Systemic sclerosis, also called scleroderma, progressive systemic sclerosis, or CREST syndrome, is a rare autoimmune connective tissue disease with fibrosis and vasculopathy. Patients often have sclerotic, thickened skin, but some experience significant organ damage. Immunosuppressive therapy is a common approach to patients with systemic sclerosis, but there is a subset of patients that do not respond well to treatment.A clinical trial was launched to determine the efficacy of myeloablative autologous hematopoietic stem cell transplantation versus cyclophosphamide infusion treatment. The other component of the study was to use a personalized medicine approach to identify the patients that have the greatest or least potential to respond favorably to stem cell transplantation.
The team of researchers at the Geisel School of Medicine at Dartmouth College analyzed gene expression data from peripheral blood mononuclear cells (PBMCs) of clinical trial participants with the goal to explore the gene expression changes that may be associated with positive treatment responses. Microarray analysis of PBMC gene expression at baseline and at 4 to 4.5 years was conducted. Patients were grouped by PBMC gene activity, then a machine learning algorithm was used to categorize the patients into gene expression subsets. This data was analyzed to determine how the subsets were predictive of event-free survival, a measure of treatment success.
Event-free survival for stem-cell treated patients did not differ for the subset designated as the normal-like subset (no active immune response) from that of the cyclophosphamide infusion treatment group. When the data for the fibroproliferative subset was analyzed, the patients that received stem cell transplants had better event-free survival when compared to those treated with cyclophosphamide. Interestingly, patients of the fibroproliferative subset tend not to respond well to immunosuppressive therapy.
Gene expression analysis of pre- and post-treatment PBMCs showed that patients that received stem cell transplantation had decreased expression of cell proliferation and immune response−related genes but an increase in expression of genes related to translation. There were also higher gene expression changes in these patients when compared to those treated with cyclophosphamide. This new information can help guide the development of effective personalized therapies for different groups of patients with systemic sclerosis.