Atopic Dermatitis: Reasons for Optimism

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Atopic dermatitis, the most common type of eczema, is a chronic inflammatory, relapsing disease of the skin. It is characterized by extreme dryness (ichthyosis vulgaris), intense pruritus, maculopapular or vesicular erythematous lesions, and lichenification. About 60% of cases of atopic dermatitis are categorized as mild, and 35-40% as moderate to severe.

Atopic dermatitis is linked to both allergic and non-allergic comorbidities and to an increased risk of viral and bacterial infection -- and can have a devastating impact on quality of life.

In the U.S., it is estimated that more than 30 million Americans -- or about 1 in 10 -- will be affected by atopic dermatitis at some point in their lives. Worldwide, up to 2.4% of the population are believed to be affected by the disease, although prevalence varies widely by country.

Important Recent Advances

Despite the many questions that remain, recent advances in understanding the complex pathogenesis of atopic dermatitis, along with new treatments for better long-term control, are offering hope.

"Our knowledge of the disease in individuals and families has become much more advanced in the last decade or decade and a half, and it has allowed us to increase our understanding of the disease impact on other aspects of the health of the individual," Lawrence Eichenfield, MD, vice-chair of the Department of Dermatology at UC San Diego School of Medicine, said in an interview. "We really want to get the message out that things with AD [atopic dermatitis] are different now and we have a tremendous ability to do things that we couldn't before."

Amy S. Paller, MD, the Walter J. Hamlin chair and professor of dermatology at Northwestern University Feinberg School of Medicine in Chicago, agreed: "I think we are on a really great path," Paller told MedPage Today. "Back in 2014, we were looking ahead to this being the decade of atopic dermatitis, and indeed it has been. We still have much to do, but we have certainly made tremendous advances just in the past 5 to 8 years."

The development of more effective, safer medications for patients with atopic dermatitis has been the result of "a long overdue and tremendously welcome response from industry to partner with scientists and clinicians," she added. "I'm happy to say that these medications have been life-saving for our patients."

Usually Begins in Childhood, But Can Occur at Any Age

Although atopic dermatitis usually begins in childhood, between the ages of 1 and 5 years, it can be diagnosed in the early weeks following birth. In some children, atopic dermatitis resolves in adulthood, but in others, it remains an unpredictable, lifelong disease, sometimes disappearing for years only to resurface as a devastating flare-up.

But atopic dermatitis is not confined to childhood. New-onset atopic dermatitis can be diagnosed in adults with no history of the disease, including those ages 65 and older. The estimated U.S. prevalence is 15% in children and 7% in adults.

"What we've seen over the last several years is clear evidence that atopic dermatitis can start at any time," said Paller, emphasizing, though, that "the overwhelming bulk of cases occur in the first years of life."

Physicians have had to discard the notion that "most kids with atopic dermatitis outgrow their disease," said Eichenfield, who is also chief of pediatric and adolescent dermatology at Rady Children's Hospital-San Diego. "That was the over-simplified, optimist's view," he said. "What we've learned over time is that it can start in early childhood, but it can also start in later childhood, in adolescence, or in adults."

Complex Pathophysiology

The pathophysiology of atopic dermatitis is complex and involves genetic factors, epidermal barrier dysfunction, immunologic mechanisms, and environmental triggers. It's a chicken-or-the-egg dynamic in which different bio-systems work independently, along parallel lines, to create the perfect allergic storm. Understanding how these processes enable and augment each other is akin to unraveling a nest of snakes.

"I think we're still trying to understand the relationship between the immune system, the skin barriers, and the microbiome and other environmental triggers," said Paller. "Ten years ago we were all talking about which came first, and there was talk of the extrinsic and intrinsic forms. I think we all recognize now that it's very hard to sort out any primary problem."

Perhaps the most significant factor in the development of atopic dermatitis is mutation of the gene encoding for the filaggrin protein, a critical building block in the hygroscopic barrier that moisturizes the stratum corneum. Loss-of-function filaggrin mutations also increase predisposition to intermediate-type hypersensitivities such as asthma and allergic rhinitis.

In 2006, investigators reported that two independent loss-of-function filaggrin mutations were strong predisposing factors for atopic dermatitis. That landmark study, published in Nature Genetics, also showed that about 9% of people of European origin carried these genetic variants, and that R510X and 2282del4 were highly associated with asthma in the presence of atopic dermatitis.

Alterations in cell-mediated immune responses that promote immunoglobulin (Ig)E-mediated hypersensitivity are also implicated in the development of atopic dermatitis, and in exacerbating existing disease. In the presence of atopic dermatitis skin lesions, for instance, immune dysregulation impairs the expression of beta-defensins -- antimicrobial peptides localized primarily in the epidermis -- increasing sensitization.

"This may be the leading cause of increased susceptibility to bacterial and viral infection in patients with atopic dermatitis," said Panjit Chieosilapatham, MD, PhD, of the Atopy (Allergy) Research Center at Juntendo University Graduate School of Medicine in Tokyo, and colleagues, writing in Clinical & Experimental Immunology. "Skin barrier dysfunctions combined with abnormal immune responses in atopic dermatitis allow the penetration of potential allergens and pathogens that worsen atopic dermatitis symptoms."

Role of the Environment and Chemicals

The role of the environment and the impact of chemicals such as airborne formaldehyde, harsh detergents, fragrances, and preservatives must also be taken into account, said W. David Boothe MD, of Texas Tech University Health Sciences Center in Lubbock, and co-authors in a chapter in "Management of Atopic Dermatitis."

"Use of harsh alkaline detergents in skin care products may also unfavorably alter the skin's pH, causing downstream changes in enzyme activity and triggering inflammation," the team wrote. "Environmental pollutants can trigger responses from both the innate and adaptive immune pathways."

Other common environmental triggers include tobacco smoke, mold and pollen, temperature extremes (hot and cold), humidity, pet dander, fragrances, soaps, shampoos, and detergents, and wool and synthetic clothing.

Natural History/Classification

The natural history of atopic dermatitis varies widely, based on clinical morphology, disease severity, the patient's age at presentation, disease course, and co-morbidities. Better understanding of the drivers of disease severity, including the role of gene-environment interactions, could hold the key to improving outcomes, according to researchers.

Following an analysis of data from a cohort of 11,866 children, Amy R. Mulick, MA, MSc, of the London School of Hygiene and Tropical Medicine, and colleagues identified four phenotypes of atopic dermatitis based on symptom severity and disease trajectory, labeling them:

• Severe-frequent

• Moderate-frequent

• Moderate-declining

• Mild-intermittent disease

Results from the 2021 analysis also showed that the presence of filaggrin null mutations, atopic dermatitis polygenic risk score, female gender, parental history of atopic dermatitis, and comorbid asthma were all associated with a higher risk for some or all subtypes. These subtypes progressed from more severe to less severe phenotypes.