Cryoglobulinemia Research Articles

Managing refractory cryoglobulinemic vasculitis: challenges and solutions.

Cryoglobulinemia is thought to be a rare condition. It may be an isolated disorder or secondary to a particular disease. According to immunoglobulin composition, cryoglobulinemia is classified into three types. In mixed cryoglobulinemia (types II and III), vascular deposition of cryoglobulin-containing immune complexes and complement may induce a clinical syndrome, characterized by systemic vasculitis and inflammation – cryoglobulinemic vasculitis (CryoVas). Most common clinical manifestations in CryoVas are skin lesions (orthostatic purpura and ulcers), weakness, peripheral neuropathy, Raynaud’s phenomenon, sicca syndrome, membranoproliferative glomerulonephritis, and arthralgia and seldom arthritis. In patients with mixed cryoglobulinemia, prevalence of anti-hepatitis C virus (HCV) antibodies and/or HCV RNA, detected by polymerase chain reaction (PCR), is reported to be up to 90%, indicating a significant role of HCV in the development of this condition. The goals of therapy for mixed cryoglobulinemia include immunoglobulin level reduction and antigen elimination. CryoVas not associated with HCV infection should be treated according to treatment recommendations for small-vessel vasculitides. CryoVas associated with chronic HCV infection should be treated with antivirals along with immunosuppressive drugs, with or without plasmapheresis, depending on disease severity and organ involvement. Patients who do not respond to first-line therapy may achieve remission when treatment with rituximab is started as second-line therapy. In HCV-related CryoVas, antiviral therapy should be given along with rituximab in order to achieve complete or partial remission. Moreover, rituximab has proven to be a glucocorticoid-sparing medication. Other potential therapies for refractory CryoVas include mycophenolate mofetil and belimumab, while tumor necrosis factor (TNF) inhibitors are not effective.

Virological and Clinical Response to Interferon-Free Regimens in Patients with HCV-Related Mixed Cryoglobulinemia: Preliminary Results of a Prospective Pilot Study

Mixed Cryoglobulinemia (MC) is the most frequent extrahepatic manifestation of Hepatitis C virus (HCV) infection. MC is an autoimmune /B-cell lymphoproliferative disorder characterized by circulating immune-complexes, named cryoglobulins. MC patients exhibit symptoms due to a systemic vasculitis of small/medium size vessels (mixed cryoglobulinemia syndrome, MCS) in a percentage going from 5 to 30%. The first-line therapeutic option in MCS patients is the etiologic treatment and, in the past fifteen years, antiviral therapy with Pegylated-Interferon (Peg-IFN) plus Ribavirin (RBV) represented the standard of care. Lately, the arrival of direct acting antivirals (DAAs) significantly modified the cure of HCV infection, consenting the use of IFN-free regimens. Here we report a review of the literature about the role of antiviral treatment, following its evolution, in treating HCVrelated MC. Furthermore, we report the results, after 8 weeks of treatment, of a preliminary pilot prospective study, counting 17 patients with HCV-related MC with or without MCS, treated with new generation DAAs in IFN-free regimens. After 8 weeks of DAA administration, all the subjects were HCV RNA negative. Moreover, in 6/17 (35%) patients cryoglobulins disappeared and, on the whole, in all patients a decrease of the cryocrit values was observed (p<0.05). Furthermore, three MCS-HCV patients (30%) resulted to be complete clinical responders and 5 subjects (50%) partial clinical responders. Therefore, IFN-free anti-HCV treatment appears to be safe and effective in MC patients from virological and clinical points of view, thus supporting the importance of HCV eradication in leading MC remission.

Pharmacogenetic analysis of hepatitis C virus related mixed cryoglobulinemia.

Mixed cryoglobulinemia (MC) is an extra hepatic hepatitis C virus related problem and different studies suggested genetics' role in predicting this complication. We evaluated the influence of SNPs in IL-28B, SLC29A1, SLC28A2, NT5C2, HNF4 and ABCB1 genes in MC prediction. SNPs were evaluated through real-time PCR. ABCB1 (gene encoding P-glycoprotein) 3435C>T SNP was associated with MC presence (p = 0.034): related to T allele carriers (CC vs CT/TT), we reached a p-value of 0.013. In the logistic regression analysis baseline viral load >600.000 IU/ml (p < 001), IL28B rs8099917/rs12979860 TT/CC (p < 0.001), NT5 (gene encoding for 5' nucleotidase) 153 TC (p = 0.012) and ABCB1 3435 CT/TT (p = 0.034) genotypes predicted MC presence. These data could help clinicians to identify patients with higher probability to show MC extra hepatic complication.

