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Summary: Background: Autoimmune hepatitis requires long‐term therapy, and systemic corticosteroids are the backbone of therapeutic management. Prolonged use of corticosteroids may lead to adverse events but data from long‐term studies are mainly derived from studies in rheumatic diseases. Aim: To assess cataract, diabetes and fractures in relation to corticosteroid doses in the long‐term maintenance treatment of patients with autoimmune hepatitis. Methods: We retrospectively collected data on 476 patients (77% women) with an established diagnosis of autoimmune hepatitis. Binary logistic regression with a generalised estimating equation was used to analyse the association between current corticosteroid use and the incidence of cataract, diabetes and fractures with onset after autoimmune hepatitis diagnosis. We corrected for sex, age, cirrhosis at diagnosis and predniso(lo)ne use in the prior 3 years to account for possible ongoing effects. Results: A total of 6634 years, with a median of 13 (range 1‐40) per patient were recorded. The median age at diagnosis was 44 years (range 2‐88). Adverse events were documented in 120 (25%) patients. Low‐dose predniso(lo)ne (0.1‐5.0 mg/d) increased the odds of fractures whereas higher doses (>5.0 mg/d) increased the odds of cataracts and diabetes. Budesonide increased the odds of cataract and fractures; this effect was independent of predniso(lo)ne use in the prior 1, 2 or 3 years. Conclusions: Even low doses of corticosteroids frequently lead to substantial adverse events refuting the assumption that adverse events are prevented by administering low doses. [ABSTRACT FROM AUTHOR]

Background & Aims: HIV/hepatitis B virus (HBV) coinfected subjects are thought to have faster progression to end‐stage liver disease (ESLD) than HBV mono‐infected subjects. We assessed whether this remains in the current cART‐era. Methods: Data from subjects with follow‐up completion post‐2003 were compared between HIV/HBV coinfected subjects in the Dutch HIV Monitoring database and HBV mono‐infected subjects from two centres. The primary outcomes of composite ESLD included portal hypertension, decompensated cirrhosis, hepatocellular carcinoma, liver transplantation and liver‐related mortality. Outcomes were analysed using time‐dependent cause‐specific Cox regression models adjusted for follow‐up time and relevant covariates. Subset‐analyses were done in subjects with follow‐up pre‐2003. Results: In the 1336 co‐ vs 742 mono‐infected subjects, coinfected subjects had no increased probability for ESLD compared to mono‐infected subjects (cHR 0.7 (95% CI 0.4‐1.1), but had increased probabilities for all‐cause (cHR 7.4 [4.9‐11.1]) and liver‐related mortality (cHR 3.4 [1.6‐7.5]). In the current combined cohort, treatment with tenofovir or entecavir was inversely associated with ESLD, all‐cause and liver‐related mortality (cHR 0.4 [95% CI 0.3‐0.7], cHR 0.003 [0.001‐0.01]), cHR 0.007 [0.001‐0.05]). Other predictors for ESLD were older age, being of Sub‐Sahara African descent, increased alanine aminotransferase levels and hepatitis C virus coinfection. While the probability for all‐cause mortality was increased in coinfected subjects, this rate decreased compared to pre‐2003 (HR 40.2 (95% CI: 8.7‐186.2). Conclusions: HIV/HBV coinfected patients no longer seem to be at increased risk for progression to ESLD compared to HBV mono‐infected patients, likely due to widespread use of highly effective cART with dual HBV and HIV activity. [ABSTRACT FROM AUTHOR]

