Cryoglobulinemia Research Articles

Noninfectious mixed cryoglobulinaemic glomerulonephritis and monoclonal gammopathy of undetermined significance: a coincidental association?

BackgroundCryoglobulins are cold-precipitable immunoglobulins that may cause systemic vasculitis including cryoglobulinaemic glomerulonephritis (CGN). Type 1 cryoglobulins consist of isolated monoclonal immunoglobulin (mIg), whereas mixed cryoglobulins are typically immune complexes comprising either monoclonal (type 2) or polyclonal (type 3) Ig with rheumatoid activity against polyclonal IgG. Only CGN related to type 1 cryoglobulins has been clearly associated with monoclonal gammopathy of undetermined significance (MGUS) using the conventional serum-, urine- or tissue-based methods of paraprotein detection.Case presentationWe present four patients with noninfectious mixed (type 2 or 3) CGN and MGUS. Two patients had type 2 cryoglobulinaemia, one had type 3 cryoglobulinaemia, and one lacked definitive typing of the serum cryoprecipitate. The serum monoclonal band was IgM-κ in all four cases. Treatments included corticosteroids, cyclophosphamide, plasma exchange, and rituximab. At median 3.5 years’ follow-up, no patient had developed a haematological malignancy or advanced chronic kidney disease. Other potential causes of mixed cryoglobulinaemia were also present in our cohort, notably primary Sjögren’s syndrome in three cases.ConclusionOur study raises questions regarding the current designation of type 2 CGN as a monoclonal gammopathy of renal significance, and the role of clonally directed therapies for noninfectious mixed CGN outside the setting of haematological malignancy.

Clinical characteristics and treatment outcome of type I cryoglobulinemia in Chinese patients: a single-center study of 45 patients.

To explore the clinical characteristics and outcomes in Chinese patients with type I cryoglobulinemia (CG), we retrospectively analyzed the clinical data, management, and outcomes of 45 patients diagnosed with type I CG in our hospital from January 2015 to March 2019. In our study, all type I CGs were secondary to hematologic diseases, and monoclonal gammopathy of unknown significance was the most common primary disease, accounting for 48.9% (n = 22). Additionally, B cell non-Hodgkin lymphoma, Waldenström's macroglobulinemia, and multiple myeloma accounted for 24.4% (n = 11), 20.0% (n = 9), and 6.7% (n = 3), respectively. In patients with type I CG, skin damage was the most common symptom, presenting in 57.8% of the patients, followed by peripheral neuropathy (22.2%) and renal involvement (15.6%). Treatment was initiated in 29 patients (64.4%), and the most common choice was a rituximab-based regimen in 13 patients (44.8%), followed by bortezomib-based regimen in 11 patients (37.9%). Clinical symptoms were significantly improved after treatment, and the clinical remission rate was 86.2%, including 34.5% of complete clinical remission, while the laboratory response rate was 88.9%, including 33.3% of complete response and 55.6% of partial response. The expected 1-year overall survival was 97.8%. In conclusion, for patients with multisystemic involvement, such as skin damage, kidney damage, or peripheral neuropathy, the diagnosis of type I CG should be considered, and the underlying disease needs to be explored. Symptoms and primary diseases should be taken into consideration before choosing initial management.

Hepatitis C virus- related cryoglobulinemic vasculitis: A review of the role of the new direct antiviral agents (DAAs) therapy.

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.

Mixed cryoglobulinemic glomerulonephritis and vasculitis in primary Sjögren’s syndrome

