A genome-wide association study identified PTPN2 as a population-specific susceptibility gene locus for primary biliary cholangitis.

BACKGROUND AIMS: Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-non-specific) and non-shared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC. APPROACH RESULTS: Protein tyrosine phosphatase non-receptor type 2 (PTPN2) was identified as a novel PBC susceptibility gene locus through a GWAS and subsequent genome-wide meta-analysis involving 2,181 cases and 2,699 controls from the Japanese population (GWAS-lead variant: rs8098858, p=2.6×10-8). In-silico and in-vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells (Tfh) and plasmacytoid dendritic cells (pDCs). Infiltration of PTPN2-positive T-cells and pDCs were confirmed in the portal area of the PBC-liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in-vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758. CONCLUSIONS: PTPN2, a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC via an insufficient negative feedback loop caused by the PTPN2 risk allele of rs2292758 in IFN signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment.

Experience and impact of stigma in people with chronic hepatitis B: a qualitative study in Asia, Europe, and the United States.

BACKGROUND: People with chronic hepatitis B (CHB) commonly experience social and self-stigma. This study sought to understand the impacts of CHB-related stigma and a functional cure on stigma. METHODS: Adults with CHB with a wide range of age and education were recruited from 5 countries and participated in 90-minute qualitative, semi-structured interviews to explore concepts related to CHB-associated stigma and its impact. Participants answered open-ended concept-elicitation questions regarding their experience of social and self-stigma, and the potential impact of reduced CHB-related stigma. RESULTS: Sixty-three participants aged 25 to 71 years (15 from the United States and 12 each from China, Germany, Italy, and Japan) reported emotional, lifestyle, and social impacts of living with CHB, including prejudice, marginalization, and negative relationship and work experiences. Self-stigma led to low self-esteem, concealment of CHB status, and social withdrawal. Most participants stated a functional cure for hepatitis B would reduce self-stigma. CONCLUSIONS: CHB-related social and self-stigma are widely prevalent and affect many aspects of life. A functional cure for hepatitis B may reduce social and self-stigma and substantially improve the health-related quality of life of people with CHB. Incorporating stigma into guidelines along with infectivity considerations may broaden the patient groups who should receive treatment.

Zinc supplementation with polaprezinc was associated with improvements in albumin, prothrombin time activity, and hemoglobin in chronic liver disease.

Zinc deficiency occurs in a variety of diseases, including chronic liver disease (CLD). We investigated the correlation between zinc levels and biochemical and hematological tests in CLD and the effect of zinc supplementation with polaprezinc on these values. The first study (Study 1) was a retrospective observational study of 490 patients with CLD not receiving zinc supplementation, with data available from September 2009 to August 2021. Univariate and multiple regression analysis showed that serum zinc levels correlated most strongly with albumin (Alb) and also significantly with prothrombin time activity (PT%) and hemoglobin (Hb). A subsequent study (Study 2) focused on patients with advanced CLD who used polaprezinc for more than 90 days between January 2005 and August 2021. Using a self-controlled design with the 6-month period prior to polaprezinc as the control period, comparisons showed that Alb (p<0.0001), PT% (p<0.0005), and Hb (p<0.01) were significantly improved in the polaprezinc-treated patients compared to the control group. In conclusion, serum zinc levels were correlated with serum Alb, Hb, and PT% in patients with CLD, and zinc supplementation with polaprezinc was associated with improvements in Alb, Hb, and PT% within at least 6 months.

Genetic risk factors for autoimmune hepatitis: implications for phenotypic heterogeneity and biomarkers for drug response.

Autoimmune hepatitis (AIH) is a rare chronic progressive liver disease with autoimmune features. It mainly affects middle-aged women. AIH is occasionally complicated with liver cirrhosis that worsens the prognosis. Genetic and environmental factors are involved in the pathogenesis of AIH. Genetic studies of other diseases have been revealing of pathogenesis and drug efficacy. In this review, we summarize the genetic risk factors for AIH, including human leukocyte antigen (HLA) and non-HLA genes. A genome-wide association study (GWAS) on European AIH revealed the strongest associations to be with single nucleotide variants (SNVs) in HLA. Predisposing alleles for AIH were DRB1*03:01 and DRB1*04:01 in Europeans; DRB1*04:04, DRB1*04:05, and DRB1*13:01 in Latin Americans; and DRB1*04:01 and DRB1*04:05 in Japanese. Other risk SNVs in non-HLA genes for AIH were found by a candidate gene approach, but several SNVs were confirmed in replication studies. Some genetic factors of AIH overlapped with those of other autoimmune diseases. Larger-scale GWASs of other ethnic groups are required. The results of genetic studies might provide an explanation for the phenotypic heterogeneity of AIH and biomarkers for drug responses.

