Difficulty accurately assessing disease activity and prognosis are major challenges to clinical trials of SSc therapeutics. Although the Modified Rodnan Skin Score and Forced Vital Capacity have served as valuable tools for measuring the extent of skin and pulmonary disease, it would be valuable for clinical trials and management to find new measures that are more sensitive to change and that can detect changes in disease activity over shorter periods of time. A further major obstacle to conducting clinical trials in SSc is the highly variable progression of skin and lung fibrosis, compounded by continuing difficulties in identifying patients at risk for progressive disease. Microarray analysis of dermal gene expression has been shown to accurately separate normal from SSc skin. More recently we have found that both skin immunochemistry for myofibroblasts (a TGF-beta induced cell type) and a microarray detected TGF-beta gene signature correlate highly with clinical measures of skin fibrosis. These data support the notion that dermal gene expression might serve as a potent biomarker for assessing the efficacy of therapeutic interventions and that expression of an overlapping or non-overlapping set of genes might also serve to predict future disease progression. We propose to coordinate the large SSc patient population and SSc clinical trial experience of the Boston University Medical Center with the SSc microarray expertise of Dr. Whitfield's group at Dartmouth Medical Center to identify microarray biomarkers of SSc disease activity and progression.
The first aim will better define the utility of dermal gene expression as a biomarker of pulmonary and dermal fibrosis. Dermal microarray gene expression of patients in past and ongoing studies of cyclophosphamide and other therapeutics will be compared to currently used clinical measures of disease activity.
The second aim will seek to define a gene array profile that captures the likelihood of future skin and pulmonary disease. Using a prospective longitudinal cohort, dermal gene expression in SSc patients showing progression of skin or lung fibrosis will be compared to patients showing no progression of skin or lung disease. The minimal number of genes required for robust biomarker performance will be studied in each aim and alternative methodologies for measuring identified biomarker genes that might permit broader use in clinical trials, such as real-time PCR and immunohistochemistry, will be examined. ? ? ?
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