Finding Connections to Psoriasis
By Cliff Collins
Two researchers who received financial support from the National Psoriasis Foundation have made noteworthy discoveries this year in our understanding of psoriatic diseases.
The respective findings of scientists Nicole L. Ward, Ph.D., and Anne M. Bowcock, Ph.D., offer shining examples of how the Foundation's investments in research can yield significant advances.
Treating psoriasis reduces cardiac risk
Recently published research conducted by Ward and her colleagues at Case Western Reserve School of Medicine in Cleveland broke new ground on two fronts: It established that psoriasis can cause cardiovascular disease and also demonstrated that treating psoriasis helps reduce the risk of heart disease.
Researchers have been studying a connection between psoriasis and both heart disease and strokes for some time, but now they have found evidence that psoriasis, as an inflammatory skin disease,actually can lead to cardiovascular disease, and that aggressively treating psoriasis lowers cardiovascular risk.
This discovery represents a dramatic change in the way researchers will think about the disease connections, says Ward, an assistant professor of dermatology and neurosciences and senior author of the study. She is a scientist with the Murdough Family Center for Psoriasis at University Hospitals Case Medical Center in Cleveland and has a doctorate in anatomy and neurobiology.
Previously, epidemiologic evidence—that is, population studies—from thousands of patients provided strong evidence that people with psoriasis had a much greater-than-average chance of developing cardiovascular disease and dying from it.
Up until now, epidemiological studies have not been able to show that the skin disease directly promotes vascular inflammation or that it directly brings about outcomes related to heart attack and stroke, she says.
In their study, published in the Journal of Investigative Dermatology, Ward and her colleagues were able to do both. They found that mice engineered to over-express a protein called Tie2 in the skin develop a skin condition similar to human psoriasis. Using this model, they showed that persistent, chronic inflammation in the skin can result in inflammation in large arteries, such as the aorta of the heart.
Ward’s research also found that the presence of sustained skin inflammation causes blood clots to form much more quickly. “Importantly for patient care, we also demonstrated that if you aggressively treat the skin inflammation and reverse the skin disease, the effect on blood clot formation is also reversed.” This finding suggests that if you target psoriasis with aggressive treatment, patients’ risk for developing and dying of cardiovascular disease should also be decreased, she says.
Ward’s work closely complements that of Dr. Nehal N. Mehta, a preventive cardiologist now conducting his research at the National Institutes of Health in Bethesda, Md. (His study was described in the spring 2012 issue of Psoriasis Advance.) In fact, Ward and Mehta currently are collaborating to enable her Case Western research team to use Mehta’s methods with whole-body imaging to detect vascular inflammation.
Ward and her colleagues’ work examining the direct link between skin inflammation and large-vessel inflammation in the aorta was a direct result of work done by Mehta and colleague Dr. Joel M. Gelfand. They used sophisticated imaging technology to find inflammation in the liver, joints, tendons and aorta of patients with psoriasis, even though the study participants had no symptoms or apparent risk factors for diseases that affect those organs. The test subjects who didn’t have psoriasis did not show inflammation.
Ward credits the National Psoriasis Foundation for supporting this project “right from the start. We have received two $50,000 grants for this work, in 2009 and then again in 2010.” The grants funded her work to the point where she had enough data to apply for and receive a five-year, $2 million grant from the National Institutes of Health (NIH) to allow her to continue work on this project.
Ward will continue to focus her work on demonstrating definitively that skin inflammation—in the form of psoriasis—causes cardiovascular disease, specifically hardening of the arteries, inflamed blood vessels and the risk of blood clotting. Her team also wants to examine whether biologic drugs that reduce psoriasis in patients will prevent heart disease in genetically engineered mice.
Along with continuing this project, Ward also is planning a new study that will focus on the contributions of a molecule called IL-17C in the development of psoriasis. She will use funding from a third $50,000 Psoriasis Foundation Discovery Grant she received earlier this year.
Identifying the first gene linked to psoriasis
Dr. Anne Bowcock and her colleagues at Washington University School of Medicine in St. Louis have identified the first gene directly linked to the most common form of psoriasis, a discovery that may lead to more effective, targeted treatments for plaque psoriasis and other forms of the disease.