Characteristics and Healthcare Costs in the Aging Hepatitis B Population of Japan: A Nationwide Real-World Analysis.

INTRODUCTION: Advancing age, comorbidity, and financial burden have been observed in chronic hepatitis B (CHB) patients globally. As Japan is leading the world in aging demographics, similar real-world data are urgently needed for its CHB population to inform all stakeholders. METHODS: This cross-sectional study characterized the demographics, comorbidities, and healthcare costs of a large Japanese real-world adult (≥18 years) CHB patient (ICD-10: B18.1) population from the Medical Data Vision database from January 01, 2012, to December 31, 2016. Comorbidities were identified by ICD-10 codes, and the annual point prevalence and Charlson Comorbidity Index (CCI) score were calculated. Annual mean and median all-cause healthcare utilization and costs per patient were calculated. Comparison tests were conducted for CCI scores, prevalence of comorbidities, and healthcare resource utilization and costs. RESULTS: We identified 11,125 CHB patients. Between 2012 and 2016, the mean age increased from 62.0 to 65.2 years, and the percentage of those aged ≥65 years increased from 45.6% to 60.7%. The prevalence of cirrhosis remained similar (5.8% in 2012 and 5.6% in 2016, p = 0.69) while hepatocellular carcinoma decreased from 6.3% to 4.5% (p < 0.01). The prevalence of nonliver comorbidities increased (40.9-52.0% for cancer [p < 0.01], 12.1-17.7% for osteoporosis [p < 0.01], and 10.7-15.0% for renal impairment [p < 0.01]). Healthcare resource utilization and costs also increased, with a 119.3% increase in median total healthcare costs from JPY 229,143 in 2012 to 502,467 in 2016 (p < 0.01). CONCLUSIONS: The CHB population of Japan is predominantly elderly and carry a high nonliver comorbidity burden, while incurring increasing healthcare costs.

Hepatitis B Core-Related Antigen to Indicate High Viral Load: Systematic Review and Meta-Analysis of 10,397 Individual Participants.

BACKGROUND & AIMS: To eliminate hepatitis B virus (HBV) infection, scale-up of testing and treatment in resource-limited countries is crucial. However, access to nucleic acid testing to quantify HBV DNA, an essential test to examine treatment eligibility, remains severely limited. We assessed the performance of a novel immunoassay, HBV core-related antigen (HBcrAg), as a low-cost (less than US $15/assay) alternative to nucleic acid testing to indicate clinically important high viremia in chronic HBV patients infected with different genotypes. METHODS: We searched Medline, Embase, Scopus, and Web of Science databases through June 27, 2018. Three reviewers independently selected studies measuring HBV DNA and HBcrAg in the same blood samples. We contacted authors to provide individual participant data (IPD). We randomly allocated each IPD to a derivation or validation cohort. We applied optimal HBcrAg cut-off values derived from the derivation set to the validation set to estimate sensitivity/specificity. RESULTS: Of 74 eligible studies, IPD were obtained successfully for 60 studies (81%). Meta-analysis included 5591 IPD without antiviral therapy and 4806 treated with antivirals. In untreated patients, the pooled area under the receiver operating characteristic curve and optimal cut-off values were as follows: 0.88 (95% CI, 0.83-0.94) and 3.6 log U/mL to diagnose HBV DNA level of 2000 IU/mL or greater; and 0.96 (95% CI, 0.94-0.98) and 5.3 log U/mL for 200,000 IU/mL or greater, respectively. In the validation set, the sensitivity and specificity were 85.2% and 84.7% to diagnose HBV DNA level of 2000 IU/mL or greater, and 91.8% and 90.5% for 200,000 IU/mL or greater, respectively. The performance did not vary by HBV genotypes. In patients treated with anti-HBV therapy the correlation between HBcrAg and HBV DNA was poor. CONCLUSIONS: HBcrAg might be a useful serologic marker to indicate clinically important high viremia in treatment-naïve, HBV-infected patients.

