IL-17A in Human Liver: Significant Source of Inflammation and Trigger of Liver Fibrosis Initiation.

IL-17A is considered to guide liver inflammation and fibrosis. From twenty-two human liver samples of different fibrosis stages (F0 to F4), IL-17A, IL-22, and TGFß1 protein expression in liver tissue lysates were analyzed. Ten paired samples of liver tissue (F0-F1 stage) and blood from the same patient were used to analyze intrahepatic and blood T-lymphoid IL-17A+ cells by flow cytometry. The analyses have been performed regardless of pathology, considering the stage of fibrosis. Human liver tissue was used for the primary human liver slice cultures, followed by subsequent cytokine stimulation and fibrotic markers' analysis by ELISA. IL-17A production in human liver tissue was significantly higher in the early fibrotic stage compared with the advanced stage. Th17 T cells and, to a lesser extent, MAIT cells were the main sources of IL-17A in both compartments, the liver and the blood. Moreover, the presence of liver Th17IL-17A+INFγ+ cells was detected in the liver. IL-17A stimulation of human liver slice culture increased the expression of profibrotic and pro-inflammatory markers. IL-17A, secreted by Th17 and MAIT cells in the liver, triggered fibrosis by inducing the expression of IL-6 and profibrotic markers and could be a target for antifibrotic treatment. Further amplitude studies are needed to confirm the current results.

Is elimination of HCV realistic by 2030: France.

The World Health Organization (WHO) has proposed a plan for the elimination of viral hepatitis with a goal of reducing new hepatitis infections by 30% and 90% in 2020 and 2030, and associated mortality by 10% and 65% respectively. Actions and targets to reach these goals include improving hepatitis B virus (HBV) vaccination programs, the prevention of mother-to-child transmission of HBV, improving the safety of blood products and injections, risk reduction policies and optimizing the diagnosis and treatment of hepatitis. The goal of eliminating hepatitis C virus (HCV) by 2030 is based on three main actions: increased screening, strengthening access to care and the prevention of infections and re-infections. But, can this goal be reached? The answer to this question is yes in some countries, perhaps in others and no in most countries. Success will be limited by a "diagnosis burn-out" with 5 times more new viral infections than diagnoses in 2016 and a "treatment burn-out" with cure rates that are 5 times lower than the number of new infections. Nevertheless, France, like 10 other countries, is on track to achieve the WHO elimination plan by 2030. In France, the prioritization of oral antivirals in 2013-2014 which was extended to high-risk populations in 2015 (HIV-infected patients) and 2016 (men who have sex with men, dialyzed or kidney transplant recipients), then in 2017 to universal treatment with full coverage by French national healthcare (10 to 15 000 treatments per year) has resulted in half of the 120 000 patients needed to be treated by 2022 have been treated. Renewed efforts should make it possible to reach the target announced by the French Minister of Health in May 2018 by 2025.

Adult human liver slice cultures: Modelling of liver fibrosis and evaluation of new anti-fibrotic drugs.

BACKGROUND: Liver fibrosis can result in end-stage liver failure and death. AIM: To examine human liver fibrogenesis and anti-fibrotic therapies, we evaluated the three dimensional ex vivo liver slice (LS) model. METHODS: Fibrotic liver samples (F0 to F4 fibrosis stage according to the METAVIR score) were collected from patients after liver resection. Human liver slices (HLS) were cultivated for up to 21 days. Hepatitis C virus (HCV) infection, alcohol (ethanol stimulation) and steatosis (palmitate stimulation) were examined in fibrotic (F2 to F4) liver slices infected (or not) with HCV. F0-F1 HLS were used as controls. At day 0, either ursodeoxycholic acid (choleretic and hepatoprotective properties) and/or α-tocopherol (antioxidant properties) were added to standard of care on HLS and fibrotic liver slices, infected (or not) with HCV. Expression of the biomarkers of fibrosis and the triglyceride production were checked by quantitative reverse transcription polymerase chain reaction and/or enzyme-linked immunosorbent assay. RESULTS: The cultures were viable in vitro for 21 days allowing to study fibrosis inducers and to estimate the effect of anti-fibrotic drugs. Expression of the biomarkers of fibrosis and the progression to steatosis (estimated by triglycerides production) was increased with the addition of HCV and /or ethanol or palmitate. From day 15 of the follow-up studies, a significant decrease of both transforming growth factor ß-1 and Procol1A1 expression and triglycerides production was observed when a combined anti-fibrotic treatment was applied on HCV infected F2-F4 LS cultures. CONCLUSION: These results show that the human three dimensional ex vivo model effectively reflects the in vivo processes in damaged human liver (viral, alcoholic, nonalcoholic steatohepatitis liver diseases) and provides the proof of concept that the LS examined model permits a rapid evaluation of new anti-fibrotic therapies when used alone or in combination.

Real-world evidence of tofacitinib effectiveness and safety in patients with refractory ulcerative colitis.

BACKGROUND: Phase III trials demonstrated effectiveness of tofacitinib, an oral Janus kinase inhibitor, to induce and maintain remission in patients with moderate-to-severe active ulcerative colitis (UC). AIMS: We report the real-world effectiveness and safety of tofacitinib in patients with UC in France. METHODS: From February 2017 to December 2018, we performed a national French cohort study, which included all consecutive patients with an active UC refractory to anti-TNF and vedolizumab, who received tofacitinib. Outcomes were survival without colectomy, survival without tofacitinib discontinuation and steroid-free clinical remission at weeks 14, 24 and 48. RESULTS: Thirty-eight patients were included, with a median follow-up of 41.5 (18.5-56.8) weeks. Survival without colectomy was 77% [95% confidence interval (95%CI): 59.3-87.9] at week 24 and 70% (95%CI: 50.9-82.8) at week 48. Survival without treatment discontinuation was 70% (95%CI: 52.6-82.3) at week 24. Steroid-free clinical remission was observed in 13 (34%) patients at week 48. Adverse events occurred in 14 (37%) patients, including 6 severe adverse events and three herpes zoster infections. CONCLUSION: In a highly refractory UC population, one third of patients treated with tofacitinib achieved steroid-free clinical remission at week 14 and 70% of patients avoided colectomy at one year, with an acceptable safety profile. These data confirm tofacitinib effectiveness in UC, especially after multiple biologic failures.