinemic vasculitis. • The new direct acting antivirals (DAAs) are very effective and well tolerated by HCV-patients. • This study shows DAA-induced benefits on depression and anxiety in HCV-patients that are especially evident in CV patients who usually have worse baseline mental scores. • DAA-induced benefits are observed in the short-term post-therapy follow-up, in contrast with data previously obtained in HCV patients treated with IFN-based anti-HCV therapy., (© 2021. The Author(s).)

Hepatitis B virus (HBV) chronic infection causes progressive liver damage, although about 20% of patients develop extrahepatic manifestations such as cryoglobulinemic vasculitis (CV). Clinical manifestations range from mild to moderate (purpura, asthenia, arthralgia) to severe (leg ulcers, peripheral neuropathy, glomerulonephritis, non-Hodgkin lymphoma). A comprehensive review of therapeutic options for HBV-related CV is lacking. Nucleos(t)ide analogues (NA) suppress HBV replication in 90-100% of cases and induce clinical response in most patients with mild-to-moderate CV. Plasma exchange can be performed in patients with severe CV and should be considered in severe or life-threatening cases combined with high doses of corticosteroids and antiviral treatment. A cautious use of rituximab can be considered only in association with NA treatment in refractory cases. A review of the literature and an analysis of data collected by six centers of the Italian Group for the Study of Cryoglobulinemia on 18 HBV-CV nucleotide/nucleoside analogues (NAs)-treated patients were carried out.

People with cryoglobulinaemic vasculitis (CV) have an increased risk of infections, attributed to different causes: impairment of the immune system due to the disease itself, comorbidities, and immunosuppressive therapy. Therefore, these patients may be at high risk for a more severe course of COVID-19, including hospitalisation and death. Concerns about efficacy, immunogenicity and safety of vaccines, as well as doubts, not yet fully clarified in patients with systemic autoimmune diseases, represent other important factors for a low vaccination rate in people with (CV). Indeed, providing an expert position on the issues related to SARS-CoV-2 vaccination in patients suffering from CV is of critical relevance in order to help both patients and clinicians who are treating them in making the best choice in each case. A multidisciplinary task force of the Italian Group for the Study of Cryoglobulinaemia (GISC) was convened, and through a Delphi technique produced provisional recommendations regarding SARS-CoV-2 vaccination in cryoglobulinaemic patients.

Hepatitis B virus (HBV) is a hepatotropic virus that causes hepatitis, cirrhosis and hepatocellular carcinoma. Twenty percent of HBV patients may develop extra-hepatic manifestations, such as polyarthritis nodosa, glomerulonephritis, dermatitis, poly-arthralgia and arthritis, and aplastic anemia. The association of HBV and cryoglobulinemic vasculitis (CV) has been highlighted by several epidemiological investigations. CV can develop in 0.5-4% of HBV infected patients. It has been demonstrated that suppression of HBV replication by nucleot(s)ide analogues (NAs) effectively induces clinical response in most patients with mild to moderate CV, but low responses are seen in severe CV. Based on this evidence, NAs therapy represents the first line therapeutic option in subjects with mild or moderate HBV related CV. Peg-interferon-Alfa can be an alternative treatment for HBV related CV, but the few studies published so far have shown no encouraging results. In patients with severe vasculitis and/or skin ulcers, peripheral neuropathy and glomerulonephritis treatment with rituximab (RTX) and NAs should be considered as a first line treatment. The long-term administration of low-medium glucocorticoid doses has been widely used in few studies to control clinical symptoms, but it should be used as a second option, when RTX is ineffective or not tolerated and in association with NAs. This review focuses on novel treatments for HBV related CV.

