Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - IMCIS (Individualised medicine in chronic inflammatory skin diseases)

Teaser

More than 100 million EU citizens suffer from chronic inflammatory skin diseases such as psoriasis and atopic eczema (AE). The diseases imply a devastating life quality similar to that of cancer, and cause direct socio-economic costs in the magnitude of 100 billion Euro each...

Summary

More than 100 million EU citizens suffer from chronic inflammatory skin diseases such as psoriasis and atopic eczema (AE). The diseases imply a devastating life quality similar to that of cancer, and cause direct socio-economic costs in the magnitude of 100 billion Euro each year in the EU. Despite all efforts, psoriasis and AE remain undertreated and the concept of individualised (also called precision) medicine could not be established in the field. Consequently, intensified research is demanded by organisations such as the WHO. Unmet medical needs are 1) a diagnostic gap, 2) lack of prediction possibilities to define the optimal therapy for an individual patient, and 3) a substantial number of non-responders to therapies. Reasons for these shortcomings are the heterogeneity of both psoriasis and AE and insufficient collaboration of clinical specialists, basic researchers, and bio-informaticians. This proposal aims at improving health care of inflammatory skin diseases by implying the concept of individualised medicine. The crucial step towards this goal is the ground-breaking idea to link deep clinical phenotyping to molecular signatures in lesional skin. Deep phenotyping means each patient is characterised by 100 clinical, histological, and laboratory attributes rather than the imprecise state-of-the art approach of rough diagnosing. Each attribute gets assigned to molecular events in lesional skin. Gene regions as well as key pathogenic molecules are identified in a novel gene network of inflamed skin. Candidate targets get validated using state-of-the-art cell culture systems and full skin models. This innovative and ambitious approach will substantially improve our knowledge of the pathogenesis and primary triggers of both psoriasis and AE, safe European health care systems direct costs, and have a model character for complex diseases in general.

Work performed

The ultimate goal of IMCIS is to improve patient´s quality of life and reduce socio-economical costs of inflammatory skin diseases by implementing the concept of individualised Medicine. That includes 1) identification of biomarkers predicting clinical Outcome or risk for comorbidities; 2) assessment of novel therapeutics; and 3) molecular diagnostics in the field.
In the first 2,5 years since the start of IMCIS, we achieved the following aims:
1. Preparations of the the main publication: the main Outcome of IMCIS links Deep clinical phenotyping and transcriptomics and is expected for Q4 2019. In the first period of IMCIS, we have established a clinical database as well as the biobank Biederstein with currently 800 patients with inflammatory Skin diseases; performed high Resolution RNA sequencing of lesional and nonlesional Skin; developed a script to Analyse which genes contribute to a given Attribute and vice versa; and established Validation Methods in the lab, including three-dimensional Skin equivalents, viral transfection, and short-term full Skin culture.
2. A Major Achievement of IMCIS so far is the contribution to a new disease ontology at inflammatory Skin diseases. Rather than the historically descriptive classification, we Need a molecular-driven one to take Benefit from recent specific therapeutics. We have shown that one hallmark of several inflammatory and autoimmune Skin diseases, the so-called interface Dermatitis, is caused by type 1 lymphocytes that induce keratinocyte necroptosis (Lauffer et al, JID 2018). These type I immune cells can be targeted e.g. by JAK Inhibitors. Thus, Skin diseases with interface Dermatitis as hallmark should be grouped and treated similarly. A simplified, but comprehensive proposal for a molecular disease ontology was published by the PI in 2018 (Eyerich et al, JEAD 2018).
3. Several novel therapeutic compounds have been investigated using the preclinical Pipeline of IMCIS, publications are in preparation or in Revision.
4. With the molecular classifier of NOS2 and CCL27 that distinguishes Psoriasis from eczema a first easy-to-handle molecular diagnostics is available. In a POC grant, we are currently transferring this classifier to a medical device, a Point-of-care microfluidic disk System that automatically fulfills the Analysis required from lesional Skin samples. This medical device will be transferred to a start-up (Dermagnostix) that is to be founded in Q2 2019. Through IMCIS, we have now established a second small-size classifier to distinguish early lymphoma from eczema, a manuscript is in preparation.

Final results

Our so far published studies confirm it is possible and demanding to revise the disease ontology of inflammatory Skin diseases towards a molecular- and pathogenesis-driven classification. This is important, because therapeutic developments are enormous, but address only a minority of the individual diagnoses within inflammatory Skin diseases. A revised classification would allow most patients Access to specific and highly effective Treatments.
By the end of the Project, we aim at redefining inflammatory Skin diseases at a much higher Level. IMCIS has the potential to identify biomarkers predicting the individual clinical Course of the disease, the Risk to develop comorbidities, and to predict the most suitable therapy. By now, we have already proven that molecular diagnostics in inflammatory Skin diseases is feasible. We are currently working at a Point-of-care medical device to Transfer our first molecular classifier into daily clinical use, a Project that Comes from IMCIS and is further supported by an ERC POC grant (pe-LabDisk, 2017).