Cryoglobulinemia Research Articles

Cutaneous manifestations of HAV, HBV, HCV.

Hepatotropic viral infections are a relevant global health problem and present multiple extrahepatic manifestations in addition to hepatic disease. Along with generic cutaneous symptoms correlated to the cholestatic liver disease that may arise during the infection, some cutaneous manifestations of hepatotropic viral infections are characteristic, enabling to suspect the underlying infection. This review will present the principal cutaneous manifestations of hepatotropic virus infection. Cutaneous manifestations are rare in HAV infections: these include urticaria, panniculitis, scarlatiniform eruption, evanescent skin rash, maculopapular prolonged rash, serum sickness-like illness rash, cutaneous vasculitis, cryoglobulinemia. The commonest cutaneous manifestation associated to HBV infection is serum sickness-like syndrome. Polyarteritis nodosa (PAN) is among the most common and serious cutaneous manifestations of HBV infection. In children, HBV infection may acutely manifest as papular acrodermatitis of childhood (Gianotti-Crosti Syndrome), with non-pruritic, non-coalescing, round papules. Patients with chronic HBV infection may also develop mixed cryoglobulinemia, that is, inter alia, the most documented extrahepatic manifestation of HCV infection. Cutaneous lichen planus has been associated to HBV and HCV infection. As for oral lichen planus, the association with HBV and HCV is more debated. Interestingly, patients with oral lichen planus with HCV have a higher risk of developing oral squamous cell carcinoma. Dermatologists should be aware of the possible cutaneous manifestations associated to viral hepatitis.

Role of different direct-acting antiviral drugs on hepatitis C virus-associated mixed cryoglobulinemia in Egyptian patients

BackgroundSeveral extrahepatic manifestations have been reported and mixed cryoglobulinemia is a clonal disorder of B cells which is strongly associated with hepatitis C virus (HCV).New regimens of direct-acting antiviral agents (DAAs) have recently been approved for the treatment of genotype 4 HCV which offer improved results of sustained virologic response (SVR) in the treatment-naive and previously treated patients.AimTo assess the prevalence of cryoglobulinemia for evaluating the efficacy of DAA therapy on it.Patients and methodsPatients received one of the following regimens: sofosbuvir, daclatasvir±ribavirin, or sofosbuvir plus ledipasvir±ribavirin follow-up for 24 weeks after treatment.ResultsA total of 132 patients were involved in our study: 65 men and 67 women. Cryocrit-positive patients clinically presented with clinical manifestations in 32 (53.3%) patients out of the 60 patients. After 12 weeks of DAAs treatment, there was a significant reduction in cryoprecipitate level and rheumatoid factor (RF) level with improvement of glomerular filtration rate, basal C4, and clinical improvement of purpura, Raynaud’s phenomenon, and this was the same when 38 patients continued treatment for 24 weeks. However, comparing 12 and 24-week therapy showed significant improved difference in cryoprecipitate level but improved glomerular filtration rate, basal C4, and decreased level of RF, proteinuria, purpura, and peripheral neuropathy although it did not reach statistical significanceConclusionCryocrit-positive patients were old age, cirrhotics with long duration of HCV. There is significant improvement of both laboratory and clinical parameters of cryoglobulinemia after SVR12 and more significant after SVR24. There is no significant difference in using different DDA regimen with or without ribavirin on the SVR at either 12 or 24 weeks. So, we advise basal laboratory and clinical parameters of mixed cryoglobulinemia before designing treatment regimens of HCV patients in Egypt.

The role of interleukin-17 gene polymorphism (RS612242 C11139G) in the formation of the cryoglobulinemic syndrome in patients with chronic hepatitis C

Background. Chronic hepatitis C (CHC) is characterized by the development of extrahepatic symptom manifestations, which leads to an increased risk of mortality in these patients. Today, the factors contributing to the development of extrahepatic manifestations of CHC are being studied. Particular attention is paid to determining the clinical significance of cytokine gene polymorphism. Therefore, the aim of our work was study the role of interleukin-17 gene polymorphism (rs612242 C11139G) in the mixed cryoglobulinemia (MC) formation and manifestation of cryoglobulinemic syndrome in patients with chronic hepatitis C.Materials and methods. The study included 149 patients with CHC and 45 healthy people. Determination of single-nucleotide IL-17 gene polymorphism (rs 612242 C11139G) was performed by real-time polymerase chain reaction. Statistical processing was performed in program "STATISTICA for Windows 13" (StatSoft Inc., No. JPZ804I382130ARCN10-J).Results. We found that most often in patients with CHC (140 - 94.0%) and in healthy people (39 - 86.7%) was detected СС-genotype. It was found that the GG genotype was found to be significantly more likely in healthy subjects (χ2=20.5, p<0.0001). It was determined that patients with MC were significantly more likely to have a CC-genotype compared with healthy people (χ2=5.08, p<0.05), but the frequency of detection of this genotype was not statistically different compared with patients without MC (p>0.05). In patients with CHC carriers of the CC genotype of the IL-17 gene polymorphism significantly more likely (p<0.05), clinical signs associated with MC, namely weakness (65.6% vs. 40.0%), arthralgia (58.9% vs. 30.0%), vasculitis (14.4% vs. 2.0%) with the formation of the Meltzer’s triad (14.4% vs. no formation). It was showed that type 2 diabetes was significantly more likely to be detected in patients without MC (χ2=5.52, p<0.05).Conclusion. Allele C of the IL-17 gene polymorphism has an effect on the chronicity of hepatitis C according to a multiplicative model of inheritance. The CC-genotype plays a role in the formation of HCV-associated MC. Weakness, arthralgia and vasculitis with the formation of the Meltzer’s triad are the most common manifestations of cryoglobulinemic syndrome.

