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.

British Society of Gastroenterology guidelines for the diagnosis and management of cholangiocarcinoma.

These guidelines for the diagnosis and management of cholangiocarcinoma (CCA) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included a multidisciplinary team of experts from various specialties involved in the management of CCA, as well as patient/public representatives from AMMF (the Cholangiocarcinoma Charity) and PSC Support. Quality of evidence is presented using the Appraisal of Guidelines for Research and Evaluation (AGREE II) format. The recommendations arising are to be used as guidance rather than as a strict protocol-based reference, as the management of patients with CCA is often complex and always requires individual patient-centred considerations.

Patient-reported quality of care in primary sclerosing cholangitis.

BACKGROUND: Management and follow-up strategies for primary sclerosing cholangitis (PSC) vary. The aim of the present study was to assess patient-reported quality of care to identify the most important areas for improvement. METHODS: Data were collected via an online survey hosted on the EU Survey platform in 11 languages between October 2021 and January 2022. Questions were asked about the disease, symptoms, treatment, investigations and quality of care. RESULTS: In total, 798 nontransplanted people with PSC from 33 countries responded. Eighty-six per cent of respondents reported having had at least one symptom. Twenty-four per cent had never undergone an elastography, and 8% had not had a colonoscopy. Nearly half (49%) had never undergone a bone density scan. Ursodeoxycholic acid (UDCA) was used in 90-93% in France, Netherlands and Germany, and 49-50% in the United Kingdom and Sweden. Itch was common (60%), and 50% of those had received any medication. Antihistamines were taken by 27%, cholestyramine by 21%, rifampicin by 13% and bezafibrate by 6.5%. Forty-one per cent had been offered participation in a clinical trial or research. The majority (91%) reported that they were confident with their care although half of the individuals reported the need for more information on disease prognosis and diet. CONCLUSION: Symptom burden in PSC is high, and the most important areas of improvement are disease monitoring with more widespread use of elastography, bone density scan and appropriate treatment for itch. Personalised prognostic information should be offered to all individuals with PSC and include information on how they can improve their health.

Quality of life (QoL) for people with primary sclerosing cholangitis (PSC): a pragmatic strategy for identifying relevant QoL issues for rare disease.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a rare incurable disease of the bile ducts and liver which can significantly impair quality of life (QoL). No existing QoL tools are entirely suitable for people living with PSC (PwPSC). We aimed to develop a measure of QoL for PwPSC in the UK, beginning by identifying relevant QoL issues. This paper describes our approach to this first stage, and discusses related benefits and limitations. METHODS: Scientific consensus on how to reliably stage PSC is lacking, due to its rarity and heterogeneity. We initially hypothesised four categories for PSC severity. After beginning the study, these were revised to six. For such a rare disease, the study could not recruit sufficient participants in each of these categories, particularly the more severe, in the time available. We therefore modified the design, adapting standard methodology for identifying potentially relevant issues. We started by conducting a thematic analysis of data from a previous survey of PwPSC, and extracting QoL issues from a literature review of QoL questionnaires of relevance to PwPSC. We then conducted group and individual interviews with PwPSC and clinicians, investigating the relevance, importance, phrasing, and breadth of coverage of issues identified. We also explored the validity of our hypothesised categories for disease severity. RESULTS: We identified 1,052 potentially relevant QoL issues from the survey and literature review and took 396 of these forwards for discussion with 28 PwPSC. We found 168/396 issues were considered relevant by ≥ 60% of these participants. We then discussed this subset of 168 issues with 11 clinicians. PSC and clinician participants identified some problematic phrasing with 19 issues, due to potential upset (n = 12) or problems with understanding (n = 7). We included one new issue from those suggested. CONCLUSION: We identified a range of QoL issues relevant to PwPSC, with a good breadth of coverage, although lacking an in-depth understanding of the PSC experience. Our strategy effectively identified relevant QoL issues for people living with this rare condition, for which there is no consensus on stratifying for its severity. This strategy should however be considered specific to such circumstances, not a general recommendation for an alternative approach.

Non-alcoholic fatty liver disease: A patient guideline.

