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Steroid, Calcineurin Inhibitor Best for AD at Different Times


 

GLASGOW, SCOTLAND — A rational approach to the treatment of atopic dermatitis is to use calcineurin inhibitors and topical corticosteroids in different therapeutic niches, based on a scientific understanding of the effects of the drugs on the stratum corneum and a recognition of the associated genetic-environmental interplay, Michael J. Cork, M.B., said at the annual meeting of the British Association of Dermatologists.

Topical corticosteroids, particularly the potent ones, have profound thinning effects on not only the dermis, but also the epidermis, including the stratum corneum.

In areas such as the face where the stratum corneum is normally thinner than on other body sites, corticosteroid-induced thinning of the skin can result in a low barrier reserve, leaving the skin vulnerable to insult such as from allergens and irritants, Dr. Cork said.

“Pimecrolimus appears to have no effect on the skin barrier. We have not yet looked at tacrolimus but we think it is a class effect,” he said. The two drugs have similar molecular weights, but pimecrolimus is more lipophilic, appears to have a higher affinity to skin, and tends to remain trapped in the stratum corneum. With tacrolimus, the penetration through the stratum corneum and into the other layers of the skin into systemic circulation is greater than with pimecrolimus, but it still is low, said Dr. Cork, head of the academic dermatology group in the division of genomic medicine at the University of Sheffield (England).

These drug effects occur in normal as well as in abnormal skin, but in atopic dermatitis various other factors further contribute to skin vulnerability.

“Atopic eczema is a classic example of a gene-environment interaction, involving multiple genetic changes and multiple environmental factors,” Dr. Cork said.

One of the primary genetic determinants in atopic dermatitis appears to be a change in the 3′ untranslated region of the stratum corneum chymotryptic enzyme (SCCE) gene, which regulates protease activity

“We did a case-control study in our clinic and found a strong association with atopic eczema with the rare allele of the protease gene,” he said (J. Invest. Dermatol. 2004;123:62–6).

Proteases are necessary for the shedding of corneocytes from the upper layers of skin, a process that is achieved by cleavage of an adhesion protein within corneodesmosomes with SCCE.

This process, which is held in check by protease inhibitors, must be tightly regulated to prevent the skin barrier from breaking down.

The rare allele of the protease gene, which contains a repeat AACC, is likely to increase the expression of messenger RNA for the SCCE gene. The result is an increase in production of protease leading to an excessive breakdown of the corneodesmosomes and the skin barrier.

Application of topical corticosteroids to even normal skin induces the expression of protease SCCE mRNA and increases the production of SCCE protein. In atopic eczema the preexisting increase in SCCE can be further exacerbated by topical corticosteroids, inducing SCCE production, he said.

Exposure to environmental factors such as soap and detergent, which raise the pH of the skin from 5.5 to 7.5, can further contribute to skin breakdown, as proteases are pH sensitive, he said.

Further complicating the picture in the case of flare is the presence of secondary proteases from the inflammatory infiltrate.

This is the circumstance in which topical corticosteroids can be most useful and beneficial for protecting the skin barrier function. “Use of a topical steroid to suppress these high levels of secondary proteases during a flare has an overall positive, restorative effect on the skin barrier,” Dr. Cork said.

But for milder, chronic use, corticosteroids can negatively affect the skin barrier, so pimecrolimus could reduce the number of flares and prevent their progression.

And there is very little systemic absorption, potentially about 0.2% of a dose, he said.

For patients with more severe eczema, who otherwise would need greater amounts of topical corticosteroids, rotating the steroid with tacrolimus can control the symptoms and minimize exposure to potent steroids.

“So, based on our understanding of the skin barrier and how topical corticosteroids and calcineurin inhibitors interact with the skin barrier, we can begin to carve out different niches where their benefits will be greater than the adverse effects,” he said.

Dr. Cork disclosed that he has received research grants from Novartis and that he is on the company's advisory board.

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