Virologic Clearance of Hepatitis C Is Associated with Improved Outcomes in African American Patients with Lymphoma

Background: Association of hepatitis C virus (HCV) infection and B-cell non-Hodgkin Lymphoma (B-NHL) is well-established. Directly-acting antiviral HCV therapy (DAA) results in very high rates of sustained viral response (SVR) and HCV cure. Studies of the impact of successful antiviral therapy on lymphoma outcomes in HCV-infected patients can have important implications for patient management and for understanding of the biology of different lymphomas. The strongest evidence of positive impact of HCV antiviral therapy on lymphoma regression is available for indolent lymphomas, especially marginal zone lymphoma. Impact of antiviral therapy on HCV-associated aggressive B-NHL is still under investigation. Furthermore, there is no data on outcomes for HCV-associated B-NHL in African-American (AA) patients. The aim of this study was to evaluate lymphoma characteristics and outcomes in HCV-associated B-NHL, in a predominantly AA population. Methods: All consecutive patients with lymphoma and reactive HCV Antibody (HCV Ab+) diagnosed and treated at our center between January 2003 and December 2017 were studied. Patients with HCV-associated mixed cryoglobulinemia without any overt lymphoma, HCV-associated paraproteinemia and patients who did not have antiviral treatment history available were excluded. All information was obtained by review of electronic medical records. Baseline patient characteristics including age, sex, race, comorbidity including HIV infection, lymphoma stage, histology, prognostic score and baseline lactate dehydrogenase (LDH) were recorded. Lymphomas were classified according to the 2016 WHO classification. Prognostic score was calculated using International Prognostic Index (IPI) for aggressive lymphomas, Follicular Lymphoma International Prognostic Index (FLIPI) for indolent lymphomas other than chronic lymphocytic leukemia (CLL) and CLL-IPI for CLL. Details of lymphoma treatment and antiviral therapy were recorded. Virologic clearance (VC) was used to collectively describe both SVR (undetectable HCV RNA 12 weeks after completion of antiviral treatment) and spontaneous clearance of HCV without treatment. Study outcomes were overall response rate (ORR), complete response rate (CR), overall survival (OS) and progression free survival (PFS). Results: We found 397 patients with lymphoma at our institution, of which, 40 patients had HCV. Thirty-eight patients had complete lymphoma and antiviral treatment history available and were included in the analysis. Median age was 58 years, 90% were AA; 68% were men. Diffuse large B-cell lymphoma (DLBCL) was the predominant histology (50%). Advanced stage (64%), aggressive lymphoma (60%), good prognostic score (74%) and elevated LDH (66%) were common. A total of 21 patients were treated, 18 with DAA and 3 with interferon-based therapy. Twenty-two patients had VC, either spontaneous or with antiviral therapy. Patients with VC, had significantly higher ORR (95% vs 69%, RR 2.4, CI95 1.3-4.4, p<0.05) and CR (73% vs 38%, 2.29, CI95 1.1-5.0.0, p<0.05) compared to patients without VC. Median OS was also significantly higher in patients with VC than patients without VC (not reached vs 89 months, RR 0.4, CI95 0.2-0.6, p<0.05) . Median PFS was not significantly different between two groups. We analyzed ORR and CR in subgroups of aggressive lymphoma, indolent lymphoma and DLBCL. Patients with VC had significantly higher CR then patients without VC in the subgroups of aggressive lymphoma and DLBCL (100% vs 46% and 100% vs 45% respectively, p<0.05), while ORR was not different. Conclusions: Hepatitis C VC is associated with improved CR and OS in predominantly AA lymphoma patients including patients with aggressive B-NHL. The precise role and timing of HCV antiviral therapy in HCV-associated aggressive B-NHL should be assessed in large prospective studies that include AA patients. Disclosures No relevant conflicts of interest to declare.

Understanding the Cryoglobulinemias.

