Successful Rituximab Treatment in Thrombotic Thrombocytopenic Purpura Patients Complicated by Other Autoimmune Disorders: Two Case Reports

We herein report two cases of thrombotic thrombocytopenic purpura (TTP) complicated by other autoimmune disorders, autoimmune hepatitis and immune thrombocytopenia, respectively. In both cases, corticosteroids were continuously administered for the treatment of preceding autoimmune disorders. However, a sufficient objective response for TTP was not obtained by plasma exchange and corticosteroid treatment. Once a week rituximab (375 mg/m²) treatment for 4 times was initiated within 2 weeks from the diagnosis. Both patients achieved a sufficient response, and have never had any recurrence as of the last follow-up dates. The early introduction of rituximab could be an effective treatment option in TTP patients complicated with other autoimmune disorders.     

Considerations in the Management of Hepatitis C Virus-related Thrombocytopenia with Eltrombopag

Thrombocytopenia is a common clinical problem in HCV-infected cases. Multiple studies have consistently shown a rise in platelet count following a successful HCV treatment thus proving a cause-effect relationship between the two. Although, many therapeutic strategies have been tried in the past to treat HCV-related thrombocytopenia (e.g. interferon dose reductions, oral steroids, intravenous immunoglobulins, splenectomy etc), the success rates have been variable and not always reproducible. After the cessation of clinical trials of PEG-rHuMGDF due to immunogenecity issues, the introduction of non-immunogenic second-generation thrombopoietin-mimetics (eltrombopag and Romiplostim) has opened up a novel way to treat HCV-related thrombocytopenia. Although the data is still sparse, eltrombopag therapy has shown to successfully achieve the primary endpoint platelet counts of ≥50,000/μL in phase II & III, randomized, double-blind, placebo-controlled trials. Likewise, though it is premature to claim safety of this drug especially in high-risk patient groups, reported side effects in the published literature were of insufficient severity to require discontinuation of the drug. Based on the current and emerging evidence, a review of the pharmacologic basis, pharmacokinetics, therapeutic efficacy, safety profile and future considerations of eltrombopag in the context of HCV-related thrombocytopenia is given in this article. A MEDLINE search was conducted (1990 to August 2009) using the search terms eltrombopag, HCV, thrombocytopenia.     

Proliferative Glomerulonephritis with Monoclonal IgG Deposits and Refractory Ascites: Successful Treatment with Rituximab and Cell-free and Concentrated Ascites Reinfusion Therapy

A 49-year-old woman presented with nephrotic-range proteinuria, microhematuria, and moderate renal dysfunction. Diuretic-resistant refractory ascites associated with nephrotic syndrome were observed. Based on the histopathological findings, the patient was diagnosed with proliferative glomerulonephritis with monoclonal immunoglobulin G deposits (PGNMID). Rituximab was administered due to steroid and immunosuppressive drug resistance, and partial remission was achieved after six months. Cell-free and concentrated ascites reinfusion therapy (CART) performed to treat the refractory ascites improved the ascites and anasarca. Rituximab successfully treated the PGNMID, while CART effectively treated the refractory ascites associated with nephrotic syndrome.     

The Successful Treatment of a Case of HCV-associated Cryoglobulinemic Glomerulonephritis with Rituximab,Direct-acting Antiviral Agents,Plasmapheresis and Long-term Steroid Despite Serologically Persistent Cryoglobulinemia

Novel treatments with rituximab or direct-acting antiviral agents (DAAs) were expected to improve the clinical outcomes of hepatitis C virus (HCV)-associated cryoglobulinemia in the last decade. Recently, however, persistent cases of cryoglobulinemia have been reported, and the ideal approach to treating such cases has not been established. We herein report a case of the successful treatment of HCV-associated cryoglobulinemic glomerulonephritis with rituximab, DAAs, occasional plasmapheresis and long-term steroid, with the patient''s renal function and proteinuria improving over the long term despite serologically persistent cryoglobulinemia. This case suggests the efficacy of combination treatment with rituximab, DAAs, occasional plasmapheresis and long-term steroid for persistent cryoglobulinemia.     

