An open-label randomised-controlled trial of azathioprine vs. mycophenolate mofetil for the induction of remission in treatment-naive autoimmune hepatitis.

BACKGROUND & AIMS: Patients with autoimmune hepatitis (AIH) almost invariably require lifelong immunosuppressive treatment. There is genuine concern about the efficacy and tolerability of the current standard combination therapy of prednisolone and azathioprine. Mycophenolate mofetil (MMF) has emerged as an alternative option. The aim of this study was to compare MMF to azathioprine as induction therapy for AIH. METHODS: In this 24-week, prospective, randomised, open-label, multicentre superiority trial, 70 patients with treatment-naive AIH received either MMF or azathioprine, both in combination with prednisolone. The primary endpoint was biochemical remission defined as normalisation of serum levels of alanine aminotransferase and IgG after 24 weeks of treatment. Secondary endpoints included safety and tolerability. RESULTS: Seventy patients (mean 57.9 years [SD 14.0]; 72.9% female) were randomly assigned to the MMF plus prednisolone (n = 39) or azathioprine plus prednisolone (n = 31) group. The primary endpoint was met in 56.4% and 29.0% of patients assigned to the MMF group and the azathioprine group, respectively (difference, 27.4 percentage points; 95% CI 4.0 to 46.7; p = 0.022). The MMF group exhibited higher complete biochemical response rates at 6 months (72.2% vs. 32.3%; p = 0.004). No serious adverse events occurred in patients who received MMF (0%) but serious adverse events were reported in four patients who received azathioprine (12.9%) (p = 0.034). Two patients in the MMF group (5.1%) and eight patients in the azathioprine group (25.8%) discontinued treatment owing to adverse events or serious adverse events (p = 0.018). CONCLUSIONS: In patients with treatment-naive AIH, MMF with prednisolone led to a significantly higher rate of biochemical remission at 24 weeks compared to azathioprine combined with prednisolone. Azathioprine use was associated with more (serious) adverse events leading to cessation of treatment, suggesting superior tolerability of MMF. IMPACT AND IMPLICATIONS: This randomised-controlled trial directly compares azathioprine and mycophenolate mofetil, both in combination with prednisolone, for the induction of biochemical remission in treatment-naive patients with autoimmune hepatitis. Achieving complete remission is desirable to prevent disease progression. Patients assigned to the mycophenolate mofetil group reached biochemical remission more often and experienced fewer adverse events. The findings in this trial may contribute to the re-evaluation of international guidelines for the standard of care in treatment-naive patients with autoimmune hepatitis. TRIAL REGISTRATION NUMBER: #NCT02900443.

Assessing the efficacy and safety of mycophenolate mofetil versus azathioprine in patients with autoimmune hepatitis (CAMARO trial): study protocol for a randomised controlled trial.

BACKGROUND: Currently, the standard therapy for autoimmune hepatitis (AIH) consists of a combination of prednisolone and azathioprine. However, 15% of patients are intolerant to azathioprine which necessitates cessation of azathioprine or changes in therapy. In addition, not all patients achieve complete biochemical response (CR). Uncontrolled data indicate that mycophenolate mofetil (MMF) can induce CR in a majority of patients. Better understanding of first-line treatment and robust evidence from randomised clinical trials are needed. The aim of this study was to explore the potential benefits of MMF as compared to azathioprine, both combined with prednisolone, as induction therapy in a randomised controlled trial in patients with treatment-naive AIH. METHODS: CAMARO is a randomised (1:1), open-label, parallel-group, multicentre superiority trial. All patients with AIH are screened for eligibility. Seventy adult patients with AIH from fourteen centres in the Netherlands and Belgium will be randomised to receive MMF or azathioprine. Both treatment arms will start with prednisolone as induction therapy. The primary outcome is biochemical remission, defined as serum levels of alanine aminotransferase and immunoglobulin G below the upper limit of normal. Secondary outcomes include safety and tolerability of MMF and azathioprine, time to remission, changes in Model For End-Stage Liver Disease (MELD)-score, adverse events, and aspects of quality of life. The study period will last for 24 weeks. DISCUSSION: The CAMARO trial investigates whether treatment with MMF and prednisolone increases the proportion of patients in remission compared with azathioprine and prednisolone as the current standard treatment strategy. In addition, we reflect on the challenges of conducting a randomized trial in rare diseases. TRIAL REGISTRATION: EudraCT 2016-001038-91 . Prospectively registered on 18 April 2016.

