Virus-associated Cryoglobulinemia Research Articles

THU-221 - Efficacy of direct-acting antivirals in patients with hepatitis C virus-associated cryoglobulinemia and monoclonal gammopathy

THU-221 - Efficacy of direct-acting antivirals in patients with hepatitis C virus-associated cryoglobulinemia and monoclonal gammopathy

POS-021 C4 COMPLEMENT DEFICIENCY AND TYPE III CRYOGLOBUINEMIA IN A PATIENT WITH MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS

POS-021 C4 COMPLEMENT DEFICIENCY AND TYPE III CRYOGLOBUINEMIA IN A PATIENT WITH MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS

Cutaneous Pedal Manifestations in Patient With Hepatitis C Virus-Associated Cryoglobulinemia: Case Report and Review of Literature.

Cryoglobulinemia is an uncommon blood dyscrasia that can manifest itself in the lower extremity. Due to the insidious nature of this disease, dermatological symptoms and ulcerations can easily be mistaken for more common entities. The authors present an overview of cryoglobulinemia and a case report of a patient with lower extremity manifestations of this disorder. This can provide specific guidance on the steps necessary to accurately establish the diagnosis of cryoglobulinemia or rule it out and pursue other etiologies causing lower extremity ulceration.

The dilemma of treating hepatitis C virus-associated cryoglobulinemia.

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

Hepatitis E virus-associated cryoglobulinemia in solid-organ-transplant recipients.

An association between hepatitis E virus (HEV) infection and cryoglobulinemia has been suggested. The aims of this study were to assess the prevalence of cryoglobulinemia during HEV infection in solid-organ-transplant (SOT) recipients, to describe its outcomes under ribavirin therapy and to evaluate its effects on kidney function and histology. Between November 2005 and June 2016, 128 cases of HEV infection were diagnosed among SOT recipients followed in our institution. Cryoglobulinemia data obtained from 66 patients during acute-phase HEV and 51 patients during chronic-phase HEV were compared to a historical control group of 89 SOT recipients without HEV markers. Cryoglobulins were also monitored in a group of 43 patients treated by ribavirin. The prevalence of cryoglobulinemia was increased in HEV-infected SOT patients during a chronic phase (52.9%) compared to HEV-infected SOT patients at acute phase (36.4%) (P=.1) and to HEV-negative SOT patients (23.6%) (P<.001). HEV infection was identified as an independent predictive factor for cryoglobulinemia (OR 2.3, CI 95%: 1.17-4.55, P=.02). After ribavirin therapy and HEV clearance, the prevalence of cryoglobulin was significantly decreased from 53.5% to 20.9% (P=.003). Kidney function was significantly worse and proteinuria tended to be higher in chronically HEV-infected patients with cryoglobulinemia compared to those without cryoglobulinemia. Membranoproliferative glomerulonephritis was diagnosed in 2 patients, of which 1 had detectable cryoglobulinemia. In conclusion, a relationship between HEV and cryoglobulin formation seems to exist. However, the clinical impact of cryoglobulinemia in SOT patients infected with HEV has to be confirmed.

Long-term Efficacy of Interferon-Free Antiviral Treatment Regimens in Patients With Hepatitis C Virus–Associated Cryoglobulinemia Vasculitis

In small-size and short-term studies of hepatitis C virus-associated cryoglobulinemia vasculitis (HCV-CryoVas), patients had a higher rate of response and tolerance to direct-acting antiviral (DAA) agents than interferon-containing regimens. We collected follow-up data from a clinical trial to determine the long-term effectiveness and tolerance of all-oral, interferon-free DAA regimens in patients with CryoVas. We collected follow-up data from a prospective international multicenter cohort study of 148 patients with symptomatic HCV-CryoVas (53.7% with cirrhosis and 49.3% naive to treatment with DAAs). All patients received DAA (sofosbuvir plus daclatasvir, n= 53; sofosbuvir plus ribavirin, n= 51; sofosbuvir plus ledipasvir, n= 23; or sofosbuvir plus simeprevir, n= 18), for 12 or 24 weeks, from 2014 through 2017; the median follow-up timewas 15.3 months. A complete clinical response was defined as improvement of all organs involved at baseline and the absence of clinical relapse; a partial response wasdefined as improvement in some but not all organs involved at baseline. The primaryend point was clinical response of CryoVas symptoms at week 12 after stopping DAA therapy. A complete response was reported for 106 patients (72.6%), a partial response for 33 patients (22.6%), and no response for 7 patients (4.8%). Cryoglobulins were no longer detected in bloodsamples from 53.1% of patients, and 97.2% of the patients had a sustained virologic response to therapy. Premature DAA withdrawal was reported for 4.1% of patients. Factors associated with no or partial response to therapy included a severe form of CryoVas (odds ratio, 0.33; 95% CI, 0.12-0.91; P= .03) and peripheral neuropathy (odds ratio, 0.31; 95% CI, 0.11-0.84; P= .02). After a median follow-up time of 15.3 months, 4 patients (2.8%) died. The CryoVas manifestation of purpura was cleared from 97.2% of patients, renal involvement from 91.5% of patients, arthralgia from 85.7% of patients, neuropathy from 77.1% of patients, and cryoglobulinemia from 52.2%. In a long-term follow-up analysis of data from a clinical trial, we found that more than 95% of patients with HCV-CryoVas have a full or partial response of symptoms to different DAA treatment regimens. Fewer than 5% of patients stop therapy prematurely and less than 3% die. A severe form of CryoVas and peripheral neuropathy were associated with a lack of response of HCV-CryoVas to DAA therapy.

