AF-Funded Researcher Discovers Scleroderma Gene Signatures
Results of a study -- funded in part by the Arthritis Foundation and published in PLoS ONE -- found distinct genetic profiles can discern different groups of patients with scleroderma. The scientists’ discovery of distinguishing molecular subtypes within the disease offers new insight into the complexity of a poorly understood and hard-to-treat illness and opens a window for better diagnosis and targeted therapies.
Patient complications are variable and hard to predict, explains Dr. Michael Whitfield, of Dartmouth Medical School, who headed the research team. "We show that we can divide the patients even more finely than what is currently done clinically, and found a clear association between disease severity and gene expression. "
"We show for the first time that we can classify patients with a systemic autoimmune disease into different groups by gene expression patterns alone," says Whitfield. "Now that we have discovered new subsets at the molecular level, we can begin to map the genetic pathways to see if we can we use these signatures to predict who will progress to different clinical endpoints." The researchers hope to begin to understand which patients should be treated aggressively, for example, and which drugs benefit which patients.
William Rigby, MD, a rheumatolgist who treats scleroderma, comments, "Since no one understands the basic processes that cause scleroderma, it has been largely categorized by the distribution of clinical findings, such as the location of skin thickening (torso relative to the hands). These studies, utilizing objective measures, establish that distinct genetic programs account for the ways this disease manifests itself and hold out the possibility for an improved ability to treat and induce remission of this potentially fatal disease," adds Rigby.
The new research is considered the largest scleroderma gene expression study to date. The investigators analyzed gene activity in 28 patients with varying types of scleroderma and six healthy control subjects, using skin biopsies from an arm and back.
The patients split into four major groups, each with a distinct gene profile. One group with severe disease had a proliferation signature, indicating dividing cells. An inflammatory group included several forms of the disease with a signature for T cells and other characteristics of inflammation. Another signature was limited to patients with more serious vascular and less skin involvement, while a fourth, normal-like group included healthy controls as well as patients diagnosed as having the more severe diffuse disease, and limited disease. The researchers also identified a gene signature that highly correlated with increased severity of skin disease.
The results, according to Whitfield, help tie together basic and clinical science for scleroderma and could potentially be used as an outcome measure in clinical trials. Studies are in progress, he adds, to help define response signatures for specific therapies and determine which drugs will work best for different patient profiles.
The article was adapted from a press release issued by Dartmouth Medical School.