Summary: Background: Azathioprine (AZA) and mercaptopurine (MP) are the cornerstone of steroid‐sparing strategies in autoimmune hepatitis (AIH). Up to 20% of patients do not tolerate or respond to these regimens. Aim: To evaluate retrospectively the tolerability and efficacy of tioguanine (thioguanine) (TG) therapy in selected patients with AIH and AIH variant syndromes. Methods: Records of 52 patients who received TG therapy were retrieved from nine hospitals in the Netherlands. Indications for TG treatment were intolerable side effects on AZA or MP (n = 38), insufficient response (n = 11) or first‐line treatment (n = 3). Treatment efficacy was defined as normalisation of serum aminotransferases and serum immunoglobulin G. Results: No serious adverse events occurred in patients treated with TG during a median follow‐up of 18 months (range 1‐194). Treatment was well tolerated in 41 patients (79%), whereas four had tolerable (8%) and seven (13%) intolerable side effects. Thirty‐eight patients were treated with TG after intolerable side effects on AZA or MP; 29 patients continued TG therapy of whom 24 (83%) achieved complete biochemical remission, four (14%) had incomplete and one (3%) had no response; nine discontinued treatment. Seven of 11 patients with insufficient response to AZA or MP were responsive to TG, three with complete and four with incomplete biochemical remission; four discontinued due to intolerance (n = 2) and non‐response (n = 2). TG was effective in all AIH patients as first‐line maintenance treatment. Conclusion: In our retrospective review of TG therapy in selected patients with AIH or AIH variants who previously failed on AZA or MP, TG appeared tolerable with biochemical efficacy. [ABSTRACT FROM AUTHOR]

Background & Aims In low-endemic countries it is debated whether first-generation migrants should be screened for chronic hepatitis B infection. We describe the clinical impact of five large-scale Dutch screening projects for hepatitis B in first-generation Chinese migrants. Methods Between 2009 and 2013 five independent outreach screening projects for hepatitis B targeting first-generation Chinese migrants were conducted in five main Dutch regions. To explore the relevance of our screening we defined clinical impact as the presence of an indication for: (i) antiviral therapy, (ii) strict follow-up because of high hepatitis B DNA levels and/or (iii) surveillance for hepatocellular carcinoma. Results In total, 4423 persons participated in the projects of whom 6.0% ( n = 264) were HBsAg positive. One hundred and twenty-nine newly diagnosed HBsAg-positive patients were analysed in specialist care. Among these patients prevalence of cirrhosis was 6.9% and antiviral therapy for hepatitis B was started in 32 patients (25%). In patients without a treatment indication, strict follow-up because of high hepatitis B DNA levels and/or surveillance for hepatocellular carcinoma was considered indicated in 64 patients (50%). Conclusions In our screening project in first-generation Chinese migrants, antiviral treatment, strict follow-up because of high hepatitis B DNA levels and/or surveillance for hepatocellular carcinoma were considered indicated in three of four analysed HBsAg-positive patients. These data show that detection of hepatitis B in Chinese migrants can have considerable impact on patient care. [ABSTRACT FROM AUTHOR]

Background & Aims Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. We used a genome-wide approach to identify genetic variants that predispose individuals to AIH. Methods We performed a genome-wide association study of 649 adults in The Netherlands with AIH type 1 and 13,436 controls. Initial associations were further analyzed in an independent replication panel comprising 451 patients with AIH type 1 in Germany and 4103 controls. We also performed an association analysis in the discovery cohort using imputed genotypes of the major histocompatibility complex region. Results We associated AIH with a variant in the major histocompatibility complex region at rs2187668 (P = 1.5 x 10-78). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3 x 10-49) as a primary susceptibility genotype and HLA-DRB1*0401 (P = 2.8 x 10-18) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P = 7.7 x 10-8) and CARD10 (rs6000782, 22q13.1; P = 3.0 x 10-6). In addition, strong inflation of association signal was found with single-nucleotide polymorphisms associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with single-nucleotide polymorphisms associated with other genetic traits. Conclusions In a genome-wide association study, we associated AIH type 1 with variants in the major histocompatibility complex region, and identified variants of SH2B3and CARD10 as likely risk factors. These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases. [ABSTRACT FROM AUTHOR]

Background & Aims Single nucleotide polymorphisms ( SNP) in the Cytotoxic T lymphocyte antigen-4 gene ( CTLA-4) have been associated with several autoimmune diseases including autoimmune Hepatitis ( AIH). In this chronic idiopathic inflammatory liver disease, conflicting results have been reported on the association with a SNP at position +49 in the CTLA-4 gene in small patient cohorts. Here, we established the role of this SNP in a sufficiently large cohort of AIH patients. Methods The study population consisted of 672 AIH patients derived from academic and regional hospitals in the Netherlands and was compared with 500 controls selected from the 'Genome of the Netherlands' project cohort. Genotype frequencies were assessed by PCR for patients and by whole genome sequencing for controls. Results No significant differences in allele frequencies were found between patients and controls (G Allele: 40% vs 39%, P = 0.7). Similarly, no significant differences in genotype frequencies between patients and controls were found. Finally, there was no relation between disease activity and the G allele or AG and GG genotypes. Conclusion The Cytotoxic T Lymphocyte Antigen-4 +49 A/G polymorphism does not represent a major susceptibility risk allele for AIH in Caucasians and is not associated with disease severity at presentation. [ABSTRACT FROM AUTHOR]

