Evolving perspectives on pathogenesis, management of AD

Issue: March 2013

ByLawrence F. Eichenfield, MD

There has been a tremendous evolution in our understanding of atopic dermatitis in the past few years.

But with so much information coming at us in so many different ways, many pediatric practitioners are not aware of new information giving insight into eczema pathogenesis and therapy, despite the 9% to almost 20% prevalence of atopic dermatitis (AD) in the first few years of life in the United States and other industrialized countries.

Understanding how specific gene mutations are risk factors for not only AD, but for asthma, food allergy and allergic rhinitis, as well as persistent AD, makes us look at infants at risk for AD and other atopic conditions in a new way. We are learning more about microbial colonization and infection in AD and how commensal bacteria change with eczema flares, as well as how bleach baths may be helpful in some eczema patients. In addition, several studies have pointed out that behavioral and psychological conditions may be associated with AD, such as attention-deficit disorder, beyond that expected in the population.

Lawrence F. Eichenfield

Change in pathogenesis

Although older discussions of AD pathogenesis emphasized immune dysregulation, recent advances have shown us that mutations in the filaggrin gene (FLG), a very interesting and apparently important gene in the epidermis, are associated with defective function of the skin barrier in patients with AD. The gene encodes a protein that is normally highly expressed in the epidermis but is missing or decreased in patients with innate dry skin (ichthyosis vulgaris; IV). Interestingly, pediatric dermatologist Virginia P. Sybert, MD, had proposed filaggrin abnormalities as the cause of ichthyosis vulgaris in 1985; it took 20 years for the revolution in genetic techniques to allow the identification of the FLG gene by Alan D. Irvine, MD, FRCPI, Irwin McLean, PhD, DSc, FRSE, FMedSci, and colleagues.

The clinical findings of IV, dry skin on the extensor surfaces and hyperlinearity of the hands and feet, are highly associated with the development of AD. Check your own hypothenar eminence to see if you are “smooth,” “semi-liney” or really “liney.” Mutations in FLG are very common but variable in populations. Ten percent of children of European ancestry will be heterozygous carriers of the mutation, missing 50% of the filaggrin that is normally in the epidermis, and almost 50% of patients with AD in Ireland have filaggrin mutations. A recent US study found 28% of white children with AD had FLG mutations vs. 6% of blacks.

Normally, filaggrin gets broken up into hygroscopic, sponge-like amino acids that hold water in the skin, known as “natural moisturizing factor.” Decreased filaggrin from mutations leaves less of this in the epidermis, making the epidermis dryer. In addition, the skin barrier is more porous, letting out epidermal fluid, making the skin more permeable and apparently more prone to being sensitized to proteins that come in contact with the skin. This may contribute to immunologic stimulation and IgE sensitization (that is, specific IgE antibodies or positive skin-prick tests). So FLG mutations are associated with a higher risk for AD, and AD patients with FLG mutations have higher rates of developing asthma, severe and persistent AD, peanut allergy and eczema herpeticum.

Skin in children with AD is known to be commonly colonized with Staphylococcus aureus. Impetiginized lesions are common, and pustules, cellulitis or, rarely, systemic infections can be associated. Our eyes are being opened to a much broader set of microbes colonizing the skin through the NIH Human Microbiome Project, using DNA sequence analysis besides traditional culture techniques to assess “our second genome” hanging around our skin surface. In patients with AD, there is tremendous microbial diversity, with bacterial “communities” that are markedly different than controls. Flares of AD are associated with decreased microbial diversity and increased S. aureus, and treatment is associated with more diverse skin bacteria preceding clinical improvement. This early research work led by Heidi H. Kong, MD, MHSc and Julie A. Segre, PhD, at the NIH, shows us the fascinating role skin plays as a barrier and interface for the human organism and so many others.

Antimicrobial therapy is commonly used in AD, but the evidence basis for its use is weakened by inconsistent definitions of skin infection, limited studies and knowledge that good skin care and topical anti-inflammatory medications (generally, topical corticosteroids) can be effective in disease control without antibiotics. There is some evidence that dilute bleach baths can be helpful in management in AD, showing the benefits of the broad anti-infective qualities of sodium hypochlorite. There are several commercial products utilizing technologies that can be used as convenient, albeit, more expensive alternatives, for bleach bath-like effects.

Another interesting set of research has shown that comorbidities in AD are not limited to asthma, allergic rhinitis and food allergy. It is apparent that children with AD have higher prevalence of emotional and behavioral issues than children without AD. Although it was appreciated that sleep disturbance, scratching, irritability and fussiness could be seen with AD, there is evidence now that attention-deficit/hyperactivity disorder is more common in children with AD, with higher rates in those with more severe AD. This may be true of autism as well. Sleep disturbance is considered by many experts to be a potential mechanism for this, although it is uncertain if other factors, such as systemic inflammation, are important. This emerging data clearly argues for better disease treatment and active therapy that minimizes dermatitis, itching and sleep disturbance.

AD recognized as chronic disease

The recognition of AD as a chronic disease that benefits from intensive education as part of therapy has been slow in coming. The data are now strong; that similar to several other pediatric chronic diseases that require reactive and proactive care, AD therapeutic patient education (or TPE, as it is known in the trade) yields better care and improved outcomes. There are now several eczema centers in the United States, which have also contributed Web-based education that can help practitioners, patients and families wherever they may be. For example, the Eczema and Inflammatory Skin Disease Center at Rady Children’s Hospital supports www.eczemacenter.org. Getting families to know how to use topical corticosteroids and calcineurin inhibitors safely and appropriately, as well as the many methods and tricks of optimal skin care with gentle bathing and frequent use of moisturizers, is  crucial.

Knowing more about the pathogenesis of the compromised skin barrier in eczema, as well as contributors to inflammation and infection, helps us work with our families to devise good care regimens to keep the skin in good shape and minimize the impact of eczema on the child and the family.

Lawrence F. Eichenfield, MD, is professor in the Departments of Pediatrics and Medicine (Dermatology) and Chief of Pediatric and Adolescent Dermatology at the University of California, San Diego, School of Medicine. He is also Director of the Division of Pediatric and Adolescent Dermatology at Rady Children’s Specialists of San Diego. In addition, Eichenfield is a member of the Infectious Diseases in Children Editorial Board. He can be reached at Pediatric and Adolescent Dermatology, 3030 Children’s Way, Suite 408, San Diego, CA 92123.

Disclosure: Eichenfield reports no relevant  financial disclosures.