Factors Associated with Significant Platelet Count Improvement in Thrombocytopenic Chronic Hepatitis C Patients Receiving Direct-Acting Antivirals

To clarify the predictive factors of significant platelet count improvement in thrombocytopenic chronic hepatitis C (CHC) patients. CHC patients with baseline platelet counts of <150 × 10³/μL receiving direct-acting antiviral (DAA) therapy with at least 12-weeks post-treatment follow-up (PTW12) were enrolled. Significant platelet count improvement was defined as a ≥10% increase in platelet counts at PTW12 from baseline. Platelet count evolution at treatment week 4, end-of-treatment, PTW12, and PTW48 was evaluated. This study included 4922 patients. Sustained virologic response after 12 weeks post-treatment was achieved in 98.7% of patients. Platelet counts from baseline, treatment week 4, and end-of-treatment to PTW12 were 108.8 ± 30.2, 121.9 ± 41.1, 123.1 ± 43.0, and 121.1 ± 40.8 × 10³/μL, respectively. Overall, 2230 patients (45.3%) showed significant platelet count improvement. Multivariable analysis revealed that age (odds ratio (OR) = 0.99, 95% confidence interval (CI): 0.99–1.00, p = 0.01), diabetes mellitus (DM) (OR = 1.20, 95% CI: 1.06–1.38, p = 0.007), cirrhosis (OR = 0.66, 95% CI: 0.58–0.75, p < 0.0001), baseline platelet counts (OR = 0.99, 95% CI: 0.98–0.99, p < 0.0001), and baseline total bilirubin level (OR = 0.80, 95% CI: 0.71–0.91, p = 0.0003) were independent predictive factors of significant platelet count improvement. Subgroup analyses showed that patients with significant platelet count improvement and sustained virologic responses, regardless of advanced fibrosis, had a significant increase in platelet counts from baseline to treatment week 4, end-of-treatment, PTW12, and PTW48. Young age, presence of DM, absence of cirrhosis, reduced baseline platelet counts, and reduced baseline total bilirubin levels were associated with significant platelet count improvement after DAA therapy in thrombocytopenic CHC patients.     

Management of Hepatitis C Virus-related Mixed Cryoglobulinemia

Mixed cryoglobulinemia is a chronic immune complex-mediated disease strongly associated with hepatitis C virus (HCV) infection. Mixed cryoglobulinemia is a vasculitis of small and medium-sized arteries and veins, due to the deposition of complexes of antigen, cryoglobulin and complement in the vessel walls. The main clinical features of mixed cryoglobulinemia vasculitis include the triad of palpable purpura, arthralgias, and weakness, and other pathological conditions such as glomerulonephritis, peripheral neuropathy, skin ulcers, and widespread vasculitis. The treatment of HCV-related mixed cryoglobulinemia is difficult due to the multifactorial origin and clinical polymorphism of the syndrome. It can be directed to eradicate the HCV infection, suppress the B-cell clonal expansion and cryoglobulin production, or ameliorate symptoms. The choice of the most appropriate treatment is strictly related to the assessment of disease activity, and to the extent and severity of organ involvement.     

Hepatitis C virus evasion mechanisms from neutralizing antibodies

Hepatitis C virus (HCV) represents a major public health problem, affecting 3% of the world's population. The majority of infected individuals develop chronic hepatitis, which can progress to cirrhosis and hepatocellular carcinoma. To date, a vaccine is not available and current therapy is limited by resistance, adverse effects and high costs. Although it is very well established that cell-mediated immunity is necessary for viral clearance, the importance of host antibodies in clearing HCV infection is being increasingly recognized. Indeed, recent studies indicate that neutralizing antibodies are induced in the early phase of infection by patients who subsequently clear viral infection. Conversely, patients who do not clear the virus develop high titers of neutralizing antibodies during the chronic stage. Surprisingly, these antibodies are not able to control HCV infection. HCV has therefore developed mechanisms to evade immune elimination, allowing it to persist in the majority of infected individuals. A detailed understanding of the mechanisms by which the virus escapes immune surveillance is therefore necessary if novel preventive and therapeutic treatments have to be designed. This review summarizes the current knowledge of the mechanisms used by HCV to evade host neutralizing antibodies.     

