Tacrolimus as an Effective and Durable Second-Line Treatment for Chronic Autoimmune Hepatitis: A Multicentric Study.

BACKGROUND: Autoimmune hepatitis (AIH) is a chronic liver disease able to progress to acute liver failure, cirrhosis, and liver cancer. A significant proportion of patients fail to first-line therapy or develop severe toxicity. AIMS: To assess safety and effectiveness of tacrolimus as a second-line therapy in AIH patients. METHODS: Multicentric retrospective study of AIH patients treated with tacrolimus for at least 3 months as a second-line therapy. Effectiveness was defined as complete normalization of transaminases and IgG. RESULTS: A total of 23 AIH patients were included in the final analysis. In 13% of patients tacrolimus was initiated because of toxicity to previous first-line treatments and the rest were switched because of previous non-efficacy. Tacrolimus was effective in 18 patients (78%; 95%CI: 55.20-91.92%). The median time receiving tacrolimus was 16 months (IQR 20). There was a sustained response with a significant improvement in all liver enzymes and IgG on last follow-up. Only one patient discontinued tacrolimus at the third month because of severe neuropathy, and ototoxicity. Responders were significantly older at diagnosis of AIH (41 ± 13 vs. 27 ± 10 years old; p = 0.0496). CONCLUSION: Tacrolimus is effective and well tolerated as a second-line therapy in patients with AIH.

Higher seroprevalence of hepatitis E virus in autoimmune hepatitis: Role of false-positive antibodies.

BACKGROUND AND AIMS: Recent studies have found an increase in the seroprevalence of hepatitis E virus (HEV) infection in patients with autoimmune hepatitis (AIH). We aimed to assess the prevalence of positive anti-HEV IgM and IgG, and HEV-RNA in a cohort of patients with AIH, to determine the impact of positive HEV serology on patient outcome, and to evaluate the role of hypergammaglobulinemia and positive autoantibodies in the presence of positive anti-HEV serology. METHODS: One hundred and five patients tested for HEV infection between 2014 and 2018 were included in the study: 50 with chronic AIH (more than 1 year on treatment), and 55 with an acute hepatitis (30 patients with acute AIH and 25 with non-AIH). RESULTS: Seroprevalence of HEV was higher in patients with acute AIH (17% vs 10% in patients with chronic AIH and 8% in patients with non-AIH). Patients with acute AIH and positive anti-HEV IgG were older (58 vs 40; P = .006), had higher IgG levels (27 g/dL vs 13 g/dL; P = .03) and antismooth muscle antibodies (ASMA) titres (1:160 vs 1:80; P = .045), and were more likely to have another autoimmune disease (60% vs 16%; P = .03). At the time of HEV testing, anti-HEV IgG positive patients had significantly higher serum IgG levels (17 g/L vs 11 g/L; P = .009), ANA (1:160 vs 1:60; P = .026) and ASMA titres (1:80 vs 1:40; P = .021). CONCLUSION: Seroprevalence of HEV in patients with AIH in Catalonia does not differ from that of the general population. The higher HEV seroprevalence in patients with acute AIH with higher levels of gammaglobulins and high antibody titres suggest the presence of cross-reactivity between HEV and liver antigens.

Ductular reaction and hepatocyte ballooning identify patients with fibrosing cholestatic hepatitits after liver transplantation.