Cryoglobulins are immunoglobulins with the ability to precipitate at temperatures <37°C. They are related to hematological disorders, infections [especially hepatitis C virus (HCV)], and autoimmune diseases. In this article, the state of the art on Cryoglobulinemic Vasculitis (CV), in a helpful and schematic way, with a special focus on HCV related Mixed Cryoglobulinemia treatmentare reviewed. Direct - acting antivirals (DAA) against HCV have emerged as an important key in HCV treatment torelated Cryoglobulinemic Vasculitis, and should be kept in mind as the initial treatment in non-severe manifestations. On the other hand, a recent consensus panel has published their recommendations for treatment in severe and life threatening manifestations of Mixed Cryoglobulinemias. HCV-Cryoglobulinemic vasculitis is the most frequent form of CV. There are new treatment options in HCV-CV with DAA, with an important number of patients achieving complete response and sustained virologic response (SVR). In cases of severe forms of CV, treatment with Rituximab and PLEX are options. Thelack of data on maintenance therapy could impulse future studies in this setting.

Diagnostic and Treatment of Cryoglobulinemiс Vasculitis: What is Important for Real Clinical Practice?

Cryoglobulinemia is a condition in which circulating cryoprecipitate immune complexes are detected in serum. The cryoglobulin concentration above 50 mg/l is considered diagnostically significant for the statement of cryoglobulinemia. The production of cryoglobulins, as a rule, is a consequence of the underlying disease, which requires etiological evaluation. The diagnosis of cryoglobulinemic vasculitis (CV) is based on laboratory detection of serum cryoglobulinemia in combination with characteristic clinical signs and symptoms. The main clinical manifestations include common symptoms (severe fatigue, unexplained fever with or without weight loss), skin lesions (orthostatic palpable purpura, necrotic ulcers), joints (arthritis, arthralgia), peripheral nervous system (mononeuritis, polyneuritis) and kidney (membranoproliferative glomerulonephritis). Given the many signs and symptoms, a patient with CV rarely turns primarily to a rheumatologist. First contact doctors are often family doctors or dermatologists, along with the fact that the awareness of doctors of other specialties about this pathology is insufficient. The article presents modern data on the etiological factors, CV types and variants of the clinical course and treatment. CV classification criteria are highly informative and available to practitioners. Treatment of CV remains a challenge due to serious specific target organ damage and sometimes life-threatening manifestations. In secondary cryoglobulinemia, treatment of the underlying disease is crucial. In case of CV on the background of mixed cryoglobulinemia, the treatment strategy is based on antiviral, anti-inflammatory and immunosuppressive therapy. The therapy goals for CV include reducing the immunoglobulin level and removing the antigen. The first goal can be achieved with immunosuppressants, while the second goal depends on whether the antigen is known or not. With CV associated with HCV, antiviral therapy reduces the number of antigens. However, in autoimmune diseases, the potential antigen is usually not recognized, and only non-specific immunosuppressants are used.

Sustained virologic response to direct-acting antiviral agents predicts better outcomes in hepatitis C virus-infected patients: A retrospective study

BACKGROUNDDirect-acting antiviral agents (DAAs) are extremely effective in eradicating hepatitis C virus (HCV) in chronically infected patients. However, the protective role of the sustained virologic response (SVR) achieved by second- and third-generation DAAs against the onset of hepatocellular carcinoma (HCC) and mortality is less well established.AIMTo examine the occurrence of HCC or death from any cause in a retrospective-prospective study of patients treated with DAAs.METHODSPatients were enrolled from a tertiary academic hospital center for liver disease management that collects subject data mainly from northeastern Italy. The study was conducted in 380 patients (age: 60 ± 13 years, 224 males, 32% with cirrhosis) treated with DAAs with or without SVR (95/5%), with a median follow up of 58 wk (interquartile range: 38-117). The baseline anthropometric features, HCV viral load, severity of liver disease, presence of extra-hepatic complications, coinfection with HIV and/or HBV, alcohol consumption, previous interferon use, alpha-fetoprotein levels, and renal function were considered to be confounders.RESULTSThe incidence rate of HCC in patients with and without SVR was 1.3 and 59 per 100 person-years, respectively (incidence rate ratio: 44, 95%CI: 15-136, P < 0.001). Considering the combined endpoint of HCC or death from any cause, the hazard ratio (HR) for the SVR patients was 0.070 (95%CI: 0.025-0.194, P < 0.001). Other independent predictors of HCC or death were low HCV viremia (HR: 0.808, P = 0.030), low platelet count (HR: 0.910, P = 0.041), and presence of mixed cryoglobulinemia (HR: 3.460, P = 0.044). Considering SVR in a multi-state model, the independent predictors of SVR achievement were absence of cirrhosis (HR: 0.521, P < 0.001) and high platelet count (HR: 1.019, P = 0.026). Mixed cryoglobulinemia predicted the combined endpoint in patients with and without SVR (HR: 5.982, P = 0.028 and HR: 5.633, P = 0.047, respectively).CONCLUSIONDAA treatment is effective in inducing SVR and protecting against HCC or death. A residual risk of HCC persists in patients with advanced liver disease or with complications, such as mixed cryoglobulinemia or renal failure.

