Cryoglobulinemia Syndrome Research Articles

Non HCV-Related Mixed Cryoglobulinemic Vasculitis With Biopsy-Proven Renal Involvement: The Effects of Rituximab.

In the countries where HCV infection is still endemic, about 90% of subjects with mixed cryoglobulinemia had previously been infected with HCV and about 80% are RNA positive. Remarkable results in severe HCV-related cryoglobulinemic vasculitis have been obtained with Rituximab. Details of the clinical characteristics and effective treatment of non HCV-related cryogloulinemic syndromes are presently lacking. This paper reports on a prospective single-Center open study aimed at evaluating the clinical presentation and effects of Rituximab administered alone in patients with severe non HCV-related cryoglobulinemic syndrome. The study group included 11 patients followed for at least 6 months. Three patients had type I cryoglobulinemia, 6 had type II and the remaining 2 patients had type III. Mean cryocrit was 2.5%. Four out of 11 patients had symptomatic sicca complex with anti-SSA (Ro)/anti SSB (La) antibodies. All 11 patients presented with biopsy-proven renal involvement, 4 out of 11 with leukocytoclastic vasculitis, and 8 with involvement of the peripheral nervous system. Renal biopsy revealed diffuse membranoproliferative glomerulonephritis (MPGN) in 9 out of 11 patients. Extracapillary proliferation and necrosis of the glomerular tuft was observed in 1 of these 9 cases. Interstitial nephritis together with mesangial expansion and capillary immune deposits were observed in 1 patient. Prevalent interstitial fibrosis and glomerular sclerosis were detected in the remaining case. Patients underwent treatment with rituximab alone. After 6 months we observed a remarkable improvement in the necrotizing skin ulcers and a substantial amelioration of the electrophysiological parameters of motor and sensory peripheral neuropathy. Improvement in both renal function (from 2.8 to 1.4 mg/dl, p < 0.001) and proteinuria (from 4.2 g/24 to 0.4 g/24 h, p < 0.001) was found in 10 out of 11 patients, while 1 could not be fully treated because of a severe infusion reaction and sudden development of anti-Rituximab antibodies. Good renal response was confirmed at the end of follow-up (38.4 months). Three patients had a relapse at 6, 12, and 48 months, respectively. In our cohort the administration of 4 once-weekly infusions of Rituximab followed by 2 more infusions after 1 and 2 months proved to be effective in the management of these rare patients.

Взаємозв’язки імунологічних та клініко-морфологічних показників у хворих на хронічний гепатит С залежно від наявності змішаної кріоглобулінемії

Актуальність. Змішана кріоглобулінемія є найчастішим позапечінковим проявом хронічної HCV-інфекції. Питання ролі цитокінів та особливостей ураження печінки при хронічній HCV-інфекції за наявності змішаної кріоглобулінемії дискусійні. Мета дослідження — визначити взаємозв’язок між змінами імунологічних параметрів (кріоглобуліни, інтерферон γ, інтерлейкін‑4) та клініко-морфологічними показниками хронічного гепатиту С у хворих зі змішаною кріоглобулінемією. Матеріали й методи. Обстежені 82 хворі на хронічний гепатит С. Стадію фіброзу печінки визначали при морфологічному дослідженні гепатобіоптатів. Вміст інтерферону γ та інтерлейкіну‑4 визначали методом імуноферментного аналізу. Вміст кріоглобулінів визначали спектрофотометричним методом. Результати. У хворих зі змішаною кріоглобулінемією виявлено нижчий вміст інтерферону γ та найвищий вміст інтерлейкіну‑4 у сироватці крові, зареєстровано кореляцію між концентрацією кріоглобулінів та вмістом інтерферону γ (r = –0,32; р &lt; 0,05) та інтерлейкіну‑4 (r = 0,36; р &lt; 0,05). Виявлено вищий вміст змішаних кріоглобулінів у хворих зі стадіями фіброзу F3–4 (р &lt; 0,05). Зареєстровано більшу частоту клінічних ознак кріоглобулінемічного синдрому в пацієнтів зі стадіями фіброзу печінки F3–4. Підвищення вмісту змішаних кріоглобулінів асоціюється з появою та кількістю ознак кріоглобулінемічного синдрому (виражена загальна слабкість, шкірна пурпура й синдром Рейно) і вираженістю фіброзу печінки. Підвищення вмісту інтерлейкіну‑4 асоціюється з появою загальної слабкості, шкірної пурпури та тяжким фіброзом печінки. Висновки. Підвищення вмісту змішаних кріоглобулінів асоціюється з появою та кількістю ознак кріоглобулінемічного синдрому та вираженістю фіброзу печінки. Підвищення вмісту інтерлейкіну‑4 корелює з концентрацією кріоглобулінів та асоціюється з клінічними проявами кріоглобулінемічного синдрому та фіброзом печінки F3–4. Для покращення діагностики перебігу хронічного гепатиту С доцільно визначати вміст кріоглобулінів та інтерлейкіну‑4.