Bowcock believes that mutations in the gene, called CARD14, play an important role in the development of psoriasis and psoriatic arthritis. She will test this hypothesis by generating genetically altered mice that express the mutant gene.
Bowcock, professor of genetics, pediatrics and internal medicine, says her study so far shows that, when activated by some type of trigger in the environment, rare mutations in the CARD14 gene can lead to plaque psoriasis, the type characterized by dry, raised, red patches covered with silvery scales—patches that can be itchy and painful.
The discovery of the gene linked to plaque psoriasis is exciting, Bowcock says, because “it really starts to allow us to put together a pathway leading to psoriasis… We now want to understand that pathway better.”
Published in two separate papers in The American Journal of Human Genetics in May 2012, Bowcock’s research enhances understanding of the origin of psoriatic diseases, she says. The new findings also indicate that mutations in CARD14 can be involved in psoriatic arthritis and in some forms of the rare pustular form of psoriasis, which is characterized by clearly defined, raised bumps on the skin.
An 18-year quest
Eighteen years ago, Bowcock’s laboratory published the first research linking psoriasis and a region on chromosome 17, a project supported by what was then called the National Psoriasis Tissue Bank, created by the National Psoriasis Foundation. The tissue bank preceded the National Psoriasis Victor Henschel BioBank, established in 2007, which collects DNA samples for psoriasis research (see www.psoriasis.org/ biobank). At the time, Bowcock, who has a doctorate in human genetics, was the tissue bank’s laboratory director.
The researchers in the project found a family in Kentucky with more than 20 members who had either psoriasis or psoriasis with psoriatic arthritis. “Our research indicated that a single gene could be mutated in this family and lead to these diseases,” she says. “The gene that we found recently that is mutated in this family, and other rare mutations that we have found, confer a high risk for the disease, and we think they will be important in the search to find new, more effective treatments.”
This research also suggests that these mutations may be present in at least some patients with different forms of psoriasis. In a separate case, Bowcock and her colleagues identified a mutation in the CARD14 gene in a young Haitian girl who had a severe form of pustular psoriasis. This mutation was not in her parents, so her psoriasis apparently had developed spontaneously and was not inherited. She had developed psoriasis in infancy.
“Our discoveries with this patient and the families with psoriasis used to identify CARD14 are significant because they tell us that CARD14 mutations alone are enough to lead to psoriasis, possibly after an early trigger such as an infection,” Bowcock says.
In their research, Bowcock and her colleagues obtained and examined DNA samples from about 10,000 patients, made available through the National Psoriasis Victor Henschel BioBank, as well as DNA samples from collaborators in Michigan, Utah, California, Toronto and Newfoundland.
The researchers also found 15 other rare mutations in CARD14. In a finding that Bowcock says is statistically significant, these mutations occurred more often in 6,000 patients with psoriasis than they did in 4,000 people who did not have the disease.
How CARD14 mutations spark psoriasis
Here’s how Bowcock and her colleagues believe that mutations in CARD14 are linked to psoriasis. Their research showed that, in specialized skin cells called keratinocytes, mutations in CARD14 increase the activity of a protein that turns on genes. This protein increases the production of certain molecules that attract inflammatory cells to the skin. This process unleashes the vicious cycle of inflammation that’s seen in psoriasis.
Psoriasis affects the life cycle of skin cells, causing them to mature rapidly in just a few days and accumulate to form thick, scaly patches. In patients with CARD14 mutations, the study showed that the gene’s activity increased in the skin’s upper layers, where the flakiness that characterizes psoriasis appears.
Bowcock says the discovery of the gene linked to plaque psoriasis suggests promise for the next step: finding effective treatments and, the scientists hope, a pathway to a cure. She is excited by the discovery because “it really starts to allow us to put together a pathway leading to psoriasis, going directly from triggers in the skin, to the immune cell, and then back to the skin. We now want to understand this pathway better.”
Bowcock says she wants to start screening for novel drugs that disrupt this pathway. With funds from a two-year, $200,000 Psoriasis Foundation Translational Grant she received earlier this year, she plans to use a mouse with an altered CARD14 gene that will potentially develop psoriasis and psoriatic arthritis. The researchers would then be able to test these novel drugs as possible treatments for psoriatic diseases.
Cliff Collins is a Portland, Ore.-based freelance writer and a regular contributor
to Psoriasis Advance.