Sentinel biomarkers in HCV positive patients with mixed cryoglobulinemia

BackgroundInfections, autoimmunity and cancer play a role as determinants of etiology in Hepatitis C virus (HCV) related mixed cryoglobulinemia (MC). Several factors of risk have been suggested as markers of pathogenesis and progression of HCV-related MC into B cell Non-Hodgkin's Lymphoma (B-NHL). Here, we evaluated IgG subclass distribution, free light chains (FLCs) and vascular endothelial growth factor (VEGF) as a new combination of biomarkers. MethodsWe measured IgG1–4 subclasses, FLCs and VEGF levels in sera 53 from HCV-related MC, in comparison with 40 sera from HCV negative patients with rheumatoid arthritis (RA) and 30 from healthy blood donors (HBD). ResultsIgG3 levels were significantly higher in HCV-MC patients with a decrement of IgG2 and IgG4; FLC levels significantly increased in both MC and RA patients' groups; serological VEGF was higher in HCV-MC patients than in HBD in correlation with k and λ levels. ConclusionOur results suggest that a specific IgG subclasses pattern together with raised levels of FLCs and VEGF could represent the biomarker “signature” of an inflammation multistage of acquired immune system.

Direct-Acting Antiviral Agents for HCV-Associated Glomerular Disease and the Current Evidence.

Glomerular disease is an extra-hepatic manifestation of hepatitis C virus infection (HCV) and membranoproliferative glomerulonephritis is the most frequent glomerular disease associated with HCV. It occurs commonly in patients with HCV-related mixed cryoglobulinemia syndrome. Patients with HCV-related glomerular disease have been historically a difficult-to-treat group. The therapeutic armamentarium for HCV-related glomerular disease now includes antiviral regimens, selective or non-specific immunosuppressive drugs, immunomodulators, and symptomatic agents. The treatment of HCV-associated glomerular disease is dependent on the clinical presentation of the patient. The recent introduction of all-oral, interferon (IFN)-free/ribavirin (RBV)-free regimens is dramatically changing the course of HCV in the general population, and some regimens have been approved for HCV even in patients with advanced chronic kidney disease. According to a systematic review of the medical literature, the evidence concerning the efficacy/safety of direct-acting antiviral agents (DAAs) of HCV-induced glomerular disease is limited. The frequency of sustained virological response was 92.5% (62/67). Full or partial clinical remission was demonstrated in many patients (n = 46, 68.5%) after DAAs. There were no reports of deterioration of kidney function in patients on DAAs. Many patients (n = 29, 43%) underwent immunosuppression while on DAAs. A few cases of new onset or relapsing glomerular disease in patients with HCV successfully treated with DAAs have been observed. In summary, DAA-based combinations are making easier the management of HCV. However, patients with HCV-induced glomerular disease are still a difficult-to-treat group even at the time of DAAs.

PALPABLE PURPURA, RENAL FAILURE, AND DIFFUSE ALVEOLAR HEMORRHAGE SECONDARY TO STREPTOCOCCAL MUTANS INFECTION: A CASE REPORT

