Atopic dermatitis: Breaking it down

National report - More basic research into atopic dermatitis (AD) needs to be conducted to understand the subsets of the condition and to generate new therapies to expand the therapeutic choices for the patient, according to Lawrence Chan, M.D., professor and head of the department of dermatology at the University of Illinois. Specifically, differentiating between "intrinsic" and "extrinsic" AD is critical.

Where extrinsic AD is associated with elevated serum IgE levels and with food allergy, intrinsic AD is non-IgE-mediated, is not associated with a high serum level of IgE, and does not have any detectable allergen sensitization. Recent studies by European investigators suggest that extrinsic AD makes up the bulk of cases, with 70 percent to 80 percent of cases being extrinsic, while intrinsic AD represents the minority of cases, or 20 percent to 30 percent.

"We need to find what distinguishes the two forms of AD," Dr. Chan tells Dermatology Times. "We can then target the particular mechanisms of the two forms of the disease. They present similarly in clinical phenotype and histopathology. All the existing treatments are general in how they attack the disease. If we find new pathways distinct in these subsets of disease, we can develop new and more specific approaches to targeting the disease."

One study published in the Journal of Allergy and Clinical Immunology in 2004 concluded, after reviewing several studies assessing the value of measuring IgE antibodies to diagnose AD, that two-thirds of patients with the diagnosis of AD are not actually "atopic." It suggested that longitudinal studies are necessary to compare treatment response and prognosis in both IgE-associated and non-IgE-associated AD. Moreover, the study indicated that the presence of two different types of dendritic cells, myeloid versus plasmacytoid, may represent two subtypes of the condition with different pathophysiologies.

Topical calcineurin inhibitors such as tacrolimus (Protopic ointment, Astellas) and pimecrolimus (Elidel cream, Novartis) should act as complementary agents to the standard treatment of corticosteroids, Dr. Chan explains. The calcineurin inhibitors are immunosuppressants and were developed as alternatives to corticosteroids.

"There are no major differences in efficacy and tolerability amongst the calcineurin inhibitors," Dr. Chan says. "I do not see them as a primary therapy. They can act as an adjunct therapy. For one thing, the calcineurin inhibitors do not have a strong anti-inflammatory property for the purpose of treating acute inflammation in AD. Steroids are still the regimen of choice for initial treatment of acute AD, but they have to be used judiciously and sparingly."

Dr. Chan emphasizes that concerns over the use of corticosteroids as a therapeutic agent can also be lessened through promoting the patient's use of mild soaps and encouraging the patient to avoid contact with chemicals that will aggravate AD.

He referred to the most recent position paper from the European Task Force on AD, published this year in the Journal of the European Academy of Dermatology, which set forth guidelines for using topical corticosteroids as first-line treatment for AD. These guidelines indicate that systemic anti-inflammatory agents should be kept to a minimum, that topical calcineurin inhibitors are an additional treatment option that can help reduce steroid usage, and that systemic antihistamines have not proven to be effective as therapy. Phototherapy with UVA or UVB radiation may also prove beneficial, according to the paper.

Ongoing research

Extrinsic and intrinsic AD need to be examined at the research level in both human patients and animal models, Dr. Chan notes. Unfortunately, all available animal models are extrinsic in nature, and there is no intrinsic model of AD available at the present time.

"Studies with animal models will help us explore the two subsets of the disease," Dr. Chan explains. "We have learned that only a small percent of AD cases are associated with food allergy."

A study that Dr. Chan published last year in Clinical Experimental Immunology demonstrated that Th1-type, Th2-type and non-Th-type cytokines are involved in the disease development of a transgenic mouse model of AD. Specifically, there was an early upregulation of Th2-type cytokine followed by a late surge of Th1-type cytokine messenger RNAs in the skin of these interleukin-4-transgenic mice.