INTRODUCTION: Diagnosis of severe hepatitis C recurrence is based on analytical and histological criteria but there is little information about their correlation. AIM: To assess the accuracy of laboratory criteria for the diagnosis of fibrosing cholestatic hepatitis (FCH). PATIENTS AND METHODS: Retrospective analysis of prospectively collected data form HCV positive patients who underwent liver transplantation (LT) between 2000 and 2014 in two European university hospitals. Patients were classified according to laboratory criteria such as FCH, cholestatic hepatitis (CH) and non-cholestatic acute hepatitis (NCAH). Histological characteristics were also evaluated. RESULTS: Seventy patients with acute HCV recurrence within the first year after LT with an available liver biopsy were included in the study. Most patients were male (70%) with a median age of 58 years (50-64) and infected with genotype 1b (71.4%). Median time from LT to diagnosis of recurrence was 2.96 months (2.1-5.3). Thirty-nine patients were classified as FCH, 21 as CH and 10 as NCAH. Marked hepatocyte ballooning and ductular reaction were associated with the presence of FCH with an OR of 4.66 (p=0.047) and 20.58 (p=0.025), respectively. Considering liver biopsy as the gold standard, the sensitivity, specificity, positive and negative predictive values of the analytical criteria were 0.8, 0.5, 0.3 and 0.9, respectively. However, correlation between histological and analytical criteria was poor (k=0.033). DISCUSSION: Analytical criteria may be used to rule out the presence of FCH, but a biopsy is mandatory to confirm the diagnosis. Ductular reaction and hepatocyte ballooning were independent predictors of FCH.

Presentation and Outcomes of Pregnancy in Patients With Autoimmune Hepatitis.

Autoimmune hepatitis (AIH) frequently affects women of childbearing age in whom the desire to have a family raises the question regarding the potential risks for the fetus and the mother. The information on AIH in pregnant patients is scarce.1 The aims of this study were (1) to identify the risk factors associated with flares in pregnant patients diagnosed with AIH, (2) to determine the course of AIH in patients with pregnancy-related flares, and (3) to describe the outcome of AIH diagnosed in the postpartum period.

Elimination of hepatitis C virus infection from a hemodialysis unit and impact of treatment on the control of anemia.

INTRODUCTION: In the interferon era, the treatment of hepatitis C virus (HCV) infection in patients on haemodialysis (HD) was limited due to the significant number of treatment-related adverse events (AEs). Direct-acting antivirals (DAAs) have demonstrated their efficacy and safety in the treatment of HCV in patients with advanced chronic kidney disease on haemodialysis. The objective of the study was to evaluate the success in eliminating HCV infection from our dialysis unit using DAAs, and to assess the impact of HCV elimination on clinical and analytical outcomes. PATIENTS AND METHODS: This is a prospective, interventional, single-center study at Hospital Clínic de Barcelona. All HCV-RNA positive patients who received antiviral therapy with DAAs within a 3-year period (2014-2017) were analyzed (n=20). Data on virologic response, adverse events, and biochemical and hematological parameters during and after DAA therapy were analyzed. RESULTS: All patients achieved sustained virologic response (SVR) and only 40% of patients presented with mild AEs. None of the patients presented with HCV reinfection after a 1-year follow-up period, and thus HCV was eliminated from our HD unit. SVR was associated with a significant increase in hemoglobin and hematocrit, and a tendency toward the need for lower doses of iron supplementation with no changes in darbepoetin dose. CONCLUSION: HCV infection can be safely eliminated from HD units with the use of DAAs, preventing new infections in patients and healthcare staff. In the short term, the achievement of SVR is associated with an improvement in the control of anemia.

Molecular profiling of subclinical inflammatory lesions in long-term surviving adult liver transplant recipients.