Switching from entecavir to tenofovir disoproxil fumarate for HBeAg-positive chronic hepatitis B patients: a phase 4, prospective study.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is widely used and recommended as first-line treatment for patients infected with the hepatitis B virus (HBV). However, current data are limited regarding the efficacy and safety of switching to TDF for the treatment of chronic hepatitis B in hepatitis B e-antigen (HBeAg)-positive patients who are virologically suppressed with another nucleos(t)ide analogue. The primary objective of this study was to evaluate the hepatitis B surface antigen (HBsAg) reduction potential of switching from entecavir (ETV) to TDF at week 48 in HBeAg-positive chronic hepatitis B patients with undetectable serum HBV-DNA. METHODS: In this multicenter, single-arm, open-label, phase 4 clinical study, 75 participants currently treated with ETV 0.5 mg once daily were switched to TDF 300 mg once daily for 96 weeks. RESULTS: At week 48, 3/74 participants (4%) achieved 0.25 log10 reduction of HBsAg levels from baseline (the primary endpoint). Mean HBsAg reduction was -0.14 log10 IU/mL and 12% (9/74) achieved 0.25 log10 reduction by 96 weeks. No participants achieved HBsAg seroclearance. HBsAg reduction at weeks 48 and 96 was numerically greater in participants with higher alanine aminotransferase levels (≥ 60 U/L). Seventeen participants (25%) achieved HBeAg seroclearance up to week 96. No participants experienced viral breakthrough. All drug-related adverse events (18 participants [24%]) were mild in intensity, including an increase in urine beta-2-microglobulin (15 participants [20%]). CONCLUSIONS: In conclusion, HBsAg reduction was limited after switching from ETV to TDF in this study population. Further investigation is warranted to better understand the clinical impact of switching from ETV to TDF. ClinicalTrials.gov: NCT03258710 registered August 21, 2017. https://clinicaltrials.gov/ct2/show/NCT03258710?term=NCT03258710&draw=2&rank=1.

Real-world hospital mortality of liver cirrhosis inpatients in Japan: a large-scale cohort study using a medical claims database: Prognosis of liver cirrhosis.

AIM: Prognosis of liver cirrhosis patients is poor when ascites is present and liver function is impaired, but such up-to-date information from a large-scale, real-world setting is limited in Japan. We aimed to investigate the hospital mortality of Japanese liver cirrhosis inpatients. METHODS: This retrospective cohort study included data on liver cirrhosis inpatients between January 2011 and September 2018 extracted from an administrative claims database. The outcome was in-hospital mortality. The 1- and 3-year cumulative survival rates were examined for liver cirrhosis etiology, Child-Pugh classification, or ascites presence/absence using Kaplan-Meier analysis. The survival up to 1 year for tolvaptan prescription/nonprescription was examined. RESULTS: We analyzed the data of 57 769 inpatients. Survival rates did not substantially differ among etiologies, with a better prognosis for alcohol etiology and poorer prognosis for hepatitis C virus. According to the Child-Pugh classification, the 1- and 3-year survival rates were 90.2% and 75.3% for grade A, 73.5% and 53.9% for grade B, and 41.9% and 28.9% for grade C, respectively. Patients without ascites had a higher survival rate (83.2% and 67.0% at 1 and 3 years, respectively) than those with ascites (51.9% and 36.3%, respectively). Based on examining matched patients with ascites using a propensity score, prognosis was poor in general but was better at 6 months (58.1%) or similar at 1 year (47.1%) in patients prescribed tolvaptan compared to those not prescribed tolvaptan (54.8% and 47.5%, respectively). CONCLUSIONS: Poorer prognosis was suggested in inpatients with cirrhosis who had a worse Child-Pugh grade and ascites.

Treatment algorithm for thrombocytopenia in patients with chronic liver disease undergoing planned invasive procedures.

