Keen Eye Forms Original Research Program

 

 

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Rheumatologist Victoria Shanmugam, MD, began noticing something rather odd in her patients with autoimmune diseases — any open wound they had was very slow to heal. Their recovery was even more protracted than in patients with wounds who have diabetes, a disease that is notoriously damaging to blood vessels and to normal skin repair.

She saw a number of patients with such problems because they had been referred to her by the Center for Wound Healing at Georgetown University Hospital, which is known to offer the region’s most advanced wound care. Some of the patients being treated for their wounds had not known they also had an autoimmune disease, others were aware of the diagnosis, but were not being aggressively treated for the disorder. Shanmugam was intrigued. She did a quick study of people being seen at the wound care clinic over a 3-month period in 2009, and selected patients with open wounds — usually leg ulcers. Of those 340 patients, 49 percent had diabetes, which she says was typical. “But what was surprising is that 23 percent had an underlying autoimmune disease, and the connection between these disorders, which are rare, and wounds that don’t heal had not been recognized,” she says.

These non-healing wounds can be “incredibly emotionally draining and financially costly” because they require doctors visits over many months as well as an ever present risk of serious infections. Often they eventually require surgery with placement of skin grafts or use of skin substitutes, which may still not solve the problem.

So Shanmugam, who did her residency at Georgetown University School of Medicine in 2003, and who joined the attending faculty in 2007, combed through the scientific literature to see if there was a discussion that linked wound healing to a number of different autoimmune disorders, including rheumatoid arthritis, lupus, and scleroderma.

She found little. An Italian study had tested the use of erythropoietin, which stimulates production of blood cells, in fourteen patients with scleroderma, six of whom had complete healing of their ulcer and 8 had significant reduction in the wound surface area. All patients showed significant improvements in quality of life measures compared to baseline. However, the drug is not commonly used for this condition since the U.S. Food and Drug Administration issued a black box warning on erythropoietin because of safety concerns related to increased risk of cancer spread when it is used in patients with malignancy. It has been suggested that the reason for this might be that erythropoietin encourages new blood vessel formation.

Guessing that erythropoietin might have helped the scleroderma patients because it overcame possible abnormal blood vessel formation in these patients, Shanmugam began consulting Georgetown faculty including her mentor Virginia Steen, MD, a rheumatologist who has conducted extensive research in scleroderma, for their views. She talked with Christopher Attinger, MD, a plastic and reconstructive surgeon who is Chief of the Division of Wound Healing at Georgetown University Medical Center. And she went to see tumor biologist Anton Wellstein, MD, PhD, who is an expert on angiogenesis (growth of blood vessels) in cancer. Wellstein noted that one of the major complications of use of Avastin®, which inhibits angiogenesis in cancer patients, is impaired wound healing. Because of that, Avastin® also has a black box warning.

It was a bit of an “aha” moment, Shanmugam says. One drug that promotes blood vessel formation helps wound healing in autoimmune patients, and another that shuts down new blood vessel growth inhibits normal wound healing. “These two drugs show us that then when you modify this angiogenesis pathway, you have downstream wound healing effects, beneficial or not,” she says. With this insight, Wellstein helped Shanmugam put together a grant application to study angiogenesis molecular pathways in people with autoimmune disorders.

“We don’t have a good model to study this medical problem,” she says. “In order to develop a hypothesis, we need a molecular understanding of the mechanism in play, and the risk it poses to patients.”

With Attinger, Wellstein, and six other GUMC collaborators, Shanmugam also developed a novel biorepository, the Wound Etiology and Healing Study (WE-HEAL). The WE-HEAL study will collect wound fluid, tissue, and blood serum from consenting patients, in order to search for angiogenic and vasculogenic pathways that are dysregulated in people whose wounds don’t heal properly.

Her innovative investigation earned Shanmugam one of the first two KL2 Mentored Career Development Program Scholar grants from Georgetown-Howard Universities Center for Clinical & Translational Science. (The Center was established in 2010 and is funded by a Clinical and Translational Science Award from the National Institutes of Health.) The KL2 Scholarship funds junior faculty members starting translational research programs and Shanmugam says her work couldn’t be a better example of cross-collaboration between scientists and physicians. “We are taking a clinical observation and moving it into the lab in order to find the relevant biomolecular pathways. We hope that one day we will be able to manipulate these pathways, and then bring those findings back to the bedside.”

Shanmugam is preparing a scientific journal publication about her observations in the clinic, and she hopes that, eventually, the link she has made between autoimmune diseases and wound healing will make its way into the consciousness of the general practitioner. “If a doctor has a patient with a leg ulcer that won’t heal after three or four months and they have done all the appropriate treatments, I hope they will look for the presence of an autoimmune disorder,” she says. “Sometimes a non-healing wound can be the first presenting feature of an autoimmune disease, and unless they are properly evaluated patients will not receive the correct treatment.”

June is National Scleroderma Awareness Month

By Renee Twombly, GUMC Communications