BACKGROUND & AIMS: Subclinical inflammatory changes are commonly described in long-term transplant recipients undergoing protocol liver biopsies. The pathogenesis of these lesions remains unclear. The aim of this study was to identify the key molecular pathways driving progressive subclinical inflammatory liver allograft damage. METHODS: All liver recipients followed at Hospital Clínic Barcelona who were >10 years post-transplant were screened for participation in the study. Patients with recurrence of underlying liver disease, biliary or vascular complications, chronic rejection, and abnormal liver function tests were excluded. Sixty-seven patients agreed to participate and underwent blood and serological tests, transient elastography and a liver biopsy. Transcriptome profiling was performed on RNA extracted from 49 out of the 67 biopsies employing a whole genome next generation sequencing platform. Patients were followed for a median of 6.8 years following the index liver biopsy. RESULTS: Median time since transplantation to liver biopsy was 13 years (10-22). The most frequently observed histological abnormality was portal inflammation with different degrees of fibrosis, present in 45 biopsies (67%). Two modules of 102 and 425 co-expressed genes were significantly correlated with portal inflammation, interface hepatitis and portal fibrosis. These modules were enriched in molecular pathways known to be associated with T cell mediated rejection. Liver allografts showing the highest expression levels for the two modules recapitulated the transcriptional profile of biopsies with clinically apparent rejection and developed progressive damage over time, as assessed by non-invasive markers of fibrosis. CONCLUSIONS: A large proportion of adult liver transplant recipients who survive long-term exhibit subclinical histological abnormalities. The transcriptomic profile of these patients' liver tissue closely resembles that of T cell mediated rejection and may result in progressive allograft damage. LAY SUMMARY: A large proportion of adult liver transplant recipients who survive for a long time exhibit subclinical histological abnormalities. The expression profile (a measurement of the activity of genes) of liver tissue from a large fraction of these patients closely resembles the profile of T cell mediated rejection. Liver allografts showing the highest expression levels of rejection-related genes developed progressive damage over time.

Treating Hepatitis C in Patients with Renal Failure.

BACKGROUND: There is a strong relationship between hepatitis C virus (HCV) infection and the kidney. Approximately 10-16% of the patients with HCV infection develop renal disease, and the prevalence of HCV infection in patients with renal dysfunction is higher than that of the general population (9.5 vs. 1.6%). Moreover, HCV-positive patients on hemodialysis (HD) have higher mortality rates as compared to HCV-negative patients also on HD, not only due to liver-related complications but also owing to cardiovascular disease. Key Messages: In the interferon era, the treatment of HCV infection in patients on HD was hampered due to a significant number of treatment-related adverse events (predominately anemia and infectious complications). The development of direct-acting antivirals (DAAs) has revolutionized the field allowing viral eradication in these very sick patients. Two recently published clinical trials assessed the efficacy and safety of DAAs in patients with end-stage renal disease (ESRD). The combination of grazoprevir and elbasvir has been studied in the C-SURFER trial with 94% of the patients achieving sustained virological response (SVR). Adverse events were mild and only a small number of patients discontinued therapy early due to adverse events. The 3D regimen was evaluated in the RUBY-I trial. Here, a 90% SVR rate was achieved in 20 patients with ESRD, most of them on HD. Although sofosbuvir is eliminated by the kidney and its use in patients with glomerular filtration rate <30 mL/min is not recommended, real-life data have shown good results for this drug in terms of efficacy and safety. CONCLUSIONS: The use of DAAs has safely permitted the treatment of patients with renal dysfunction with excellent efficacy results.

[Treatment of hepatitis C before and after liver transplantation]. / Tratamiento de la hepatitis C en el pre- y postrasplante hepático.

Hepatitis C recurrence after liver transplantation is universal and increases morbidity and mortality in these patients. The development of new direct antiviral agents against the hepatitis C virus is a major treatment advance. Pre-transplant treatment avoids graft infection and sometimes improves liver function, allowing the patient to be withdrawn from the transplant waiting list. Delaying treatment until the postpostransplant period may be advisable in patients with advanced cirrhosis. Generally, antiviral therapy after liver transplantation is provided in patients with histological evidence of the disease. In these patients, treatment is more effective in the initial stages of the disease. The choice of antiviral therapy in these patients is based on the degree of liver function, the presence of renal failure, and potential drug-drug interactions.

Economic impact of inflammatory bowel disease in Catalonia: a population-based analysis.