Introduction: Cryoglobulinemia is a condition where complexes of one or more different classes of immunoglobulins precipitate at low temperatures and become soluble again at higher temperatures. Cryoglobulins are typically categorized as types I to III, based on their immunoglobulin composition. Mixed cryoglobulinemia (type II and III) is most often associated with constitutional symptoms, such as fatigue, myalgia, arthralgia, sensory or motor changes (peripheral neuropathy) and palpable purpura (cutaneous vasculitis). Twenty to thirty percent of the affected patients suffer from membranoproliferative glomerulonephritis. Case Presentaion: We discuss a case of a 45-year-old woman with a history of Sjogren’s syndrome and mixed cryoglobulinemia who presented with acute renal failure, nephritic syndrome, vasculitislike rash on the legs and non-healing skin ulcer. Further investigations confirmed type II mixed cryoglobulinemia associated with cutaneous leukocytoclastic vasculitis and membranoproliferative glomerulonephritis leading to end-stage renal disease (ESRD). Conclusion: Mixed cryoglobulinemia secondary to primary Sjogren’s syndrome (pSS) is rare and reported in 22.5% of cases of non-infectious cryoglobulinemic glomerulonephritis. Long-term renal prognosis is good with only 9% of these patients evolving to ESRD. Nevertheless, the long-term overall survival is poor with severe infections as the leading cause of death.

P0230IMMUNOSUPPRESSIVE TREATMENT DOES NOT IMPROVE KIDNEY SURVIVAL IN PATIENTS WITH HCV CRYOGLOBULINAEMIA TREATED WITH DIRECT-ACTING ANTIVIRALS

Abstract Background and Aims Since the introduction of direct-acting antivirals (DAAs), few data have been published about kidney outcome in hepatitis C virus related mixed cryoglobulinaemia (HCV-MC) patients treated with combined DAAs and rituximab. We aimed to asses if combined treatment with DAAs and rituximab in patients with HCV-MC improves kidney survival and immunological response. Method Observational, multicentre, cohort study of 100 patients with HCV-MC from 14 Spanish centres treated with DAAs. Patients were followed up for a median duration of 138 months (11.5 years). Long-term kidney survival and immunological response were evaluated based on immunosuppressive treatment received. Kidney event was defined as duplication of creatinine level or 50% decrease in glomerular filtration rate, dependence on renal replacement therapy or non-reduction of proteinuria by 50% compared to baseline. Immunological response was defined as the decrease in cryocrit ≤1%. Results Sustained virological response was attained in 98 (98%) patients. 49 patients were treated with immunosuppressive treatment associated with DAAs, 26 with rituximab and the rest (23) with steroids and/or cyclophosphamide. Patients receiving immunosuppressive treatment had higher basal cryocrit (6.3±4.5 vs 3.8±3.9%, p=0.011), lower glomerular filtration rate (55±27 vs 68±25 ml/min/1.73 m2) and more haematuria (p=0.001). The 26 patients treated with rituximab had more severe disease: higher viral load (p=0.001), cryocrit (p=0.011), proteinuria (p=0.004), microhaematuria (p=0.012) and hypertension (p=0.012) and lower glomerular filtration rate (p=0.001). 15 patients had a kidney event at the end of follow-up. Predictive variables of kidney events were lower age (HR 0.94, 95%CI 0.89-0.99; P= 0.038) and lower glomerular filtrate rate (HR 0.97, 95%CI 0.94-0.99; p=0.026), in a model adjusted to proteinuria and microhaematuria. Immunosuppressive treatment with or without rituximab did not change kidney survival. Regarding the immunological response, only 19 patients had a cryocrit >1% at the end of follow-up. There were no differences in age, viral load, proteinuria and basal glomerular filtration rate between these patients with no immunological response and those who had a sustained immunological response over time. The only differences between these two groups were a higher basal cryocrit and a minor C4 levels. Immunosuppressive treatment with or without rituximab did not changed the immunological response. Conclusion Patients with more severe HCV-MC are those receiving immunosuppressive treatment. However, immunosuppressive treatment does not change kidney survival nor immunological response of these patients in the long term.