Chemokines in the Pathogenesis and as Therapeutical Markers and Targets of HCV Chronic Infection and HCV Extrahepatic Manifestations.

Cytokines and chemokines, hepatitis C virus (HCV) infection-induced, participate in viral control and liver damage. The complex cytokine network, operating during initial infection allows a coordinated and effective development of innate and adaptive immune responses. "HCV interferes with cytokines at various levels and escapes immune response by inducing a T helper (Th)2/T cytotoxic 2 cytokine profile". A predominance of the Th1 immune response (and related cytokines) has been evidenced in chronic hepatitis C infection and in extrahepatic manifestations. Interferon (IFN)-γ and IFN-γ-inducible chemokine (C-X-C motif) ligand (CXCL)9, -10 and -11 recruit inflammatory infiltrates into the liver parenchyma due to the incapability to control the infection process, resulting in extensive liver damage and liver cirrhosis. "The most important systemic HCV-related extrahepatic diseases - mixed cryoglobulinemia, lymphoproliferative disorders, diabetes and autoimmune thyroid disorders - are associated with a complex dysregulation of the cytokine/chemokine network and involve pro-inflammatory and Th1 chemokines. The therapeutical administration of cytokines such as IFN-α may result in viral clearance during persistent infection and reverts this process" reducing circulating CXCL10 levels. "Several studies have reported interleukin (IL)-28B polymorphisms, and circulating CXCL10, may be prognostic markers for HCV treatment efficacy in HCV infection". Other studies have also shown that HCV clearance by directly acting antiviral agents therapy decreases circulating CXCL10 levels. "Theoretically agents that selectively neutralize CXCL10 could increase patient responsiveness to traditional IFN-based HCV therapy", simultaneously reducing inflammatory immune cell activation.

Cryoglobulinemic vasculitis in chronic hepatitis C: Genetic aspects

Cryoglobulinemia (CG) is detected in more than 50% of patients with chronic hepatitis C (CHC); however, only 15-25% of them develop cryoglobulinemic vasculitis (CV) that is a systemic vasculitis due to the formation of immune deposits, which affects small (less than medium-sized) vessels and which is frequently fatal for the patient. The causes of CG only in some patients with CHC and the pathogenesis of CV remain unstudied; however, the accumulated data allow one to identify the special contribution of the patient's genetic factors to the development of the disease. The paper considers the genetic aspects of the development of CG and CV in CHC.

Direct-acting antiviral agents in the therapy of hepatitis C virus-related mixed cryoglobulinaemia: a single-centre experience

BackgroundThe efficacy and safety of direct-acting antiviral agents (DAAs) were evaluated in a cohort of prospectively enrolled patients with hepatitis C virus (HCV)-related mixed cryoglobulinaemia (MC), an immune complex-mediated vasculitis of small and medium vessels in which the pathogenetic role of HCV has been clearly established.MethodsTwenty-two patients received DAAs. Clinical and laboratory features were recorded at baseline, every 4 weeks until the end of treatment (EoT), and 12 weeks afterwards. Primary efficacy endpoints were (a) sustained virological response 12 weeks after therapy completion (SVR12), (b) regression of symptomatology (clinical response) and (c) cryoglobulin disappearance or cryocrit reduction ≥50% (immunological response). Complete response (CR) was defined as the occurrence of all three primary endpoints; partial response (PR) was defined as the occurrence of SVR12, with or without either immunological or clinical response; and no response was defined as missing the achievement of all three endpoints.ResultsAll patients reached SVR12. Compared with basal values, mean cryocrit values were significantly decreased at EoT and SVR12. A significant reduction of alanine transaminase and a parallel increase of complement component C4 levels were also detected. Rheumatoid factor activity was significantly reduced at EoT but not at SVR12. At SVR12, a CR was established in 14 patients (63.7%) and a PR in 8 patients (36.3%). In one patient with small lymphocytic lymphoma, the tumour progressed despite viral clearance. Mild adverse events were recorded in nine patients (40.9%).ConclusionsThe response rates induced by the use of DAAs in patients with MC were remarkably higher than those previously achieved with pegylated interferon-α/ribavirin, with or without rituximab. A much longer follow-up is desirable to achieve useful information in terms of persistent viral clearance and clinical response.

Hepatitis C virus and its cutaneous manifestations: treatment in the direct-acting antiviral era.

