Repairing the barrier: New research may hold key to future AD therapies

April 1, 2008

With no new breakthrough therapies for atopic dermatitis having emerged in recent years and the FDA black box warning limiting prescription of topical immunomodulators, doctors are looking the to future of exciting new research on the manifestation of the disease with the hopes of the emergence of a new generation of innovative and effective therapies.

Key Points

Chicago-With no new breakthrough therapies for atopic dermatitis (AD) and with the Food and Drug Administration "black box" warning limiting prescription of topical immunomodulators, doctors are looking to new research on the manifestation of the disease, and hoping for the emergence of a new generation of innovative and effective therapies.

"We were very excited to have the availability of nonsteroidal anti-inflammatory agents a few years ago, and those really revolutionized how we were able to care for these kids," Dr. Paller tells Dermatology Times.

"Although there is still no evidence of a cancer risk in humans, the need for safe, effective therapy remains, Dr. Paller says."

Focus has, meanwhile, shifted to new research on the role of the skin barrier in AD, with particular interest in groundbreaking research showing that genetic mutations appear to play a critical role in the skin barrier function as it relates to atopic dermatitis.

The research, first published by researchers at the University of Dundee, Scotland, found the loss-of-function mutations in the gene encoding for the epidermal barrier protein filaggrin were important predisposing factors for AD.

The study also indicated that the mutations are also linked to asthma when associated with AD, but not to asthma alone (Nat Genet. 2006 Apr:38(4):441-446).

The filaggrin mutations were originally linked to ichthyosis vulgaris, when families affected with ichthyosis vulgaris were found to have the mutation.

"Many years ago, atopic dermatitis was considered a keratinocyte disorder, but more recently, the focus has been entirely on the immune system," Dr. Paller says.

"With the clear link to ichthyosis vulgaris and barrier, based on the discovery of mutations in the gene encoding profilaggrin, attention has once again focused on the importance of barrier and the role of the keratinocyte, as well," she says.

Additional research has looked at the deficiency of ceramides as being further contributory to barrier defects in AD.

"The clear issue with barrier in AD has translated into the increasing availability of 'barrier repair' emollients that attempt to correct the lipid abnormality," Dr. Paller says.

Meanwhile, targeted therapy, such as with supplemental filaggrin for those with filaggrin deficiency, holds promise for the future, she adds.

Yet another approach to treating AD considers the Staphylococcus aureus colonization of both involved and uninvolved skin of patients with the disease.

The colonization, which makes patients highly prone to infection, is blamed in part on the inability of skin affected by AD to express the antimicrobial peptides beta defensins and cathelicidins.

"Recent data shows that in situations of inflammation, normal or psoriatic skin produces these peptides, but they are not expressed in the inflamed skin of patients with AD."

"The increasing presence of MRSA adds another layer of concern about use of traditional antibiotics," Dr. Paller says.

Antimicrobial peptides are currently being studied as a novel way to decrease infections on atopic skin, not only from S. aureus, but also potentially herpetic and molluscum infections, Dr. Paller says.

One therapy that Dr. Paller says has been significantly helpful is dilute bleach (sodium hypochlorite) baths.

"These baths have clearly shown to not only help with keeping down rates of infection, but also in decreasing the severity of AD when used on a chronic basis," she says,

Meanwhile, developments in systemic therapies for AD are uninspiring, Dr. Paller says.

A recent paper looking at efalizumab showedabenefit for some patients with severe AD, but Dr. Paller is unsure.

"I am not convinced efalizumab works as well as immunosuppressants, and there certainly can be toxicity," she says.

In addition, the use of probiotics is still extremely controversial.

"The barrier research, the role of immunity and antimicrobial peptides and the whole role of S. aureus are the big areas of interest right now," Dr. Paller says.