This patient guideline is intended for all patients at risk of or living with non-alcoholic fatty liver disease (NAFLD). NAFLD is the most frequent chronic liver disease worldwide and comes with a high disease burden. Yet, there is a lot of unawareness. Furthermore, many aspects of the disease are still to be unravelled, which has an important impact on the information that is given (or not) to patients. Its management requires a close interaction between patients and their many healthcare providers. It is important for patients to develop a full understanding of NAFLD in order to enable them to take an active role in their disease management. This guide summarises the current knowledge relevant to NAFLD and its management. It has been developed by patients, patient representatives, clinicians and scientists and is based on current scientific recommendations, intended to support patients in making informed decisions.

Prevalence of COVID-19 in patients with autoimmune liver disease in Europe: A patient-oriented online survey.

BACKGROUND: During the current SARS-CoV-2 pandemic it is important to identify risk factors for COVID-19. Registry studies are providing growing evidence on the elevated risk of mortality from COVID-19 in patients with chronic liver disease, especially in advanced stages. Results may, however, have a selection bias towards severe cases. Limited data is available on COVID-19 in patients with autoimmune liver disease (AILD). AIM: To perform an online survey to capture the prevalence of COVID-19 and the state of medical care of patients with AILD in Europe during the pandemic. METHODS: Data was collected via an anonymous patient-oriented, online survey, which was available on the EUSurvey platform in nine European languages between 24th June 2020 and 14th October 2020. Of 1834 contributions, 51 were excluded because participants did not name an underlying AILD, and four were excluded because of duplicate data entry. RESULTS: Of 1,779 participants, 1,752 resided in 20 different countries of the European Union and the United Kingdom (UK). The five countries with the highest numbers of contributions were France (n = 450), Germany (n = 318), the Netherlands (n = 267), Spain (n = 225), and the UK (n = 183). 2.2% of participants (39/1779) had been diagnosed with COVID-19. There were no differences regarding age, sex, AILD, the status of liver cirrhosis, or status post liver transplantation between COVID-19 and non-COVID-19 cases. Of the 39 COVID-19 cases, five patients were admitted to a regular ward, one patient was admitted to ICU and required ventilation. CONCLUSION: In our Europe-wide, patient-oriented survey on COVID-19 in patients with AILD, we detected a low rate of COVID-19, comparable to the period prevalence of the general population. These results suggest that patients with AILD are not at elevated risk of COVID-19.

The Primary Sclerosing Cholangitis (PSC) Wellbeing Study: Understanding psychological distress in those living with PSC and those who support them.

INTRODUCTION: The impact of living with Primary Sclerosing Cholangitis (PSC) on psychological wellbeing is not well-known. A recent scoping review by the authors found that both depression and anxiety frequently featured in the accounts of those living with the illness. However, less clear were the factors that led to such psychological distress, the impact that the illness had on families and how to best support those living or supporting someone living with the illness. In light of this, the aim of this study was to explore how the illness impacted the lives of both those diagnosed with the illness and those supporting them. METHOD AND RESULTS: This study adopted a phenomenological approach to understand the subjective experiences of individual participants. A total of 30 individuals took part in Asynchronous Virtual Focus Groups hosted on a Virtual Learning Environment for a four-week period. Chronological narratives of individuals' lived experiences from diagnosis to post-transplant are presented below. These narratives centred upon individuals' and families' experiences of receiving a diagnosis, and adjusting to life post-diagnosis, particularly in regard to their relationships with health professionals and other family members, and in preparing for the possibility of transplant. DISCUSSION: The present article provides an in-depth look at how PSC can impact psychological wellbeing, how psychological distress arises and includes advice tailored to individuals, families and health professionals on how to best support each other.

Rare but heard: using asynchronous virtual focus groups, interviews and roundtable discussions to create a personalised psychological intervention for primary sclerosing cholangitis: a protocol.