Membranoproliferative Glomerulonephritis and Mixed Cryoglobulinemia as a Form of Presentation of Visceral Leishmaniasis

Patient: Male, 69-year-oldFinal Diagnosis: LeishmaniasisSymptoms: Acute renal failure • purpuric skin lesionsMedication: —Clinical Procedure: Bone marrow biopsy • renal biopsy • ultrasonographySpecialty: NephrologyObjective:Rare co-existance of disease or pathologyBackground:Visceral leishmaniasis (VL) is an endemic systemic disease in the Mediterranean countries, including Spain. This vector-borne infection can present with several clinical presentations, from asymptomatic to severe forms. Renal impairment is frequently described in VL but is usually mild and related to interstitial nephritis, being that glomerular involvement is rarely found.Case Report:We describe a case of a 69-year-old Spanish male presenting with subacute renal failure due to membranoproliferative glomerulonephritis and mixed cryoglobulinemia accompanied by other autoimmune features (hypocomplementemia, antinuclear and antiDNA antibodies). No hepatosplenomegaly was found with abdominal ultrasound. Hepatotropic viruses and human immunodeficiency virus serological markers were negatives. We initially suspect the presence of an autoimmune disease and the patient was treated with steroids without improvement. After an extensive study including renal and bone marrow biopsy, a correct diagnosis of visceral leishmaniasis was made, and treatment with liposomal amphotericin B was initiated, achieving renal function recovery and normalization of immunological manifestations.Conclusions:Renal involvement can be an important feature of VL and it might be associated with increased morbidity and mortality. The association between mixed cryoglobulinemia and renal involvement in VL have rarely been described. VL is frequently associated with diverse autoimmune manifestations and it can be initially misdiag-nosed, which could lead to fatal consequences. The role of the immune system in the formation of cryoglobulins are discussed. In our case, an autoimmune disease was initially suspected, and starting treatment with steroids pulses was initiated. However, the presence of mixed cryoglobulinemia in this patient who was hepatitis C serological marker negative and who had poor renal function recovery after immunosuppressive treatment made us suspect other pathologies. The presence of cryoglobulinemia with renal disease in endemic areas of Leishmania should make us exclude this infection before starting immunosuppressive treatment.

Cryoglobulinemia after the era of chronic hepatitis C infection

ObjectivesHistorically chronic hepatitis C virus (HCV) infection accounted for the majority of mixed cryoglobulinemia (MC). The advent of direct-acting antivirals (DAA) against HCV has dramatically changed the management and the prevalence of chronic HCV infection. We aimed to describe the spectrum of MC in the era of DAA agents. MethodsWe performed a longitudinal cohort study between 2011 and 2018 from a single-center French university hospital's database of 15 970 patients screened for MC. Epidemiological, clinical and immunological data of MC were recorded. We evaluated the incidence and evolution of MC before and after the era of DAA agents and compared HCV and non-HCV related MC. ResultsAmong 742 patients who tested positive for cryoglobulin, 679 [mean age 55.5 years, 54.5% female and 381 (56.1%) with chronic HCV infection] patients with persistent MC were included in the study. 373 (54.9%) had type II and 306 (45.1%) type III cryoglobulin, and 139 (21.5%) had cryoglobulinemia vasculitis (CryoVas). The incidence of MC decreased steadily with 395 and 284 incident cases during 2011–2014 and 2015–2018, respectively. In 2011, the leading cause was chronic HCV infection (62.5% of all MC). Currently, autoimmune diseases [systemic lupus erythematosus (28.9%) and Sjögren's syndrome (10.7%)] are the main cause of MC. The incidence of CryoVas was similar between HCV-and non HCV-related MC. ConclusionDirect-acting antivirals have dramatically changed the landscape and the incidence of MC.

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

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

A Case of Cryoglobulinemia after Successful Hepatitis C Virus Treatment

Cryoglobulinemic vasculitis is a complex and destructive disease process that affects multiple organ systems. The pathophysiology includes formation of immune complex deposits that create an inflammatory response in various organs, yielding distinct presentations such as purpura, arthralgias, neuropathy, fever, and pulmonary vasculitis. Over 30% of cryoglobulinemic vasculitis cases present with glomerulonephritis, which carries a worse prognosis. The majority of mixed cryoglobulinemia cases are due to active infection with hepatitis C virus (HCV). Treatment of cryoglobulinemic vasculitis involves treatment of underlaying HCV, as well as high doses of immunosuppressive agents such as steroids and rituximab, often for multiple months, but with resolution of symptoms.