Thrombocytopenia is highly prevalent in patients with chronic liver disease (CLD) and these patients often require invasive procedures that carry a risk of bleeding. To prevent bleeding, guidelines recommend increasing platelet counts in patients with CLD who have thrombocytopenia and are planned to undergo invasive procedures. There are currently two options to increase platelet counts in patients in this setting: platelet transfusion or thrombopoietin receptor agonists (TPORAs). Several treatment algorithms have been developed in the US to help physicians choose the best course of treatment for each patient; however, to date, no such algorithm has been proposed in other countries, where the choice of treatment has been based on each physician's judgment and experience. Here, we discuss the pathogenesis and treatment of thrombocytopenia in patients with CLD, we review and present current evidence of the efficacy of TPORAs for the treatment of thrombocytopenia in patients with CLD, and we present our expert opinion on a Japanese treatment algorithm for thrombocytopenia in patients with CLD who are planned to undergo invasive procedures. This algorithm aims to provide guidance for optimal decision making in the selection of TPORA therapy or platelet transfusion based on the latest evidence and according to actual clinical practice.

Prognosis of patients with liver cirrhosis: A multi-center retrospective observational study.

AIM: Despite advances in the management of liver diseases and changes in the etiology of cirrhosis, few studies have updated the prognosis of cirrhosis. This study aimed to clarify the recent prognosis of cirrhosis and identify risk factors for death. METHODS: In this retrospective observational study by the Hepatic Disease Network of the National Hospital Organization in Japan, chart reviews were performed to follow patients with cirrhosis beginning in 2011. We conducted Kaplan-Meier survival time analyses stratified by Child-Pugh classification and albumin-bilirubin grade. Cox regression analysis was used to identify risk factors for death. RESULTS: We identified 444 eligible patients from 25 hospitals, including 303 (68%), 110 (25%), and 31 (7%) patients with Child-Pugh classes A, B, and C, respectively. Hepatitis C virus infection was the cause of cirrhosis for 63% of the patients. The 1-year and 5-year cumulative survival rates of patients with Child-Pugh classes A, B, and C were 90% and 61%, 78% and 42%, and 65% and 25%, respectively. The 1-year and 5-year cumulative survival rates of patients with albumin-bilirubin grades 1, 2, and 3 were 98% and 80%, 91% and 56%, and 58% and 23%, respectively. Cirrhosis classification (Child-Pugh and albumin-bilirubin), age, liver cancer, and untreated esophageal varices were associated with increased hazard of death. CONCLUSIONS: Little improvement was observed in the prognosis of cirrhosis compared with previous reports, and the prognosis of Child-Pugh class C cirrhosis remained poor. Untreated esophageal varices were identified as a risk factor for death.

Indications and waiting list priority for deceased donor liver transplantation in HIV/HCV co-infected hemophilic patients in Japan through contaminated blood product.

HIV/HCV co-infection from blood products for hemophilia has been a social problem in Japan. Liver transplantation (LT) is an important treatment option for hepatic failure and cirrhosis of the liver in co-infected patients, and appropriate indications for LT, especially organ form deceased donors, are required by society. The aim is to propose priority status for the waiting list for deceased donor (DD) LT in HIV/HCV co-infected patients in Japan based on medical and scientific considerations. Since 2009, we have been working on the subject in research projects under grants-in-aid for health and labour sciences research on AIDS measures provided by the Ministry of Health, Labour and Welfare (the Kanematsu project and Eguchi project). Our research showed that hepatic fibrosis is advanced in HIV/HCV co-infected Japanese patients, especially those with hemophilia who became infected from blood products at a faster rate than HCV mono-infected patients. In addition, those patients who developed portal hypertension had a poor prognosis at a young age. The results of our research contributed to increasing the priority score of those patients on the deceased donor liver transplantation (DDLT) waiting list in 2013 and to establishing a scoring system for DDLT corresponding to the Model for End-stage Liver disease (MELD) score in 2019. This paper introduces changes in priority and the current state of priority of the DDLT waiting list for HIV/HCV co-infected patients in Japan.

Developmental outcome after corpus callosotomy for infants and young children with drug-resistant epilepsy.