The Effect of Combination Therapy with Interferon and Cryofiltration on Mesangial Proliferative Glomerulonephritis Originating from Mixed Cryoglobulinemia in Chronic Hepatitis C Virus Infection

Abstract: Cryofiltration, which has developed from double filtration plasmapheresis (DFPP) with a cooling unit, is an on-line technique to remove cryoglobulin. We report on a patient who suffered from progressive edema and renal insufficiency caused by cryoglobulinemic membranoproliferative glomerulonephritis (MPGN), probably due to chronic hepatitis C virus (HCV) infection. To remove cryoglobulins and terminate the HCV infection, we utilized combination therapy with cryofiltration and interferon-α injection with corticosteroids. Interferon-α was capable of decreasing proteinuria but not diminishing cryoglobulin. Additional cryofiltration could remove cryoglobulin to an undetectable level. This combination therapy was partially successful to reduce proteinuria and prevent the progressive deterioration of renal function. The major adverse effects of this therapy were bleeding and myelosuppression. We conclude that this combination therapy may be effective and should be considered as treatment for cryoglobulinemic MPGN.     

Hepatitis B Surface Antigen Decline during Sofosbuvir and Ribavirin Therapy in Hepatitis B Inactive Carriers Who Were Co-infected with Hepatitis C

Direct-acting antiviral (DAA) therapy carries a potential risk of inducing hepatitis B virus (HBV) reactivation. However, the HBV kinetics during and after DAA therapy in patients co-infected with hepatitis C virus (HCV) and HBV remain unknown. We retrospectively evaluated the HBV kinetics during and after sofosbuvir/ribavirin therapy in four HBV inactive carriers co-infected with HCV. HCV was eradicated in all patients. Changes in HBV-DNA levels during treatment differed among patients. The hepatitis B surface antigen (HBsAg) levels uniformly decreased (mean -0.530 logIU/mL) by the end of treatment and returned to near the baseline in all patients. Sofosbuvir/ribavirin therapy thus demonstrated a suppressive effect on HBsAg.     

Hepatitis C and hepatocellular carcinoma

Abstract Hepatitis C virus (HCV) infection is aetiologically very closely associated with hepatocellular carcinoma (HCC). World-wide, hepatitis B virus infection is the predominant aetiological factor in developing countries, whereas in industrialized countries, HCV has a far more important role in hepatocarcinogenesis. The varying weights of the aetiological role of HCV infection are compared among countries. The speed of progression of chronic hepatitis C to cirrhosis, thenceforth to HCC, and certain discrepancies between an American study and the Japanese experience are described. The reason for the recent surge of HCV infection and subsequent increase in the incidence of HCC is also discussed. The genetic mechanism of HCV-induced hepatocarcinogenesis is still poorly understood.     

The New Era of Hepatitis C Virus Therapy

The hepatitis C virus (HCV) has a significant medical and economic impact on societies around the world, and it has been estimated that 130-180 million people are infected with HCV. Therapies for HCV are currently undergoing a revolution. In recent years, several new treatments have been approved by the United States Food and Drug Administration, and many other treatments are in phase II or III clinical trials, including direct antiviral agents (DAAs). Due to recent major advances in the field of HCV therapy, a summary of findings on new HCV therapies are provided in this review article, including reports on new DAAs.     

Progressive Massive Splenomegaly in an Adult Patient with Kabuki Syndrome Complicated with Immune Thrombocytopenic Purpura

Kabuki syndrome is characterized by multiple systemic anomalies and intellectual disability. It is complicated with immunodeficiencies and autoimmune disorders. The syndrome is caused by a mutation in the KMT2D gene. We herein report a case of a Kabuki syndrome with developing immune thrombocytopenic purpura (ITP) and progressive splenomegaly. Laparoscopic splenectomy was performed and the patients'' symptoms quickly disappeared with platelet recovery. After this operation, the patient had no severe complications. A sequence analysis of the KMT2D gene identified a pathogenic mutation frequently associated with ITP. Laparoscopic splenectomy is therefore considered to be a good therapeutic option for recurrent ITP and symptomatic splenomegaly with Kabuki syndrome.     