New all-oral direct-acting antivirals (DAA) have changed the hepatitis C virus (HCV) treatment landscape. Given that dermatologists frequently encounter HCV-infected patients, knowledge of the current treatment options and their utility in treating HCV-associated dermatologic disorders is important. In addition to highlighting the new treatment options, we review four classically HCV-associated dermatologic disorders - mixed cryoglobulinaemia (MC), lichen planus (LP), porphyria cutanea tarda (PCT) and necrolytic acral erythema (NAE) - and examine the role for all-oral direct-acting antiviral (DAA) regimens in their treatment. A literature search of English-language publications was conducted of the PubMed and EMBASE databases using search terms including 'hepatitis C', 'direct acting antivirals', 'cutaneous', 'mixed cryoglobulinemia', 'necrolytic acral erythema', 'lichen planus', 'porphyria cutanea tarda', 'rash', as well as specific drug names, related terms and abbreviations. Currently, limited data exist on the use of DAAs in HCV-infected patients with cutaneous side-effects, although treatment of the underlying HCV is now recommended for nearly all patients, with the new drugs offering much-improved dosage schedules and side-effect profiles. The most data exist for MC, in which several studies suggest that DAAs and achievement of sustained virologic response (SVR) improve cutaneous symptoms. Studies of both older and newer regimens are limited by their small size, retrospective nature, lack of appropriate controls and wide variability in study protocols. Given the strong association, screening for HCV should be considered in patients with MC, LP, PCT and NAE.

Efficacy and Safety of Direct Acting Antivirals for the Treatment of Mixed Cryoglobulinemia.

Mixed cryoglobulinemia is strongly associated with hepatitis C virus (HCV) infection and ranges from being asymptomatic to causing life-threatening vasculitis. In those with symptoms, treatment with pegylated interferon (pegIFN) and ribavirin (RBV) reduces mortality. However, few data are available on the safety and efficacy of antiviral therapy with direct acting antivirals (DAAs) in the treatment of HCV-related cryoglobulinemia. Patients treated for HCV-related cryoglobulinemia with DAA±pegIFN were retrospectively evaluated at a tertiary care center. Primary outcomes were virological, immunological, and clinical response. Complete (normalization), partial (>50% reduction), or non-response (<50% reduction) were used to describe change in cryocrit or vasculitic manifestations at week 12 post treatment. Side effects, hospitalizations, and decompensating events were recorded. Eighteen symptomatic and 65 asymptomatic patients were reviewed (61% male, median age 58 years) including 10 with severe/life-threatening vasculitis. Sixty-six (79.5%) patients received pegIFN-free therapy. Sustained virological response (SVR) was attained in 16 (88.9%) symptomatic and 59 (90.8%) asymptomatic patients. Cryoglobulins disappeared in 5 (29.4%) symptomatic and 27 (52.9%) asymptomatic patients. Of symptomatic patients with SVR, clinical response was complete in 7 (38.8%) and partial response in 4 (22.2%). Of the 5 viral relapsers, 1 had a complete response during therapy with no symptomatic recurrence, while the other patients had no clinical response. Among 7 with severe vasculitis, 6 achieved SVR but only 1 had a complete clinical response, with 3 showing a partial response and 2 showing no improvement. All four with life-threatening vasculitis required plasmapheresis and three received rituximab. All achieved SVR leading to partial clinical response in two, but no response in two. Skin manifestations (39% reduction) were most likely to completely resolve with lower responses seen in renal (11.2% reduction) and neurological symptoms (11.1%). Eighty-two (98.8%) patients completed therapy, with 19 (22.8%) reporting adverse events. Hospitalization for decompensation or worsening vasculitis occurred in five (6.0%) and four (22.2) patients respectively. DAAs resulted in high rates of SVR in patients with cryoglobulinemia. Safety and tolerability were excellent; however, most patients did not have a complete clinical or immunological response, suggesting a delay to clinical response particularly in those with severe/life-threatening vasculitis. Further follow-up will be required to determine if clinical improvement continues after viral clearance.

Hepatitis C and Its Relation to B-Cell Lymphoma

Hepatitis C virus (HCV) infection is a global health concern, with millions of people chronically infected. The course of this chronic disease may lead to lymphoproliferative disorders ranging from benign mixed cryoglobulinemia to malignant non-Hodgkin lymphoma (NHL). In this article, we reviewed the current knowledge of the different pathologic mechanisms involved in the occurrence of HCV-related lymphoproliferative diseases. Hepatitis C virus directly or indirectly causes different steps of progressive alterations. A chronic antigenic stimulation will select a B-cell clone that will gain immortality via alterations in coding DNA in proto-oncogenes and tumour-suppressor regions. The main challenge in the treatment of HCV-induced NHL is to obtain a sustained virologic response before HCV induced irreversible damages leading to everlasting cell survival. The new interferon-free therapies introduce a new era of management of HCV-NHL, with recent published data to be promising. Nevertheless, further studies are required to assess the safety of those drugs, particularly in association with chemotherapy.