AIM: To examine the developmental and seizure outcomes after corpus callosotomy (CC) in early childhood. METHODS: We retrospectively identified 106 patients who underwent CC for drug-resistant epilepsy before the age of 6 years, at the Nagasaki Medical Center, between July 2002 and July 2016. Patients' developmental outcomes were evaluated one year after CC using the Kinder Infant Development Scale. RESULTS: The mean preoperative developmental quotient (DQ) was 25.0 (standard deviation [SD], 20.8), and the mean difference between preoperative DQ and one-year postoperative DQ was -1.6 points (SD, 11.6). However, 42.5% of patients had a mean DQ increase of 6.5 points (SD, 6.4), one year after CC from that before surgery. Factors related to the improvement in postoperative DQ were 'low preoperative DQ', 'developmental gain 1 month postoperatively', and 'postoperative seizure-free state'. Approximately 21.7% of patients were seizure-free 1 year after CC. INTERPRETATION: Performing CC, in infancy and early childhood for patients with drug-resistant epilepsy and severe developmental impairment, was associated with improved development in 42.5% of patients. Remission of seizures, even if only for a short period, contributed to developmental improvement. From a developmental perspective, CC for drug-resistant epilepsy in early childhood is an effective treatment.

Uric acid-mediated inflammasome activation in IL-6 primed innate immune cells is regulated by baricitinib.

OBJECTIVES: Gout is an inflammatory arthropathy caused by the deposition of monosodium urate (MSU). The synthesis and release of IL-1ß is crucial for MSU-induced synovial inflammation. The aim of the present study was to investigate the mechanism of MSU crystal-induced autoinflammatory processes. METHODS: In vitro studies were used to evaluate the role of IL-6 in inflammasome activation in human neutrophils cultured with MSU crystals. Human neutrophils were stimulated with MSU in the presence or absence of IL-6 priming to determine NLRP3 inflammasome activation and subsequent cleaved caspase-1 induction or IL-1ß production. RESULTS: IL-6 or MSU stimulation alone did not result in the efficient IL-1ß production from human neutrophils. However, MSU stimulation induced marked IL-1ß production from IL-6-primed neutrophils. Pretreatment with baricitinib, which blocks IL-6 receptor signaling, prevented MSU-induced cleaved caspase-1 or IL-1ß induction in IL-6-primed neutrophils. Tocilizumab pretreatment also inhibited MSU-mediated IL-1ß production from IL-6-primed neutrophils. CONCLUSION: Priming of human neutrophils with IL-6 promotes uric acid-mediated IL-1ß secretion in the absence of microbial stimulation. These results suggest that an endogenous cytokine, IL-6, is involved in MSU-mediated NLRP3 inflammasome activation and subsequent IL-1ß production from innate immune cells and has a crucial role in MSU crystal-induced synovial inflammation. These findings provide insights into uric acid-mediated autoinflammation in the innate immune system.

JAK inhibitors impair GM-CSF-mediated signaling in innate immune cells.

BACKGROUND: Innate immune cells play a crucial role in the pathophysiology of rheumatoid arthritis (RA) via release of cytokines. Small-molecule inhibitors of Janus kinases (JAKi) are clinically efficacious in patients with RA. However, the isoform-specific action of each JAKi is difficult to assess, since JAKs form heterodimeric complexes with cytokine receptors. We assessed the effects of several JAKi on GM-CSF-primed human innate immune cells. RESULTS: Treatment with JAKi (tofacitinib, baricitinib, upadacitinib) prevented GM-CSF-induced JAK2/STAT5 phosphorylation at higher concentrations (400 nM) in THP-1 cells. Whereas compared with baricitinib or upadacitinib, the inhibitory effects of tofacitinib on the GM-CSF-induced JAK2/STAT5 phosphorylation were weak at lower concentrations (≤ 100 nM). All JAKi inhibited GM-CSF-induced IL-1ß production by human neutrophils. However, the inhibitory effects of baricitinib on IL-1ß production were larger compared to those of tofacitinib or upadacitinib at lower concentrations (≤ 100 nM). Similarly, all JAKi inhibited GM-CSF-induced caspase-1(p20) production by human neutrophils. CONCLUSION: We conclude that incubation with JAKi prevents GM-CSF-mediated JAK2/STAT5 activation in human innate immune cells. Although baricitinib and upadacitinib almost completely blocked GM-CSF-mediated JAK2/STAT5 signaling, the inhibitory effects of tofacitinib were weaker at lower concentrations suggesting that variation exists among these JAKi in the inhibition of JAK2 signaling pathways.

Wisteria floribunda agglutinin-positive human Mac-2-binding protein as a predictive marker of liver fibrosis in human immunodeficiency virus/hepatitis C virus coinfected patients.

