Periodic Reporting for period 4 - IMCIS (Individualised medicine in chronic inflammatory skin diseases)
Okres sprawozdawczy: 2021-01-01 do 2021-10-31
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 substantially improves 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.
The ultimate goal of IMCIS is to improve patient´s quality of life and reduce socio-economical costs of inflammatory skin diseases (ncISD) 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.
IMCIS was successful and has achieved the following aims:
1. A cohort of more than 400 patients with several inflammatory skin diseases was built up. Of all patients, detailled clinical phenotyping and transcriptome data are uploaded to general databases. They build a unique data resource.
2. New disease ontology: We demonstrated that characterising patients with just a clinical diagnosis is insufficient - both to cluster patients according to the clinical phenotype as well as to explain the molecular variability in lesional skin. Thus, we need a more granular, ideally objective, way of describing ncISD patients (Lauffer at al, JID 2018; 1 under consideration, 1 in preparation).
3. Identifying molecular drivers of biologically relevant phenotypes: amongst ncISD, several biological processes are conserved, e.g. infiltration of neutrophil granulocytes or pathological broadening of the epidermis. These processes might occur within a given diagnosis, but might also be absent. We have developed a biocomputational pipeline to identify hidden molecular drivers of such processes within a heterogeneous dataset, the so-called AUGER approach (1 manuscript under consideration). Amongst others, AUGER has identified the transcription factor CEBPB a central for neutrophil biology. Further evaluations showed that the isoform Lip of CEBPB is associated with Th17 immunity and represents a promising therapeutic target (2 manuscripts in preparation).
4. Molecular diagnostics: Our first molecular classifier of NOS2 and CCL27 expression in lesional skin distinguishes Psoriasis from eczema. In a POC grant, we transferred this classifier to a medical device, a Point-of-care microfluidic disk System. The success of peLabDisk resulted in a award-winning start-up company, Dermagnostix (https://www.dermagnostix.com/). Through IMCIS, we have now established further classifiers, amongst them a classifier to distinguish venous ulcers from pyoderma gangrenosum or eraly lymphoma from eczema (2 manuscripts in preparation).
5. Prediction of natural course of disease: some ncISD patients experience a life-long severe inflammation, in others the clinical course is rather self-limited. Based on our approach, we identified clinical attributes as well as molecular markers that help to predict the natural clinical course of atopic dermatitis (Lauffer et al, Allergy 2021) as well a early response biomarkers to immunoadsorption therapy of atopic dermatitis (Thomas et al, J Invest Dermatol 2021).
6. Prediction of therapeutic outcome: Before IMCIS, there was no way to predict the therapeutic outcome at an individual patient´s level. As a proof of principle, 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 there is a high translational value in the mechanistic isnights (Seiringer et al, Acta DV 2020). Currently, we validate molecular classifiers to predict the therapeutic response to methotrexate or to IL-17 inhibitors, respectively (2 manuscripts in preparation).
IMCIS was successful and has achieved the following aims:
1. A cohort of more than 400 patients with several inflammatory skin diseases was built up. Of all patients, detailled clinical phenotyping and transcriptome data are uploaded to general databases. They build a unique data resource.
2. New disease ontology: We demonstrated that characterising patients with just a clinical diagnosis is insufficient - both to cluster patients according to the clinical phenotype as well as to explain the molecular variability in lesional skin. Thus, we need a more granular, ideally objective, way of describing ncISD patients (Lauffer at al, JID 2018; 1 under consideration, 1 in preparation).
3. Identifying molecular drivers of biologically relevant phenotypes: amongst ncISD, several biological processes are conserved, e.g. infiltration of neutrophil granulocytes or pathological broadening of the epidermis. These processes might occur within a given diagnosis, but might also be absent. We have developed a biocomputational pipeline to identify hidden molecular drivers of such processes within a heterogeneous dataset, the so-called AUGER approach (1 manuscript under consideration). Amongst others, AUGER has identified the transcription factor CEBPB a central for neutrophil biology. Further evaluations showed that the isoform Lip of CEBPB is associated with Th17 immunity and represents a promising therapeutic target (2 manuscripts in preparation).
4. Molecular diagnostics: Our first molecular classifier of NOS2 and CCL27 expression in lesional skin distinguishes Psoriasis from eczema. In a POC grant, we transferred this classifier to a medical device, a Point-of-care microfluidic disk System. The success of peLabDisk resulted in a award-winning start-up company, Dermagnostix (https://www.dermagnostix.com/). Through IMCIS, we have now established further classifiers, amongst them a classifier to distinguish venous ulcers from pyoderma gangrenosum or eraly lymphoma from eczema (2 manuscripts in preparation).
5. Prediction of natural course of disease: some ncISD patients experience a life-long severe inflammation, in others the clinical course is rather self-limited. Based on our approach, we identified clinical attributes as well as molecular markers that help to predict the natural clinical course of atopic dermatitis (Lauffer et al, Allergy 2021) as well a early response biomarkers to immunoadsorption therapy of atopic dermatitis (Thomas et al, J Invest Dermatol 2021).
6. Prediction of therapeutic outcome: Before IMCIS, there was no way to predict the therapeutic outcome at an individual patient´s level. As a proof of principle, 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 there is a high translational value in the mechanistic isnights (Seiringer et al, Acta DV 2020). Currently, we validate molecular classifiers to predict the therapeutic response to methotrexate or to IL-17 inhibitors, respectively (2 manuscripts in preparation).
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).
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).