麻豆传媒

SAN DIEGO -- Following the therapeutic model of psoriasis, treatment for atopic dermatitis (AD) increasingly focuses on identifying and targeting specific molecules involved in etiology and pathogenesis, experts said here.

The potential for applying the psoriasis model to AD did not become apparent until recently, as AD is a more complex condition, involving abnormalities in both immune response and the skin barrier, said Emma Guttman-Yassky, MD, PhD, of Mount Sinai Health System in New York City, at the American Academy of Dermatology meeting.

Under the microscope, the epidermis and dermis of patients with psoriasis and AD appear similar, characterized by large T-cell infiltrates. However the T-cells produce different cytokines. Psoriasis is a Th17/interleukin (IL)-17/IL-23-focused disease, whereas AD is the "polar opposite," emerging from the Th2 pathway and involving expression of multiple cytokines and chemokines, including IL-13, IL-4, IL-51, and IL-22.

All AD subtypes exhibit robust Th2 activation, but the subtypes differ in their immune profiles, suggesting a need for different approaches to treatment, said Guttman-Yassky. Like psoriasis, AD is a systemic disease, but AD is associated with even greater immune activation, including higher levels of activated T cells, circulatory cytokines, and cardiovascular-associated markers.

The clinical development of dupilumab (Dupixent), which inhibits IL-4 and IL-13, and its subsequent clinical success in AD strongly supported the strategy of developing targeted therapies for the disease, following the model applied successfully in psoriasis.

"Unlike psoriasis, AD cannot be explained by a single cytokine pathway," said Guttman-Yassky. "But the consistent cytokine axis activated across all phenotypes appears to be Th2. Thus far, dupilumab shows similar in intrinsic/extrinsic and filaggrin-positive and negative AD phenotypes."

"It is a systemic disease with a high need for safe treatment options that can be given long term; a 'quick fix' may not be possible," she added. "It is currently unclear how many immune axes need to be targeted, and to what extent, to fully reverse the pathogenic AD phenotype across the disease spectrum."

Recent evidence from studies of dupilumab suggested that effective targeted therapies might have the potential to reverse specific AD phoenotypes, she added.

TEWL

Prevention of AD might also be a possibility, said Amy Paller, MD, of Northwestern University in Chicago. Studies involving newborn mice examined the impact of (TEWL) as a measure of the functional status of the skin barrier.

Investigators found that TEWL in the upper quartile in 2-day-old mice predicted a seven-fold increased risk of AD at 12 months. The lowest quartile of TEWL at 2 days afforded protection against AD at 12 months. Moreover, 2-day TEWL values in the upper quartile predicted more than a three-fold increase in the at 2 years as compared with TEWL values in the lowest quartile.

"This raises the question of whether there might be a window of opportunity for prevention," said Paller. "If we reverse the early barrier impairment, can we reduce the risk of AD and the later development of allergies?"

Several recent clinical studies have shown that early moisturization with emollients can in high-risk infants. Ongoing laboratory studies are evaluating the potential for identifying and replacing specific deficiencies associated with abnormal barrier function.

With regard to conventional therapeutic approaches to AD, topical steroids remain the cornerstone of therapy. An aggressive approach to intervention is required to suppress inflammation, eventually "dialing down" to two- or three-times-weekly use of a topical steroid or calcineurin inhibitor to maintaining clear or almost clear skin.

Attention to adherence is a key factor in treatment success, said Paller. Methods to encourage adherence should be personalized to patients and their families. Education may be needed to overcome phobias related to the safety of topical steroids and calcineurin inhibitors.

New therapeutic options for AD include crisaborole (Eucrisa), the first approved topical PDE4. The therapy achieved significant improvement in investigator global assessment in children and adults in . The trials produced no safety signals regarding crisaborole.

Several other PDE4 inhibitors are in various stages of development, Paller said.

Targeted strategies in development for AD include Janus kinase (JAK) inhibitors, already widely used in the treatment of psoriasis. JAK1/3 and STAT6 are all involved in Th2/IL-4 signaling, providing a rationale for clinical evaluation in AD.

A small, randomized, vehicle-controlled study of showed a 52% greater reduction from baseline in the Eczema Area and Severity Index (EASI) as compared with vehicle and a 55% greater improvement in Physician Global Assessment.

JTE-052, a topical pan-JAK inhibitor, met primary and secondary endpoints in a with vehicle and tacrolimus control groups. The results showed EASI improvement of 42% to 73% with various concentrations of the JAK inhibitor as compared with 12% for vehicle and 62% for tacrolimus.

"Newer topical nonsteroidal medications, such as PDE4 inhibitors, JAK inhibitors, and tapinarof, an AhR inhibitor, show promise as steroid-sparing agents and may be particularly important for sensitive sites, maintenance therapy, and proactive intervention," said Paller.

Systemic Approaches

Beyond topical therapies, various systemic approaches are under evaluation for AD, said Eric Simpson, MD, of Oregon Health and Science University in Portland. Multiple biologic agents are in phase II evaluation. They include lebrikizumab (IL-13), mepolizumab (IL-5), nemolizumab (IL-31), and fezakinumab (IL-22).

JAK inhibitors have opened the door to the possibility of blocking multiple cytokine pathways simultaneously, said Simpson. For that reason, they are attracting a lot of attention in dermatology clinical research

Several small studies tofacitinib (Xeljanz) have shown dramatic improvements in AD disease activity and symptoms, including itch and pruritus. However, off-label use of the drug requires ongoing monitoring with lab work because of black box warnings related to infection and malignancy risks, said Simpson.

Multiple oral JAK inhibitors are in clinical evaluation in heterogeneous patient populations, with and without concomitant topical steroids. Collectively, the results have been favorable, at least comparable to those observed with tofacitinib.

"I think it works," Simpson said.

However, the potential benefits of potent inhibition of multiple cytokines carries an increased risk of adverse events.

"Let's hope that the phase III studies help us find the 'sweet spot' of JAK inhibitors," said Simpson. "How do we improve the disease in a very safe manner."

Comment