The main aim of the project is to identify key-factors involved in the development and progression of Systemic Sclerosis (SSc), a chronic invalidating rheumatic disease characterized by high mortality and insufficient treatment options. A cohort of patients with SSc will be collected at the Sahlgrenska University Hospital in Gothenburg, Skaraborg Hospital in Skövde, and Södra Älvsborg Hospital in Borås (Sweden). Thanks to a holistic approach including integrated analysis of blood, and skin samples as well as DNA, and with the use of state-of-the-art methods, this project aims to identify factors (e.g. genes, proteins, metabolites, and immune cell types) associated with the development of SSc and with the progression to a more aggressive phenotype. Functional studies using in vitro model systems and patient specimens will be also implemented. The findings of the current project could lead to the identification of possible diagnostic and prognostic markers for the disease as well as potential drug targets. This cohort will be also linked to the European Scleroderma Trial and Research (EUSTAR), which is an international SSc research network aiming to coordinate research activities on SSc from groups all over Europe in order to improve treatment, quality of life and mortality of patients with SSc.
Participants diagnosed with SSc according to the ACR and EULAR classification criteria
Diagnosis of Mixed connective tissue disease
Not speaking or reading Swedish
With severe cognitive impairment
With blood count below specified limits
Data and samples from patients diagnosed with SSc from the Sahlgrenska University Hospital in Gothenburg, Skaraborg Hospital in Skövde, and Södra Älvsborg Hospital in Borås (Sweden) as well as from healthy controls will be collected. The cohort includes 65 participants with SSc and between 27 healthy controls. * Participants with SSc will be included if they fulfil the American College of Rheumatology (ACR)-European League Against Rheumatism (EULAR) criteria for systemic sclerosis, independently of the time of the diagnosis11. Participants with mixed connective tissue disease will not be included. * Healthy controls will not have diagnosis of systemic sclerosis or other rheumatic disease.
Case-control
Prospective
No Intervention: Observational Cohort
Other interventionno intervention
Predictors of disease activity and progression in plasma samples
Here we will analyse plasma circulating molecules (including but not limited to metabolites, cytokines, lipids, proteins, antibodies, exosomes etc) to identify factors involved in the pathogenesis of SSc by comparing those factors in plasma from subjects with SSc vs. healthy subjects. We also aim to identify factors involved in the prognosis of SSc by comparing circulating molecules in plasma from subjects with limited form SSc vs. diffuse form SSc. We plan to screen plasma samples from study participants for molecules that can be relevant for the pathogenesis and the prognosis of SSc.
Genetic markers of progression to an aggressive phenotype in subjects with SSc
all DNA samples from our cohort will be subjects to either next generation sequencing or GWAS as well as epigenetic studies. Single nucleotide polymorphisms of interest will also analysed in these specimens. Data will be analysed independently and/or merged with those of other large cohorts from all over Europe to identify genetic factors associated with the development of SSc as well as the prognosis and the response to treatment.
Characterisation of skin cells in relation to SSc pathogenesis and progression
Here we will study skin cells involved in the fibrotic processes in the skin, i.e. fibroblasts and keratinocytes, as well as skin immune cells. We aim to define factors that trigger the fibroblasts to switch to a pro-fibrotic phenotype and factors associated with the progression of the skin disease. Fibroblasts, keratinocytes and immune cells will be isolated and cultured from skin biopsies. Metabolomics, lipidomics, and proteomics will be performed on cell extracts. We will also perform functional studies. Single-cell RNA-Seq in skin biopsies will be performed.
Memory B cell compartment and prognosis of SSc
The overall aim of this WP is to identify how the memory B cell compartment (CD27dull and/or CD27bright memory B cells) are modulated in patients in the initial phase of SSc, therefore only subjects with onset of Raynaud's phenomenon \<5 years will be included, plus up 6 controls. We will determine this by flow cytometry and by immunoglobulin sequencing as well as RNA sequencing in patients during the initial phase of the disease with the goal to find prognostic markers during early disease.
PBMCs subsets and activation in the pathogenesis of SSc.
We aim to identify specific subsets of PBMCs associated with pathogenesis of SSc, especially T and B lymphocytes.
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Sahlgrenska University Hospital
Lead sponsor
Göteborg University
Sponsor institution