Hepatitis C virus-associated cryoglobulinemia with membrano-proliferative glomerulonephritis treated with prednisolone and interferon: A case report.

Hepatitis C virus (HCV) is a major cause of liver-associated morbidity and has an increasing prevalence worldwide. Hepatitis C virus infection may lead to chronic hepatitis, cirrhosis and liver failure. However, it is also associated with a wide range of extra-hepatic complications, such as cryoglobulinemia, an immune complex disease associated with cryoglobulin leading to multiple organ damage and, while the major symptom is vasculitis. The present study reported on a-58-year-old woman who was diagnosed with HCV-associated cryoglobulinemia with skin, kidney and blood system damage and biopsy-proven cryoglobulinemia membrano-proliferative glomerulonephritis. HCV RNA clearance occurred within a few weeks of interferon treatment and the patient was then treated by prednisolone and sustained interferon. While the therapeutic effect was obvious at first, the disease reappeared in combination with refractory infection and multiple organ failure, and the patient finally died. HCV-associated cryoglobulinemia is uncommon in developing countries such as China, while treatment guidelines remain to be established, particularly if complex complications are present.

Virologic, Clinical, and Immune Response Outcomes of Patients With Hepatitis C Virus-Associated Cryoglobulinemia Treated With Direct-Acting Antivirals.

Cryoglobulins (circulating immune complexes of polyclonal IgG, monoclonal IgM, and rheumatoid factor) are detected in the circulation of 40% to 60% of patients with chronic hepatitis C virus infection, and cryoglobulinemic vasculitis (CV) is observed in approximately 10% of patients. We aimed to assess the clinical and immune effects of direct-acting antiviral treatment. We performed a prospective study of 64 patients with HCV infection with circulating cryoglobulins receiving direct-acting antiviral therapy at a single center in Barcelona, Spain, from January 2014 through April 2016. Patients were classified as having CV (n= 35) or asymptomatic circulating cryoglobulins (ACC, n= 29). Clinical response was considered complete if a patient's Birmingham Vasculitis Activity Score (version 3) was 0, or if all affected organs improved 12 weeks after the end of therapy. A complete immunologic response (CIR) was defined as no detection of circulating cryoglobulins and normalized levels of complement and/or rheumatoid factor. Clinical manifestations of CV included purpura (65%), weakness (70%), arthralgia (31%), myalgia (20%), peripheral neuropathy (50%), and renal involvement (20%). At baseline, patients with CV had significantly higher levels of rheumatoid factor and lower levels of C4 complement than patients with ACC, whereas cryocrits were similar between groups (3.2% vs 2.6%). Overall, 60 patients (94%) had a sustained viral response 12 weeks after therapy. Among patients with CV, the median Birmingham Vasculitis Activity Score (version 3) decreased from 9 (range, 2-31) to 3 (range, 0-12) (P < .001). Twenty-five patients with CV (71%) achieved a complete clinical response. Immune-suppressive therapy was reduced for 4of 13 patients and withdrawn for 6 of 13. Overall, 48% of patients achieved a CIR. A low baseline cryocrit level (<2.7%) was the only factor associated with CIR (odds ratio, 9.8; 95% confidence interval, 2.2-44; P= .03). Viral eradication was associated with clinical improvement in most patients with CV. Markers of immune activation, including circulating cryoglobulins, persisted in 52% of patients with CV or ACC, despite a sustained viral response 12 weeks after therapy. A longer follow-up period after viral eradication might be necessary to ensure a normal immune response.