SESSION TITLE: Wednesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: Cryoglobulins are defined as immunoglobulins that precipitate in the cold and dissolve upon rewarming. Mixed cryoglobulinemia is a condition characterized by the presence of cryoglobulins in the serum that have both IgG and IgM components. Although typically associated with hepatitis C, this disease can also be due to an infectious etiology. Cryoglobulins can occasionally deposit in small blood vessels throughout the body, leading to a mixed cryoglobulinemic vasculitis. CASE PRESENTATION: A 66-year-old male presented with an extensive purpuric lower extremity rash and shortness of breath. Lab work initially was remarkable for acute renal failure and a normocytic, normochromic anemia. The patient was found to be bacteremic with Streptococcus mutans and started on a four-week course of penicillin. Transesophageal echocardiogram showed aortic valve thickening without frank vegetations, leading to a diagnosis of presumed endocarditis. Five days into his hospital stay, the patient developed hemoptysis and acute hypoxic respiratory failure. He was subsequently intubated and transferred to intensive care. Bronchoscopy revealed diffuse alveolar hemorrhage (DAH). Rheumatologic work up was positive for C3 hypocomplementemia and cryoglobulinemia; however, the patient was negative for hepatitis C. Extensive autoimmune workup was unremarkable. Renal biopsy ultimately revealed focal necrotizing and crescentric glomerulonephritis (GN) with mesangial C3 staining, most consistent with endocarditis-associated GN. The patient had improvement in symptoms with antimicrobial therapy alone and demonstrated no benefit from corticosteroids or plasma exchange. He was ultimately extubated and discharged home. DISCUSSION: Mixed cryoglobulinemic vasculitis typically presents with palpable purpura and arthralgias. One atypical sequela is pulmonary capillaritis, leading to diffuse alveolar hemorrhage. While there is no clear association with endocarditis-associated GN and mixed cryoglobulinemia, they are both immune-mediated conditions that result in the deposition of immune complexes. The standard treatments of those diagnosed with mixed cryoglobulinemic vasculitis are immunosuppressive therapy and plasma exchange. However, initiating immunosuppressive therapy without antimicrobial therapy in patients with disease secondary to infection could lead to increased mortality and recurrence rates. CONCLUSIONS: This was a patient who not only presented with S. mutans bacteremia but also developed multiple potentially fatal sequelae that are not typically seen. He was fortunate to have recovered following antimicrobial therapy. Therefore, although mixed cryoglobulinemic vasculitis is typically secondary to hepatitis C infection, less common etiologies must remain on the differential in order to ensure prompt and appropriate treatment. Reference #1: Cryoglobulinemia. Background, Pathophysiology, Epidemiology. https://emedicine.medscape.com/article/329255-overview. Published February 3, 2019. Accessed March 14, 2019. Reference #2: Belizna CC, Hamidou MA, Levesque H, Guillevin L, Shoenfeld Y. Infection and vasculitis. Rheumatology (Oxford, England). https://www.ncbi.nlm.nih.gov/pubmed?term=19258377. Published May 2009. Accessed March 14, 2019. DISCLOSURES: No relevant relationships by Soorya Aggarwal, source=Web Response No relevant relationships by Nathan Brewster, source=Web Response No relevant relationships by Breanna Goldner, source=Web Response no disclosure on file for Jennifer Rovella

Lack of association between Vitamin D status and free light chains profile with different chronic HCV-related liver and extrahepatic disorders.

A still uncertain association between vitamin D levels and HCV chronic liver diseases has been reported. Increased levels of serum-free light chains (FLCs) and an altered k/λ FLC ratio correlate with Mixed Cryoglobulinemia (MC) vasculitis and/or B-cell non-Hodgkin's lymphoma in HCV-positive patients. We aimed to investigate the possible role of vitamin D, vitamin D Binding Protein (DBP), and FLCs levels as a tool for discriminating different stages of HCV- related MC and chronic liver diseases. Sixty-five untreated patients were retrospectively enrolled and 21 healthy blood donors (HBD) were used as controls. Vitamin D, DBP, FLCs, and cryoglobulins levels were measured. Based on cryoglobulins, patients were divided in three subgroups (without cryoglobulins, type II, and type III). We didn't find any significant differences in vitamin D and DBP levels between HCV patients' main groups and HBD. Serum FLCs levels were significantly higher in HCV patients than in HBD. FLCs ratio among patients' subgroups did not reveal differences. Our results confirm the presence of an increased serum level of FLCs in HCV patients and suggest that nor vitamin D and DBP or FLC levels can be considered reliable biomarkers for discriminating different stages of HCV-associated chronic liver diseases and/or HCV-associated extrahepatic manifestation. We confirm that serological FLCs levels are significantly higher in patients than in HBD as a signature of B cell activation in course of HCV infection.

The dilemma of treating hepatitis C virus-associated cryoglobulinemia.

The present review focuses on the new therapeutic opportunities offered by the combination of biological drugs, mainly Rituximab, with direct-acting antiviral agents (DAAs). Hepatitis C virus (HCV) is known to be the etiologic agent in the majority of patients with mixed cryoglobulinemia syndrome. Clinical research has been focused on antiviral drugs and, more recently, on the new, highly potent DAAs. New DAAs assure sustained virologic response (SVR) rates greater than 90% with relief of mild-to-moderate symptoms. Mixed cryoglobulinemia may present with multiorgan vasculitis involving kidneys, joints, skin, and peripheral nerves. Data on DAAs efficacy in HCV-associated cryoglobulinemic vasculitis are disappointing possibly because of the inability of these drugs to suppress the immune-mediated process once it has been triggered. Immunosuppression has often been employed in the past as a first-line therapy in cryoglobulinemic vasculitis despite the potential risk of the infection exacerbation. However, more manageable Rituximab-based therapeutic approaches have been more recently used without increase of viral load. Rituximab substantially changed the outcome of HCV-associated cryoglobulinemic vasculitis by providing long-term remission. A combination schedule of DAAs and Rituximab may result in eradication of both cryoglobulinemic vasculitis and HCV infection.

Cryoglobulinemic vasculitis and glomerulonephritis: concerns in clinical practice.