COVID-19 and Nurse-Sensitive Indicators: Using Performance Improvement Teams to Address Quality Indicators During a Pandemic.

BACKGROUND: Nurse-sensitive quality indicators have historically been used as a metric of nursing care quality in health care organizations. PROBLEM: At our academic medical center, critically ill COVID-19 patients led to a dramatic change in the organizational standard of care resulting in an increase in nurse-sensitive health care-associated infections. APPROACH: Nursing performance improvement teams provided the structure for development of innovative strategies implemented in real time by our frontline clinicians to address the quality and safety issues found with these elevated health care-associated infections. OUTCOMES: A new COVID-19 CLABSI (central line-associated bloodstream infection) Tip Sheet and a Prone Positioning Kit for HAPI Prevention are strategies developed to address quality of care issues experienced with the COVID-19 patients. CONCLUSIONS: Deployment of these innovative practice strategies has led to a decline in health care-associated infections and instituted a new care standard for the COVID-19 patients.

Does mucosal inflammation drive recurrence of primary sclerosing cholangitis in liver transplantion recipients with ulcerative colitis?

BACKGROUND: Liver transplantation remains the only effective evidence based treatment for advanced primary sclerosing cholangitis. However, recurrence of disease occurs in approximately 18%. AIMS: This study aimed to assess risk factors of recurrence of primary sclerosing cholangitis. METHODS: A retrospective cohort study was performed on patients undergoing transplantation for recurrence of primary sclerosing cholangitis in two academic centers (Leuven, Belgium and Leiden, The Netherlands). Besides other risk factors, the degree of mucosal inflammation was assessed as a potential risk factor using histological Geboes scores. RESULTS: 81 patients were included, of which 62 (76.5%) were diagnosed with ulcerative colitis. Seventeen patients (21.0%) developed rPSC during a median follow-up time of 5.2 years. In a subset of 42 patients no association was found between the degree of mucosal inflammation and recurrence, using both original Geboes scores and multiple cut-off points. In the total cohort, cytomegaloviremia post-transplantation (HR: 4.576, 95%CI 1.688-12.403) and younger receiver age at time of liver transplantation (HR: 0.934, 95%CI 0.881-0.990) were independently associated with an increased risk of recurrence of disease. CONCLUSION: This study found no association between the degree of mucosal inflammation and recurrence of primary sclerosing cholangitis. An association with recurrence was found for cytomegaloviremia post-liver transplantation and younger age at time of liver transplantation.

Systematic review with meta-analysis: risk factors for recurrent primary sclerosing cholangitis after liver transplantation.

BACKGROUND: After liver transplantation primary sclerosing cholangitis (PSC), the condition returns in the transplanted liver in a subset of patients (recurrent primary sclerosing cholangitis, rPSC). AIM: To define risk factors for rPSC. METHODS: We searched Pubmed, Embase, Web of Science, and Cochrane library for articles published until March 2018. Studies addressing risk factors for developing rPSC were eligible for inclusion. A random effects meta-analysis was conducted using hazard ratios (HR) as effect measure. Study quality was evaluated with the Newcastle Ottawa scale. Statistical analysis was performed using Cochrane Review Manager. RESULTS: The electronic database search yielded 449 results. Twenty-one retrospective cohort studies met the inclusion criteria for the review; 14 were included in the meta-analysis. The final cohort included 2159 patients (age range 31-49 years, 68.8% male), of whom 17.7% developed rPSC. Colectomy before liver transplantation, HR 0.65 (95% CI: 0.42-0.99), cholangiocarcinoma before liver transplantation, HR 2.42 (95% CI: 1.20-4.86), inflammatory bowel disease, HR 1.73 (95% CI: 1.17-2.54), donor age, HR 1.24 (95% CI 1.0-1.45) per ten years, MELD score, HR 1.05 (95% CI: 1.02-1.08) per point and acute cellular rejection, HR of 1.94 (95% CI: 1.32-2.83) were associated with the risk of rPSC. CONCLUSIONS: Multiple risk factors for rPSC were identified. Colectomy before liver transplantation reduced the risk of rPSC.

