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A Systems medicine approach to chronic inflammatory disease

Periodic Reporting for period 3 - SYSCID (A Systems medicine approach to chronic inflammatory disease)

Reporting period: 2020-01-01 to 2021-06-30

SYSCID constitutes an interdisciplinary consortium of researchers from 9 European countries with expertise ranging from medical sciences, immunology, genomics, molecular biology, bioinformatics to even computer sciences. The consortium aims to deliver first insights into personalized medicine approaches to chronic inflammatory diseases (CIDs). 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. CIDs show extensive overlap in their genetic risk maps and environmental risk factors, suggesting the existence of a shared underlying disease mechanisms.
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 tackles 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 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. Clinical trajectories with high heterogeneity and activation of signal transduction pathways of CIDs share significant similarities with impaired immune responses in a severe SARS-CoV2 infection. Therefore and in response to the pandemic situation evolving in the past reporting period, researchers in SYSCID have contributed to molecular knowledge generation around COVID-19 as a potentially devastating disease.
Patient selection and sample ascertainment: Final selection of all patients and controls had been conducted until early 2020, only few molecular data sets had to be generated at that point. Main task was the bioinformatic analysis and validation of the planned 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. Due to lab closures and lockdown this analysis was slowed down, but is expected to be finalized until the end of the project. 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) are also under final analysis. Clinical data and scoring systems were harmonized between participating clinicians in the last reporting period. Pseudonomized data from the large cohorts, respective sample metadata and analysis results are continously transferred to central data management project. SYSCID researchers used the time of the lockdown/restrictions in 2020 to significantly contribute to COVID-19 research, as lab/computational work on SARS-COV-2 infections was still allowed by most institutions. The respective work outputs thus acknowledge SYSCID in the respective sections and emphasize the impact of SYSCID as a consortium that has flexibly and signficantly reacted to the pandemic threat.
Data production and analyses: Using the harmonized production pipeline, molecular analysis on most cohorts described above (cross-sectional and longitudinal therapy response cohorts, additional cohorts from Greece, Switzerland, UK and Belgium) has been finalized, only few microbiome data sets were not finished due to the pandemic restrictions, but are about to be released. Integrative analysis is well under way. Several joined publications have resulted from the reporting period, e.g. on the longitudinal analysis of IL-6 transsignalling inhibition and therapy response, which may pave the way for a new individualized therapy in IBD patients. Additional publications focused on impaired inflammatory responses in COVID-19 using tools developed for SYSCID analyses, e.g. on single cell signatures. 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 is important to recognize that in 2020 many of the original conferences were cancelled. SYSCID remains an official partner of IHEC and organizes in 2022 the IHEC meeting in Kiel. SYSCID partners serve as a use case in the EU systems medicine initiative “STANDS4PM” for harmonizing data sets and predictive pharmacodynamic models.
SYSCID continues to actively contribute to the development of precision medicine by identifying a new molecular taxonomy of CID. The project is now at its apex and develops predictive markers and mechanistic insights for clinical decision support. Results from this period have identified first integrated molecular signatures, which may be able predict the efficacy of anti-TNF therapy in IBD SLE and RA patients. We have used the time of lockdown/restrictions on lab work to generate significant knowledge on molecular processes involved in the pathogenesis of COVID-19. This was only possible as tools and methods had been already in place in SYSCID. Despite the delay from COVID-19 we will now finalize our integrative analyses on CID in order to refine outcome and therapy predictor patterns. Our work thrives from the well-characterized patient cohorts with longitudinal molecular and clinical data, most of which are directly exported from electronic health records.
In the remaining months, we will focus on 1) finishing cross-sectional analyses, 2) finalizing ongoing single-cell related work and 3) work on longitudinal stability of obtained signatures.
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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