Синдром змішаної кріоглобулінемії: особливості клінічного перебігу та лікування. Огляд літератури та опис клінічного випадку, асоційованого з COVID-19

Abstract. The aim of the study was to analyze the literature rewiew regarding modern methods of diagnosis and treatment of mixed cryoglobulinemia. Mixed cryoglobulinemia syndrome (MCS) is a unique systemic inflammatory syndrome, which includes small- and medium-sized vessel vasculitis caused by cryoglobulin-containing immune complexes. MCS is potentially caused by hepatitis C virus infection. It may also be associated with autoimmune or lymphoproliferative disorders or, rarely, may be idiopathic. The diagnosis of MCS should be suspected in any patient who presents with one or more of the following clinical features: palpable purpura, skin ulcers, arthralgias and/or arthritis, peripheral neuropathy, and/or microscopic hematuria or proteinuria with or without chronic kidney disease. The general approach of management of moderate to severe mixed cryoglobulinemia should include targeted treatment of the underlying disease causing the cryoglobulinemia along or with additional immunosuppressive therapy. In some cases, immunosuppressive therapy is started first, and then, after stabilization of disease, therapy for the underlying disease is added. The main indication for immunosuppressive therapy is a progressive systemic disease of the kidneys, nervous system, gastrointestinal tract, skin, or vasculitis with necrosis. The prognosis is variable and depends on the severity of the disease and the response of the underlying disease to therapy. In this publication, we also describe a rare clinical case of mixed cryoglobulinemia associated with COVID-19. Thus, the syndrome of cryoglobulinemia is quite difficult both in diagnosis, taking into account the heterogeneity of clinical and laboratory data, and in treatment which makes it necessary to select effective immunosuppressive therapy in specific clinical cases.

ІМУНОЗАЛЕЖНІ МЕХАНІЗМИ ТА МОЛЕКУЛЯРНО-ГЕНЕТИЧНІ ОСОБЛИВОСТІ У ХВОРИХ НА СИСТЕМНІ ХВОРОБИ СПОЛУЧНОЇ ТКАНИНИ З КРІОГЛОБУЛІНЕМІЧНИМ СИНДРОМОМ

