Skin Biopsy Specimens as Biomarkers of Systemic Sclerosis and Response to Mycophenolate Mofetil
Condition: Systemic Sclerosis
MeSH terms: Scleroderma, Systemic; Scleroderma, Diffuse; Sclerosis
Study type: Observational

Summary: 
      The purpose of this study is to assess whether skin biopsy specimens from patients with
      diffuse cutaneous systemic sclerosis (dcSSc) can be used as biomarkers (measures of activity
      and type) of disease to predict response to various experimental treatments. There are
      various experimental treatments being used in the treatment of slceroderma, but there is no
      way to predict response to any given therapy. The investigators will use DNA microarray to
      analyze the changes in gene expression in skin biopsies in response to various treatments.
      Our hypothesis is that the investigators will see changes in gene expression in response to
      various treatments that will give us insight into the cause of scleroderma. The investigators
      predict that they will be able to use this information to predict which experimental
      treatments will be beneficial to individual patients
    

Detailed description: 
      Systemic sclerosis (SSc) is an autoimmune connective tissue disease primarily affecting young
      to middle-aged women. The pathogenesis of SSc is complex involving interplay of three
      seemingly diverse processes: autoimmunity, vasculopathy, and fibrosis. Patients experience
      varying degrees of disabling skin thickening and potentially life-threatening internal organ
      fibrosis and vasculopathy, but there is no way to accurately predict disease subtype and risk
      for severity and progression. Current experimental treatments for SSc include oral and
      intravenous cyclophosphamide and mycophenolate mofetil that blunt the immune response,
      autologous stem cell transplant that may reset the immune system, and imatinib mesylate that
      may reduce fibrosis.

      Recent exciting genomics research from our lab and our collaborator suggests that skin biopsy
      samples obtained from patients with SSc have robust alterations in gene expression profiles
      compared to controls. Changes in expression of genes known to be involved in profibrotic
      pathways were prominent. The present proposal describes novel experiments to evaluate genomic
      approaches coupled with clinical data to identify patient subsets, predict response to
      treatment, and to better understand the molecular basis for disease pathogenesis, and
      treatment response.

      The Northwestern Scleroderma Program (NSP) is a novel multidisciplinary program to accelerate
      SSc research and provide comprehensive care to >400 SSc patients. Standardized clinical
      information including demographic, laboratory, and diagnostic data (echocardiography, high
      resolution chest computerized tomography, and pulmonary function testing) as well as DNA is
      currently collected on all patients and entered into a clinical database. NSP patients will
      be offered the option to donate dermal tissue for genomic analysis using a previously
      established, optimized approach to extract RNA from tissue samples.

      We hypothesize that our DNA microarray technique will permit analysis of changes in gene
      expression from the skin of patients undergoing dermal biopsies before and after treatment
      and will identify unrecognized profibrotic pathways in addition to providing new, important
      information regarding known fibrotic pathways. The knowledge gained will not only deepen our
      understanding of the molecular pathways involved in fibrosis, but also provide a means to
      reliably predict which patients are likely to respond to various treatments.

      Relevance:

      SSc is a devastating orphan connective tissue disease with no known cure. There are no
      disease biomarkers that can accurately predict disease subtype or risk for internal organ
      involvement and progression at present. Using well-established genomic techniques, the
      current proposal will investigate if changes in gene expression of profibrotic pathways in
      dermal biopsies before and after various treatments correlates with clinical response. If so,
      genonic analysis of dermal tissue may be useful to better understand the molecular
      pathogenesis of SSc and as a disease biomarker.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        patients with diffuse cutaneous systemic sclerosis
      
Biospecimen description: 
      skin biopsy samples
    
Keywords: systemic sclerosis; biomarkers; microarray