Vascular adhesion protein-1 blockade in primary sclerosing cholangitis: Open-label, multicenter, single-arm, phase II trial.

BACKGROUND: Primary sclerosing cholangitis is a progressive inflammatory liver disease characterized by biliary and liver fibrosis. Vascular adhesion protein-1 (VAP-1) is important in the inflammatory process driving liver fibrosis. We evaluated the safety and efficacy of VAP-1 blockade with a monoclonal antibody (timolumab, BTT1023) in patients with primary sclerosing cholangitis. METHODS: BUTEO was a prospective, single-arm, open-label, multicenter, phase II trial, conducted in 6 centers in the United Kingdom. Patients with primary sclerosing cholangitis aged 18-75 years had an alkaline phosphatase value of >1.5 times the upper limit of normal. The dose-confirmatory stage aimed to confirm the safety of timolumab through the incidence of dose-limiting toxicity and sufficient trough levels of circulating antibody to block VAP-1 function. The primary outcome of the dose-expansion portion of the trial was patient's response to timolumab at day 99, as measured by a reduction in serum alkaline phosphatase by 25% or more from baseline to day 99. RESULTS: Twenty-three patients were recruited: 7 into the initial dose-confirmatory stage and a further 16 into an expansion stage. Timolumab (8 mg/kg) was confirmed to be safe for the duration of administration with sufficient circulating levels. Only 2 of the 18 evaluable patients (11.1%) achieved a reduction in alkaline phosphatase levels of 25% or more, and both the proportion of circulating inflammatory cell populations and biomarkers of fibrosis remained unchanged from baseline. CONCLUSIONS: The BUTEO trial confirmed 8 mg/kg timolumab had no short-term safety signals and resulted in sufficient circulating levels of VAP-1 blocking timolumab. However, the trial was stopped after an interim assessment due to a lack of efficacy as determined by no significant change in serum liver tests.

Intrahepatic macrophage populations in the pathophysiology of primary sclerosing cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammatory and fibrotic injury to the biliary tree. We sought to further delineate the contribution of macrophage lineages in PSC pathobiology. METHODS: Human liver tissues and/or blood samples from patients with PSC, primary biliary cholangitis, other non-cholestatic/non-autoimmune diseases, including alcohol-related liver disease and non-alcoholic steatohepatitis, as well as normal liver, were sourced from our liver transplantation program. Liver fibrosis was studied using Van Gieson staining, while the frequencies of infiltrating monocyte and macrophage lineages, both in the circulation and the liver, were investigated by flow cytometry, including the expression of TGR-5, a G protein-coupled receptor (GPBAR1/TGR-5). RESULTS: Significantly higher frequencies of CD68+CD206+ macrophages were detected in the livers of patients with PSC (median 19.17%; IQR 7.25-32.8%; n = 15) compared to those of patients with other liver diseases (median 12.05%; IQR 5.61-16.03%; n = 12; p = 0.0373). CD16+ monocytes, including both intermediate (CD14+CD16++) and non-classical (CD14dimCD16++) monocytes, were preferentially recruited into chronically diseased livers, with the highest recruitment ratios in PSC (median 15.83%; IQR 9.66-29.5%; n = 15), compared to other liver diseases (median 6.66%; IQR 2.88-11.64%, n = 14, p = 0.0152). The expression of TGR-5 on CD68+ intrahepatic macrophages was increased in chronic liver disease; TGR-5 expression on intrahepatic macrophages was highest in PSC (median 36.32%; IQR 17.71-63.61%; n = 6) and most TGR-5+ macrophages were CD68+CD206+ macrophages. CONCLUSIONS: Underlying a potential role for macrophages in PSC pathobiology, we demonstrate, using patient-derived tissue, increased CD16+ monocyte recruitment and a higher frequency of CD68+CD206+ macrophages in the livers of patients with PSC; the CD68+CD206+ macrophage subset was associated with significantly higher TGR-5 expression in PSC. LAY SUMMARY: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease associated with progressive inflammation of the bile duct, leading to fibrosis and end-stage liver disease. In this study we explore the role of a type of immune cell, the macrophage, in contributing to PSC as a disease, hoping that our findings direct scientists towards new treatment targets. Our findings based on human liver and blood analyses demonstrate a greater frequency of a particular subset of immune cell, the CD68+CD206+ macrophage, with significantly higher TGR-5 expression on this subset in PSC.

Reliability and validity of the sexual life quality questionnaire (SLQQ).

The sexual life quality questionnaire (SLQQ) was developed to evaluate sexual quality of life (QOL) and satisfaction with treatments for erectile dysfunction among patients and their sexual partners. This paper describes the development of the instrument and reports its psychometric properties as observed in two studies involving patients under treatment for erectile dysfunction. The instrument consists of 16 items, 10 of which deal with dimensions of sexual QOL that can be summed to a sexual QOL scale measure. The remaining six items comprise a scale measuring satisfaction with treatment dimensions. The composite sexual QOL and treatment satisfaction scales met established psychometric goals overall and within select subgroups (length of time quartiles, patient/partner). A significant correlation between the treatment satisfaction scale score and the patients' responses to a question asking their likelihood of selecting the method for continued treatment (r: 0.89) showed the measure to be a good indicator of treatment preference. Finally, there were significant differences in sexual QOL scale scores between screening and first treatment, indicating the instrument was responsive and able to detect changes in sexual QOL.