AIM: In human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfected patients, the progression of liver failure is reported to be more aggressive than that in HCV mono-infected patients. Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA+ -M2BP) is well recognized as a liver fibrosis glycobiomarker with a unique fibrosis-related glycoalteration. We analyzed HIV/HCV coinfected patients' M2BP levels as a possible marker for predicting liver fibrosis. METHODS: M2BP was measured in 31 HIV/HCV coinfected patients, and we analyzed the correlation between WFA+ -M2BP and several markers of fibrosis, liver function, and tumor markers. We compared the WFA+ -M2BP levels in HIV/HCV coinfected patients with those of HCV mono-infected patients by performing a propensity score matching analysis. RESULTS: In the HIV/HCV coinfected patients, the serum level of WFA+ -M2BP was well correlated with the markers type IV collagen, hyaluronic acid, and alpha-fetoprotein, but not protein induced by vitamin K absence-II. In the propensity score matching with HCV mono-infected patients, the WFA+ -M2BP levels were significantly higher in the HIV/HCV coinfected patients compared with the levels in the HCV mono-infected patients. CONCLUSION: In conclusion, WFA+ -M2BP might be a feasible predictive marker of fibrosis in HIV/HCV coinfected patients.

Validity of administrative database detection of previously resolved hepatitis B virus in Japan.

The risk of hepatitis B virus (HBV) reactivation has increased owing to advances in the immunosuppressive therapy field. However, the HBV reactivation incidence among patients with previously resolved HBV (prHBV) infection during immunosuppressive therapy for rheumatoid arthritis (RA) remains unclear. The objective of this work is to describe the validity of detecting prHBV infection from administrative data through comparisons with chart abstraction and determine the incidence of HBV reactivation during immunosuppressive therapy for RA in Japan. In this retrospective cohort study, data on selected patients were extracted from administrative claims data. To identify patients with prHBV infection and de novo hepatitis, and HBsAg carriers, we conducted chart abstraction. The incidence rate of de novo hepatitis was 1.23 of 100 person-years. The positive predictive value (PPV) and its 95% confidence interval (CI) of administrative data for the identification of suspected prHBV infections was 85.8% (95% CI: 81.7%-89.3%). This study evaluated the PPV of the algorithm of HBV-DNA testing with immunosuppressive therapy performed four times or more per year for the detection of prHBV infection from administrative data. Additionally, we determined the incidence rate of HBV reactivation among preHBV infections during immunosuppressive therapy for RA to be 1.23 of 100 person-years.

Association of a single nucleotide polymorphism in TNIP1 with type-1 autoimmune hepatitis in the Japanese population.

Several studies reported that autoimmune diseases share a number of susceptibility genes. Of these genes, a SNP rs7708392 in TNIP1 was reported to be associated with systemic lupus erythematosus (SLE). Autoimmune hepatitis (AIH), a rare chronic progressive liver disease, shares some clinical features with SLE. Therefore, we investigated whether the SNP is associated with Japanese AIH. An association study of rs7708392 was conducted in 343 Japanese AIH patients and 828 controls. We found that rs7708392 is associated with AIH (P = 0.0236, odds ratio (OR) 1.26, 95% confidence interval (CI): 1.03-1.54), under the allele model for C allele. Significant differences of clinical characteristics of the AIH patients with or without G allele of rs7708392 were not detected. Of interest, the association was stronger in AIH without HLA-DRB1*04:05 allele (P = 0.0063, Q = 0.0127, OR 1.48, 95% CI: 1.12-1.96), though the association was not detected in AIH with DRB1*04:05. The C allele of rs7708392 was associated with AIH, especially AIH without DRB1*04:05, an already established risk factor.

Ledipasvir-sofosbuvir for treating Japanese patients with chronic hepatitis C virus genotype 2 infection.