Cryoglobulinemia and cryoglobulinemic vasculitis: etiological aspects and pathophysiological associations

The term cryoglobulinemia (CG) is used when detecting serum immunoglobulins that reversibly precipitate and form a gel at a temperature below 37 °C and dissolve when the temperature rises above 37 °C. Type I CG consists of only one isotype or a subclass of monoclonal immunoglobulins, while types II and III are classified as mixed CG (MCG) that is primarily characterized by the presence of immunoglobulins G and M. Types II and II-III MCG can result in cryoglobulinemic vasculitis (CGV) more frequently, whereas type III can lead to this condition less frequently. The presence of type I cryoglobulins is always associated with B-cell lymphoproliferative diseases. On the contrary, type II or type III MCG is more commonly associated with systemic autoimmune diseases and chronic infections. Thus, hepatitis C virus infection contributes to the development of MCG in 80–90% of cases. CGV is considered a rare disease worldwide (<5 cases per 10,000 people in the general European and North American populations). Among autoimmune diseases, primary Sjögren's syndrome (Sjögren's disease), systemic lupus erythematosus, and rheumatoid arthritis are most often associated with MCG. The pathogenetic role of cryoglobulins in inducing vasculitis is associated with both leukocyte recruitment to the vessels and deposition of immune complexes, with complement system activation and microvascular damage. The pathogenesis of MCG is associated with B-cell lymphoproliferation, autoantibody production, immunoglobulin synthesis, rheumatoid factor activity and the subsequent formation of cryoprecipitated immune complexes in conjunction with ineffective cryoglobulin clearance by monocytes and/or macrophages. This review contains updated information on the epidemiology, etiology, and pathogenesis of CG, with particular emphasis on MCG and CGV.

SUN-440 RENAL DISEASE PRESENTATION IN MIXED CRYOGLOBULINEMIA TYPE 2 A CASE REPORT AND A LITERATURE REVIEW

Mixed cryoglobulinemia (MC) results of cryoprecipitable immunocomplexes. In type II MC, a combination of polyclonal and monoclonal immunoglobulin is found. Renal involvement (RI) is one of the most serious complications in MC and may affect the overall prognosis. Case presentation: A diagnosis of essential mixed cryoglobulinemia (EMC) was established in a 36-year-old female patient. Eight years earlier, shedevelopedpurpuraof the lower extremities, arthralgia, peripheral neuropathy andpulmonary renal syndrome. A skin biopsy revealed a leukocytic vasculitis.A mixed cryoglobulin and hypocomplementemia were found. Urinary protein excretion was at 12 g per 24h. Initial treatment included pulse methylprednisolone followed by prednisone (1 mg/kg daily). Despite the clinical improvement in the renal disease, palpable purpuric lesions with arthralgia recurred periodically. So methotrexate was introduced but was rapidly interrupted owing to liver toxicity. On June 2019, she was admitted for pneumonia. An outbreak of her disease with dermal, peripheral nerve and renal involvement was objectified. Urinary protein excretion was at 3 g per 24h. A mixed cryoglobulin with monoclonal IgM Kappa and polyclonal immunoglobulin persisted. A Renal biopsy (RB) was done in July 2019, revealed diffuse endocapillary proliferation with granular IgM, C3 deposits. Plasmapheresis with twice exchanges per weak was conducted. Five days after the initiation of therapy, her purpura disappeared and serum complement values returned to normal. Review of the literature: The results of a long-term prospective, randomized controlled trial of rituximab (RTX) monotherapy in patients with cryoglobulinemia vasculitis (CV). RTX was found to be superior to standard immunosuppressive therapy for severe CV over the long term. A multicenter retrospective study included 14 patients with EMC who were successfully treated with lenalidomide. A study, included 21 patients with severe type II EMC unresponsive to immunosuppressive regimens, showed that IFN-a, as a single agent, is able to determine a response rate as high as 77%. A case report demonstrated that 2-Chlorodeoxyadenosine (2CdA) induced a dramatic and prolonged clinical response for a patient with progressive, symptomatic cryoglobulinemia, in whom corticosteroid and alkylating therapy failed. Some studies suggest that plasma exchange alone might be indicated in the treatment of a rapidly progressive glomerulonephritis complicating MC. We presented this case of EMC with renal involvement. The clinical presentation is characterized by a normal kidney function without nephrotic syndrome with membranoproliferative glomerulonephritis (MPGN) at the renal biopsy. This case reveals the importance of RB for the diagnosis of MPGN even in front of an atypical clinical picture.

