Intestinal CCL25 expression is increased in colitis and correlates with inflammatory activity

AbstractCCL25-mediated activation of CCR9 is critical for mucosal lymphocyte recruitment to the intestine. In immune-mediated liver injury complicating inflammatory bowel disease, intrahepatic activation of this pathway allows mucosal lymphocytes to be recruited to the liver, driving hepatobiliary destruction in primary sclerosing cholangitis (PSC). However, in mice and healthy humans CCL25 expression is restricted to the small bowel, whereas few data exist on activation of this pathway in the inflamed colon despite the vast majority of PSC patients having ulcerative colitis. Herein, we show that colonic CCL25 expression is not only upregulated in patients with active colitis, but strongly correlates with endoscopic Mayo score and mucosal TNFα expression. Moreover, approximately 90% (CD4+) and 30% (CD8+) of tissue-infiltrating T-cells in colitis were identified as CCR9+ effector lymphocytes, compared to <10% of T-cells being CCR9+ in normal colon. Sorted CCR9+ lymphocytes also demonstrated enhanced cellular adhesion to stimulated hepatic sinusoidal endothelium compared with their CCR9– counterparts when under flow. Collectively, these results suggest that CCR9/CCL25 interactions are not only involved in colitis pathogenesis but also correlate with colonic inflammatory burden; further supporting the existence of overlapping mucosal lymphocyte recruitment pathways between the inflamed colon and liver

Quantitative MRCP and metrics of bile duct disease over time in patients with primary sclerosing cholangitis:A prospective study

Background: Imaging markers of biliary disease in primary sclerosing cholangitis (PSC) have potential for use in clinical and trial disease monitoring. Herein, we evaluate how quantitative magnetic resonance cholangiopancreatography (MRCP) metrics change over time, as per the natural history of disease. Methods: Individuals with PSC were prospectively scanned using non‐contrast MRCP. Quantitative metrics were calculated using MRCP+ post‐processing software to assess duct diameters and dilated and strictured regions. Additionally, a hepatopancreatobiliary radiologist (blinded to clinical details, biochemistry and quantitative biliary metrics) reported each scan, including ductal disease assessment according to the modified Amsterdam Cholangiographic Score (MAS). Results: At baseline, 14 quantitative MRCP+ metrics were found to be significantly different in patients with PSC (N = 55) compared to those with primary biliary cholangitis (N = 55), autoimmune hepatitis (N = 57) and healthy controls (N = 18). In PSC specifically, baseline metrics quantifying the number of strictures and the number and length of bile ducts correlated with the MAS, transient elastography and serum ALP values (p &lt; 0.01 for all correlations). Over a median 371‐day follow‐up (range: 364–462), 29 patients with PSC underwent repeat MRCP, of whom 15 exhibited quantitative changes in MRCP+ metrics. Compared to baseline, quantitative MRCP+ identified an increasing number of strictures over time (p &lt; 0.05). Comparatively, no significant differences in biochemistry, elastography or the MAS were observed between timepoints. Quantitative MRCP+ metrics remained stable in non‐PSC liver disease. Conclusion: Quantitative MRCP+ identifies changes in ductal disease over time in PSC, despite stability in biochemistry, liver stiffness and radiologist‐derived cholangiographic assessment (trial registration: ISRCTN39463479)

Frequency and significance of IgG4 immunohistochemical staining in liver explants from patients with primary sclerosing cholangitis

Dense tissue infiltrates of IgG4(+) plasma cells >50/high-powered field (HPF) are purportedly highly specific for IgG4-related disease. However, the frequency and significance of liver-infiltrating IgG4(+) plasma cells in primary sclerosing cholangitis (PSC) applying these cut-offs has not been determined. We sought to determine the incidence of intrahepatic IgG4-positive staining in PSC patients undergoing transplantation, correlating findings with clinical parameters. Immunohistochemical staining was performed on liver explants obtained between 1991 and 2009. Of 122 explants obtained, hilar IgG4(+) staining was found to be mild (10–29 IgG4(+) cells/HPF) in 23.0%, moderate (30–50/HPF) in 9.0% and marked (>50/HPF) in 15.6%. Marked hilar lymphoplasmacytic infiltration was significantly associated with marked hilar IgG4(+) staining (P < 0.001). No patient had marked peripheral IgG4(+) staining, although mild and moderate staining was observed in 24.5% and 3.3% respectively. Marked hilar IgG4(+) staining was significantly associated with the presence of dominant biliary strictures (P = 0.01) and need for biliary stenting (P = 0.001). There did not, however, exist any significant differences in the age at PSC diagnosis, presence of inflammatory bowel disease or extrahepatic autoimmune disease, frequency of cholangiocarcinoma, interval between diagnosis and transplantation, or post-transplant PSC recurrence or survival. Of 51 control liver sections (PBC = 18; HCV = 19; HBV = 8; AIH = 6), none had marked or moderate hilar IgG4(+) staining, whereas mild staining was seen in only 10% (P < 0.001). Marked (>50/HPF) hilar IgG4(+) lymphoplasmacytic infiltration is frequently observed in PSC and associated with the presence of dominant biliary strictures. However, unlike serum IgG4(+)(,) this does not seemingly associate with clinical disease course

Protocol for the development of a core outcome set for clinical trials in primary sclerosing cholangitis