Introduction: Cryoglobulinemic syndrome (CGS) is an immune-related process caused by cryoglobulins composition in the blood in small or medium vessels. Most frequently, CGS is triggered by lymphotropic viruses, immune-related and oncological diseases. Objectives: Studying the immune-related mechanisms, molecular and genetic characteristics of patients with systemic autoimmune diseases (SAD) against the cryoglobulinemic syndrome. Methods: Among 380 patients with SAD, in 94 (57.6%) progressing chronic EBV-infection was diagnosed, and 22.1% of patients were diagnosed with progressing chronic HSV 1/2-infection based on DNA virus identification through the polymerase chain reaction (PCR) in three biological media (blood, saliva, mucus membrane scraping). Results: Analysis of the cryoglobulins in such patients showed that CGS was diagnosed in 118 (31.1%) patients with the mean concentration of CG1.68±0.33 g/l at a rate of 0.48 ±0.10g/l. The patients with the systemic connective tissue diseases with CGS demonstrated statistically lower miR-146а expression which resulted in the abnormal production of pro-inflammatory cytokines, the highest TLR9 expression on monocytes, slightly lower on lymphocytes, and the lowest on granulocytes; the increase in the relative amount of cytolytic T-lymphocytes, IL2 receptor lymphocytes, activated CD HLA DR+-lymphocytes against the reduction of NK-cells and regulatory suppressor CD4+/25+-cells was observed. The idiopathic and initiated oxidative monocyte capacity in CGS patients distinctly tended to increase, as compared to patients without CGS and normal individuals. Conclusions. Cryoglobulins may act as the so-called bridge between viral infections and the autoimmune processes. CGS was diagnosed in 31.1% of patients. Despite a substantial number of studies dedicated to the cryoglobulinemic syndrome, the peculiarities of the immune reaction of such patients need further research, since they create the risks of secondary vasculitis against SAD

Pharmacotherapy of Systemic Vasculitis Combined with Cryoglobulinemic Syndrome Using Pharmacoeconomic Approaches

BACKGROUND: It was substantiated the relevance and necessity of the chosen research topic as a result of a review of the scientific literature on the epidemiology and pharmacotherapy of patients with systemic vasculitis associated with cryoglobulinemic syndrome.&#x0D; &#x0D; OBJECTIVE: In this study were selected drugs that have the diagnostic ATC-code J05 Antiviral agents for systemic use; J05A Antivirals of direct action; J05AB01 antiviral agents for systemic use according to INN Aciclovir.&#x0D; &#x0D; METHODS: This study is based on pharmacoeconomic, organizational and legal, forensic and pharmaceutical approaches to pharmacotherapy with using literature review. Experimental data were processed on the basis of the Department of Internal Medicine of the Lviv Medical Institute and the Department of Medical and Pharmaceutical Law, General and Clinical Pharmacy of the Kharkiv Medical Academy of Postgraduate Education. &#x0D; &#x0D; RESULTS: Clinical and pharmacological analysis of basic therapy of systemic vasculitis was performed. Pharmacoeconomic studies have been conducted. According to the results of ABC analysis, drugs according to INN Aciclovir ATC-code J05AB01 for pharmacotherapy of patients with systemic vasculitis combined with cryoglobulinemic syndrome were distributed in descending order of value. According to the results of VEN-analysis, it is estimated that category V drugs accounted for the largest number of prescriptions and the cost of therapy (100%). &#x0D; &#x0D; CONCLUSION: This study provide an opportunity to make administrative and managerial decisions in determining the pharmacotherapy of patients with systemic vasculitis combined with cryoglobulinemic syndrome to improve the use of drugs in hospitals.

Impact of direct acting antivirals on hepatitis C virus-related cryoglobulinemic syndrome.

Mixed cryoglobulinemia (MC) is a B-cell lymphoproliferative disorder largely attributable to Hepatitis C virus (HCV) infection. MC clinical manifestations are determined by systemic vasculitis of low/medium sized vessels (mixed cryoglobulinemia syndrome or cryoglobulinemic vasculitis [CV]) caused by the deposition of cryoglobulins in blood vessels. A systematic review was performed via the Medline and Scopus databases to evaluate studies concerning CV treatment with new direct antiviral agents (DAAs) and their effect on the syndrome. The introduction of interferon-free protocols has led to more evident positive effects than those observed in the treatment of hepatitis C. In fact, IFN-free, DAA-based therapy minimized side effects permitting the treatment of previously contraindicated patients and led to a particularly high SVR rate and to a clinical/immunological response in the majority of patients, even if at different levels in different patients, from restitutio ad integrum to partial response. In view of the clearly positive evolution in CV management, the persistence of CV manifestations, in partial or non-responders continues to pose problems in the clinical approach to patients who represent a new condition that is still not completely known. Results of DAA-based therapy strongly confirm the use of anti-HCV therapy as the first-line therapeutic option in CV patients. However, growing evidence of a possible persistence or late relapse of CV suggests the need for longer/more accurate post-DAA follow-ups as well as biomarkers that are capable of predicting the risk of clinical relapse/persistence to allow for the design of rational post-HCV eradication clinical flow-charts.

