Towards personalised treatment in Crohn’s disease: using proteomics at diagnosis to identify markers of treatment outcomes and disease trajectory, and new drug targets

Background and aims Despite the search for biomarkers to guide therapy in Crohn’s disease, many previous studies have been confounded by previous or concomitant drug treatments, environmental factors, disease activity, and - perhaps most importantly - disease duration. Indeed the dynamic nature of immune profiles in Crohn’s disease over time has long been recognised. One solution would be to study cohorts with large numbers of newly-diagnosed patients. Our proposed study, using serum from patients sampled at diagnosis as part of the PROFILE trial, provides a unique opportunity to interrogate the proteome in Crohn’s disease without many of the confounders that have hindered interpretability of previous studies, so gaining novel insights into markers of activity and outcome. Methods We will perform high-throughput proteomic profiling (Olink Explore HT) of serum samples from 386 newly-diagnosed, treatment-naïve patients with active inflammation recruited to the PROFILE trial. All baseline pre-treatment samples will undergo proteomic profiling on the new Olink Reveal platform. This uses proximity extension assay (PEA) technology combined with a next-generation sequencing (NGS) readout - highly sensitive over a 10-log dynamic range, enabling detection of both high and low abundance proteins. Anticipated impact PROFILE provided pivotal evidence for the benefits of early anti-TNF treatment. However, not all patients achieve durable inflammatory control despite early anti-TNF therapy. Furthermore, some patients follow a mild disease trajectory even without immunosuppressive therapy. Consequently, developing biomarkers that from diagnosis predict future disease trajectory and anti-TNF response remains an important area of unmet need. The proposed analysis will seek to: 1. Deliver biomarkers that facilitate personalised medicine by enabling selection of the optimal treatment strategy from diagnosis. 2. Further understand biological mechanisms of early inflammation in Crohn’s disease 3. Deliver pQTL results that help pinpoint causal genes in IBD GWAS studies 4. Help identify new drug targets for Crohn’s disease.