TYPE II MIXED CRYOGLOBULINEMIA-INDUCED HEART FAILURE

Type II mixed cryoglobulinemia can cause immune complex-mediated vasculitis with involvement of multiple organs. The impact of mixed cryoglobulinemia on the heart is controversial. We report a rare case of cryoglobulinemia-induced heart failure. A 66-year-old male with no significant past medical

Clinical epidemiology of extrahepatic manifestations of chronic hepatitis C virus infection

Extrahepatic manifestations occur in more than half of patients with chronic hepatitis C virus infection and may be no less dangerous to the health and life of the patient than the isolated pathology of the liver. Chronic hepatitis C virus infection is often accompanied by the formation of neurocognitive disorders, clinically manifested by general weakness, fatigue and the inability to maindoi tain concentration for a long time. Every fifth patient with chronic hepatitis C develops depression. The development of type 2 diabetes among patients with chronic hepatitis C virus infection is observed 1.7 times more often than among non-infected individuals. Mixed cryoglobulinemia is observed in at least 30% of patients, however, the clinical manifestations of this pathology develop only in 4.9% of cases, of which 69–89% of skin lesions, 19–44% of distal sensory and sensorimotor polyneuropathy, 30% of membranoproliferative glomerulonephritis, 28% of joint damage. Among patients with chronic hepatitis C virus infection, higher prevalence than among non-infected individuals is observed, the prevalence rates of such nosologies as lymphoma from cells of the marginal zone are 2.47 times, diffuse large cell B cell lymphoma – 2.24 times, hypothyroidism – 3.1 time. Significantly more rarely encountered extrahepatic manifestations of chronic hepatitis C virus infection are skin lesions that are not associated with the development of cryoglobulinemic vasculitis: acquired late skin porphyria, necrolytic acral erythema and lichen planus. The question of the pathogenetic relationship of chronic hepatitis C virus infection with cardiovascular pathology remains open.

Direct-acting antiviral therapy improves kidney survival in hepatitis C virus-associated cryoglobulinaemia: the RENALCRYOGLOBULINEMIC study.

BackgroundDirect-acting antiviral agents (DAAs) have shown high rates of sustained virological response in chronic hepatitis C virus (HCV) infection. However, the influence of DAAs on the course of kidney involvement in HCV-associated mixed cryoglobulinaemia (HCV-MC) has been little studied. The aim of this study was to analyse the effects of antiviral treatment on kidney prognosis and evolution in patients diagnosed with HCV-MC.MethodsThe RENALCRYOGLOBULINEMIC study is an observational multicentre cohort study of 139 patients with HCV-MC from 14 Spanish centres. Clinical and laboratory parameters were measured before and after antiviral treatment. Primary endpoints were kidney survival and mortality after HCV-MC diagnosis. Secondary endpoints were clinical, immunological and virological responses after antiviral treatment.ResultsPatients were divided into three groups based on the treatment received: treatment with DAAs (n = 100) treatment with interferon (IFN) and ribavirin (RBV) (n = 24) and no treatment (n = 15). Patients were followed up for a median duration of 138 months (interquartile range 70–251. DAA treatment reduced overall mortality {hazard ratio [HR] 0.12 [95% confidence interval (CI) 0.04–0.40]; P < 0.001} and improved kidney survival [HR 0.10 ( 95% CI 0.04–0.33); P < 0.001].ConclusionsResults from the RENALCRYOGLOBULINEMIC study indicated that DAA treatment in patients with HCV-MC improves kidney survival and reduces mortality.