Hepatitis C virus (HCV) infection affects about 70 million people worldwide. HCV is responsible for both hepatitis and extra-hepatic manifestations. Chronic infection has been shown to develop in about 70% of cases and can progress to cirrhosis or hepatocellular carcinoma. Ten percent of HCV patients may develop extra-hepatic manifestations, including mixed cryoglobulinemia (MC) and non-Hodgkin lymphomas. Many studies have demonstrated that, after antiviral therapy, MC can disappear along with HCV eradication. After the introduction of the new direct antiviral agents (DAAs), the combination of pegylated interferon and ribavirin has been abandoned. Several studies on new DAAs have reported remarkable 90% to 100% eradication rates, regardless of HCV genotype. Treatment with DAAs has comparable efficacy on viral eradication in patients with MC, but definite clinical improvements of vasculitis can be observed only in half the patients. On the contrary, the regression of renal disease and lympho-proliferative disorders, induced by HCV, appears to have a lower remission rate after viral eradication with DAAs and most cases need immunosuppressive treatments. In HCV related CV, the main clinical goal must be early eradication of HCV, to avoid organ complication and manifestation of lympho-proliferative diseases. This review focuses on the role of DAAs in treatment of HCV-related cryoglobulinemic vasculitis., Competing Interests: Declaration of Competing Interest The authors have no conflict of interests to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Cryoglobulinemic vasculitis (CV) can develop in 1.2-4% of hepatitis B virus (HBV)-infected patients. HBV infection affects about 350 million people worldwide. It can progress from acute or fulminant hepatitis to chronic hepatitis, cirrhosis or hepatocellular carcinoma. Twenty per cent of HBV patients may develop extra-hepatic manifestations, such as polyarteritis nodosa, glomerulonephritis, dermatitis, polyarthralgias and arthritis, lung disease, aplastic anaemia. Our review focuses on the role of antiviral agent nucleot(s)ide analogues (NAs) in treatment of HBV-related CV. The studies in literature have demonstrated that NAs therapy in HBV-related CV yields high virological and satisfying clinical responses in most patients with mild-and-moderate CV, but a low response in severe CV. Overall, NAs represent a promising therapeutic option for HBV-related CV. Obtaining early suppression of HBV viral load should be the main virological and clinical goal in order to prevent organ complications and lymphoproliferative disorders., (© 2019 The Association for the Publication of the Journal of Internal Medicine.)

Background & Aims: Hepatitis C virus (HCV)-related mixed cryoglobulinaemia vasculitis (MCV) is characterized by the expansion of rheumatoid factor-producing B-cell clones. The aim of this study was to assess whether B-cell clones may persist in these patients after the clearance of the virus with antiviral therapy, and whether their persistence influences clinical outcomes., Methods: Forty-five HCV-cured MCV patients were followed up for a median of 18.5 (range 9-38) months after the clearance of HCV. Circulating B-cell clones were detected using flow cytometry either by the skewing of kappa/lambda ratio or by the expression of a V H 1-69-encoded idiotype., Results: The clinical response of vasculitis was 78% complete, 18% partial and 4% null. However, cryoglobulins remained detectable in 42% of patients for more than 12 months. Circulating B-cell clones were detected in 18 of 45 patients, and in 17 of them persisted through the follow-up; nine of the latter patients cleared cryoglobulins and had complete response of vasculitis. Several months later, two of these patients had relapse of MCV., Conclusions: B-cell clones persist in MCV patients long after HCV infection has been cleared but halt the production of pathogenic antibody. These 'dormant' cells may be reactivated by events that perturb B-cell homeostasis and can give rise to the relapse of cryoglobulinaemic vasculitis., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This study aims to evaluate the efficacy and safety of repeated treatments with low-dose rituximab for relapsing mixed cryoglobulinemia vasculitis. Thirty-seven patients with mixed cryoglobulinemia vasculitis refractory to standard of care treatment, 34 of which were HCV-positive, were treated with rituximab at the reduced dosage of 250 mg/m 2 given twice 1 week apart per cycle. Thirty patients (81%) achieved a clinical response; 5 of them remain in remission, 3 were lost to follow-up or died, and 22 relapsed after a mean of 15.7 months. Eleven relapsers were retreated with one (6 patients), 2 (3 patients), or 3 (2 patients) additional rituximab cycles given at each relapse. Clinical and laboratory efficacy and side effects of long-term treatment were evaluated. Clinical response to retreatment was 91% (10/11) at the first relapse, 80% (4/5) at the second relapse, and 100% (2/2) at the third relapse. The mean (±SD) time to relapse was 17.1 ± 14.1 months in 30 patients who were treated with only one cycle (from first cycle to the first relapse) and 45.7 ± 30.6 months (from first cycle to the last observed relapse) in 11 patients treated with 2 or more cycles (p = 0.0037). Severe adverse reactions occurred in 3 patients, in 2 of whom at the first cycle. Our results suggest that repeated treatment of relapsing mixed cryoglobulinemia with a low-dose rituximab regimen is efficacious, safe, and cost-effective for the long-term management of this disorder.

Hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC) vasculitis commonly regresses upon virus eradication, but conventional therapy with pegylated interferon and ribavirin yields approximately 40% sustained virologic responses (SVR). We prospectively evaluated the efficacy and safety of sofosbuvir-based direct-acting antiviral therapy, individually tailored according to the latest guidelines, in a cohort of 44 consecutive patients with HCV-associated MC. In two patients MC had evolved into an indolent lymphoma with monoclonal B-cell lymphocytosis. All patients had negative HCV viremia at week 12 (SVR12) and at week 24 (SVR24) posttreatment, at which time all had a clinical response of vasculitis. The mean (±standard deviation) Birmingham Vasculitis Activity Score decreased from 5.41 (±3.53) at baseline to 2.35 (±2.25) (P < 0.001) at week 4 on treatment to 1.39 (±1.48) (P < 0.001) at SVR12 and to 1.27 (±1.68) (P < 0.001) at SVR24. The mean cryocrit value fell from 7.2 (±15.4)% at baseline to 2.9 (±7.4)% (P < 0.01) at SVR12 and to 1.8 (±5.1)% (P < 0.001) at SVR24. Intriguingly, in the 2 patients with MC and lymphoma there was a partial clinical response of vasculitis and ∼50% decrease of cryocrit, although none experienced a significant decrease of monoclonal B-cell lymphocytosis. Adverse events occurred in 59% of patients and were generally mild, with the exception of 1 patient with ribavirin-related anemia requiring blood transfusion., Conclusion: Interferon-free, guideline-tailored therapy with direct-acting antivirals is highly effective and safe for HCV-associated MC patients; the overall 100% rate of clinical response of vasculitis, on an intention-to-treat basis, opens the perspective for curing the large majority of these so far difficult-to-treat patients. (Hepatology 2016;64:1473-1482)., (© 2016 by the American Association for the Study of Liver Diseases.)

The host genetic basis of mixed cryoglobulin vasculitis is not well understood and has not been studied in large cohorts. A genome-wide association study was conducted among 356 hepatitis C virus (HCV) RNA-positive individuals with cryoglobulin-related vasculitis and 447 ethnically matched, HCV RNA-positive controls. All cases had both serum cryoglobulins and a vasculitis syndrome. A total of 899 641 markers from the Illumina HumanOmni1-Quad chip were analyzed using logistic regression adjusted for sex, as well as genetically determined ancestry. Replication of select single-nucleotide polymorphisms (SNPs) was conducted using 91 cases and 180 controls, adjusting for sex and country of origin. The most significant associations were identified on chromosome 6 near the NOTCH4 and MHC class II genes. A genome-wide significant association was detected on chromosome 6 at SNP rs9461776 (odds ratio=2.16, P=1.16E-07) between HLA-DRB1 and DQA1: this association was further replicated in additional independent samples (meta-analysis P=7.1 × 10(-9)). A genome-wide significant association with cryoglobulin-related vasculitis was identified with SNPs near NOTCH4 and MHC Class II genes. The two regions are correlated and it is difficult to disentangle which gene is responsible for the association with mixed cryoglobulinemia vasculitis in this extended major histocompatibility complex region.

Objective: To investigate the contribution of inherited and acquired thrombophilic defects to the clinical manifestations of mixed cryoglobulinaemia vasculitis., Methods: The following thrombophilic defects were investigated in 64 consecutive patients with HCV-associated mixed cryoglobulinaemia: aPLs, lupus anti-coagulant, homocysteinaemia, protein C and protein S concentrations, activated protein C resistance, plasminogen activator inhibitor-1 4G4G and 5G5G genotypes, and the presence of mutations of factor V (Leiden and H1299R), of prothrombin (G20210A) and of methyl tetrahydrofolate reductase (C677T and A1298C). Additional variables were demographic data, duration of the disease, cryocrit level and vascular risk factors (diabetes, hypertension, hypercholesterolaemia and smoking habit). The following clinical manifestations of mixed cryoglobulinaemia were analysed as dependent covariates: severity of purpura, presence of necrotic skin ulcers, presence of peripheral neuropathy and presence of kidney disease., Results: Logistic regression analysis identified hyperhomocysteinaemia as a risk factor for severe purpura (P < 0.0001) and for the presence of skin ulcers (P < 0.0001), whereas none of the other thrombophilic defects influenced the clinical presentation of mixed cryoglobulinaemia. Purpura improved in two patients after lowering homocysteine with vitamin supplementation., Conclusions: Hyperhomocysteinaemia may be a risk factor for severe cutaneous manifestations in mixed cryoglobulinaemia.