Research begins to unlock mysteries behind AD, psoriasis in children

Wailea, Hawaii - Dermatologists' evolving understanding of inflammatory skin diseases in children is changing the way these diseases are managed, according to Lawrence F. Eichenfield, M.D.

"Atopic dermatitis (AD) involves a mixture of barrier dysfunction, infection, inflammation, allergy and pruritus, which can drive the disease process. Our understanding of AD is still evolving" and includes the acknowledgment that a significant subset of patients with AD - but possibly not all of them - have genetic mutations that cause skin barrier dysfunction, says Dr. Eichenfield, chief of pediatric and adolescent dermatology at Rady Children's Hospital-San Diego, and professor of pediatrics and medicine (dermatology) at the University of California, San Diego School of Medicine. "These mutations can compromise the skin and create a setup for the inflammation of AD.”

Filaggrin mutations
Perhaps 30 to 40 percent of patients with AD possess filaggrin mutations, Dr. Eichenfield says.

"These mutations are associated with a decrease in natural moisturizing factor. They cause an increase in permeability, which allows the skin to be more easily sensitized and probably stimulates the immune system,” he says. “They also increase skin pH, or decrease the natural acid mantle. This negatively impacts cell-to-cell cohesion, permeability and inflammation."

Recent research links filaggrin insufficiency and barrier abnormalities not only with higher rates of AD and AD-associated asthma, "But they're also associated with a fivefold increased risk of developing peanut allergy (Irvine AD, McLean WH, Leung DY. N Engl J Med. 2011;365(14):1315-1327. Review), Dr. Eichenfield says.

Because filaggrin mutations are part of the skin, not the mucosa, the new information regarding peanut allergy raises the question of whether the allergies are occurring because patients are becoming sensitized to peanuts through their skin, he says.

"This is fueling more interest in investigating whether early treatment and/or very good control of the skin barrier and hydration might decrease the development of allergies associated with AD. These include food allergy, allergic rhinitis and asthma," Dr. Eichenfield says.

However, "Filaggrin is only part of the story (Kim BE, Leung DY. Allergy Asthma Immunol Res. 2012;4(1):12-16. Epub 2011 Sep 21),” Dr. Eichenfield says. “While 30 percent to 40 percent of patients with AD have the filaggrin mutations, most of these children outgrow their AD. Additionally, 40 percent to 50 percent of patients with no active filaggrin in their skin never develop AD. So we don't know the whole story yet."

Clinically, he says that recent findings regarding filaggrin support what had already been standard interventions for AD: using proper skincare, moisturizing after bathing, liberally using emollients and attempting to improve skin barrier repair. "These are part of maintenance care for children and adults, and they're primary interventions for mild AD in infants,” he says.

First-line treatment
Topical corticosteroids remain the first-line treatment for the inflammatory component of AD. Dr. Eichenfield says that dermatologists typically either prescribe the weakest steroid necessary to get the disease under control or they start with a stronger steroid and taper down to a less potent one once the disease is under control.

Over time, he says, dermatologists tend to prescribe more prolonged use of less potent agents and/or intermittent use (a few times weekly) of stronger agents, and/or a mix and match of topical corticosteroids and nonsteroidal topicals such as topical calcineurin inhibitors (TCIs) or barrier repair products.

Regarding TCIs, a systematic review of epidemiologic studies found no evidence that melanoma or nonmelanoma skin cancers are associated with TCI use, and little evidence of an association between TCIs and the types of malignancies seen with systemic immunosuppressive agents (Tennis P, Gelfand JM, Rothman KJ. Br J Dermatol. 2011;165(3):465-473. Epub 2011 Jun 30).

Some data have linked tacrolimus use with an increased risk of T-cell lymphoma, Dr. Eichenfield says. "However, most experts believe that this is almost certainly a matter of tacrolimus being used on cutaneous T-cell lymphoma that has not yet been diagnosed."

For severe, difficult AD, Dr. Eichenfield says, "What's needed for adequate maintenance therapy varies greatly depending on the individual. However, physicians should focus on achieving adequate control of the disease, which includes not only diminishing the rash, but also controlling the itch to the degree that it's not influencing sleep."

Several studies have shown a higher rate of attention deficit disorder in patients with AD. "Many experts believe this is secondary to sleep disturbance,” Dr. Eichenfield says. “Therefore, we are informing our patients and their families about this. It pushes us to ensure that we have more control of the disease, to minimize sleep disruption and its impact."