ЕФЕКТИВНІСТЬ ПРОТИВІРУСНОЇ ТЕРАПІЇ ТА ДИНАМІКА ПОКАЗНИКІВ ЯКОСТІ ЖИТТЯ ХВОРИХ НА ХРОНІЧНИЙ ГЕПАТИТ С ЗАЛЕЖНО ВІД НАЯВНОСТІ ЗМІШАНОЇ КРІОГЛОБУЛІНЕМІЇ

У роботу включено 71 хворого на хронічний гепатит С (ХГС) зі стадіями фіброзу печінки F3-F4, які отримали противірусне лікування. Показано, що наявність змішаної кріоглобулінемії у цих хворих негативно впливала на частоту досягнення стійкої вірусологічної відповіді (42,1 проти 71,4 %, p&lt;0,05) та потребувала медикаментозної корекції побічних ефектів лікування у 10,5 % хворих. Серед хворих з наявністю стійкої вірусологічної відповіді (СВВ) у 70,8 % пацієнтів зафіксоване зникнення змішаних кріоглобулінів проти 3,0 % хворих, які не відповіли на лікування (p&lt;0,01). У хворих з наявністю змішаної кріоглобулінемії якість життя виявилася гірше за рахунок нижчих показників емоційно-рольового функціонування та соціального функціонування, порівняно зі здоровими людьми (р&lt;0,05). У хворих на ХГС з тяжким фіброзом печінки та змішаною кріоглобулінемією, які досягли стійкої вірусологічної відповіді, якість життя вище, ніж у пацієнтів, які не відповіли на лікування або мали рецидив (р&lt;0,05-0,01).

Efficacy and safety of long-term treatment with low-dose rituximab for relapsing mixed cryoglobulinemia vasculitis.

This study aims to evaluate the efficacy and safety of repeated treatments with low-dose rituximab for relapsing mixed cryoglobulinemia vasculitis. Thirty-seven patients with mixed cryoglobulinemia vasculitis refractory to standard of care treatment, 34 of which were HCV-positive, were treated with rituximab at the reduced dosage of 250mg/m2 given twice 1week apart per cycle. Thirty patients (81%) achieved a clinical response; 5 of them remain in remission, 3 were lost to follow-up or died, and 22 relapsed after a mean of 15.7months. Eleven relapsers were retreated with one (6 patients), 2 (3 patients), or 3 (2 patients) additional rituximab cycles given at each relapse. Clinical and laboratory efficacy and side effects of long-term treatment were evaluated. Clinical response to retreatment was 91% (10/11) at the first relapse, 80% (4/5) at the second relapse, and 100% (2/2) at the third relapse. The mean (±SD) time to relapse was 17.1±14.1months in 30 patients who were treated with only one cycle (from first cycle to the first relapse) and 45.7±30.6months (from first cycle to the last observed relapse) in 11 patients treated with 2 or more cycles (p=0.0037). Severe adverse reactions occurred in 3 patients, in 2 of whom at the first cycle. Our results suggest that repeated treatment of relapsing mixed cryoglobulinemia with a low-dose rituximab regimen is efficacious, safe, and cost-effective for the long-term management of this disorder.

FRI-265 - Benefit of direct-acting antiviral therapy in hepatitis C virus (HCV) monoinfected and HIV-HCV coinfected patients with mixed cryoglobulinemia

FRI-265 - Benefit of direct-acting antiviral therapy in hepatitis C virus (HCV) monoinfected and HIV-HCV coinfected patients with mixed cryoglobulinemia

Resolution of Q Fever-Associated Cryoglobulinemia With Anti-CD20 Monoclonal Antibody Treatment.

Immunologic phenomena can complicate chronic infections with Coxiella burnetii (Q fever), including immune complex deposition causing vasculitis, neuropathy, and glomerulonephritis. We describe the case of a man with Q fever endocarditis, mixed cryoglobulinemia, and life-threatening vasculitis driven by immune complex deposition who was successfully treated with B cell depleting therapy (rituximab).

A mouse model for hepatitis C virus infection: are we there yet?