Background: Inflammatory bowel disease (IBD) has a major economic impact on healthcare costs. Objectives: The aim of this study was to evaluate the current healthcare expenditure associated with IBD in a population-wide study in Catalonia. Design: Retrospective observational study. Methods: All patients with IBD included in the Catalan Health Surveillance System (CHSS) were considered eligible. The CHSS compiles data on more than 7 million individuals in 2020 (34,823 with IBD). Data on the use of healthcare resources and its economic impact were extracted applying the International Classification of Diseases, 10th revision, Clinical Modification codes (ICD-10-CM codes). Health expenditure, comorbidities, and hospitalization were calculated according to the standard costs of each service provided by the Department of Health of the Catalan government. The data on the IBD population were compared with non-IBD population adjusted for age, sex, and income level. IBD costs were recorded separately for Crohn's disease (CD) and ulcerative colitis (UC). Results: Prevalence of comorbidities was higher in patients with IBD than in those without. The risk of hospitalization was twice as high in the IBD population. The overall healthcare expenditure on IBD patients amounted to 164M€. The pharmacy cost represents the 60%. The average annual per capita expenditure on IBD patients was more than 3.4-fold higher (IBD 4200€, non-IBD 1200€). Average costs of UC were 3400€ and 5700€ for CD. Conclusion: The risk of comorbidities was twice as high in patients with IBD and their use of healthcare resources was also higher than that of their non-IBD counterparts. Per capita healthcare expenditure was approximately 3.4 times higher in the population with IBD. Trial registration: The study was not previously registered.

Economic impact of inflammatory bowel disease in Catalonia The manuscript includes data of the most recent epidemiologic data about the high economic impact of IBD in Catalonia.

Incidence of Myelotoxicity and Other Adverse Effects Related to Thiopurine Starting in Patients with Inflammatory Bowel Disease: Retrospective Observational Study in a Third-Level Hospital.

BACKGROUND AND OBJECTIVES: Thiopurines are an effective treatment for the maintenance of remission in inflammatory bowel disease (IBD). They can present adverse effects (AEs), with myelotoxicity being the most relevant. This study aims to determine the incidence of AEs related to the starting of thiopurines in our centre. METHODOLOGY: Retrospective study. The AEs in patients that were started on thiopurines between January 2016 and June 2020 were registered, with a two-year follow-up. The mean and standard deviation were used to describe the quantitative variables, and percentages and confidence intervals were used for the qualitative variables. The statistical significance was set at a p-value < 0.05. RESULTS: 98 patients were included, with 64 AEs detected in 48 patients (49%). Most of the AEs appeared in the first 6 months. The most relevant were: 21 neutropenia (21.4%), 19 hypertransaminasemia (19.4%), 13 digestive intolerances (13.2%), 6 acute pancreatitis (6.12%), 3 phototoxicity (3%), and 2 unknown origin fevers (2%). In 29 patients (29.4%) the treatment had to be suspended due to AEs. In 11 cases (11.2%), azathioprine (AZA) was switched to 6-mercaptopurine (6 MP) as 5 showed tolerance and 6 patients needed suspension due to AEs. Eight patients required hospital admission, but none of them needed intensive care unit admission. There were no fatal adverse effects. CONCLUSIONS: Thiopurines are a safe drug with few AEs, especially after the first months of treatment. These results suggest that periodic analytic follow-up may not be necessary after the initial period of treatment.

Heterogeneity in pharmacological treatment and outcomes in Crohn's disease patients in Catalonia: a population-based observational study.

BACKGROUND: Heterogeneity in the treatment of a disease is a marker of suboptimal quality of care. The aim of this study is to evaluate the heterogeneity in the treatment used and the outcomes for Crohn's disease (CD) in Catalonia. METHODS: All patients with CD included in the Catalan Health Surveillance System (data on more than seven million individuals from 2011 to 2017) were identified. The different Catalonian health areas were grouped into 19 district groups (DG). Treatments used rates (systemic corticosteroids, non-biological and biological immunosuppressant) and outcomes rates (hospitalization and surgery) were calculated. RESULTS: The use of systemic corticosteroids presented a decreasing trend over the study period, with an average rate of use in the different territories between 11% and 17%. The use of non-biological immunosuppressant treatment has remained stable, with an average rate of use ranging from 22% to 40% per year depending on the DG. The use of biological immunosuppressant treatment increased with an average rate of use in the different territories ranging from 10 to 23%.Hospitalizations for any reason showed an increasing trend between 2011 and 2017 with an average rate of between 23% and 32% per year depending on the area. Hospitalizations for CD presented a decreasing trend, with an average rate of between 5% and 11% per year. Surgical treatment remained stable over time, rates per year were between 0.5% and 2%. CONCLUSION: A remarkable geographical heterogeneity in the use of different treatments and in outcomes of CD was observed between different geographical areas of Catalonia. KEY MESSAGEThere is a notable geographical heterogeneity in the administration of biological and immunosuppressive treatments to Crohn's disease patients in Catalonia.There is also a geographical heterogeneity in their rates of hospitalization and surgical intervention.