Lymphoproliferative disease-related mixed cryoglobulinemia treated with rituximab and prednisolone.

Mixed cryoglobulinemia is often associated with hepatic C virus infection and is less common with hepatitis B virus infection, and it often progresses into lymphoproliferative diseases. Rituximab is known to achieve systemic B-cell depletion and clinical remission of the systemic effects of cryoglobulins in hepatitis C virus-associated cryoglobulinemia. Conversely, there are few reports regarding the use of rituximab in hepatitis B virus-associated cryoglobulinemia. We report here the case of a 65-year-old Japanese female who presented with lymphoproliferative disease-related cryoglobulinemia with hepatitis B virus, including membranoproliferative glomerulonephritis with renal failure. The vasculitis was refractory to conventional and antiviral therapy, but rituximab use led to control the disease. Our case highlights the benefit and efficacy of rituximab in association with antiviral therapy in small vessel vasculitis related to lymphoproliferative disease-related cryoglobulinemia with hepatitis B virus.

The two-edged sword: vasculitis associated with HIV and hepatitis C coinfection

Vasculitis has long been associated with chronic viral infections, thus the twin perils of the infection and the immune response against it that bedevils the specialties of infection and immunity. After HIV was identified, it too became associated with vasculitic syndromes. Later, hepatitis C virus was also isolated, identified and described with its own spectrum of vasculitic diseases, including hepatitis C virus-associated cryoglobulinaemia. With the increasing prevalence of HIV and hepatitis C virus coinfection, there has come an increasing recognition of the range of vasculitides that can occur in this population leading to significant morbidity, diagnostic and treatment challenges. In this review, we examine the epidemiology, pathogenesis and general principles of treatment of these systemic diseases in HIV/hepatitis C virus coinfected individuals.

Safety and efficacy of rituximab treatment for vasculitis in hepatitis B virus-associated type II cryoglobulinemia: a case report

IntroductionSystemic B-cell depletion and clinical remission of the systemic effects of cryoglobulins have already been achieved using rituximab in hepatitis C virus-positive immunocompetent patients. Conversely, to the best of our knowledge there are no reports in the literature regarding the use of rituximab in hepatitis B virus-associated cryoglobulinemia.Case presentationWe report here the case of a 60-year-old Caucasian man who presented with hepatitis B virus-associated type II cryoglobulinemia with severe multisystem disease, including membranoproliferative glomerulonephritis with acute renal failure. The vasculitis was refractory to conventional and antiviral therapy but rituximab use led to a fall in cryoglobulin levels and disease control. The B-cell depletion was safe and efficient to induce a complete remission of the disease.ConclusionOur case highlights the benefit and the efficacy of rituximab in association with antiviral therapy in small vessel vasculitis related to hepatitis B virus-associated mixed cryoglobulinemia.

Long-term efficacy of rituximab in hepatitis C virus-associated cryoglobulinemia

Mixed cryoglobulinemia is one of the most closely related extrahepatic manifestations of hepatitis C virus and requires a challenging therapeutic approach depending on the severity of the symptoms. Here, we describe the long-term follow-up of a patient with important cutaneous, articular and neural manifestations of cryoglobulinemia associated with chronic hepatitis C treated with rituximab. A 42-year-old woman who did not respond to previous interferon-based treatments (standard and pegylated interferon plus ribavirin) and corticosteroids was subjected to treatment with rituximab at a dose of 375 mg/m(2) per week for 4 consecutive weeks. The drug was well tolerated and complete improvement of arthralgia was immediately evident. There was gradual improvement of lower limbs paresthesia and healing of a leg ulcer that had been active for 5 years. The clinical and immunological responses induced by rituximab are sustained over long-term follow-up, and this case illustrates the drug efficacy for non-responder patients to antiviral therapy.