INTRODUCTION: Primary sclerosing cholangitis (PSC) is a rare and chronic disease characterised by inflammation and fibrosis of the liver's bile ducts. There is no known cause or cure for the illness, which often progresses to end-stage liver disease requiring liver transplantation. Symptoms of PSC can be very burdensome on those living with the illness, leading to restrictions in daily living, as well as a greater risk of colorectal and biliary tract cancers. Limited voices from lived experience suggest that living with PSC can cause considerable psychological distress. This study, therefore, aims to explore how the illness impacts the psychological well-being of those living with the illness, and those supporting them. It also aims to create a personalised psychological intervention to support all groups. METHODS AND ANALYSIS: This project will take a layered qualitative approach to understanding the ways in which people experience living with PSC within their day-to-day lives. There will be two stages to this study, which will pilot a unique methodological process using online resources. The first stage will consist of asynchronous virtual focus groups (AVFGs) with those living with PSC and those who provide support for those diagnosed with PSC, and narrative interviews with both groups and health professionals. Both the AVFGs and the narrative interviews will be analysed using thematic narrative analysis. The second stage will comprise a roundtable discussion where the researchers and health professionals will devise a personalised psychological intervention to help to support those living with PSC and their supporters. The study duration is expected to be 18 months. ETHICS AND DISSEMINATION: The proposed study has been approved by the UK Health Research Authority and London-Queen Square Research Ethics Committee as application 18/LO/1075. Results from the AVFGs and the narrative interviews will be submitted for peer-reviewed publication. The findings of the study will also be presented nationally to PSC and medical communities, and a summary of the findings will be shared with participants.

British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis.

These guidelines on the management of primary sclerosing cholangitis (PSC) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included medical representatives from hepatology and gastroenterology groups as well as patient representatives from PSC Support. The guidelines aim to support general physicians, gastroenterologists and surgeons in managing adults with PSC or those presenting with similar cholangiopathies which may mimic PSC, such as IgG4 sclerosing cholangitis. It also acts as a reference for patients with PSC to help them understand their own management. Quality of evidence is presented using the AGREE II format. Guidance is meant to be used as a reference rather than for rigid protocol-based care as we understand that management of patients often requires individual patient-centred considerations.

Top research priorities in liver and gallbladder disorders in the UK.

OBJECTIVES: There is a mismatch between research questions considered important by patients, carers and healthcare professionals and the research performed in many fields of medicine. The non-alcohol-related liver and gallbladder disorders priority setting partnership was established to identify the top research priorities in the prevention, diagnostic and treatment of gallbladder disorders and liver disorders not covered by the James-Lind Alliance (JLA) alcohol-related liver disease priority setting partnership. DESIGN: The methods broadly followed the principles of the JLA guidebook. The one major deviation from the JLA methodology was the final step of identifying priorities: instead of prioritisation by group discussions at a consensus workshop involving stakeholders, the prioritisation was achieved by a modified Delphi consensus process. RESULTS: A total of 428 unique valid diagnostic or treatment research questions were identified. A literature review established that none of these questions were considered 'answered' that is, high-quality systematic reviews suggest that further research is not required on the topic. The Delphi panel achieved consensus (at least 80% Delphi panel members agreed) that a research question was a top research priority for six questions. Four additional research questions with highest proportion of Delphi panel members ranking the question as highly important were added to constitute the top 10 research priorities. CONCLUSIONS: A priority setting process involving patients, carers and healthcare professionals has been used to identify the top 10priority areas for research related to liver and gallbladder disorders. Basic, translational, clinical and public health research are required to address these uncertainties.

Factors Associated With Outcomes of Patients With Primary Sclerosing Cholangitis and Development and Validation of a Risk Scoring System.

We sought to identify factors that are predictive of liver transplantation or death in patients with primary sclerosing cholangitis (PSC), and to develop and validate a contemporaneous risk score for use in a real-world clinical setting. Analyzing data from 1,001 patients recruited to the UK-PSC research cohort, we evaluated clinical variables for their association with 2-year and 10-year outcome through Cox-proportional hazards and C-statistic analyses. We generated risk scores for short-term and long-term outcome prediction, validating their use in two independent cohorts totaling 451 patients. Thirty-six percent of the derivation cohort were transplanted or died over a cumulative follow-up of 7,904 years. Serum alkaline phosphatase of at least 2.4 × upper limit of normal at 1 year after diagnosis was predictive of 10-year outcome (hazard ratio [HR] = 3.05; C = 0.63; median transplant-free survival 63 versus 108 months; P < 0.0001), as was the presence of extrahepatic biliary disease (HR = 1.45; P = 0.01). We developed two risk scoring systems based on age, values of bilirubin, alkaline phosphatase, albumin, platelets, presence of extrahepatic biliary disease, and variceal hemorrhage, which predicted 2-year and 10-year outcomes with good discrimination (C statistic = 0.81 and 0.80, respectively). Both UK-PSC risk scores were well-validated in our external cohort and outperformed the Mayo Clinic and aspartate aminotransferase-to-platelet ratio index (APRI) scores (C statistic = 0.75 and 0.63, respectively). Although heterozygosity for the previously validated human leukocyte antigen (HLA)-DR*03:01 risk allele predicted increased risk of adverse outcome (HR = 1.33; P = 0.001), its addition did not improve the predictive accuracy of the UK-PSC risk scores. Conclusion: Our analyses, based on a detailed clinical evaluation of a large representative cohort of participants with PSC, furthers our understanding of clinical risk markers and reports the development and validation of a real-world scoring system to identify those patients most likely to die or require liver transplantation.