Objective:Cryoglobulinemia often causes systemic vasculitis, thereby damaging to skin and internal organs including kidneys, even life-threatening. This review aimed to introduce the advances in understanding, detection, and treatment of this disease in recent years, with a particular concern to clinical practice.Data sources:All the data in this review were from the English or Chinese literature in the PubMed and China National Knowledge Infrastructure databases as of March 2019.Study selection:This review selected important original articles, meaningful reviews, and some reports on cryoglobulinemia published in recent years and in history, as well as the guidelines for treatment of underlying diseases which lead to cryoglobulinemia.Results:Diagnosis of cryoglobulinemia relies on serum cryoglobulin test, in which to ensure that the blood sample temperature is not less than 37°C in the entire pre-analysis phase is the key to avoid false negative results. Cryoglobulinemic vasculitis (Cryo Vas), including cryoglobulinemic glomerulonephritis (Cryo GN), usually occurs in types II and III mixed cryoglobulinemia, and can also be seen in type I cryoglobulinemia caused by monoclonal IgG3 or IgG1. Skin purpura, positive serum rheumatoid factor, and decreased serum levels of C4 and C3 are important clues for prompting types II and III Cryo Vas. Renal biopsy is an important means for diagnosis of Cryo GN, while membranous proliferative GN is the most common pathological type of Cryo GN. In recent years, great advances have been made in the treatment of Cryo Vas and its underlying diseases, and this review has briefly introduced these advances.Conclusions:Laboratory examinations of serum cryoglobulins urgently need standardization. The recent advances in the diagnosis and treatment of Cryo Vas and GN need to be popularized among the clinicians in related disciplines.

Severe Guillain-Barr\xe9 syndrome associated with chronic active hepatitis C and mixed cryoglobulinemia: a case report

BackgroundWe describe a case of severe Guillain-Barre syndrome (GBS) associated with chronic active hepatitis C and mixed cryoglobulinemia (MC). To our knowledge, this association between GBS and hepatitis C virus (HCV) infection has been rarely reported.Case presentationA 56-year-old man developed symmetrical muscle weakness in all extremities, areflexia and sensorial disorder followed by acute respiratory failure associated with chronic active hepatitis C, which was confirmed by the presence of anti-HCV antibodies in the serum and persistence of HCV RNA viral load for more than 6 months. Chronic hepatitis C was further complicated by type 3 MC. Electromyography showed peripheral nerve injury (mainly in axon). A severe acute motor sensory axonal neuropathy (AMSAN) was diagnosed. After treatment with intravenous immunoglobulin and plasma exchange followed by antiviral therapy by direct-acting antiviral agent, patient showed progressive recovery and was transferred 3 months after his first admission to a rehabilitation center.ConclusionsOur case reported a severe GBS associated with HCV infection and MC. EMG classified for the first time the subtype of GBS (severe AMSAN) correlated with severe clinical form. HCV infection should be screened in high-risk patients to prevent silent progression of the chronic hepatitis C and its potentially severe extra-hepatic manifestations.

Rheumatoid factor and immunoglobulin M mark hepatitis C-associated mixed cryoglobulinaemia: an 8-year prospective study

ObjectivesThe prevalence and factors of hepatitis C virus (HCV) -associated mixed cryoglobulinaemia in Asia remain elusive, and we aimed to investigate these topics. MethodsAn 8-year prospective cohort study was conducted in 678 consecutive Taiwanese individuals with chronic HCV infection (438 completed an anti-HCV therapy course). ResultsOf 678 individuals, 437 (64.5%) had mixed cryoglobulinaemia and 20 (2.9%) had mixed cryoglobulinaemic syndrome. At baseline, IgM (cut-off >122 mg/dL), triglycerides and IgG levels, and HCV genotype 3 were independently associated with mixed cryoglobulinaemia. Rheumatoid factor (RF) levels were associated with mixed cryoglobulinaemic syndrome (cut-off >12.2 IU/mL). At 24 weeks post-therapy, the 362 individuals with a sustained virological response (SVR) had higher cured (106/362 (29.3%) versus 10/76 (13.2%), p = 0.003) and lower persistent (100/362 (27.6%) versus 33/76 (43.4%), p = 0.003) mixed cryoglobulinaemia rates than non-SVR patients. Among SVR patients, compared with baseline levels, RF, IgG and IgM levels decreased, except in individuals with new mixed cryoglobulinaemia. Pre-therapy IgM levels were associated with 24-week post-therapy new (95% CI of OR 1.002–1.023) and persistent (95% CI of OR 1.004–1.015) mixed cryoglobulinaemia in SVR patients. After up to 8 years, 24-week post-therapy IgM levels were associated with mixed cryoglobulinaemia in SVR patients (9/51; 17.64%; 95% CI of HR 1.004–1.011). Among 17 SVR patients with pre-therapy mixed cryoglobulinaemic syndrome, 5 (29.4%) had long-term mixed cryoglobulinaemia and 4 (23.5%) had mixed cryoglobulinaemic syndrome. ConclusionsOver 60% of chronic HCV-infected individuals had mixed cryoglobulinaemia, and 17.64% of SVR patients had mixed cryoglobulinaemia 8 years post-therapy. Pre-therapy RF and IgM levels marked HCV-associated mixed cryoglobulinaemic syndrome and mixed cryoglobulinaemia, respectively.