For managing acute flares that don't respond to typical topical steroids, Dr. Eichenfield says, "Increasing evidence shows that wet wraps with topical corticosteroids are highly useful for inducing remissions (Dabade TS, Davis DM, Wetter DA, et al. J Am Acad Dermatol. 2011 Oct 4. [Epub ahead of print])."

To fight parents' steroid phobias, Dr. Eichenfield says it's extremely important to educate parents regarding both the efficacy and safety of prescribed products.

"I find it highly useful to quantify the amount of medicine that patients are using over time and to prescribe specific amounts of medicines to help people to understand that they can safely utilize a particular medicine in a certain number of grams per week over a few weeks,” he says. “This helps to minimize undertreatment, which is known to be a great problem with therapeutic regimens" for AD in children.

Additional treatments
Dr. Eichenfield says that dermatologists' use of bleach baths also continues to evolve. Here, he says that several new products may offer more convenient equivalents to immersion bathing, though they haven't been studied in comparison to bleach baths. "CLn Body Wash (sodium hypochlorite, TopMD) is like a bleach bath in a can,” he says. “It can be administered locally and washed off."

Somewhat similarly, the HyalatopicPlus-Aurstat Kit (Onset Dermatologics) includes a broadly antimicrobial hydrogel (Aurstat) that patients can smear on their skin to decrease Staphylococcus aureus counts within 30 seconds, as well as Hyaltopic Emollient Foam (hyaluronic acid, lipids; Onset Dermatologics), he says.

As for preventing AD, Dr. Eichenfield says, "We're not there yet." In fact, a large review analyzed a broad set of interventions attempting to decrease development of AD - including dietary manipulations, allergen avoidance, changes in baby formulas and the timing of solid feeding. The review showed that to date, none of these interventions have had any impact in reducing AD development (Foisy M, Boyle RJ, Chalmers JR, et al. Evidence-based Child Health. 2011 Sept. 6(5):1322-1339).

Pediatric psoriasis
Regarding psoriasis, "It's been well-documented that psoriasis in adults is associated with a significant set of comorbidities including obesity and higher rates of clinically relevant atherosclerotic heart disease," Dr. Eichenfield says. This has raised the question of whether this occurs because psoriasis is an inflammatory disease, or whether psoriasis occurs more commonly in individuals with these overlapping risk factors, he explains.

Several studies have found higher-than-expected rates of obesity in children with psoriasis, he says. Other ongoing studies, including a large case-control study, are examining signs of inflammation in children.

"In seeing pediatric patients with psoriasis, dermatologists should remember to screen for psoriatic arthritis,” Dr. Eichenfield says. “This is easily done by asking not only about joint swelling, but also morning stiffness, which is a fairly reliable indicator."

Treatment mainstays for pediatric psoriasis include topical corticosteroids, topical vitamin D analogues and products that combine these agents, Dr. Eichenfield says. Additionally, "Phototherapy can be very important for treating moderate-to-severe psoriasis, with narrowband UVB being the most studied." A variety of combination products also are under study for pediatric use, he adds.

Biologics concern
"Systemic therapy is still very difficult for physicians in that there is no approved systemic therapy for children or adolescents with psoriasis," Dr. Eichenfield says. Literature regarding the safety and efficacy of etanercept in this population has accumulated, "But there have also been warnings issued in relation to biologic agents and malignancy in children, including a potential increased risk of malignancy with TNF alpha antagonists."

Overall, "These are very complicated issues because most of the patients being assessed have more complicated systemic diseases than psoriasis, including inflammatory bowel disease, juvenile rheumatoid arthritis and others,” he says. “And almost all of these patients have used immunosuppressants other than biologic drugs."

Accordingly, Dr. Eichenfield says that it remains unclear whether cancer rates in children using biologic drugs for psoriasis are higher than background rates in unexposed children. "However, counseling about potential risks of malignancy with the use of biologic agents and/or methotrexate seems appropriate,” he says.

To help patients learn about psoriasis in general, he says, "The National Psoriasis Foundation has superb materials for children with psoriasis, including a specific part of their website that's geared for children (PsoMe; www.psoriasis.org/kids)."

As for the future, Dr. Eichenfield says, "We look forward to more information about optimal systemic therapies for both AD and psoriasis from the Pediatric Dermatology Research Alliance (PeDRA), a multicenter group that's studying optimal dosing, efficacy and safety of systemic treatments."

Disclosures: Dr. Eichenfield has been an investigator (uncompensated) for Amgen, Astellas, Galderma and Leo Pharma. He is also a consultant/advisory board member for Galderma, Onset, Valeant, Bayer/Intendis and GlaxoSmithKline/Stiefel, and he is an adviser to TopMD.