Primary Sclerosing Cholangitis and Psychological Wellbeing: A Scoping Review.

Primary sclerosing cholangitis (PSC) is a chronic liver disease resulting from the inflammation and scarring of an individual's hepatic bile ducts. With no curative treatment available and a risk of potentially severe complications and death, it is likely that those diagnosed with the illness may experience impairments in their psychological wellbeing. The aim of this scoping review is to locate, chart, and summarize all available literature on how PSC affects mental health and psychological wellbeing, as well as the factors that may or may not impact on the psychological wellbeing of those who have this diagnosis. This exercise identified five key themes within the literature: prevalence and characteristics of mental health problems, quality of life, unmet needs, medical treatment, and biomarkers. Three key recommendations for clinical practice emerge from this review.

The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines.

Primary biliary cholangitis (formerly known as primary biliary cirrhosis, PBC) is an autoimmune liver disease in which a cycle of immune mediated biliary epithelial cell injury, cholestasis and progressive fibrosis can culminate over time in an end-stage biliary cirrhosis. Both genetic and environmental influences are presumed relevant to disease initiation. PBC is most prevalent in women and those over the age of 50, but a spectrum of disease is recognised in adult patients globally; male sex, younger age at onset (<45) and advanced disease at presentation are baseline predictors of poorer outcome. As the disease is increasingly diagnosed through the combination of cholestatic serum liver tests and the presence of antimitochondrial antibodies, most presenting patients are not cirrhotic and the term cholangitis is more accurate. Disease course is frequently accompanied by symptoms that can be burdensome for patients, and management of patients with PBC must address, in a life-long manner, both disease progression and symptom burden. Licensed therapies include ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), alongside experimental new and re-purposed agents. Disease management focuses on initiation of UDCA for all patients and risk stratification based on baseline and on-treatment factors, including in particular the response to treatment. Those intolerant of treatment with UDCA or those with high-risk disease as evidenced by UDCA treatment failure (frequently reflected in trial and clinical practice as an alkaline phosphatase >1.67 × upper limit of normal and/or elevated bilirubin) should be considered for second-line therapy, of which OCA is the only currently licensed National Institute for Health and Care Excellence recommended agent. Follow-up of patients is life-long and must address treatment of the disease and management of associated symptoms.

Guidelines on the management of abnormal liver blood tests.

These updated guidelines on the management of abnormal liver blood tests have been commissioned by the Clinical Services and Standards Committee (CSSC) of the British Society of Gastroenterology (BSG) under the auspices of the liver section of the BSG. The original guidelines, which this document supersedes, were written in 2000 and have undergone extensive revision by members of the Guidelines Development Group (GDG). The GDG comprises representatives from patient/carer groups (British Liver Trust, Liver4life, PBC Foundation and PSC Support), elected members of the BSG liver section (including representatives from Scotland and Wales), British Association for the Study of the Liver (BASL), Specialist Advisory Committee in Clinical Biochemistry/Royal College of Pathology and Association for Clinical Biochemistry, British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN), Public Health England (implementation and screening), Royal College of General Practice, British Society of Gastrointestinal and Abdominal Radiologists (BSGAR) and Society of Acute Medicine. The quality of evidence and grading of recommendations was appraised using the AGREE II tool. These guidelines deal specifically with the management of abnormal liver blood tests in children and adults in both primary and secondary care under the following subheadings: (1) What constitutes an abnormal liver blood test? (2) What constitutes a standard liver blood test panel? (3) When should liver blood tests be checked? (4) Does the extent and duration of abnormal liver blood tests determine subsequent investigation? (5) Response to abnormal liver blood tests. They are not designed to deal with the management of the underlying liver disease.