Dr Palak Trivedi

PSC600 - A UK-PSC Initiative

UKPSC and PSCSupport and Birmingham University logos

Awarded to the University of Birmingham

Dr Palak Trivedi, Consultant Hepatologist / Clinician Scientist, NIHR Birmingham BRC and Centre for Liver Research

The total grant awarded is £20,000

Duration of award: 06 September 2019 to 06 September 2024

Award details: PSC600: A UK-PSC Initiative

PSC Support is delighted to be funding the PSC600, a UK-PSC initiative.

Summary

The PSC600 will study annual blood samples from 600 patients already registered in the UK-PSC biobank for up to 5 years. In addition, newly registered UK-PSC biobank patients will be approached to take part. Data from the blood samples will be compared to information from health records including changes in symptoms, phenotypic variation, IBD and liver disease activity, and routine test results.

This unique data will allow us to understand the true value and use of a range of biomarkers, and ultimately boost research to find treatments and efforts to improve clinical care for people with PSC.

Importantly, the valuable data will also be made available to future researchers to build on this work (subject to approval by the UK PSC steering committee). It will be an invaluable resource for prospective biomarker discovery (and validation) across multiple other platforms; including those that relate to immune cell function and migration, liver fibrosis, and proteomic / metabolic technologies that facilitate early cancer detection.

Background

Predicting PSC progression

Accurate prediction of disease behaviour is key to understanding the outcomes that patients experience.

All who are concerned with evaluating new treatments for PSC, as well as those seeking to personalise cancer surveillance strategies, wish to do so in a more risk-adjusted and systematic way.

Lack of proven biomarkers

Determining which individuals are likely to develop advanced disease, and at what rate (so called risk stratification), is currently prevented by lack of a proven biomarker distinguishing high-risk disease behaviour from that which follows a milder course.

Furthermore, in a disease with variable and often long natural history where prospectively evaluated patient cohorts are lacking, and no therapies are proven to improve clinical outcomes, there is a critical lack of surrogate markers which can be utilised in clinical trials.

Challenges for patients

These challenges are well-recognised by the patient population; and in a recent survey by PSC Support for patients and their families (n=636), nearly three-quarters of respondents felt that the emotional impact was one of the most difficult aspects of having PSC, largely as a result of uncertainty about what the future brings1. An excerpt taken from this report identified 79% of emotional impact responses related to the fact that “when a PSC patient is diagnosed, it is not possible to give a prognosis;” and that for patients “a clinically meaningful change means a biomarker directly associated with the disease process that has a convincing ability to predict (risk of) progression of disease35.

Developing biomarkers

Directly responding to this ‘research question,’ a number of studies are being undertaken to explore putative biomarkers, such as the VAPoR study.

However, VAPoR and most other studies remain hampered by lack of a prospective cohort of PSC patients, which would allow correlation between biomarkers and disease progression to be evaluated contemporaneously, with the added benefit of determining whether and how changing values over time impact the clinical course that patients experience.

Other stratification tools

Several other stratification tools have been evaluated in collaboration with UK PSC researchers, including the enhanced liver fibrosis (ELF) testTM, markers of extracellular turnover, and liver histology. Each of these has only been tested at a single point during the patient journey and may reflect disease that is already advanced.

We don't know how these biomarkers relate to changes in PSC over time

Moreover, their utility for identifying patients having early yet rapidly progressive PSC has yet to be evaluated; and none have been performed comparing the independent, interactive or additive properties to one another, neither the stability nor utility of changing values over time for individual patients. Discriminatory panels for identifying patients who develop bile duct cancer (cholangiocarcinoma) also appear to be distinct to those highlighted above.

PSC600 addresses the problem

PSC600 seeks to overcome some of these limitations, by moving from single point testing to serial sampling across a large, well-characterised population . We will also determine the relative independent and additive predictive value of a range of proposed biomarkers – for instance, sVAP1, ProC3, ProC5 and the ELF testTM and new biomarkers for cholangiocarcinoma. The prospectively accrued serum library will also provide an invaluable resource for prospective biomarker discovery (and validation) across multiple other platforms; including those that relate to immune cell function and migration, liver fibrosis, and proteomic / metabolic technologies that facilitate early cancer detection.

UK-PSC biobank

UK-PSC was set up in 2009 as a UK PSC genetics study with PSC Support funding. PSC Support is also part of the UK-PSC steering committee, demonstrating a commitment to patient collaboration.

UK-PSC became part of the NIHR Rare Disease Research collaboration in April 2015 and expanded its scope to include PSC patients of all ages.

Professor Douglas Thorburn (Royal Free Hospital, London) is Chair of UK-PSC and Dr Palak Trivedi (University of Birmingham) is Chief Investigator.

For information about UK-PSC and to register with the UK-PSC biobank if you are a patient, check out 'Give a Blood Sample'.

1 M. Walmsley, A. Leburgue, D. Thorburn, G. Hirschfield, P. Trivedi, Identifying research priorities in primary sclerosing cholangitis: Driving clinically meaningful change from the patients’ perspective, J. Hepatol. 70 (2019) e412–e413. doi:10.1016/S0618-8278(19)30812-6.

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