Recommendations for managing the manifestations of severe and life-threatening mixed cryoglobulinemia syndrome

Some of the manifestations of mixed cryoglobulinemia syndrome (MCS) can be severe or life-threatening, and should be rapidly contained but, as the therapeutic approaches to such conditions are largely based on anecdotal data, a consensus conference was organised by the Italian Group for the Study of Cryoglobulinemia (GISC) with the aim of providing a set of recommendations based on an in-depth survey of the available data and expert opinion. The consensus panel, which included specialists working in different medical fields involved in the management of MCS patients, was first asked to divide the manifestations of MCS into severe or life-threatening conditions on the basis of their own experience, after which a complete literature review was carried out in accordance with the Cochrane guidelines for systematic reviews. Therapeutic plasma exchange (TPE) was considered the elective first-line treatment in the case of life-threatening manifestations of MCS (LT-MCS) and patients with severe clinical symptoms (S-MCS) who fail to respond to (or who are ineligible for) other treatments. The data supporting the combined use of cyclophosphamide and TPE were considered limited and inconclusive. High-dose pulsed glucocorticoid (GCS) therapy can be considered the first-line treatment of severe MCS, generally in association with TPE. Rituximab (RTX)-based treatments should be considered in patients with skin ulcers, peripheral neuropathy or glomerulonephritis, and in patients with persistent LT-MCS after TPE. In patients with hepatitis C virus-related MCS with S-MCS, viral eradication should be attempted as soon as a patient's condition allows the use of direct-acting antivirals.

CD5/CD20 expression on circulating B cells in HCV-related chronic hepatitis and mixed cryoglobulinemia

The role of CD5+ B cells in patients with HCV infection and HCV-related disorders, including mixed cryoglobulinemia (MC), has been addressed in previous reports with conflicting results. We established a correlation between CD5/CD20 expression on circulating B lymphocytes, characterizing monoclonal B cell lymphocytosis (MBL), and clinical features in a cohort of 45 patients with chronic HCV hepatitis [without MC: 23 patients (MC- group); with MC: 22 patients (MC+ group)], and 45 HCV-negative healthy subjects as controls. By flow cytometry analysis, three B cells phenotypes were singled out: 1) CD5+CD20dim (CLL-like phenotype); 2) CD5+CD20bright (atypical phenotype); and 3) CD5-CD20+ phenotype. CD5+CD20bright cells were reduced in MC- patients (p=0.049). CD5+CD20dim B cells were significantly higher in group B than in the control group (p=0.003). ROC curve analysis in MC+ patients showed the highest positive likelihood ratio at ≥7.35% (p=0.008) for CLL-like phenotype and at ≤63.6% (p=0.03) for the CD5-CD20+ B cell phenotype. HCV infection was associated with a higher frequency of CLL-like (odds ratio=16, p=0.002) and a lower frequency of atypical (odds ratio: 3.1, p=0.02) and CD5-CD20+ (odds ratio: 11, p=0.01) phenotypes. The association with higher levels of CLL-like phenotype progressively increased from group of MC- patients (odds ratio: 9.3, p=0.04) to the group of MC+ patients (odds ratio: 25.1, p=0.0003). ConclusionsThe occurrence of a CLL-like pattern may allow to identify HCV-infected patients at risk of developing MC and eventually non-Hodgkin lymphoma, who should require a closer surveillance and a longer follow-up.

Interaction of polymorphism of the interleukin-6 gene with immunological damages and their role in the development of mixed cryoglobulinemia in patients with chronic hepatitis C

