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AD update: New insight into pathogenesis, prevention, and treatments.

LAS VEGAS -- Recent research has provided a rare triple whammy in the world of atopic dermatitis (AD). Over the last few years, studies have provided valuable insight into not just treatments for AD but also its roots and strategies for prevention, Linda F. Stein Gold, MD, said at Skin Disease Education Foundation's annual Las Vegas Dermatology Seminar.

AD affects an estimated 7% of adults in the United States and 13% of children under age 18 years, according to the National Eczema Association. An estimated one-third of the affected children (3.2 million) have moderate to severe disease.

New information about AD includes more information pinpointing the genetic link. Dr. Stein Gold, director of clinical research in the department of dermatology at the Henry Ford Health System, Detroit, pointed out that about 70% of patients with AD have a family history of atopic conditions.

Mutations in filaggrin appear to play a role in the development of AD, but a significant proportion of people with AD do not have evidence of filaggrin mutations, and about 40% of people with defects never develop AD, she noted.

Emollients may be key to preventing AD. To explore the theory that defects on the skin barrier "might be key initiators of atopic dermatitis and possibly allergic sensitization," investigators conducted a randomized controlled study of 124 babies at risk of AD in the United States and United Kingdom; parents of 55 babies applied emollients to their whole bodies from shortly after birth until 6 months while a control group used nothing (J Allergy Clin Immunol. 2014 Oct; 134[4]:818-23).

At 6 months, those in the emollient group were half as likely to have developed AD (relative risk, 0.50; P = .017).

Bleach baths have received attention on the AD prevention front. Dr. Stein Gold pointed to a 2017 systematic review and meta-analysis of five studies that found both bleach and water baths reduced AD severity. Bleach baths were effective but not more so than water baths (Ann Allergy Asthma Immunol. 2017 Nov; 119[5]:435-40). Also, there was no difference in skin infections or colonization with Staphylococcus aureus between the two.

So are water baths just as good as bleach baths? "I'm not 100% sure I buy into this," Dr. Stein Gold said. "I'm still a bleach bath believer."

Topical calcineurin inhibitors (TCIs) can be used as a "proactive," steroid-sparing treatment to prevent relapses in AD, research suggests. For this purpose, the recommended maintenance dosage is two to three applications per week on areas that tend to flare; the TCIs can be used in conjunction with topical corticosteroids (J Am Acad Dermatol. 2014 Jul;71[1]:116-32).

TCIs come with boxed warning because of concerns about such cancers as lymphoma. But recent research has not found a higher risk of lymphoma in patients with AD who are treated with the medication. "We've had these drugs for a long time, and they do appear to be safe," Dr. Stein Gold said.

She referred to a 2015 review of 21 studies of almost 6,000 pediatric patients with AD who were treated with a TCI that concluded that the drugs are safe and efficacious over the long term (Pediatric Allergy Immunol. 2015 Jun;26[4]:306-15).

"Everyone wants to know which ones are better," Dr. Stein Gold said in regard to TCIs. But there aren't head-to-head studies, she said, and it's difficult to compare the available data on response rates between certain topical treatments because the studies are designed differently.

For example, with crisaborole (Eucrisa), the topical phosphodiesterase-4 (PDE4) inhibitor approved in 2016 for mild to moderate AD in patients aged 2 years and up, clear/almost clear rates are 49%-52%, compared with 30%-40% with placebo, a 10%-20% difference. Rates with OPA-15406, an investigational topical selective PDE4 inhibitor, and with the TCI pimecrolimus (Elidel cream 1%) have been about 20% higher than with controls, but studies are designed differently, and the results cannot be compared, according to Dr. Stein Gold.

Dupilumab (Dupixent), a monoclonal antibody that inhibits signaling of both interleukin-4 and interleukin-13, approved in 2017 for adults with moderate to severe AD, has been a "game changer" for this population, Dr. Stein Gold said. "It looks like this drug has a good, durable effect," she added (Lancet (2017 Jun 10;389[10086]:2287-303).

However, she cautioned that up to 10% of patients treated with dupilumab --or more--may develop conjunctivitis. Researchers studying dupilumab in asthma have not seen this side effect, she said, so it may be unique to AD. "It's something that's real," she said, noting that it's not clear if it's viral, allergic, or bacterial. Researchers are exploring the use of the drug in children, she added.

Dr. Stein Gold said there are other drugs in development for AD, but she cautioned that "the field is crowded ... and not all of them are going to make it."

Drugs in development for AD include nemolizumab (a humanized monoclonal antibody that inhibits interleukin-31 signaling), upadacitinib (a JAK1 selective inhibitor), baricitinib (an oral JAK1 /2 inhibitor), and topical tapinarof (an agonist of the aryl hydrocarbon receptor).

SDEF and this news organization are owned by the same parent company.

Dr. Stein Gold disclosed relationships with Galderma, Valeant, Ranbaxy, Promius, Actavis, Roche, Dermira, Medimetriks, Pfizer, Sanofi/Regeneron, Otsuka, and Taro.



The world of pediatric atopic dermatitis (AD) is undergoing many changes, with the evolution of understanding of pathogenesis, two relatively newly approved therapies, and many treatments under study. Dr. Stein Gold's talk at the SDEF Las Vegas Dermatology Seminar is an excellent summary of this fast-moving field, but with practitioners' grounding care in the basics of excellent skin care and regular use of moisturizers. There is a push for all practitioners to get on the "long-term disease-control" bandwagon, using anti-inflammatory medications to control disease not just during flares but also in a proactive (vs. reactive) manner.

Dr. Stein Gold highlighted nonsteroidal agents, including crisaborole (Eucrisa), approved for ages 2 years and older. This is the first topical medication that is a phosphodiesterase type 4 (PDE4) inhibitor and has no restriction in duration of use or for region of skin treated; is not a corticosteroid; and is not associated with skin thinning. The TCIs (topical calcineurin inhibitors) also were discussed in regimens to prevent disease recurrence, with application to areas that tend to flare. Using nonsteroids on "hot spots" to prevent recurrence is akin to using an asthma controller therapy.

The first biologic agent for AD has been approved for adults for about 1 year, and there is off-label experience in children and adolescents that has been published (Pediatr Dermatol. 2019 Jan;36[l ]:172-6), as well as phase 3 studies for children aged 12-17 years as a basis for expansion of the indication to adolescents. Dupixent is a monoclonal antibody that targets two interleukins (IL-4 and IL-13)--cytokines associated withTH-2 cells--is given as an injection every other week. The same medication already has received approval for ages 12 and older as an add-on maintenance treatment in patients with moderate to severe asthma (with an eosinophilic phenotype or with oral corticosteroid dependence), another TH-2 mediated disease. This medication is the first targeted systemic therapy for AD and can truly change the lives of severely affected individuals.

Dr, Stein Gold mentioned that there is a broad set of therapeutic agents in development for AD, which includes topicdl and systemic medications (both biologic agents and small molecules). And the timing is good for this because other research has shown the spectrum of associated problems (comorbidities) associated with AD, which includes traditional "atopic" conditions (allergic rhinoconjunctivitis, food allergy, asthma), neurodevelopmental and psychological issues (ADHD, anxiety, depression), infections (bacterial and viral), and others (Am J Clin Dermatol. 2018; 19:821-38). The next 5-10 years will be intriguing as we become more conscious of this disease and its impact, given the evolving approaches to management.





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Author:Dotinga, Randy
Publication:Pediatric News
Geographic Code:1U8NV
Date:Jun 1, 2019
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