Dermatological diseases associated with Hepatitis B virus infection

Hepatitis B virus (HBV) infection is a critical public health issue worldwide. The prompt recognition of skin diseases associated with HBV enables the earlier diagnosis of undetected HBV infection. This review article aims to provide a guide for physicians to increase awareness of possible HBV infection when encountering skin diseases. The frequencies of HBV infection were highest in telangiectasia macularis multiplex acquisita, followed by mixed cryoglobulinemia (MC), polyarteritis nodosa (PAN), and Gianotti-Crosti syndrome (GCS). Serology tests for HBV are recommended for patients with the above diseases. Lichen planus is not associated with HBV according to the most recent evidence. Chronic urticaria and porphyria cutanea tarda are associated with HBV infection although the detection rate of HBV was only 2% in these two diseases. The mechanism behind the associations between HBV and these skin disorders remains unknown and virus-associated immune-mediated processes or direct injury caused by viral replication are frequently proposed. The clinical manifestation was not discrepant between the HBV-associated skin disorder and the non-HBV-associated counterpart. The duration of HBV infection did not show any statistically significant correlations with the development of skin disorders. Antiviral medication yielded improvement in HBV-associated PAN, MC and GCS.

Impact of DAA-Based Regimens on HCV-Related Extra-Hepatic Damage: A Narrative Review.

Two-third of patients with chronic hepatitis C show extrahepatic manifestations due to HCV infection of B lymphocytes, such as mixed cryoglobulinemia and non-Hodgkin B-cell lymphoma, or develop a chronic inflammatory status that may favor the development of adverse cardiovascular events, kidney diseases or metabolic abnormalities.DAAs treatments induce HCV eradication in 95% of treated patients, which also improves the clinical course of extrahepatic manifestations, but with some limitations. After HCV eradication a good compensation of T2DM has been observed, but doubts persist about the possibility of obtaining a stable reduction in fasting glucose and HbA1c levels.Chronic HCV infection is associated with low total and LDL cholesterol serum levels, which however increase significantly after HCV elimination, possibly due to the disruption of HCV/lipid metabolism interaction. Despite this adverse effect, HCV eradication exerts a favorable action on cardiovascular system, possibly by eliminating numerous other harmful effects exerted by HCV on this system.DAA treatment is also indicated for the treatment of patients with mixed cryoglobulinemia syndrome, since HCV eradication results in symptom reduction and, in particular, is effective in cryoglobulinemic vasculitis. Furthermore, HCV eradication exerts a favorable action on HCV-related lymphoproliferative disorders, with frequent remission or reduction of clinical manifestations.There is also evidence that HCV clearance may improve impaired renal functions, but same conflicting data persist on the effect of some DAAs on eGFR.

Mixed cryoglobulinemia associated with chronic HCV infection in the era of modern antiviral therapy: Can the problem be considered solved?

Mixed cryoglobulinemia is the most common extrahepatic manifestation of chronic HCV infection. The disease can occur both asymptomatically and in the form of systemic vasculitis with a wide range of clinical manifestations. The development of cryoglobulinemia is based on relatively benign lymphoproliferation, which, as pathological clones increase and their malignancy can lead to the appearance of B-cell non-Hodgkin's lymphomas. The new treatment of HCV infection with direct acting antivirals allows to achieve an increase in the rate of virus elimination. However, the clinical and, especially, immunological responses associated with the disappearance of cryoglobulins, as well as the normalization of the rheumatoid factor and C4 complement components, were significantly weaker compared to the virological response. Recently, it became known about the possible positive dynamics of these parameters in the future course, but the timing and volume of such observations are clearly insufficient. The persistence of elevated rheumatoid factor values, hypocomplementemia, and, especially, cryoglobulinemia after achieving a sustained virologic response as a result of antiviral therapy raises a number of serious questions relevant for clinical practice. Among the main issues are how often and how quickly normalization of these immunological disorders is possible? What are the consequences of their persistence? Under what conditions is it appropriate to consider alternative approaches to antiviral therapy and to use immunobiological drugs aimed at suppressing B-lymphocyte proliferation? These problems, as well as some aspects of the pathogenesis, clinical course, and treatment of extrahepatic manifestations of chronic HCV infection based on virus-induced lymphoproliferation are discussed in this literature review.

Treatment of chronic hepatitis C-associated cryoglobulinemia vasculitis at the era of direct-acting antivirals.