Discusses the pretreatment of intrahepatic CD8 cell count correlating to virological response to antiviral therapy in chronic hepatitis C virus infection. Virological response to baseline immune factors in some 17 patients; Measurement of intrahepatic CD8 cells present in the portal tract; Relationship between immune factor and therapeutic response.

Overall treatment results of chronic hepatitis C have improved markedly with the introduction of pegylated interferon-alpha (PEG–IFN-α) and ribavirin combination therapy. However, cure rates in the most common genotype 1 infection are still unsatisfactory. IFN-α dose–response studies on viral kinetics suggest that inadequate dosing might be a key factor but drug levels have hardly been tested, which is in part due to difficulties in measuring this cytokine in patient samples. We have shown recently that hepatitis C virus (HCV) replicons are highly sensitive to IFN-α. In this report we tested whether the replicon system could be used as a sensitive bioassay to determine the amount of biologically active IFN-α in serum or heparinized plasma of patients under therapy. To facilitate the measurements, a stably replicating subgenomic HCV RNA was developed that carries the gene encoding the firefly luciferase. Dose response studies with IFN-α demonstrate that the amount of expressed luciferase directly correlates with the level of HCV replication. By using this cell-based assay, serum samples of HCV patients treated with different types and doses of IFN-α were analyzed in parallel to IFN-α standards made by serial dilutions of the same type of IFN-α the patient was treated with. Based on nonlinear logistic models serum concentrations corresponding to 1.3–19 U/ml were determined in patients under standard or high dose IFN-α therapy, and from 3.8 to 4.1 ng/ml in patients treated with PEG IFN-α. In conclusion, the HCV-replicon based bioassay allows determining the levels of biologically active IFN-α in serum and heparinized plasma of patients under treatment. [Copyright &y& Elsevier]

Background & Aims There have been few reproducible studies of mortality in patients with autoimmune hepatitis (AIH) and its variants. We calculated mortality in a large national cohort of patients with AIH, with vs without cirrhosis, in the Netherlands. Methods We collected data from 449 patients with established AIH (77% female), from 6 academic and 10 non-academic hospitals in the Netherlands. We identified 29 patients with AIH and primary biliary cholangitis and 35 patients with AIH and primary sclerosing cholangitis (AIH-PSC). Mortality and liver transplantation data were assessed from August 1, 2006 through July 31, 2016. Standardized mortality ratios (SMR) were calculated using age-, sex-, and calendar year-matched mortality for the general Dutch population. Results During the 10-year follow-up period, 60 patients (13%) died (mean age, 71 years; range, 33–94 years). Twenty-six causes of death were liver related (43%), whereas the others could not be attributed to liver disease. Patients with AIH and cirrhosis had significantly higher mortality than the general population (SMR, 1.9; 95% CI, 1.2–3.4), whereas patients without cirrhosis did not (SMR, 1.2; 95% CI, 0.8–1.8). Patients with AIH-PSC had the largest increase in mortality, compared to the general population (SMR, 4.7; 95% CI, 1.5–14.6), of all groups analyzed. Mortality in patients with AIH and primary biliary cholangitis was not greater than the general population. Four or more relapses per decade or not achieving remission was associated with an increase in liver-related death or liver transplantation. Nine patients underwent liver transplantation; 2 died from non-liver related causes. Four of 9 patients on the waitlist for transplantation died before receiving a donated liver. Conclusion In an analysis of data from a large national cohort of patients with AIH, we found increased mortality of patients with cirrhosis, but not of patients without cirrhosis, compared to the general Dutch population. Survival was significantly reduced in patients with AIH and features of concurrent PSC. [ABSTRACT FROM AUTHOR]