Hepatitis C virus genotypes in chronic hepatitis C of children

SUMMARY. Several hepatitis C virus (HCV) genotypes have been recently identified and genotype 1b has been correlated with severe liver disease and a poor response to interferon therapy. HCV infection in children is an interesting model for evaluation of the relationship between HCV genotypes and liver disease, because of its relatively short duration and the infrequent association with confounding cofactors. We have investigated HCV genotypes, using a dot-blot hybridization assay with genotype-specific probes, in 36 Italian children with chronic hepatitis C who were otherwise well and had no other underlying disease. Only four patients were symptomatic; liver histology, obtained in 3 3 patients, showed minimal hepatitis in 17 and mild chronic hepatitis in 16. Infection with HCV genotype Ib was found in 55.5% of patients, with a peak prevalence of 83% in children from southern Italy (P < 0.05 vs other regions). The remaining children were infected with HCV genotype la (16.6%), genotype 2 (11.1%). and mixed (10.9%) or undetermined (2.7%) genotypes. In one patient, HCV viraemia was never detected. There was no statistically significant correlation between genotype and age, sex, source of infection, alanine aminotransferase pattern and histological activity index. These results indicate that genotype 1b is widespread among Italian children with chronic hepatitis C, although with significant geographical variations. It is not associated with a more severe liver disease, therefore suggesting that the greater severity of liver disease recently reported in adults could reflect the cumulative effects of disease duration and of interfering cofactors.     

Hepatitis C transmission between spouses

To examine inter-spouse transmission as one of the potential routes of infection for hepatitis C virus (HCV), 121 patients with HCV-related chronic liver disease who tested positive for antibodies to HCV (anti-HCV) and their spouses were studied. Of these, 21 (17.4%) patients had spouses with anti-HCV. In 12 couples, the HCV genotype matched (type II: 10 couples, type III: two couples). The genotype differed in six couples. One patient was positive for anti-HCV, but negative for HCV-RNA, while the spouse was positive for both. The remaining two couples were only positive for anti-HCV. Genetic heterogeneity in the hypervariable region 1 of HCV was analysed in 11 couples with matched genotypes. In two couples, no mutation was recognized in the putative E2/NS1 genes using the heteroduplex method. The present study provides evidence to verify household transmission of HCV between patients and their spouses. These results suggest that inter-spouse transmission may be a potential route of transmission of HCV infection. However, other environmental factors (e.g. the duration of the marriage) cannot be ignored.     

Hepatitis C virus risk: a hepatitis C virus related syndrome

BACKGROUND: The association between mixed cryoglobulinemia (MC) and hepatitis C virus (HCV) infection has been recently described in many reports. OBJECTIVE: The aim of this study was to evaluate the long-term prognosis of hepatitis C virus-positive patients affected by mixed cryoglobulinemia with or without kidney involvement. PATIENTS: At total of 119 hepatitis C virus-positive patients affected by mixed cryoglobulinemia were divided in two groups. Group A: mixed cryoglobulinemia without kidney involvement (103 cases); group B: mixed cryoglobulinemia with glomerulonephritis (GN) (16 cases). A further 37 patients affected by mesangio-proliferative glomerulonephritis (MPGN) were evaluated as controls (group C). METHODS: Anti-hepatitis C virus antibodies were determined by commercial kits and hepatitis C virus-RNA was detected by polymerase chain reaction (PCR) amplification of the 5' untranslated region (5'UTR) of the virus. The hepatitis C virus genotype was determined according to Okamoto. Liver biopsy was performed in 62 patients, bone marrow biopsy in 65 patients, and kidney biopsy in all patients with proteinuria. RESULTS: In group A, 46 patients (45%) were affected by chronic liver disease (CLD), 21 (20%) by low-grade non-Hodgkin's lymphoma (NHL) and 16 (15%) by both diseases. All patients of group B were affected by type I membrano-proliferative glomerulonephritis, 3 (19%) by chronic liver disease, 6 (37%) by low-grade non-Hodgkin's lymphoma, and 7 (44%) by both diseases. Several genotypes of hepatitis C virus were found, but Type 1b was prevalent. In group C, no patient showed chronic liver disease or non-Hodgkin's lymphoma. Younger age, higher mean blood pressure, lower C4 serum level, and poorer survival significantly distinguished group B from group A. Survival rates at 5 years were: 87.4% for group A, 89.5% for group C, and 50.0% for group B. None of the patients of group B developed kidney failure requiring dialysis, whilst infections were the leading cause of death. CONCLUSIONS: In hepatitis C virus-positive patients, the presence of mixed cryoglobulinemia associated with kidney involvement seems to indicate a new syndrome characterized by immune system impairment, lack of progression to kidney failure, and poor survival (hepatitis C virus-Risk syndrome).     

