Skin Disorders: A Yale Dermatologist Looks to Science for Answers

Keith Choate, MD, PhD, looks at the skin through the lens of science. This means that when he is caring for a patient who has been struggling with a debilitating skin condition, and who may be losing hope after years of misdiagnoses, discomfort, and ineffective treatments, he takes a deeper approach to the problem. He looks below the surface—sometimes at the body’s genes and cells—with the goal of identifying the cause of the condition and determining the safest, most effective treatment.

People don’t always think of skin diseases as going deeper than the rash, discoloration, blistering, or itchy bumps that can be seen on the surface. But often, closer scrutiny is needed. This may mean taking all available information to a laboratory and doing research to learn more, and maybe even identify an underlying disease or genetic cause, he says.

“We frequently are the last stop on a patient’s search for answers,” says Dr. Choate, who is chair of Dermatology for Yale Medicine, and a professor of dermatology, genetics, and pathology for Yale School of Medicine (YSM). “Most of our patients have already seen three or four other doctors, and everything they’ve tried has failed. So, we try to think differently—and in thinking differently about the biology behind the disease, we often can make a patient better.”

As many as 84.5 million Americans are affected by skin diseases, from common but potentially disfiguring conditions such as acne, to melanoma, the most serious skin cancer.

In addition to leading Yale’s dermatology department, Dr. Choate is a pioneer and collaborator in several groundbreaking discoveries and treatments. His work in the laboratory has led to the identification of genetic defects in more than 18 rare skin disorders, and he is internationally known for his research on ichthyosis, a potentially disfiguring disease that causes dry, scaly, or thickened skin, and sometimes affects other organs and even the entire body.

He is known as a doctor who takes on especially complicated cases. “These are essentially conditions that are unknown, undescribed, and difficult to treat,” he says. But often there are solutions, he adds.

We spoke with Dr. Choate about his work, and how combining science and dermatology can help with finding solutions.

It’s true that patients who haven’t found solutions to their illnesses come through our doors, and I think all of us on the Yale School of Medicine faculty would like to be that person who approaches a problem with a unique way of thinking.

But the reality is that this work can’t always be done by a single provider; when you have a difficult case, it’s better to have a doctor working in the context of an academic medical center with a variety of specialists, a place that gives them the tools they need to work together toward a treatment. So, I would say that we at Yale are an institution full of “Houses.” We want patients to come here because this is a place where many individual specialists have answers. And when one of our specialists doesn’t, collectively, I think we often do.

And Yale Medicine Dermatology sees everyone—not just the undiagnosed or misdiagnosed patients. We care for people who have poison ivy and people who have a mole that may be changing, or eczema that’s scaly and itchy and interfering with sleep. We treat everyone in the community and provide the highest level of care. That’s not so much about medical mysteries as it is about matching people to the right therapeutics.

I entered dermatology with the idea that I wanted to treat patients with severe systemic diseases, and I did it in the early 2000s. Patients had been treated for decades with drugs that didn’t always work well, including remedies that damaged their DNA, causing a host of adverse side effects. At the time, a molecular revolution was underway with translational scientists giving us new insight into disease pathogenesis. As I began my clinical practice, the first generation of molecular therapies that precisely targeted disease-specific inflammation was being used, and we were seeing complete responses in patients with previously intractable diseases.

At the same time, through my work with a patient support organization, The Foundation for Ichthyosis and Related Skin Types, I also realized that there were many patients with genetic diseases who remained undiagnosed and for whom we had few therapeutic options. Yale was leading the development and application of approaches to sequencing DNA, which would unlock our capacity to gain a new understanding of the genetic basis of disease, and has helped our group to identify multiple new genetic causes of rare and common disease. These genetic insights have helped us, in many cases, to choose better therapies or to develop completely new ones.

Since then, we've come to recognize that a large fraction of disorders have genetic underpinnings, and in cases of skin disease, it's incredibly easy to see how genetic events affect the body. They are the basis of the moles we find on our skin and of other growths and cancers that can develop over time.

Today, we can use relatively simple technologies to rapidly identify new pathways underlying disease, which can inform new approaches to treatment. We tell many patients with complex dermatologic symptoms, "Not only are we going to give you a clinical diagnosis, but we're also going to try to understand the ‘why’ of your disease. If you are interested in participating in research, a DNA or skin sample can give us new information that might ultimately be relevant to both treating you now and making you eligible to be a part of potential clinical trials and basic science investigations about the disease."

