Exabis Library

To provide an overview of expanding treatment options in IBD
To provide expert opinion of how to navigate through the different therapeutic options in IBD

Educational objectives:
1. To review IBD-associated alterations in microbial composition and metabolite production, which contribute to regulation of intestinal inflammation
2. To discuss how these microbiome alterations may serve as future therapeutic targets for precision intervention

The management of inflammatory bowel disease (IBD) requires a personalized approach to manage a heterogeneous group of patients with variable disease courses. Precision care in IBD involves identifying patients at high risk for rapid progression to complications, selecting the most appropriate therapy for a given patient, predicting response to therapy and safety of drugs. Personalized medical decisions may allow specific therapeutic plans to draw on serologic, genetic, and microbial data to optimise treatment outcome.

The HLA-DQ polymorphism is likely to become important for patient stratification. Over 30% of patients with IBD have this polymorphism. Variants in the HLA-DQA1*05 allele are associated with greater likelihood of immunogenicity and this risk can be greatly reduced by use of a concomitant immunomodulator. Patients with high levels of a blood cytokine level, Oncostatin M, are also less likely to respond to anti‑TNF. Integrating multi-omics including faecal metagenomic, serum metabolomic and proteomic profiles can predict differential response to anti-cytokine or anti-integrin therapy. In predicting treatment safety, leukopenia-free survival is improved when genotyping for NUDT15 prior to therapy initiation with subsequent genotype-based dosing in a Japanese cohort.

Patients with a more diverse baseline microbiome and higher microbial diversity showed better response to anti-TNF agents, vedolizumab, and ustekinumab. Fewer mucus-colonising bacteria, a higher abundance of short-chain fatty acid-producing bacteria, and lower abundance of pro-inflammatory bacteria are also associated with a favourable outcome. The microbiome may also play a role in determining which patients can stop treatment once they are in deep remission. In the future, the combination of metabolomic, metataxonomic, or metagenomic profiling can further enhance precision medicine in IBD.

1. Overview about Precision medicine
2. Strategies to prevent disease complications: what is in the clinic already?
3. Data on precision medicine in IBD patienst aiming to prevent disease complications

Monitoring has become an essential component of up-to-date IBD patient care. Calprotectin and imaging (ultrasound, endoscopy, MRI) will be discussed as precision monitoring tools with their advantages and disadvantages. A practical algorithm for precision monitoring will be suggested.

The insufficient effects of current medical IBD therapies have led to the contention that therapeutic approaches can be improved by personalizing care using precision medicine.  This process entails an effort to combine clinical patient characteristics and mechanistic drug effects and align them with therapeutic outcomes, thereby providing biomarkers for selecting the appropriate drug for individual patients. Significant challenges for identification of response biomarkers include patient heterogeneity and the complexity of drug response mechanisms.

An analytic approach based on molecular correlation networks may allow to perturbate this complexity and provide necessary insights to employ this strategy.
We used the comparison of disease versus healthy immune landscape and immune system dynamics during therapy, combined with assessment of individual immune responses to approach this complex landscape.

Using this approach, we identified peripheral blood baseline expression of the cytoskeleton RAC/PAC pathway as a response biomarker for infliximab therapy, both in Crohn’s disease and Rheumatoid arthritis patients, thus identifying a patient-specific rather than disease-specific biomarker.
Notably, this pathway was also associated with the TREM adaptor (TYROBP/DAP12) downstream to TREM-1, which we previously found to be predictive for anti-TNF response. When tested in a control cohort of vedolizumab responsive patients, this biomarker was found to be infliximab-specific and responsive to therapy. Pathway expression was predominantly driven by intermediate monocytes.

Furthermore, identification of the RAC/PAC pathway as central to infliximab response, provides an additional potential mechanistic explanation for the documented synergistic effects of anti-TNF thiopurines combination, translating the findings into clinically relevant established observations.
Leveraging this approach may also allow for future discovery of other effective drug combinations and novel therapeutic compounds.  

1. To understand the therapeutic gap for which predictive biomarkers are needed. 
2. To review the current state-of-the art in IBD predictive precision medicine
3. To emphasise the main challenges in biomarker development 
4. To prioritise the key areas for research in biomarker development

A major challenge of future IBD patient care is the definition of actionable disease subphenotypes, e.g. to reliably predict disease progression and to provide a rationale for individual therapy selection. Although advances have been made in the description of genetic risk factors and formal pathophysiology (e.g. the description of inflammatory signal transduction), the diagnostic application of non-standard molecular markers in this setting is rather limited. Many studies have focused on investigating pre-selected sets of cellular or transcriptomic signatures at a single timepoint and thereby do not exploit the dynamic molecular changes that may explain individual disease trajectories.Thus, there is an urgent need for improved longitudinal biomarkers and clinical trial designs, which aim to translate such biomarker sets into actual clinical care . Future long-term strategies will likely include diagnostic features from different molecular ( i.e. omics-) layers. I will review selected pivotal molecular studies and aim to delineate promising clinical questions, which could be solved by collaborative efforts across Europe.   

1. To understand why predicting disease course is important
2. To understand the limitations of existing methods for doing this.
3. To recognise the importance of validating the predictive performance of potential biomarkers
4. To understand methods that are currently being investigated for biomarker development
5. To highlight the first biomarker-stratified trial in IBD (PROFILE) that will determine whether personalised therapy is deliverable from diagnosis