Anti-Hepatitis C Virus Serology in Immune Thrombocytopenia: A Retrospective Analysis in 101 Patients

Hepatitis C virus (HCV), an RNA virus, is known to be the major cause of post-transfusion non-A, non-B hepatitis. HCV can induce several expressions of autoimmunity, including both serological abnormalities and clinical disorders. The relationship between the HCV infection and anti-platelet autoimmunity has been occasionally described, but is still far from well-defined. We retrospectively analysed 101 serum specimens, collected between 1988 and 1994, from patients with immune thrombocytopenia (ITP) for the presence of anti-HCV antibodies. Eighty-seven patients were classified as having idiopathic, and 14 secondary ITP (4 systemic lupus erythematosus, 9 non-Hodgkin's lymphoma and 1 Evan's syndrome).

Anti-HCV antibodies were determined by second generation tests (ELISA + RIBA). A specimen was considered positive for HCV antibodies in the presence of ELISA reactivity (sample optical density/cut-off > 1.00) accompanied by RIBA reactivity to at least one HCV specific antigen. 20 sera (20%) were positive, with a prevalence higher in secondary than in idiopathic ITP (43% vs. 16%, p < 0.05). No differences were found between anti-HCV positive and negative patients regarding gender, platelet count, platelet associated immunoglobulins, hepatitis B virus serology and liver enzyme profile. On the contrary, mean age was higher in the HCV positive vs HCV negative ones (58±18SD vs. 44±20yrs, p < 0.01), in keeping with the increasing prevalence of HCV infection with ageing. HCV positive patients, showed a poor response to treatment (platelet count lower than 50,000/μl after conventional medical therapy for immune thrombocytopenia) compared to anti-HCV negative ones, (50% versus 7.3%, p < 0.001). When we excluded patients who were exposed to risk factors for HCV infection after ITP diagnosis and before the serum collection, the prevalence of anti-HCV antibodies was not very different (17.6%) from that found in the series as a whole (19.8%). Our results seem to indicate that HCV infection may play a role in triggering several cases ITP, and moreover might constitute a negative prognostic factor for therapy response.     

Immunologic thrombocytopenic purpura as presenting symptom of hepatitis C infection

We report on 3 female patients with immunologic thrombocytopenic purpura (ITP) for whom diagnostic procedures evidenced a chronic Hepatitis C virus (HCV) infection. In 2 cases, a transfusion performed more than 10 years ago represented the probable way of contamination. One patient received a course of steroids, which normalized the platelet counts. Another one has been treated with repeated IV immunoglobulins, which induced partial responses of variable duration. HCV is responsible for many autoimmune manifestations and a search for this virus seems warranted for exploring patients with ITP. Am. J. Hematol. 57:338–340, 1998. © 1998 Wiley-Liss, Inc.     

Liver dysfunction after chemotherapy in lymphoma patients infected with hepatitis C

Reactivation of hepatitis B virus (HBV) infection in asymptomatic hepatitis B surface antigen carriers undergoing chemotherapy or immunosuppressive therapy is a well-documented complication. However, data on the consequence of chemotherapy on the course of hepatitis C virus (HCV) infection in HCV+ patients have been controversial. Here, we review the current knowledge about the complications related to HCV in lymphoma patients receiving chemotherapy/immunosuppressive therapy. Although less frequent than HBV, these complications occur in a subset of patients with mortality rates up to 45%. Therefore, baseline screening for HBV and HCV before initiation of chemotherapy is crucial. High-risk patients having chronic active hepatitis, high baseline HCV viral load, HBV co-infection and receiving cytotoxic drugs, corticosteroids and rituximab (particularly if combined) should be closely monitored for serum transaminase, bilirubin and HCV RNA levels.