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

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.

Cryoglobulins: putative effectors of adaptive immune response.

Cryoglobulinaemia consists of circulating monoclonal and/or polyclonal immunoglobulins with rheumatoid factor (RF) activity that precipitate at temperatures <37°C. Cryoglobulinaemic syndrome, characterised by clinical signs of systemic vasculitis, is associated with chronic infection of hepatitis C virus (HCV) and might evolve in B-cell malignancies. In about one third of all HCV infection cases, serum autoantibodies are commonly found. This is probably due directly to the transformation of infected B cells but, also, indirectly, to the viral chronic stimulation of a pool of autoreactive B cells. The pattern of IgG subclasses seems to contribute to the worsening progression of HCV infection into lymphoproliferative and/or autoimmune diseases. Many evidences showed that B cells circulating in patients with HCV-associated mixed cryoglobulinaemia (MC) are profoundly abnormal; moreover, in most of cases, normal B cells are replaced by expanded clonal B cells characterized by the low expression of CD21. After viral eradication, these cells persist in circulation and their occurrence does not correlate with serum cryoglobulins nor with vasculitis response or relapse. It is probably due to the persistence of monoclonal B cells producing RF, that in course of MC can be reactivated by circulating immune complexes, highly produced during infections or tumours. Here, we aimed to review current literature focusing the pathogenesis of MC referring to specificity and immunochemical characteristics of the immunoglobulins involved in cryoprecipitation.

P0283LONG-TERM FOLLOW-UP OF CRYOGLOBULINEMIC SYNDROME WITH RENAL INVOLVEMENT AFTER DAA

Background and Aims To date, the literature shows that HCV eradication with DAA leads to remission from HCV-related cryoglobulinemic syndrome (CS). The goal of our study is to evaluate the effect of DAA treatment on cryoglobulinemic kidney disease. Method Since 2015, 58 patients (pts) have been treated in our Centre; among them we have selected 12 pts with active kidney disease at the time of treatment. Clinical manifestations, renal function and immunological tests were monitored during follow-up (range 6-48 months). Results General characteristics of the population are shown in Table 1. At the time of treatment 6 pts had nephritic syndrome (sdr), 1 had nephrotic sdr and 5 pts had mixed nephritic-nephrotic sdr. It should be noted that 8/12 pts had been treated with Rituximab (RTX) in the 6 months preceding the DAA; despite that they had active disease at baseline. Ten out of 12 pts went into complete remission after HCV-eradication, 1 went into partial remission. One pt, never treated, did not respond clinically to HCV eradication and therefore underwent RTX therapy. Other 2 pt with a recent diagnosis of cryoglobulinemic syndrome came to our attention with a clinical picture of nephritic sdr: they’d never been treated with immunosuppressive therapy and get remission only whit HCV eradication. One pt, although complete CS remission, started hemodialysis for ESRD secondary to ADPKD. During follow-up 3 pts underwent CS relapse: 2 pts, one with lymphoma, were retreated with RTX after 12 and 48 months respectively; 1 pt, with type I cryoglobulinemia and clinical manifestation of vasculitis, died of acute disease reactivation in Cameroon after 9 months from the end of DAA. By evaluating the overall population there is a rapid and prolonged clinical response to DAA therapy, in particular a complete resolution of skin ulcers (Tab 2). Cryocrit decreases and C3 and C4 increase early and persistently after treatment; vice versa the rheumatoid factor does not undergo significant variations. Proteinuria is reduced at the end of the treatment (EOT) and shows a decreasing trend also afterwards; urinary sediment is drastically reduced at EOT and further decreases during follow-up up to the presence of only isolated urinary anomalies in almost all patients (Tab 3). Conclusion The eradication of HCV, and therefore the removal of the immunological stimulus underlying the cryogloblinemic syndrome, appears to be crucial in the control of cryoglobulinemic glomerulonephritis, also after failure of RTX treatment. However, relapses at variable interval from DAA therapy do not allow us to lose these patients to follow-up even after several years from disease remission.