Background: Primary sclerosing cholangitis (PSC) is a progressive immune-mediated liver disease, for which no medical therapy has been shown to slow disease progression. However, the horizon for new therapies is encouraging, with several innovative clinical trials in progress. Despite these advancements, there is considerable heterogeneity in the outcomes studied, with lack of consensus as to what outcomes to measure, when to measure and how to measure. Furthermore, there has been a paradigm shift in PSC treatment targets over recent years, moving from biochemistry-based endpoints to histological assessment of liver fibrosis, imaging-based biomarkers and patient-reported outcome measures. The abundance of new interventional trials and evolving endpoints pose opportunities for all stakeholders involved in evaluating novel therapies. To this effect, there is a need to harmonise measures used in clinical trials through the development of a core outcome set (COS). Methods and analysis: Synthesis of a PSC-specific COS will be conducted in four stages. Initially, a systematic literature review will be performed to identify outcomes previously used in PSC trials, followed by semistructured qualitative interviews conducted with key stakeholders. The latter may include patients, clinicians, researchers, pharmaceutical industry representatives and healthcare payers and regulatory agencies, to identify additional outcomes of importance. Using the outcomes generated from the literature review and stakeholder interviews, an international two-round Delphi survey will be conducted to prioritise outcomes for inclusion in the COS. Finally, a consensus meeting will be convened to ratify the COS and disseminate findings for application in future PSC trials. Ethics and dissemination: Ethical approval has been granted by the East Midlands—Leicester Central Research Ethics Committee (Ref: 24/EM/0126) for this study. The COS from this study will be widely disseminated including publication in peer-reviewed journals, international conferences, promotion through patient-support groups and made available on the Core Outcomes Measurement in Effectiveness Trials (COMET) database. Trial registration number: 1239

Protocol for the development of a core outcome set for clinical trials in primary sclerosing cholangitis

Background: Primary sclerosing cholangitis (PSC) is a progressive immune-mediated liver disease, for which no medical therapy has been shown to slow disease progression. However, the horizon for new therapies is encouraging, with several innovative clinical trials in progress. Despite these advancements, there is considerable heterogeneity in the outcomes studied, with lack of consensus as to what outcomes to measure, when to measure and how to measure. Furthermore, there has been a paradigm shift in PSC treatment targets over recent years, moving from biochemistry-based endpoints to histological assessment of liver fibrosis, imaging-based biomarkers and patient-reported outcome measures. The abundance of new interventional trials and evolving endpoints pose opportunities for all stakeholders involved in evaluating novel therapies. To this effect, there is a need to harmonise measures used in clinical trials through the development of a core outcome set (COS). Methods and analysis: Synthesis of a PSC-specific COS will be conducted in four stages. Initially, a systematic literature review will be performed to identify outcomes previously used in PSC trials, followed by semistructured qualitative interviews conducted with key stakeholders. The latter may include patients, clinicians, researchers, pharmaceutical industry representatives and healthcare payers and regulatory agencies, to identify additional outcomes of importance. Using the outcomes generated from the literature review and stakeholder interviews, an international two-round Delphi survey will be conducted to prioritise outcomes for inclusion in the COS. Finally, a consensus meeting will be convened to ratify the COS and disseminate findings for application in future PSC trials. Ethics and dissemination: Ethical approval has been granted by the East Midlands—Leicester Central Research Ethics Committee (Ref: 24/EM/0126) for this study. The COS from this study will be widely disseminated including publication in peer-reviewed journals, international conferences, promotion through patient-support groups and made available on the Core Outcomes Measurement in Effectiveness Trials (COMET) database. Trial registration number: 1239

Number needed to treat with ursodeoxycholic acid therapy to prevent liver transplantation or death in primary biliary cholangitis

Objective: The clinical benefit of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) has never been reported in absolute measures. The aim of this study was to assess the number needed to treat (NNT) with UDCA to prevent liver transplantation (LT) or death among patients with PBC. Methods: The NNT was calculated based on the untreated LT-free survival and HR of UDCA with respect to LT or death as derived from inverse probability of treatment weighting-adjusted Cox proportional hazard analyses within the Global PBC Study Group database. Results: We included 3902 patients with a median follow-up of 7.8 (4.1-12.1) years. The overall HR of UDCA was 0.46 (95% CI 0.40 to 0.52) and the 5-year LT-free survival without UDCA was 81% (95% CI 79 to 82). The NNT to prevent one LT or death within 5 years (NNT5y) was 11 (95% CI 9 to 13). Although the HR of UDCA was similar for patients with and without cirrhosis (0.33 vs 0.31), the NNT5y was 4 (95% CI 3 to 5) and 20 (95% CI 14 to 34), respectively. Among patients with low alkaline phosphatase (ALP) (≤2× the upper limit of normal (ULN)), intermediate ALP (2-4× ULN) and high ALP (>4× ULN), the NNT5y to prevent one LT or death was 26 (95% CI 15 to 70), 11 (95% CI 8 to 17) and 5 (95% CI 4 to 8), respectively. Conclusion: The absolute clinical efficacy of UDCA with respect to LT or death varied with baseline prognostic characteristics, but was high throughout. These findings strongly emphasise the incentive to promptly initiate UDCA treatment in all patients with PBC and may improve patient compliance