Hepatitis C virus (HCV) infection is responsible for both hepatic and extrahepatic manifestations. Before the era of direct-acting antivirals (DAA), cryoglobulinemia was related to HCV infection in 70–90% of cases. Observed in 30% to 40% of patients with hepatitis C, mixed cryoglobulinemia is mainly asymptomatic. Conversely, symptomatic cryoglobulinemia vasculitis (CV) can occur in 5–10% of patients with HCV-associated cryoglobulinemia. CV is a small-vessel systemic vasculitis, and organ damage results from circulation and precipitation of cryoglobulins and complement activation. A wide range of clinical symptoms can be observed during CV, and manifestations are potentially life-threatening. The most frequent manifestations occurring in CV are cutaneous, with recurrent purpura, articular with joint pains, neurologic with peripheric neuropathy, and renal with membranoproliferative glomerulonephritis. DAA have drastically changed chronic HCV therapy. DAA induce sustained virological response (SVR) rates greater than 95%, and also improve extrahepatic manifestations such as CV. We review recent studies investigating the clinical and immune effects of DAA therapy on HCV-CV.

Impact of mixed cryoglobulinemia on patients with spontaneous hepatitis C virus clearance: A 13-year prospective cohort study.

The prevalence and associations of mixed cryoglobulinemia (MC) in patients with spontaneous clearance of hepatitis C virus (HCV) remain elusive. A 13-year prospective cohort study of patients with spontaneous HCV clearance was conducted in a tertiary care centre. Baseline characteristics, incident cardiovascular and neurologic events and cancers were analysed. Of 104 consecutive patients (mean age: 54.08years old; females: 71 [68%]), 37 (34.6%) had MC and 6 (5.8%) had cirrhosis. MC (+) patients were more female (86% vs 58%, P=.002), had higher rate of cirrhosis (14% vs 1.5%, P=.012), higher levels of Immunoglobulin G (IgG; P=.001), IgM (P=.002) and fibrosis-4 (FIB-4) (P=.004), but lower levels of complement C4 (P=.034) than the MC (-) patients. Female gender (95% confidence interval [CI] of odds ratio: 1.402-26.715), levels of IgG (1.000-1.004), IgM (1.009-1.037) and FIB-4 (1.217-3.966) were independently associated with MC. Baseline rheumatoid factor (RF) levels were independently associated with incident cancer (95% CI hazard ratio [HR]: 1.001-1.030 [HR: 1.015], P=.039). With a cut-off value of 11.3IU/mL, RF levels significantly predicted incident cancer (area under curve: 0.865, P=.002). No different cumulative incidences of cardiovascular and neurologic events, cancers or mortalities were identified between MC (+) and MC (-) patient. Approximately 1/3 of patients with spontaneous HCV clearance yielded MC, which harboured similar characteristics of MC in patients with chronic hepatitis C. Despite the negligible role of MC in the prognosis of patients with spontaneous HCV clearance, the connection between RF and incident cancer demands further investigation.

PREDICTION OF THE DEVELOPMENT OF INSOLVENCY OF ANASTOMOSES ACCORDING TO THE LEVEL OF CRYOBILK

Abstract. The aim of the study was to create individualized surgical treatment tactics in patients who underwent anastomosing intestinal surgery using the express method for determining cryoglobulins. The study was based on a study of the results of treatment in 96 patients who underwent resection of segments of the small intestine with the formation of inter-intestinal anastomoses, in the SI «ZIGUS NAMSU» during the period from 2015 to 2018 years. Using a high-quality rapid method for the determination of cryoglobulinemia (CGE) during surgery can significantly affect surgical tactics: with a low level of cryobilk in blood serum, it can perform a resection of a segment of the small intestine with the formation of primary small intestinal anastomoses; when the level of cryobilk in blood serum is more than 80 mg / l, which corresponds to a positive rapid test for cryobilk, one should refrain from the formation of primary anastomoses, and use the tactics of the formation of “delayed” anastomoses, in severe general condition of patients (and a high level of CGE – more 600 mg/l) – also the formation of the final small intestinal stoma.