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&lt;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&lt;0.05), but the frequency of detection of this genotype was not statistically different compared with patients without MC (p&gt;0.05). In patients with CHC carriers of the CC genotype of the IL-17 gene polymorphism significantly more likely (p&lt;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&lt;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.

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

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

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.

IGG subclasses, free light chains and vascular endothelial growth factor in HCV-related mixed cryoglobulinemic syndrome

IGG subclasses, free light chains and vascular endothelial growth factor in HCV-related mixed cryoglobulinemic syndrome

Epidemiological, demographic and clinical data on chronic viral hepatitis C in Tuscany

Background: Recent introduction of direct antiviral agents (DAAs) has completely changed the scenario regarding hepatitis C virus (HCV) treatment. Certain countries’ economic health programs prioritize DAAs according to specific clinical features of HCV-infected patients. The aim of this study was to define epidemiological, demographic and clinical characteristics of HCV-infected patients in the Tuscany region of central Italy.Methods: We enrolled HCV patients with chronic viral hepatitis who were referred to the outpatient services of 16 hospitals in Tuscany from 1 January 2015 to 31 December 2015. Case report forms contained patient information including main demographic data, blood chemistry data, viral hepatitis markers, instrumental evaluations (liver biopsy or transient elastometry, liver ultrasound), eligibility for DAAs, and liver transplantation or therapy already in progress.Results: Of all patients considered, 2919 HCV patients were enrolled (mean age: 57.44 ± 15.15; 54% males, 46% females). All routes of transmission were well represented (intravenous drug use in 20.7%; nosocomial/dental care in 20.6%; and coagulation factors/blood transfusions in 13.3%). Diabetes was the highest represented comorbidity (20.8%), followed by metabolic syndrome (15.5%) and ischemic heart disease (6.2%). The most prevalent HCV genotypes were 1b (47.4%) and 2 (16.5%). In the whole cohort of patients, 32.8% were cirrhotic (40 patients were listed for liver transplantation). Signs of portal hypertension were present mostly in the group older than 45 years (92.3%). Extrahepatic HCV-related diseases were present in 13.3% of cases (cryoglobulinemic syndrome in 58.3% and B-cell non-Hodgkin’s lymphoma in 10.5%).Conclusions: Our study provides evidence of a high prevalence of epidemiological changes in HCV infection with a major prevalence of advanced liver disease, such as portal hypertension, in this elderly cohort of patients.

Fibronectin gene polymorphisms in HCV related type II mixed cryoglobulinemia: risk of development of B-cell lymphoma

B-cell non-Hodgkin lymphoma (B-NHL) are clonal malignancies with diverse clinical presentations, pathogenesis, and biologic behavior. Hepatitis C virus (HCV) is a major leading cause of liver-related morbidity and B-cell lymphoproliferative diseases such as mixed cryoglobulinemic syndrome (MCns) and B-NHL. Fibronectin (FN) is a multifunctional glycoprotein of 250 kDa which is encoded on a gene that is 75 kb in length, located on chromosome 2q34–36 and consists of 50 exons. Polymorphisms of the fibronectin gene are as follows: HindIII, HaeIII, TaqI, and MspI. The aim of the current study was to investigate the possible link between the two FN polymorphisms (called MspI “CC genotype, CD genotype and DD genotype” and HaeIII “AA genotype, AB genotype and BB genotype”) and the development of lymphoma in HCV-positive patients with mixed cryoglobulinemic syndrome compared to healthy age- and sex-matched individuals. The present study included 75 patients; 25 HCV-positive patients with MCns and 50 B-NHL patients, in addition to 25 healthy controls. To achieve this aim, genotyping for FN gene was done by PCR-RFLP technique and screening for HCV infection was performed by ELISA and confirmed by RT-PCR, cryoglobulins have been detected by cold precipitation (4 °C for 72–96 h) and plasma FN levels have been assessed by ELISA. The study revealed that HaeIII-AB genotype can be considered as a risk factor for NHL development and high HaeIII-A allele frequency seems to be associated with NHL development. We did not find any significant difference between all patients’ groups and controls regarding MspI genotyping. It was also found that plasma FN level did not show any significant difference between B-NHL patients and each of HCV positive patients with MCns and controls. Our study provides further evidence for the role of HaeIII-AB FN gene polymorphism as a risk factor for B-NHL development in sub-population of Egyptian HCV-positive patients with MCns. We also found that HaeIII-A allele has been significantly increased in overall B-NHL patients.

