Understanding inflammation’s role in atopic dermatitis

When you’re in the middle of an eczema flare, do you ever feel like your skin is on fire? The ancient Romans would sympathize. After all, they coined the word inflammare—the Latin root of the English word inflammation—meaning “to set on fire.”

In the first century A.D., a Roman physician named Cornelius Celsus documented the four signs of inflammation: redness, swelling, heat and pain. These are still considered the hallmarks of inflammation today, even as advances in molecular biology are deepening our understanding of a process that is as common as it is biologically diverse.

But inflammation certainly isn’t all bad. More often than not, it’s a normal and even healthy phenomenon. That’s what makes it so tricky for doctors to deal with when it turns chronic and destructive.

On the one hand, said Dr. Eric Simpson, professor of dermatology at Oregon Health Sciences University (OHSU), “inflammation is the immune system’s normal response to infection or injury. It’s the body’s way of protecting us from disease-causing viruses, bacteria, fungi and other potentially harmful invaders, along with cuts, sprains and injuries of all kinds.

“However,” he continued, “there are times when the body mounts an inflammatory response even when no invader is present.”

For a complex tangle of reasons, the immune system can get stuck in the “on” position. That’s exactly what happens in atopic dermatitis (AD), allergies, asthma and other inflammatory conditions.

Chronic inflammation can lead to destructive changes in the skin and in other organs and tissues. Its precise form and its severity depend on the molecular pathways along which the inflammatory response begins, travels and intensifies.

Digging deeper into skin inflammation

It’s easier to understand the “what” of inflammation—its signs and symptoms—than the “why” and “how,” said Simpson, who served as co-chair of the National Eczema Association’s 2017 Scientific Advisory Committee and is a leading researcher in the field of chronic skin disease prevention and treatment.

“At a molecular level, inflammation is extremely complex,” added Dr. Lawrence Eichenfield, chief of pediatric and adolescent dermatology at Rady Children’s Hospital in San Diego. “For example, the immune cells implicated in psoriasis are different from those seen in AD. These cells secrete different inflammatory molecules, called cytokines, that are specific to the disease in question.

“That’s why biologic drugs that block TNF-alpha—a cytokine associated with psoriasis—don’t work for patients with AD,” he continued. By contrast, “Dupilumab (Dupixent) is effective precisely because it targets IL-4 and IL-13, two cytokines known to drive the inflammatory response in AD.”

Then, there’s the outside-inside question: Is inflammation in the skin the dominant issue in AD, or is systemic inflammation the main offender? Eichenfield said the answer is that the two are intricately interconnected.

“In moderate to severe AD, you can find inflammatory cells in both inflamed and unaffected skin, as well as in the blood,” he explained. In other words, it’s impossible to answer the outside-inside question with certainty.

As for the “how” of AD, Eichenfield stressed the interplay of genetic and environmental factors.

“Some people are born with a genetic tendency to have compromised skin function,” he said. “They’re missing a little protein that would normally allow their skin to hold on to water. That tiny missing molecule leaves their skin dry and vulnerable to allergy-like reactions.”

Underlying, genetically determined inflammation shows up in the skin as sensitization—hyper-reactivity to environmental irritants, he explained. Skin sensitization can worsen with repeated exposure to the substance, including certain metals, foods, fabrics, perfumes or chemical additives in personal care or household products.

“We may not have a cure for AD just yet,” said Eichenfield, “but patients can reasonably aim to manage and minimize the impact of the disease. Here, tackling inflammation is key. Treatments range in strength from over-the-counter topicals all the way to biologic agents that target the cytokines at play in moderate to severe AD.”

The many faces of inflammation and eczema

Jill Harris, a 28-year-old from Greenville, North Carolina, said she can tell when her eczema is about to flare when her skin starts to “tingle.”

She associates that sensation with inflammation, and the minute she starts to feel it, she applies a small amount of topical steroid to the affected area. Sometimes, that’s enough to calm her skin, at least for a while.

Harris had eczema as a child, but she outgrew it—or so she thought, until the birth of her daughter, Meredith, in October 2015. Shortly after giving birth, her eczema erupted so violently that she could barely function.

She spent the next two years under the care of a trusted dermatologist, and her eczema has been under control since the start of 2018.

