WS1 aims to establish the UK-AILD cohort; collect biosamples; undertake comprehensive phenotyping using the WS1 platforms, and deliver data to WS2 for integrated statistical analysis. Given their linked nature, WS1 and WS2 are described together. Of note, the patient-facing core of WS1 will capitalise on the unique infrastructure and experience that we have acquired during the development and delivery of individual autoimmune liver disease (AILD) cohorts: UK-PBC, UK-AIH and UK-PSC. This infrastructure and experience will substantially reduce the risk associated with any programme reliant on cohort development.

To establish the UK-AILD cohort, we will utilize the existing research infrastructure established as part of the MRC-funded UK-PBC Nested Cohort Study, which has been highly successful at recruiting patients into a detailed phenotyping programme that includes liver biopsy. A total of 600 incident, treatment-naïve patients with AILD will be recruited from 35 hospitals across seven regions of England into three approximately equal groups:

  • ‘PBC-spectrum’: defined by the presence of elevated ALP ± GGT and PBC-specific autoantibodies or florid duct lesion on liver histology. This group will encompass ‘pure’ PBC and PBC with AIH-like features;
  • ‘AIH-spectrum’: defined by the presence of lymphoplasmacytic interface hepatitis and disproportionate elevation of the IgG and serum transaminases in the absence of potential viral or drug-related causes;
  • ‘PSC-spectrum’: defined by the presence of stricturing intra ± extra-hepatic cholangiopathy in the absence of biliary obstruction. This group will encompass ‘pure’ PSC and PSC with AIH-like features.

Participants in the cohort will attend a single Research Visit at one of seven Research Centres, each recruiting from a region containing on average five Participant Identification Centres (PICs). All are active collaborating centres in UK-PBC, UK-AIH and UK-PSC. The Research Visit will take place before the participant starts conventional disease-modifying therapy. At the Research Visit, each participant will undergo full clinical evaluation (including symptom impact and quality of life assessment); complete a questionnaire designed to explore his or her exposome; undergo anthropomorphic measurements; provide blood, urine and stool samples, and undergo a FibroScan® and abdominal ultrasound scan. All participants in the AIH group will undergo a pre-treatment liver biopsy as part of standard clinical care. Participants in the PBC and PSC groups will be selected for liver biopsy if they have features of high risk disease or AIH overlap. Twelve months after the Research Visit, each participant’s clinical care team will complete a brief Case Record Form providing up-to-date clinical information.

Research samples will be processed by local research staff according to SOPs developed and validated by the respective WS1 platforms.

Discovery and validation panels for each WS1 platform will be derived from the UK-AILD cohort. Of critical importance, recruitment, sampling and sample selection for analysis will be centrally coordinated to ensure that for each platform, the discovery and validation panels are enriched for participants who fulfil the current European Association for the Study of the Liver (EASL) definitions of PBC/AIH overlap or PSC/AIH overlap, respectively (EASL 2009, 2015 & 2017). The discovery and validation panels of each platform will therefore contain participants with PBC, AIH, PSC, PBC/AIH overlap or PSC/AIH overlap, as well as those with mixed features that fall short of current EASL definitions of overlap. In this way, the entire spectrum of AILD will be represented in analysis. This approach will also allow any newly defined molecular taxonomy of AILD or its underlying biological drivers (e.g. drivers of autoimmune, cholestatic or fibrotic liver injury) to be linked to the conventional clinical classification.

The WS1 phenotyping platforms are as follows:

  • Cytometry by Time-Of-Flight (CyTOF) for immunophenotyping of PBMCs (Oo, University of Birmingham);
  • scRNAseq for transcriptional profiling of PBMCs and disaggregated liver cells (Teichmann, WTSI);
  • NMR and UPLC-MS for metabolic phenotyping of biofluids and desorptive electrospray ionisation mass spectrometric imaging (DESI) for in situ liver tissue characterisation (Holmes, Imperial College, London);
  • 16S rRNA gene profiling for mapping the gut microbiome (Marchesi, Imperial College, London);
  • Proteomic profiling of liver extracellular matrix and micro-dissected areas of liver fibrosis (Pinzani, University College London).