Pediatric dermatologists say a renewed interest in studying atopic dermatitis treatments could mean exciting times for the millions of children who suffer with the quality-of-life-altering itch and more.
San Diego - Research on new agents for atopic dermatitis holds promise for children with the skin disease. This is while dermatologists continue to face challenges in effectively managing eczema in their pediatric patients.
“Atopic dermatitis is the most prevalent chronic inflammatory skin condition in children. In the United States and other industrialized countries, the estimated prevalence of atopic dermatitis (AD) is between 10 and almost 20 percent in the first few years of life,” says Lawrence F. Eichenfield, M.D., chief of pediatric dermatology and professor of pediatrics and medicine (dermatology), at University of California, San Diego, and Rady Children’s Hospital San Diego. Dr. Eichenfield is an author on atopic dermatitis guidelines released this year by the American Academy of Dermatology.
Among the strides in atopic dermatitis: an improved understanding of the epidemiology and pathogenesis of the disease.
“Over the last several years, identification of mutations in the skin responsible for skin barrier dysfunction, associated with the dry skin of eczema, as well as a set up for its inflammation, have been emphasized,” Dr. Eichenfield says. “Research has shown there are mutations in certain genes expressed in the epidermis that fundamentally influence the skin barrier function.”
Filaggrin gene mutations have been shown to have a strong predictive value for higher risk of atopic dermatitis development. The gene mutations are also associated with increased rates of asthma, allergic rhinitis, IgE sensitization, as well as more severe atopic dermatitis that can persist into late childhood and adulthood, according to Dr. Eichenfield.
“…In the U.S., David Margolis evaluated DNA from almost 900 children and found that about 16 percent of them had filaggrin mutations while less than 6 percent of African-Americans had these mutations,” Dr. Eichenfield says (Margolis DJ, Gupta J, Apter AJ, et al. J Invest Dermatol. 2014;134(8):2272-2274)
From a clinical standpoint, the knowledge about skin barrier dysfunction helps to reassure dermatologists that an approach emphasizing good skin care and liberal moisturizer use can help to minimize the disease’s impact, Dr. Eichenfield says.
“Moisturizing after bathing is standardly recommended and frequent use of moisturizers can minimize both inflammation and xerosis,” he says.
Another area of interesting research relates to colonization on the skin and infection of atopic dermatitis.
“It has been well known that Staph aureus (Staphylococcus aureus/S. aureus) is a bacteria that commonly colonizes atopic dermatitis, and can impact atopic dermatitis with clinical infection and flaring of the disease,” Dr. Eichenfield says. “Recent studies using techniques to assess genetic material of microbes is helping to show the tremendous diversity of microorganisms on normal and clinically impacted skin.”
Studies have shown that the diversity of microbes decreases during AD flares, as S. aureus increases, he says.
“Generally in nonaffected atopic dermatitis the broad use of antibiotics is not recommended. However, infected eczema might benefit from systemic treatments,” Dr. Eichenfield says. “In the future, there might be studies that look at both skin colonization as well as the potential of course of gut colonization in the development of atopic dermatitis and/or its course.”
An area related to colonization of the skin is the use of bleach baths as adjuvant therapy in atopic dermatitis. Dilute sodium hypochlorite soaks can decrease skin colonization and have been shown to be useful in improving AD.
“Interestingly a set of studies by Thomas Leung at Stanford and published in the Journal of Clinical Investigation showed that sodium hypochlorite solution may be antiinflammatory, influencing N F kappa beta expression. Dilute sodium hypochlorite solution also decreased radiation dermatitis in a rat model,” Dr. Eichenfield says.
New meds on the block
There are new topical and systemic agents in the drug development pipeline, several of which are in advanced clinical trials, including a boron-based phosphodiesterase inhibitor (PDE-4, AN2728), studied by Anacor, and a biologic agent being developed for atopic dermatitis, studied by Regeneron/Sanofi.
“We’ve spent more than a decade studying the underlying pathogenesis of psoriasis and translating that information into new therapies,” says Amy Paller, M.D., professor and chairwoman of dermatology and professor of pediatrics, Northwestern University Feinberg School of Medicine, Chicago. “Now it’s time for atopic dermatitis … and a growing number of pharmaceutical companies are taking an interest. It’s going to be extremely exciting. Of course, early trials always tend to be in adults, but some of these studies have evaluated adolescents and even young children.”
PDE-4, the boron-based phosphodiesterase inhibitor in phase 3 trials in adult patients, looks promising for mild-to-moderate atopic dermatitis and has not shown evidence of toxicity, according to Dr. Paller. Anacor Pharmaceuticals announced positive results from a phase 2 trial in December 2012, following a trial on adolescents with mild-to-moderate atopic dermatitis using its PDE-4 inhibitor, AN2728.
“One of the most exciting new developments in atopic dermatitis is the testing of the first biologic designed based on our understanding of the mechanism underlying atopic dermatitis,” she says. “And the clinical results look so promising. It’s called dupilumab and continues in trials in adults right now. Once safety is established in adults, dupilumab can be tested in pediatric patients as well.”