Cryoglobulinemia and renal disease

Cryoglobulinemia occurs in a variety of clinical settings including lymphoproliferative disorders, infection and autoimmune disease. The worldwide pandemic of hepatitis C virus infection has resulted in a significant increase in its extrahepatic complications including cryoglobulinemia and renal disease. Here we review the types of cryoglobulins, mechanisms of cryoglobulin formation, links between hepatitis C virus and renal disease, and current approaches to therapy. The prevalence of cryoglobulinemia in hepatitis C virus-infected individuals is surprisingly large and may be found in more than 50% of some infected subpopulations. Most of these patients will not have overt renal disease, but there is a population of unknown size of patients with subclinical glomerular disease that has the potential to become clinically significant. In cases of hepatitis C virus-associated cryoglobulinemia, treatment remains focused on eradication of viremia, but interventions directed at B lymphocytes are increasingly utilized. The mechanisms of cryoglobulin formation and renal injury remain largely obscure, but recent evidence implicates the innate immune system in the initiation of disease. The most common renal injury associated with hepatitis C virus infection, in patients both with and without evidence of cryoglobulinemia, is membranoproliferative glomerulonephritis. There has been increasing focus on defining the mechanisms that link these processes and the evolution of renal injury in all clinical settings of cryoglobulinemia.

Efficacy and safety of treatment with pegylated interferon and ribavirin for hepatitis C virus-associated cryoglobulinemia: A multicenter study

Efficacy and safety of treatment with pegylated interferon and ribavirin for hepatitis C virus-associated cryoglobulinemia: A multicenter study

Rituximab combined with Peg-interferon-ribavirin in refractory hepatitis C virus-associated cryoglobulinaemia vasculitis

Objectives:To report the results of a pilot study using rituximab combined with Peg-interferon (IFN) α2b-ribavirin in severe refractory hepatitis C virus (HCV) related mixed cryoglobulinaemia (MC) vasculitis.Methods:Sixteen consecutive patients with...

Management of virus-induced systemic vasculitides.

The best therapeutic strategy in virus-induced vasculitides should take into account the etiology of the disease and be adapted to the pathogenesis. The combination of antiviral treatments and plasma exchanges has been proven effective in polyarteritis nodosa. In HIV-related vasculitis, this strategy is effective and does not jeopardize the outcome of AIDS, as do cytotoxic agents. In vasculitis related to hepatitis C virus-associated cryoglobulinemia, plasma exchanges improve the outcome, but the poor effectiveness of antiviral drugs usually does not favor a definite recovery of the patients. Relapses are frequent.

In vitro reactivity of cryoglobulin IgM and IgG in hepatitis C virus-associated mixed cryoglobulinemia

Background/Aims: Mixed cryoglobulinemia is frequently associated with chronic hepatitis C virus infection. We aimed to clarify the mechanism, kinetics and participating proteins in cryoprecipitate formation, whcih are still being debated. Methods: Eighteen patients with cryoglobulinemia were studied. Isolated serum cryoprecipitates and purified cryoglobulin IgM and IgG fractions were analyzed in vitro by turbidimetry for temperature-dependent complex formation. Immunoglobulin reactivity, i.e., in cryoprecipitates and in cryoglobulin-free sera, was studied using immunoblot and enzyme immunoassays. HCV RNA was detected by reverse transcriptase/polymerase chain reaction. Results: By turbidimetry, purified cryo-IgM precipitated (in the absence of HCV RNA) with cryo-IgG as well as with non-cryoglobulin IgG and with IgG Fc or F(ab′) 2 fragments. In contrast, purified cryo-IgG did not precipitate with non-cryoglobulin IgM. Anti-HCV IgG reactivity was found in cryoglobulin-free sera, in cryoprecipitates and in purified cryoglobulin IgG fractions. The respective titers were similar. Purified cryo-IgM did not react to HCV-encoded proteins. Binding of cryo-IgM to heterologous IgG was inhibited by intact IgG (up to a mean of about 52%) as well as by IgG Fc (33%) and F(ab′) 2 fragments (17%). Binding of cryo-IgM to IgG was enhanced at low temperature (4°C vs. 37°C), particularly for type III cryoglobulin IgM. Conclusions: In hepatitis C virus-associated cryoglobulinemia the vitro precipitate formation depended on cryo-IgM, while IgG appeared to act as an unspecific antigenic partner. Hepatitis C viral particles were probably not required. Cryo-IgM binding occurred primarily to intact IgG. Anti-HCV reactivity of either cryo-IgM or cryo-IgG was not necessary for precipitate formation. Regarding the pathogenesis, a direct hepatitis C virus protein-dependent stimulation of B-cells producing cryo-IgM seems to be unlikely.

Prolonged, Complete Remission After 2-Chlorodeoxyadenosine Therapy in a Patient With Refractory Essential Mixed Cryoglobulinemia

Prolonged, Complete Remission After 2-Chlorodeoxyadenosine Therapy in a Patient With Refractory Essential Mixed Cryoglobulinemia