Collectively, viral hepatitis remains a global epidemic causing an estimated 1.4 million deaths per year, of which hepatitis C virus (HCV) is the leading cause (1). Despite the availability of new antivirals that are capable of effective cure, the number of HCV infections and re-infections continue to rise worldwide. In addition to progressive liver disease and hepatocellular carcinoma (HCC), HCV is associated with metabolic disorders and co-morbidities including obesity, insulin resistance, type 2 diabetes mellitus, cardiovascular disease, mixed cryoglobulinemia among others (2-4)—all adding to the morbidity and mortality associated with this disease. HCV continues to be a challenge to control, due, at least in part, to the lack of a tangible animal model. Chimpanzees are susceptible to HCV and played a major role in understanding the natural history of the disease. But with limitations on the use of chimpanzees in biomedical research and an attenuated disease course, a tangible animal model could provide information on several gaps in HCV knowledge such as viral pathogenesis and persistence, immune correlates of protection, and importantly vaccine development and testing.

Hepatitis C and Neurological Disorders: A Patient’s Case Report

Introduction: Neurological disorders associated with hepatitis C is most often related to mixed cryoglobulinemia. The aim of this study is to show the severity of neurological disorders during hepatitis C infection. Observation: Mrs. S A, 60 years old, who had been in purpuric rash for six months, associated with physical and psychic asthenia and weight loss at 16 kg in 8 months. The evolution was marked by an alteration of the neurological state of the patient with an installation of motor deficit affecting the 04 limbs, abolition of the osteotendinous reflexes, and a hypoesthesia of the upper and lower limbs. The electromyogram (EMG) showed a sensorimotor polyradiculoneuropathy, and the etiological diagnosis was in favor of a peripheral neuropathy secondary to a cryoglobulinemia, related to hepatitis C. In addition, the patient presented after a few days of headaches, a sharp drop in visual acuity and high blood pressure, this is complicated by two episodes of convulsive seizures. A cranial CT scan is performed in an emergency without abnormalities, with no sign in relation to thrombophlebitis after injection of contrast agent. The diagnosis retained is a central neurological disease secondary to infection with the virus c associated with peripheral neurological disease. Conclusion: Neurological disorders associated with hepatitis C are rare but poor prognosis threatening the functional and vital prognosis of patients.

FRI-211 - Direct Acting Antivirals in patients with HCV-associated mixed cryoglobulinemia: real life safety and efficacy

FRI-211 - Direct Acting Antivirals in patients with HCV-associated mixed cryoglobulinemia: real life safety and efficacy

FRI-216 - Sofosbuvir/Ribavirin treatment in patients with genotype 2, Hepatitis C Virus infection and symptomatic mixed cryoglobulinemia: an interim analysis on safety, efficacy and impact on quality of life

FRI-216 - Sofosbuvir/Ribavirin treatment in patients with genotype 2, Hepatitis C Virus infection and symptomatic mixed cryoglobulinemia: an interim analysis on safety, efficacy and impact on quality of life

HCV-ІНФЕКЦІЯ Й ЛІМФОПРОЛІФЕРАЦІЯ (ОГЛЯД ЛІТЕРАТУРИ)

У статті описано роль HCV-інфекції у розвитку лімфопроліферативних порушень. Представлено деякі ланки патогенезу позапечінкових проявів, таких, як аутоімунні порушення й неходжкінська лімфома (НХЛ), пов’язаних з HCV-інфекцією. Змішана кріоглобулінемія є найпоширенішим станом, пов’язаним з HCV-індукованою лімфопроліферацією і в деяких випадках здатна призвести до клінічних проявів, таких, як геморагічний васкуліт, пурпура, артралгії тощо, а також розвитку В-клітинної НХЛ. HCV-лімфогенез заснований на безперервній В-клітинній активації й інгібуванні В-клітинного апоптозу, що, імовірно, відіграє ключову роль у розвитку позапечінкових проявів, пов’язаних з HCV- інфекцією.

Successful ledipasvir + sofosbuvir treatment of active synovitis in a rheumatoid arthritis patient with hepatitis C virus-related mixed cryoglobulinemia

Sir,Hepatitis C virus (HCV)-related arthritis is one of the most common extrahepatic manifestations of HCV infection. Like rheumatoid arthritis (RA), HCV infection also causes various immune disord...

Clinical and Immune Effects of Direct-Acting Antivirals in HCV-Associated Cryoglobulinemia

A recent study showed that direct-acting antiviral regimens (DAAs) are effective in clearing hepatitis C virus (HCV) in patients with virus-associated