Dupilumab, a human monoclonal antibody that blocks interleukin-4 and interleukin-13, showed promising results from a trial of adult patients with moderate-to-severe atopic dermatitis in a July 2014 paper published in the New England Journal of Medicine (Beck LA, Thaçi D, Hamilton JD, et al. N Engl J Med. 2014;371(2):130-139).
Beck et al concluded, “Patients treated with dupilumab had marked and rapid improvement in all the evaluated measures of atopic dermatitis disease activity. Side-effect profiles were not dose-limiting.”
There’s more research on atopic dermatitis going on in the areas of AD biomarkers, triggers and better tools for judging treatment efficacy in research trials, according to Elaine C. Siegfried, M.D., professor of pediatrics and dermatology, Saint Louis University, St. Louis.
“A sizable group of dedicated clinicians and investigators is working with various agencies to try to define the best measure of atopic dermatitis improvement,” Dr. Siegfried says. “Implementing a uniform measure into new clinical trials protocols is very important in order to have a uniform measure to compare different drugs.”
Prescribing can be a challenge
Topical anti-inflammatory therapy is still a standard approach for the inflammation of atopic dermatitis, focused on use of topical corticosteroids and topical calcineurin inhibitors, Dr. Eichenfield says.
“As emphasized in the new American Academy of Dermatology Atopic Dermatitis guidelines, both sets of agents may be used as proactive therapy, rather than reactive therapy. The principle of proactive therapy is that the use of intermittent topical corticosteroid or calcineurin inhibitors to clinical normal skin may be useful to decrease flares of the disease and render the patient relatively pruritus or inflammation free,” he says.
The biggest breakthrough in atopic dermatitis treatment has been the development of topical corticosteroids, Dr. Siegfried says.
“Before (topical corticosteroids), treatment was incredibly difficult. After topical corticosteroids were developed, acute relief was possible for the majority of patients,” she says.
But long-term use of topical corticosteroid monotherapy carries the risk of side effects. Potential problems include cyclic rebound of the skin disease, cutaneous atrophy and corticosteroid contact allergy. Compounding the reality of side effects is a prevailing phobia surrounding topical corticosteroid use. “Steroid phobia,” or “corticosteroid phobia” is more fear-based than research-based, according to Dr. Siegfried.
The perceived dangers of topical corticosteroids often lead to noncompliance. According to research, parents and adult atopic patients surveyed reported fearing topical corticosteroids, and more than a third admitted nonadherence to treatment (Aubert-Wastiaux H, Moret L, Le Rhun A, et al. Br J Dermatol. 2011;165(4):808-814).
“You can overuse corticosteroids, but, if you don’t use them at all, it can be very difficult to keep the disease under control,” Dr. Siegfried says. “In my practice … corticosteroids are always first-line. They’re the most well studied and have been around for the longest period of time. But … in people whose disease can’t be controlled on a safe amount of corticosteroids, you have to add a steroid-sparing agent. Options include a calcineurin inhibitor or phototherapy. Some people still use tar, although most patients don’t like it and there’s a concern about carcinogenicity.”
Calcineurin inhibitors, she says, are safe and well tolerated.
“… it’s wonderful to have those options. The most well-studied are the topical calcineurin inhibitors, Elidel and Protopic,” Dr. Siegfried says. “They don’t work as fast or as dramatically as corticosteroids but they maintain skin health and help control inflammation long term, without causing cutaneous atrophy.”
But there is the black box warning on tacrolimus ointment and pimecrolimus cream, which limits access to the options for children with atopic dermatitis, Dr. Siegfried says.
The warning states the use of these medications may increase the risk of certain cancers, specifically skin cancer and non-Hodgkin’s lymphoma. The American Academy of Dermatology, however, published this quote by Dr. Eichenfield: “… Patients should know that studies have not demonstrated an increased cancer risk from (topical calcineurin inhibitor) use.”
“New drug development for atopic dermatitis suffered from the black box warning on calcineurin inhibitors, so there were no drugs in the pipeline for a long time,” Dr. Siegfried says. “Finally, people are starting to recognize the epidemiologic importance and unmet medical need of (atopic dermatitis).”
In clinical practice, educating patients about atopic dermatitis can be crucial to appropriately controlling the disease.
“There is an international movement emphasizing therapeutic patient education of atopic dermatitis, recognizing that like other chronic diseases, giving patients and families the skill to manage their life in the best possible way to mediate the course of disease can be highly useful,” Dr. Eichenfield says. “Therapeutic patient education, can be especially useful to improve the outcomes of atopic dermatitis, educating families about appropriate and safe steroid strengths and safety and integrating these therapies into regimens of care.”
The journey toward optimal AD management has its challenges, but these are exciting times, according to Dr. Paller.
“We’re still struggling with finding new treatments for children. But we’re very encouraged by the trials in pediatric patients for the PDE4 inhibitor - and we’re also very encouraged by the success in adults with dupilumab,” Dr. Paller says. “Of course, we continue to use our ‘gold standards’ in dermatology, like bleach baths, which have made such a difference for so many families and children with atopic dermatitis.
“But there’s so much more to study, and a lot of attention is now being directed towards a better understanding of the mechanism of itch and how the impact of itch affects sleep and neurocognitive function,” she says. “Our better understanding will hopefully lead to new therapies that can be directed not at just at inflammation but also at itch and a better way to help people sleep.”