Aim. To determine the role of the relationship of immunological disorders with interleukin-6 gene polymorphism in the formation of HCV-associated mixed cryoglobulinemia. Materials and methods. The study included 149 patients with chronic hepatitis C. The polymorphism of the IL-6 gene (rs1800795) was determined by the method of polymerase chain reaction, the quantitative content of IL-6, RF IgM and IgG by enzyme immunoassay, cryoglobulins by spectrophotometric method. The patients were divided into groups depending on the polymorphism of the IL-6 gene and the presence of mixed cryoglobulinemia. Results. The frequency of formation of HCV-associated mixed cryoglobulinemia depended on the polymorphism of the IL-6 gene. In patients with chronic hepatitis C with mixed cryoglobulinemia, the frequency of registration of the CC genotype of the IL-6 gene was lower than in patients without mixed cryoglobulinemia, namely, in 9.7 % versus 28.6 % of patients. The presence of the G-allele, namely the CG/GG genotypes of the IL-6 gene polymorphism, was more often detected in patients with mixed cryoglobulinemia, namely, in 90.3 % of patients against 71.4 % of patients without signs of mixed cryoglobulinemia (χ 2 = 8.94, P = 0.003). In the presence of G-allele, the quantitative content of IL-6 inthe serum of the general group of patients with CHC was higher than in healthy people (P 0.05). The highest levels of IL-6 were recorded in patients with HCV-associated mixed cryoglobulinemia who had the G-allele. The content of IL-6 in the blood serum of these patients exceeded the indicators of both healthy people (P < 0.001) and the results of patients without mixed cryoglobulinemia (P < 0.01). In patients with chronic hepatitis C with mixed cryoglobulinemia, even in the presence of the CC genotype, the content of IL-6 in serum was higher both in comparison with healthy (P < 0.01) and in comparison with patients without signs of this extrahepatic manifestation (P < 0.01). In patients with chronic hepatitis C with mixed cryoglobulinemia, the presence of CG/GG genotypes was associated not only with the highest serum IL-6 content, but also with the presence of more pronounced autoimmune disorders due to a higher content of RF IgM (P = 0.04) and mixed cryoglobulins (P = 0.03) in serum, in comparison with patients who had the CC genotype. Moreover, the presence of more pronounced immune disorders in patients with HCV-associated mixed cryoglobulinemia in the presence of CG/GG genotypes was accompanied by more frequent manifestation of severe general weakness (P = 0.003), arthralgia (P = 0.02) and the formation of Meltzer’s triad. Conclusion. The frequency of detection of the G-allele, namely the CG/GG genotypes of the IL-6 gene polymorphism, is the highest in patients with HCV-associated mixed cryoglobulinemia (90.3 %). The presence of CG/GG genotypes in patients with chronic hepatitis C with mixed cryoglobulinemia contributes to more pronounced immunological disorders due to the highest content of IL-6, mixed cryoglobulins, and RF IgM in serum, which causes the manifestation of the clinical symptoms of this hepatic manifestation.

A novel biomarker score for the screening and management of patients with plasma cell proliferative disorders.

Monoclonal plasma cell proliferative disorders comprise a wide spectrum of diseases associated to clonal B-cell expansion. Serum protein electrophoretic profile (SPEP) and circulating free light chains (FLCs) levels are the mainstay of diseases management. Recently, soluble (s) Syndecan-1 (SDC1, CD138) produced by myeloma plasma cells has been suggested in the monitoring and follow-up of patients with myeloma. The aim of our study is to evaluate sCD138 in addition with FLCs and SPEP for the screening of patients with different evolutive disease pathways. Sera from 73 patients with monoclonal gammopathy of undetermined significance (MGUS), 120 smoldering and 42 multiple myeloma (SMM and MM, respectively), 70 HCV-related mixed cryoglobulinemia (MC), 35 B-cell non-Hodgkin's lymphoma (B-NHL) and sera from 50 healthy donors (HD), were tested for sCD138, FLCs (assessed by means of ELISA and turbidimetric assay, respectively) and electrophoresis pattern (performed on Capillarys system) for the generation of a novel biomarker score (BS). Our results were grouped according to the two main lines of disease progression (vs. MM or B-NHL): in one group we found BS mean values of 0.2, 3.4, 5.3, 7.1 for HD, MGUS, SMM and MM, respectively; in the other group of 0.2, 4.4, 6.7 for HD, MC and B-NHL. We showed that BS mean values follow the ingravescence disease status towards the two main lines of progression to cancerous conditions; it could represent an additional useful tool in the management of screening and/or follow-up.

&lt;p&gt;Sofosbuvir–daclatasvir improves hepatitis C virus–induced mixed cryoglobulinemia: Upper Egypt experience [Corrigendum]&lt;/p&gt;

Sofosbuvir-daclatasvir improves hepatitis C virus-induced mixed cryoglobulinemia: Upper Egypt experience [Corrigendum] Hassan AM, Osman HA, Mahmoud HS, et al. Infect Drug Resist. 2018;11:895–901.On page 896, “Investigatory workup” section, first bullet point, second sentence should read from “Four milliliters of blood was taken in a plain glass tube, and after clotting, the tube was centrifuged at 3,000 rpm for 5 min. Then, the serum was separated for use in estimating liver function (including liver enzymes, albumin, bilirubin-total and direct, prothrombin time, prothrombin concentration, and INR), serum creatinine, protein:creatinine ratio, and RF . . . ” to “Two milliliters of blood was taken in citrated tubes and after centrifugation, the separated citrated plasma has been used for estimation of prothrombin time, prothrombin concentration, and INR, while the remaining two milliliters of blood was taken in a plain glass tube, and after clotting, the tube was centrifuged at 3,000 rpm for 5 min. Then, the serum was separated for use in estimating liver function (including liver enzymes, albumin, bilirubin-total and direct), serum creatinine, RF and in addition to urinary protein:creatinine ratio, all were measured . . . ” Following a review of our paper post-publication, we found the incorrect information for these sentences. This correction of sentences has no impact to the findings of the study. The authors apologize for this error.Read the original article