“I started with a low dose of a topical steroid cream, and my doctor gradually upped the dose until it had the desired effect,” she said. “I’d take antihistamines at night and during the day. I used plenty of coconut oil and dermatologist-tested skincare products. I was basically dealing with my eczema around the clock.”

Harris also underwent allergy testing to identify her potential triggers. Most of these turned out to be fairly common among people with eczema and allergies, but one was surprising. She’s allergic to sulfites—a substance present in red wine and tofu.

“On a special date night with my husband, Lee, last year, I had just one glass of wine, and my eyes got inflamed and swelled up. I don’t mind giving up tofu, but red wine!?” Harris lamented.

The young mother is also a full-time employee at East Carolina University and the owner-manager of an all-natural cleaning service. With her 24/7 schedule, Harris says she can easily get stressed out.

But “ever since I started taking yoga and Pilates, I have been coping better and making better use of my downtime.” She’s learning to be more mindful during the day—and that has made all the difference at night.

The link between inflammation and emotional health

Dr. Charles Raison, professor of psychiatry at the University of Wisconsin-Madison School of Medicine and Public Health, points to good sleep as essential to good health. If you have a chronic skin disease, he said, your sleep may be interrupted by pain and itch but also by anxiety—yet another example of the complex nature of human biology.

“When people are stressed, they experience higher levels of inflammation,” Raison explained. “Conversely, people with inflammatory conditions like AD show higher rates of depression, anxiety and other mental health disorders.

“Just having AD alone can increase a patient’s risk for depression,” he continued. “But our biological processes are round robins. They flow in both directions. Inflamed skin ‘talks’ to the brain, fostering anxiety and depression.

“On the other hand, many people with AD report feelings of shame and self-consciousness, and these emotions can fuel anxiety, depression and other mental health disorders,” he explained. “Once a mental health disorder sets it, it can activate inflammatory pathways”—and around and around we go, from inflammation to emotion and back again.

Putting your life together piece by piece

People with eczema like Harris have harnessed the power of mindfulness to interrupt the stress-inflammation circuit. Her experience, Raison noted, is consistent with recent evidence supporting the ability of mindfulness and other meditation practices to “quell inflammatory responses in the body.”

Meditation is an excellent, low-impact anti-depressant, he said, but some patients on biologics also find that when their skin clears, their mood improves.

Does their emotional state improve due to the anti-inflammatory effects of the medication? Or do they become less depressed as they lose the shame and stigma associated with inflamed skin? Probably both, in Raison’s view.

The next stop on the lifestyle train is diet. Doctors across every specialty encourage their patients to move away from processed foods and toward sound nutrition.

“What you eat can change the level of inflammation in your body,” Simpson added. “Many of my patients do well on the Mediterranean diet, but so far there isn’t enough evidence to say just how strongly anti-inflammatory it is.”

The good news is that Mediterranean, Paleo, vegetarian, vegan and low-carbohydrate diets all have one thing in common: they lead to weight loss.

Reaching and maintaining a healthy weight is vital, Raison said, and not only for the sake of cardiovascular health and overall fitness.

“Belly fat is the largest source of inflammation in the body. If you’re overweight and have AD, you’re adding fuel to the fire.” Raison’s advice? Eat more healthfully. Eat less. And, of course, get regular exercise.

To recap, Raison proposes a five-point lifestyle program:

• Get enough sleep.
• Adopt a consistent meditation practice.
• Eat well but less.
• Stay active.
• Connect regularly and often with friends and family.

The importance of this last item—social support—can’t be overstated, he said. “Humans are astoundingly social animals. As a species, we need to have at least one person in our lives who really knows us and is on our side. Our social connections are a biological necessity.”

Leading-edge research for atopic dermatitis

It’s an exciting time in AD research, Eichenfield said. “Two advanced treatments for AD—Dupixent and Eucrisa—were approved in 2017, and 35 biologic drugs are in clinical trials right now.

“Researchers are also studying the influence of microbial factors in AD—the viruses, fungi and bacteria present in our bodies and our environment,” he added. “Probiotics also are under investigation as a treatment for babies and very young children with inflammatory skin conditions.”

Even with the range of treatments that are available right now, you may not need to work on managing your eczema 24/7 the way Harris did. But if you decide to try a mosaic of approaches to self-care, you may get a lot busier! In the meantime, no need to get stressed out. It’s all in how you put it together.