Treatment of hepatitis C virus infection in patients with mixed cryoglobulinemic syndrome and cryoglobulinemic glomerulonephritis.

Cryoglobulinemia is a common extrahepatic manifestation of infection with hepatitis C virus (HCV). When signs and symptoms of systemic vasculitis or glomerulonephritis occur in the presence of circulating cryoglobulins, this syndrome is called "mixed cryoglobulinemia syndrome" (MCS). Historically, interferon-based therapies in HCV have been associated with lower rates of viral cure in patients with MCS than in the general HCV-infected population. The advent of direct-acting antiviral therapies have revolutionized the treatment of HCV, dramatically increasing rates of cure. Early studies of first-generation protease inhibitors (telaprevir and boceprevir) in combination with interferon and ribavirin demonstrated HCV cure rates of 67% and complete clinical response rates of vasculitis symptoms in 60% of patients with MCS; however, regimens were poorly tolerated by patients, 22% discontinued treatment early. More recently, all-oral, interferon-free regimens have become available and combination therapies are now being approved for patients with and without renal impairment. Patients with HCV-MCS achieved sustained virologic response in 297 out of 313 patients (95%) treated with direct-acting antiviral therapy, and 85% had a complete or partial clinical response of MCS symptoms. Current direct-acting antiviral therapies are well tolerated in patients with HCV-MCS and only 1.6% discontinued treatment early. Patients with cryoglobulinemic glomerulonephritis also had an excellent cure rate (94%). The majority improved; 17/52 (33%) experienced full remission and 15/52 (29%) experienced partial remission. There were no reports of worsening kidney function in patients treated with direct-acting antiviral therapies. Less than 5% of patients with HCV-MCS treated with IFN-free direct-acting antiviral therapy required immunosuppression. However, patients with severe vasculitis appear to still require concomitant immunosuppression.

A case of rapid amelioration of hepatitis C virus-associated cryoglobulinemic membranoproliferative glomerulonephritis treated by interferon-free directly acting antivirals for HCV in the absence of immunosuppressant.

Mixed cryoglobulinemic syndrome, which is a systemic vasculitis characterized by the immune complex deposition in small- and medium-sized arteries and most often due to chronic hepatitis C virus (HCV) infection, sometimes clinically manifests as refractory glomerulonephritis or nephritic syndrome. Patients with mixed cryoglobulinemic nephropathy who have a rapidly progressive glomerulonephritis should receive immunosuppressive therapy. After disease stabilization, patients should receive concurrent therapy for the underlying HCV infection. The standard therapy of a chronic HCV infection is IFN monotherapy or IFN combined with ribavirin; however, after the introduction of direct-acting antivirals (DAAs), the standard therapy for patients with HCV genotype 1 has dramatically changed. We report a case of HCV-associated cryoglobulinemic membranoproliferative glomerulonephritis (MPGN) successfully treated by daclatasvir and asunaprevir, which are IFN-free DAAs for HCV, in combination with angiotensin II receptor blocker without immunosuppressive therapy. The patient developed severe nephrotic syndrome with progressive kidney dysfunction. Blood examination revealed a high copy number of HCV-RNA (6.4 log IU/mL, type 1), cryoglobulinemia, paraproteinemia of IgM-κ, and hypocomplementemia. Histological analysis showed MPGN type 1. These findings were compatible with those observed in HCV-associated cryoglobulinemic MPGN. This case offers original evidence for the application of newer generation of IFN-free DAAs in the treatment of HCV-associated cryoglobulinemic nephropathy.