Psoriasis may be the cardinal example of a common disease for which we now have therapies. Psoriasis occurs when an overactive immune system speeds up the growth of skin cells, causing itchy, burning plaques and scales on the skin. My dad dealt with it for decades, and I still remember hearing the sun lamp treatment he used every night. Around 11:30 p.m., I'd hear this “tick, tick, tick, tick, ding.” He was terribly affected for decades by the disease and psoriatic arthritis, which is related.

When I began my training, we were still treating psoriasis with broad immunosuppressive therapies like methotrexate, which can have significant side effects, ranging from increased risk of infection to changes in blood counts or hair loss, among others. It was translational research studies that enabled the development of highly targeted biologic agents—drugs that act like molecular heat-seeking missiles, which block certain cells and proteins that cause psoriasis with minimal risk to the patient. These drugs have transformative results, not only on the skin disease but also on the related arthritis.

In terms of rare diseases, one of the biggest examples is Olmstead syndrome, a rare congenital [present at birth] disorder that causes extreme thickening of the skin on the palms, soles of the feet, and other parts of the body. It can be both painful and disfiguring.

We had an undiagnosed patient who was requesting amputation because of this kind of disfigurement and pain, and I told my colleague, “‘We should figure out her genetics, because if she happens to have a mutation that causes Olmstead syndrome, treatment with an epidermal growth factor receptor [EGFR] inhibitor is going to dramatically improve her disease.” We found that she did have Olmstead syndrome, and we prescribed an EGFR inhibitor called erlotinib, a type of cancer cell growth blocker, and it led to such complete alleviation of her pain and symptoms that she started running again.

These are the moments that are so exciting. You can identify patients who might benefit from different treatments early in the course of their disease and prevent a lifetime of confusion and suffering.

Our work is always centered on our patients. When a patient walks into the room, they are coming with a problem, with a skin disease that tends to be visible. It has a significant impact on quality of life and can be associated with a significant amount of shame. We realize that from the moment we walk into the room, the most important thing we can do is gain the trust of the patient. We sit down, listen to their story—what treatments have worked and what haven’t—and get a sense of whether they are willing to try something new.

It's always a conversation about risks and benefits. I always think, "If you were a member of my family, what would I want to say to you?" Seeing it that way can give us a certain degree of clarity about what we need to do next.

Sometimes the conversations are simple and we're saying, "We've got the right drug, it’s low risk, let's get going." And sometimes there are hard decisions about therapies with side effects and risks that can be managed so we can improve the disease.

What is important is that we can provide patients with information and data regarding their situation. In dermatology, we also have so many tools at our fingertips now that it's relatively rare for us not to be able to make a significant difference in the life of a patient. Sometimes, we will recommend treatments that are experimental or off-label [not approved by the Food and Drug Administration (FDA) for the condition it’s being recommended for] to really push things forward. But in the great majority of cases, there are simple treatments that can make a huge difference.

Our lab has a major focus on ichthyosis, a lifelong condition that causes symptoms from itchy, dry skin to problems with eyesight and hearing. We created one of the largest international registries of individuals with this group of disorders, which has helped us to create a resource of patient data and to connect patients with researchers and clinical trials. As a part of this work, I and others from my lab attend patient support meetings and hold pop-up clinics around the country that are incredibly powerful because, often, they offer the first opportunity for patients to meet doctors who are experts in their disease.

The other class of disorders that we study in the laboratory are mosaic disorders, which typically arise during fetal development. These are disorders that involve two or more genetically different populations of cells existing side by side within the skin, and they appear on the surface as birthmarks, color changes, or other abnormalities.

We identified the genetic basis of a mosaic disorder called linear porokeratosis, characterized by raised bumps on the skin that can become scaly. We found that patients with this condition have a mutation in a gene that is key in cholesterol biosynthesis [the process by which the body produces cholesterol], and with that knowledge, we were able to create a simple topical therapy—a cholesterol-lovastatin combination. We then used the treatment for a related disorder called disseminated superficial actinic porokeratosis, which affects a larger population of patients who have been treated with myriad therapies with no success. But with this treatment, we can cure them, so it is now commonly used in clinical practice.

I believe medicine is a calling. It’s an incredible privilege to have the opportunity to enter into someone’s life, hear their story, and ultimately try to effect change. I think it gives you a certain perspective on how lucky we are to be living and breathing and walking and spending time with our families every day.

There are, of course, always aspects such as working too much, not knowing when you are going to be home, and all those things. But it's funny, my son is 9 and really keyed into the meaningfulness of this work. His question, at the end of the day, is often, "What did you do today? Did you help someone?"