Noninvasive Prediction of Outcomes in Autoimmune Hepatitis-Related Cirrhosis.

The value of noninvasive tools in the diagnosis of autoimmune hepatitis (AIH)-related cirrhosis and the prediction of clinical outcomes is largely unknown. We sought to evaluate (1) the utility of liver stiffness measurement (LSM) in the diagnosis of cirrhosis and (2) the performance of the Sixth Baveno Consensus on Portal Hypertension (Baveno VI), expanded Baveno VI, and the ANTICIPATE models in predicting the absence of varices needing treatment (VNT). A multicenter cohort of 132 patients with AIH-related cirrhosis was retrospectively analyzed. LSM and endoscopies performed at the time of cirrhosis diagnosis were recorded. Most of the patients were female (66%), with a median age of 54 years. Only 33%-49% of patients had a LSM above the cutoff points described for the diagnosis of AIH-related cirrhosis (12.5, 14, and 16 kPa). Patients with portal hypertension (PHT) had significantly higher LSM than those without PHT (15.7 vs. 11.7 kPa; P = 0.001), but 39%-52% of patients with PHT still had LSM below these limits. The time since AIH diagnosis negatively correlated with LSM, with longer time being significantly associated with a lower proportion of patients with LSM above these cutoffs. VNT was present in 12 endoscopies. The use of the Baveno VI, expanded Baveno VI criteria, and the ANTICIPATE model would have saved 46%-63% of endoscopies, but the latter underpredicted the risk of VNT. Conclusions: LSM cutoff points do not have a good discriminative capacity for the diagnosis of AIH-related cirrhosis, especially long-term after treatment initiation. Noninvasive tools are helpful to triage patients for endoscopy.

Time Trends of Crohn's Disease in Catalonia from 2011 to 2017. Increasing Use of Biologics Correlates with a Reduced Need for Surgery.

BACKGROUND AND AIMS: Data from clinical trials suggest that biological drugs may improve the outcomes in Crohn's disease (CD) by reducing the need for surgery or hospitalization. The aim of this study is to evaluate the time-trends of the use of biological drugs and other treatments for CD, and its relationship with outcomes in Catalonia. MATERIALS AND METHODS: All patients with CD included in the Catalan Health Surveillance System (containing data on a population of more than 7.5 million) from 2011 to 2017 were identified. The exposures to different treatments for inflammatory bowel disease were retrieved from electronic invoicing records. RESULTS: Between 2011 and 2017, the use of salicylates, corticosteroids and immunosuppressive treatment fell from 28.8% to 17.1%, 15.8% to 13.7%, and 32.9% to 29.6%, respectively (p < 0.001). Biological treatment use rose from 15.0% to 18.7% (p < 0.001). Ostomy rates per 1000 patients/year fell from 13.2 in 2011 to 9.8 in 2017 (p = 0.003), and surgical resection rates from 24.1 to 18.0 (p < 0.001). The rate of CD-related hospitalizations per 1000 patients/year also fell, from 92.7 to 72.2 (p < 0.001). CONCLUSIONS: Biological drug use rose from 15.0% to 18.7% between 2011 and 2017. During this period, we observed an improvement in the outcomes of CD patients.