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A Systems medicine approach to chronic inflammatory disease

Periodic Reporting for period 2 - SYSCID (A Systems medicine approach to chronic inflammatory disease)

Reporting period: 2018-07-01 to 2019-12-31

Chronic inflammatory diseases (CIDs) comprise a group of incurable disorders of the immune system with a lifetime prevalence of over 10% in the EU and a globally rising incidence in countries adopting the Western industrialized lifestyle. CID are systemic disorders that differ in their main target organ(s), which include the gut (e.g. inflammatory bowel disease - IBD), skin (e.g. psoriasis), lung (e.g. bronchial asthma), vessels/kidney (e.g. systemic lupus erythematosus) and joints (e.g. rheumatoid arthritis). CID show extensive overlap in their genetic risk maps and environmental risk factors, suggesting the existence of a shared underlying disease mechanisms. The diseases usually manifest at a specific time window during adult life and are associated with a significant degree of long-term disability.
SYSCID constitutes an interdisciplinary consortium of researchers from nine European countries with expertise ranging from medical sciences, immunology, genomics, molecular biology, bioinformatics to even computer sciences. The SYSCID network aims to delineate a new molecular stratification for personalized medicine approaches to CID. The consortium focuses on 3 archetypal CIDs: inflammatory bowel disease, rheumatoid arthritis and systemic lupus erythematosus. Patient availability and pre-existing longitudinal multiple OMICs-datasets were the main criteria to select indications for the first level analysis.
SYSCID has set out to tackle several unmet clinical needs in CIDs:
• A clear diagnosis of disease: Current diagnostic methods are not sufficient to accurately predict early disease manifestation. Time from first symptoms to diagnosis of CID even in Western Europe still suffers from a diagnostic delay of 12-24 months. Diagnostic algorithms employing multimodal marker sets for early and unequivocal detection of disease are thus a major unmet need in CID.
• Disease progression and comorbidities: Early identification of patients with aggressive disease behavior or prediction of complications such as malignancies, are decisive elements for a future individualized clinical treatment. First results have demonstrated that an exhaustion signature of specific immune cells may predict complicated disease behavior across several CID.
• Therapy Response: Several different targeted therapies neutralizing specific factors of the immune system (so called “biologicals”, e.g. antibodies to TNF or IL6) have been approved. Such therapies are cost-intensive and suffer from significant primary and secondary non-response rates. So far on the individual patient level, a molecular rationale (biomarker) for employing a specific compound in an indication situation is missing. SYSCID will follow different layers of molecular information in individual patients over time in order to develop systems-based decision support to select the right therapy at the right time.
The consortium employs a variety of patient sample types derived from peripheral blood: whole blood and sorted blood immune cell types to single cell analysis. The project also comprises experimental strategies to develop epigenome editing therapies to reprogram specific cell types e.g. macrophage polarization defects.
The context and overall objectives remain unchanged in the 2nd reporting period.
Patient selection and sample ascertainment: Final selection of all patients and controls was conducted for the large scale experiments, which aim to develop predictive markers for (1) disease severity and outcome across CID (CAU: 1022 patients and 303 controls) and (2) response to targeted therapies (anti-TNF, anti-integrin, Anti-Blys) with >170 newly treated patients (CAU) with up to 8 timepoints for longitudinal multi-Omics analysis. Several additional cohorts (early arthritis prediction (UNIGE), disease liability in “healthy” control cohorts (ULG), purified subsets of cells from IBD, RA and SLE, (ULG, UCAM) have been extracted and are currently analyzed. Clinical data and scoring systems were harmonized between participating clinicians in the last reporting period. Pseudonomized data from the large cohorts and respective sample metadata have been transferred to central data management project.
Quality control and protocol harmonization: The production centers (USAAR, UNIGE, CAU, UCAM, ULG, UBO) have continued data production using the SOP-like protocols for cell purification, sample extraction, quality controls and molecular data generation. The consortium focused on (a) finalizing the longitudinal data sets for the therapy response cohorts and (b) implementing the production pipeline for single cell RNA analysis. The QC steps included comparative analyses between labs (e.g. single cell analyses at UBO and CAU, RNA at UNIGE and CAU, EPIC arrays at CAU and USAAR) and standardized documentation of RNA/DNA extraction quality.
Production: Using the harmonized production pipeline, molecular analysis on the major cohorts described above (cross-sectional and longitudinal therapy response cohorts) has been finalized. Integrative analysis has been started in the respective work packages. Several joined publications have resulted from the reporting period, e.g. on the association of metabolic properties of the intestinal microbiota with response to anti-TNF, which may pave the way for new predictive microbial markers for individualized therapy selection in IBD patients. Another publication identified the interplay of genetic and transcriptomal programs and disease course prediction in Systemic Lupus erythematosus. For the remaining analytical tasks, data analysis plans have been laid out and progress is monitored in regular discussions among the partners.
Outreach: The consortium has continued to present its aims and results on international conferences. It has further organized an outreach symposium at the UEGW. SYSCID remains an official partner of IHEC and organizes in 2020 the IHEC meeting in Kiel. SYSCID partners serves as a use case in the EU systems medicine initiative “STANDS4PM” for harmonizing data sets and predictive pharmacodynamic models.
SYSCID actively contributes to the development of precision medicine by identifying a new molecular taxonomy of CID. It aims to develop predictive markers and mechanistic insights for clinical decision support. Results from the 2nd reporting period have identified first microbial marker sets, which may be able predict the efficacy of anti-TNF therapy in IBD and RA patients. We will continue to perform integrative analysis on the available data sets in order to refine outcome and therapy predictor patterns. We will focus on the development of single-cell derived data sets to decipher the heterogeneity of diseases. Main driver of the analyses are the well-characterized patient cohorts with longitudinal molecular and clinical data, most of which are directly exported from electronic health records.
Ultimately, SYSCID will help to develop molecularly defined disease endotypes and dynamic models of therapy response that will enable efficient patient stratification for future care of CID patients
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