Influence of HCV and HIV on development of cryoglobulinemia.

Cryoglobulinemic syndrome refers to a systemic inflammatory process that involves small and medium-sized vessels accompanied by multi-organ damage. The aim of the present study was to determine the incidence of cryoglobulinemia among patients infected with human immunodeficiency virus (HIV), hepatitis C virus (HCV) and HCV/HIV co-infection, as well as evaluation of cryoglobulinemia type. The association was evaluated between cryoglobulinemia and clinical symptoms, selected biochemical measures of liver and kidney function, virologic measures, as well as histopathological changes in the liver. One hundred and forty-one patients were enrolled (59 HCV mono-infected, 48 HIV mono-infected, and 34 HCV/HIV co-infected). Cryoglobulinemia was nearly five times less frequent among HIV mono-infected patients (10%) than HCV mono-infected (53%) and HCV/HIV co-infected patients (59%). Cryoglobulinemia was more frequent in patients infected with genotype 1 HCV than genotype 3 (63% vs. 46%, p=0.12). There was a lower incidence of cryoglobulinemia in HIV mono-infected patients treated with antiretroviral drugs (p=0.04). Cryoglobulinemia correlated with ALT activity (p=0.01) and HIV viral load (p<0.001). Symptoms were significantly more frequent among cryoglobulinemic patients than those without cryoglobulinemia (38% vs. 9%, p<0.001). The most common symptoms related to cryoglobulinemia, regardless of cryoglobulinemia type, were fatigue (38%), arthralgia (20%), polineuropathy (18%), and skin lesions (14%). In conclusion, HCV mono-infection and HCV/HIV co-infection, regardless of HCV genotype, are potent stimulators of cryoglobulinemia, with its symptomatic form occurring in about 40% of cases. Effective antiretroviral therapy seems to be protective against cryoglobulinemia development in HIV mono-infected patients.

Pain management in cryoglobulinaemic syndrome.

Cryoglobulinaemic syndrome (CS) includes clinical signs and symptoms that range from the classic triad of Meltzer and Franklin (purpura, weakness and arthralgias) to multiple organ involvement, and it may be characterised by nociceptive or neuropathic pain. Both types of pain use the same pathways and neurotransmitters, but nociceptive pain has an adaptive system and biological function whereas neuropathic pain does not. Managing CS means dealing with often very different clinical patterns, activity and severity with the aim of preventing irreversible organ damage, reducing pain, improving the patients' quality of life and reducing social costs. However, treatment is still largely empirical, and it is often delayed. The Italian Group for the Study of Cryoglobulinaemia (GISC) strongly recommended a low-antigen-content diet and colchicine for all symptomatic CS patients. Patients with mild-moderate symptoms (such as purpura, weakness, arthralgia and initial neuropathy) have been treated with low or medium doses of steroids, and, in the presence of chronic hepatitis C virus (HCV)-related hepatitis, an attempt has been made to eradicate HCV with pegylated interferon plus ribavirin. In the case of severe or rapidly progressive disease (glomerulonephritis, neuropathy, leg ulcers, widespread vasculitis or hyperviscosity syndrome), more aggressive treatment should be used (e.g., high doses of corticosteroids, plasma exchange plus cyclophosphamide or rituximab). Pain management in CS therefore depends on the type of pain (nociceptive, neuropathic or mixed), the characteristics of the patients and their co-morbidities. Drug therapy should be carefully monitored in order to obtain prompt and beneficial results.

AB0566 Arthritis in Systemic Vasculitis: A Retrospective Analysis

BackgroundFew data are available on the prevalence of arthritis in vasculitides.ObjectivesTo evaluate the prevalence and the features of arthritis in our cohort of patients with systemic vasculitis.MethodsData were collected from...