BACKGROUND & AIMS: Japanese patients with chronic hepatitis C virus (HCV) genotype 2 infection have high rates of sustained virological response (SVR) following 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir in combination with ribavirin, which was the standard of care at the time this study was undertaken. We assessed the efficacy of 12 weeks of treatment with a ribavirin-free regimen of ledipasvir-sofosbuvir. METHODS: In an open-label, Phase 3 trial we enrolled Japanese patients with chronic HCV genotype 2 infection, with or without compensated cirrhosis. In Cohort 1, participants were randomized 1:1 to receive ledipasvir-sofosbuvir (n = 106) or sofosbuvir + ribavirin (n = 108) for 12 weeks. In Cohort 2, 25 ribavirin-intolerant or -ineligible patients received ledipasvir-sofosbuvir for 12 weeks. The primary endpoint was SVR 12 weeks after therapy (SVR12). In Cohort 1 non-inferiority was assessed with a prespecified margin of 10%. RESULTS: One-third (33%) of patients were treatment experienced, and 14% had cirrhosis. In Cohort 1, SVR12 rates were 96% (95% CI, 91% to 99%) with ledipasvir-sofosbuvir and 95% (95% CI, 90% to 98%) with sofosbuvir plus ribavirin, thus achieving non-inferiority. Among ribavirin-intolerant/ineligible patients in Cohort 2, SVR12 was 96% (95% CI, 80% to 100%) with ledipasvir-sofosbuvir. Overall, the most common adverse events were nasopharyngitis, anaemia, and headache; anaemia was only observed in patients receiving ribavirin. The percentage of patients who discontinued treatment because of an adverse event was low (1%). CONCLUSIONS: Among Japanese patients with HCV genotype 2, 12 weeks of treatment with ledipasvir-sofosbuvir resulted in high rates of SVR12 that were non-inferior to sofosbuvir + ribavirin.

TNF-α potentiates uric acid-induced interleukin-1ß (IL-1ß) secretion in human neutrophils.

OBJECTIVE: Monosodium urate (MSU) has been shown to promote interleukin-1ß (IL-1ß) secretion in human monocytes, but the priming signals for NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway remains elusive. In this study, we investigated the role of Tumor necrosis factor-alpha (TNF-α) on MSU-mediated IL-1ß induction in human neutrophils. METHODS: Human neutrophils were stimulated with MSU, in the presence or absence of TNF-α priming. The cellular supernatants were analyzed for IL-1ß, IL-18, and caspase-1 by enzyme-linked immunosorbent assay (ELISA) methods. Pro-IL-1ß mRNA expressions in human neutrophils were analyzed by real-time PCR method. RESULTS: TNF-α stimulation induced pro-IL-1ß mRNA expression; however, MSU stimulation did not induce pro-IL-1ß mRNA expression in human neutrophils. TNF-α alone or MSU stimulation did not result in efficient IL-1ß secretion in human neutrophils, whereas in TNF-α-primed neutrophils, MSU stimulation resulted in a marked IL-1ß and IL-18 secretion. TNF-α-primed neutrophils secreted cleaved caspase-1 (p20), in response to MSU stimulation. CONCLUSION: Our data demonstrate that priming of human neutrophils with TNF-α promotes uric acid-mediated IL-1ß secretion in the absence of microbial stimulation. These findings provide insights into the neutrophils-mediated inflammatory processes in gouty arthritis.

Association of a single nucleotide polymorphism upstream of ICOS with Japanese autoimmune hepatitis type 1.

Autoimmune hepatitis (AIH) is an uncommon chronic autoimmune liver disease. Several studies reported the association of polymorphisms between CD28, CTLA4 and ICOS gene cluster in 2q33.2 with autoimmune or inflammatory diseases. The previous genome-wide association study on type 1 AIH in a European population has reported a risk G allele of a single nucleotide polymorphism (SNP), rs4325730, in this region. Here, we conducted an association study of this SNP with type 1 AIH in a Japanese population, as a replication study.An association study of rs4325730 was conducted in 343 Japanese AIH patients and 315 controls.We found that rs4325730 is associated with AIH (P=0.0173, odds ratio (OR) 1.30, 95% confidence interval (CI) 1.05-1.62, under the allele model for G allele, P=0.0070, OR 1.62, 95% CI 1.14-2.31, under the dominant model for G allele). This SNP was strongly associated with definite AIH (P=0.0134, OR 1.36, 95% CI 1.07-1.74; under allele model for G, P=0.0035, OR 1.85, 95% CI 1.22-2.81, under dominant model for G).This is the first replication association study of rs4325730 upstream of ICOS with AIH in the Japanese population and rs4325730G is a risk allele.