Flushing the liver with urokinase before transplantation does not prevent nonanastomotic biliary strictures.

The aim of the present study was to assess whether flushing the donor liver with urokinase immediately before implantation reduces the incidence of nonanastomotic biliary strictures (NASs) after liver transplantation, without causing increased blood loss, analyzed as a historical cohort study. Between January 2005 and October 2012, all liver (re-)transplantations were included. Of the 185 liver transplant recipients included, 63 donor livers between January 2010 and October 2012 received urokinase (study group), whereas the donor liver of 122 consecutive recipients, who served as a historical control group, between January 2005 and January 2010 did not receive urokinase. Basic donor (Eurotransplant donor risk index) and recipient (age, body mass index, laboratory Model for End-Stage Liver Disease score) characteristics did not significantly differ in both groups. Thirty-three recipients developed NASs: 22 in the control group (18%) and 11 (17.5%) in the study group (P = 0.68). Analyzed separately for donation after circulatory death (P = 0.42) or donation after brain death (P = 0.89), there was no difference between the groups in incidence of NAS. Of all the recipients developing NAS, 7 (21%) needed retransplantation and all others were treated conservatively. Autologous blood transfusion requirements did not differ significantly between both groups (P = 0.91), whereas interestingly, more heterologous blood transfusions were needed in the control group (P < 0.001). This study has its limitations by its retrospective character. A multi-institutional prospective study could clarify this issue. In conclusion, arterial flushing of the liver with urokinase immediately before implantation did not lead to a lower incidence of NAS in this study, nor did it lead to increased blood loss.

Elderly donor liver grafts are not associated with a higher incidence of biliary complications after liver transplantation: results of a national multicenter study.

BACKGROUND: Liver transplantation with livers grafts from elderly donors has been associated with a higher risk of biliary complications. The aim of this study was to examine whether our national protocol could contribute to a lower incidence of biliary complications. METHODS: All adult recipients in the Netherlands transplanted with a liver from an elderly donor (≥ 65 yrs; n = 68) in the period January 2000-July 2011 were matched with recipients of a liver from a donor <65 yr (n = 136). Outcome parameters were 90-d, one-yr, and three-yr patient/graft survival rates, biliary complications (non-anastomotic stricture, anastomotic stricture, biliary leakage, and post-transplant cholangitis), and postoperative hepatic ischemic injury serum markers (AST/ALT). RESULTS: The median cold ischemia time (CIT) was 7:25 (h:min) in the group recipients of an elderly donor liver graft. Ninety-day, one-yr, and three-yr patient/graft survival rates were similar between the group with an elderly donor liver and their younger controls. Moreover, no differences were found in the incidence of biliary complications and postoperative levels of AST/ALT between the two groups. CONCLUSION: Transplantation of livers from elderly donors (≥ 65 yr) is not associated with a higher incidence of biliary complications, in a national policy wherein the CIT is kept short.

High peak alanine aminotransferase determines extra risk for nonanastomotic biliary strictures after liver transplantation with donation after circulatory death.

