“When you look at skin from lymphedema patients under the microscope, you see a dramatic increase in cell density and increase in connective tissues and fluid around the cells,” he said. “What we saw in skin biopsies after the four months of ketoprofen was a reduction in that thickness. All that cell density went away.”
Results showed that ketoprofen made the skin healthier and more elastic, Rockson said.
“Anecdotally, we also got the impression that the patients who were treated saw a dramatic decrease in infections, although this analysis wasn’t part of the study,” Rockson said.
After the four months, the patients in the second trial were “unblinded” and given the option to continue using the drug by prescription, Rockson said. All chose to continue taking the drug, including Hanson, who has now taken the ketoprofen for several years.
“Over time, the swelling has gone down,” she said. “It’s not a cure. It doesn’t make it go away, but it has been easier to take care of my leg.” She still wears the compression stockings, but they’re much easier to tug on, and the nightly pumping now takes just a fraction of the time it used to.
Hanson, like other participants in the trial, was warned by researchers that past studies have shown gastrointestinal and cardiovascular side effects from long-term use of ketoprofen in some patients, but she still decided to keep taking the drug.
“For me, the choice of being comfortable and not having so much burden in terms of care is a much greater benefit and outweighs the risk,” she said.
An inflammatory response
Just how ketoprofen was working at a molecular level, though, remained unclear early on. To further examine this while continuing his ketoprofen trials in humans, Rocksonjoined forces with Nicolls, whose lab had been studying the molecular pathways of inflammation in pulmonary hypertension.
“We were excited to finally figure out that the drug worked by blocking an inflammatory molecule called leukotriene B4,” said Nicolls referring to a study published in May 2017.
The researchers found that the buildup of lymph fluid is actually an inflammatory response within the tissue of the skin, not merely a “plumbing” problem within the lymphatic system, as previously thought. They discovered that the naturally occurring inflammatory molecule LTB4 is elevated in both animal models of lymphedema and in humans with the disease, and that at elevated levels it causes tissue inflammation and impaired lymphatic function.
Further research in mice showed that using ketoprofen to target LTB4 induced lymphatic repair and reversed the disease processes. This indicated that perhaps other therapies could reverse the negative impact of inflammation on lymphatic repair by targeting LTB4.
Other Stanford authors are postdoctoral scholars Wen “Amy” Tian, PhD, and Xinguo Jiang, PhD, who are also affiliated with the Veterans Affairs Palo Alto Health Care System; François Haddad, MD, clinical associate professor of cardiovascular medicine; Leslie Roche, RN, clinical research coordinator at the Stanford Center for Lymphatic and Venous Disorders; and Jinah Kim, MD, PhD, a dermatological pathologist.
Researchers at the University of Leuven in Belgium and Memorial Sloan Kettering Cancer Center in New York City also contributed to the study.
The study was funded by the Stanford endowment and startup funds.
Stanford’s Department of Medicine also supported the work.