Orthotopic liver transplantation (OLT) with donation after circulatory death (DCD) often leads to a higher first week peak alanine aminotransferase (ALT) and a higher rate of biliary nonanastomotic strictures (NAS) as compared to donation after brain death (DBD). This retrospective study was to evaluate whether an association exists between peak ALT and the development of NAS in OLT with livers from DBD (n = 399) or DCD (n = 97) from two transplantation centers. Optimal cutoff value of peak ALT for risk of development of NAS post-DCD-OLT was 1300 IU/l. The 4-year cumulative incidence of NAS after DCD-OLT was 49.5% in patients with a high ALT peak post-OLT, compared with 11.3% in patients with a low ALT peak. (P < 0.001). No relation between peak ALT and NAS was observed after DBD-OLT. Multivariate analysis revealed peak ALT ≥1300 IU/l [adjusted hazard ratio (aHR) = 3.71, confidence interval (CI) (1.26-10.91)] and donor age [aHR = 1.04, CI 1.00-1.07] to be independently associated with development of NAS post-DCD-OLT. A peak ALT of <1300 IU/l carries a risk for NAS similar to DBD-OLT. Thus, in DCD-OLT, but not in DBD-OLT, peak ALT discriminates patients at high or low risk for NAS.

MMP-2 is a disease-modifying gene in primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the bile ducts, frequently necessitating orthotopic liver transplantation (OLT), often accompanied by inflammatory bowel disease (IBD). Matrix metalloproteinases (MMPs) are associated with fibrotic diseases caused by the involvement in tissue remodelling. AIM: To evaluate the contribution of MMP-2 and -9 promoter polymorphisms to disease severity in PSC, as assessed by death or need for OLT. METHODS: Matrix metalloproteinase-2 (-1306 C/T) and -9 (-1562 C/T) gene promoter polymorphisms were analyzed in 132 PSC patients. Follow-up was from onset PSC until death, OLT or end of follow-up. RESULTS: Twenty-year cumulative incidence (CI) of death or OLT for PSC patients with MMP-2 CT genotype was 86.5% compared to 52.8% for CC genotype (P = 0.030) and reached 100% at 11.3 years for TT genotype. In patients with IBD, CIs were similar: 20-years CI of death or OLT for MMP-2 CT genotype was 86.0% compared to 49.0% for CC genotype and 100% at 11.3 years for TT genotype. Patients without IBD showed a similar trend in 20 years CI for MMP-2 CT (77.8%) compared to CC (57.8%) and CI for TT genotype reached 100% at 9.3 years. Multivariate analysis showed, along with age at diagnosis, a stepwise increase in hazard ratio for MMP-2 T-allele polymorphism for death or OLT. MMP-9 genotype was not associated with disease severity in PSC. CONCLUSION: Matrix metalloproteinase-2 C to T-1306 gene promoter polymorphism in PSC is an independent risk factor for disease severity as reflected by the need for OLT or disease progression leading to mortality.

Matrix metalloproteinase 2 genotype is associated with nonanastomotic biliary strictures after orthotopic liver transplantation.

BACKGROUND: Nonanastomotic biliary strictures (NAS) are a serious complication after orthotopic liver transplantation (OLT). Matrix metalloproteinases (MMPs) are involved in connective tissue remodelling in chronic liver disease and complications after OLT. AIM: To evaluate the relationship between MMP-2 and MMP-9 gene polymorphisms and NAS. METHODS: MMP-2 (-1306 C/T) and MMP-9 (-1562 C/T) gene promoter polymorphisms were analysed in 314 recipient-donor combinations. Serum levels of these MMPs were determined in subgroups of patients as well. NAS were identified with various radiological imaging studies performed within 4 years after OLT and defined as any stricture, dilation or irregularity of the intra- or extrahepatic bile ducts of the liver graft followed by an intervention, after exclusion of hepatic artery thrombosis and anastomotic strictures. RESULTS: The average incidence of NAS was 15%. The major clinical risk factor for the development of NAS was PSC in the recipient. The presence of the MMP-2 CT genotype in donor and/or recipient was associated with a significantly higher incidence of NAS, up to 29% when both donor and recipient had the MMP-2 CT genotype (P=0.003). In the multivariate analyses, pre-OLT PSC (hazard ratio 2.1, P=0.02) and MMP-2 CT genotype (hazard ratio 3.5, P=0.003) were found to be independent risk factors for the development of NAS after OLT. No obvious association was found between NAS and the MMP-9 genotype and serum levels of the MMPs. CONCLUSION: MMP-2 CT genotype of donor and recipient is an independent risk factor, in addition to PSC, for the development of NAS after OLT.